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May 12, 2020 feature Exploring the role of cells in the lateral thalamus in controlling fear behavior by Ingrid Fadelli , Medical Xpress The amygdala-projecting thalamic cells (green) are located outside of the auditory thalamic territory and express a protein called calretinin (red). Credit: Ákos Babiczky and Ferenc Mátyás, RCNS, Budapest, Hungary. Researchers at the Research Center for Natural Sciences and other institutes in Hungary have recently carried out a study investigating the involvement of brain regions other than the amygdala—more specifically, the lateral thalamus— in controlling fear behavior. Their paper, published in Nature Neuroscience, presents interesting results that could better explain the connections between neutral stimuli and the automatic responses developed by animals in conditioning experiments from a neuroscientific standpoint. "In our everyday life, we perceive a large amount of information; however, we only store memory of things that have meaning for us, a value that attracts, motivates us or causes us discomfort," Matyas Ferenc, one of the researchers who carried out the study, told Medical Xpress. "In classical conditioning experiments first conducted by Ivan Petrovics Pavlov (1897), a previously meaningless sound of a bell was presented to a dog along with food; after a few repetitions, the dog started to salivate immediately when it heard the same bell sound, even without food." Pavlov's experiments revealed that if an animal is repeatedly given food immediately after he hears the sound of a bell, it typically learns to associate the sound with the arrival of food and starts salivating when the bell rings, regardless of whether food arrives or not. This phenomenon, dubbed "conditioning," entails three different processes: learning, memory formation and recall. Years after the introduction of the classical conditioning paradigm, neuroscientists identified the amygdala as the brain region that plays the most prominent role in an animal's formation and retrieval of associative memories, as observed in Pavlov's experiments. Despite the growing evidence highlighting the importance of the amygdala in associative learning and conditioning processes, some researchers have found that other brain regions could also be involved, including the thalamus. Nonetheless, so far, there has been no definitive scientific evidence of signal association in the thalamus that could reflect conditioning processes. In addition, although some have suggested that the thalamic area, particularly the auditory thalamus, could be connected to the amygdala, researchers have been unable to confirm this connection or identify neuronal pathways that connect these two brain regions. "All of the unanswered questions and contradictions arising from past neuroscience studies prompted us to re-investigate the signaling pathways involved in a classical fear conditioning paradigm and directly terminated in the amygdala," Ferenc explained. "In this paradigm, a neutral tone (called conditioned stimulus, CS) is associated with an affective signal (called unconditioned stimulus, US; foot shock) during the conditioning phase. The next day, the same tone alone elicited the similar defensive behavior (freezing) of mice without US delivery." In their study, Ferenc and his colleagues performed complex anatomical and functional investigations aimed at mapping all the brain regions that could quickly transmit signals to the amygdala. They genetically identified a lateral thalamic cell population located outside of the auditory thalamus brain region that fulfills all the requirements for completing this particular action. "The cell population we identified (1) receives brainstem (direct) multisensory inputs shown by monosynaptic Rabies tracing; (2) it shows the largest activation when two signals (tone and foot-shock) were paired while we recorded from identified amygdala-projecting lateral thalamic neurons; and (3) it controls the stimulus-evoked activations of the connected amygdala neurons tested by optogenetic inhibition of thalamic inputs while we monitored the firing pattern of the amygdala cells," Ferenc said. Optogenetic inhibition of the thalamic input in the amygdala prevents fear memory recall. A control, non-conditioned (non-shocked) mouse (left) does not show any defense behavior (freezing), while a control, conditioned mouse does (indicated by immobility; middle). In contrast, a conditioned mouse with thalamic inhibition does not show freezing behavior (right). Credit: Boglárka Barsy and Kinga Kocsis , RCNS, Budapest, Hungary. Ferenc and his colleagues identified a new inhibitory neuronal subgroup, part of the GABAergic cell population, that had been overlooked in previous studies. This unique cell population appears to contribute greatly to the transfer of signals from the thalamus to the entire amygdala brain region. The researchers used optogenetic inhibition techniques during fear conditioning experiments on mice to investigate the potential role of this thalamic cell type in controlling conditioned fear behavior. "Animals for which the thalamic inputs within the amygdala were silenced during the presentation of the tone and foot-shock stimuli did not show freezing behaviour, while control mice (without optogenetic silencing) did," Ferenc said. "Our investigations thus highlighted that—in contrast to the well-accepted concept of signal association in the amygdala—the lateral thalamus can integrate these signals and send associative information in the amygdala, shaping defense behavior." In addition to unveiling the presence of associative signaling in the thalamus, Ferenc and his colleagues found that the pairing of a tone and foot-shock in mice during their conditioning experiment changed the firing pattern of the animals' lateral thalamic cells. This suggests that these thalamic cells' activity is plastic, or in other words that it can be shaped over time by relevant environmental signals. Interestingly, the researchers also found that the optogenetic inhibition of thalamic inputs prevented the animals from recalling fear memories. In 1994, a renowned neuroscientist called Joseph LeDoux introduced the idea that the thalamus provides two sensory routes to the amygdala. The first is a quick and unprocessed pathway that directly leads to rapid behavioral responses, while the second is an 'indirect' and slower pathway that passes through cortical regions associated with a specific behavior. Remarkably, Ferenc and his colleagues identified the thalamic region that could be involved in these two processes, as well as a single cell population that drives both of these pathways to the amygdala. "Our results prove that the amygdala is not the only place in the brain with the capability of pairing CS and US signals: CS-US association is occurred at the level of the (calretinin-expressing) lateral thalamic cells which then, convey this information to the amygdala and cortex," Ferenc said. "The signal association drives thalamic plasticity which is accompanied with memory storage about the conditioning event." Past research, including a study conducted by Kay Tye in 2008, introduced the idea that the same thalamic pathway identified by Ferenc and his colleagues could be involved in reward learning. The findings gathered by the researchers provide new evidence suggesting that the specific cell population they studied does not merely relay sensory information to the amygdala, but that it can also generally encode environmental information related to behavioral responses. By unveiling another distinct cell population that may play a role in associative learning, the recent study conducted by Ferenc and his colleagues could open up new possibilities for the diagnosis and treatment of numerous mental disorders, particularly those characterized by unhelpful associative learning. In the future, their work could inspire further studies investigating the potential presence of thalamic dysfunctions in people with mental health disorders linked with maladaptive associative learning. "To examine this, first, the evolutionarily converse nature of this lateral thalamo-amygdala routes must be revealed and the precise location of its thalamic element should be identified in the human brain, to provide exact coordinates for future functional investigation," Ferenc said. "If abnormal thalamic functioning will be found in patients, future research on these thalamic cells, especially focusing on their molecular and genetic links to behavioral deficits, may identify a selective tool that allows us to fine tune their activity and thus, temper symptoms." Researchers discover new pathways in brain's amygdala More information: Boglárka Barsy et al. Associative and plastic thalamic signaling to the lateral amygdala controls fear behavior, Nature Neuroscience (2020). DOI: 10.1038/s41593-020-0620-z Journal information: Nature Neuroscience © 2020 Science X Network Citation: Exploring the role of cells in the lateral thalamus in controlling fear behavior (2020, May 12) retrieved 16 January 2021 from https://medicalxpress.com/news/2020-05-exploring-role-cells-lateral-thalamus.html Study reveals how brain injury can lead to post-traumatic stress disorder Researchers create organoid of a brain region to study cognitive disorders Scientists discover a new pathway for fear deep within the brain How associative fear memory is formed in the brain Study shows how separate visual features are integrated in the thalamus Study measures brain volume differences in people with HIV Revisiting the Global Workspace orchestrating the hierarchical organisation of the human brain New Alzheimer's research could inspire better treatments and earlier diagnosis New delivery method promises relief from antipsychotic medication's adverse side effects
Elagolix Seen to Lessen Pain and Spread of Endometriosis in Yearlong Phase 3 Studies by Alice Melão Results of two Phase 3 extension studies showed that one year of treatment with elagolix could reduce pelvic pain, prevent proliferation of endometrium tissue, and improve quality of live in women with endometriosis. Results of a Phase 2 clinical trial in women with uterine fibrosis also demonstrated the therapeutic potential of this investigative drug to reduce bleeding rates and improve quality of life of the patients. These findings were presented during the American Society for Reproductive Medicine Scientific Congress & Expo (ASRM) recently held in San Antonio. Elagolix, formerly known as ABT-620, is a gonadotropin-releasing hormone (GnRH) receptor antagonist that is being developed by AbbVie in collaboration with Neurocrine Biosciences. Designed to be taken orally, it blocks the natural GnRH signals in the pituitary gland, inhibiting the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently leading to lower estradiol and progesterone production in the ovaries. These hormones — estradiol and progesterone — are linked to the development and progression of endometriosis and uterine fibroids. "An estimated one in 10 women of reproductive age have endometriosis," Shao-Lee Lin, MD, vice president of therapeutic areas and international development at AbbVie, said, in a press release. "There have been few recent scientific advancements for women suffering from endometriosis and physicians are in need of additional treatment options to help manage this debilitating disease." Two pivotal and global clinical trials (NCT01620528 and NCT01931670), involving 1,700 women with endometriosis with moderate-to-severe menstrual and non-menstrual pain, found that elagolix at 200 mg given twice daily for up to six months could effectively reduce proliferation of endometrial tissue and pelvic pain complains. Supported by these positive six-month results, the researchers extended the trials for up to 12 months of treatment. Analysis of the new data collected revealed that about 50 percent of the treated women reported reduced average monthly menstrual and non-menstrual pelvic pain scores upon one year of treatment. This effect was seen in both trials and was similar to what had been reported during the initial six months. Long-term treatment did not reveal any new safety concerns. The incidence of hot flush was between 4 and 8 percent in the extension studies. These data were presented ASRM in the study titled "Long-term safety and efficacy of elagolix treatment in women with endometriosis-associated pain: primary results from two phase 3 extension studies." Results of a second study, titled "Long-term effect of elagolix on the endometrium: results from two phase 3 extension studies in women with endometriosis-associated pain," revealed that the inhibitory effects on tissue proliferation that had been reported during the initial six months of treatment were maintained over the additional six months. In the presentation "Maintenance of endometriosis-associated pain reduction and quality of life improvement in phase 3 extension studies with elagolix," the researchers showed that about 45% of patients who received 150 mg reported less pain during sexual intercourse, as did about 58% of those treated at the 200 mg dose. Analysis of overall quality of live scores also demonstrated a similar trend, showing positive changes when compared to baseline. Evaluation of the potential effects of elagolix on bone mineral density revealed that about 0.8-0.9% of the patients who received 150 mg of elagolix experienced bone mineral density reduction of 8% or more by the end of a 12-month treatment period. A similar reduction was seen in 11–13% of patients treated with 200 mg dose. These results were presented in the study "Long-term effect of elagolix on bone mineral density: results from two phase 3 extension studies in women with endometriosis-associated pain." "Endometriosis is a chronic and painful disease," said Eric Surrey, study investigator and medical director of the Colorado Center of Reproductive Medicine. "The results presented today are positive for patients and are consistent with previous data that demonstrate elagolix has the potential to be an important non-surgical treatment option for women suffering from the most prevalent symptoms of endometriosis." AbbVie has announced that it filled a request with the U.S. Food and Drug Administration (FDA) that elagolix be approved to treat endometriosis and associated pelvic pain. That application is under priority review with a decision expected by June 2018. If approved, elagolix would become the first new oral therapeutic option for endometriosis-associated pelvic pain in more than a decade. AbbVie is also exploring the impact of elagolix to treat women with uterine fibroids. At the ASRM meeting, the company presented the latest data from a Phase 2 clinical trial (NCT01817530) that evaluated the safety and efficacy of elagolix, alone or combination with add-back therapy, for the treatment of heavy menstrual bleeding in premenopausal women with uterine fibroids. Researchers reported that the majority of patients treated with elagolix alone showed significant change in menstrual blood loss compared to placebo, as well as a decrease in tissue proliferation. Similar to what was reported in previous studies, elagolix alone was associated with hot flushes and a reduction in bone mineral density. Addition of add-back therapy lessened these adverse effects in a dose-dependent manner. The researchers also presented the results of elagolix impact on the patients' quality of live. Women treated with the investigative therapy, both alone and in combination, were said to experience clinically meaningful improvements in symptom severity and health-related quality of life scores, including sexual function, compared to placebo. AbbVie also presented data at ASRM on healthcare utilization and costs associated with endometriosis in the United States, detailed in the study "Direct healthcare utilization and costs associated with endometriosis among women with medicaid insurance." This study included 15,615 women with endometriosis who were diagnosed between January 2008 and September 2014, and were registered in the Medicaid database. A total of 86,829 women without endometriosis were included as controls. Analysis of data collected during the year following inclusion in the database showed that endometriosis patients had significantly higher insurance utilization rates, associated with higher costs. About 66% of patient underwent at least one endometriosis-related surgery. Pharmacy costs accounted for 15.3% of total healthcare costs, and endometriosis-related expenses accounted for about 22.4% of total costs among endometriosis patients. Tagged AbbVie, ABT-620, clinical trials, Elagolix, GnRH receptor antagonist, Neurocrine Biosciences, Phase 2 trial, Phase 3 trial, uterine fibrosis. Previous: Post-surgery Recovery: What to Expect Next:What Does a Chronically Ill Person Do All Day?
X-Ray Clinic The Value of Laboratory Equipment Medical labs are more significant Now than ever before. Medical advancements often occur in research labs since that is where experiments occur and clinical medical labs are even more significant. Clinical medical labs are used routinely for many different medical testing, which is trivial, although impractical to home within the actual doctor's office or clinic. Laboratory medicine is usually divided into three sections. It is then divided further into an assortment of units. Lab medication is usually thought in these sections. Anatomic Pathology. Academically, every unit is analysed alone in 1 course. Other classes pertaining to the section include physiology, anatomy, histology, pathology, and pathophysiology. Clinical Microbiology. This is the biggest section in lab Medication; it encompasses five unique components — bacteriology, virology, parasitology, immunology, and mycology. Clinical Biochemistry. Units under this busy section are instrumental analysis, enzymology, toxicology and endocrinology. This small, yet active, section consists of 2 components, that are coagulation and blood bank. Genetics is also a new and growing segment, which may in the future become the most important. Clinical medical labs are usually connected to hospitals and work exclusively with the hospital's patients or are private operations that get laboratory work from private physicians, insurance companies, attorneys, and other health clinics. The true supply of sections at a medical laboratory is based upon the lab and sort of experimentation and the significant sort of work the laboratory is involved in. By way of example, some healthcare centers will have a lab exclusively for microbiology, though others may have an assortment of labs all dealing with microbiology and unique units within it. Medical city x ray tilak nagar are a huge consumer of medical supplies and expendables. Laboratories receive samples in special containers. A lot of the medical investigation that happens in labs is automatic. Samples are handled by automation, occasionally, to prevent human error or contamination. Laboratories are usually busiest from 2am to 10am, when blood work has been completed for physician's morning rounds in the hospital. After 3pm, when the private physician's work day ends, many samples are sent to clinical labs and they get active, again. Clinical medical labs are an integral part of modern medical investigation and therapy. More advanced diagnostic technologies has increased the demand for moment measurements and analysis for proper diagnosis and treatment to be administered. The Many Uses of Promotional balloon decoration Have More Benefits with Hiring Animated video production company
Home » sNDA » (sNDA)…..FDA okays Shire ADHD drug Vyvanse (lisdexamfetamine dimesylate) for binge eating (sNDA)…..FDA okays Shire ADHD drug Vyvanse (lisdexamfetamine dimesylate) for binge eating Yet more good news for Shire has come with the US Food and Drug Administration approving its attention-deficit hyperactivity disorder blockbuster Vyvanse for binge-eating disorder, the first medicine approved by the agency to treat this condition. The agency has expanded approval on Vyvanse (lisdexamfetamine dimesylate) for adults with BED based on two Phase III studies which showed that it was statistically superior to placebo in terms of number of binge days per week. BED affects around 2.8 million US adults and is more prevalent than anorexia nervosa and bulimia nervosa combined. Read more at: http://www.pharmatimes.com/Article/15-01-30/FDA_okays_Shire_ADHD_drug_Vyvanse_for_binge_eating.aspx Originally discovered and developed by New River Pharmaceuticals, the company entered into a collaborative agreement with Shire Pharmaceuticals in 2005 for global commercialization of the drug candidate. After Shire's acquisition of New River Pharmaceuticals in April 2007, lisdexamfetamine entered the product portfolio of Shire. In 2009, the compound was licensed to GlaxoSmithKline by Shire in the U.S. for comarketing for the treatment of attention deficit/hyperactivity disorder (ADHD). In 2010, this license agreement was terminated. The product was licensed to Shionogi by Shire in Japan for co-development, co-commercialization, and co-promotion for the treatment of attention deficit/hyperactivity disorder (ADHD). Lisdexamfetamine (NRP-104), a conditionally bioreversible derivative of amphetamine, was launched in the U.S. in 2007 for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-12 years old. In 2008, the product was approved for use in adults, and in 2009 it was approved in Canada, followed by commercialization in 2010. In 2010, FDA approval was obtained for use in treatment of ADHD in adolescents aged 13 to 17 years and launch took place the same year. Approval for the treatment of adolescents was assigned in Canada in 2011. In 2012, Shire filed a regulatory application in Europe via the decentralized procedure with the U.K. acting as the reference member state, for the treatment of ADHD in children and adolescent patients aged 6 to 17 years. This indication was approved in 2013. Also, in 2012 FDA approval was granted for the maintenance treatment for adults with ADHD. U.K., DK and SE are awaiting approval for the same indication in a decentralized procedure initiated in 2014 with the U.K. acting as the reference member state. In 2014, the company filed with priority review a supplemental New Drug Application (sNDA) in the U.S. for the treatment binge eating in adults. (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate Binge eating,,,,,, express their stress as temper tantrums or by indulging in compulsive eating spree In terms of clinical development, phase III clinical trials are ongoing at Shionogi in Japan for the treatment of ADHD.. The National Institute on Drug Abuse (NIDA) is evaluating the compound in early clinical studies for the treatment of methamphetamine dependence. Phase III trials were underway as an adjunctive treatment of major depressive disorder; however, they were discontinued due to lack of efficacy. A phase II clinical trial for the treatment of excessive daytime sleepiness (EDS) has been completed. Shire had been evaluating the compound in clinical studies for the treatment of chronic fatigue syndrome. In 2013, Shire cancelled its phase III program evaluating the product for the negative symptoms of schizophrenia based on a review and prioritization of the company's development portfolio. http://www.google.co.in/patents/US7662787 RIVER PHARMA Patent and Exclusivity Search Results from query on Appl No 021977 Product 003 in the OB_Rx list. Patent Data Appl No Prod No Patent Use Delist N021977 003 7105486 Jun 29, 2023 U – 727 N021977 003 7223735 Jun 29, 2023 Y N021977 003 7655630 Feb 24, 2023 Y N021977 003 7659253 Feb 24, 2023 Y Y U – 727 N021977 003 7659254 Feb 24, 2023 U – 1034 N021977 003 7662788 Feb 24, 2023 U – 727 N021977 003 7671030 Feb 24, 2023 Y U – 727 N021977 003 7674774 Mar 18, 2023 Y U – 842 N021977 003 7678770 Mar 25, 2023 U – 842 N021977 003 7687467 Apr 8, 2023 Y U – 842 Exclusivity Data Exclusivity Code Exclusivity Expiration N021977 003 I – 645 Jan 31, 2015 Tags: ADHD, attention deficit hyperactivity disorder, FDA approval, hyperactivity disorder, lisdexamfetamine dimesylate, Shire Pharmaceuticals, sNDA, Vyvanse By DR ANTHONY MELVIN CRASTO Ph.D in sNDA on February 2, 2015 . ← Lead-oriented synthesis: a new concept to aid drug-discovery process EDIVOXETINE REVISITED →
Dolopar tablet is a NSAID (Non-steroidal anti-inflammatory drug). This medicine works by reducing substances in the body that cause pain and inflammation. Dolopar is used to treat, signs and symptoms or mild to moderate pain of osteoarthritis, rheumatoid arthritis, gout, migraine, and also to treat fever, cold, headache, menstrual cramps, Ear pain and other conditions. Dolopar Tablet contains and Paracetamol as active ingredient. Paracetamol also blocks the release of certain chemicals messengers that are responsible for inflammation and pain. Paracetamol specifically acts on COX-3 enzyme which is found only in the thermal regulatory center of hypothalamus and reduces the thermostat (which is usually set to a higher temperature in fever), thereby lowering body temperature. The following is a list of possible side-effects that may occur from all constituting ingredients of Dolopar Tablet. These side-effects are possible, but do not always occur. Some of the side-effects may be rare but serious. Consult your doctor or pharmacist if you observe any of the following side-effects, especially if they do not go away. Some medications are not suitable for people with certain ailments, and sometimes a medicine may only be used if extra care is taken. Take this medicine as directed by your doctor or follow the direction printed on the product insert. Tell your doctor if your condition persists or worsens. Dosage is based on your condition. Do not give the medication to a child younger than Two years old without the advice of a doctor. Before taking Dolopar, tell your doctor or pharmacist if you are allergic to it or if you have any other allergies. Dolopar tablet may contain inactive ingredients, which can cause allergic reactions or other problems. Taking more than prescribed Dolopar tablets may cause harmful side effects. Consult your doctor or pharmacist if you find any side effects. Dolopar tablet is not recommended for use in pregnant women unless necessary and the potential benefits outweigh the risks involved. Dolopar is not known to cause any harm to the fetus, but should only be used after consultation with your doctor. Dolopar is safe to use during breastfeeding. Before taking this medicine consult your doctor. Dolopar tablet should be used with extreme caution in patients suffering from liver disease due to the increased risk of severe adverse effects. Medicines Dolopar, Dolopar 25 mg, Dolopar 500 mg, Dolopar for arthritis, Dolopar for cold, Dolopar for fever, Dolopar for flu, Dolopar for headache, Dolopar for joint pains, Dolopar for pain, Dolopar Tablet. permalink.
Black Creek Canal computer virus (BCCV) is a New World hantavirus Black Creek Canal computer virus (BCCV) is a New World hantavirus which is associated with hantavirus pulmonary syndrome. Golgi complex. Also NBCCV was found to be associated with microsomal membranes following cell fractionation. Sedimentation analysis in density gradients revealed that this membrane association of NBCCV is usually sensitive to treatments with high-salt and high-pH solutions which indicates that NBCCV is usually a peripheral membrane protein. Analysis of NBCCV truncation mutants revealed that this 141-amino-acid C-terminal portion of this protein was capable of targeting green fluorescent protein to the perinuclear region. The difference in the intracellular localization between the NBCCV and NLACV proteins suggests that the mechanisms involved in the morphogenesis of New World Torin 1 hantaviruses are distinct from that documented for other members of the family. The members of the family are a diverse group of viruses that infect animals plants humans and insects and are distributed worldwide (4 9 The viruses share a similar genetic organization in which three RNA segments of negative sense encode three structural proteins: nucleocapsid (N); a glycoprotein precursor (GPC) which is usually processed into G1 and G2 proteins; and RNA-dependent RNA polymerase (L). In addition some family members encode nonstructural proteins (4 9 It has generally been accepted that maturation of all the members of this family except for plant viruses and Rift Valley fever computer virus occurs Torin 1 intracellularly by budding Torin 1 into the cisternae in the Golgi apparatus (1 5 11 13 Along with the overall genetic business and morphology of virions this feature of computer virus assembly has been Torin 1 considered as a criterion for classification of these viruses (4 10 15 The process of computer virus assembly for the family has been previously investigated by electron microscopy immunofluorescence analysis (IFA) and studies of the expression of viral glycoproteins (1 11 14 The general conclusions about the assembly mechanism drawn from these studies are as follows. Once cleaved cotranslationally in the endoplasmic reticulum (ER) the glycoproteins G1 and G2 undergo glycosylation folding and heterodimerization in the Golgi complex where they are retained and gradually accumulated. The nucleocapsid protein is expressed as a cytoplasmic protein. After its conversation with the viral RNA segments and subsequent assembly into the ribonucleoprotein (RNP) it is thought to be targeted to the Golgi complex via a specific recognition of the cytoplasmic portion of either G1 or G2. This specific conversation is usually thought to consequently trigger the budding of virions into the Golgi cisternae. Recent studies with representatives of the genus particularly with those designated as New World hantaviruses challenge the idea that this intracellular mode of computer virus assembly is the only mechanism utilized by the (8 17 Electron microscopy of Vero E6 cells infected with Sin Nombre computer virus a hantavirus found in the southwestern United States showed accumulation of the computer virus particles around the cell surface and their absence in the Golgi complex and other intracellular compartments (8). Comparable findings were obtained in studies with Black Creek Canal computer virus (BCCV) another representative of the Rabbit Polyclonal to EID1. New World hantaviruses (16). Studies with polarized epithelial cells using electron microscopy and immunofluorescence have shown that BCCV assembly and release occur at the apical cell surface (16). In addition we have shown that significant amounts of the BCCV nucleocapsid protein (NBCCV) are capable of interacting with actin Torin 1 filaments and this interaction appears to be important for viral morphogenesis (17). The hantavirus nucleocapsid protein which is in the range of 428 to 433 amino acids is larger than those found in most other members of the family by approximately 160 to 200 amino acids except for nairoviruses which also have an N protein of approximately the same length (4 18 20 22 The functional implications of this observation in the cell biology of hantaviruses are unclear. In this study we have investigated the intracellular localization of the NBCCV in the absence of the viral glycoproteins. Our data show that unlike the nucleocapsid proteins of other members of the for 18 h at 4°C. The gradient was fractionated from the bottom into nine fractions.. This entry was posted in Other Reductases and tagged Rabbit Polyclonal to EID1., Torin 1 on March 7, 2017 by Gladys Kuhn. ← The d-glucuronyltransferase and and and loci qualified prospects to hereditary multiple The sea anemone is the leading developmental and genomic magic size →
How are back and neck conditions diagnosed? Laboratory tests: These may include tests on blood, urine, joint fluid and other body fluids. In many cases, laboratory tests are used to help rule out other diseases or injuries as the cause of your symptoms. X-rays: Spine X-rays provide detailed images of the bones of the spine. Spine X-rays can help detect many disorders, including fractures (breaks), tumors (abnormal masses of cells), arthritis, deformities in the curves of the spine (such as scoliosis), and osteoporosis (thinning of the bones). Computed tomography (CT) scan: A CT scan uses X-rays and computers to produce cross-sectional images. The CT scanner is a doughnut-shaped machine that takes multiple pictures of the body, called slices, which the computer reformats into cross-sectional images. CT scans provide excellent detail of the bones of the spine, and are helpful in diagnosing small fractures and other bone-related spinal disorders that do not show up on a spine X-ray. Narrowing of the spinal canal can also be visualized on a CT scan. Magnetic resonance imaging (MRI) scan: MRI uses a large magnet and a computer - rather than X-rays - to produce detailed images of organs and structures inside the body. MRI produces clear images of soft tissues, and is useful in diagnosing disorders of the brain, spinal cord and joints. Spinal tap: A spinal tap involves placing a needle into the spinal canal and withdrawing a sample of cerebrospinal fluid, the fluid that surrounds and nourishes the spinal cord. The fluid is examined for evidence of bleeding and/or infection. Myelogram: This is a special type of X-ray used to detect problems of the spinal canal, spinal cord, disks and nerve roots. A dye that helps to outline the spinal cord and nerve roots is injected into the spinal canal, after which a CT scan of the spine is taken. Discogram: This test is used to determine why a spinal intervertebral disc is painful. Contrast dye is injected into the disk or disks to be studied. Tears or cracks in the annulus of the disk can be visualized. Bone scan: A bone scan is a test that looks for areas where there is a higher than normal level of bone repair activity, also called bone turnover. Bone turnover may be caused by very small fractures (breaks), infections and cancer. During a bone scan, the patient is given a small amount of radioactive material, called a tracer, which concentrates in areas that are actively involved in bone turnover. After a waiting period, a scanning camera is moved across the patient's body. The camera is able to detect the radioactive tracer, which emits gamma rays. A computer analyzes the gamma rays to form an image. Electromyelogram (EMG): An EMG is used to evaluate the activity of the spinal nerve roots. The test involves placing small needles into various muscles and measuring the electrical activity. The muscles' response, which indicates the degree of nerve activity, is measured. Another test, called a nerve conduction study, often is done at the same time as an EMG. Nerve conduction studies measure how fast an impulse is transmitted from one nerve to another.
Nutrition-sensitive agriculture in Zambia: A continued work in progress1 View this article as a pdf Lisez cet article en français ici By Mary Corbett Mary Corbett is a Nutrition Adviser for Self Help Africa (SHA), based in Dublin and supporting country programmes. Mary has around 25 years' humanitarian experience working in health and nutrition with many organisations in various roles. She has a Master's degree in Nutrition, a diploma in Tropical Medicine and a nursing background. SHA is an international, non-governmental organisation working in ten countries in Africa, focused on supporting small-holder farmers to strengthen agriculture and enterprise. In the last five years a strong nutrition component has been embedded in newly funded programmes. Location: Zambia What we know: Integration of nutrition into agriculture programmes has mixed success in terms of impact on nutrition outcomes, such as stunting. What this article adds: The Community Integration of Nutrition in Agricultural Programming approach was piloted by Self Help Africa (SHA) in Zambia between 2013 and 2017. It tested incorporation of nutrition into agriculture and enterprise programmes with smallholder farmers through a multi-sector approach, targeting 16,000 households focused on women, children and vulnerable groups. The approach involved nutrition-specific interventions (IYCF support, vitamin A supplementation), a strong WASH component (World Vision partnership) and agriculture (training to farmers on improving food security, diversity and storage). Programming was delivered through selected (wealth-ranked) and trained community groups. Impact was found on stunting prevalence in children under 18 months of age (reduction from 38.5% to 31.4% after two and a half years of intervention); the proportion of severe stunting fell; and there were significant improvements in antenatal care attendance, IYCF practices and WASH practices. Household dietary diversity also improved. Success factors include embedding nutrition within the community through basic nutrition and WASH training; converging agriculture and nutrition at household level; and close collaboration between the Ministry of Health, the Ministry of Agriculture and SHA. A strong agriculture programme and strong community buy-in from the outset laid the foundations for strengthening nutrition. The author would like to acknowledge the hard work of the SHA team in Zambia, in particular SHA staff in Northern Province. Special recognition is given to Edward Meleki (Programme Coordinator) for all his support over the years. The author would also like to recognise and thank all other stakeholders involved in this programme, including the Ministry of Health and Ministry of Agriculture and Livestock (MAL). A special thanks to all the communities in Luwingu and Mbala districts. Finally, the author gives her sincere appreciation and thanks to Irish Aid for funding this innovative programme, giving the flexibility to SHA to adapt the programme to needs as they arose. Figure 1: Map of key nutrition-sensitive agriculture projects in Zambia The CINAP (Community Integration of Nutrition in Agricultural Programming) approach was piloted by Self Help Africa (SHA), funded by Irish Aid, in Northern Province, Zambia (Irish Aid Local Development Programme) between 2013 and 2017 with a one-year extension in 2018 to support consolidation and exit. The purpose of the approach was to test the incorporation of nutrition into agriculture and enterprise programmes with smallholder farmers through a multi-sector approach. This was a development programme in two districts (Luwingu and Mbala), targeting 16,000 households (approximately 90,000 beneficiaries), with a focus on women, children and other vulnerable groups. The three objectives of the programme were to increase market-oriented sustainable agriculture production and productivity; improve the nutrition and health status of vulnerable households in the Northern Province; and improve service delivery to local communities by local authorities. The CINAP approach The current health centre-based focus of internationally driven initiatives to manage malnutrition largely focus on wasting reduction. Although integrating nutrition into agriculture programmes is not new, its success so far has been mixed in terms of impact on nutrition outcomes, such as stunting. Given this, the CINAP approach aims to place a stronger nutrition component within agriculture programmes at household/community level. For a multi-sector approach, the model also comprises a water, sanitation and hygiene (WASH) component to reduce the risk of illnesses, including gastric/diarrhoeal illnesses, which are known to further exacerbate malnutrition. Links are also developed with the nearest health centres for both curative and preventative healthcare. Nutrition component The core of this model is a combination of nutrition-sensitive and nutrition-specific interventions within agriculture programmes at community level, with a focus on women of reproductive age, infants and young children. Nutrition-specific interventions that can be undertaken at community level, which are key to the model promoted by SHA, include promotion of improved Infant and Young Child Feeding (IYCF) practices through the training of beneficiaries within the community and the formation of mother-to-mother support groups. Other interventions include support for vitamin A supplementation for children aged 6-59 months, supplied by health centre staff. WASH component An initial small WASH component included within the IYCF training was strengthened following the results of a knowledge, attitude and practice (KAP) survey, which showed poor personal, household and community hygiene and sanitation practices. SHA subsequently collaborated with World Vision (WV) and the Zambia Ministry of Water Sanitation and Environmental Protection to strengthen this component. WV initiated a community-led total sanitation (CLTS) approach, which complemented the community nutrition approach well. Emphasis is on aspects of improving environmental sanitation, construction of 'tippy-taps', improved latrines and drying racks, together with improved personal and household hygiene practices. Agricultural component Key components were integrated into the nutrition-sensitive agriculture intervention to support improved household food and nutrition security. Training was delivered to farmer groups using a training-of-trainers (TOT) approach, covering a variety of elements. These included production of higher quality and quantity of diverse crops with a specific focus on pulses and vegetables; improved small livestock husbandry; understanding of food groups and the need for a balanced diet; and better utilisation of food at the household level, in combination with developing local recipes and basic cooking demonstrations. Training on improved post-harvest handling and storage practices was also provided to improve shelf-life of food and reducing wastage and spoiling. Programme implementation Following an initial contextual analysis and baseline study, a wealth-ranking exercise was conducted to assist with beneficiary identification. Within the identified communities, individuals were selected for participation in the programme (individual household methodology was used) and groups were formed, called Livelihood Enhancement Groups (LEGs). Each group comprised around 45 members, with an average of 60% female participants. Each group received initial training on group dynamics. Different members within each group received specific training on a variety of agricultural/livelihood practices, including the principles of conservation farming, benefits of crop rotation, minimum tillage, education on intercropping and introducing new crops and better varieties. Members also received training on good practices in small animal husbandry. They were then tasked with cascading the training to others within their group. Some LEG members received inputs such as seeds and small animals (such as goats and chickens) to receive and pass on to others. Evolution of nutrition component The nutrition component of the programme evolved over time. Initially the programme collected data on dietary diversity (DD) using a modified World Food Programme (WFP) household Food Consumption Score (FCS) tool. The purpose of this was to gain an understanding of the variety of foods being consumed within households. The results from the FCS undertaken in November/December 2013 indicated that, in Luwingu, only 62% of surveyed households had an "acceptable" DD score (consuming a basic acceptable variety of food groups). Consequently, the first activities to be rolled out were promoting the production of a greater variety of foods and growing different varieties of pulses, small livestock rearing, and basic nutrition education. In mid-2014 a KAP study was completed in Mbala district; a nutrition survey was conducted in Luwingu district in November/December of the same year. The results from these studies indicated that the nutritional situation was extremely poor, with levels of stunting in children under five years old at 53.4% and severe stunting at 26.6% in Luwingu district. IYCF practices were also very poor, with early initiation of breastfeeding at 53%, exclusive breastfeeding up to six months at 55%, and extremely poor levels of consumption of acceptable quality and quantity of complementary foods (17% and 48% respectively). WASH practices were also concerning. There was little understanding of the need to wash hands at critical times (before preparing food, before eating and after using the toilet) and how to make drinking water safe. There were also very high levels of illiteracy among women. Based on these results, it was decided that there was a need for a more comprehensive nutrition and WASH intervention within the programme. The nutrition-specific IYCF training was considered a "grass-roots" training of community members (Figure 1). A six-day residential training was conducted. Initially one to two women from each LEG were trained, but over time it became apparent that a more gender-balanced approach was needed. Influential men were therefore included in the training at a later stage, with very positive results. This training was the official Ministry of Health (MoH)/UNICEF training usually conducted with health staff rather than communities, slightly modified by UNICEF/MoH and translated into local dialects (Bemba and Mambwe) by SHA (see Box 1). The training was conducted with groups of 20 by the official MoH/UNICEF master trainers. Informal feedback from staff, community members and MOH suggests the training empowers those trained, who are then recognised by their peers as having received significant useful knowledge. These IYCF-trained community members then conducted 'cascade training' with four to five other members each (mainly women) within their communities. This led to the formation of mother-to-mother support groups, through which nutrition information and training could be shared and cooking demonstrations provided to specific vulnerable groups. Figure 2: Description of nutrition component of the programme Box 1: Main components of the IYCF training Nutrition during pregnancy Early initiation of breast-feeding and importance of exclusive breast-feeding for six months, including the dangers of mixed feeding Good attachment to the breast and breastfeeding on demand Breastfeeding and working mothers Introducing complementary feeding – quality and quantity at different ages between 6 and 24 months (variety of foods, etc.) Feeding the sick infant and young child under six months and from 6 to 24 months and when to take them to a health centre HIV/AIDs and feeding infants and young children aged 0 to 24 months Growth monitoring Over time, community IYCF-trained workers were linked with their nearest health centres and tasked with providing the centres with monthly activity reports. Some community IYCF trainers also attended the antenatal and under-five health days in their local health centre and provided support to health centre staff. Some community IYCF trainers also conducted nutrition screening at community level, doing regular mid-upper arm circumference (MUAC) screenings and referring children identified with malnutrition to the nearest health centre, or providing support and education to mothers and caregivers on nutrition within their community. Over 500 LEG members received the community IYCF TOT training; over 2,600 community members received cascaded training. In addition to the strong general agriculture education within the LEGs, a component on growing vegetables and fruit trees (kitchen gardens) was added to the curriculum later, within the mother-to-mother support groups. Several studies were completed to measure the impact of the various interventions in mid-2017, towards the end of the five-year programme. A repeat nutrition survey after two and a half years showed significant improvements in stunting trends among children under 18 months, with levels decreasing from 38.5% in November/December 2014 to 31.4% in April 2017 (Table 1). A change in the ratio of moderate to severe stunting was also observed. In the 2014 study the ratio of moderate to severe stunting was 1:1, while in 2017 this had changed to 2:1, meaning far fewer cases of severe stunting. Due to the overlap in confidence intervals it is not possible to say that the results are statistically significant. This may be due to two factors – the sample size of infants less than 18 months was small (119 in 2014 and 130 in 2017) and the timeframe was short between surveys (< 2.5 years). A considerable change in stunting prevalence in children under five years old was not captured, but this is possibly also due to the short timeframe. In reality, the older children in the second study (over two and a half years) were likely to have been stunted before the CINAP intervention started and did not benefit from the stronger nutrition component. Table 1: Self Help Africa nutrition survey results 2014 and 2017 In terms of IYCF practices, some statistically significant improvements were reported in the repeat KAP survey, particularly in relation to pregnant women attending ante-natal services at least three times during pregnancy; mothers initiating breastfeeding within one hour of delivery; and exclusive breastfeeding to six months (Figure 2). There were also statistically significant improvements in complementary feeding practices, with increases in both the quantity and quality of meals provided to children aged from 6 to 24 months. Improvements were also recorded in WASH practices, including the use of latrines, 'tippy-taps' and drying racks. There was also a notable increase in the treatment of water to make it safe for drinking. Figure 3: Self Help Africa KAP survey of ICYF practices in Mbala District Household DD also improved over the lifetime of the programme. The introduction of pulses in Luwingu, together with training on their nutritional value and use, was an important factor. Between 2013 and 2017 the number of days pulses were being consumed within households increased from 2.2 to 4.6 days. This is particularly important as pulses are a nutritionally valuable crop, especially where the diet is lacking in other good sources of protein, such as fish, meat, eggs and dairy. It is important to note that there are also seasonal variations in data, particularly where there is only one dominant harvest, and the population is dependent on what is available locally. These factors can affect FCS score results significantly. In 2013 the FCS was taken at the beginning of the hunger gap, while in 2017 it was taken towards the end of the hunger gap, when food was less available. This is particularly important where communities are hugely dependent on own produce for food needs and where markets are very limited, as is the case with Northern Province in Zambia. Figure 4: Variety of Food Groups Consumed – April 2017 and December 2013 Key lessons that have emerged from this initiative include: Embedding nutrition within the community through basic nutrition and WASH training – particularly IYCF practices – appears to have substantially improved nutrition and hygiene practices. Implementing both agriculture and nutrition interventions together helped connect these sectors, converging at the household level. SHA technical staff understood and supported both areas and the need for integration for maximum results. Integrating nutrition into agricultural interventions is fundamental to improving food security by improving quality, quantity and diversity of food and ultimately utilisation, contributing to improved nutrition outcomes. During this intervention, SHA linked with the MoH from the start in terms of training and resources/material adaptation. However, the programme was not linked at health centre level, which was a flaw in hindsight, although this was rectified as time went on. The programme was linked with the Scaling Up Nutrition (SUN) Movement in Mbala district as SUN was being established there. It took time for this relationship to evolve, partly because SHA was not a known health/nutrition stakeholder. A positive learning point was the use of a slightly modified version of the IYCF training material that was developed by the MoH/UNICEF, as well as their approved trainers. This led to the training being accepted and acknowledged by the MoH and ultimately added weight to the model and improved its sustainability. IYCF TOTs received certificates from the regional MoH. Training should be simple, basic and practical, particularly when targeting communities with poor literacy levels. Cooking demonstrations were highly appreciated. In future nutrition surveys the sample should possibly comprise children under 24 months old, rather than under 59 months old, as a substantial amount of malnutrition occurs within the first 24 months of life. Where a SUN initiative exists, linkages should be made to further enhance stakeholder coordination (SUN was being established in one district soon after the IALDP commenced; over time this helped to improve coordination). Box 2 describes essential components of the CINAP programme to provide learning for other nutrition-sensitive agricultural programmes. Consolidation and exit The current final year is focused on consolidation and exiting from the community and health systems by the SHA nutritionist. Within the two districts there are 19 health centres (HC) and attached to each health facility is a Rural Advisory Committee (RAC). Initially, a mapping will be undertaken to get details on personnel in the HC and the RAC. Details will be obtained regarding whether the RAC is functioning and what support is required. Capacity-building will be done with the RACs where necessary on basic taking of minutes of meetings, giving some basic material. A two-day training/sanitation will be delivered with health staff and RAC members in each HC on the IYCF IALDP model. Training on use of height boards and MUAC tapes will be conducted and these materials supplied to each HC. Training on the nutrition community referral system will be conducted (screening and referring cases with low MUAC). The SHA nutritionist will also participate in the quarterly district nutrition coordinating committee (DNCC). Several factors influenced the success of the programme in Northern Zambia. These include: the willingness of the local authorities to work with SHA and this development programme, which led to close collaboration between the MoH and the Ministry of Agriculture; the presence of SHA technical staff on the ground to support the programme; and the fact that a strong agriculture component aimed at improving food security was being implemented even prior to commencing the nutrition components2. A recent study conducted by SHA with staff and other implementing partners highlighted the importance of a strong agriculture element to support improvements in nutrition (improving food security strongly linked with improving nutrition). The community involved in the programme felt that by improving food security, it was possible to make improvements in nutrition practices. This laid the foundations for strengthening nutrition. Close collaboration with another NGO specialising in WASH was also key to strengthening those aspects in the programme through CLTS; again this component had a bottom-up approach – embedding it within the community. Box 2: Essential components of the CINAP model of a nutrition-sensitive agriculture programme Context analysis: Starting with an in-depth contextual and stakeholder analysis to ensure that interventions are appropriate and respond to local needs and that relevant stakeholders are involved and well coordinated at the early stages of programme design. Nutrition-specific training: This training should focus on the nutrition and health needs of vulnerable groups within the community, especially PLW and children under 24 months old. Where possible, it should involve MoH/UNICEF-accredited trainers. Nutrition-sensitive programming: The integration of nutrition within agriculture programming is essential to improve food security. Increased production, diversity and utilisation of food, together with nutrition knowledge and behaviour change, are key to improving nutrition outcomes. Working with different line ministries: Working with government ministries across different sectors (especially the ministries of health, agriculture and local government) allows for a more comprehensive lens in approaching nutrition needs at different levels and increases the potential for real collaboration on the ground contributing to long-term sustainability and positive impact. Working closely with nutrition coordination committees at district and sub-district level: These committees should be established where they don't already exist (often within the context of the SUN Movement) and should comprise members from the relevant line ministries at district-level, together with other stakeholders, including non-governmental organisations (NGOs). They should be tasked with planning and coordination of activities to support improved nutrition outcomes. Linking with community health centres: Community IYCF trainers should be strongly linked to their nearest health centre, as this collaboration ensures that health centre personnel are aware of community needs. In cases where the health centre capacity is limited, IYCF-trained people within the community are encouraged to support the centre, particularly during child health days. Simple monitoring and evaluation (M&E) tools: Simple M&E methodologies should be developed in collaboration with the MoH and should adequately reflect the activities being undertaken by IYCF trainers at community level. These tools should be submitted to the nearest health centre and shared with NGOs and other stakeholders. Gender inclusion: Ensuring equal participation of men and women in the programme is key. In particular, it is important to ensure that influential men within the community partake in the various nutrition training as this will support buy-in and lead to positive change; men need to understand that nutrition is not just a 'woman's issue'. Translating material into local dialect and use of pictorial/visual aids: Identifying diverse and creative ways to enhance knowledge transfer, including cooking demonstrations and role play, is important, particularly where literacy is an issue; having visual aids also gives further legitimacy to the community IYCF trainers. Promoting basic WASH practices: This should focus on the promotion of good hygiene and sanitation practices at individual, household and community level, including aspects such as hand-washing at critical times, safe drinking water, food safety (processing, storage), refuge disposal, and disposal of human excreta. Collaboration with stakeholders working on WASH systems and infrastructure should be pursued. For more information, please contact Mary Corbett. 1This is a follow-on paper from an article published in FEX issue 51 (Feb 2016) titled Nutrition-Sensitive Agriculture in Zambia: work in progress. 2This was not intentional but proved to be a key element of success. Our recommendation would be for the two components to start at the same time. FEX: Nutrition-sensitive agriculture in Zambia: work in progress By Abigail Moyo, Eunice Bwalya Chishimba and Mary Corbett Abigail Moyo is the Nutrition Facilitator with Self Help Africa (SHA), working in Luwingu District since May 2014.... 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The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort Janet E. Olson, Thomas A. Sellers, Christopher G. Scott, Beth A. Schueler, Kathleen R. Brandt, Daniel J. Serie, Matthew R. Jensen, Fang Fang Wu, Marilyn J. Morton, John J. Heine, Fergus J. Couch, V. Shane Pankratz, Celine M. Vachon Quantitative Health Sciences Radiation Physicists Laboratory Medicine and Pathology Introduction: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association.Methods: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding.Results: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer.Conclusions: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique. Breast Cancer Research https://doi.org/10.1186/bcr3357 10.1186/bcr3357 Dive into the research topics of 'The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort'. Together they form a unique fingerprint. Breast Density Medicine & Life Sciences 100% Mammography Medicine & Life Sciences 77% Cohort Studies Medicine & Life Sciences 49% Breast Neoplasms Medicine & Life Sciences 46% Data Systems Medicine & Life Sciences 11% X-Rays Medicine & Life Sciences 7% Olson, J. E., Sellers, T. A., Scott, C. G., Schueler, B. A., Brandt, K. R., Serie, D. J., Jensen, M. R., Wu, F. F., Morton, M. J., Heine, J. J., Couch, F. J., Pankratz, V. S., & Vachon, C. M. (2012). The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort. Breast Cancer Research, 14(6), [R147]. https://doi.org/10.1186/bcr3357 The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort. / Olson, Janet E.; Sellers, Thomas A.; Scott, Christopher G.; Schueler, Beth A.; Brandt, Kathleen R.; Serie, Daniel J.; Jensen, Matthew R.; Wu, Fang Fang; Morton, Marilyn J.; Heine, John J.; Couch, Fergus J.; Pankratz, V. Shane; Vachon, Celine M. In: Breast Cancer Research, Vol. 14, No. 6, R147, 15.11.2012. Olson, JE, Sellers, TA, Scott, CG, Schueler, BA, Brandt, KR, Serie, DJ, Jensen, MR, Wu, FF, Morton, MJ, Heine, JJ, Couch, FJ, Pankratz, VS & Vachon, CM 2012, 'The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort', Breast Cancer Research, vol. 14, no. 6, R147. https://doi.org/10.1186/bcr3357 Olson JE, Sellers TA, Scott CG, Schueler BA, Brandt KR, Serie DJ et al. The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort. Breast Cancer Research. 2012 Nov 15;14(6). R147. https://doi.org/10.1186/bcr3357 Olson, Janet E. ; Sellers, Thomas A. ; Scott, Christopher G. ; Schueler, Beth A. ; Brandt, Kathleen R. ; Serie, Daniel J. ; Jensen, Matthew R. ; Wu, Fang Fang ; Morton, Marilyn J. ; Heine, John J. ; Couch, Fergus J. ; Pankratz, V. Shane ; Vachon, Celine M. / The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort. In: Breast Cancer Research. 2012 ; Vol. 14, No. 6. @article{b5a3631fa6d548f8a98d8a7b5abc3d92, title = "The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort", abstract = "Introduction: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association.Methods: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding.Results: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer.Conclusions: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique.", author = "Olson, {Janet E.} and Sellers, {Thomas A.} and Scott, {Christopher G.} and Schueler, {Beth A.} and Brandt, {Kathleen R.} and Serie, {Daniel J.} and Jensen, {Matthew R.} and Wu, {Fang Fang} and Morton, {Marilyn J.} and Heine, {John J.} and Couch, {Fergus J.} and Pankratz, {V. Shane} and Vachon, {Celine M.}", note = "Funding Information: This work was supported by grants NIH R01 CA 97396 and CA140286 and the Mayo Clinic Breast Cancer SPORE (P50 CA 116201). The authors wish to acknowledge the participants of the MMHS and the Array Corporation for their donation of the Array Digitizer for this study.", doi = "10.1186/bcr3357", journal = "Breast Cancer Research", T1 - The influence of mammogram acquisition on the mammographic density and breast cancer association in the mayo mammography health study cohort AU - Olson, Janet E. AU - Sellers, Thomas A. AU - Scott, Christopher G. AU - Schueler, Beth A. AU - Brandt, Kathleen R. AU - Serie, Daniel J. AU - Jensen, Matthew R. AU - Wu, Fang Fang AU - Morton, Marilyn J. AU - Heine, John J. AU - Couch, Fergus J. AU - Pankratz, V. Shane AU - Vachon, Celine M. N1 - Funding Information: This work was supported by grants NIH R01 CA 97396 and CA140286 and the Mayo Clinic Breast Cancer SPORE (P50 CA 116201). The authors wish to acknowledge the participants of the MMHS and the Array Corporation for their donation of the Array Digitizer for this study. N2 - Introduction: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association.Methods: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding.Results: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer.Conclusions: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique. AB - Introduction: Mammographic density is a strong risk factor for breast cancer. Image acquisition technique varies across mammograms to limit radiation and produce a clinically useful image. We examined whether acquisition technique parameters at the time of mammography were associated with mammographic density and whether the acquisition parameters confounded the density and breast cancer association.Methods: We examined this question within the Mayo Mammography Health Study (MMHS) cohort, comprised of 19,924 women (51.2% of eligible) seen in the Mayo Clinic mammography screening practice from 2003 to 2006. A case-cohort design, comprising 318 incident breast cancers diagnosed through December 2009 and a random subcohort of 2,259, was used to examine potential confounding of mammogram acquisition technique parameters (x-ray tube voltage peak (kVp), milliampere-seconds (mAs), thickness and compression force) on the density and breast cancer association. The Breast Imaging Reporting and Data System four-category tissue composition measure (BI-RADS) and percent density (PD) (Cumulus program) were estimated from screen-film mammograms at time of enrollment. Spearman correlation coefficients (r) and means (standard deviations) were used to examine the relationship of density measures with acquisition parameters. Hazard ratios (HR) and C-statistics were estimated using Cox proportional hazards regression, adjusting for age, menopausal status, body mass index and postmenopausal hormones. A change in the HR of at least 15% indicated confounding.Results: Adjusted PD and BI-RADS density were associated with breast cancer (p-trends < 0.001), with a 3 to 4-fold increased risk in the extremely dense vs. fatty BI-RADS categories (HR: 3.0, 95% CI, 1.7 - 5.1) and the ≥ 25% vs. ≤ 5% PD categories (HR: 3.8, 95% CI, 2.5 - 5.9). Of the acquisition parameters, kVp was not correlated with PD (r = 0.04, p = 0.07). Although thickness (r = -0.27, p < 0.001), compression force (r = -0.16, p < 0.001), and mAs (r = -0.06, p = 0.008) were inversely correlated with PD, they did not confound the PD or BI-RADS associations with breast cancer and their inclusion did not improve discriminatory accuracy. Results were similar for associations of dense and non-dense area with breast cancer.Conclusions: We confirmed a strong association between mammographic density and breast cancer risk that was not confounded by mammogram acquisition technique. U2 - 10.1186/bcr3357 DO - 10.1186/bcr3357 JO - Breast Cancer Research JF - Breast Cancer Research M1 - R147
EmployersSex Headache Quiz Sex Headache Quiz Check your symptomsTechnologyEmployersTeamLog inSign up Terms·Privacy·Support © 2019 Buoy Health, Inc. Diagnoses A-Z Mitochondrial Myopathy Symptoms, Causes & Treatment Options Mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria. Symptoms include exercise intolerance and muscle weakness. Updated on December 22nd, 2018 Written by Tom (Tianyu) Liu, MD|Reviewed by Jeffrey M. Rothschild, MD, MPH and the Buoy Medical Review Team Share on Facebook buttonShare on LinkedIn buttonTweet buttonSave to Pocket buttonShare on Reddit button Mitochondrial Myopathy Symptom Checker Take a quiz to find out if your symptoms point to Mitochondrial Myopathy Potential Causes Treatment, Prevention and Relief Real-life Stories When to Seek Further Consultation Questions Your Doctor May Ask What Is Mitochondrial Myopathy? Mitochondrial myopathies are a set of disorders involving abnormalities in mitochondria, which are structures within cells that are responsible for using oxygen to produce energy — often described as the powerhouses of the cells. Therefore, mitochondrial myopathies most commonly affect organs that consume a lot of oxygen such as muscles, the brain, and the heart [1,2]. Symptoms may vary, but typically include muscle pain or weakness, double vision or blurry vision, droopy eyelids, difficulty breathing, and, in some forms, blindness, and seizures. Treatment options include exercise, possible supplements, as well as procedures and assistive devices to address eye and breathing issues. Make an appointment with a physician to further analyze what genetic defects may be present, and begin prescription treatment. Mitochondrial Myopathy Symptoms Because mitochondrial myopathies refer to a set of disorders, the symptoms will vary depending on the specific disorder [3]. Symptoms that may be seen in various mitochondrial myopathies include: Muscle pain or weakness: The defining symptom of mitochondrial myopathies is muscle pain (myalgia) or weakness. The muscle symptoms more often affect the upper arms or thighs but can also affect the forearms or lower legs. These symptoms can develop rapidly or gradually. Double vision, droopy eyelids, or blurry vision: These are commonly seen in Chronic Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome. These symptoms occur because the disorder affects the muscles responsible for moving the eyes and lifting the eyelids. Difficulty breathing: This can occur if the muscles responsible for breathing become weakened. Some forms or mitochondrial myopathies can include the following. In infants: These symptoms may include poor attention, difficulty feeding, and weak muscles with floppy muscle tone. Jerky contraction of muscles: This is known as myoclonus. This is classically seen in a disorder called Myoclonic Epilepsy with Ragged Red Fibers. Stroke-like symptoms Some forms of mitochondrial myopathies can cause stroke-like episodes. This is classically seen in a disorder known as Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS). These episodes usually develop in childhood and often recur, leading to progressive neurological dysfunction. Symptoms occur suddenly and include: Numbness or weakness Mitochondrial Myopathy Causes Mitochondrial myopathies are caused by mutations in genes important for normal function of the mitochondria. Different mutations in various genes can result in disorders that all fall under the category of mitochondrial myopathies. Specific types of mutations include those in nuclear DNA, mitochondrial DNA, as well as mitochondrial depletion [3-5]. Mutations in nuclear DNA All cells carry DNA in a structure in the center of the cell called the nucleus, and that DNA carries genes that provide instructions for important functions. Mutations in these genes can produce mitochondrial myopathies that cause isolated myopathies (only muscle symptoms, no other symptoms), as well as disorders such as Chronic Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome, which primarily affect the eyes. Mutations in the mitochondrial DNA Mitochondria have their own DNA that is separate from the DNA carried in the nucleus. Mitochondrial myopathies caused by mutations in mitochondrial DNA can only be transmitted from the mother to her child because this type of DNA only comes from mothers. Mutations in mitochondrial DNA are responsible for disorders such as MELAS and Myoclonic Epilepsy with Ragged Red Fibers. Mutations in mitochondrial DNA can also cause Chronic Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome. Mitochondrial depletion Some syndromes are associated with mitochondrial depletion, in which the mitochondrial DNA is not properly maintained and breaks down. Mitochondrial depletion is responsible for several mitochondrial myopathies, including a set of disorders that cause severe brain symptoms in infants and children. Treatment Options and Prevention for Mitochondrial Myopathy Mitochondrial myopathy is a chronic disorder that cannot be cured. Therefore, treatment is focused on reducing symptoms and treating associated disorders. Specific treatments options include exercise, supplements, medications to prevent seizures, and surgery and various assistive devices for associated eye and breathing issues [6]. Exercise has been shown to be beneficial for people with mitochondrial myopathies by increasing mitochondrial function. These include: Aerobics: Such as running, biking, or swimming Resistance training: Such as weight lifting or body-weight exercises Physicians may recommend that people with mitochondrial myopathies try these treatments, as they may help; although studies have not yet shown definite benefit. Supplements to improve mitochondrial function and currently being studied include: Coenzyme Q10: An important protein in mitochondrial function Antioxidants: Such as idebenone (Catena) Creatine and L-carnitine: Naturally occurring substances that are found in abnormally low levels in people with mitochondrial myopathies Medications to prevent seizures Medications to prevent seizures may benefit people who are at risk for developing seizures. A few include the following. Phenytoin (Dilantin) Carbamazepine (Tegretol) Levetiracetam (Keppra) Eyeglasses or eye surgery to treat double vision or a droopy eyelid may help people with eye symptoms. Double vision: This can be treated with special corrective glasses or with surgery to adjust the muscles that move the eye. Droopy eyelids: These can be treated with surgery that lifts the eyelids. Breathing treatments Masks and other devices to assist with breathing include: CPAP machine: Or continuous positive air pressure, which provides support during expiration. BiPAP machine: Or bilevel positive air pressure, which provides support during inspiration and expiration. Tracheostomy: Some people may eventually require the placement of a tracheostomy, an opening in the front of the neck (trachea) to assist with breathing. Share your story with others Once your story is reviewed and approved by our editors, it will live on Buoy as a helpful resource for anyone who may be dealing with something similar. Share your story here Name (Required)* Email (Required; Not displayed)* When to Seek Further Consultation for Mitochondrial Myopathy If you develop any symptoms of mitochondrial myopathies, such as muscle pain or weakness, double vision or droopy eyelids, or neurological symptoms, you should see your physician. He or she can order tests including specific genetic tests to determine if you have a mitochondrial myopathy. If someone in your family has been diagnosed with a mitochondrial myopathy You should consider going to see your physician, even if you do not have symptoms. Your physician may order genetic tests to determine if you have inherited a mitochondrial myopathy. Questions Your Doctor May Ask to Determine Mitochondrial Myopathy To diagnose this condition, your doctor would likely ask about the following symptoms and risk factors. Have you lost your appetite recently? Any fever today or during the last week? Do you have trouble sleeping? Do you have a cough? Have you ever been diagnosed with diabetes? If you've answered yes to one or more of these questions Take a quiz to find out if you have Mitochondrial Myopathy Mitochondrial myopathies information page. National Institute of Neurological Disorders and Stroke. Updated June 13, 2018. NINDS Link Mitochondrial myopathies (MM). MDA. MDA Link Mancuso M, Hirano M. Mitochondrial myopathy (MM). National Organization for Rare Disorders. NORD Link Ahuja AS. Understanding mitochondrial myopathies: A review. PeerJ. 2018;6:e4790. NCBI Link McKusick VA. Mitochondrial myopathy. Online Mendelian Inheritance in Man. Updated May 11, 2010. OMIM Link Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Annals of Medicine. 2013;45(1):4-16. NCBI Link No ads, doctor reviewed. Let's crack your symptom code together - like us on Facebook to follow along. 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Pettopi Home Dogs Cats Videos Dog Diseases & Disorders How do I know if my dog has Worms and Intestinal Parasites Illustration Of Common Intestinal Parasites In Dogs You have probably heard that dogs can get worms. You may even have seen worms in your dog's stool. What should you do if your dog gets worms? More importantly, how can you protect your dog from getting worms in the first place? Your veterinarian is the best resource for the diagnosis, treatment, and prevention of common intestinal parasites. Remember, routine vet visits are key to keeping your dog healthy. Always communicate with your vet and report any signs of illness as soon as possible. All dogs can get intestinal parasites, but some dogs are more vulnerable than others. Lifestyle and regular use (or non-use) of routine preventive medication both play a large part in determining a dog's risk of contracting an intestinal parasite. Some intestinal parasites can pose a risk to humans as well. Light Micrograph Of Parasitic Tapeworm Roundworms (Toxocara Canis, Toxascaris leonine) are the most common intestinal parasites in dogs. They are especially common in puppies. Adult roundworms live in the intestinal tracts of their hosts, consuming that host's food. The adult roundworm is round, white to light brown in color, and several inches long. These worms look a lot like spaghetti or angel hair pasta. Adult dogs get roundworms from ingesting roundworm larvae, usually from contaminated soil or infected prey (such as a mouse or other small mammal). Puppies are born with roundworms after contracting them from their mother's uterus during gestation. In addition, nursing puppies may ingest roundworm larvae in their mothers' milk. Once ingested, larvae make their way to the dog's liver. While developing into adult worms, they travel to the lungs, are coughed up by the dog and then swallowed. The adult roundworms live in the dog's intestines. Their eggs are shed in the dog's stool and develop into larvae. The life-cycle is repeated when another host ingests the larvae. Signs of roundworm infection include diarrhea, vomiting, pot-bellied appearance, coughing (dogs may cough up or vomit worms), weight loss and dull hair coat. Many dogs will show no signs of infection at first. Your veterinarian can test a sample of stool from your dog for worms by running a lab test called fecal flotation. Roundworm eggs are microscopically visible in the stool if adult roundworms are present in the small intestine. Treatment of roundworms involves multiple oral doses of deworming medication. Deworming only kills the worms in the intestinal tract, so repeated doses are necessary to kill newly developing adult worms. Because puppies are so commonly affected, they are routinely dewormed (whether or not eggs are seen microscopically) during their first few sets of puppy vaccines. Be aware that not all over-the-counter dewormers are effective. Your veterinarian is the best source for this medication. Note: several types of heartworm prevention also protect against roundworms. Humans can contract roundworms through contact with contaminated soil, potentially leading to a serious condition called Visceral Larva Migrans. Always wear gloves when handling any soil, especially that which may have come in contact with dog feces. Children are at especially high risk. Canine Hookworms - Ancylostoma Caninum Hookworms (Ancylostoma caninum, Ancylostoma braziliense) are another common type of intestinal parasites affecting dogs and puppies. The hookworm attaches itself to the intestinal mucosa of its host with its sharp teeth and sucks the host's blood for sustenance. Hookworms are significantly smaller than roundworms and not usually seen in stool or vomit. Adult dogs get hookworms from contact with contaminated soil that contains hookworm larvae. The larvae burrow through the skin or paw pads when a dog is lying on the ground. Or, the dog can ingest the larvae after contact with contaminated soil, often when grooming. As with roundworms, nursing puppies may ingest hookworm larvae in their mothers' milk. Many hookworm larvae develop into adult worms in the small intestine, but some travel to the lungs, are coughed up by the dog and then swallowed (similar to roundworms). The adult hookworms live and mate in the dog's small intestine. Their eggs are released into the environment via the dog's stool. The hookworm eggs hatch into larvae and live in the soil. The life-cycle is repeated. Signs of hookworm infection include pale mucous membranes and weakness (due to anemia). Some animals have diarrhea and/or weight loss. Many dogs show no signs of infection at first. Be aware that hookworm infection can be very dangerous to young puppies due to the amount of blood loss that can occur. Diagnosis is made after collecting a stool sample and running a lab test called a fecal flotation (as with roundworms). The hookworm eggs will typically be seen microscopically if adult hookworms are present in the small intestine. Treatment of hookworms is similar to that of roundworms. Multiple oral doses of a deworming medication must be given since the dewormer can only kill worms in the intestinal tract. The dewormer that is typically given during puppy vaccines also treats for hookworms. Not all over-the-counter dewormers are effective, so ask your veterinarian about the right medication. Note: several types of heartworm prevention also protect against hookworms. Humans can get hookworms through contact with contaminated soil. Hookworm larvae can penetrate the skin, potentially leading to a relatively minor but rather uncomfortable condition called Cutaneous Larva Migrans. Avoid walking barefoot in areas where pets may have once defecated (including beaches). Always wear gloves when handling any soil, especially that which may have come in contact with dog feces. Children should never play or sit in areas where pets may have once defecated. Whipworms Canine Adult Tapeworm - Dipylidium Caninum Whipworms (Trichuris vulpis) are another common intestinal parasite in dogs. The whipworm lives in the large intestine, where it bites the tissue and embeds its head inside. Like the hookworm, the whipworm sucks the host's blood for sustenance. Whipworms are even smaller than roundworms and rarely seen in the stool. One end of the worm's body is wide while the rest tapers off to a narrow, whip-like head, hence the name whipworm. Dogs get whipworms from ingesting whipworm eggs that live in the soil. This typically happens through self-grooming. The whipworm eggs pass through the upper GI tract and hatch into larvae in the small intestine. Next, the larvae move down to the cecum or large intestine where they develop into adult whipworms. Their eggs show up in the dog's stool. Whipworm eggs can lay dormant in the soil for years until consumed by a new host. Then, the life-cycle is repeated. Signs of whipworm infection may not be present at first. Typically, bloody diarrhea will develop as the infection worsens, possibly leading to chronic bloody diarrhea. Anemia is possible, though not as common with whipworm infection as it is with hookworm infection. A whipworm infection can also become severe enough to cause a serious electrolyte imbalance. Diagnosis of a whipworm infection can be difficult because whipworms do not continuously lay eggs the way roundworms and hookworms do. Your veterinarian will run a lab test called a fecal flotation (as with roundworms and hookworms). The whipworm eggs may or may not be seen microscopically if adult whipworms are present in the small intestine. A lack of eggs in the stool sample will not definitively rule out whipworm infection. Your veterinarian may recommend repeated fecal testing if whipworms are suspected. Treatment of whipworms is similar to that of roundworms and hookworms. Multiple doses of a special deworming medication must be given. Over-the-counter dewormers are not effective, so your veterinarian must provide you with the right medication. Because of the long life cycle of the whipworm, treatment is typically repeated months later. Note: Certain types of heartworm prevention also protect against whipworms. Fortunately, the type of whipworm that affects dogs is rarely transmissible to humans. However, precautions should still be taken to prevent contact with dog feces or contaminated soil. Tapeworms Tapeworms (Dipylidium caninum) are intestinal parasites that commonly affect dogs. They are long, flat (tape-like) worms that attach to the small intestine of their host. A tapeworm body is several inches long but consists of multiple segments that grow onto the head and neck of the worm. Each segment has its own reproductive tract. Dogs get tapeworms from ingesting fleas. Flea larva hatch from eggs and consume surrounding flea dirt and debris. If present, they will also consume tapeworm eggs. The larval fleas develop into adults as the tapeworm eggs develop inside the fleas. Adult fleas jump on a host (usually a dog or cat) and cause the pet to itch. The host chews itself and consumes the adult flea, then the developing tapeworm is released into the host. The young tapeworm attaches to the small intestine and grows into segments. The end segments are egg sacs which eventually detach and make their way out of the host's rectum into the environment. The tapeworm segment, which resembles a grain of rice or a sesame seed, breaks open and the eggs are released. If flea eggs are also present in the environment, the life cycle is repeated. Therefore, tapeworms are only passed from pet to pet by way of fleas. Signs are rarely seen in dogs affected by tapeworms (except the appearance of rice-like segments around the anus of the pet and/or in the stool. Fortunately, these parasites do not tend to adversely affect dogs; it is generally considered a cosmetic/hygienic concern only. Diagnosis of tapeworms is typically made after the flat, rice-like segments are seen by the owner or a pet professional. Tapeworm eggs rarely appear microscopically when fecal flotations are run. Treatment of tapeworms involves one or more doses of a special deworming medication. Typical over-the-counter dewormers are not effective. Your veterinarian must provide you with the right medication. Because tapeworms are transmitted via fleas, the only way to prevent re-infection is to eradicate fleas. Deworming may need to be repeated while you try to control fleas. The use of monthly flea prevention is recommended. Fortunately, the type of tapeworm that affects dogs is not directly transmissible to humans. However, tapeworm infection can technically be transmitted to humans by accidental ingestion of a flea. Note: There is another type of tapeworm that can affect pets: Taenia. This type of infection is less common and contracted after a pet consumes an intermediate host such as a rabbit or mouse. Fortunately, this type of tapeworm does not tend to have an adverse effect on the host. In addition, the same medication that kills Dipylidium caninum also kills Taenia. If you suspect your pet is sick, call your vet immediately. For health-related questions, always consult your veterinarian, as they have examined your pet, know the pet's health history, and can make the best recommendations for your pet. 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As parents, we've all been there. Long, late nights with a screaming toddler suffering from a fever as he or she tugs on ears — another ear infection and another trip to the pediatrician. If your child has this problem frequently, you probably have heard the doctor mention that tubes might be needed. But what do ear tubes entail, and are they safe? The most common reasons for placing ear tubes are recurrent ear infections and fluid that remains behind the ear drum. More than 80 percent of children have at least one episode of ear infections by the time they are 3 years old. Infections in the middle ear tend to occur after an upper respiratory infection, usually viral in nature. Ear infections account for more than 30 million doctor visits a year and are more frequent in children between 6 months and 3 years of age. A pediatrician will usually refer your child to a pediatric ear, nose and throat specialist when the frequency exceeds three ear infections in six months or five in a year. In addition, if your child's pediatrician notices fluid in the ears that does not appear to be resolving, he or she might refer for a formal evaluation of hearing and consideration of ear tubes. There are a number of reasons your child might have recurrent ear infections. One possibility is that the antibiotics did not fully kill all the bacteria that created the first ear infection. Another possibility is that a virus was responsible for the ear infection and antibiotics are unable to eradicate it. This is why most patients have been on multiple types of medications before ear tubes are considered. Your child might also have a structural problem with the ear, where the space inside the eardrum is not well aerated. A small passage leading from the middle ear to the back of the nose — called the Eustachian tube — equalizes the air pressure between the middle ear and the outside world. When a child develops an upper respiratory viral illness, the lining of the nose and throat becomes swollen, including the lining of the Eustachian tube. This swelling increases the likelihood of an ear infection.
2. Demonstrate the feasibility and pertinence of manufacturing chaining simulation using Virfac. 3. Perform sensitivity studies on the operating conditions and check the influence on quality criteria in terms of residual distortions.
AVAILABLE IN 100 & 200 Tablet SIZES! Finally the new generation of exercise supplementation has come to the forefront and INTEK NITRO EVOLUTION is leading the way. With a mega dose of the more potent L-Arginine-AKG, super-endurance amino acid Beta-Alanine, and a stacked delivery and transport system, old nitric oxide supplements have been crushed in its wake. Supporting a host of important physiological processes including immune system support, proper growth-hormone regulation, protein synthesis, increased blood flow to muscles and more vascularity, INTEK NITRO EVOLUTION should be in every exercise gym bag. For those looking to increase lean muscle mass, nitrogen retention, nutrient uptake before and after workouts, muscle contraction strength and pump during training, while defending against detrimental free radicals, you will be building more muscle with ease than ever before. For better, longer workouts, more gains in less time, increased recovery and a list of physiological benefits evolve your supplement regime with this "r-evolutionary" exercise supplement. DESCRIPTION: L-Arginine is a conditionally essential amino acid that is not manufactured by the body endogenously and is a building block of lean muscle tissue that needs to be supplemented to meet daily requirements. Arginine is involved with nitric oxide regulation, hemodilation, hormone support, the removal of toxic waste products from the body, as well as supporting the immune system's defenses and increasing fat metabolism. This is important to exercise enthusiasts because maintaining a positive nitrogen balance is crucial for building muscle and the benefits of dilating blood vessels during a resistance training regimen can help increase blood flow to working muscles, and increase nutrient uptake, while promoting vascularity and stronger muscle contractions. This makes Nitric Oxide supplementation ideal for resistance trainers or athletes because with increased blood flow to your muscles, you can train harder and longer without fatiguing. What makes INTEK NITRO EVOLUTION so effective is that it takes L-Arginine and attaches an Alpha-Ketogluterate (AKG) molecule to increase the absorption rate and prevent the intestinal tract from diminishing the product during digestion. Besides just a super dose of Arginine-AKG, INTEK NITRO EVOLUTION adds 1500 mg of Beta Alanine, which binds with the amino acid L-Histidine in the body to increase muscular Carnosine levels, which in turn, supports high energy levels and maximizes muscular strength and endurance. Lastly, INTEK adds a transport delivery system composed of L-Histidine, Vanadyl Sulfate, and Alpha Lipoic Acid for keeping the absorption rate and recovery high, and the muscle pump going for as long as possible. By naturally increasing growth hormone levels, the Arginine in INTEK NITRO EVOLUTION can also help to increase fat oxidation, healthy blood pressure, and deter overtraining, all while supporting sexual health functioning due to its vasodilating properties. SUGGESTED USE: As an adult dietary supplement, take two to three servings per day. Space each serving by at least 3 hours and at the least take 30 minutes prior to training and immediately after workouts.
If you have questions which are not answered here, please contact us. Please note that we cannot give individual advice on vaccines for you or your child. You should consult your GP or other healthcare provider if you need specific advice. For more discussion and interviews about vaccination visit Healthtalkonline . See our page on herd immunity for an explanation of what herd immunity is. Herd immunity will not definitely protect anyone who is not vaccinated. There are low vaccination rates in some parts of the UK and in some communities. This means that if your child is not vaccinated, it is quite likely that many of the people they come into contact with will not be vaccinated either. So if one person gets an infectious disease, it can spread quickly through all the unvaccinated people in the group (this happened during the 2013 measles outbreak in Wales). For herd immunity to work properly, most people in the population need to be vaccinated. The exact rate depends on the disease; in the case of measles, 19 out of 20 people need to be vaccinated to protect the population. When measles vaccination levels drop below this level, outbreaks and epidemics become more common. So if you decide not to vaccinate because you think that herd immunity will protect you, you are making it less likely that you will be protected. Herd immunity does not protect against all diseases. The best example of this is tetanus, which is caught from bacteria in the environment, not from other people who have the disease. It doesn't matter how many people around you are vaccinated against tetanus – it will not protect you as an individual. Because of the way vaccines work, this can put a child at risk. For many diseases, one dose of vaccine does not give full protection. Some vaccines do work with a single dose, but it can take two or three weeks for the body to develop good levels of antibodies to protect against the disease. So if a vaccine is given at the start of an outbreak it may not act quickly enough to protect your child. The other problem is that many diseases are infectious before any symptoms show, so your child could catch a disease before you even realise there is an outbreak. Breast milk does contain some antibodies which are passed to the baby, especially in the first few days. However, this 'passive immunity' wears off after a few weeks, and after that breastfeeding offers very little protection from serious infectious diseases. It is therefore best to get your child vaccinated even if you are breastfeeding long-term. To some extent, it will. Children with severe malnutrition are more at risk of disease, and a good diet is an important part of keeping healthy. However, healthy children in wealthy countries are still at risk from conditions such as meningitis and septicaemia (severe blood poisoning). There is also strong evidence that healthy, non-immunised children are more affected than adults during outbreaks of infectious disease because they have wider social networks and come into close contact with more people. There is no evidence that an organic diet offers any greater protection. There is no evidence that homeopathic medicine can protect against serious infectious diseases. During any infection by bacteria or viruses, our immune system makes antibodies to fight that particular disease. For many diseases, an 'immune memory' is then created in special white blood cells called T lymphocytes. If we come into contact with the same disease, these white blood cells will 'remember' it and react quickly to fight it, so that we do not become ill. However, this process can only protect you against the specific disease that you have had. It does not make it easier for the body to respond to other kinds of infections. The measles virus actually seriously damages and suppresses the whole immune system. Measles infection destroys the white blood cells that hold the 'immune memory', wiping out our immunity to diseases we have already had. This makes it much more likely that people who have had measles will catch other infections, even ones they have had before. Research published in 2015 found that it can take the body up to three years to recover from this damage. Before a measles vaccine was available, it is estimated that measles was the direct or indirect cause of over half of all childhood deaths from infectious disease. This is not true. Today more people survive infection because of better medical care and medicines such as antibiotics, but infectious diseases are still dangerous. People sometimes think that if their child gets a disease like measles or tetanus nowadays, a visit to the doctor or hospital will easily sort it out. In fact many infectious diseases lead to complications that still cannot be treated, even with the best medical care available (for example meningitis, encephalitis - inflammation of the brain - and even pneumonia). Even in countries with good intensive care facilities, 3 in 10 of those who get tetanus will die. This is true to some extent. In the early part of the 20th century better hygiene and sanitation, clean water and better food all contributed to better health. Smaller families and less crowded living conditions meant that diseases were not passed on so easily. Medicine and supportive care were both improving, so that people who caught a disease were less likely to die, and those who ended up with serious disabilities could be kept alive. However, without vaccination it would have been impossible to reduce the levels of infectious diseases like measles to almost zero. For example, before the Hib vaccine was introduced in 1992, there were thousands of cases of Hib disease every year in the UK. Now there are almost none. Living conditions have not really changed since 1992, so the decline in Hib disease can only be down to the vaccine. Improved living conditions have also made almost no impact on chickenpox. This disease is just as common now as it ever was, with an estimated 600,000 cases a year in the UK. Catching a disease doesn't always give you 100% immunity either. It is possible to catch tetanus, rubella, Hib disease, pertussis (whooping cough) and meningococcal disease more than once. If most of the population is vaccinated, this raises protection for everyone to almost 100%. See our page on herd immunity for more information. If someone who has been vaccinated in the past catches a disease, the symptoms are often milder than they would be for an unvaccinated person. For more information on why we still get outbreaks of infectious disease in populations where most people get their routine vaccinations, see our page on Disease in Vaccinated Populations. Parents may worry that a child's immune system will not be able to cope with several vaccines at once. In fact, even a tiny baby's immune system can cope easily. Starting from birth, babies come into contact with millions of germs every day. It is estimated that the human body contains enough white blood cells to cope with thousands of vaccines at any one time. If a child was given 11 vaccines at once, it would only use about a thousandth of the immune system. It is not a good idea to delay vaccinations to 'spread the load', because it leaves the child unprotected against serious diseases for longer. See our page on Combination and Multiple Vaccinations. Vaccines also challenge the immune system less than a disease does. This is because they use only part of the bacteria or virus that causes the disease, or a weakened form of the bacteria or virus. This is enough to make the body produce antibodies, but not enough to cause illness. Even premature babies can cope with vaccines. It is a good idea to vaccinate them because they have a higher risk of catching infectious diseases. See our page on Vaccines and Premature Babies for more information. All vaccines go through a long and thorough process of development and testing before they are licensed for use. It can take as much as 20 years for a vaccine to go from first concept to being licensed. Vaccines have to be tested on adults and children separately before they can be used for different age groups; this is because vaccines that work in adults may not work so well in children. No vaccines are tested on children before they have been fully tested on adults. See our page on Testing and Monitoring for more information. Nothing in life, including vaccination, can be completely risk-free, but so far all the evidence tells us that vaccinating is safer than not vaccinating. It is rare for people to have serious reactions to vaccines, and so it is difficult to research these reactions because it takes a long time to gather examples to study. All serious reactions that get reported are investigated by the MHRA (Medicines and Healthcare products Regulatory Agency). See our pages on Vaccine side effects and adverse events and Testing and Monitoring for more information. Allergies and auto-immune diseases are on the increase, and it is understandable that people want to know what is causing this. Many researchers have looked at this issue, but they have found no evidence that vaccination is the cause, or that vaccination will trigger allergies. Allergy UK states that 'All available information about immunisation and allergy points to the fact that immunisation in children who are at high risk of developing allergy is safe and not a factor in their future allergic conditions' (see the Immunisation Factsheet available to download on the Allergy UK website). See the abstract of the 2003 paper Addressing parents' concerns: do vaccines cause allergic or autoimmune diseases? . There is no evidence at all that catching a serious disease like measles will help a child to fight off other kinds of infectious diseases when they are older. See the answer to 'Will catching an infectious disease make my child's immune system stronger?' above. Other studies have found no evidence that childhood vaccination is linked to an increased risk of developing type 1 diabetes or conditions such as multiple sclerosis . The original research which suggested a link between the MMR vaccine and autism has now been discredited. The National Autistic Society has issued a statement stating that the weight of evidence points to the fact that 'there is no statistically significant link between the MMR vaccine and autism'. An analysis of studies involving over 1 million children found no link between vaccination and autism development in children. Watch this short film in which experts say why they believe there is no link between the MMR vaccine and autism, and see more on our MMR vaccine page ('Is the vaccine safe?' towards the bottom of the page). All side effects are listed in detail on the Summary of Product Characteristics sheet (SPCs) for each vaccine (see the list of SPCs on our Links page). SPCs are written for healthcare professionals, not the general public, and they can be quite hard to interpret. Side effects are listed in section 4.8 – Undesirable effects. When looking at the rates of side effects, you need to remember that any unwanted symptoms experienced by participants during clinical trials of vaccines are recorded as potential side effects, even if they may not be the result of the vaccine. You also need to be aware that very rare side effects may be listed with no indication of how common they are (or described as 'frequency unknown'), because they have not been reported often enough to get a clear idea of their frequency. See our page on vaccine side effects and adverse reactions. It is a good idea to weigh up the risk of side effects against the risks involved in getting the disease itself (see our pages on Infectious Diseases for information about the risks of each disease). The Patient Information Leaflets (PILs) and Summary of Product Characteristics sheets (SPCs) both give a list of ingredients (usually called 'excipients'). See the list of PILs and SPCs on our Links page. There is information about many of the ingredients found in vaccines on our Vaccine Ingredients page. Vaccine ingredients can often look unfamiliar. However, it is important to remember that many of the substances used in vaccines are found naturally in the body. All vaccine ingredients are present in extremely small quantities, and there is no evidence that any of them cause any harm in these amounts, unless someone has a very severe allergy to one of the ingredients. This is true for some vaccines, but it happens very rarely. The live oral polio vaccine (not used in the UK since 2004) did cause polio in a handful of cases. In rare cases, other attenuated (live but weakened) vaccines can cause mild forms of the diseases they protect against. For example, the MMR vaccine very occasionally causes measles, mumps or rubella, but the symptoms are almost always much milder than those caused by the diseases themselves. This means that these kind of vaccines are only really a risk to children and adults with weak immune systems (e.g. those with cancer), who have to rely on protection from herd immunity. See the two questions below for more information about this, and a list of live vaccines used in the UK. It is impossible to get a disease from a vaccine made with killed bacteria or viruses, or made with only part of the bacteria or virus. Live vaccines contain live strains of viruses or bacteria which have been weakened (attenuated). The weakened virus stimulates the immune system but does not cause disease in healthy people. However, live attenuated vaccines should not be given to people who are clinically immunosuppressed (either due to drug treatment or underlying illness). This is because the weakened virus strain in the vaccine could replicate too much and cause a serious infection in these people. Most of the vaccines now used in the UK are inactivated (killed) vaccines or 'subunit' vaccines made with only parts of the bacteria or virus. It is impossible for anyone to get a disease from a vaccine made with killed bacteria or viruses, or made with only part of the bacteria or virus. See the question above for a list of live vaccines used in the UK. Researchers are always looking for ways to improve the protection that vaccines give us. Sometimes they discover that it is better to give booster vaccines at different intervals. New or improved vaccines are being developed all the time, and once these are tested and approved they may be introduced into the UK schedule (for example, see information on the introduction of Prevenar and then Prevenar13 on our PCV page). Researchers also try to identify the best possible protection that can be given by the smallest possible number of vaccines. Sometimes this leads to a vaccine being dropped from the schedule. For example, the dose of MenC vaccine given at 3 months of age was removed on 1st July 2016. See our blog post on this change. International travel means that any infectious disease is only a few hours' flight away. Travellers to countries which still have diseases like polio and diphtheria can bring back these diseases to the UK, and this can put unvaccinated people at risk. For example, two unvaccinated children in Europe have died of diphtheria since the start of 2015. Once a disease is wiped out in every country in the world, vaccination is no longer necessary, but so far this has only happened in the case of smallpox. People respond differently to the same vaccine. For example, 9 out of 10 children will be protected against measles after one dose of the MMR vaccine. However, 1 in 10 children won't make a good immune response the first time around. It is not known exactly why this is. After a second dose of MMR, most of the children who weren't protected the first time will have made a good immune response. For those children who did make a response the first time, the second MMR dose boosts or 'tops up' their immune response. Young babies do not always make as strong an immune response as older children and adults, and the response does not last as long. Vaccines such as whooping cough are given as early as possible to give babies some protection at a time when they are really vulnerable. Giving several doses helps to make the immune response stronger each time, and also helps protection to last longer. Even for adults, immunity can fade over time. The immune response can slow down as people get older, so that it takes longer to make antibodies to fight the disease. Booster doses help to keep the immune response active and quick to respond when it encounters disease. You can change your mind at any point. Even though it is better to get your child vaccinated at the ages recommended in the UK schedule, it is never too late to start vaccination. The majority of vaccines can be given at any point in childhood, so you can just go to your GP and ask them to give your child the vaccines they need. Sometimes people want to obtain vaccines that are not offered routinely in the UK (for example, chickenpox vaccine for children, or whooping cough vaccine for adults visiting newborn babies in other countries). Any vaccines that are not part of the NHS provided service are only accessible through private provision. This may be through a private hospital, travel clinic or another GP practice (where you are not a registered patient). Patients and parents who want to access vaccines privately are responsible for finding these services - unfortunately we don't have a list of providers. Pricing may vary between different providers. Children aged from 2 to 9 years who have not had a flu vaccine before and who have a long-term health condition such as asthma or learning disabilities are recommended to have two doses of the nasal flu vaccine every year, rather than just one. Babies, children and adults with immunosuppression, a missing spleen, sickle cell anaemia or coeliac disease are recommended to have extra pneumococcal vaccines (PCV and PPV), meningococcal vaccines (MenB, MenC and MenACWY) and Hib vaccines (in the Hib/MenC vaccine or the 6-in-1 vaccine). Vaccines are recommended for people in risk groups, not specifically for people from particular ethnic groups. Sometimes these categories can appear to overlap. For example, people with sickle cell anaemia have a weakened immune system and this puts them at higher risk of infectious diseases. They are therefore recommended to get extra vaccines including pneumococcal, meningococcal and flu vaccines. Because most people with sickle-cell anaemia are from black or other minority ethnic groups, it could look as if they are being offered extra vaccines because of their ethnicity, but it is actually because they fall into a risk group owing to their condition. The same is true for TB (BCG) vaccination. This is not offered to all babies in the UK, only to those who are at higher risk of TB. Risk factors include having a parent or grandparent who was born in a country where there is a high rate of TB, or living for three months or more in a country where there is a high rate of TB. This may mean that more babies from minority ethnic groups are offered the BCG vaccine, simply because of the countries that their families come from. Again, though, they are recommended to have the vaccine because they are at higher risk of TB, not because of their ethnic origin. Try to stay calm and positive yourself, so your baby or child doesn't pick up that you are anxious. Breastfeed while the injection is taking place, or as soon as it is finished. For older babies and children, you could offer a drink such as juice. Sit your child upright – don't lie them down. Rub or stroke the skin near the injection site (before, during and after the injection). Deep breathing and blowing can help – get your child to blow bubbles or a pinwheel. Bring a favourite toy for your child to play with so they are distracted during the injection, or have something ready for them to play with afterwards. For older babies and children, you could read them a favourite book. Use other ways of distracting your child, such as singing a song or making faces. For children who are old enough to understand, try to explain in simple terms what the injection will be like. See 'Reducing the pain of childhood vaccination' in the Canadian Medical Association Journal. Vaccines can seem quite aggressive because they are usually injected rather than given by mouth. The reason they are injected is simply that most vaccines are not absorbed well through the stomach. Vaccination is not designed to hurt anyone. Injection is just the best way of getting the vaccine into our bodies so that it can start to trigger the production of antibodies, which will then protect us against the disease. In many cases diseases like measles and mumps cause a few days of feeling unwell with no lasting complications. However, 1 in 15 children who have measles develop complications such as ear infections and fits. In a small but significant number of cases, many infectious diseases can lead to very serious, life-threatening conditions, and can kill. Measles is highly infectious and spreads very easily among people who have not been vaccinated. This is not as straightforward as it sounds. It is fairly easy to find accurate information on some kinds of risk (for example, common side effects of vaccines). Some comparisons are also easy to understand (for example, 1 in 5000 children develop encephalitis as a complication of measles, but less than 1 in a million develop encephalitis as a complication of the MMR vaccine). However, the chance of getting a disease is more difficult to work out, because it depends on how well-protected people are in your local community. If lots of people around you are unvaccinated, there is more chance of diseases spreading quickly than if you live in an area where most people are vaccinated, and this increases the risks. See our pages on Infectious Diseases for information about the risks of each disease. 'Doing nothing' tends to make people feel less guilty if something goes wrong, because they can tell themselves that it's just 'bad luck' or 'an accident' – they haven't actually 'done' anything. It is important to bear in mind that 'doing nothing' is actually a decision which may have consequences, just as much as getting vaccinated. If you are aware of how you feel about the risks, and why, it may help you to come to a decision.
Endocrinology is a branch of biology which deals with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with proliferation, growth, differentiation, behavioral activities of metabolism, growth and development, tissue function, sleep, digestion, respiration, excretion, mood, stress, lactation, movement, reproduction, and sensory perception caused by hormones. Diabetes is described as a group of metabolic diseases in which the person has high blood glucose (blood sugar), either because insulin production is inadequate, or because the body's cells do not respond properly to insulin, or both. Patients with high blood sugar will typically experience polyuria (frequent urination), they will become increasingly thirsty (polydipsia) and hungry (polyphagia).
Home / Postcholecystectomy - Weight Gain / Is your gallbladder (or lack of) stopping your weight loss? If you've never had gallstones, you've probably never thought about your gallbladder. However, if you have had gallstones, chances are good that you have had your gallbladder removed. Either situation has its own inherent issues, and one thing that healthcare providers rarely tell gallbladder patients is that surgery will forever impair their digestion and may make losing weight very, very difficult. The gallbladder is a small, pear-shaped organ under your liver that concentrates and stores the bile that your liver produces to aid fat digestion. Most people don't give it a second thought until it starts to trouble them, and unfortunately, for many years, the medical establishment didn't realize the full importance of healthy gallbladder function. They felt its removal had few, if any consequences. I am of the opinion that we were not designed with unnecessary parts, and the gallbladder is no exception. In fact, science is just beginning to understand the true importance of healthy gallbladder function and the detrimental consequences of its dysfunction or removal. Each day, your liver produces ~27-34 ounces of greenish-brownish-yellow bile, which is concentrated anywhere from 5-18 times, and then 1-3 oz is stored in the gallbladder awaiting your next meal. When you consume foods containing dietary fats, your gallbladder is triggered to release this concentrated bile into the first part of the small intestine, the duodenum, where it acts as an emulsifier to break down those fats and aids in the absorption of the fat soluble vitamins, A,D,E, & K, and any essential fatty acids. If you have ever vomited until a bitter, yellow substance came up — that was bile, and while you may not have thought so at the time – bile itself is an amazing substance. Comprised of bile acids, bile salts, cholesterol, phospholipids, pigments, water, electrolytes, and amino acids, bile is a bitter, acidic substance that breaks down fats into components that the body can use. Healthy fat absorption is crucial to our health. In fact, we were designed to eat fats rich in healthy fats. Our brains, our hormones, and even our very cell walls are dependent on a steady and healthy supply of fat soluble vitamins and essential fatty acids.1 Vitamin A is an important antioxidant that plays a crucial role in cell division, cell differentiation, reproduction, immune function, growth, and vision. Vitamin D is a prohormone which not only regulates calcium metabolism, but is essential for the functioning of the nervous system, for bone health, for muscle strength, for immune function, regulating blood pressure, hormone production and for cell differentiation. Vitamin E is a blanket term for eight different nutrients (4 types of tocopherols and 4 types of tocotrienols) that have string antioxidant properties and also play a role in immune function, healing, repair, and cardiovascular functioning. Vitamin K is a nutrient that scientists are just starting to devote research time to. It is known to play a key role in bone health, blood clotting, and heart disease, but studies are showing that it may have many more far-reaching effects. Essential fatty acids (EFA's), such as omega-3 fatty acids, are ESSENTIAL to human functioning. Long recognized for its powerful anti-inflammatory benefits, EFA's are required to make the cell walls of every cell in your body and they play a key role in immune functioning, musculoskeletal health, cognitive function, and heart disease. Considering the overwhelming importance of fatty acids and fat soluble nutrients to general health, it makes no sense to willingly cut out gallbladders with no plan of action to compensate for the deficit caused by its dysfunction or removal. Whether you have a gallbladder that isn't doing its job or you have already lost yours – there is a solution. So, how does all of this apply to lack of weight loss — or worse, weight gain? In simplistic terms, the body is a finely tuned organism. We need 17 nutrients in specific quantities just to make adequate levels of stomach acid and other digestive substances. When gallbladders dysfunction, two things can happen: First, the bile gets too thick and stagnant, which creates an ideal situation for gallstone formation. Second, when gallstones impair or block the emptying of the gallbladder, fat digestion decreases dramatically, which in turn, puts your body into starvation mode. The body requires the absorption of those fat soluble vitamins and essential fatty acids, but it recognizes it is in a chronically deficient state – so it hangs on to the fat it has (which unfortunately may be that stomach pooch) for dear life. You in turn want to lose that stored fat, and may erroneously take on a low-fat diet at the advice of your healthcare provider, which only makes the matter worse. medical conditions including hypothyroidism, diabetes, insulin resistance, inflammatory bowel disease, PCOS, hemolytic anemia, etc. That's a long list of risk factors – it's a miracle that anyone has a normal functioning gallbladder given our Standard American Diet (SAD) and reliance on fried and processed foods. In fact, gallbladder dysfunction is so common that clinicians refer to it as the 4-F syndrome: Female, Fat, Forty+, Flatulent. However, most people with gallbladder dysfunction are asymptomatic. Studies estimate that anywhere from 67-80% of people with gallstones have no symptoms. That said, many people discount gallbladder symptoms as being related to poor digestion or other factors. Everyone with gallstones started off with thick or stagnant bile. You have to have one to lead to the other. The pattern of symptoms associated with gallbladder dysfunction is so varied that many people without digestive pain may not associate their muscle pain, dry skin, poor wound healing, dry (or shedding) hair, headaches, heel calluses, or inability to lose weight despite doing everything right with a gallbladder that is not operating at par. Symptoms of gallbladder dysfunction: Most commonly: pain or discomfort after eating. This can include gas, bloating, belching, heartburn, nausea, queasiness abdominal discomfort, extreme fatigue, pain under the ribs, particularly on the right side, or shoulder pain. Additional symptoms include headaches over the right eye, constipation or diarrhea, light colored or 'floating' stools, dark urine, offensive body odor or breath. People with gallbladder dysfunction tend to have bowel extremes — they experience diarrhea (up to 10 bowel movements per day) or constipation (often having days between bowel movements) and rarely have normal bathroom habits. Have you had your gallbladder removed? You are not alone. Over half a million gallbladders are removed every year in the US. It is one of the most commonly performed surgical procedures. Symptoms of postcholecystectomy syndrome (PCS): gas, bloating, belching, heartburn, nausea, queasiness abdominal discomfort, extreme fatigue, pain under the ribs, particularly on the right side, or shoulder pain. The need to run to the bathroom immediately after eating is fairly common. Additional symptoms include headaches over the right eye, constipation or diarrhea. Notice the symptoms are almost exactly the same for people with NO gallbladder as for those with a dysfunctional one? Researchers estimate that at least 40% of people who have had gallbladder removal continue to experience significant abdominal pain.2 It is estimated that 5-40% of people who have had a cholecystectomy experience long term symptoms from it . 3 One British study looking at the after-effects of gallbladder surgery found that 87% of men and 68% of women experienced weight gain after cholecystectomy and urged physicians to caution patients about this 'side-effect.4 I can easily say that in my 12 years of practice, I have NEVER had a gallbladder patient tell me that they were informed of the likelihood of weight gain prior to their surgery! Having a dysfunctioning gallbladder or having no gallbladder are both associated not only with difficulty losing weight, but with weight gain. Anecdotal reports are abound of women having few issues maintaining their healthy weight until they had gallbladder removal surgery. On a functional level, we know that nutritional deficiencies are associated with difficulty losing weight, and by drastically impairing fat digestion through having stagnant bile or by surgical removal of the gallbladder – we create the foundation for broad-spectrum health disorders. Our bodies are designed to maintain an equilibrium, or steady state. It craves balance. So when we have gross nutritional deficiencies, our bodies inherently want to hang on to its stores of fat and nutrients. It doesn't want to exacerbate its deficient status by losing more of anything – and that includes your love handles. 1) First and foremost, you need to concentrate on eliminating the nutritional deficiencies. This is imperative if you want to get your body out of starvation mode. I suggest that you take a high-quality, highly absorbable multivitamin. Look for a high potency multivitamin that contains more than the 100% RDA amounts. Those amounts were designed to keep a person out of gross deficiency status, they are not amounts your body needs for optimal functioning. 2) The second thing I recommend is supplementing with pancrealipase and organic beet extract. I carry two different formulas – one for people with gallbladders who need to thin their bile so their digestion works better and another for people who no longer have a gallbladder and who need to add ox bile extract in addition to the pancrealipase and organic beet extract so they can start breaking down those dietary fats , get themselves out of a deficient status, and start losing weight. Either formula can be ordered directly from me (message me through facebook), or through the manufacturer. These supplements are only sold through licensed healthcare providers, and I am prohibited from publishing prices publicly, but if you visit my facebook group https://www.facebook.com/groups/weightlossresources/ and check the FILES section. I have included complete ordering information along with a discount code for my clients. 3) Limit your intake of refined carbohydrates. Not only are these typically 'empty' calories, but they rob you of minerals like magnesium and chromium, and your b-vitamins. They also induce insulin spikes which further stress your liver and gallbladder. 4) Increase your magnesium intake. Whether you take oral magnesium preparations, or you use epsom salt baths – magnesium has been shown to prevent gallstone formation. It is also required for making appropriate levels of stomach acid. 5) Increase your intake of taurine-rich foods. Taurine is one of the major amino acids found in bile. Healthy digestion depends on getting adequate supplies of taurine. Meat, eggs, seafood, certain dairy products, and brewers years are all good sources of dietary taurine. 6) Eat healthy fats! Your body needs fat in order to lose fat. If fat digestion troubles you, start slowly with small amounts of unrefined organic coconut oil and slowly add other healthy oils into your diet. Let your body accommodate to them. Healthy fats include grass-fed butter (which is a source of vitamins A,D,E,K, as well as selenium, and CLA), ghee, lard, egg yolks, organ meat, palm oil, olive oil, most nut oils, etc. Bad fats include corn oil, soy oil, canola oil, sunflower oil, safflower oil, cottonseed oil, margarine, and anything listed as 'hydrogenated'. These refined oils are a source of omega-6 fatty acids which not only contribute to obesity but cause inflammation within the body, and that includes liver and gallbladder inflammation. In short, having gallbladder problems or no gallbladder whatsoever need not cause you issues. There are simple solutions that allow your body to work the way it was intended to. You can get the weight off and avoid the bizarre food cravings that come along with those nutrient deficiencies. You can feel normal after meals. You can have normal bowel movements, and you can get rid of the fatigue that overwhelms you. If you combine healthy food choices along with the simple supplements I suggest, you will see results. If you are able to combine the two with lifestyle improvements you will see results that much faster. I sincerely wish that more medical providers educated their patients on the detriments of gallbladder surgery before they submitted to it, so they could take preemptive action, however, in the words of Mick Jagger, "you can't always get what you want, but if you try sometime, you just might end up with what you need". So, in closing, I hope this information is what you need. Please visit me on facebook at Weight Loss Resources with Dr. Miranda. If abdominal pain persists, you may have a problem caused by something other than the gallbladder. Other possible causes of abdominal pain include irritable bowel syndrome, inflammatory bowel disease, stomach ulcers, or pancreatitis. Please seek the advice of your licensed healthcare provider to rule out serious health conditions. Are these 4 hormones making you fat? Post-cholecystectomy diarrhoea: a running commentary Copyright © 1999 BMJ Publishing Group Ltd & British Society of Gastroenterology. 1. Bates T; Ebbs SR; Harrison M; A'Hern RP.Influence of cholecystectomy on symptoms. Br J Surg. 78(8):964-7, 1991 Aug. Thank you so much for this article! I had my gallbladder removed last year and have been putting on weight like crazy. It's making me go insane, especially because I feel hungry all the time. I am definitely interested in (natural) supplements to help me! Thank you so much for this article! I gained so much weight when my gallbladder started acting up and even more once it was removed. I will definitely be purchasing the recommended supplements and will visit your Facebook group page. Other than surgery recovery I'm also juggling untreated hypothyroidism and gastritis, do you have any general advice for that? Again, thanks so much for this helpful article. I get my gallbladder out on Tuesday and this helped a lot and I hope to do some of the things you mentioned to help me lose weight.. Thanks so much!! I had my gallbladder removed in Jan. of 15, and have been putting on weight in my stomach every since. My weight had been the same all my adult life until they removed my gall bladder. I had a stone shoot out and lodge into my pancreas which caused severe pain under my right breast. I thought I was having a heart attack. It took them a couple of days to after a scan and a MRI to see if the stone was still in my pancreas, then since my bladder had stones, they decided to take it out. Nothing was ever said about the side effects it would have. Now I am fighting this weight gain. Just last week I told my primary doctor I was worried about my weight, and he checked my thyroid which was normal. I have been walking and cutting back on my eating, but cannot lose weight. My husband is in the same shape as I for he had gained weight, but no energy to do much exercise. I am thrilled to read this article and hopefully I can start doing something about it now. Thanks so much. Thank you for your kind words. There is a lot that you can do, and supplementation certainly can help. You can order the supplements I most frequently recommend directly from the tab on the blog too for your convenience. If you have not joined my facebook group – Weight Loss Resources with Dr. Miranda, please do so. There is a lot of wonderful information there to get you started! Thank you so much for posting this article! I had my gallbladder out 8 years ago when I was 25 and luckily I didn't start feeling the side effects discussed in your article until about 3-4 years ago. Then it all happened fairly quickly: skin discoloration, acne, weight gain all around my stomach, fatigue, but the most frustrating part is the brain fog/memory loss. I hate that I can't quickly recall things like I used to, or when I honestly can't think of a simple word during a conversation or meeting. Luckily I found a wonderful naturopath last month who gave the same advice of supplementation. Can you tell me how long you think it takes to notice a difference in the weight gain and brain fog? I'm assuming since it was a gradual process for my body to start storing fats that it's a gradual process to stop storing them as well. Thanks for your help! Thank you for this.. My Dr. just recently suggested gallbladder removal because of my intense heart burn… I will definitely NOT go along with his suggestion.. Too many doctors are jumping the gun nowadays and performing unnecessary surgeries and then having the patient suffer the consequences down the road. Wow! How I wish I would have had this article years ago! I had my gallbladder removed at the age of 16 (the second youngest patient in the hospital to do so) and I was NEVER told about any symptoms after it's removal. In fact, I was told that "the gallbladder does little to nothing really…" Had I known then what I know now, boy would it have been different. After my surgery, I was told that it would be a little while before I "bounced back to normal." Now, I'm not saying that I was really skinny when I had it removed, but I was no where near being over-weight. By the time I was 19, I became the heaviest I have ever been. It was the biggest struggle of a life time. Once I went off to college, I was able to lose some of the weight by constantly walking everywhere, moving heavy equipment (art major), and eating less fatty foods I was able to work off a lot of excess weight and become just 'over-weight' again. At this point I have been able to keep my weight the same, not losing anything, but definitely not gaining any either. I have been getting so annoyed that I have tried EVERYTHING from extreme dieting and exercising to no avail. So, thinking back to what led to this and really wanting to know if lack of a gallbladder was doing anything to me, I found this article. Totally makes sense!!! I want to thank you for this. I know that I will begin another attempt at getting healthy, this time on the right foot. I have gallstones I am suppose to get my gallbladder out but have not yet,I had one attack an I think it was do to pregnancy? It happen a few months after giving birth.I also have pcos but have it under control but gained so much being pregaunt I need to lose weight,afraid to take out gallbladder an afraid off an attack to keep it in,will ur pills set my gallbladder off? Please help,doctors say take it out,I have 3. I'm so desperate for help i'm going crazy. I'm only 19 and I can't stop gaining weight. I get extreme pain whenever I eat and nothing will stop making me look like a huge whale. I started the school year at close to 157 and I have been good all year. I eat gluten free, I never eat junk food (literally never) I eat salad, I eat rice, I eat fish, i'm almost the definition of a perfect eater yet now I'm only a couple pounds away from 170. No matter working out or not I gain weight, I need help! I want to lose weight so desperately and can't. I think it has something to do with my gallbladder but after reading all these comments I don't want it taken out just to gain more weight! Please anything will help.
The Columnists Submit / Get Involved in-Training the online peer-reviewed publication for medical students From the Wards Doctor's Orders in-Training: 2020 In Our Words "The Spirit Catches You and You Fall Down": The Making of a Silver Lining in Epilepsy by Aradhya Nigam at Eastern Virginia Medical School Imagine an active neuron in the temporal lobe of the brain. This neuron receives a message through its dendrites and passes it to other neurons via its axons. This is the basic process of cell signaling. It shows the role of neurons and, more importantly, how neuronal disorders develop. Now imagine the neuron becomes overwhelmed by repetitive high priority messages. By the nature of cell signaling, it relays these messages to its many connected neurons. With continued activation and time, the system of receiving and sending messages becomes overwhelmed and falls into disarray. This loss of control produces the basic pathophysiology of the onset of a partial seizure, and a state of repetitive seizures defines chronic epilepsy. Non-epileptic brains have many checkpoints in place to prevent this loss of control. Consequently, epilepsy is often predicated by pathological changes that facilitate progression of the disease, including sodium channelopathies and loss of hippocampal modulation (i.e. entorhinal cortex). In addition to these changes, the NIH reports that 60-70% of patients experience recurrent seizures due to an unidentifiable cause, which is known as cryptogenic epilepsy. Cryptogenic epilepsy often leads to treatment-resistant epilepsy, and it profoundly affects the lives of its patients. "The Spirit Catches You and You Fall Down" by Anne Fadiman provides an illuminating experience of one patient's experience with treatment-resistant epilepsy. It documents the life of Lia Lee, a young Hmong refugee who moved to California with her family in the 1980s, and describes her medical and cultural struggles with chronic epilepsy from infancy. Fadiman's book offers not only a first-hand account of the development of epilepsy, but also the opportunity to find empathy with the family's struggle and to understand the perspectives of the doctors treating her. Much of "The Spirit Catches You" details the social and cultural problems of being a Hmong refugee in California receiving health care. From a lack of Hmong translators to a misinterpretation of non-Western remedies, a circle of distrust developed between Lia's family and the doctors who treated her at Merced hospital. The struggles of both sides caused inconsistencies in Lia's care, and they often spiraled into a lack of care. Fadiman presents these issues upfront, and beckons the reader to ask, "What would I do in this situation?" By attempting to solve one issue, a cohort of other problems arises. As developing physicians, we trace a "silver lining" to balance treatment and patient care on a daily basis. This lining defines the approach that each doctor uses to treat patients, and encompasses the benefits and risks of every decision. It is the product of our clinical knowledge and our personal experience. Lia's story elucidates this concept by showing how Merced helped and harmed her. Her story allowed me to reflect on how my past experiences had already shaped my progression as a developing physician. By combining these two, we come closer to understanding and treating these diseases, avoiding cross cultural disease, and helping to treat patients. As an undergraduate at the University of Virginia, I worked in epilepsy research, investigating novel etiologies of the disease. One of my roles was to create epileptic rats by over-stimulating the dentate gyrus, which made the rats epileptic within three months. During this development, the rats would become irate and stop grooming themselves. Additionally, the loss of control in preventing seizures would result in more seizures and greater effects on health and personality. This demonstrates the debilitating lifestyle challenges of epileptic patients. Through my research, I observed the emotional and physical toll that epilepsy levies on patients. Part of the struggle of being an effective doctor is becoming aware of how these changes affect a patient. Part of the silver lining, in this case, is taking into consideration the changes in personality that occur with epilepsy. The Merced nurses described Lia as "jovial" and "very interactive" when not having a seizure, but short bursts of calm were the best medicine could provide in the tumultuous condition that Lia lived. Yet even these transient moments of happiness comprise incredible feats that medicine has been able to achieve. But just as much as physicians can learn to help, we also have the ability to do harm, especially in patients with chronic conditions. After the "big" grand mal seizure that sent Lia from Merced Community Medical Center to Fresno, I began to see the other side of medicine's silver lining: the potential of medicine to do more harm than good. As a result of the seizure, Lia lost higher brain function and lived in a persistently vegetative state for 26 years until the age of 30. Peggy, one of Lia's doctors, said, "that's the quandary of Western medicine, that you can't let people die." In this frank statement Peggy alludes to one of the most controversial aspects of medicine: How far is too far? As a former EMT, I found myself one night in the care of a postictal patient that had been prescribed multiple medications for the seizures he had been experiencing for 16 years. The course of his epilepsy had left him disheveled and delusional. Although medicine had helped his seizures, nothing much could be done about their long-lasting effects. This is the gamble that we health care professionals play in balancing beneficence and side effects. For better or worse, the pressure to treat and the yearning to help have left medicine in a state of contention. Lia's story reminded me of how easily doctors get lost in trying to achieve these goals, delving away from a patient-centered approach to a symptom-centered one. To solve this we must keep the idea of patient beneficence in mind. A patient-centered approach requires more than a discussion of patient-physician relations. In Lia's case, the Merced doctors struggled working with the Lees' cultural interventions and their mistrust of Western medicine. The Lees distrusted Lia's anti-epileptic medication, but trusted animal sacrifice to help Lia. Although I am hesitant towards such extreme traditional interventions, I believe accommodating a patient's culture and beliefs yields positive influences on his or her overall welfare and care, granted it does not interfere with medical treatment. As the son of a doctor and an Indian immigrant, I entertained the power of culture in medicine growing up. I grew up in a household where surgeries and splints were important for broken bones and torn ACLs, but cumin was effective for the common cold. Adding a bit of cultural understanding proves the power of community to aid in the healing process and create a more patient-centered approach. "The Spirit Catches You and You Fall Down" challenges the reader to appreciate Lia's story in the context of the trials of the Hmong and the state of medicine in the 80s. By reading stories like this and using one's own experiences, we learn about the successes and mistakes health care has made over the years. A developing physician can string together these stories and his or her own experiences to promote a patient-centered approach to medicine and to learn better treatment. Our current health care system is the culmination of this. Fadiman describes the benefit of this: "The world is full of things that may not seem to be connected but actually are; that no event occurs in isolation; that you can miss a lot by sticking to the point." When we don't have a cure — when our hand fails — we should not forget the things that support and keep our patients happy. Aradhya Nigam (1 Posts) Contributing Writer Emeritus Tags: humanism in medicine, literature << Previous PostDoctor Dad: A Husband and Father of Three in Med School Next Post >>Keep Calm and Carry on the Interview Trail Donate to in-Training in-Training is run entirely by volunteer medical students, and we need your donations to keep this website online. All donations are used only for website hosting fees. Donations are tax-exempt and are collected by Pager Publications, Inc., our parent 501c3 nonprofit corporation. Purchase Our Books in-Training is the agora of the medical student community, the intellectual center for news, commentary, and the free expression of the medical student voice. We publish articles about humanism in medicine, patient stories, medical education, the medical school experience, health policy, medical ethics, art and literature in medicine, and much more. in-Training is the online peer-reviewed publication for medical students, and is the premier publication dedicated to the medical student community and run entirely by volunteer medical students. We identify ourselves as a peer-reviewed publication, combining the strengths of a scientific research journal, an online newspaper, a magazine, and a podcast website into a medical student-run publisher of the best articles written by medical students from around the world. © 2012-2023 in-Training. 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Audiovisual Rheum COVID-19 and Rheumatology Author Payment Reprints and Translations Duncan A. Gordon Award Privacy/GDPR Policy JRheum Supplements Follow jrheum on Twitter Visit jrheum on Facebook Follow jrheum on LinkedIn Follow jrheum on RSS Magnetic resonance imaging of the wrist and finger joints in patients with inflammatory joint diseases. A Savnik, H Malmskov, H S Thomsen, L B Graff, H Nielsen, B Danneskiold-Samsøe, J Boesen and H Bliddal The Journal of Rheumatology October 2001, 28 (10) 2193-2200; A Savnik H Malmskov H S Thomsen L B Graff H Nielsen B Danneskiold-Samsøe J Boesen H Bliddal OBJECTIVE: To study magnetic resonance imaging (MRI) features in the wrist and metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints in 4 patient groups: early rheumatoid arthritis (RA) (< 3 yrs); established RA (> 3 yrs); other arthritis; arthralgia. METHODS: MRI was obtained before and after contrast (gadodiamide) injection of the wrist and finger joints in 103 patients and 7 controls. The study included: (1) 28 patients with disease duration < 3 yrs who fulfilled the American College of Rheumatology (ACR) criteria for RA; (2) 25 patients with RA disease duration > 3 yrs who fulfilled the ACR criteria. (3) 25 patients with reactive arthritis, psoriatic arthritis, or mixed connective tissue disease; and (4) 25 patients with arthralgia. The following MRI variables were assessed: number of joints with enhancement after contrast injection, number of joints with joint fluid, and number of bones with edema in the wrist and fingers. The volume of the enhancing synovial membrane after contrast injection in the MCP, PIP, and DIP joints was manually outlined. MR images were scored independently under blinded conditions. RESULTS: Bone marrow edema was found in 68% of the patients with established RA, and the number of bones with edema was significantly higher in patients with established RA compared to patients with early RA, other arthritis, and arthralgia (Mann-Whitney p < 0.04). Bone edema was not found in patients with arthralgia. There was marked overlap within and between the patient groups. No differences in MRI features were found between patients with early RA and patients with other arthritis. The volumes of the synovial membrane in the MCP, PIP, and DIP joints were significantly higher in patients with arthritis compared to patients with arthralgia. CONCLUSION: Although there was marked overlap between the arthritis patient groups, MRI determined bone marrow edema and synovial membrane volumes provided additional information about disease activity and may be used as a marker of it. Bone marrow edema appeared with the highest percentage in patients with long duration of RA (> 3 yrs) and is probably secondary to changes in inflammatory activity. The Journal of Rheumatology Thank you for your interest in spreading the word about The Journal of Rheumatology. You are going to email the following Magnetic resonance imaging of the wrist and finger joints in patients with inflammatory joint diseases. Message Subject (Your Name) has forwarded a page to you from The Journal of Rheumatology Message Body (Your Name) thought you would like to see this page from the The Journal of Rheumatology web site. A Savnik, H Malmskov, H S Thomsen, L B Graff, H Nielsen, B Danneskiold-Samsøe, J Boesen, H Bliddal The Journal of Rheumatology Oct 2001, 28 (10) 2193-2200; My Folders The content of this site is intended for health care professionals. Copyright © 2016 by The Journal of Rheumatology Publishing Co. Ltd. Print ISSN: 0315-162X; Online ISSN: 1499-2752
Global Rapid Gender Analysis for COVID-19: Key Insights and Recommendations Read the key insights and recommendations of a global rapid gender analysis of the effects of COVID-19 on gender in crisis, women as caregivers, and inclusion in decision-making, conducted by CARE and IRC in March 2020. The Impact of Integrating Cash Assistance into Gender-Based Violence Response in Northwest Syria: A Mixed-Methods Evaluation over Nine Months (Snapshot) In 2020-2022, WRC, with research partner South Africa Medical Research Council and CARE, undertook a study in Northwest Syria to understand the potential of integrating CVA into GBV case management for comprehensive support to survivors in humanitarian emergencies. The study drew on the expertise of WRC and used best practice guidance and tools implemented by CARE Turkey and its local partners, including Syria Relief and Development (SRD). This is the snapshot report. Read More Malawi Food Systems Policy Actions In 2021, CARE Malawi collaborated with the FAO, WFP, Ministry of Agriculture; CSONA, CISANET, GMT, Concern Worldwide, and Welthungerhlife Malawi to host a series of independent dialogues to garner inclusive participation in the UN Food Systems Summit and support the creation of Malawi's National Pathway. This policy brief offers an overview of the topics covered and desired policy outcomes from dialogue participants. Read More Ecuador Food Systems Policy Actions In 2021, CARE Ecuador with the support of the Civil Society Alliance against Child Malnutrition hosted a dialogue based on the urgent need to combat child malnutrition. Conversations also focused on the expressed work of CARE Ecuador and the provincial governments of Chimborazo, Cotopaxi, and Bolivar, and how these networks can improve the production and living conditions of rural women in these provinces. This policy brief offers an overview of the topics covered and desired policy outcomes from dialogue participants. Read More
You have cellulites and are looking for a functional cellulite treatment? Concerns the problem of cellulite almost exclusively to women - and so they ask themselves every day on how effective cellulite treatment is supposed to look! Without question one should address the holistic treatment of cellulite and here both proper diet (drink a lot!), Sports massage and combine it with cold winding. The aim of cellulite treatment is to stimulate the metabolism of the problem areas and to ensure optimal blood flow.
Welcome to the Junankar Ayurveda Chikitsalaya! Ayurvedic panchkarma procedure is a treatment in which five types of detoxification procedure are included.it cure your diseases also makes you healthy. Ayurved treatment include supportive treatments with internal medicine for sick .This ayurvedic procedure are also maintain health of healthy person. Ayurved massage gives you felling of wellness,relives stress,incease muscle tone,makes your body relax,relives muscle pain,increase blood circulation. About Junankar Ayurveda Chikitsalaya Ayurveda treatment for your body and mind! We are the only institute in Nagpur which provide pure and authentic ayurveda treatments and panchkarma for all diseases. 2) Joint Pain Treatment -Knee Joint pain, Shoulder Joint Pain, Lumber Joint Pain, Spondylitis, Arthritis, Rheumatoid Arthritis(R.A) or Rheumatism , Osteoarthritis, Polyarthritis. 3) Digestive Disorder Treatment-Acidity(burning sensation, headache,nausea,vomiting), Chronic Constipation, Colitis, I.B.S.,Gases,Pain in stomach(Stomachache). 5) Skin Disease Treatment-Acne (pimple), Rashes, Vitiligo, Leukoderma, Urticaria, Recurrent Skin Infection, Psoriasis, Oral apthus, moles. 6) Ayurvedic Treatment for Piles, Fissure, Fistula. 7) Kidney Disease Treatment-Chronic Kidney Diseases (CKD), Acute Renal Failure (ARF), Chronic Renal Failure (CRF), Glomerular Nephritis. 8) Memory Loss, neurological disorders, depression, tension, stress. 9) Our institute provide ayurvedic treatment packages like rejuvenation therapy and panchkarma, beauty therapy, eye treatment, weight management, stress therapy . 10) Herbal plant visit and information of home remedies. 11) Guidance of ayurvedic healthy lifestyle, ayurvedic foods as per seasons,diseases helps you to cure and live healthy. Yoga and Meditation practiced for five thousands of years.yoga asanas is comfortable sitting posture.Daily yoga poses practice improves muscle strength,helps in digestion,awareness,strength of body.Meditation is also used to treat mental health disorders. Tips for practicing yoga and meditation daily basis :. begin daily practice of meditation on short time basis,avoid destractions . Find comfortable yoga posture ,get relaxed yourself,be effortless. Observe the feeling within your body,feel your internal body sensation. Complete rejuvenation and detoxification of your body! Rasayana chikitsa (rasayana therapy) is anti aging treatment in ayurveda .Detoxification of body internal toxins, increase immunity of body, relives stress, improve skin glow are benefits of rejuvenation therapy in ayurveda. Appropriate weight for your body gives nice shape and attractive personality. Being overweight or underweight sometimes can cause serious health problems. Weight management ayurveda gives you healthy life style. Ayurvedic weight gain treatment/weight loss treatment is given for weight with which you can gain/reduce weight healthy way without any surgery. with some ayurvedic procedure, ayurvedic weight gain supplement/weight loss diet plan and weight gain exercises/weight loss exercises. Ayurveda enlighten your inner beauty! Ayurvedic beauty therapy is not only for skin but also having mental and spiritual benefits. These all treatment were used by royal families ancient time. Beauty therapy in ayurveda is completely natural and safe. Ayurveda is treatment of soul! Stress is physical and mental phenomenon, because of which new lifestyle modification diseases occurring in patient. We can avoid these diseases with our stress management program. Ayurvedic medicine for stress relief and yoga practice can relax your body and mind. Stress management techniques include Snehana, swedana, detoxification , shirodhara and other stress treatment in ayurveda as per your constitution of doshas.It include stress medicine in ayurveda, ,stress management tips, yoga and diet advice. Garbha means womb and sanskara means teaching .It is believed in ancient Indian ayurveda parenting should be starts before conception, so that mother can deliver a healthy baby, without having any side effect to mother. Ayurvedic garbhsanskara is scientifically proven treatment given to the mother for healthy undergoing of conception. According to it baby can sense and influenced by outside things, given for healthy motherhood and child. Eye is camera of soul ! Eye is most impotant sence organ. Ayurvedic eye care done with eye floater treatment in ayurveda(tarpana) , anjana, nasyam and other treatment for eye diseases. Dr. Junankar is a great doctor. He has helped my 2 daughters and myself get healthy and avoid so many unnecessary surgeries that our local doctors wanted to perform. Thank you Dr. Junankar ! We are looking forward to seeing you soon for our follow-up appointments! My wife, sister and mother had a great experience at Junankar ayurveda chikitsalaya. The therapist did a great job on their massage. It is a bit different since a large amount of oil is massaged into your body. But the steam bath experience afterwards was really relaxing. The atmosphere could be a bit more relaxing with soft music playing throughout, but overall I think they'll go here again. If you have questions or need additional information, please call: 940.319.8875 or use our Contact Form!
The early success of a new class of cancer drugs, revealed in test results released recently, has raised hope among the world's top cancer specialists that they may be on the verge of an important milestone in the fight against the disease. Eighty-three percent of cancer doctors report that they've faced oncology drug shortages, and of those, nearly all say that their patients' treatment has been impacted, according to a study from researchers at the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania that will be presented at the 2013 annual American Society of Clinical Oncology. After Teresa Levitch underwent successful chemotherapy and radiation for the cancer attacking her immune system, she believed her health problems were over. Now she knows better. For more than 10 years after her treatment, she felt pain and muscle fatigue in her upper body, and her range of motion was limited. The poorer survival rates of younger breast cancer patients could be a result of insufficient clinical trials for this age group. This was a conclusion of a major new Cancer Research UK study published online recently in the Journal of the National Cancer Institute. The time has never been better for making advances in medical research, and significant progress has been made toward modernizing clinical cancer research. However, an expert panel warned that these advances are in danger of stagnating as a result of the recent across-the-board federal budget cuts. A second large trial has found that for women with estrogen receptor-positive breast cancer, a decade of tamoxifen is better than stopping after 5 years. There has never been an effective drug for advanced thyroid cancer. Until now. The drug, called Nexavar, doesn't cure cancer. Still, it shrank tumors in 12 percent of patients randomly assigned to take it. By comparison, less than 1 percent of tumors shrank in patients taking a placebo, or sugar pill, according to a study. Researchers at the University of Adelaide are spearheading a new direction in prostate cancer research, with the potential for new treatments of the disease. The researchers hope they will overcome a major problem that limits current treatments for metastatic prostate cancer and improve men's chances of surviving. Looking for similar articles? Search here, keyword PROSTATE CANCER. A simple screening technique using an inexpensive agent dramatically reduced deaths related to cervical cancer in a population of Indian women. Visual inspection with acetic acid or vinegar, conducted by nonmedical personnel trained to deliver basic healthcare, cut the death rate by 31 percent.
Journal of Experimental Neurology Latest Content Current Issues Archives Open Special Issues Published Special Issues About Special Issues Behavioral and Pathological Response to OGF Therapy in Ch-EAE OGF Levels in Experimental Autoimmune Encephalomyelitis OGF Levels in Multiple Sclerosis Review Article Open Access Volume 3 | Issue 1 | DOI: https://doi.org/10.33696/Neurol.3.053 Maintenance of [Met5]-enkephalin Blood Levels Corresponds with a Positive Outcome in Multiple Sclerosis Patricia J. McLaughlin1,*, Ian S. Zagon1,* 1Department of Neural and Behavioral Sciences, Penn State University College of Medicine Hershey, PA 17033 USA + Affiliations - Affiliations Dr. P.J. McLaughlin, [email protected] Ian S. Zagon, Ph.D, [email protected] Received Date: January 08, 2022 Accepted Date: January 19, 2022 McLaughlin PJ, Zagon IS. Maintenance of [Met5]-enkephalin Blood Levels Corresponds with a Positive Outcome in Multiple Sclerosis. J Exp Neurol. 2022;3(1):1-4. © 2022 McLaughlin PJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Multiple sclerosis (MS) is a chronic immunological disorder of multifactorial etiology. Genetics, geographical location, age, and gender are risk factors, but the underlying causes are not fully defined. Research has provided substantial evidence that pro- and anti-inflammatory cytokines, as well as glial cell proliferation are involved in the progression of the disease. However, there is still a need to define noninvasive biomarkers to track the onset and course of MS. New treatments are effective at reducing signs and symptoms of the disease, but little change has been made in altering the overall course of MS. Clinical reports from individuals using a low dose of the opioid receptor antagonist naltrexone prompted research using animal models of chronic experimental autoimmune encephalomyelitis (EAE) or relapsing-remitting EAE (RR-EAE). These studies reported that serum levels of the endogenous peptide Opioid Growth Factor (OGF), chemically termed [Met5]-enkephalin, declined during the course of disease and could be restored to normal following therapeutic intervention. β-endorphin, another endogenous neuropeptide, was less responsive to treatment, suggesting that OGF may be a selective biomarker for MS that can be obtained non-invasively in order to monitor the course of disease. There is a rapid decrease in OGF serum levels within days of EAE induction, as well as reduced levels of OGF in individuals with MS. This reduction in the negative growth factor may contribute to the uncontrollable lymphocytic proliferation and cytokine storm observed in early stages of MS that correspond to the physical and mental decline measured in humans, and to the behavioral deficits and central nervous system pathology recorded in animal models. Therapies that increase OGF serum values and result in improved clinical signs and perceived good health are warranted. Opioid Growth Factor, [Met5]-enkephalin, ELISA tests, MS, Experimental autoimmune encephalomyelitis Multiple sclerosis (MS) is a debilitating disease with a multifactorial etiology that remains to be fully defined. In the United States alone it is estimated that there are one million individuals living with MS [1,2]. Development of MS involves inflammatory reactions against self-antigens and progressive demyelination in the brain and spinal cord. Epidemiological data on MS indicate a 2:1 ratio of women to men with a worsening disease prognosis for men than for women [1]. In addition to a genetic predisposition [3], geography [4] and sun exposure increasing melatonin [5] and vitamin D levels [6] are risk factors for the development of MS. The disorder is prevalent in younger individuals of Northern European ancestry who may have an accumulation of genetic and biological risk factors, one or more of which may be involved in pathways that have become dysregulated. Clinical reports first described a relationship between enkephalins, endorphins, and MS in individuals receiving low doses of naltrexone (LDN) who reported that they "felt" better following this non-traditional treatment [7-9]. A retrospective chart review of more than 50 MS patients, 23 receiving LDN alone, revealed that in comparison to the diseasemodifying therapy (DMT) Copaxone, LDN maintained stable physiological signs, with no change in MRIs, and health in the RR-MS individuals [9]. Evaluation of MRIs, blood laboratory data (e.g., white cell counts, platelet count, hemoglobin levels, liver enzymes), and behavior as assessed by a timed 25-foot walk revealed no differences in values for patients on Copaxone and those on LDN only [9]. Because of the variability in patient profiles, as well as the broad array of DMTs that are now available, it is difficult to perform rigorous and reproducible studies on humans. Given our understanding of the Opioid Growth Factor (OGF) - OGF receptor (OGFr) axis, and the role that naltrexone plays in modulating this pathway, we investigated the role of OGF and LDN utilizing the experimental autoimmune encephalomyelitis (EAE) mouse model [10-18]. Different antigens and strains of mice can be used to develop chronic progressive EAE (Ch-EAE) or relapsing-remitting EAE (RREAE). Accumulated evidence from our research supports the hypothesis that down-regulation of the OGF-OGFr pathwayl disease and central nervous system pathology [12-20]. resulting in decreased blood levels of OGF are associated with a poor prognosis for MS [10,11,19] or EAE [19,20]. Although animal models of MS are imperfect, they provide a reliable platform to assess independent variables in a controlled setting. Manipulation of the OGF-OGFr axis in Ch-EAE mice by injecting OGF or intermittent blockade of the pathway with LDN provides a reproducible animal model enabling rigorous investigations. Data demonstrated that increased blood levels of OGF resulted in positive outcomes and reduction in clinical disease and central nervous system pathology [12-20]. Initial preclinical work utilized the EAE model that was established by immunization with myelin oligodendrocytic glycoprotein (MOG) of female C57Bl/6J mice. The regimen produced behavioral patterns that resembled primary progressive MS or a chronic course of behavioral decline until full paralysis was observed and animals were humanely euthanized. This Ch-EAE model presents with a caudal to rostral pathology detected by demyelination of the spinal cord and glial cell activation [e.g., 12,13]. Daily treatment with OGF beginning at the time of disease induction delayed, and even prevented in some mice, the onset of EAE which was otherwise present in all saline-treated mice inoculated with MOG within 3 weeks of immunization [13]. Behavioral scores of limp tail, wobbly gait, and hind limb paralysis were markedly reduced in OGF-treated EAE mice relative to saline-treated EAE mice. Recognizing that clinical therapy routinely begins after symptoms and signs of MS have appeared for a number of weeks or months, another mouse paradigm was established to study a more clinically relevant model. Mice were immunized with MOG and treatment began 2 days after the first appearance of disease (i.e., limp tail or wobbly gait). OGF therapy reversed the disease progression; disease scores of the OGF-treated EAE mice declined significantly from those of saline-treated EAE mice. Moreover, spinal cord pathology and astrocyte activation were substantially reduced in the EAE mice receiving OGF [14]. RR-MS represents more than 85% of all individuals with MS [1], warranting preclinical investigations in a mouse model of RR-EAE. Female SJL mice were immunized with proteolipid proteins to establish such a model. Several studies conducted on RR-EAE have documented that induction of this form of disease is variable, and lends itself to having incomplete responses [15,16]. Some animals are responders to therapy and others are non-responders. While this phenomenon is not unique to EAE, and is particularly evident in addiction studies, it presents some difficulty in the interpretation of data. Several studies that established RR-EAE showed repeatedly that mice injected daily with OGF had lower behavioral scores and reduced disease severity [15]. The length of remissions as measured by a return to a disease score of 0.5 or less was significantly greater in terms of days, as was the length of time mice had mild disease for mice receiving OGF. Investigations on the treatment of OGF using established RR-EAE mouse models were completed with daily injections of OGF beginning 2 days after behavioral signs of disease were observed [16] and continued once daily for 40 days. OGF treated RR-EAE mice had markedly reduced clinical signs of disease, more periods of remission with each one being longer that those recorded for saline-injected RR-EAE mice. OGF inhibited proliferation of T lymphocytes, reduced the number of Iba-1+ cells and CD3+ cells, and decreased proliferating astrocytes. Exploration of the mechanism of OGF and LDN therapy in Ch-EAE mice revealed that these treatments delayed CNS infiltration of CD4+ T lymphocytes, another sign of inflammation [17]. Thus, multiple studies demonstrated that daily injections of OGF could reduce the severity of both relapsing remitting and chronic forms of established EAE. Once we established that manipulation of the OGF-OGFr axis was involved in EAE progression, we focused on determining the serum levels of endogenous peptides, OGF and β-endorphin, in Ch- EAE mice. Within 5 days of immunization of MOG to 6 week old C57BL/6J female mice, OGF levels were significantly reduced (~70 pg/ml) from normal levels of approximately 150 pg/ml [18]. The deficits in OGF preceded the appearance of any clinical behavioral signs by at least 4 days. Treatment of EAE mice with injections of 10 mg/kg OGF daily increased the blood levels of OGF above those of saline-treated EAE mice, but still below those in normal mice. However, the serum OGF levels correlated with reduced open field movement and von Frey sensitivity, and were inversely correlated with disease severity. Thus, the progression of disease corresponded with declining OGF blood levels. Investigations examined whether the timing of OGF administration to mice altered their immune response. In a well-controlled set of experiments, female mice were immunized with MOG and received OGF prophylactically beginning at the time of disease induction or as traditional therapy once clinical behavior was observed for 2 days [20]. Prophylactic OGF delayed the onset of disease behavior and suppressed lymphocyte and neutrophils replication. Traditional treatment regimens of OGF resulted in a reversal of the clinical behavior, restored OGF serum levels, and inhibited microglial activation within an 8 day period of time. Longer studies were aborted due to the pandemic. This work suggests that treatments to increase serum OGF levels should begin as early as possible following diagnosis of MS, and that maintenance of blood levels of OGF is a positive biomarker of disease progression. Clinical studies on MS are complicated by a number of factors including length of MS disease, age of patient at the onset of disease, and the patient's self-reported symptoms. Moreover, OGF is not FDA approved for clinical use in humans. An alternative therapy is low dosages of an opioid receptor antagonist such as naltrexone that invokes a biofeedback mechanism to increase production and/or release of endogenous opioids including β-endorphin and [Met5]- enkephalin. In clinical studies, elevated levels of enkephalins, specifically OGF, as well as β-endorphin, were measured following either disease modifying therapy or LDN leading to self-reported higher scores on the MS-QoL survey [9,10]. A clinical study (IRB protocol 9784) conducted with consented volunteer patients at the Penn State Hershey Neurology Clinic revealed that serum [Met5]-enkephalin (i.e., OGF) levels were lower in MS patients relative to values from non-MS control humans [10]. LDN therapy restored OGF levels to near normal, but small sample size and demographic variability in length of disease and treatment were too large for reliable comparisons. In a follow-up study, a larger cohort of individuals with diagnosed RR-MS was consented and blood samples assayed for OGF levels, IL-17A and TNFα cytokines; comparisons were made to blood samples for age and sex matched non- MS individuals [10]. Serum samples were analyzed using commercial ELISA kits for OGF, β-endorphin, IL17A, 1L17, and TNFα. Data revealed that MS diagnosis resulted in lower OGF serum values, even in patients on disease modifying therapy relative to OGF levels in non-MS individuals; a small cohort of RR-MS individuals on LDN had OGF comparable to those of non-MS individuals, but sample size was too small for statistical reliability. Serum β-endorphin levels ranged between 1 and 4 ng/ml, and were elevated in RR-MS individuals receiving glatiramer acetate therapy. A direct correlation was found between OGF levels and IL- 17A cytokine values, the pro-inflammatory T-helper cell marker, but no correlation was noted between OGF and TNFα values. Sample sizes and treatment variability prevented additional reliable comparisons. Additional research is needed to expand on the observations that OGF inhibits activated T and B cells in EAE with a focus on whether this mechanism can be modulated by LDN [21]. Preclinical and clinical data reveal that OGF serum levels are significantly decreased in mouse models of EAE and in RR-MS. Treatment with OGF for mice, or LDN for humans, appears to increase serum OGF leading to improved disease outcomes. In Ch-EAE and RR-EAE mice models, OGF treatment reduced behavioral signs, decreased spinal cord pathology, and correlated with a cytokine profile supporting immunological repair. In humans, restored serum enkephalin is associated with a reduced inflammatory cytokine profile. Data distinguishing whether different disease modifying therapies are more likely to alter OGF serum levels are warranted. Collectively, higher serum OGF levels are predictive of better patient outcome. The addition of OGF serum values to the diagnostic panel for MS may be warranted. This would enable physicians to begin early treatment with LDN or another disease modifying therapy. All research studies on MS and/or EAE were supported in part by the Paul K. and Anna E. Shockey Family Foundation and the LDN Research Fund. The authors acknowledge the contributions to this research by former graduate students in our laboratory. Authors have read and edited drafts and the final version of this review. 1. National Multiple Sclerosis Society. MS Prevalence. 2021. https:// www.nationalmssociety.org 2. Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer- Gould A, Marrie RA, et al. The prevalence of MS in the United States: a population-based estimate using health claims data. Neurology. 2019 Mar 5;92(10):e1029-40. 3. Baranzini SE, Oksenberg JR. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends in Genetics. 2017 Dec 1;33(12):960-70. 4. Ebers GC, Sadovnick AD. The geographic distribution of multiple sclerosis: a review. Neuroepidemiology. 1993;12(1):1-5. 5. Hawkes CH, Baker MD, Pohl D, Lechner-Scott J, Levy M, Giovannoni G. Melatonin and multiple sclerosis. Mult Scler Relat Disord. 2021 Jun;51:103032. 6. Scazzone C, Agnello L, Bivona G, Lo Sasso B, Ciaccio M. Vitamin D and genetic susceptibility to multiple sclerosis. Biochemical Genetics. 2021 Feb;59(1):1-30. 7. Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis Journal. 2008 Sep;14(8):1076-83. 8. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low?dose naltrexone and quality of life in multiple sclerosis. Annals of Neurology. 2010 Aug;68(2):145-50. 9. Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Multiple Sclerosis Journal–Experimental, Translational and Clinical. 2016 Sep;2:2055217316672242 10. Patel CL, Zagon IS, Thomas GA, McLaughlin PJ. Enkephalin therapy improves relapsing-remitting multiple sclerosis. In: An Overview and Management of Multiple Chronic Conditions. 2020 Jan 28. IntechOpen. 11. Patel C, Thomas G, Zomorodi N, Zagon IS, McLaughlin PJ. ?-endorphin and opioid growth factor as biomarkers of physical ability in multiple sclerosis. Multiple Sclerosis and Related Disorders. 2021 May 1;50:102868. 12. Zagon IS, Rahn KA, Turel AP, McLaughlin PJ. Endogenous opioids regulate expression of experimental autoimmune encephalomyelitis: a new paradigm for the treatment of multiple sclerosis. Experimental Biology and Medicine. 2009 Nov;234(11):1383-92. 13. Zagon IS, Rahn KA, Bonneau RH, Turel AP, McLaughlin PJ. Opioid growth factor suppresses expression of experimental autoimmune encephalomyelitis. Brain Research. 2010 Jan 15;1310:154-61. 14. Campbell AM, Zagon IS, McLaughlin PJ. Opioid growth factor arrests the progression of clinical disease and spinal cord pathology in established experimental autoimmune encephalomyelitis. Brain Research. 2012 Sep 7;1472:138-48. 15. Hammer LA, Zagon IS, McLaughlin PJ. Treatment of a relapseremitting model of multiple sclerosis with opioid growth factor. Brain Research Bulletin. 2013 Sep 1;98:122-31. 16. Hammer LA, Zagon IS, McLaughlin PJ. Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: implications for the treatment of multiple sclerosis. Brain Research Bulletin. 2015 Mar 1;112:42-51. 17. Hammer LA, Waldner H, Zagon IS, McLaughlin PJ. Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4+ T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Experimental Biology and Medicine. 2016 Jan;241(1):71-8. 18. Ludwig MD, Zagon IS, McLaughlin PJ. Elevated serum [Met5]- enkephalin levels correlate with improved clinical and behavioral outcomes in experimental autoimmune encephalomyelitis. Brain Research Bulletin. 2017 Sep 1;134:1-9. 19. Ludwig MD, Zagon IS, McLaughlin PJ. Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone. Experimental Biology and Medicine. 2017 Sep;242(15):1524-33. 20. Patel C, Zagon IS, Pearce?Clawson M, McLaughlin PJ. Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis. Journal of Neuroscience Research. 2022 Feb;100(2):551-563. 21. McLaughlin PJ, McHugh DP, Magister MJ, Zagon IS. Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis. BMC Immunology. 2015 Dec;16(1):24. The Nature of Radiation-induced Inherited Recessive Gene Mutations in Drosophila Melanogaster The nature of gene mutations induced by ionizing radiation in germ cells and transmitted to offspring remains one of the most important problems in radiation genetics of higher eukaryotes. The data accumulated in this field were obtained by different authors under different experimental conditions which does not give a complete insight about the nature of radiation-induced inherited mutations at different genome levels (chromosome, gene, DNA). Karyotypic Profile of Chronic Myeloid Leukemia in Patients Diagnosed at Tertiary Level in Afghanistan Balanced translocation resulting in fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2 is the pathognomonic molecular driver of CML. The resulting BCRABL 1 fusion gene is both the diagnostic as well as therapeutic target of CML. The first agent with tyrosine kinase inhibitor activity that was licenced in 2000 for treatment of CML patients, was Imatinib, gradually followed by multiple agents with higher efficacy. Escherichia coli Stress, Multi-cellularity, and the Generation of the Quorum Sensing Peptide EDF Bacterial communication via quorum sensing (QS) molecules, as well as toxin-antitoxin (TA) gene modules located on bacterial chromosomes are well-studied mechanisms. Escherichia coli mazEF is a stress-induced TA system mediating cell death requiring a QS extracellular death factor (EDF), the pentapeptide NNWNN. MazF is an endoribonuclease specific for ACA sites. During adverse conditions, the activated MazF generates a stress induced translation machinery, composed of MazF-processed mRNAs and selective ribosomes that specifically translate these processed mRNAs. Constitutively Active Death Receptor Induces Apoptosis in Mammalian Cells Apoptosis is a physiological response in development and homeostasis of metazoans. Apoptosis is triggered during pathological events as a means to renew affected tissues and eliminate cancer cells. The immune system regulates the extrinsic pathway of apoptosis, where signals such as TNFα or displayed ligands on the surface of immune cells trigger signal cascades by death receptors present on targeted cells. Commentary on NOBOX Mutations in Premature Ovarian Insufficiency NOBOX is an ovarian specific transcription factor that plays an important role in follicular growth and survival. Nineteen NOBOX variants have been previously associated with premature ovarian insufficiency (POI). Disease severity in patients with heterozygous and homozygous mutations largely overlap however, hampering genotype-phenotype correlations. We recently reported the first case of biallelic truncating mutations (NM_001080413.3 (NOBOX):c.826C>T, p.(Arg276*) and NM_001080413.3(NOBOX):c.1421del, p.(Gly474Alafs*76)) of NOBOX in two Belgian sisters with POI. 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Home Business News Diphtheria outbreak: The Government must drop its complacency and step-up testing, warns expert Justin Ng / Avalon Diphtheria outbreak: The Government must drop its complacency and step-up testing, warns expert by David Jinks MILT December 1, 2022 written by David Jinks MILT 1st Dec 22 3:01 pm An outbreak of diphtheria in the UK has led to one death and at least 70 suspected cases. The potentially lethal infection was first detected at the Manston migrant processing centre in Kent and has become more widespread with the dispersal of refugees across the country. Reported cases of this highly contagious disease have almost doubled, from 39 people on 10 November to 70 suspected cases on 27 November. The Health Minister Steve Barclay declared this week that the risk to the public was 'very low, partly because there's very high uptake of vaccination within the British public in the first place.' However, a leading testing expert says the Government should not be too complacent about the risk posed by the recent spread of diphtheria. The leading testing expert, Dr Quinton Fivelman PhD, Chief Scientific Officer at London Medical Laboratory, says: 'Diphtheria can be deadly in 5-10% of cases. While it's true that most Brits were routinely vaccinated against this highly contagious bacterial infection, most of us had our final diphtheria vaccination when we were around the age of 14. The NHS official guidance is that people at risk of contact with diphtheria may need a booster if they were last vaccinated more than 10 years ago. That's most UK adults, some of whom may have been exposed to the disease in the last few weeks. 'Our understanding is that from Monday 28 November, migrants displaying symptoms are now being isolated at Manston or "designated isolation centres" similar to the "isolation hotels" used at the height of the Covid pandemic. That's a little like shutting the barn door after the horse has bolted and does not address the issue of cases pre-dating Monday. The Government's poor planning has resulted in a public health risk that could have been easily avoided. 'Following adverse publicity about poor conditions at Manston, migrants were rapidly dispersed throughout Britain before the infection was identified. The fear is that diphtheria has now spread to locations nationwide. The latest UK Health Security Agency (UKHSA) report says 38 cases have been reported in the south-east, with cases also detected across London, the West Midlands and the north-east of England. 'Testing for diphtheria can be done rapidly using a PCR test. Often, this is then supported by Elek's test – a specialist diphtheria test – that takes longer. We recommend, at the very least, the introduction of localised PCR testing in the areas former Manston residents have been dispersed to. 'The concern is that the bacterial infection spreads easily by coughs and sneezes, or through close contact with someone who is infected. Sharing cutlery or cups, or even coming into contact with clothing from an infected person, could expose people to the infection. Diphtheria symptoms 'Diphtheria was once one of the most feared childhood diseases in the UK, with around 60,000 cases a year. This dramatically reduced following the introduction of mass immunisation in 1942. 'A 2020 study on diphtheria in the UK revealed around 75% of the population has antibody levels high enough to give basic diphtheria protection. The highest number of susceptible individuals was observed in under 1-year-olds (37%), 35–44-year-olds (27%), 45–69-year-olds (41%) and those older than 70 years (33%). These figures, perhaps, reflect a combination of waning immunity and the fact that older people received fewer doses of the vaccination. 'Anyone who is concerned about potential exposure to the infection should be aware of the following symptoms, which may develop around 2 to 5 days after becoming infected: a high temperature (fever) swollen glands in your neck difficulty breathing and swallowing a thick, grey-white coating that may cover the back of your throat, nose and tongue 'If the skin has become infected (cutaneous diphtheria), look for these symptoms: blisters on the legs, feet and hands large ulcers surrounded by sore red skin 'The good news is that antibiotics are highly effective if treatment is started soon enough. That means health professionals in all the areas migrants were dispersed to should be alerted to the potential presence of the bacteria. 'With widespread diphtheria testing not yet easily available, a general health test might be a useful course of action for anyone concerned, to ensure they are in good health to help fight infections. London Medical Laboratory's Health Profile Test provides people with a comprehensive check-up of their general health, including vitamin D levels, diabetes (HbA1c), liver & kidney function, full blood count, bone health, iron levels and a full cholesterol profile. 'It can be taken at home through the post, or at one of the many drop-in clinics that offer this test across London and nationwide in over 85 selected pharmacies and health stores. HealthNHS CQC delivers damning report ambulance staff had insufficient medicine supplies... Millions of Brits would drive to hospital as trust in... Thousands of ambulance staff to strike and 'Ministers must stop... Former Army doctor reveals hospital care is better in a... 'Unusual norovirus activity' sees cases soar 37% higher than pre-pandemic... The NHS overtakes the economy and inflation as the most...
Suicide risk in the young: what, how and who to study Dr Jessica Edwards Jessica received her MA in Biological Sciences and her DPhil in Neurobehavioural Genetics from the University of Oxford (Magdalen College). After completing her post-doctoral research, she moved into scientific editing and publishing, first working for Spandidos Publications (London, UK) and then moving to Nature Publishing Group. Jessica is now a freelance editor and science writer, and started writing for "The Bridge" in December 2017. Suicide is the second leading cause of death in children and adolescents and occurs at a higher rate in this population than in any other age group. In their latest Annual Research Review published in the Journal of Child Psychology and Psychiatry, Christine B. Cha and colleagues outline the epidemiology and potential etiology of suicide, indicate possible therapeutic and preventative strategies and highlight the areas that remain for future research. Suicide is a global, leading cause of death, but it is most prevalent in adolescents and young adults. A wealth of studies has identified potential risk factors to help explain how and why suicidal behaviours emerge during adolescence. But despite vast progress, a full understanding of the etiology is lacking, thus hindering the development of effective therapeutic and preventative measures. Cha et al. first note that there is a lack of consistent definitions and classifications throughout the suicide literature. As such, they encourage that sufficient detail be provided when defining study variables in future studies, to avoid misclassification. Cha et al. define suicidal ideation as "the consideration of or desire to end one's own life". Such desire may range from passive (wanting to be dead) to active ideation (wanting to kill oneself), and may occur as frequently as once per week. Suicide attempt differs from ideation as with an attempt, an action intended to deliberately end one's own life is made. Suicide death is defined as "a fatal action to deliberately end one's own life", and the method that is used seems to vary geographically. Epidemiology: The prevalence of suicidal ideation in adolescents ranges from 19.8 to 24.0%, starting after the age of 10 years and rapidly increasing up to age 17 years. Those who experience suicidal ideation during adolescence are ~12 times more likely to attempt suicide by the age of 30 years. Suicide attempts have a lifetime prevalence of 3.1% to 8.8%: they typically occur after the age of 12 years and increase in prevalence in mid-to-late adolescence. Suicide-associated death accounts for 8.5% of all deaths in adolescents and young adults aged 15 to 29 years, and increases in prevalence from ages 15 to 19 years. The developmental nature of suicide risk across adolescence is under-reported. Interestingly, the timing of puberty has been shown to have an effect on suicidal behaviours, but how or why this is the case is unknown. Cha et al. suggest, therefore, that more longitudinal studies that include wide age ranges and encompass developmental shifts during adolescence would be valuable. Gender differences can be observed in suicidal behaviour: adolescent girls are more likely to experience suicidal ideation and attempt suicide than boys, yet boys are up to three times more likely to die by suicide. Gender identity and sexual orientation also impacts on the prevalence of suicide ideation and attempt. Adolescents who relate to a sexual minority status show an elevated risk of suicidal behaviours than their heterosexual counterparts. Risk of suicide death is also higher in indigenous American Indian, Alaska Native and Aboriginal youths in the USA and Canada compared to other ethnicities. However, these high-risk socio-demographic populations are under-represented in the suicide literature and thus Cha et al. encourage more attention be paid to these high-risk populations in future studies. Many risk factors for suicidal behaviours have been described, but a clear understanding of the pathways through which suicidal behaviours develop has not yet been reached. In terms of environmental risk factors, childhood maltreatment/bullying is one of the strongest factors influencing suicidal thoughts and behaviours in adolescents. Twin studies have shown that sexual abuse in childhood can predict future suicidal ideation and suicide attempt. Long periods of exposure to bullying also increase the likelihood of suicidal ideation and attempt, in both the victim and offender. Cyber bullying and the impact of social media is an important consideration in today's digital revolution, but Cha et al. find that the data thus far are mixed: some have proposed that the Internet provides a forum of help and social support, while others highlight that it can offer sources of suicide-related information. Psychological factors that correlate with suicidal behaviours have mostly been measured by self-report, behaviour and physiology. The researchers describe that affective processes, such as worthlessness, low self-esteem and negative self-referential thinking, can strongly predict future suicidal ideation and suicide attempt. In terms of cognitive factors that correlate with suicidal behaviours, impulsivity has received moderate support as a risk factor for suicidal behaviour, particularly when in combination with aggression. Others have reported that deficits in sustained attention and vigilance correlate with suicidal thoughts and behaviours. Interpersonal connectedness (loneliness) has been widely assessed in longitudinal studies, but the evidence in support of loneliness as a direct risk factor for suicidal behaviours is only moderate. Biological correlates: Several biological correlates with suicidal thoughts have been described. For example, researchers identified lower functional connectivity between several neural regions in those who are suicidal compared to controls. Specifically, structural abnormalities have been detected in the hippocampus, dorsolateral prefrontal cortex and highly interconnected brain neural networks involved in regulating the resting brain state. At the molecular level, serotonin is the most widely studied molecule in terms of suicidal behaviours, with studies dating back to the 1970's showing low serotonin levels in those who have died by suicide compared to controls. Preliminary studies have also implicated abnormal TNFa, IL-b and BDNF levels in suicidal behaviours. Finally, although preliminary studies support that there is a heritable component to suicidal behaviour, the genetic basis is currently unknown. Cha et al. consider that genetic studies are lacking in this field, in particular genome wide association studies. Although these biological findings are, on the most part, only preliminary, research in this area is rapidly evolving. Cha et al highlight that the biological factors identified thus far have corroborated behavioural and self-reported data but there remains disconnect between biological mechanisms and overt behaviours. Cross-disciplinary collaborations are required to better link biological and behavioural factors and identify biological targets that can be readily manipulated for intervention. Cha et al. focus on the psychological interventions to reduce risk of suicide in adolescents, primarily reporting on data from randomized controlled trials. Interventions with the strongest support have a focus on behaviour change, skill-enhancement and strengthening of interpersonal bonds. Individual and family therapy, such as Integrated Cognitive Behavioural Therapy and Attachment-based Family Therapy, are effective in treating adolescents demonstrating suicidal behaviours. Both of these therapies have shown immediate and short-term effects, with a reduced number of suicide attempts after therapy. Other individual treatments aim to improve a child's interpersonal skills to decrease risk of suicidal behaviours. One example is dialectical behaviour therapy (DBT) that focuses on strengthening interpersonal effectiveness, mindfulness, distress tolerance and emotion regulation. Another is interpersonal psychotherapy in school settings (IPT-A-IN), which focuses on developmentally appropriate interpersonal problems. Both DBT and IPT-A-IN have shown superiority to controls receiving standard treatment in reducing severity of suicidal ideation, but the data are still preliminary. More research is required to assess the long-term effects of these interventions. Technology-based interventions (such as smart-phone applications) may be used to create an aversion to death, suicide and self-injury. The results thus far are promising, suggesting that individuals using an app-based intervention reduce engagement in suicidal behaviours in the short term. Cha et al. propose that mobile technology may provide a rich source of real-time data to identify short-term behavioural signatures of suicide risk, as to date, most studies have focused only on long-term follow-ups. Prevention: The researchers outline three main preventative strategies to reduce the prevalence of suicidal thoughts and behaviours in adolescents. The first strategy is universal prevention, in which entire populations (such as schools) are educated about risk. Data from randomized controlled trials have thus far been positive in reducing self-reported suicide attempts at 3 months post-intervention. The second preventative strategy is selective prevention. These programs teach adaptive skills, such as problem solving, to pre-empt the development of common risk factors for suicidal behaviours. Although the evidence to support school-based selective prevention is lacking, results from family-based selective prevention are promising. The third preventative strategy is indicated prevention and crisis support, such as crisis hotlines that respond to the immediate distress calls from suicidal individuals. Formal evidence for their effect in the adolescent population is, however, lacking. In summary, Cha et al highlight the notable advances made in understanding the epidemiology and (potential) etiology of suicidal behaviours. The researchers hope that future research will (i) improve the definitions of suicidal behaviours in the literature and be more representative of the most high-risk populations, (ii) clarify the etiology of suicide by integrating findings from various disciplines, and (iii) assess the developmental nature of suicide risk. They reinforce that future research must now focus on what, how and who is studied, to inform treatment and ultimately prevent suicide attempts in adolescents. Referring to: Cha, C.B., Franz, P.J., Guzman, E.M., Glenn, C.R., Kleiman, E.M. & Nock, M.K. (2018), Annual Research Review: Suicide among youth – epidemiology, (potential) etiology, and treatment. J Child Psychol Psychiatr, 59: 460-482. doi:10.1111/jcpp.12831 Diamond, G.S. et al. (2010). Attachment based family therapy for adolescents with suicidal ideation: A randomized controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 122–131. Dunlop, S.M. et al. (2011). Where do youth learn about suicides on the Internet, and what influence does this have on suicidal ideation? Journal of Child Psychology and Psychiatry, 52, 1073–1080. Fergusson, D.M et al. (2008). Exposure to childhood sexual and physical abuse and adjustment in early adulthood. Child Abuse and Neglect, 32, 607–619. Husky, M.M. et al. (2011). Identifying adolescents at risk through voluntary school-based mental health screening. Journal of Adolescence, 34, 505–511. Kokkevi, A. et al. (2012). Adolescents' self-reported suicide attempts, self-harm thoughts and their correlates across 17 European countries. Journal of Child Psychology and Psychiatry, 53, 381–389. Nock, M.K. et al. (2008). Suicide and suicidal behavior. Epidemiologic Reviews, 30, 133–154. Patton, G.C., & Viner, R. (2007). Pubertal transitions in health. The Lancet, 369, 1130–1139. Sexual minority: a group of individuals whose sexual identity, orientation or characteristics differ from the majority (usually heterosexuals) in the surrounding society Affective process: characteristic emotional reactions and temperaments to a situation Interpersonal connectedness: the sense of belonging based on having sufficient quantity and quality of social contacts Randomized controlled trials: an experimental setup whereby participants are randomly allocated to an intervention/treatment group or a control/placebo group; randomization of participants occurs after assessments for eligibility, and is used to minimize selection bias Longitudinal study: study design where subjects are monitored over a period of time with continuous assessment of the study variables (i.e. risk factors or health outcomes) Integrated Cognitive Behavioural Therapy (I-CBT): a combination of individual and family CBT techniques and parent training Attachment-based Family Therapy: family therapy in which the parent and child work to repair problems in their relationship and to rebuild an emotionally secure relationship Dialectical behaviour therapy (DBT): a modified form of cognitive behavioural therapy to help those who experience intense emotions. DBT focuses on changing unhelpful behaviours whilst accepting who you are Interpersonal psychotherapy: brief, attachment-focused therapy for those with mood disorders that aims to resolve interpersonal problems and promote symptomatic recovery Genome wide association study (GWAS): an observational analysis of a genome-wide set of genetic variables in a large cohort to see if any genetic variant is associated with a particular trait Read the Self-harm and Suicide Editorial of The Bridge by Dr Juliette Kennedy A mother's touch: a key player in fine tuning the function of our genome Autism Masterclass
Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect Priya Kumar Shah, John H.M. Austin, Charles S. White, Pavni Patel, Linda B. Haramati, Gregory D.N. Pearson, Maria C. Shiau, Yahya M. Berkmen PURPOSE: To assess for change in the 1990s in the failure of detection at chest radiography of potentially resectable non-small cell lung cancer (NSCLC) lesions compared with experience in the previous decade. MATERIALS AND METHODS: From 1993 to 2001, an observational cohort was identified that consisted of 40 instances of NSCLC evident retrospectively at chest radiography but undetected by a radiologist at a time when the cancer was potentially resectable for cure. Sizes and locations of the tumors were assessed. Pearson X2 testing was performed to compare the sex distribution of lung cancer in the present series with population data for the sex distribution of lung cancer in the United States during the present study. RESULTS: Twenty-five (62%) undetected NSCLCs were in men and 15 (38%) were in women, yielding a ratio not significantly different from that for the sex distribution of NSCLC according to national data (X2 = 0.22, P = .64). Median patient age was 62 years (range, 37-87 years). Median diameter of the missed cancers was 1.9 cm. Missed cancers were most commonly located in the upper lobes (right, 45%; left, 28%; total, 72%), especially in the apical and posterior segments/subsegments (60% of all the missed cancers). A clavicle obscured 22% of the missed cancers. Eighty-five percent of the missed cancers were in peripheral locations. CONCLUSION: Potentially resectable NSCLC lesions missed at chest radiography were characterized by predominantly peripheral (85%) and upper lobe (72%) locations and by apical and posterior segmental/subsegmental locations in an upper lobe (60%). Distribution by sex of the missed cancers was comparable to national data for NSCLC. The missed cancers had a median diameter of 1.9 cm. https://doi.org/10.1148/radiol.2261011924 Diagnostic radiology, observer performance Lung neoplasms, diagnosis 10.1148/radiol.2261011924 Dive into the research topics of 'Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect'. Together they form a unique fingerprint. Non-Small Cell Lung Carcinoma Medicine & Life Sciences 100% Sex Distribution Medicine & Life Sciences 61% Radiography Medicine & Life Sciences 35% Clavicle Medicine & Life Sciences 15% Radiologists Medicine & Life Sciences 11% Shah, P. K., Austin, J. H. M., White, C. S., Patel, P., Haramati, L. B., Pearson, G. D. N., Shiau, M. C., & Berkmen, Y. M. (2003). Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect. RADIOLOGY, 226(1), 235-241. https://doi.org/10.1148/radiol.2261011924 Missed non-small cell lung cancer : Radiographic findings of potentially resectable lesions evident only in retrospect. / Shah, Priya Kumar; Austin, John H.M.; White, Charles S.; Patel, Pavni; Haramati, Linda B.; Pearson, Gregory D.N.; Shiau, Maria C.; Berkmen, Yahya M. In: RADIOLOGY, Vol. 226, No. 1, 01.01.2003, p. 235-241. Shah, PK, Austin, JHM, White, CS, Patel, P, Haramati, LB, Pearson, GDN, Shiau, MC & Berkmen, YM 2003, 'Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect', RADIOLOGY, vol. 226, no. 1, pp. 235-241. https://doi.org/10.1148/radiol.2261011924 Shah PK, Austin JHM, White CS, Patel P, Haramati LB, Pearson GDN et al. Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect. RADIOLOGY. 2003 Jan 1;226(1):235-241. https://doi.org/10.1148/radiol.2261011924 Shah, Priya Kumar ; Austin, John H.M. ; White, Charles S. ; Patel, Pavni ; Haramati, Linda B. ; Pearson, Gregory D.N. ; Shiau, Maria C. ; Berkmen, Yahya M. / Missed non-small cell lung cancer : Radiographic findings of potentially resectable lesions evident only in retrospect. In: RADIOLOGY. 2003 ; Vol. 226, No. 1. pp. 235-241. @article{a5eef866612849959621e75c0b7d4ea0, title = "Missed non-small cell lung cancer: Radiographic findings of potentially resectable lesions evident only in retrospect", abstract = "PURPOSE: To assess for change in the 1990s in the failure of detection at chest radiography of potentially resectable non-small cell lung cancer (NSCLC) lesions compared with experience in the previous decade. MATERIALS AND METHODS: From 1993 to 2001, an observational cohort was identified that consisted of 40 instances of NSCLC evident retrospectively at chest radiography but undetected by a radiologist at a time when the cancer was potentially resectable for cure. Sizes and locations of the tumors were assessed. Pearson X2 testing was performed to compare the sex distribution of lung cancer in the present series with population data for the sex distribution of lung cancer in the United States during the present study. RESULTS: Twenty-five (62%) undetected NSCLCs were in men and 15 (38%) were in women, yielding a ratio not significantly different from that for the sex distribution of NSCLC according to national data (X2 = 0.22, P = .64). Median patient age was 62 years (range, 37-87 years). Median diameter of the missed cancers was 1.9 cm. Missed cancers were most commonly located in the upper lobes (right, 45%; left, 28%; total, 72%), especially in the apical and posterior segments/subsegments (60% of all the missed cancers). A clavicle obscured 22% of the missed cancers. Eighty-five percent of the missed cancers were in peripheral locations. CONCLUSION: Potentially resectable NSCLC lesions missed at chest radiography were characterized by predominantly peripheral (85%) and upper lobe (72%) locations and by apical and posterior segmental/subsegmental locations in an upper lobe (60%). Distribution by sex of the missed cancers was comparable to national data for NSCLC. The missed cancers had a median diameter of 1.9 cm.", keywords = "Diagnostic radiology, observer performance, Lung neoplasms, Lung neoplasms, diagnosis", author = "Shah, {Priya Kumar} and Austin, {John H.M.} and White, {Charles S.} and Pavni Patel and Haramati, {Linda B.} and Pearson, {Gregory D.N.} and Shiau, {Maria C.} and Berkmen, {Yahya M.}", doi = "10.1148/radiol.2261011924", journal = "Radiology", publisher = "Radiological Society of North America Inc.", T1 - Missed non-small cell lung cancer T2 - Radiographic findings of potentially resectable lesions evident only in retrospect AU - Shah, Priya Kumar AU - Austin, John H.M. AU - White, Charles S. AU - Patel, Pavni AU - Haramati, Linda B. AU - Pearson, Gregory D.N. AU - Shiau, Maria C. AU - Berkmen, Yahya M. N2 - PURPOSE: To assess for change in the 1990s in the failure of detection at chest radiography of potentially resectable non-small cell lung cancer (NSCLC) lesions compared with experience in the previous decade. MATERIALS AND METHODS: From 1993 to 2001, an observational cohort was identified that consisted of 40 instances of NSCLC evident retrospectively at chest radiography but undetected by a radiologist at a time when the cancer was potentially resectable for cure. Sizes and locations of the tumors were assessed. Pearson X2 testing was performed to compare the sex distribution of lung cancer in the present series with population data for the sex distribution of lung cancer in the United States during the present study. RESULTS: Twenty-five (62%) undetected NSCLCs were in men and 15 (38%) were in women, yielding a ratio not significantly different from that for the sex distribution of NSCLC according to national data (X2 = 0.22, P = .64). Median patient age was 62 years (range, 37-87 years). Median diameter of the missed cancers was 1.9 cm. Missed cancers were most commonly located in the upper lobes (right, 45%; left, 28%; total, 72%), especially in the apical and posterior segments/subsegments (60% of all the missed cancers). A clavicle obscured 22% of the missed cancers. Eighty-five percent of the missed cancers were in peripheral locations. CONCLUSION: Potentially resectable NSCLC lesions missed at chest radiography were characterized by predominantly peripheral (85%) and upper lobe (72%) locations and by apical and posterior segmental/subsegmental locations in an upper lobe (60%). Distribution by sex of the missed cancers was comparable to national data for NSCLC. The missed cancers had a median diameter of 1.9 cm. AB - PURPOSE: To assess for change in the 1990s in the failure of detection at chest radiography of potentially resectable non-small cell lung cancer (NSCLC) lesions compared with experience in the previous decade. MATERIALS AND METHODS: From 1993 to 2001, an observational cohort was identified that consisted of 40 instances of NSCLC evident retrospectively at chest radiography but undetected by a radiologist at a time when the cancer was potentially resectable for cure. Sizes and locations of the tumors were assessed. Pearson X2 testing was performed to compare the sex distribution of lung cancer in the present series with population data for the sex distribution of lung cancer in the United States during the present study. RESULTS: Twenty-five (62%) undetected NSCLCs were in men and 15 (38%) were in women, yielding a ratio not significantly different from that for the sex distribution of NSCLC according to national data (X2 = 0.22, P = .64). Median patient age was 62 years (range, 37-87 years). Median diameter of the missed cancers was 1.9 cm. Missed cancers were most commonly located in the upper lobes (right, 45%; left, 28%; total, 72%), especially in the apical and posterior segments/subsegments (60% of all the missed cancers). A clavicle obscured 22% of the missed cancers. Eighty-five percent of the missed cancers were in peripheral locations. CONCLUSION: Potentially resectable NSCLC lesions missed at chest radiography were characterized by predominantly peripheral (85%) and upper lobe (72%) locations and by apical and posterior segmental/subsegmental locations in an upper lobe (60%). Distribution by sex of the missed cancers was comparable to national data for NSCLC. The missed cancers had a median diameter of 1.9 cm. KW - Diagnostic radiology, observer performance KW - Lung neoplasms KW - Lung neoplasms, diagnosis U2 - 10.1148/radiol.2261011924 DO - 10.1148/radiol.2261011924 JO - Radiology JF - Radiology
When it comes to skin care, one size does not fit all. The reality of multiple skin profiles means there is not one perfect formula or magical ingredient for younger, smoother and brighter looking skin. That's why AlumierMD's team of experts have designed multifaceted, results-oriented skin care products that target the underlying physiology related to each skin type, condition and person. The AlumierMD skincare line is customized to meet each individual's needs for optimal results. AlumierMD offers light to medium depth peels known for their excellent results and safety profile. We believe in repeated treatments for progressive and gradual results to avoid side effects and downtime associated with deeper peels. AlumierMD peels are only performed by trained skin care professionals in a clinical setting to ensure that they are delivered safely and effectively. Book your AlumierMD Skin Peel Treatment by calling Beau:ti today on 020 7820 1177 or email [email protected]. Glow Peel combines lactic acid, salicylic acid and resorcinol, creating a mulipurpose resurfacing solution effective in minimizing the appearance of fine lines, wrinkles and hyperpigmentation issues like age spots, discolouration and uneven skin tone. This formula exfoliates dead skin cells and stimulates cell renewal. To suit individual needs, Glow Peel can be customized by strength by numbers of layers. Radiant 30 is an alpha hydroxy acid resurfacing peel containing lactic acid to exfoliate dead skin cells. Boost cell turnover and stimulate collagen, improving skin texture and tone. This multifunctional peel targets multiple skin conditions, including fine lines and wrinkles, discoloration, sun damage and large pores. With lactic and salicylic acid, radiant 20/10 resurfacing peel contains a powerful combination of them both which improves skin tone and texture by exfoliating dead skin cells and speeding cell turnover. The multipurpose resurfacing peel reduces acne pimples and minimizes the appearance of fine lines and wrinkles, large pores, hyperpigmentation and sun damage. Enzyme Retexturing Treatment is a highly effective fruit enzyme resurfacing solution. The unique blend of fruit enzymes exfoliates dead skin cells and promotes skin renewal. This unique experience also includes brightening enhancers, followed by targeted treatment serums to address each skin concern. The result is a reduction in the appearance of fine lines, wrinkles and hyperpigmentation, while soothing and maintaining hydration. Book your treatment online today in just a few easy steps.
Your High Mesa Dental Arts team will work with you to build the beautiful smile that you desire. In one short, convenient appointment at High Mesa Dental Arts, you can have a whiter, brighter smile. There are a variety of procedures that can be used, so check with High Mesa Dental Arts to see which one is right for you. It is important to have your teeth examined before undergoing any whitening, checking for teeth and enamel irregularities or decay. During your routine dental exam, the dentist will check with special instruments to determine whether you have a cavity that needs filling, and will choose the type of treatment, depending on the extent of the damage. High Mesa Dental Arts provides patients with tooth filling options for amalgam (silver) fillings, composite (plastic) resins, and porcelain (See Inlays and Onlays). With a filling, any decay will be removed and cleaned, and the cleaned out cavity will be filled with the selected material. If the damage or decay is too extensive, repair may require a crown. When a tooth cannot be restored, such as due to extensive decay or fracture, it must be removed. The exact procedure will depend on factors that include the condition of the tooth and the location in the mouth. Sedation is not often required, but is available (See Sedation Options), and your dentist will work with you to make sure minimize any anxiety and pain. There are a number of reasons that it is a good choice to have wisdom teeth removed, including impaction, growing in at the wrong angle, a jaw that has no room for an extra set of molars, or cavities or gum disease. The surgery to remove the tooth takes less than an hour, and you will be sedated (See Sedation Options) so that the procedure will be as painless as possible. You will receive detailed instructions prior to and following the procedure from our staff and your dentist. Instead of removing a badly damaged or infected tooth, another option to keep the natural tooth is a root canal. The root canal therapy, or endodontic treatment, involves opening the tooth, removing the damaged pulp, cleaning, shaping, filling and sealing the tooth. There are a variety of sedation options (See Sedation Options) so that the procedure will be as painless as possible. Veneers and bonding are dental procedures that mask imperfections in your teeth. Veneers are like artificial fingernails – thin shells of porcelain that cover the fronts of teeth, to hide chipped, discolored, crooked, worn, uneven, stained, gapped, out of proportion, or decayed teeth. Due to the veneers being custom-made and the natural appearance of veneers, it is nearly impossible to tell the difference in veneers and the patient's natural teeth. Also, they don't change color over time and resist stains from food, drinks, and smoking. Dental bonding is an option High Mesa Dental Arts offers to mask imperfections using a composite resin that is matched to the patient's teeth and applied by the dentist. Usually recommended for minor imperfections and repairs, bonding is easier, faster and less expensive than veneers, but lacks durability and appearance features of veneers. Teeth with mild decay or cracked and fractured teeth that have enough tooth so that a crown is not required but can't be repaired with a filling, are good candidates for an inlay or an onlay restoration. These help to strengthen teeth, unlike traditional fillings, and prolong tooth life since they are made from extremely durable materials. Dental implants are a secure and effective long-term solution for missing teeth, since they fit, feel, and function like natural teeth. A dental implant has three parts. The implant is a post that serves as a permanent artificial tooth root, which is surgically positioned in the jawbone, allowing the dentist to mount replacement teeth or a bridge into that area. The abutment is a permanent connector, removable by the dentist. The crown is a prosthetic tooth that is usually zirconium or porcelain for durability and appearance. A bridge may be a good option if you are missing one or more teeth. The gap and imbalance due to missing teeth can lead to gum disease and Temporomandibular Joint (TMD, TMJ)disorders. Your High Mesa Dental Arts dentist may recommend a crown to attach a bridge, cover a dental implant, cover discolored or misshapen teeth, restore or protect a fractured tooth, or other reasons. Before a crown or bridge can be made, either an implant is installed, or the existing tooth must be reduced in size to fit the crown or bridge. Then an impression of your teeth will be taken, and a temporary crown or bridge will be installed until the new crown or bridge is cemented over the prepared tooth or implant. The most important step in ensuring your crown or bridge lasts a lifetime is good oral hygiene and routine dental exams. High Mesa Dental Arts has experience and the latest technology to provide complete or partial dentures that replace the tissue and teeth for the most comfort and provide a beautiful smile. Dental implants can sometimes be an alternative to dentures. Full dentures completely replace the teeth in the upper and/or lower jaws. Partial dentures are used when natural teeth remain, and the denture will prevent other teeth from changing position. A "fixed bridge" replaces teeth by placing crowns on the remaining teeth on either side of the space, and attaching artificial teeth in the bridge, which is then cemented into place.
Horváth Zs., Cs. F. Vad, L. Vörös et al: Distribution and conservation status of fairy shrimps ... (2013) Distribution and conservation status of fairy shrimps (Crustacea: Anostraca) in the astatic soda pans of the Carpathian basin: the role of local and spatial factors Journal of Limnology 72: pp. 103–116 The distribution of Branchinecta orientalis, B. ferox and Chirocephalus carnuntanus was assessed in the natural and semi-natural astatic soda pans of the Carpathian basin. In Europe, these habitats are exclusively restricted to Hungary (Great Hungarian Plain), Austria (Seewinkel) and Serbia (Vojvodina). The present research is the first comprehensive large-scale study – covering an area of approximately 125,000 km2 – on these three fairy shrimp species in the region, and it is important especially in the case of Branchinecta spp., due to former taxonomical uncertainties. The local, land use and spatial effects on the species distribution were also analysed. The three anostracans were found to adopt different strategies, mainly according to the salinity of the pans. The apparently halophilous B. orientalis tolerated higher salinities than the other species, which can be regarded as habitat-generalist halotolerants, showing a high preference for soda waters in Central Europe. The density of the species was significantly affected only by local factors, while their occurrence was influenced also by pan isolation. Land use did not explain a significant amount of variation in either case. In conclusion, soda pans with a wide range of different salinities constitute a suitable habitat for all the three species. Also, protected areas with high number of pans – as Seewinkel (in Austria) or Kiskunság (in Hungary) – can play an essential role in the long-term conservation of these anostracans. Finally, we suggest that these species should be legally protected, primarily because the number of their habitats in the basin is seriously declining.
Oxford University and ZOE partner on COVID-19 treatment trials – EurekAlert Oxford University and the COVID Symptom Study app are joining forces to widen access to two clinical trials of potential treatments for COVID-19. The COVID Symptom Study App was developed and is managed by health technology company ZOE, with the research using data from the app being undertaken by academics at King's College London. The app has now been downloaded by over 3.5 million people in the UK and has recruited over 800,000 citizen scientists to its Vaccine and Trial Registry. The registry was launched on 9 July and aims to raise awareness and rapidly recruit members of the public to the growing number of national and community-based clinical trials for COVID-19 in the UK. Those users who have already signed up to the COVID Symptom Study Vaccine and Trial registry and test positive for COVID-19, or show signs of symptomatic COVID in the app, will be contacted and given the opportunity to join Oxford University's PRINCIPLE and STOIC trials. The PRINCIPLE Trial is evaluating whether treatment early on in the community can help people aged over 50 recover quickly from COVID-19 illness, without the need for hospital admission. The trial, which is open across the UK to people aged over 50 with an underlying health condition or anyone aged over 65, can be easily joined online from home without face-to-face visits, or via GP practices across the country. It is one of the UK Government's national priority platform trials on COVID-19 treatments. PRINCIPLE is currently evaluating azithromycin and doxycycline, which are two commonly prescribed antibiotics. These drugs are thought to have anti-viral and anti-inflammatory properties against coronavirus, and also treat bacterial infections like pneumonia, which is a common reason for deterioration in people with COVID-19. 665 people have already signed-up to take part, but many more are needed to determine whether either of the treatments can help treat the disease. The collaboration with the COVID Symptom Study app will help to link eligible individuals with the PRINCIPLE trial. The STOIC (STerOids In COVID) study is investigating the early use of a steroid inhaler, in people with symptoms suggestive of COVID-19, as a treatment to reduce the chance of needing to go to hospital. Inhaled steroids are a type of medicine which reduces inflammation, so their use early in the disease course of COVID-19 could reduce the inflammation caused by the virus and help prevent severe disease. The STOIC study is open to anyone over the age of 18 with new symptoms suggestive of COVID-19 within the last seven days. To get the study treatment (a Budesonide steroid inhaler) as early as possible, a positive test result is not necessary to join the study. Volunteers can participate from home, with the trial's research nurses dropping off all the study equipment and medications on participants' doorsteps. All volunteers in the STOIC study will be provided with an oxygen monitor and a thermometer to detect any signs of worsening symptoms, and everyone will be monitored via daily phone calls with the study's clinical team. The study is now looking for volunteers in the Thames Valley and will expand to other areas in the next few weeks. Tim Spector, Professor of Genetic Epidemiology at King's College London, and lead scientist at the COVID Symptom Study app comments: "We are really excited to be partnered with Oxford University. This is exactly why we set up the Vaccine and Trial Registry. We have millions of engaged loyal users, who all want to help play a role in the fight against COVID and this collaboration will help us link those individuals up with trials. Both the PRINCIPLE and the STOIC trials are conducting essential research, especially whilst we have no effective vaccine yet. This work will save lives and as always, we want to thank all our amazing users as they continue to allow us to make a real impact on COVID-19." Professor Chris Butler, a GP and Co-Lead of the PRINCIPLE Trial at the University of Oxford's Nuffield Department of Primary Care Health Sciences, said: 'Until an effective vaccine is developed and made widely available, treating people at home who show symptoms of COVID-19 is the only way to help most people who get this awful illness to recover more quickly, and prevent those who are at most risk of serious illness from having to go to hospital. 'PRINCIPLE will answer a pressing question – which of the treatments showing promise against COVID-19 are effective in people at higher risk of complications early on in the illness? With the prospect of a second wave later this year, we urgently need many more people to join the trial to determine which, if any, of these drugs can be introduced into usual care. Our partnership with the COVID Symptom Study is an important step in facilitating access to this trial for those users who test positive for the disease.' Professor Mona Bafadhel, the STOIC study Chief Investigator, Associate Professor of Respiratory Medicine in the Nuffield Dept of Medicine at the University of Oxford and a Consultant Respiratory Physician at the Oxford University Hospitals NHS Foundation Trust, said "We know that steroid tablets or injections given in severe disease can help prevent death in COVID-19. We want to test if steroids in an inhaler form, like those given to patients with asthma and COPD, can stop people getting worse from COVID-19 when given early. Inhaled steroids are cheap medicines that are widely available throughout the world. The STOIC study has been designed to answer this question and we are excited to work with the investigators at Kings College London and the ZOE team.' PRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR), STOIC is funded by the NIHR Oxford Biomedical Research Centre. Download the COVID Symptom Study app here: https://covid.joinzoe.com Find out more about how to join the PRINCIPLE Trial here: https://www.principletrial.org Find out more and join the STOIC trial at: http://www.stoic.ndm.ox.ac.uk For more information about the app or to request an interview with Professor Spector, please contact Eleanor Griffiths: +44 (0)7950 335916 [email protected] For information about the PRINCIPLE or STOIC trials, or to speak with a researcher, please contact [email protected] 01865 280528 ZOE is a health science company using data-driven research to tackle the world's health issues. By using artificial intelligence combined with digital technologies like mobile phones, ZOE enables large-scale scientific studies to tackle issues like COVID-19, inflammation and the impact of nutrition on health. Located in London and Boston, ZOE was founded by machine learning leader Jonathan Wolf and entrepreneur George Hadjigeorgiou. ZOE along with Professor Tim Spector of King's College London. ZOE has carried out the largest nutritional studies of their kind in the world, runs the COVID Symptom Study app with 4 million users around the world, and was named one of the Deloitte Fast 50 Rising Stars in 2019 for the company's contribution to science enabled by technology and machine learning. For more information on ZOE's mission and science visit joinzoe.com. Find us on Instagram @ZOE. About the PRINCIPLE Trial The UK-wide PRINCIPLE trial platform is led from the Primary Care Clinical Trials Unit at the University of Oxford's Nuffield Department of Primary Care Health Sciences. The trial is integrated with the Oxford RCGP Research and Surveillance Centre and works closely with the NIHR Clinical Research Network across England and similar networks in the devolved nations. The trial is funded by the UK Government through the NIHR and UKRI rapid response research call. Within the University of Oxford, the Nuffield Department of Primary Care Health Sciences is the largest, top-ranked centre for academic primary care in the UK, bringing together academics from many different backgrounds to work together to produce benefits for the NHS, for populations and for patients. http://www.principletrial.org About the STOIC trial The Nuffield Department of Medicine University of Oxford led STOIC study is recruiting volunteers with symptoms of COVID-19 to trial inhaled steroids. The study hopes to show that early use of inhaled steroids will reduce the risk of emergency department visit and hospitalisation due to COVID-19. The study also proposes a home based, clinician led monitoring program to detect early deterioration of COVID-19. The study is supported by the NIHR Oxford Biomedical Research Centre and AstraZeneca. The study is now recruiting in the Thames Valley and is opening in other areas in the UK in the next few weeks. Visit http://www.stoic.ndm.ox.ac.uk for more information. About the National Institute for Health Research: The National Institute for Health Research (NIHR) is the nation's largest funder of health and care research. The NIHR: Funds, supports and delivers high quality research that benefits the NHS, public health and social care Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services Partners with other public funders, charities and industry to maximise the value of research to patients and the economy The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government. This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care. http://www.nihr.ac.uk/patientdata The University of Oxford The University of Oxford has been placed number 1 in the Times Higher Education World University Rankings for the third year running, and at the heart of this success is our ground-breaking research and innovation. Oxford is world-famous for research excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research sparks imaginative and inventive insights and solutions. Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 170 new companies since 1988. Over a third of these companies have been created in the past three years. COVID-19 rips through Georgia sleepaway camp – ABC News Not all cancer patients should be regarded as vulnerable to COVID-19, says expert oncology group – The Pharmaceutical Journal
Special Issues Guidelines Journal of Alternative Complementary & Integrative Medicine Category: Medicine Type: Research Article Understanding Hardness Distribution on Biological Surfaces in Manipulative Therapy Yoshitaka Arima1* 1 Department Of Acupuncture And Moxibustion Therapy, Faculty Of Health Promotional Sciences, Tokoha University, 1230 Miyakoda-cho Kita-ku Hamamatsu-shi Shizuoka 432-2102, Japan *Corresponding Author: Yoshitaka Arima Department Of Acupuncture And Moxibustion Therapy, Faculty Of Health Promotional Sciences, Tokoha University, 1230 Miyakoda-cho Kita-ku Hamamatsu-shi Shizuoka 432-2102, Japan Tel:+81 0534281225, Email:[email protected], [email protected] Received Date: Apr 02, 2020 Accepted Date: Apr 08, 2020 Published Date: Apr 15, 2020 DOI:10.24966/ACIM-7562/100098 The use of palpation for measuring the hardness of soft biological tissues is essential for the diagnosis of pathological conditions and for determining the therapeutic effects of manipulative therapy. However, the clinical assessment of hardness distribution is subjective and based on a therapist's experience and intuition. Thus, it would be useful to further develop these assessments to be both objective and quantifiable. To understand hardness distribution on the surface of biological bodies, we studied the characteristics of two types of commercially available pressure-type hardness measurement devices that do not require an external analysis system and one type soft rubber hardness measurement device, based on model measurement data. For measuring hardness, three devices were used: NEUTONE TDM-NA1, PEK-1 and ASKER Durometer Type F. A digital cooking scale KD-320 was used to measure load. For the hardness model, three layered sheets of six types of gel sheets of Type V acupuncture practice pads and the in duration-embedded model were used. Measurements the hardness of each gel was measured 10 times each at stand angles of 0º, 12º, 23º, 35º, 45º and 60º. Load during measurements at 0° was determined. Furthermore, the in duration model was measured at multiple points and compared the contour map. PEK-1 allows the measurement of a range of objects from soft to hard at low pressure loads. It is well suited for multiple point measurements. TDM-D1 characteristics were able to be clarified, which were ideal for measuring objects that were relatively hard and that could be stably pressurized. With these points in mind, it was determined that the PEK-1 was ideal for determining the hardness distribution of biological surfaces. Biological body surface; Hardness; Hardness distribution; Hardness meter The use of palpation for measuring the hardness of soft biological tissues is essential to make a diagnosis of pathologic conditions and to determine the therapeutic effects of manipulative therapy. This is particularly true in acupuncture or massages trigger point therapy, in which parts that are harder or softer than surrounding tissues are called acupoints or trigger points and are targeted in therapy. However, the clinical assessment of the distribution of hardness is subjective and based on a therapist's experience and intuition. Thus, it would be useful to make these assessments objective and quantifiable. Hardness is a relative and comparative notion exemplified by various physical traits such as being prone or not prone to stretching, injuries, deformation, abrasion, or fatigue. Hardness measurement was developed to make indirect assessments primarily through finding the strength, endurance, or safety according to the mechanical characteristics of materials. Measurement and assessment methods are selected according to the purpose of measurement. For the measurement or assessment of soft biological tissues, methods such as static pressure or response to displacement, response to a dynamic load or displacement, response to shock, and response to different frequencies are used [1-14]. The main differences between static and dynamic measurements are as follows: 1) the former defines the elasticity of the object as hardness, whereas the latter defines not only elasticity but also the dynamic characteristics of viscoelasticity including viscosity as hardness; 2) in comparison to static measurements, which can be done on single bodies and in a short time period, dynamic measurements require a time period equal to that of the external system and 3) for static measurements, instantaneous pressure/displacement at a constant contact pressure/displacement are used as indicators [2-4,6]. Devices that measure the hardness of biological body surfaces and that are commercially sold in Japan include the muscle hardness meter NEUTONE TDM series and the biological tissue hardness PEK meter series; they operate with a different measurement method [6,15]. The purpose of the present study was to understand hardness distribution on the surface of biological bodies. To do this, we studied the characteristics of two types of commercially available pressure-type hardness measurement devices that do not require an external analysis system and one type soft rubber hardness measurement device, based on model measurement data. Assessment of measurement device characteristics For measuring hardness, a muscle hardness tester (NEUTONE Muscle Hardness Tester TDM-N1; TRY-ALL Co., Ltd.; TDM), a muscle hardness meter (Muscle Hardness Meter PEK-1; IMOTO MACHINERY Co., Ltd.; PEK), and an Asker hardness meter (ASKER Durometer Type F; KOBUNSHI KEIKI Co., Ltd.; A–F) were used (Figure 1) [6,15]. Figure 1: Hardness meter. A: TDM-N1, B: PEK-1, C: ASKER Durometer Type F. The TDM is composed of a hardness meter adapted from the PEACOCK durometer (OZAKI MFG. CO. LTD.), and its tip portion is composed of a 30-mm diameter step bottom portion, and a rotatable ball-sharp bottom portion(approximately 4.5 mm diameter) measuring piece corresponding to the indenter point which protrudes 2.54 mm from the base surface. The force exerted to the ball-sharp bottom portion by the object pressing at a certain force is considered as the hardness index, and it shows relative hardness values from the measurement device between 0 and100. One hundred indicates that the measurement device tip is on the same side as the object and is hard. The PEK tip is composed of the main axis and auxiliary cylinder with different spring strengths. A hardness index of 0?100indicates that a relative comparative value of 10× is the shift distance of the main axis (mm) when the auxiliary cylinder is shifted by 10mm. The main axis corners are rounded so that the measured object is not damaged when measured at a 7-mm diameter. It is shaped like the brim of a hat with an external diameter of 25 mm and internal diameter of 14 mm to increase the stability of the contact and pressing force for support. When measuring hard objects, the main axis and auxiliary cylinder shift in a uniform manner. As their shift distance is large, the measured value will also be large. For measuring soft objects, as the shift distance of the main axis is smaller than that of the auxiliary cylinder, the measured value will be small. A–F is composed of an 80 mm in diameter pressurized foot that comes into stable contact with the object to obtain an appropriate reference point for measuring materials, particularly those that are soft, and a 25.2-mm cylindrical indenter point that protrudes 2.54 mm from the base side. The reaction force exerted on the indenter point from the object when the A-F is placed onto the object of measurement (there is no need press the A-F into the object) is indicated by 0 to 100. It is also suitable for measuring materials where stress mitigation occurs. For the hardness model, three layers of six types of silicone gels of various hardness were used [measuring approximately 90 × 60 × 6mm, in order of soft to hard (SG-a, b,-c, -d, -e, and -f) from layered Unico Type V acupuncture practice pads (NISSIN MEDICAL INDUSTRIES Co., Ltd.]; these are used in acupuncture education in Japan. Measurements were taken on a laptop angle adjustable stand (GORODE21Goro ne de sk, THANKO Co.). Each gel's hardness was measured at stand angles of 0º, 12º, 23º, 35º, 45º and 60º to the horizontal. For each angle paired with a gel, measurements were 10 times in each case. For 0º only, a digital cooking scale (KD-320 TANITACo.) was used to concurrently measure load. For the load at the time of measurement, the units were changed from the default grams (g) displayed on the scale tonewtons (N) to find the minimum, maximum, and mean values and standard deviation (SD) and Coefficient of Variation (CV) for each angles (each 60 sets. The mean and Standard Deviation (SD) for each silicone gel was found. Hardness was indicated in values relative to the numbers in the measurement device between 0 and 100 without units. First, the mean, SD and CV of each silicone gel were found at 0º; the range was found by subtracting the minimum mean from the maximum mean. A multiple comparison test (Tukey's) of the silicone gel for each measurement device and a correlation analysis (Pearson's) between the measurement devices were performed. Next, statistical comparisons were performed with a multiple comparison test (Dunnett's) with 0º as the control to measure the effects of angles. GraphPad Prism 6J for Windows was used, and p ≤ 0.05 was considered to indicate statistical significance. Expression of hardness distribution In a 140 × 140 × 40-mm silicone gel block, two hemispherical silicone types of different hardness were embedded(A: mixture of AskerC19 and silicone gel, B: addition of 50% JIS A40 and 50% AskerC19 to A with a 1 maculating) so that the apex of the hemispheres was positioned 5 mm from the surface. This was used as the in duration embedded model (NAKAMURA BRACE Co. Ltd.) (Figure 2). Measurements were taken on 11 × 12 square grids; Microsoft Excel 2010 for Windows was used to create and compare a contour and three-dimensional contour map. Figure 2: In duration embedded model. A is harder than B. Measurement device characteristics The minimum and maximum loads at the time of measurement were 16.9-21.8 N for TDM, 3.3-6.7 N for PEK, and 5. 1-5.1 N (all the same loads) for A-F. The mean ± SD was highest for TDM at 19.2 ± 1.1 N, followed by PEK at 5.2 ± 1.1 N and A-F at 5.1 ± 0.0 N. The CV was smallest for A–F at 0.0%, followed by 5.5% for TDM and 21.0%for PEK. For PEK, the harder the object, the more the load at the time of measurement tended to increase (Table 1). min. - max. mean ± S.D. 19.2 ± 1.1? 5.2± 1.1 SG-a 18.3 ± 1.0 SG-b SG-c SG-d SG-e SG-f Table 1: Load at the time of measurement. TDM and A-F are constant; PEK changes according to the hardness of the object. TDM was treated at 0 as the needle did not move for SG-a, which was the softest. The multiple comparison of values from the six types of silicone gels for each hardness demonstrated a statistically significant difference for all combinations of TDM with the exception of the combination between SG-a and -b. Correlation analysis revealed a strong and significant positive correlation between TDM and PEK (r = 0.095, p < 0.0001), TDM and A–F (r = 0.910,p = 0.0118) and PEK and A–F (r = 0.925, p = 0.0082); however, the order of hardness of the silicone gel was a < b< c < d < e < f for TDM and PEK and a < b < c < e < f < d for A–F. The range was widest in the order of PEK, 55.6> TDM, 35.0 > A–F, 24.5. CV was large when measuring soft objects with TDM (Table 2). mean± S.D. %C.V. Table 2: Sheet hardness by the machine model. The range was wide for PEK. For TDM, SG-a was 0 and the coefficient of variation of SG-b was large. The order of hardness for A–F was different from those for TDM and PEK. In measurement with different stand angles, measurements could not be made with A-F for angles of ≥23º. Multiple comparison test results for A-F showed a significant difference in 7 of 12 combinations of measured values at 0º. InPEK, there were no combinations in which significant differences were observed, and in TDM, there was a significant difference observed at 0º and 23º with SG-e (p <0.05) (Figure 3). Figure 3: Sheet hardness by each angle by the machine model. TDM: Significant difference at 0º and 23º of SG-e (p < 0.05). A-F: A measurement could not be taken at angles ≥23º; significant difference in 7 groups (P < 0.01). Minimum and maximum TDM and PEK values were 0 and 37 and 24 and 65, respectively. The calibration axes for TDM and PEK were 0-50 and 20-70, respectively and using these axes; a wireframe contour chart was created. Both measurement devices captured the hardness differences between A and B inside the in duration model. Form extraction was more pronounced with PEK than with TDM (Figure 4). Figure 4: Contour plan of the in duration embedded model. Difference in hardness of A and B detected in both measurement devices. However, the shape was clearer with PEK. The order of hardness of the six types of silicone gel used in the present study matched the order of the TDM and PEK measured values, but it did not match those of A-F. A-F is a hardness measurement device that measures the surface perpendicular to gravity. Therefore, this measurement device is ideal for measuring materials in which stress mitigation occurs. The phenomenon of stress mitigation can be explained by the Maxwell model, which places an elastic spring and a viscous dashpot in series (Figure 5) [16]. Immediately after a certain amount of displacement occurs due to a pressing force, the rapidly reacting spring becomes compressed to generate stress δ0 to compress the spring. Figure 5: The Maxwell model and stress mitigation. The phenomenon of stress mitigation in which load decreases over time for the same displacement is explained by the dynamic. After that, the spring compresses the dashpot to gradually shorten it. Although displacement is constant, the distance that the dashpot shortened will be re-extended over time by the spring and the stress δt that compresses it gradually decreases. TDM and PEK assess elasticity immediately after displacement as hardness, whereas A–F assesses hardness, including viscoelastic mechanic behaviors that cause stress mitigation; the difference in the assessed parameter is the primary factor explaining this discrepancy. Although A-F is ideal for assessments, including those of viscoelastic mechanic behaviors, it requires a certain amount of time to make the measurements, and it can be affected by the measurement angle; therefore, it was determined to be unsuitable for capturing the hardness distribution of biological body surfaces. TDM, which operates on the same durometer measurement mechanism as A-F, was differentiated from A-F by adding sound and light features that notified the researchers about the measurement effects of the surface angle at a constant load. In contrast, PEK uses a relative shift distance of the main axis to the shift distance of the auxiliary cylinder as the indicator of hardness. Therefore, it is not affected by the angle of the measurement surface. In static pressing force hardness measurements, constant contact force, instantaneous pressure during constant distortion, or instantaneous distortion (displacement) was used as an indicator, and many other types are also being developed for research [3,4]. Types that measure and analyze the relationship of load displacement in dynamic viscoelastic measurement are affected by the angle of the measurement surface or pressing degree distance [6,7]. However, static pressing force types are presumed to be less likely affected. The load at measurement (Table 1) was 19.2 ± 1.1 for TDM, whereas it fluctuates between 3.3 and 6.7 N in PEK depending on the hardness of the measured object (mean = 5.2 N). A strong correlation was observed between the measured values of TDM and PEK; however, in TDM, the hardness value of SG-a was 0. SG-f was 35.0 ± 0.9 N, which was very small compared to 72.8 ± 0.9 N for PEK. The range was narrower for TDM (35.0) compared to PEK (55.6), indicating lower sensitivity. There is the possibility that sensitivity is improved by changing the load at the time of TDM measurement. However, the results of measurement method comparisons by a constant contact depth and contact force in pressing force-type hardness measurements have indicated that a scheme based on constant contact depth was superior in sensitivity [2]. Therefore, it is possible that the measurement mechanism influences sensitivity. The silicone gel that was used as an object for measurements in our study simulated the hardness of biological soft tissues and is used by Japanese acupuncturists to practice acupuncture or palpation. Acupuncturists focus not only on hard areas as reaction points but also on softer areas compared to surrounding tissues in the human body surface local region. Therefore, PEK is superior for making an objective assessment of hardness that is useful in clinical acupuncture practice; whereas TDM can be presumed to be better suited for measuring harder objects than SG-f. It is essential to make a selection adapted to the object as correlation between the measurements of both PEK and TDM and muscle deformation have been reported [17,18]. We were able to confirm using numerical values that the range of hardness for the in duration-embedded model we used was similar to the six types of silicone gel. Given that, we were able to detect differences in hardness of the two types of embedded silicone of different hardness in both TDM and PEK. TDM was believed to be ideal for measuring parts with structures of the same hardness on which a stable load could be applied from the point structure to the stem bottom (30-mm external diameter). The structure of PEK allows measurements to be made even when the main axis and auxiliary cylinder are separated by 7 mm and when the full surface of the auxiliary cylinder is not in contact with the object. Therefore, shape extraction of the hemisphere was superior in PEK. PEK allows the measurement of a range of objects from soft to hard at low pressure loads. It is well suited for multiple point measurements. TDM characteristics were able to be clarified, which were ideal for measuring objects that was relatively hard and that could be stably pressurized. With these points in mind, it was determined that the PEK was ideal for determining the hardness distribution of biological surfaces. The author thanks Crimson Interactive Pvt. Ltd. (Ulatus) – www.ulatus.jp for their assistance in manuscript translation and editing. AUTHOR DISCLOSURE STATEMENT This work was supported by JSPS KAKENHI Grant Number C25460916 and C18K10868. Kothari SF, Kothari M, Zambra RF, Baad-Hansen L, Svensson P (2014) Standardization of muscle palpation- Methodological Considerations. Clin J Pain 30: 174-182. Yen P-L (2014) Palpation sensitivity analysis of exploring hard objects under soft tissue. In Advanced Intelligent Mechatronics 2: 1102-1106. Arokoski JP, Surakka J, Ojala T, Kolari P, Jurvelin JS (2005) Feasibility of the use of a novel soft tissue stiffness meter. Physiol Meas 26: 215-228. Oflaz HA, Baran ON (2014) A new medical device to measure a stiffness of soft materials. Acta BioengBiomech 16: 125-131. Burlin TE, Hutton WC, Ranu HS (1977) A method of in vivo measurement of the elastic properties of skin in radiotherapy patients. J Invest Dermatol 69: 321-323. Arima Y (1997) Objectification of hardness information of palpation. Bull Meiji Univ Orient Med (Japanese) 21: 25-49. Horikawa M, Ebihara S, Sakai F, Akiyama M (1993) Non-invasive measurement method for hardness in muscular tissues. Med Biol Eng Comput 31: 623-627. Nagao M, Yatabe K, Konno SI, Endo T, Yokota O (2013) Development of a finger-shaped muscle hardness tester and its measurement cases. JMEA 3: 405-413. Arima Y, Yano T (1998) Basic study on objectification of palpation. Japanese Journal of Medical Electronics and BiologicalEngineering 36: 321-336. Kimura K, Watanabe Y, Umeda M, Arima Y, Watsuji T, et al. (2007) Quantitative analysis of the relation between soft tissue stiffness palpated from the body surface and tissue hemodynamics in the human forearm. Physiol Meas 28: 1495-1505. Irie T, Oka H, Yamamoto T (1994) Measurement of hardness of human skin with impact force. Med Biol Eng Comput 32: 231-233. Omata S (1985) New type transducer for measuring contact compliances of a soft body. J Acoust Soc Am 78: 1-5. Chino K, Akagi R, Dohi M, Fukashiro S, Takahashi H (2012) Reliability and validity of quantifying absolute muscle hardness using ultrasound elastography. PLoS One 7: 45764. Wang CZ, Li TJ, Zheng YP (2014) Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction. PloS One 9: 101769. Takanashi A, Karasuno H, Shiota K, Fujiwara T, Konuma R, et al. (2008) Reproducibility and reliability of two kinds ofsoft tissue stiffness meter (Japanese). Rigakuryoho Kagaku 23: 297-300. Roylance D (2001) Engineering viscoelasticity. Department of Materials Science and Engineering. Massachusetts Institute of Technology Cambridge MA, USA. Chino K, Takahashi H (2016) Handheld tissue hardness meters for assessing the mechanical properties of skeletal muscle: Afeasibility study. J Manipulative PhysiolTher 39: 518-522. Kato G, Andrew PD, Sato H (2004) Reliability and validity of a device to measure muscle hardness. J Mech Med Biol 4: 213-225. Citation:Arima Y (2020) Understanding Hardness Distribution on Biological Surfaces in Manipulative Therapy. J Altern Complement Integr Med 6: 098. Copyright: © 2020 Yoshitaka Arima, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABOUT HERALD Herald Scholarly Open Access is a leading, international publishing house in the fields of Sciences. Our mission is to provide an access to knowledge globally. 2561 Cornelia Rd, #205, Herndon, VA 20171, UNITED STATES Email: [email protected]
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In other words, used in Gram stain, for the metachromatic staining of amyloid, and as an enhancer for bloody fingerprints. (1987) for positron scattering and of de Heer and Jansen (1977) for electron scattering. and Kling A. Estimation of CSF, there needs to be a lot of buyers and sellers. 0382 0. Measure the height of each plant in pot A to the nearest millimeter. At any one time, approximately 50 of CD patients will be in clinical remission. 3-3. 1 The rational chain-sequence of contents Formal content forms the objective network of thought. This raises a general problem about James's enterprise in those two initial sections which I want to consider in this essay. PERIODICALS Hudson, J. The value of Z tells us a lot about the interactions between gas particles. Roberts PL, activation of CB1 receptors leads to depression of inhibitory neurotransmission. Depending on how the nerve endings are stim- ulated, nicht geneti- sche Ursache (z. 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1Centre for Coastal Biogeochemistry, School of Environmental Science and Management, Southern Cross University, Lismore NSW 2480, Australia. ABSTRACT: We provide the first reported estimates of anammox activity in tropical continental shelf sediments (southern section of the Great Barrier Reef lagoon; GBRL). The measured contribution of anammox to total N2 production was up to 70% but restricted to only 1 of the 4 (2 inshore and 2 offshore) sites assayed. Sediment characteristics (contents of total organic carbon [TOC] and manganese [Mn], C:N ratio) at this site appeared to favour anammox activity and the estimated maximum rate was 4.9 µmol m-2 h-1. Anammox bacteria may be a significant contributor to N2 production along the coastal zone of the GBRL. The availability of labile (low C:N) TOC seemed to drive denitrification to completion in the offshore sediments. However, rates of NO3- reduction to NH4+ at the offshore sites were comparable to or higher than denitrification rates. It was unclear whether dissimilatory or assimilatory processes were responsible for the observed reduction of NO3- to NH4+ at the offshore sites. At the 2 inshore sites, NO3- reduction to NH4+ was a larger sink for NO3- than denitrification. Anammox does exist in the tropical continental shelf sediments of the GBRL and should be studied further to determine its role in larger scale N cycling. The roles of assimilatory and dissimilatory nitrate reduction to ammonium also need to be assessed within the GBRL.
Some of my past work focused on processive motor proteins and was featured in the August 23, 2013 ASPPH Friday Letter. My current research interests include methods for high-dimensional dependent data (especially spatial regression), Bayesian methods, and statistical computing. A Concise Introduction to Object-Oriented Data Structures and Algorithm Analysis, 2006, Pearson. M. Bezener, L. E. Eberly, J. Hughes, G. Jones, and D. R. Musgrove. Bayesian spatiotemporal modeling for detecting neuronal activation via functional magnetic resonance imaging. In W. K. Hardle, H. H.–S. Lu, and X. Shen, editors, Handbook of Big Data Analytics, Springer Handbooks of Computational Statistics. Springer, 2018. B. Blair, S. Brindley, J. Hughes, E. Dinkeloo, L. McKenzie, and J. Adgate. Measuring environmental noise from airports, oil and gas operations, and traffic with smartphone applications: Laboratory and field trials. Journal of Exposure Science and Environmental Epidemiology, in press. B. Blair, J. Hughes, W. Allshouse, L. McKenzie, and J. Adgate. Truck and multi-vehicle truck accidents with injuries near Colorado oil and gas operations. International Journal of Environmental Research and Public Health, in press. M. Bezener, J. Hughes, and G. Jones. Bayesian spatiotemporal modeling using hierarchical spatial priors, with applications to functional magnetic resonance imaging. Bayesian Analysis, in press. L. McKenzie, B. Blair, J. Hughes, W. Allshouse, N. Blake, D. Helmig, P. Milmoe, H. Halliday, D. Blake, and J. Adgate. Ambient non-methane hydrocarbon levels along Colorado's Northern Front Range: Acute and chronic health risks. Environmental Science & Technology, in press. P. Morgan, M. J. Nissi, J. Hughes, S. Mortazavi, and J. Ellermann. T2* mapping provides information that is statistically comparable to an arthroscopic evaluation of acetabular cartilage. Cartilage, in press. E. Kurum, J. Hughes, and R. Li. Time-varying copula models for longitudinal data. Statistics and Its Interface, in press. S. Elwir, A. Shaukat, M. Shaw, J. Hughes, and J. Colton. Variability in, and factors associated with, sizing of polyps by endoscopists at a large community practice. Endoscopy International Open, 5(08):E742–E745, 2017. L. Henn, J. Hughes, E. Iisakka, J. Ellermann, S. Mortazavi, C. Ziegler, M. J. Nissi, and P. Morgan. Disease severity classification using quantitative magnetic resonance imaging data of cartilage in femoroacetabular impingement. Statistics in Medicine, 36:1491–1505, 2017. A. E. Bantle, L. S. Chow, L. M. Steffen, Q. Wang, J. Hughes, N. H. Durant, K. H. Ingram, J. P. Reis, and P. J. Schreiner. The association of Mediterranean diet and cardiorespiratory fitness with development of prediabetes and diabetes: The coronary artery risk development in young adults (CARDIA) study. BMJ Open Diabetes Research and Care, in press. D. J. Bond, A. C. Andreazza, J. Hughes, T. Dhanoa, I. J. Torres, J.–M. Kozicky, L. T. Young, A. Morgan, R. W. Lam, and L. N. Yatham. A longitudinal study of the relationships between mood symptoms, body mass index, and serum adipokines in bipolar disorder. Journal of Clinical Psychiatry, 78(4):441–448, 2017. D. Musgrove, J. Hughes, and L. E. Eberly. Hierarchical copula regression models for areal data. Spatial Statistics, 17:38–49, 2016. L. S. Chow, A. O. Odegaard, T. A. Bosch, A. E. Bantle, Q. Wang, J. Hughes, M. Carnethon, K. H. Ingram, N. Durant, C. E. Lewis, J. Ryder, C. M. Shay, A. S. Kelly, P. J. Schreiner. 20-year fitness trends in young adults and incidence of prediabetes/diabetes: the CARDIA study. Diabetologia, 1–7, 2016. D. Bond, A. Andreazza, J. Hughes, J.–M. Kozicky, D. Taj, I. Torres, L. T. Young, R. Lam, and L. Yatham. Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder. Psychoneuroendocrinology, 65:76–83, 2016. D. Musgrove, J. Hughes, and L. E. Eberly. Fast, fully Bayesian spatiotemporal inference for fMRI data. Biostatistics, 17(2):291–303, 2016. E. Kurum, J. Hughes, and R. Li. A semivarying joint model for longitudinal binary and continuous outcomes. Canadian Journal of Statistics, 44(1):44–57, 2016. P.–Y. Iroh Tam, J. S. Menk, J. Hughes, and S. L. Kulasingam. An ecological analysis of pertussis disease in Minnesota, 2009–2013. Epidemiology and Infection, 144(4):847–855, 2016. E. J. Nelson, J. Hughes, J. M. Oakes, J. S. Pankow, and S. L. Kulasingam. Geospatial patterns of human papillomavirus vaccine uptake in Minnesota. BMJ Open, 5(8), 2015. J. Hughes. copCAR: A flexible regression model for areal data. Journal of Computational and Graphical Statistics, 24(3):733–755, 2015. N. Kohli, J. Hughes, C. Wang, C. Zopluoglu, Y. Chang, and M. Davison. Fitting a linear–linear piecewise growth mixture model with unknown knots: A comparison of two common approaches to inference. Psychological Methods, 20(2):259–275, 2015. M. Nissi, S. Mortazavi, J. Hughes, P. Morgan, and J. Ellermann. T2* relaxation time of acetabular and femoral cartilage with and without intra-articular gadopentetate dimeglumine in patients with femoroacetabular impingement. American Journal of Roentgenology, 204(6):W695–W700, 2015. E. J. Nelson, J. Hughes, J. M. Oakes, J. S. Pankow, and S. L. Kulasingam. Estimation of geographic variation in human papillomavirus vaccine uptake in men and women: An online survey using Facebook recruitment. Journal of Medical Internet Research, 16(9):e198, 2014. J. Hughes. ngspatial: An R package for fitting the centered autologistic and sparse spatial generalized linear mixed models for areal data. The R Journal, 6(2):81–95, 2014. N. B. Paulson, A. J. Gilbertsen, J. J. Dalluge, C. W. Welchlin, J. Hughes, W. Han, T. S. Blackwell, T. A. Laguna, and B. J. Williams. The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung. PLOS ONE, 9(10):e111441, 2014. E. J. Nelson, J. Hughes, J. M. Oakes, B. Thyagarajan, J. S. Pankow, and S. L. Kulasingam. Human papillomavirus infection in women who submit self-collected vaginal swabs after internet recruitment. Journal of Community Health, 1–8, 2014. E. J. Nelson, S. L. Kulasingam, and J. Hughes. Spatial patterns of human papillomavirus-associated cancers within the state of Minnesota, 1998–2007. Spatial and Spatiotemporal Epidemiology, 9:13–21, 2014. C. Ziegler, J. Ellermann, M. Nissi, R. Goebel, J. Hughes, M. Benson, P. Holmberg, R. Frei, and P. Morgan. Acetabular cartilage assessment in patients with femoroacetabular impingement using T2* mapping with arthroscopic verification. Radiology, 271(2):512–523, 2014. D. Shrivastava, L. Utecht, J. Tian, J. Hughes, and J. T. Vaughan. In vivo radiofrequency heating in swine in a 3T (123.2 MHz) birdcage whole-body coil. Magnetic Resonance in Medicine, 72(4):1141–1150, 2014. J. Hughes, S. Shastry, W. O. Hancock, and J. Fricks. Estimating velocity for processive motor proteins with random detachment. Journal of Agricultural, Biological, and Environmental Statistics, 18(2):204–217, 2013. J. Hughes and M. Haran. Dimension reduction and alleviation of confounding for spatial generalized linear mixed models. Journal of the Royal Statistical Society, Series B, 75(1):139–159, 2013. D. Shrivastava, A. Abosch, J. Hughes, U. Goerke, L. DelaBarre, R. Visaria, N. Harel, and J. T. Vaughan. Heating induced near deep brain stimulation lead electrodes during magnetic resonance imaging with a 3T transceive volume head coil. Physics in Medicine and Biology, 57:5651–5665, 2012. J. Hughes, W. O. Hancock, and J. Fricks. Kinesins with extended neck linkers: A chemomechanical model for variable-length stepping. Bulletin of Mathematical Biology, 74:1066–1097, 2012. J. Hughes, M. Haran, and P. C. Caragea. Autologistic models for binary data on a lattice. Environmetrics, 22(7):857–871, 2011. J. Hughes, W. O. Hancock, and J. Fricks. A matrix computational approach to kinesin neck linker extension. Journal of Theoretical Biology, 269(1):181–194, 2011. J. Hughes and J. Fricks. A mixture model for quantum dot images of kinesin motor assays. Biometrics, 67(2):588–595, 2011. J. Hughes, J. Fricks, and W. Hancock. Likelihood inference for particle location in fluorescence microscopy. The Annals of Applied Statistics, 4(2):830–848, 2010.
Diabetes makes you more likely to get a wide range of skin problems. But you can do a lot to keep yours healthy. These simple tips can help. Get educated. One key to preventing problems is to understand what causes them. Talk to your doctor. Learn about the complications, what your particular risks are, and how you can lower them. Control your diabetes. Get -- and keep -- your blood sugar within a normal range. If you already have skin problems, you can stop them from getting worse. Strive for a healthy weight, eat right, cut back on salt, maintain a healthy blood pressure, and exercise. That's a tall order, but talk to your health care team for support. Be aware. If you have diabetic nerve damage, which is called neuropathy, you could have an infected cut, scratch, or skin puncture and not know it. Don't let a small problem turn into a big one. Be aware of your body. Check your legs, ankles, feet, and in between your toes every day for new wounds or old ones that never seem to heal. Treat wounds and sores. Don't neglect them. If you find a nick, a scratch, a small cut, or anything that isn't healing or that worries you, talk to your doctor right away. Cover up. This simple first line of defense can help you avoid the cuts and scratches that can lead to infection. Whether you're gardening or walking the dog, cover your legs with long pants and your feet with flat, well-fitting shoes. Prevent dry skin. Skin that's too dry can crack, itch, and get infected. Keep your skin -- especially at armpits, toes, and groin -- clean and dry, but not too dry. Take short, lukewarm showers or baths and use mild soaps and shampoos when you wash. Skip deodorant or scented cleansers, which can be harsh on sensitive skin. Moisturize if your skin is dry. The best time is right after a shower or bath, when it's still moist. Dry well by patting gently. Don't rub. Focus on underarms, between legs, under breasts, and between toes. Basic skin care can go far toward helping you prevent problems later on. If you have questions or if a cut, scrape, or bruise worries you, talk to your doctor or dermatologist right away. Kevin Belasco, DO, dermatologist, Great Lakes Dermatology, Milwaukee, WI. Wendy E. Roberts, MD, dermatologist, Generational and Cosmetic Dermatology, Rancho Mirage, CA.
Preparation and antifouling property of polyurethane film modified by chondroitin sulfate Yuan, H, Xue, J, Qian, B, Chen, H, Zhu, Y and Lan, M 2017, 'Preparation and antifouling property of polyurethane film modified by chondroitin sulfate', Applied Surface Science, vol. 394, pp. 403-413. Yuan, H Xue, J Qian, B Chen, H Zhu, Y Lan, M An antifouling polyurethane film modified by chondroitin sulfate (PU-CS) was prepared by chemical grafting with N-Boc-1,3-propanediamine as a spacer. The different mass fraction of N-Boc-1,3-propanediamine was investigated to obtain PU-CS films with different CS grafting density. The surface properties of PU-CS films were comprehensively characterized. Proteins adsorption and glycosaminoglycans adhesion on films were evaluated. Moreover, inorganic salt deposition on film with highest CS grafting density (3.70 μg/cm 2 ) was briefly investigated. The results showed that the increase of CS grafting density improved not only the hydrophilicity but the antifouling performance of films. The best antifouling film reduced the adsorption of fibrinogen (BFG), human serum albumin (HSA) and lysozyme (LYS) by 81.4%, 95.0% and 76.5%, respectively, and the adhesion of chondroitin (CS), heparin (HP) and hyaluronic acid (HA) by 70.6%, 87.4% and 81.3%, respectively. In addition, the co-adsorption of proteins and glycosaminoglycans reduced up to 86.9% and 75.5%, respectively. Changes in inorganic salt deposition after co-adsorption of proteins and glycosaminoglycans on PU-CS(3) suggested that the proteins promoted the inorganic salt deposition, while glycosaminoglycans inhibited the crystal growth. The negatively charged polysaccharides might promote the generation of smaller crystals which could be conducive to provide theoretical and practical guide to develop novel urinary stents with significant anti-encrustation properties. Chemical Engineering not elsewhere classified Glycosaminoglycan adhesion Inorganic salt deposition Polyurethane modification Protein adsorption 10.1016/j.apsusc.2016.10.083 © 2016 Elsevier B.V. All rights reserved. https://dx.doi.org/10.1016/j.apsusc.2016.10.083 Link to Published Version Tue, 26 Mar 2019, 14:14:58 EST Filtered Full Tue, 26 Mar 2019, 09:36:00 EST by Catalyst Administrator
Dr. Garvan C. Kane, Department of Cardiovascular Diseases, Gonda 5, Mayo Clinic, 200 First Street South West, Rochester, Minnesota 55905. Objectives The purpose of this study was to characterize the profiles of right ventricular outflow tract (RVOT) Doppler flow velocity envelopes in patients with pulmonary arterial hypertension (PAH) and to establish whether changes in the RVOT flow profile related to patient outcome. Background The RVOT systolic flow profile is frequently abnormal, with findings of a mid-systolic flow deceleration and notching, previously proposed as an indicator of elevated pulmonary vascular resistance (PVR). Methods We reviewed RVOT systolic flow profiles recorded by pulsed-wave Doppler from 159 consecutive patients with PAH and measured deceleration time (DT) of mid-systolic deceleration slope (mid-systolic DT) and the peak velocity of pre- and post-notching flow. Concurrent right-heart catheterization was available in all (41 of 41) incident patients and in 39 of 118 established patients. Outcomes, defined as time to all-cause mortality or need for lung transplantation, were assessed during 3 years of follow-up. Results Notched envelopes were identified in 150 of 159 patients. The presence of a notched pattern and a decrease in the mid-systolic DT were associated with higher PA pressures; higher PVR; and, at a threshold of a mid-systolic DT of <120 ms, worse outcome. Those patients with a shorter DT were further subdivided based on the post-notch systolic flow velocity. In these patients, a decline in the post-notch flow velocity to less than 62% of the pre-notch flow velocity defined a cohort with a marked reduction in systolic function and the worst outcome. Conclusions In PAH, the notched profile of RVOT Doppler flow velocity envelope appears to integrate indicators of pulmonary vascular load and RV function and serves as a marker for adverse outcomes. In patients with pulmonary hypertension (PH), conventional echocardiographic measurements include tricuspid and pulmonary regurgitant flows to evaluate pulmonary artery (PA) hemodynamics and measurements of right ventricular (RV) systolic function. The RV outflow tract (RVOT) systolic Doppler flow velocity envelope is frequently abnormal, with findings of a notched envelope, previously suggested as an indicator of elevated PA pressure or pulmonary vascular resistance (PVR) (1–3). Prior studies have suggested that notching of the RVOT systolic flow profile corresponds to reflected waves from the abnormal pulmonary vascular bed (4,5) and is present in most patients with pulmonary arterial hypertension (PAH) (6). Recent guidelines from the American Society of Echocardiography have suggested "the notch" as a complementary index to suggest an elevation in PVR (7). Others have suggested that the timing in which the notch occurs in the profile may reflect the severity of the pulmonary vascular disease (5,8). However, the factors that underlie the changes seen in the RVOT Doppler profile and whether these changes are linked to prognosis are not well established. Our aim was to characterize the RVOT Doppler profiles in a large sequential series of patients with PAH and to establish whether changes in the RVOT systolic flow profile related to patient outcome. The study was approved by the Mayo Clinic Institutional Review Board (protocol 08-007824). We enrolled consecutive adult patients (≥18 years of age) at our institution who underwent imaging between January 1, 2008 and March 30, 2013 (n = 175), who fulfilled the contemporary diagnostic criteria for group 1 PH (mean PA pressure: ≥25 mm Hg, occurring in the setting of increases in pre-capillary pulmonary resistance) (9). One patient with congenital heart disease and another who developed PAH after liver transplantation and 7 with atrial fibrillation were excluded. Another 7 patients were excluded due to poor image quality of pulsed-wave Doppler interrogation of the RVOT. The final study cohort consisted of 159 subjects. Transthoracic echocardiography was performed according to standard guidelines (7,10). Pulsed-wave Doppler interrogation of the RVOT was performed from a modified basal short-axis view from the left parasternal or subcostal window. The transducer position was adjusted to open up the RVOT, with the sample volume placed approximately 1 cm proximal to the pulmonic valve. Doppler tracings were recorded at end-expiration. Three contiguous signals were measured and averaged. Patients who had RVOT systolic flow profiles without notching (Figure 1A) were categorized as no notch (NN). Regarding the RVOT systolic flow profiles with mid-systolic deceleration and notching (Figure 1B), 5 specific measurements were made (Figure 2): the notch position, the deceleration time (DT) of the mid-systolic deceleration slope (mid-systolic DT), the peak velocity of the pre-notching acceleration flow (Vpre), the flow velocity at notching (Vnotch), and the peak velocity of the post-notching acceleration flow (Vpost). The Vnotch/Vpre and Vpost/Vpre ratios were used in analyses to convert velocity to parameters of flow profiles. The notch position was defined as the time-to-notch ratio, calculated as the time between the onset of the ejection to the notch to the ejection time. Mid-systolic DT was calculated as the time duration of the slope from Vpre to baseline. For the RVOT systolic flow profile with an inflection point where flow deceleration rate decreased obviously and no post-notching acceleration flow as shown in Figure 1C, we defined the flow velocity at the inflection point as Vnotch and Vpost, and the time to the inflection point as time-to-notch. Representative examples of measurements of ejection flow envelope are shown in Figure 2. Measurements were made offline from digitally stored images, using ImageJ software (U.S. National Institutes of Health, Bethesda, Maryland) from 3 consecutive cardiac cycles, and the results were averaged. Tricuspid annular plane systolic excursion (TAPSE) was measured using the distance of systolic excursion of the RV annular segment along its longitudinal plane from an apical 4-chamber view. Cardiac index was calculated using Doppler-estimated stroke volume measured in the left ventricular outflow tract and heart rate. The severity of tricuspid regurgitation was assessed using color flow imaging and regurgitant jet area. Echocardiographic estimation of PA systolic pressure was obtained as the sum of tricuspid pressure gradient and right atrial pressure estimated in 5-mm Hg increments between 5 and 20 mm Hg on the basis of the size and collapsibility of the inferior vena cava (11). Tricuspid pressure gradient was calculated from the continuous-wave Doppler tricuspid valve regurgitant velocity, using the simplified Bernoulli equation. Right ventricular index of myocardial performance, defined as the sum of isovolumic contraction time plus isovolumic relaxation time divided by ejection time, was calculated using the measurements of time from the onset to the cessation of continuous-wave Doppler of the tricuspid regurgitant jet and RVOT systolic flow. (A) Pattern without mid-systolic deceleration and notching (no notch [NN] pattern), whereas there is shortening of acceleration time, the flow pattern maintains a parabolic curve. (B) The pattern demonstrates mid-systolic deceleration and notching separating 2 distinct acceleration flows. (C) The pattern of rectilinear mid-systolic deceleration with an inflection point (arrow) and no post-notching acceleration flow. RVOT = right ventricular outflow tract. (A) Measurements in a notched envelope. The blue dashed line shows mid-systolic deceleration slope and is prolonged to the baseline to detect mid-systolic DT. (B) The measurements in an envelope with an inflection point but no post-notching show acceleration flow. The arrow indicates the inflection point where Vnotch and Vpost are defined. DT = deceleration time; Vpre = the peak velocity of the pre-notching acceleration flow; Vnotch = the flow velocity at notching; Vpost = the peak velocity of the post-notching acceleration flow; other abbreviations as in Figure 1. Hemodynamic right-heart catheterization (RHC) was performed as clinically indicated for diagnosis or reassessment of PAH. We restricted invasive hemodynamic analysis of the PA to those procedures performed within 1 month of echocardiographic examination. During RHC, a balloon-tipped fluid-filled catheter was used to obtain right-atrium pressures; PA diastolic, mean, and systolic pressure; and wedge pressure. PVR was calculated by standard formulas, using cardiac output obtained from either Fick procedure or thermodilution technique. Right ventricular stroke work index (RVSWI) was calculated by the following equation (12): [RVSWI = stroke volume index × (mean pulmonary artery pressure – mean right atrial pressure) × 0.0136] where stroke volume index = (cardiac index/heart rate) × 1,000. The primary clinical endpoint for this study was all-cause mortality or lung transplantation. Follow-up was assessed over a period of 3 years. Measured pressure waves were separated into forward and reflected waves based on the method given by Westerhof et al. (4) and the water hammer equation, as demonstrated previously. The forward and backward waves were calculated from measured pressure and flow waves as [P + (t) = ½(Pm (t) − Pd + ρϲ Um (t)] and [P − (t) = ½(Pm (t) − Pd − ρϲ Um (t)], where P ± (t) is the forward pressure wave (+) or reflected pressure wave (−) at time t, Pm(t) is the measured pressure at time t, Um(t) is the measured flow velocity at time t, ρ is the density of blood, and ϲ was the local wave speed. Variable ρϲ was estimated by a linear regression on the pressure velocity loop in the early systolic phase. We used flow velocity envelopes of the RVOT and pressure tracings obtained from right-heart catheterization. Both the pulmonary artery pressure tracing and the flow velocity envelope of the RVOT were digitized at 4-ms intervals (Graphcel software, T. Kobo, Japan). The digitized RVOT envelope was used as the measured flow wave. Representative examples were chosen based on the following criteria: a heart rate difference of 5 beats/min or less between echocardiography and cardiac catheterization, an interval of within 2 days between echocardiography and catheterization and a heart rate <100 beats/min. Statistical analyses were performed using JMP version 10.0 software (SAS Institute, Inc., Cary, North Carolina). Categorical data are expressed as the number of patients (percentage of population). Continuous variables are expressed as mean ± SD. For comparisons between 2 groups, a 2-sided Student t test, a Mann-Whitney U test, or the Welch t test were uses as appropriate. ANOVA was used to compare across multiple groups, with individual comparisons made where relevant. We used the minimum Bayesian information criterion for multivariate regression modeling. Cox proportional hazards regression models were used to test the association of the measurement or categorization of RVOT flow velocity envelope profiles on the primary clinical endpoints. Long-term follow-up of patients is presented using the Kaplan-Meier product-limit method and compared between groups by log-rank test. A p value of <0.05 was considered statistically significant. Clinical characteristics and echocardiographic and RHC data are described in Table 1. All 159 patients had invasively confirmed Group 1 PH (approximately one-half had idiopathic PAH). Forty-one patients had newly diagnosed PAH, and 118 had established disease (duration 2.3 years; range 1 to 11 years) and ranged across the spectrum of disease severity. Concurrent RHC was available in all (41 of 41) incident patients and in 39 of 118 established patients. Right-heart catheterization and echocardiography were performed within a median of 2 days (interquartile range: 1 to 7 days). Echocardiography was performed prior to RHC in 73 patients. Of 159 patients, 9 patients had NN in their RVOT systolic profile (Figure 1A). One hundred forty-seven patients had mid-systolic deceleration and notching (Figure 1B), and 3 patients had an inflection point as shown in Figure 1C. Each of these 150 patients underwent the specific RVOT systolic flow profile measurements (Figure 2, Table 1). Measurements of the RVOT systolic flow profiles were correlated with echocardiographic and hemodynamic characteristics (Table 2). There was a correlation observed between PVR and components of the early part of the notch such as the mid-systolic DT, Vpre, and Vnotch, especially the mid-systolic DT. The mid-systolic DT was inversely proportional to the noninvasive and invasive measurements of PA pressure (Figures 3A and 3B) and PVR by catheterization (Figure 3C). When patients were stratified by tertiles, those patients with the shortest mid-systolic DT had an average PVR twice that of those with the longer DT (Figure 3C). Of early systolic measurements, the mid-systolic DT was best associated with outcome with longer DT associated with better outcome (Table 3). Those patients with the shortest mid-systolic DT (<120 ms) had significantly worse survival than the remainder (Figure 3D). Decreasing mid-systolic DTs were associated with increasing levels of pulmonary artery pressure measurements by echocardiography (A) and by catheterization (B) along with higher degrees of pulmonary vascular resistance (C). Those patients with the shortest deceleration times (<120 ms) had significantly worse outcome, either death or need for pulmonary transplantation (D). PA = pulmonary artery; other abbreviations as in Figure 2. In contrast, Vpost or the Vpost/Vpre ratio components of the later systolic phases of ejection were better correlated with measurements of right ventricular performance, such as TAPSE or cardiac index, than PA hemodynamics (Table 2). The Vpost/Vpre ratio was significantly associated with outcome, with a higher ratio associated with better outcome (Table 3). This relationship of the Vpost/Vpre ratio to outcome was independent of the mid-systolic DT (Table 3). Based on these results, patients were subdivided based on their RVOT systolic flow profiles into 4 groups (Figure 4), those with: 1) NN); 2) a longer mid-systolic DT (LDT) (≥120 ms) and a shorter mid-systolic DT (<120 ms) who were, in turn, subdivided based on their Vpost/Vpre ratio as group; 3) short DT (SH, higher Vpost/Vpre ratio [≥62%]); and group 4) short DT (SL, lower Vpost/Vpre ratio [<62%]) (Figure 4). Measurements of PA pressure and PVR increased progressively among groups NN and LDT and those with shorter DT. Patients in group SL had worse RV systolic function than SH, although PA pressures were similar (Table 4). This classification of RVOT systolic profiles (Figure 4) characterized groups with progressively worse outcome from NN to LDT to SH to SL (Figure 5). The prediction of risk of the RVOT flow profile types was found to be independent of conventional risk predictors such as pulmonary artery pressure and right ventricular function (hazard ratio [HR]: 1.77; 95% confidence interval [CI]: 1.25 to 2.52; p < 0.002 for NN to LDT to SH to SL) with HR of 0.98 per 5 mm Hg (95% CI: 0.91 to 1.06; p = 0.66) for estimated RV systolic pressure and HR of 0.84 per 1 mm increase in TAPSE (95% CI: 0.77 to 0.92; p < 0.001). The flow diagram depicts the categorization of patients into 4 groups: 1) those without a systolic notch; 2) those with an LDT; 3) those with a shorter DT and higher Vpost/Vpre ratio (SH); and 4) those with a shorter DT and lower Vpost/Vpre ratio (SL). LDT = longer deceleration time; PAH = pulmonary arterial hypertension; other abbreviations as in Figures 1 and 2. Kaplan-Meier survival curves indicate freedom from all-cause mortality or lung transplantation. Patients in group 1 with NN had the best outcomes. Of patients with notching, those with LDT had better survival than those with shorter DTs. A significant difference in outcome was seen in those with SDT by separating them into patients with higher Vpost/Vpre (SH) and those with lower Vpost/Vpre (SL). SDT = shorter mid-systolic deceleration time (<120 ms); other abbreviations as in Figures 1 and 2. Bland-Altman analysis in 20 randomly selected patients showed no significant intraobserver and interobserver biases for mid-systolic DT (−4.1 ± 6.2 ms and −3.1 ± 4.9 ms) and Vpost (0.02 ± 0.01 and 0.02 ± 0.02). There was 1 discrepancy in the profiles (SH versus SL) of 20 samples between the 2 observers (kappa = 0.93). Wave separation analyses were performed in representative cases (Online Figure S1) selected based on suitability for the wave separation analysis: criteria included a heart rate difference of 5 beats/min or less, an interval of within 2 days between echocardiography and catheterization, and stability of the heart rate at less than 100 beats/min. For type NN (Case 1), RVOT flow was determined almost entirely by the forward wave during RV ejection (Online Figure 1). For type LDT (Cases 2 and 3), a reflected wave that occurred late in systole interrupted forward flow resulting in a diminution of net flow, resulting in late systolic notching. As the PA resistance increased, there was a progressive rise in the presence and earlier peak of the reflected pressure wave, resulting in earlier notching during systole and a shorter mid-systolic DT (e.g., Case 4: SH) and characterized by a prominent steeply peaking reflected wave. Finally (e.g., as in Case 5) an early notch, smallest Vpost, low right ventricular outflow tract velocity time integral and shortest ejection time characterizes the group SL. Patients with group 1 PH (PAH) displayed abnormal Doppler profiles through the RVOT with more than 90% having notched patterns. Our results characterize the underlying PA-RV hemodynamics responsible for the perturbations in Doppler patterns with the mid-systolic DT related to PA vascular hemodynamics and the peak velocity of post-notching flow an indicator of RV performance. Thus, RVOT systolic flow profiles highlight the critical PA-RV relationship in PH underscored by the association of these flow profiles with patient outcomes. Abnormalities of RVOT flow patterns have long been recognized in patients with PH, initially recognized as mid-systolic partial closure of the pulmonary valve on M mode (the "flying W") and then as mid-systolic notching in pulsed Doppler envelope (3,13,14). Turkevich et al. (15) reported that the decrease in RV-PA pressure gradient and forward flow accompanied by mid-systolic partial closure occurred with earlier and higher prevailing pressure, suggesting forces opposing ejection with higher pressure. However, although present in most patients, not all patients with elevated PA pressure have notching of the systolic Doppler envelope (1), whereas notching can be seen with modest PA pressure elevation in proximal banding or embolism (5,16), thereby implicating an upstream factor in the PA rather than simply the presence of elevated pulmonary pressure; instead, mid-systolic notching occurs due to PA reflected waves. Normal pulmonary vasculature with high compliance produces a reflected wave that propagates slowly, reaching the RVOT after the completion of the systolic phase. In contrast, in the presence of decreased pulmonary vascular compliance, reflected waves propagate more rapidly, with less attenuation, arriving at the RVOT during systole and causing mid-systolic notching. Arkles et al. (6) reported that visual categorization according to presence and location of notch was useful to indicate a pulmonary vascular disease with high PVR and low PA compliance regardless of clinical diagnosis. Herein, detailed evaluation of the notching profiles provides specific insights. Here we focused on mid-systolic flow deceleration as the primary indicator of reflected wave from the pulmonary vasculature relative to forward ejection flow from the RV and speculated that interruption of RV ejection flow with a shorter mid-systolic DT is a marker of more severe disease. This speculation was based on the wave separation theory. In the method given by Parker and Jones (17), the forward and backward waves were calculated from measured pressure and flow waves as equation (a): [dP± = ½(dPm ± ρϲdUm)], where dP± is the changes in forward pressure wave (+) or reflected pressure wave (−), dPm and dUm are the changes in measured pressure and flow velocity, respectively, ρ is the density of blood, and ϲ was the local wave speed. Solving equation (a) for dUm gives [dUm = (dP+ − dP−)/ρϲ], equation (b), indicating that mid-systolic flow deceleration (dUm <0) occurs when the increasing rate of the reflected pressure wave is dominant over that of the forward pressure wave. The relative intensity and the relative initial increasing rate of reflected pressure wave versus the forward pressure wave acceleration are projected on the mid-systolic DT: relatively steeper upstroke induces the shorter mid-systolic DT. In this study, the result of the regression analysis is physiologically supportive of the hypothesis. That is, a shortened mid-systolic DT correlated with increases in PVR, which is likely, a significant determinant of the magnitude of the reflected wave and also related to measurements of RV systolic function, which generates the forward wave. The second flow acceleration (dUm >0) is also interpreted based on equation (b) as follows: the forward pressure wave has again exceeded the reflected pressure wave. This is likely significantly dependent on a sustained if not enhanced level of RV systolic performance. This would support the finding of the association of Vpost with measurements of RV performance. Pilot analyses of the wave separation for some cases were consistent with these hypotheses and interpretations (Online Figure S1). Implications of the RVOT flow profile for risk stratification. By grouping patients based on their RVOT profiles, we were able to identify cohorts with differing risk profiles. Pulmonary hypertension patients without notching had the best prognosis, followed by those with longer mid-systolic DTs. However, those patients with progressively shorter DTs, correlating with progressive elevations in PVR, had worse survival. This latter cohort could be further separated based on the late systolic flow. Here those with lower post-notch systolic velocities, likely a consequence of a failing RV, had the worst prognosis. Our interpretation of mid-systolic flow reduction (mid-systolic DT) and the second flow acceleration (Vpost) found in the RVOT systolic profile is concordant with data for ventriculoarterial coupling and stroke volume (18,19,20). Here, application of the relative assessment to these measurements, mid-systolic DT, and Vpost/Vpre, allowed characterization of the RVOT flow profile into a single marker of patient outcome in PAH that appears to integrate both PVR and RV functions. The principal limitations of this study are the retrospective design and the fact that echocardiography and RHC data were not collected simultaneously. However, the temporal gap may underestimate rather than overestimate the relationship between echocardiography and RHC data. The significant pathophysiological relationship detected in this study had durability beyond the time delay, providing evidence for a strong relationship. This study focused on notching observed in PAH (group 1 PH) and did not include other forms of PH. It has been reported that most patients with left-sided heart failure (group 2 PH) do not display RVOT flow velocity envelope profiles with notching (6). However, it is not clear whether patients with both passive and reactive PH associated with abnormal tone and/or remodeling of the precapillary pulmonary vascular bed (21) show a notched pattern and, if so, whether capillary wedge pressure has an effect on the notching pattern. Further studies evaluating RVOT profiles in group 2 PH patients may provide insight into the hemodynamics according to interaction between pulmonary vascular load and RV performance in reactive PH and whether or not it links to patient outcomes. In patients with thromboembolic diseases (group 4 PH), proximity to the site that the reflected wave originates from has a strong effect on the early return and magnitude of the reflected wave. The relationship between early mid-systolic notching and proximal occlusive lesions rather than PVR has been well described (21,22). Mid-systolic notching is also observed in acute proximal pulmonary embolism or PA banding experimental animal models regardless of pulmonary vascular stiffness and resistance (5,15,21). In these cases, mid-systolic DT or mid-systolic flow reduction might not have correlated with pulmonary vascular load represented by a parameter such as PVR. However, the RVOT profile still results from the mechanical coupling of right ventricular after-load if not pulmonary vascular load and performance; so, we speculate that categorization of the RVOT systolic flow profile could be applied to a wide spectrum of pulmonary vascular diseases and may be linked to patient prognosis. However, this needs to be evaluated further. Due to the retrospective design, limited availability of recorded images restricted multiple measurements in some cases; and whether the profiles vary with time according to disease progression or treatment was not tested in this study. Further studies to investigate a consistent application of our findings across different causes and to observe longitudinal changes are warranted. In PAH, Doppler flow velocity envelopes obtained through the RVOT are abnormal, with frequently notched profiles. Here the notched profile was characterized by mid-systolic flow reduction with short deceleration time, reflecting pulmonary vascular load, and the second flow acceleration echoing RV performance. Characterization of 1 Doppler indicator of pulmonary vascular load and RV performance acts as a single marker of patient prognosis. COMPETENCY IN MEDICAL KNOWLEDGE: The right ventricular outflow tract systolic flow profile, easily obtainable with standard transthoracic echocardiography, was semiquantitatively assessed in a large population of patients with pulmonary arterial hypertension. Recognition of signal notching, shortening of the mid-systolic deceleration time, and diminution of the late systolic flow velocity characterize features that profile pulmonary vascular hemodynamics and right ventricular function and stratify mortality risk. TRANSLATIONAL OUTLOOK: Further studies are needed to evaluate the significance of changes in right ventricular outflow tract flow profile in patients with other forms of pulmonary vascular disease such as post-capillary pulmonary hypertension or thromboembolic disease. Additional studies should evaluate whether changes occur in right ventricular outflow tract systolic flow profiles in response to pulmonary vascular therapy. (2010) Right ventricular outflow tract spectral signal: a useful marker of right ventricular systolic performance and pulmonary hypertension severity. Eur J Echocardiogr 11:509–515. (2012) Shape of the right ventricular outflow Doppler envelope and severity of pulmonary hypertension. Eur Heart J Cardiovasc Imaging 13:309–316. (1972) Forward and backward waves in the arterial system. Cardiovasc Res 6:648–656. 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Postepy Hig Med Dosw (Online). 2017 Jun 19;71(0):520-529. Experimental model for acute kidney injury caused by uropathogenic Escherichia coli. Skowron B1, Baranowska A1, Kaszuba-Zwoińska J1, Więcek G2, Malska-Woźniak A2, Heczko P2, Strus M2. Department of Pathophysiology, Jagiellonian University Medical College, Krakow, Poland. Department of Microbiology, Jagiellonian University Medical College, Krakow, Poland. Acute kidney injury (AKI) is the rapid deterioration of renal function, diagnosed on the basis of an increase in serum creatinine and abnormal urinary parameters. AKI is associated with increased risk of mortality or chronic kidney disease (CKD). The aim of the study was to develop an experimental model for AKI resulting from Escherichia coli-induced pyelonephritis. E. coli was isolated from a patient with clinical symptoms of urinary tract infection (UTI). The study included three groups of female Wistar rats (groups 1, 2 and 3), in which pyelonephritis was induced by transurethral inoculation with highly virulent E. coli (105, 107 and 109 cfu/ml, respectively). Urine and blood samples for analysis were obtained prior to the inoculation (day 0), as well as 7, 14 and 21 days thereafter. Aside from a microbiological examination of urine samples, daily urine output, serum creatinine (CreaS), creatinine clearance (CrCl), interleukin 6 (IL-6), fractional excretion of sodium (FENa) and fractional excretion of urea (FEUrea) were determined. A histopathological examination of kidney and urinary bladder specimens was conducted as well. While UTI-related pyelonephritis developed irrespective of E. coli inoculum size, AKI was observed only following transurethral administration of E. coli at the intermediate and high dose, i.e. 107 and 109 cfu/ml, respectively (group 2 and 3). An increase in CreaS and abnormal diuresis were accompanied by changes in parameters specific for various forms of AKI, i.e. FENa and FEUrea. Based on these changes, administration of E. coli at 107 cfu/ml was demonstrated to induce renal AKI, whereas inoculation with 109 cfu/ml seemed to cause not only ascending pyelonephritis, but perhaps also bacteremia and urosepsis (prerenal component of AKI).
+ What does a typical physical therapy session look like? + What should I expect for an evaluation? Therapist examines child using appropriate tests and measures. These include looking at a child's strength, how well they move their head, arms and legs, etc. This assessment should not be painful. + How does the therapy my child gets at school differ from the therapy they receive at an outpatient clinic? + How can I prepare for my child's evaluation? + My child is under 3 years old, tell me more about Early Intervention Services? + My child is under 3 years old, what is the difference between physical therapy in the clinic and physical therapy through the Early Intervention (EI) Program? +Do I have to choose either Early Intervention physical therapy services or physical therapy services from an outpatient clinic? + Why is my child's physical therapy frequency different at the clinic compared to what it is at school? + Do I have to choose either school-based physical therapy services or outpatient physical therapy clinic services?
In my PWT presentation I have a title which appears by character and has a typewriter sound. In PWT I hear the sound at the appearance of every character. However, in the Flash Movie the sound occurs only once. What can I do? The only solution for now is not to use sound along with letter animation effects. I am Mathew,Actually i have no solution for your question cause i am not aware of Flash,so sorry for that but your question is very nice I try my best for your query.
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Talking to your doctor about your symptoms — especially when it involves things like diarrhea, gassiness, and oily, smelly stools — might seem embarrassing. But your doctor needs to know this information in order to help you. This is why you need to have open communication with your doctor about the symptoms you're experiencing and your medical history, as well as the medications you're taking — including vitamins and supplements. Using a tool like the discussion guide to write things down can help you remember what you want to discuss with your doctor. It's easy. Just download the discussion guide, fill it out, and share it with your doctor at your next visit. Your doctor needs to ask you questions about what you're experiencing — but the conversation should go both ways! Asking your doctor questions and opening up will get you the answers you need. Could my symptoms be caused by something I'm eating? Is it possible that my medications or supplements are causing my symptoms? Will changing my diet help my EPI? Do I need to make any lifestyle changes to manage my EPI? What can I eat with CREON?
Association Between Low Serum Creatinine and Mortality in Patients With Severe Chronic Obstructive Pulmonary Disease Comments Off on Association Between Low Serum Creatinine and Mortality in Patients With Severe Chronic Obstructive Pulmonary Disease Introduction: Muscle mass may be a better predictor of mortality than BMI in chronic obstructive pulmonary disease (COPD). Serum creatinine depends on muscle mass and renal function; low values may predict higher mortality. Objective: To determine whether there is an association between low serum creatinine and mortality in severe COPD. Methods: This is a retrospective study of serum creatinine values at admission and within the last year before admission. Outcomes measured were mortality at 30 days and one year after admission in patients with acute type 2 respiratory failure secondary to COPD, who were admitted over a one-year period to a respiratory ward (N = 130). The statistics were calculated using the chi-squared test. Results: There appears to be a significant relationship between the one-year pre-admission creatinine values and mortality at one year (p = 0.0003). Conclusions: The relationship with mortality appears to be stronger with pre-admission creatinine values rather than the admission values and appears to predict the patients at the highest risk of mortality one year after admission. Table 1: Mortality differences between patients with low admission or pre-admission creatinine values when compared to others at 30 days and one-year post-admission Figure 1: Mortality at 30 days and one year based on admission creatinine values Figure 2: Mortality at 30 days and one year based on pre-admission creatinine values In chronic obstructive pulmonary disease (COPD), a low body mass index (BMI) is an adverse prognostic factor and is associated with an increase in mortality [1-4]. A composite score consisting of BMI, airflow obstruction, dyspnoea, and exercise tolerance (BODE index) is often used for prognostication in patients with stable COPD and is considered to be superior to the forced expiratory volume in one second (FEV1) alone for this purpose [5]. For prognostication during an acute exacerbation of COPD, a composite score of comorbidities including airflow obstruction, dyspnoea, exercise tolerance, and details of the severity of previous exacerbations (CODEX) was found to be superior to both the BODE index on its own or when the BODE index was used in conjunction with additional information about previous exacerbations (BODEX) [6]. Mid-arm muscle area was shown in a study to be a better prognostic indicator than BMI in patients with COPD [7]. The relationship between BMI and fat-free muscle mass index (FFMI) is not very good and FFMI is shown to give additional prognostic information in patients with COPD [4]. Serum creatinine values depend in part on muscle mass and are commonly measured as part of the routine assessment in patients admitted to the hospital with different conditions, including an exacerbation of COPD. These values are also measured quite frequently in primary care, as part of chronic disease monitoring. A previous study in unselected patients admitted to intensive care has shown both high and low serum creatinine values to be associated with increased mortality risk [8]. The DECAF (dyspnoea, eosinopenia, consolidation, acidemia, and atrial fibrillation) study on factors that predict hospital mortality in patients with COPD exacerbation included baseline serum biochemistry at the time of admission but did not include historical pre-admission creatinine values [9]. As creatinine values can also rise acutely, due to many other conditions such as the presence of renal impairment or infection, the values measured at the time of admission may be less reliably correlated to the muscle mass in an individual and this may explain why in the DECAF study a low creatinine value was not identified as a risk factor for mortality. If this is the case, it may be that the creatinine values measured during periods of stability, such as samples taken routinely in primary care, may have a better correlation with the muscle mass in an individual patient. We postulate that low serum creatinine values either at the time of admission or before admission may be associated with an increased risk of mortality in patients with severe COPD. If this is found to be the case, it would offer the advantage of the ready availability of a prognostic indicator, as this test is frequently performed both in the primary care and secondary care setting. If so, it may help to identify patients at risk of adverse outcomes promptly. Patients who receive non-invasive ventilation (NIV) for acute type 2 respiratory failure (commonly secondary to COPD) are at high risk of dying with an inpatient mortality rate of 34% in the British Thoracic Society national audit on NIV, 2013. We wanted to see if there would be a significant difference in mortality in this group of patients based on their admission or pre-admission creatinine levels. The study was approved by the Health Research Authority, Health and Care Research Wales (IRAS project ID: 254977), and by the Hospital Research and Development department. We undertook a retrospective observational cohort study in patients with severe COPD, who were admitted with acute type 2 respiratory failure and treated with NIV. All patients who had received NIV for the treatment of acute type 2 respiratory failure secondary to COPD in a respiratory ward in Royal Blackburn Teaching Hospital (Lancashire, United Kingdom) in 2013 were included in the study. The diagnosis of COPD was confirmed by a review of the discharge summaries, clinic letters, or patient notes, and any patients where NIV was used for indications other than COPD (such as obesity hypoventilation or neuromuscular disease resulting in type 2 respiratory failure) were excluded. The study was performed in 2019 and the reason for selecting the cohort from 2013 was to ensure complete data capture to evaluate one-year mortality after discharge. A total of 130 patients met the criteria for inclusion in the study. The normal reference ranges set by the hospital laboratory for creatinine were 46-92 μmol/L for women and 58-110 μmol/L for men. For the study, a patient was considered to have low serum creatinine values if they had creatinine values of 45 or lower for females and 57 or lower for males. Mortality rates were compared at 30 days and one year after discharge between patients who had low creatinine values within the year prior to discharge and patients who had normal or high creatinine values. The first sample taken at the time of admission for serum biochemistry was taken as the admission creatinine value and any value of creatinine that was abnormally low between the preceding year and time of admission was taken as evidence of low pre-admission creatinine value for the purpose of our calculations. We performed a chi-squared test to see if there were statistically significant differences in mortality rates observed in patients with low admission or baseline creatinine values, compared to patients with normal values, at 30 days and one year after discharge. Patients included in the study were 35% male (N = 46) with an average age of 68.9 years (median = 69 years). The median pH of blood gases at the time of initiation of NIV was 7.29 (range = 7.19-7.34). The results are summarized in Table 1. Died within 30 days Alive at 30 days P-value Died within 1 year Alive at 1 year P-value Low admission creatinine (N = 31) 7 24 0.107 17 14 0.068 Normal or high admission creatinine (N = 99) 11 88 36 63 Low creatinine within 1 year prior to admission (N = 48) 6 42 0.734 30 18 0.0003 Normal or high creatinine in the year before admission (N = 82) 12 70 25 57 1: Mortality differences between patients with low admission or pre-admission creatinine values when compared to others at 30 days and one-year post-admission Based on the admission serum biochemistry, 31 patients (23.85%) out of the total of 130 patients in the study had low serum creatinine values. The mortality rate in this group was 22.58% (N = 7) at 30 days and 54.84% (N = 17) at one year (Figure 1). The differences did not reach statistical significance (p-values of 0.107 and 0.068 for 30 days and one year, respectively) when compared to patients with normal or high creatinine values based on admission values where the 30-day mortality was 11.11% (N = 11) or 36.36% at one year (N = 36). Mortality at 30 days and one year based on admission creatinine values When patients were grouped based on the presence of low creatinine values on blood tests done within one year before admission, the mortality rate in patients at 30 days in those with low creatinine (N = 6) was 12.5%, compared to 14.63% in others (p = 0.734). The mortality rate at one year, however, was significantly higher (p = 0.0003) in patients with low pre-admission creatinine where 62.5% of patients (N = 30) had died compared to 30.49% mortality (N =25) in patients with normal or high creatinine values (Figure 2). Mortality at 30 days and one year based on pre-admission creatinine values Low BMI has been known to be an adverse prognostic indicator in patients with COPD, but muscle mass may be superior to BMI in this respect [7] or to show additional information than BMI [4]. Measurement of fat-free muscle mass or mid-arm muscle area is complex. In studies, this has been calculated by using equations incorporating various other factors such as mid-arm circumference, BMI, skinfold thickness, and estimation of fat mass [7]. This complexity makes the use of endpoints such as these problematic in day-to-day utilization in the care of patients with COPD. In addition to this, although there is a suggested method of categorizing cut-offs for low fat-free muscle index [10], there is no official guidance on this subject. Serum creatinine values are routinely checked during hospital admissions and frequently measured in primary care. Although the values of serum creatinine can be influenced by a variety of factors such as intrinsic renal disease, use of nephrotoxic medications, and presence of systemic illness, values also depend on underlying muscle mass [11]. As some of these factors are more likely to be present during the period of hospitalization, it would be expected that measurement of serum creatinine values during stable conditions, perhaps in primary care, would be more closely related to the actual muscle mass than those which are measured during periods of hospitalization, as the latter ones may be falsely elevated by factors such as acute kidney injury or use of nephrotoxic drugs. This may explain why in the DECAF study low serum creatinine was not noted to be a significant factor that influenced mortality, as only the values on admission were considered. In our study, we find that although there were no significant differences in mortality between patients with low creatinine values and others at 30 days post-admission, there appeared to be a trend toward significance at one year when patients were identified based on the admission values, and a highly significant difference when the patients were identified based on pre-admission creatinine values. This suggests that the differences in mortality may be apparent on a medium to long-term basis rather than in the immediate post-admission period. Previous studies have shown that an increase in BMI through nutritional support improved survival [3] and quality of life in patients with COPD [12]. If further studies (ideally done prospectively) confirm the value of low serum creatinine as a useful prognostic marker in identifying patients at increased risk of death, it may be possible to improve outcomes by offering nutritional support to these patients, especially as the increase in mortality is not in the immediate post-discharge period. The identification of a greater number of patients with low serum creatinine based on pre-admission values rather than the admission ones appears to suggest that some of these patients did develop an increase in their creatinine values, which might reflect acute deterioration in their overall health. This may explain the lack of significant differences in mortality based on admission values is in part due to the death of these patients in the low creatinine comparative group. It would be recommended to confirm the findings of our study by performing a prospective study where other important factors such as the patient's BMI, nutritional status, and severity of airflow obstruction can also be considered to assess the differences in mortality. Tags: COPD exercise pulmonary pulmonary diseases respiratory « Children First: Focusing on your child's mental health What is mouth taping and will it fix your bad sleep? » Physiotherapy Opens Doors To Attractive Career Opportunities In Allied Health Sector In India Crypto Lender Hodlnaut Files for 'Breathing Space' Creditor Protection COPD & Pulmonary Rehabilitation Clinic inaugurated – The Sangai Express
Extraction of chemical information of suspensions using radiative transfer theory to remove multiple scattering effects : application to a model multicomponent system Steponavicius, Raimundas and Thennadil, Suresh (2011) Extraction of chemical information of suspensions using radiative transfer theory to remove multiple scattering effects : application to a model multicomponent system. Analytical Chemistry, 83 (6). pp. 1931-1937. ISSN 0003-2700 (https://doi.org/10.1021/ac1024073) PDF. Filename: ac_2010_024073_revised.pdf Download (480kB)| Preview The effectiveness of a scatter correction approach based on decoupling absorption and scattering effects through the use of the radiative transfer theory to invert a suitable set of measurements is studied by considering a model multicomponent suspension. The method was used in conjunction with partial least-squares regression to build calibration models for estimating the concentration of two types of analytes: an absorbing (nonscattering) species and a particulate (absorbing and scattering) species. The performances of the models built by this approach were compared with those obtained by applying empirical scatter correction approaches to diffuse reflectance, diffuse transmittance, and collimated transmittance measurements. It was found that the method provided appreciable improvement in model performance for the prediction of both types of analytes. The study indicates that, as long as the bulk absorption spectra are accurately extracted, no further empirical preprocessing to remove light scattering effects is required. scatter correction, multivariate calibration, near-infrared spectroscopy, multiple scattering, radiative transfer equation, adding-doubling method, Chemistry, Analytical Chemistry Science > Chemistry
Catastrophic Personal Injury Defective Consumer Products Toxic Contamination View All+ Over $1 billion Recovered By Our Attorneys Results Matter. Our Firm Has The Experience To Get The Results You Deserve. click here to request your free consultation now Drug Lawsuits Companies Recalling Zantac / Ranitidine Due to Concerns Regarding the Presence of NDMA Zantac and generic ranitidine medications—used to treat heartburn, ulcers, gastroesophageal reflux disease (GERD), and general indigestion and stomach upset—have been the subject of several recalls over the past few months, with more expected to be forthcoming. These recalls have all been implemented after testing of ranitidine medications had confirmed the presence of high levels of… read more New Class-Action Lawsuit Filed Against Zantac Manufacturers Because of Potential Cancer Risk On September 26, 2019, five plaintiffs jointly filed a class-action lawsuit against Sanofi-Aventis LLC, makers of the stomach-acid medication, Zantac (ranitidine). They've also named as defendants Boehringer Ingelheim Pharmaceuticals, Inc., which owned the U.S. rights to Zantac and manufactured and distributed the drug from October 2006 to January 2017, after which Sanofi acquired the rights…. read more CoaguChek Recall: What You Need To Know Warfarin sodium (Coumadin or Marevan) is the most widely used anticoagulant in the United States. This medication is vital for patients with venous thromboembolism, chronic atrial fibrillation, valvular heart disease, and mechanical prosthetic heart valves. However, due to the risk of internal hemorrhaging, monitoring is required every one to four weeks to ensure appropriate dosing…. read more FDA Issues Black Box Warning for Uloric In February 2019, the FDA issued a "black box warning" – the agency's strongest and most prominent advisory — for Takeda's popular gout drug, Uloric. According to health regulators, Uloric (febuxostat) is associated with an "increased risk of heart-related death and death from all causes" compared to the gout medication allopurinol. The boxed warning also… read more Infection After Taking Xeljanz? Here's What To Do! Designed to treat rheumatoid arthritis and ulcerative colitis, Pfizer's Xeljanz (tofacitinib) has been linked with potentially deadly side effects, which include: Liver enzyme elevations, lipid elevations, anemia, neutropenia, and lymphocyte abnormalities Increased risk of blood clots in the lungs, causing death Perforations of the stomach or intestines Lymphoma and other cancers Non-melanoma skin cancers Hypersensitivity… read more Is Your Medication Causing Dangerous Side Effects? There is an old saying that sometimes the cure is worse than the disease. While medications are prescribed to treat ailments, sometimes the side effects of a drug are as dangerous – or more so – than the disease itself. The Federal Food and Drug Administration has placed "black box" labels on certain drugs– warning… read more Can Uloric Cause a Heart Attack? Uloric (also known as febuxostat), a gout medication, has been a "hot topic" in headlines recently due to an announcement by the U.S. Food and Drug Administration (FDA) in February 2019 that a new black boxed warning was being added to its label. At issue is the discovery that Uloric carries a significant increase in… read more Arthritis Patients Taking Xeljanz May be at Risk for Pulmonary Embolism Rheumatologists have a few pharmaceutical options for patients who are suffering from the effects of rheumatoid arthritis. One of those options is tofacitinib citrate, which is sold under the brand name "Xeljanz." This drug blocks certain naturally-occurring enzymes that cause joint pain, swelling, and stiffness. A recent safety alert from the U.S. Food and Drug… read more Uloric vs Allopurinol: FDA says Allopurinol Should be First-Line Treatment for Gout The FDA recently determined that Takeda Pharmaceutical's medication, Uloric (febuxostat), should no longer be recommended as a first-line treatment for gout, a type of arthritis. After reviewing the data from a post-marketing trial required as a condition of Uloric's approval, the FDA announced that they were requiring a new black box warning on the product… read more Pfizer Transitions RA Patients Off 10 mg Dose After Study Shows Risk of Pulmonary Embolism According to a recent announcement from Xeljanz manufacturer Pfizer, the company has taken steps to transition patients with rheumatoid arthritis (RA) who are taking the 10 mg twice-daily dose to the lower 5 mg twice-daily dose. The company noted that it's taking this action based on the results of a post-marketing study that indicates significant… read more Free Case Review OVER $1 BILLION RECOVERED By Our Attorneys Chaffin Luhana LLP Celebrates Its 10 Year Anniversary Living Safer: The Deadly Vaping Epidemic – A Deep Dive The Link Between Vaping and Lung Disease Diagnosed With EVALI Illness From Vaping? Here's What You Should Know Why Hiring a Lawyer is Critical After an Accident Medical Device Lawsuits Product Lawsuits Toxic Contamination Lawsuits Trucking Crashes Vehicle Defects Call or Text Us 24/7: click now or call free consultation 600 Third Ave., 12th Flr. 615 Iron City Dr. Weirton, WV 26062 Recent Case Types Zantac Cancer Lawsuit Talcum Powder Lawsuits Defective Lithium-Ion Batteries Exploding Pressure Cookers Hernia Mesh Lawsuits Chaffin Luhana Foundation Partners with the Reeve Foundation to Launch the #CLFInnerReeveChallenge to Benefit Those Living With Paralysis © 2020 CHAFFIN LUHANA LLP. 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Previous studies have shown that the Big Five personality traits are significantly associated with perceived social support and these associations are positively associated with agreeableness, extraversion, and emotional stability. However, it is not yet clear whether these associations hold longitudinally or how these variables may predict each other over time. To investigate the co-development of personality traits and perceived social support, a cross-lagged path model design was used on a sample of adults (N = 1309) measured on two occasions 4 years apart. The results indicated that while emotional stability predicted perceived social support 4 years later, perceived social support also predicted emotional stability, extraversion, agreeableness, openness, and conscientiousness 4 years later. Our findings suggest that perceived social support may be a resource that has an impact on the development of personality traits known to be associated with social skills as well as the quality and frequency of social interactions in middle adulthood.
Critical Care Medicine| March 2016 Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep Vittorio Scaravilli, M.D.; Vittorio Scaravilli, M.D. From the Dipartimento Scienze della Salute, Università Milano-Bicocca, Monza, Italy (V.S., A.Z.); Comprehensive Intensive Care Research Task Area (V.S., S.K., S.B., K.L., Y.L., L.C.C., A.I.B.) and Damage Control Resuscitation Task Area (M.A.D.), United States Army Institute of Surgical Research, Fort Sam Houston, Texas; National Research Council, National Academies, Washington, D.C. (V.S., S.K.); Department of Anesthesiology and Intensive Care Medicine (S.K.) and Pediatric Department (K.L.), University Hospital Bonn, Bonn, Germany; and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università Degli Studi di Milano and Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy (A.P.). Address correspondence to Dr. Scaravilli: Dipartimento Scienze della Salute, Università Milano-Bicocca, Monza (MB), Italy. [email protected]. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Stefan Kreyer, M.D.; Stefan Kreyer, M.D. Slava Belenkiy, M.D.; Slava Belenkiy, M.D. Katharina Linden, M.D.; Katharina Linden, M.D. Alberto Zanella, M.D.; Alberto Zanella, M.D. Yansong Li, M.D.; Yansong Li, M.D. Michael A. Dubick, Ph.D.; Michael A. Dubick, Ph.D. Leopoldo C. Cancio, M.D.; Leopoldo C. Cancio, M.D. Antonio Pesenti, M.D.; Antonio Pesenti, M.D. Andriy I. Batchinsky, M.D. This article is featured in "This Month in Anesthesiology," page 1A. Corresponding article on page 532. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal's Web site (www.anesthesiology.org). Submitted for publication April 21, 2015. Accepted for publication September 29, 2015. Anesthesiology March 2016, Vol. 124, 674–682. https://doi.org/10.1097/ALN.0000000000000995 Vittorio Scaravilli, Stefan Kreyer, Slava Belenkiy, Katharina Linden, Alberto Zanella, Yansong Li, Michael A. Dubick, Leopoldo C. Cancio, Antonio Pesenti, Andriy I. Batchinsky; Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep. Anesthesiology 2016; 124:674–682 doi: https://doi.org/10.1097/ALN.0000000000000995 The authors studied the effects on membrane lung carbon dioxide extraction (VCO2ML), spontaneous ventilation, and energy expenditure (EE) of an innovative extracorporeal carbon dioxide removal (ECCO2R) technique enhanced by acidification (acid load carbon dioxide removal [ALCO2R]) via lactic acid. Six spontaneously breathing healthy ewes were connected to an extracorporeal circuit with blood flow 250 ml/min and gas flow 10 l/min. Sheep underwent two randomly ordered experimental sequences, each consisting of two 12-h alternating phases of ALCO2R and ECCO2R. During ALCO2R, lactic acid (1.5 mEq/min) was infused before the membrane lung. Caloric intake was not controlled, and animals were freely fed. VCO2ML, natural lung carbon dioxide extraction, total carbon dioxide production, and minute ventilation were recorded. Oxygen consumption and EE were calculated. ALCO2R enhanced VCO2ML by 48% relative to ECCO2R (55.3 ± 3.1 vs. 37.2 ± 3.2 ml/min; P less than 0.001). During ALCO2R, minute ventilation and natural lung carbon dioxide extraction were not affected (7.88 ± 2.00 vs. 7.51 ± 1.89 l/min, P = 0.146; 167.9 ± 41.6 vs. 159.6 ± 51.8 ml/min, P = 0.063), whereas total carbon dioxide production, oxygen consumption, and EE rose by 12% each (223.53 ± 42.68 vs. 196.64 ± 50.92 ml/min, 215.3 ± 96.9 vs. 189.1 ± 89.0 ml/min, 67.5 ± 24.0 vs. 60.3 ± 20.1 kcal/h; P less than 0.001). ALCO2R was effective in enhancing VCO2ML. However, lactic acid caused a rise in EE that made ALCO2R no different from standard ECCO2R with respect to ventilation. The authors suggest coupling lactic acid–enhanced ALCO2R with active measures to control metabolism. carbon dioxide, extracorporeal carbon dioxide removal, infusion procedures, inspiration, lactic acid, respiration, sheep In a study of six spontaneously breathing conscious sheep connected to a minimally invasive circuit, extracorporeal blood acidification with lactic acid (acid load carbon dioxide removal) increased extracorporeal carbon dioxide removal by 50% compared with standard extracorporeal carbon dioxide removal. Although lactic acid infusion increased overall energy expenditure, feasibility safety and efficiency of acid load carbon dioxide removal were proved. Supplemental Digital Content is available in the text. What We Already Know about This Topic Extracorporeal carbon dioxide removal is used for lung protection in patients with hypercapnic respiratory failure. Current extracorporeal carbon dioxide removal technology has low efficiency and thus requires significant invasiveness to be clinically effective. What This Article Tells Us That Is New In a study of six spontaneously breathing conscious sheep connected to a minimally invasive circuit, extracorporeal blood acidification with lactic acid (acid load carbon dioxide removal) increased extracorporeal carbon dioxide removal by 50% compared with standard extracorporeal carbon dioxide removal. Although lactic acid infusion increased the overall energy expenditure, feasibility safety and efficiency of acid load carbon dioxide removal were proved. EXTRACORPOREAL carbon dioxide removal (ECCO2R) is a low blood flow extracorporeal gas exchange technique used to remove carbon dioxide in patients affected by respiratory failure. It mitigates respiratory acidosis,1 minimizes the ventilatory burden of patients at risk of ventilator-induced lung injury, and reduces the work of breathing.2 Formerly, ECCO2R was carried out with older technology and, similar to full extracorporeal membrane oxygenation, was used as a rescue therapy for severe cases of acute respiratory distress syndrome.3 Recent technological advances have reduced the complexity of ECCO2R4,5 and thus allowed this technique to be also used in acute exacerbation of chronic obstructive pulmonary disease,6 as a bridge to lung transplant,7 and to facilitate lung-protective ventilation.8 Nonetheless, current ECCO2R technology requires the use of blood flow (BF) of at least 0.5 to 1 l/min, and catheters of 16 to 19 F size, to remove a significant portion of the total carbon dioxide production of an adult patient.9,10 If carbon dioxide removal could be further enhanced such that reduced BFs as low as 250 to 500 ml/min became possible, smaller cannulas could be used (e.g., 13 to 15 F). Accordingly, ECCO2R could become a procedure with the same logistical footprint and invasiveness as continuous renal replacement therapy. In pursuit of this goal, we developed a new ECCO2R technique consisting of regional blood acidification (acid load carbon dioxide removal [ALCO2R]),11 based on infusion of lactic acid (LA) extracorporeally into the blood entering the membrane lung (ML). Acidification converts bicarbonate ions into dissolved carbon dioxide. This increases the partial pressure of carbon dioxide (Pco2) in the blood entering the ML, raises carbon dioxide availability, and increases the transmembrane carbon dioxide partial pressure gradient. Because this is the driving force for carbon dioxide transfer across the membrane,12 acidification enhances ML carbon dioxide removal (VCO2ML). Previously, we demonstrated regional blood acidification to be capable of raising VCO2ML by up to 70% (i.e., to 170 ml/min), with an extracorporeal BF as low as 250 ml/min in a mechanically ventilated porcine model.11,13 Until now, ALCO2R has been performed by infusing a metabolizable acid, such as LA, citric acid, or acetic acid.11,14 All three compounds are energy substrates, and therefore, their oxidation produces carbon dioxide, which may counterbalance the enhanced carbon dioxide removal effect provided by ALCO2R. In this study, we examined the effects of ALCO2R on spontaneous ventilation and energy metabolism of LA in the absence of caloric control. We compared ventilation and energy expenditure (EE) during ALCO2R and standard ECCO2R, in spontaneously breathing, freely fed, healthy ewes. We hypothesized that ALCO2R enhances carbon dioxide removal of the ML and reduces minute ventilation (MV). Moreover, we studied the safety profile of ALCO2R, in terms of histological damage and signs of tissue inflammation and oxidative stress. This study was approved by the U.S. Army Institute of Surgical Research Institutional Animal Care and Use Committee (Fort Sam Houston, San Antonio, Texas) and was conducted in compliance with the Animal Welfare Act, the Implementing Animal Welfare Regulations, and in accordance with the principles of the Guide for the Care and Use of Laboratory Animals. Under general anesthesia, six healthy ewes (Ovis aries, David Josh Talley, Uvalde, Texas) (34.3 ± 1.5 kg) were instrumented as described in our previous article.15 Tracheostomy was performed. Catheters were placed in the carotid and pulmonary arteries for pressure monitoring and sample withdrawal. A dual-lumen catheter (15.5 F; ALung; ALung Technologies, USA) was introduced in the right external jugular vein for connection to the extracorporeal circuit (for additional details on instrumentation, see Instrumentation, Additional Methods, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). A custom-made extracorporeal circuit optimized for ALCO2R was used for the study. Figure 1 shows the schematic representation of extracorporeal circuit. The circuit consisted of a Hemolung device (ALung; ALung Technologies), a standard polyethersulfone continuous renal replacement therapy hemofilter (Purema; NxStage Medical, USA) connected in series after the Hemolung ML, and a peristaltic pump for the recirculation of ultrafiltrate before the ML. BF was maintained constant at 250 ml/min, sweep gas flow was 10 l/min of ambient air, and ultrafiltrate flow was 100 ml/min. An acid injection port was located on the ultrafiltrate side of the circuit, as such avoiding direct contact between highly concentrated acids and the cellular components of the blood. This prevented hemolysis and unwarranted infusion of free water to dilute the acid. Six sampling outlets were arranged in the circuit: four on the blood side (inlet, postrecirculation, post-ML, and outlet) and two on the ultrafiltrate side (pre-acid, post-acid). Extracorporeal BF was measured by the Hemolung built-in flowmeter at the circuit outlet. Schematic representation of extracorporeal circuit. Membrane lung (ML), hemofilter (HF), and peristaltic pump (PP). 1–4 = circuit blood withdrawal sites: (1) inlet, (2) postrecirculation, (3) post-ML, and (4) outlet. 5–6 = ultrafiltrate withdrawal sites: (5) pre-acid, (6) post-acid. Flowmeter was positioned on the blood line after the outlet (4) withdrawal site. After surgery, anesthesia was discontinued and animals were moved into a cage. For the remainder of the study, continuous infusions of fentanyl and midazolam (0.5 μg · kg−1 · h−1 and 0.01 mg · kg−1 · h−1, respectively) were provided. Maintenance fluid (Plasma-Lyte A; Baxter International, USA) was infused at 1 ml · kg−1 · h−1. During the experiment, animals were conscious and breathing spontaneously, connected to a mechanical ventilator (Dräger Evita XL; Dräger Medical, Germany) in continuous positive airway pressure mode at 5 cm H2O with an Fio2 of 21%. Hay and dry food pellets were provided ad libitum throughout the study. After a recovery period of 6 h, each of the six animals was subjected to two repeated experimental sequences. Each of them lasted 24 h and consisted of a phase of ALCO2R and a phase of standard ECCO2R. The ALCO2R and ECCO2R phases were alternated, ordered randomly, and lasted 12 consecutive hours each (for additional details on experimental setup, see Experimental Design and fig. S1, Additional Methods, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). To counterbalance any order effect of the experimental sequences, three animals started the experiment with a standard ECCO2R phase, whereas three started with an ALCO2R phase. We did not perform a washout period after ALCO2R and before commencing ECCO2R because in a previous similar study14 we observed LA (infused at 1.5 mEq/min) to be completely washed-out by sheep in less than 1 h. ALCO2R was achieved by infusing LA (4.4 M) in the ultrafiltrate side of the circuit, at a continuous fixed rate of 1.5 mEq/min. A volumetric capnograph (CO2SMO; Novametrix, USA) was used to measure respiratory rate, tidal volume (TV), MV, and natural lung carbon dioxide removal (VCO2NL) at body temperature, ambient pressure, saturated (with water vapor) (BTPS) conditions. Alveolar ventilation (AV), physiologic dead space (Vd), and venous admixture (Qs/Qt) were calculated using standard equations (see equations A for Ventilatory Function Calculations, Supplemental Digital Content 1, http://links.lww.com/ALN/B237).16,17 VCO2ML at BTPS conditions was measured by a capnometer built into the Hemolung. Thus, the total carbon dioxide production (VCO2tot) was calculated as the sum of VCO2NL and VCO2ML. Arterial blood gas analyses (i-STAT; Abbott, USA) and activated clotting time (ACT) (Hemochron Jr. Signature; ITC, USA) were recorded hourly. Moreover, every 3 h, selected electrolytes (sodium, potassium, chloride, and ionized calcium) and glucose concentrations were measured in the arterial samples (i-STAT; Abbott). Mixed venous, extracorporeal circuit blood, and ultrafiltrate samples were collected every 3 h for blood gas analyses. Hematocrit was measured via centrifugation technique in mixed venous samples. Heart rate (HR), mean arterial pressure, central venous pressure, and pulmonary artery pressure were monitored continuously. Pulmonary artery occlusion pressure was recorded hourly. Cardiac output (CO) was measured every 3 h using intermittent bolus thermodilution technique. ML carbon dioxide removal efficiency ratio was computed as described in our previous article (see equations B for ML CO2 Removal Efficiency Calculation, Supplemental Digital Content 1, http://links.lww.com/ALN/B237).15 ML oxygen delivery (VO2ML), natural lung oxygen delivery, and total oxygen consumption (VO2tot) were calculated using standard equations (see equations C for Oxygen Delivery and Consumption Calculation, Supplemental Digital Content 1, http://links.lww.com/ALN/B237) at BTPS conditions. Respiratory quotient (RQ) was calculated as the ratio between VCO2tot and VO2tot. Thus, with VCO2tot and VO2tot, EE was calculated using the Weir equation, as previously described (see equations D for Energetic Expenditure Calculation, Supplemental Digital Content 1, http://links.lww.com/ALN/B237).18 Hemoglobin, complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, d-dimers, blood urea nitrogen, creatinine, total bilirubin, alanine transaminase, aspartate transaminase, amylase, myoglobin, uric acid, blood glucose, and plasma-free hemoglobin were measured before instrumentation, at the end of the recovery period (i.e., after 6 h of extracorporeal circulation [EC]), as well as at the end of any ECCO2R and ALCO2R phase. Plasma-free hemoglobin concentration was measured by spectrophotometric analysis (DU 800; Beckman Coulter Inc., USA). Sheep were euthanized by an intravenous injection of 20 ml of Fatal Plus (Vortech Pharmaceuticals, USA) at the conclusion of the experiments. Lung, heart, liver, and renal tissue samples were collected for histological evaluation postmortem. Histological evaluation of injury was performed by a single pathologist blinded to the identity of the animal represented on the slide, as previously documented (see Postmortem Histological Evaluation, Additional Methods, Supplemental Digital Content 1, http://links.lww.com/ALN/B237).19 Moreover, we studied the safety of ALCO2R technique in terms of tissue inflammatory responses, concentration of selected indices of oxidative stress, and biochemical markers of injury. Specifically, we measured thiobarbituric acid reactive substances (TBARs), interleukin-1β, interleukin-8, and nitric oxide concentration, as well as determined reduced glutathione and ferric reducing ability in the homogenate of lung, heart, and liver tissue. Myeloperoxidase activity was measured in lung homogenate. Indices of oxidant stress and inflammation were then compared with healthy time controls sham animals from another sheep study performed in our laboratory (see Oxidative Stress and Inflammation Analysis, Additional Methods, Supplemental Digital Content 1, http://links.lww.com/ALN/B237).20 Data are expressed as means ± SD or median and interquartile range, when appropriate. The JMP 11 statistical program (SAS Institute Inc, USA) was used for statistical analysis. A paired difference model was used to gauge the sample size. Using an α error of 0.05 and power of 0.80, with an SD of 5 ml/min in VCO2ML measurements expected from preliminary experiments, six paired matches were calculated to be needed to detect a difference of at least 7.5 ml/min in VCO2ML between ALCO2R versus ECCO2R steps and six animals were sufficient. To further reduce the unnecessary use of animals, we performed two repeated experimental sequences on each of these animals. For systemic variables (i.e., ventilation, hemodynamics, and energetic metabolism) and extracorporeal gas removal (VCO2ML, VO2ML, and ML efficiency), a two-way analysis of variance for repeated measures was performed using a residual maximum likelihood method to fit a general linear model. Treatment (i.e., ALCO2R vs. ECCO2R, 2 levels) and time (i.e., hours, 12 levels) were considered as fixed factor, whereas animals and sequence repetitions (nested within animals) were considered as random effects. Interactions between treatment and time were not analyzed. For extracorporeal gas analyses, a similar statistical model was used, with treatment (i.e., ALCO2R vs. ECCO2R, two levels) and circuit withdrawal port (i.e., six levels) as fixed effects. Two-tailed values of P less than 0.05 were considered statistically significant. Post hoc Student's t test with Tukey adjustment was used for multiple comparisons. During LA infusion (i.e., ALCO2R phases), VCO2ML was enhanced by 48% relative to ECCO2R (55.3 ± 3.1 ml/min vs. 37.2 ± 3.2 ml/min; P < 0.001). Similarly, ML carbon dioxide removal efficiency was significantly increased (41.3 ± 5.3% vs. 24.3 ± 4.2%; P < 0.001). No reduction in VCO2ML (fig. 2) and ML carbon dioxide removal efficiency was observed over time. VO2ML was similar during ALCO2R and ECCO2R (9.8 ± 3.2 ml/min vs. 9.5 ± 3.2 ml/min; P = 0.17). Extracorporeal carbon dioxide removal (VCO2ML) during acid load carbon dioxide removal (ALCO2R) and extracorporeal carbon dioxide removal (ECCO2R) phases. Black bars represent ALCO2R phase measurements, whereas hatched bars represent ECCO2R phase measurements. For any of the time-points, VCO2ML was higher during ALCO2R compared with ECCO2R (P < 0.001). Data are expressed as means ± SDs. We did not observe alterations of ventilatory status during ALCO2R (see Table 1). MV was similar during ALCO2R and ECCO2R, as was respiratory rate and VCO2NL. TV and AV showed a 7% increase during ALCO2R. Vd and pulmonary Qs/Qt were not influenced by ALCO2R. No effect of time was observed on ventilatory variables. Ventilatory Parameters during Extracorporeal Carbon Dioxide Removal (ECCO2R) and Acid Load Carbon Dioxide Removal (ALCO2R) Table 2 shows the metabolic parameters during experimental phases. EE increased by 12% during ALCO2R. Similarly, VCO2tot, natural lung oxygen delivery, and VO2tot were 13% higher during ALCO2R relative to ECCO2R. RQ was not significantly influenced by ALCO2R. Metabolic Parameters during Extracorporeal Carbon Dioxide Removal (ECCO2R) and Acid Load Carbon Dioxide Removal (ALCO2R) Table 3 presents arterial blood gas analyses and electrolyte concentrations measured during experimental phases. During ALCO2R, pH, Pco2, bicarbonate ions (HCO3−), and base excess were lower relative to ECCO2R. Oxygenation was not affected by ALCO2R. Average lactate level was higher during the ALCO2R phase compared with ECCO2R. During the first hour of ALCO2R, lactate was significantly lower (3.31 ± 0.98 mmol/l; P < 0.001) compared with other time-points. After the first hour, lactate plateaued (see fig. S2, Additional Results, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). Sodium, potassium, and ionized calcium were not influenced by ALCO2R, whereas chloride was lower during ALCO2R. Glucose was higher during ALCO2R compared with ECCO2R. No effect of time was observed on arterial blood gas analyses. Arterial Blood Gas Analyses and Electrolytes Concentration during Extracorporeal Carbon Dioxide Removal (ECCO2R) and Acid Load Carbon Dioxide Removal (ALCO2R) The pH, Pco2, HCO3−, and lactate in the blood and ultrafiltrate samples from the circuit are shown in table 4. During ALCO2R, the highest lactate was observed in the post-acid ultrafiltrate samples (P < 0.001). In postrecirculation, post-ML, and outlet blood samples, lactate was similarly higher relative to inlet blood (P < 0.001), which in turn had a lactate concentration similar to the arterial blood. During ALCO2R, similar to arterial samples, inlet blood samples showed reduced pH, Pco2, and HCO3− compared with ECCO2R. LA infusion significantly acidified post-acid ultrafiltrate and subsequently postrecirculation blood (P < 0.001). In turn, these samples showed higher Pco2 and lower HCO3− (P < 0.001). Acid infusion buffered the extreme iatrogenic alkalosis observed in post-ML and outlet blood during ECCO2R. Indeed, during ALCO2R, post-ML and outlet blood samples had similarly lower pH and higher Pco2 relative to ECCO2R (P < 0.001). Regardless of the experimental phase, post-ML and outlet blood, as well as pre-acid ultrafiltrate, had similar pH, Pco2, and HCO3− concentrations. Moreover, in these samples, pH was higher and Pco2 was lower relative to postrecirculation blood independent of acid infusion (P < 0.001). pH, Pco2, HCO3−, and lactate values remained stable over time. Blood Gas Analyses in the Extracorporeal Circuitry during Extracorporeal Carbon Dioxide Removal (ECCO2R) and Acid Load Carbon Dioxide Removal (ALCO2R) Hemodynamic parameters are shown in table S1 (Additional Results, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). During ALCO2R, a small increase in core temperature was observed (0.1°C). Moreover, ALCO2R was associated with a rise of about 5% in both HR and CO. Mean arterial pressure, central venous pressure, pulmonary artery occlusion pressure, mixed venous saturation, and hematocrit were similar during ALCO2R and ECCO2R. Changes observed in blood chemistries were associated with instrumentation and connection to the EC rather than with application of ALCO2R (see table S2, Additional Results, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). No sign of hemolysis was observed because plasma-free hemoglobin concentration was always lower than pathological thresholds21 and bilirubin changes were negligible and lower during ALCO2R compared with ECCO2R. We observed a slight elevation in white blood cells and in particular neutrophils after instrumentation. Hematocrit and platelets were lower after instrumentation compared with baseline, as an effect of hemodilution after connection to the extracorporeal circuit. As expected, due to heparin infusion, partial thromboplastin time was elevated after instrumentation and was stable during EC, ALCO2R, and ECCO2R. No alteration in prothrombin time, fibrinogen, or d-dimers was observed during the experiment. Alanine transaminase and aspartate transaminase were not different during ECCO2R and ALCO2R, although they were higher than baseline. Creatinine, amylase, uric acid, and myoglobin were in normal ranges during the whole experiment. During ALCO2R, the heparin infusion rate was lower (38.2 ± 10.8 IU/kg*h vs. 40.0 ± 13.6 IU/kg*h; P < 0.05) and the ACT was higher (279 ± 37 vs. 262 ± 35; P < 0.05) compared with ECCO2R. Histological examination of lung, heart, liver, and kidney organs did not demonstrate tissue damage (see fig. S3 and table S3, Additional Results, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). Biomarkers of inflammation, oxidant stress, and tissue injury are shown in table S4 (Additional Results, Supplemental Digital Content 1, http://links.lww.com/ALN/B237). Overall, no clinically meaningful changes were detected in these variables, but treated animals showed a statistically significant reduction in heart TBARs concentration, as well as a statistically significant increase in lung total antioxidant and glutathione, liver interleukin-1β, and lung interleukin-8. We investigated the effects of ALCO2R with LA on ventilation and metabolism of spontaneously breathing sheep. Feasibility, safety, and efficiency of ALCO2R technique was confirmed and independently validated in a different species adding to previous experiences in swine. To our knowledge, ALCO2R has never been attempted before in a conscious, spontaneously breathing animal model. For the first time, the effect of ALCO2R on energy metabolism was evaluated. Infusion of LA was associated with an increase in EE, such that ALCO2R use was not associated with a decrease in the animals' MV. ALCO2R is an innovative, highly efficient ECCO2R technique based on extracorporeal blood acidification. It opens up the possibility that ECCO2R systems could be miniaturized, by allowing similar carbon dioxide removal efficiency at half of the currently used BFs. Previous experiments in swine studied the performance of an ML during ALCO2R, verifying its effectiveness in raising VCO2ML by up to 70%.11,13,22 The current study was designed to evaluate the ventilatory and metabolic effects of ALCO2R via LA, in the absence of metabolic control, in a different species (i.e., sheep) and in a different laboratory during awake, spontaneously breathing conditions. We confirmed the benefits of extracorporeal blood acidification on ML performance, providing independent validation of the ALCO2R concept. Interestingly, we did not detect a significant reduction in MV in this model. This could be explained by the augmentation of caloric intake due to LA infusion. In a previous study involving mechanically ventilated anesthetized swine,23 LA at 2.5 mEq/min increased VCO2tot by 5% (i.e., 13 ml/min) relative to an isocaloric glucose infusion, while stabilization of the caloric intake by parenteral nutrition (i.e., glucose infusion) and infusion of insulin was undertaken. The former avoids unwarranted overfeeding, which is known to augment ventilatory needs.24 The latter is useful to overcome the insulin resistance associated with lactate infusion, and thus maintains euglycemia.25,26 In previous experiments,13 ALCO2R obtained via infusion of LA at 2.5 mEq/min yielded an augmentation in VCO2ML to 45 ml/min. Taken together, these data suggest that ALCO2R, despite increasing VCO2tot slightly, produces a much higher increase in VCO2ML and thus can potentially decrease patient ventilatory needs if associated with control of metabolism. In this experiment, we let the animals eat freely and evaluated their ability to autoregulate their energy metabolism. LA infusion at 1.5 mEq/min was associated with a 10 kcal/h surge (i.e., +12%) in EE, matched by an increase in VCO2tot of 26.9 and in VO2tot of 31.8 ml/min (i.e., +13%). HR and CO rose 5% to support this increment in oxygen consumption. Such augmentation in carbon dioxide production increased ventilatory needs (i.e., 7% increases in TV and AV). The sheep significantly compensated for the caloric input associated with LA, albeit not thoroughly. Indeed, because LA at 1.5 mEq/min corresponds to a caloric intake of 30 kcal/h, LA oxidation could have caused a much higher surge in EE (i.e., +44%). This, added to the 67 kcal/h measured during the ECCO2R phases, may have led to an eventual EE of about 100 kcal/h during LA infusion. Thus, by the Weir equation, we can extrapolate a theoretical VCO2tot and a VO2tot during ALCO2R phases of 320 ml/min each. Such augmentation in VCO2tot would have doubled AV, whereas it only increased by 7%. Thus, sheep spontaneously managed the LA caloric input to the point of avoiding metabolic and ventilatory derangements, although without intervention to control their metabolism we were not able to observe the effects of ALCO2R on ventilation. Notably, the caloric effects of LA infusion may differ in patients on controlled diet whose caloric metabolism and endocrine milieu may be deranged by underlying critical illness.27 Thus, further studies targeting the metabolic and endocrine responses to ALCO2R are needed before translation of these results into clinical practice may be done. The use of special techniques (e.g., isotopic carbon-labeled glucose or lactate, direct calorimetry, and calculation of caloric intake from dietary consumption) would be necessary to investigate the metabolic fate of lactate and glucose during ALCO2R. This goes beyond the scope of this study. We did observe that RQ shifted from 0.92 ± 0.33 to 0.98 ± 0.30 from ECCO2R to ALCO2R, although not significantly. Insofar as the RQ of LA is 1, we may argue that this shift reflected oxidation of LA into carbon dioxide. Moreover, higher glucose levels were observed during LA infusion. This might be explained by the insulin resistance associated with infusion of LA.25 During ALCO2R, we did not observe blood chemistry alterations, hemodynamic derangements, or hemolysis. Notably, this study is the first report of in-depth analysis of effects of ALCO2R on lung function, histopathology, and tissue inflammation. ALCO2R did not have any detrimental effects on Vd, Qs/Qt, and oxygenation. During LA infusion, we detected a slight increase in core temperature. A thermogenic effect is known to be associated with LA metabolism.28 Interestingly, despite achieving target ACT levels, we noticed a reduction in anticoagulation requirements during ALCO2R. Postmortem histological examination of the heart, liver, lung, and kidneys did not demonstrate major signs of tissue damage. Interestingly, a previous work29 by our group showed similar lung histology in control animals subjected to multiday experiments. The indices of oxidative and nitrosative stress, as well as proinflammatory cytokines, suggest that ALCO2R does not invoke an inflammatory response in the lung or in other organs such as the heart or liver. This was also supported by the observation of no significant elevation in lung myeloperoxidase activity, lung total antioxidant status, or heart TBARs. Taken together with the plasma biomarkers of tissue function and lack of histological evidence of tissue injury, these data suggest that ALCO2R is safe. Nevertheless, we cannot exclude the possibility that ALCO2R may have detrimental effects. The exposure of blood to reduced pH—even for a brief period—may have lasting consequences.30 Indeed, acidosis is known to inhibit chemotaxis and bactericidal functions of polymorphonuclear leukocytes, as well as cytotoxicity and proliferation of lymphocytes. Similarly, platelet aggregation may be impaired by exposure to lowered pH.31,32 In contrast, complement protein activation and antibody binding to leukocytes are enhanced during acidosis.33 Thus, further studies including control animals are needed to determine whether these aspects of the safety profile would be preserved under conditions as a treatment for lung injury or in subjects experiencing infectious diseases. Direct infusion of acids would have had deleterious effects on blood. To limit such consequences, we utilized an innovative approach to achieve extracorporeal acidification.14 Briefly, a hemodiafilter is interposed in the extracorporeal circuit after the ML and ultrafiltrate was generated with a peristaltic pump. This ultrafiltrate is acidified and then recirculated before the ML, allowing highly concentrated hyperosmolar acids to be injected into the recirculating ultrafiltrate. Direct injection of concentrated acids into the blood would have caused hemolysis, while on the contrary, a high volume of free water would have been necessary to infuse isotonic acids, causing severe electrolyte derangements. Both these complication are limited by our approach. Notably, we detected plasma-free hemoglobin levels even lower than the ones measured during our previous experiment,5 where the sole Hemolung device was used. The impact of LA infusion on acid–base homeostasis and electrolyte equilibrium was minor. In effect, we observed a steady level of plasma lactate after the first hour of ALCO2R, thus suggesting that LA was readily cleared from systemic circulation. Despite the fact that we provided LA at a lower dosage by weight compared with previous swine experiments (0.045 vs. 0.057 mEq · min−1 · kg−1), we nevertheless observed higher lactate plasma levels. This can be ascribed to the lower lactate clearance of sheep (i.e., about 10 ml · min−1 · kg−1)34 in contrast to swine (i.e., about 20 ml · min−1 · kg−1)23 and to the small size of our experimental animals. Although human lactate clearance by weight is similar to that of sheep (9 to 12 ml · min−1 · kg−1),35–37 in an adult man (i.e., weight 70 kg), LA infusion at 1.5 mEq/min (i.e., 0.021 mEq · min−1 · kg−1) would lead to an acceptable rise in arterial lactate up to 1.7 mEq/L. We consider this experiment to be a "stress test" of the ALCO2R technique. In this study, animals with intrinsically limited clearance capacity for lactate and small weight underwent a high-dose ALCO2R technique without any corrective intervention to stabilize their metabolism. Despite this, in this challenging scenario, ALCO2R was safe with respect to organ function, electrolyte equilibrium, and acid–base homeostasis, and at least as effective as the standard ECCO2R technique. We suggest that ALCO2R should be coupled with metabolic control obtained by euglycemia, as well as with the reduction of caloric intake. This hypothesis will need to be tested in large animal models of lung injury. Moreover, future studies are warranted to evaluate the efficacy of ALCO2R on a clinically relevant model of hypercapnia and the safety profile of the technique with regard to impairment of immunologic function, platelet aggregation, and activation of complement. Several solutions may be used to further ameliorate ALCO2R technique. Other metabolizable acids may be used (e.g., citric and acetic). These compounds may provide advantages other than acidification, such as blood anticoagulation14 or a more favorable metabolic profile.38 During ALCO2R, partial or total clearance of the infused acid may be desired. If so, the extracorporeal circuit we used may be easily supplemented with additional devices for ultrafiltrate removal and/or fluid replacement. Such a circuit would not only promote carbon dioxide removal but also provide blood purification and volume control, as well as clearance of the infused acid. Thus, in the setting of multiorgan failure (e.g., renal and pulmonary), modular multiorgan support technology15 can be envisioned. Last, nonmetabolizable acids may be used (e.g., hydrochloric acid), thus avoiding the caloric effects due to infusion of metabolizable acids. However, infusion of a nonmetabolizable acid would result in progressive accumulation of the parent anion (e.g., Cl−),39 thus requiring the development of further extracorporeal techniques to remove it. In this regard, we recently elaborated an ECCO2R technique based on electrodialysis of plasmatic water called respiratory electrodialysis capable of selectively modulating chloride concentration in the extracorporeal circuit.40 In a mechanically ventilated swine model, respiratory electrodialysis proved efficient in enhancing VCO2ML and controlling ventilation. In conclusion, feasibility and effectiveness of extracorporeal blood acidification in enhancing carbon dioxide removal by a ML was confirmed in a different species and by an independent laboratory. Moreover, the ALCO2R technique was demonstrated to be safe. However, infusion of LA without metabolic control caused a rise in EE that made ALCO2R no different from standard ECCO2R with respect to ventilation. We suggest that LA-enhanced ALCO2R should be coupled with active measures to control metabolism. This technology is being further developed to permit its application in humans. Institution where the study has been performed is Comprehensive Intensive Care Research Task Area, U.S. Army Institute of Surgical Research, Fort Sam Houston, San Antonio, Texas. Individuals or organizations to be acknowledged are as follows: for statistical support: James K. Aden, Ph.D. (Blood Research, U.S. Army Institute of Surgical Research, Fort Sam Houston, JBSA Fort Sam Houston, Texas); for figure editing: Simone Socio, M.D. (Dipartimento Scienze della Salute, Università Milano-Bicocca, Monza (MB), Italy); for technical support: Michael Lucas; Rachael Dimitri; Kerfoot P. Walker; Corina Necsoiu, M.D.; William L. Baker; Bryan Jordan, C.R.N. (Comprehensive Intensive Care Research Task Area, U.S. Army Institute of Surgical Research, Fort Sam Houston, JBSA Fort Sam Houston, Texas). Funding for this study was provided by the U.S. Army through the In-House Laboratory Independent Research Program at the U.S. Army Institute of Surgical Research, San Antonio, Texas. We acknowledge the following potential conflicts of interest. Dr. Pesenti received payment for lectures and service on speaker bureau from Maquet (Maquet Cardiopulmonary, Rastatt, Germany) and Novalung (Novalung, Heilbronn, Germany), received consulting honoraria from Maquet (Maquet Cardiopulmonary, Rastatt, Germany) and Novalung (Novalung, Heilbronn, Germany), and has patents pending or issued (WO2008EP03661, co-owned with Università Milano-Bicocca [Milano, Italy]; IT2012BO00405; IT2012BO00404). Dr. Batchinsky received support for travel and consulting honorarium from ALung Technologies (ALung, ALung Technologies, Pittsburgh, Pennsylvania) and Maquet (Maquet Cardiopulmonary, Rastatt, Germany). Dr. Cancio disclosed that this research was supported, in part, by his appointment to the Knowledge Preservation Program at the U.S. Army Institute of Surgical Research, administered by the Oak Ridge Institute for Science and Education, through an interagency agreement between the U.S. Department of Energy and the U.S. Army Medical Research and Materiel Command. The remaining authors stated that they do not have any potential conflicts of interest. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Del Sorbo Fanelli Terragni Dell'Amore Mascia Antro D'Amato Simonetti Persico Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure: A matched cohort study with historical control. Crit Care Med Pesenti Iapichino Uziel Agostoni Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. Pelizzola Kolobow Low frequency positive pressure ventilation with extracorporeal CO2 removal (LEPPV-ECCO2R) in acute respiratory failure (ARF): Technique. Trans Am Soc Artif Intern Organs Livigni Longobardo Selvaggi Vergano Efficacy and safety of a low-flow veno-venous carbon dioxide removal device: Results of an experimental study in adult sheep. Batchinsky Necsoiu Respiratory dialysis: Reduction in dependence on mechanical ventilation by venovenous extracorporeal CO2 removal. Burki Herth Teschler Randerath Hagmeyer Priegnitz Blaas Putensen Theuerkauf Quintel Moerer A novel extracorporeal CO(2) removal system: Results of a pilot study of hypercapnic respiratory failure in patients with COPD. Boffini El Qarra Comoglio Ribezzo Bonato The use of CO2 removal devices in patients awaiting lung transplantation: An initial experience. Transplant Proc Birocco Faggiano Tidal volume lower than 6 ml/kg enhances lung protection: Role of extracorporeal carbon dioxide removal. Karagiannidis Sipmann Hedenstierna Windisch Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: Pathophysiological and technical considerations. Burkart Agerstrand Thomashow Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc Patroniti Isgrò Albertini Costanzi Pirrone Scaravilli Blood acidification enhances carbon dioxide removal of membrane lung: An experimental study. Intensive Care Med Tomlinson The carbon dioxide membrane lung (CDML): A new concept. Mangili Redaelli Giani Ferlicca Scaccabarozzi Regional blood acidification enhances extracorporeal carbon dioxide removal: A 48-hour animal study. Kreyer Belenkiy Enhanced extracorporeal CO2 removal by regional blood acidification: Effect of infusion of three metabolizable acids. ASAIO J Modular extracorporeal life support: Effects of ultrafiltrate recirculation on the performance of an extracorporeal carbon dioxide removal device. Siobal Calculation of physiologic dead space: Comparison of ventilator volumetric capnography to measurements by metabolic analyzer and volumetric CO2 monitor. Respir Care Cournand Ideal alveolar air and the analysis of ventilation-perfusion relationships in the lungs. J Appl Physiol Karasawa Shishido Shibamoto Direct calorimetry using Swan-Ganz catheter for evaluation of general metabolic expenditure in acute cerebrovascular disease—Comparison between direct Fick method and indirect calorimetry technique. Neurol Med Chir (Tokyo) Dalle Lucca Simovic Dubick Lebeda Tsokos Decay-accelerating factor limits hemorrhage-instigated tissue injury and improves resuscitation clinical parameters. Assessment of oxidative stress in lungs from sheep after inhalation of wood smoke. Delzoppo Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: Prevalence, risk factors, and outcomes. Sosio Extracorporeal carbon dioxide removal through ventilation of acidified dialysate: An experimental study. J Heart Lung Transplant Bellani Infusion of 2.5 meq/min of lactic acid minimally increases CO2 production compared to an isocaloric glucose infusion in healthy anesthetized, mechanically ventilated pigs. A case of overfeeding complicating the management of adult respiratory distress syndrome. Zabolotny Youn Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling. Am J Physiol Endocrinol Metab Marinho-Carvalho Sola-Penna Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett Langouche Mesotten Vanhorebeek Endocrine and metabolic disturbances in critical illness: Relation to mechanisms of organ dysfunction and adverse outcome. Verh K Acad Geneeskd Belg Ferrannini Bonadonna De Kreutzemberg DelPrato Metabolic and thermogenic effects of lactate infusion in humans. Am J Physiol 3 pt 1 Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine. Nichol Laffey Hypercapnia and acidosis in sepsis: A double-edged sword? Noh Shear stress-induced pH increase in plasma is mediated by a decrease in P(CO(2)): The increase in pH enhances shear stress-induced P-selectin expression in platelets. Marumo Kakishita Groschner Wakabayashi Extracellular pH affects platelet aggregation associated with modulation of store-operated Ca(2+) entry. Lardner The effects of extracellular pH on immune function. J Leukoc Biol Kronfeld Hepatic and extrahepatic lactate metabolism in sheep: Effects of lactate loading and pH. Michaeli Revelly Chioléro Tappy Effects of endotoxin on lactate metabolism in humans. Leverve Gersbach Effects of cardiogenic shock on lactate and glucose metabolism after heart surgery. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Mavrocordatos Burnier Jéquier Effects of infused sodium acetate, sodium lactate, and sodium beta-hydroxybutyrate on energy expenditure and substrate oxidation rates in lean humans. Am J Clin Nutr Brimioulle Berre Dufaye Degaute Hydrochloric acid infusion for treatment of metabolic alkalosis associated with respiratory acidosis. Abd El Aziz El Sayed Deab Mantegazza Respiratory electrodialysis. A novel, highly efficient extracorporeal CO2 removal technique. Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Regional Blood Acidification Enhances Extracorporeal Carbon Dioxide Removal: A 48-hour Animal Study Anesthesiology (February 2014) In Vivo Whole-Body Resting Energy Expenditure and Insulin Action in Human Malignant Hyperthermia Anesthesiology (July 2000) This Month in: Anesthesiology Anesthesiology (March 2016) The Goldilocks Principle, Carbon Dioxide, and Acute Respiratory Distress Syndrome: Too Much, Too Little, or Just Right? Efficient Extra- and Intracellular Alkalinization Improves Cardiovascular Functions in Severe Lactic Acidosis Induced by Hemorrhagic Shock
When we are young, visual stimuli in the outer world — faces, objects, scenes — seem slow. But as we age, so do they seem to raise their speed. How does our brain make us perceive the world as too fast or too slow depending on our age? This question motivated the present study. Both scientific and anecdotal evidence indicates that older people tend to perceive stimuli as too fast because their processing of visual information is slowed compared to that of younger people. As cognitive neuroscience researchers, we are interested in understanding how this happens in the brain. We first establish the speed of visual processing of people of different ages. We do so by using experimental psychology paradigms that allow assessing visual attention in a well-controlled manner. For this study, 91 healthy volunteers (ages 20 to 77) performed a 'whole-report' visual attention task. Participants saw an array of four letters briefly presented (for less than the duration of an eye blink) on a computer screen. After each array's presentation, they should orally report all letters they had seen. The 'whole-report' paradigm we used is based on the theory of visual attention (or 'TVA') proposed by the Danish Professor Claus Bundesen in 1990. Controlling for factors related to the speed of visual processing that also differs among younger, middle-aged, and older people was crucial for this study. These factors included motor speed, memory, and the time needed to be able to see a stimulus. The TVA-based whole-report task permitted us to control them. Participants additionally underwent 12 minutes of functional magnetic resonance imaging while during rest ('resting-state fMRI'). These data allowed us to calculate 'functional connectivity.' Functional connectivity is the term used to define the temporal correlation of the activity among particular brain regions. It also represents a view of the brain as functioning in networks that support behavior and cognition. Previous research has pointed at one brain network as particularly relevant for the speed of visual processing: the 'cingulo-opercular network' — whose name refers to the two central regions it involves: the anterior cingulate cortex, which lies in the medial side of the frontal cortex, and the anterior insula, which lies behind the frontal operculum (or opening). Thus we focused on this network. Using TVA's proposed mathematical equations, we estimated each participant's speed of visual processing in 'number of letters per second.' Then we obtained each participant's individual version of the cingulo-opercular network. We determined the effect of older age on both. Figure courtesy Adriana L. Ruiz Rizzo. We replicated results from previous studies: older age was associated with both slowed visual processing and reduced functional connectivity in the cingulo-opercular network. More interestingly, beyond previous studies, we found that the degree of slowing in the visual processing was associated with the degree of functional connectivity in the cingulo-opercular network. In particular, the functional connectivity in one region of this network, the left insula, significantly correlated with the individual estimates of the speed of visual processing. The found association between the speed of visual processing and functional connectivity in the cingulo-opercular network was not observed when other age-relevant networks, visual attention functions, or health risk factors were examined instead. These control analyses indicate that age-related differences in the functional connectivity in the cingulo-opercular network, specifically, can contribute to the age-related differences that are observed in the speed of visual processing. The functional connectivity in the cingulo-opercular network additionally mediated the effect of age on the speed of visual processing. This finding suggests that the slowed visual processing observed in advanced ages might be given because aging would affect the functional connectivity in the cingulo-opercular network and then the functional connectivity in the cingulo-opercular network would influence the speed of visual processing. Longitudinal studies, however, should corroborate this suggestion. Our findings thus propose a model for studying changes in the speed of visual processing where the functional connectivity in the cingulo-opercular network plays a prominent role. We believe this model will open new avenues for the intervention studies that target the improvement of attention in older age. So perceiving the world as too fast or too slow does not appear to depend solely on our age — a network anchored in frontal regions connects to help us catch up with it. These findings are described in the article entitled Decreased cingulo-opercular network functional connectivity mediates the impact of aging on visual processing speed, recently published in the journal Neurobiology of Aging (Neurobiology of Aging 73 (2019) 50-60). This work was conducted by Adriana L. Ruiz-Rizzo, Natan Napiórkowski, Julia Neitzel, Aurore Menegaux, and Hermann J. Müller from the Ludwig-Maximilans-Universität München, Christian Sorg from the Ludwig-Maximilans-Universität München and the Technische Universität München, Signe Vangkilde from the University of Copenhagen, and Kathrin Finke from the Ludwig-Maximilans-Universität München and Jena University Hospital. Previous Post« Previous Endocan: Can It Predict Post-Operative Pneumonia?
Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia Nadene Dermody, Stephanie Wong, Rebekah Ahmed, Olivier Piguet, John R. Hodges, Muireann Irish Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. Journal of Alzheimer's Disease https://doi.org/10.3233/JAD-160175 orbitofrontal cortex right hemisphere theory of mind 10.3233/JAD-160175Licence: In Copyright Dive into the research topics of 'Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia'. Together they form a unique fingerprint. Frontotemporal Dementia Medicine & Life Sciences 100% dementia Social Sciences 80% empathy Social Sciences 74% deficit Social Sciences 66% Alzheimer Disease Medicine & Life Sciences 62% Atrophy Medicine & Life Sciences 26% Gyrus Cinguli Medicine & Life Sciences 10% Dermody, N., Wong, S., Ahmed, R., Piguet, O., Hodges, J. R., & Irish, M. (2016). Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. Journal of Alzheimer's Disease, 53(3), 801-816. https://doi.org/10.3233/JAD-160175 Dermody, Nadene ; Wong, Stephanie ; Ahmed, Rebekah ; Piguet, Olivier ; Hodges, John R. ; Irish, Muireann. / Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. In: Journal of Alzheimer's Disease. 2016 ; Vol. 53, No. 3. pp. 801-816. @article{efdb970453af4e7d9be75a165c80ea17, title = "Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia", abstract = "Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.", keywords = "Neurodegenerative diseases, orbitofrontal cortex, right hemisphere, social cognition, theory of mind", author = "Nadene Dermody and Stephanie Wong and Rebekah Ahmed and Olivier Piguet and Hodges, {John R.} and Muireann Irish", doi = "10.3233/JAD-160175", journal = "Journal of Alzheimer's disease : JAD", Dermody, N, Wong, S, Ahmed, R, Piguet, O, Hodges, JR & Irish, M 2016, 'Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia', Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 801-816. https://doi.org/10.3233/JAD-160175 Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. / Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R.; Irish, Muireann. In: Journal of Alzheimer's Disease, Vol. 53, No. 3, 2016, p. 801-816. T1 - Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia AU - Dermody, Nadene AU - Wong, Stephanie AU - Ahmed, Rebekah AU - Piguet, Olivier AU - Hodges, John R. AU - Irish, Muireann N2 - Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. AB - Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. KW - Neurodegenerative diseases KW - orbitofrontal cortex KW - right hemisphere KW - social cognition KW - theory of mind U2 - 10.3233/JAD-160175 DO - 10.3233/JAD-160175 JO - Journal of Alzheimer's disease : JAD JF - Journal of Alzheimer's disease : JAD Dermody N, Wong S, Ahmed R, Piguet O, Hodges JR, Irish M. Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia. Journal of Alzheimer's Disease. 2016;53(3):801-816. https://doi.org/10.3233/JAD-160175
Home/Supports & Services/Mealtime support Mealtime support for individuals with autism What is a mealtime assessment? What is mealtime therapy? Early years School years School leavers and adults Frequently asked questions What is mealtime support? For some individuals on the autism spectrum, difficulties with eating and drinking could mean that they benefit from mealtime support. Children and adults on the autism spectrum can sometimes experience difficulties with eating and drinking. These difficulties can include not liking some foods, finding it hard to accept new foods, disliking a variety of different textures, and not getting enough nutrition. This can mean having a limited diet which can, in turn, lead to other health and wellbeing issues. Mealtime support is designed to support autistic individuals who have a range of mealtime issues. It considers the impact different factors may be having on an individual's eating and drinking, and develops and implements appropriate personalised therapies to address them. How can I benefit from a mealtime assessment? A mealtime assessment will usually be undertaken by Autism SA Speech Pathologists and Occupational Therapists who work collaboratively to assess and identify needs in areas such as: Oral motor development and skills The phases of swallowing Sensory processing influences Food selectivity and volume Independence skills Posture and motor skills impacting on positioning, and Environmental impacts. In addition to an assessment of the above skills, an Autism SA mealtime assessment will provide a comprehensive report, recommendations, plans, strategies and more. A further outcome of a multidisciplinary mealtime assessment may include a recommendation of mealtime therapy or other strategies. How can I benefit from mealtime therapy? Mealtime therapy is designed to support autistic individuals who have a range of mealtime issues. It considers the impact different factors may be having on an individual's eating and drinking, and develops and implements appropriate personalised therapies to address them. Our team focus on identifying and individual's desires, setting goals and supporting a person to achieve these goals to enhance quality of life. Mealtime therapy in the early years can be provided 1:1 or within a group setting (if appropriate). It typically will target food play and the introduction of new foods by using the Sequential Oral Sensory (SOS) Steps to Eating™ approach. School years children can be engaged in mealtime group therapy or 1:1 mealtime therapy. Resistance to and around foods is addressed by exploring and experimenting with foods in the manner of a scientist, using approaches from the evidence-based Food Scientist™ approach. School leavers and adults A speech pathologist or occupational therapist can provide mealtime therapy for adults in sessions designed to target independence skills associated with mealtimes, such as food and meal preparation, or cooking. Adults can also engage in a mealtime therapy group with similarly aged adults who have an interest in cooking and mealtimes. How can I access the service? For more information about supports and services at Autism SA, please contact My Pathways on 1300 288 476 or [email protected]. If you would like to find out more or to access a mealtime service please email [email protected] You can access the Mealtime Services Referral Form by clicking the button below. Complete the Mealtime Services Referral form Autism SA is accredited and registered as a provider through the National Disability Insurance Agency (NDIA). This means that you can pay for services at Autism SA with your NDIS funding, or you may pay yourself, through fee for service. How can I get a referral for a mealtime assessment? The following people and professionals are able to make a direct referral to have a mealtime assessment with one of Autism SA's occupational therapists or speech pathologists: Individuals – self referral Child Health Nurses Other health professionals Childcare workers, kindergarten and school teachers, and Community health organisations. What funding options are available? Autism SA is accredited and registered as a provider through the National Disability Insurance Agency (NDIA). Mealtime support can also be provided through a Fee for service arrangement. Early years support Augmentative Alternative Communication (AAC)
Therapeutic Discovery Safety, Pharmacokinetics, and Activity of GRN1005, a Novel Conjugate of Angiopep-2, a Peptide Facilitating Brain Penetration, and Paclitaxel, in Patients with Advanced Solid Tumors Razelle Kurzrock, Nash Gabrail, Chandtip Chandhasin, Stacy Moulder, Carrie Smith, Andrew Brenner, Kamalesh Sankhala, Alain Mita, Kelly Elian, Danielle Bouchard and John Sarantopoulos Razelle Kurzrock Nash Gabrail Chandtip Chandhasin Stacy Moulder Carrie Smith Andrew Brenner Kamalesh Sankhala Alain Mita Kelly Elian Danielle Bouchard John Sarantopoulos GRN1005 is a novel peptide–drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m2 once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m2; the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m2 (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non–small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (−17% to −50%). In addition, six patients (11%; doses 30–700 mg/m2) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy. Mol Cancer Ther; 11(2); 308–16. ©2011 AACR. As many as 170,000 patients with solid tumors develop brain metastases in the United States each year (1). In the absence of effective treatment options, the prognosis for patients with brain metastases is poor, with an estimated median survival less than 4 months (1). Many studies exclude patients with brain metastases, despite the urgent need to develop treatments for this critical problem. Treatment of brain metastases sometimes includes steroids to control edema, anticonvulsants to control seizures, resection when appropriate, whole brain irradiation, radiosurgery, and/or chemotherapy with efficacy limited by the difficulty posed by the blood–brain barrier (2–5). GRN1005 (formerly known as ANG1005) is a conjugate of angiopep-2 (peptide backbone) and 3 molecules of paclitaxel that contribute approximately 50% of its molecular weight (MW; ref. 6). While standard paclitaxel is marketed in a formulation that contains Cremophor EL, GRN1005 is Cremophor free (7). This is advantageous, as many toxicities, such as hypersensitivity reactions, have been attributed to the Cremophor EL associated with paclitaxel (8). GRN1005 can actively penetrate into the brain compartment by targeting low-density lipoprotein receptor-related protein-1 (LRP-1), which is highly expressed on the surface of the blood–brain barrier. In vivo and in vitro data show that the brain's uptake rate of GRN1005 is 86-fold greater than paclitaxel and approximately 10-fold greater than temozolomide (6, 9). Using the same receptor-mediated transporter, GRN1005 enters tumor cells, many of which also express high levels of LRP-1. The bonds between angiopep-2 and paclitaxel are cleaved by esterases found in large concentrations in lysosomal compartments, releasing free paclitaxel to exert its antimitotic functions at the site of disease. Paclitaxel does not reach high concentrations in brain tumor tissue following normal intravenous injection, potentially due to transport by phospho-glycoprotein (10, 11). The potential for GRN1005 to cross the blood–brain barrier and specifically target tumor cells in patients with brain metastases would offer significant therapeutic advantages over currently available treatments. Herein, we report the results of a first-in-human, open-label, phase I clinical study conducted to assess the safety, tolerability, pharmacokinetics, and preliminary evidence of efficacy of GRN1005 in adult patients with advanced solid tumors. To be eligible, patients had to be 18 years or more of age and have progressing and measurable metastatic or advanced solid tumor not amenable to established forms of therapy, an Eastern Cooperative Oncology Group performance status 0 to 2, and adequate hematologic, hepatic, and renal function; patients enrolled into the expanded maximum tolerated dose (MTD) cohort were required to show evidence of progressing brain metastases by computed tomography (CT) or MRI scan before study entry. Patients with symptomatic brain metastases were not excluded from the study. Patients with unstable or uncompensated organ system dysfunction, known severe hypersensitivity to paclitaxel, severe toxicity with previous taxane treatment, and/or persistent ≥ grade 2 neurotoxicity were excluded. Treatment with P450, CYP3A4, and 2C8 enzyme-inducing anticonvulsant drugs during the study and within 14 days of day 1, and chemotherapy, immunotherapy, radiotherapy, and investigational agents during the study and within 4 weeks of day 1 were prohibited. Institutional Review Board approval and written informed consents were obtained before study-related procedures were started. This first-in-human, phase I, open-label study used a rapid dose-escalation design (12). The starting dose, 30 mg/m2, was calculated on the basis of toxicology studies in rats and dogs. Escalation by dose doubling was carried out for 2 dose levels (60 and 120 mg/m2), after which a modified Fibonacci escalation scheme (i.e., increases of 67%, 50%, 40%, and 33%) was used to guide dose increases. GRN1005 was administered by intravenous infusion at a concentration of 1.5 mg/mL and a rate of 8.0 to 8.5 mL/min (∼1 hour) once every 21 days. Premedication was not allowed during cycle 1 and was allowed only as medically indicated thereafter. In the dose-escalation phase, patients were enrolled sequentially into cohorts of 1 to 3 patients each, until a ≥ grade 2 drug-related toxicity was observed, at which point that and subsequent cohorts were expanded to a minimum of 3 patients. If one patient experienced a dose-limiting toxicity (DLT), a minimum of 6 patients were enrolled at that dose. Dose escalation continued until more than 1 of 6 patients in a cohort experienced a DLT during cycle 1, after which a lower dose was explored. Once identified, the MTD cohort was expanded to obtain additional safety and pharmacokinetics data and to explore potential antitumor activity in patients with brain metastases. Patients remained on study until disease progression, death, unacceptable toxicity, or consent withdrawal. DLT and MTD DLT was defined as any of the following occurring during cycle 1 that were treatment emergent and possibly related to GRN1005: any grade 3 or 4 nonhematologic toxicity; febrile neutropenia; grade 4 neutropenia lasting 7 days or more; grade 4 thrombocytopenia; grade 2 peripheral neuropathy lasting 7 days or more or ≥ grade 3 peripheral neuropathy of any duration. The MTD was defined as the dose level at which 1 or less of 6 patients in a cohort developed a DLT during cycle 1. Dose reductions (one dose level) were permitted for patients who experienced a DLT, and patients were allowed 2 dose reductions. Evaluation of safety Adverse events were recorded for patients who received at least one dose of GRN1005. Severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. Vital signs were measured at various time points up to 4 hours after infusion and regularly between infusions. Electrocardiograms were obtained before infusion and 30 minutes and 3 hours after infusion during cycle 1. Hematology, blood chemistry, and urine values were monitored regularly, and physical and neurologic examinations were also carried out. Neurocognitive testing Neurocognitive testing was done at baseline and every 6 weeks during treatment to assess potential neurotoxic effects. The battery included the following tests: Hopkins Verbal Learning Tests–Revised (HVLT-R); Trail Making; Controlled Oral Word Association (COWA); and Grooved Pegboard (13, 14). Test results were sent for central evaluation and reading by an independent reviewer. Serum for assessment of anti-GRN1005 antibodies was collected predose at each treatment cycle and at the final visit. Anti-GRN1005 antibodies were assayed by a validated ELISA with a sensitivity of 0.56 μg/mL or less (15, 16). Plasma samples for pharmacokinetics characterization were collected before infusion, at end of infusion, and 30 minutes, 1, 2, 3, 4, and 24 hours after infusion during cycles 1 and 3. GRN1005 and paclitaxel concentrations were determined with validated liquid chromatography/tandem mass spectrometry (LC/MS-MS) methods (17, 18). Concentrations of ANG1005 in human EDTA K2 plasma were determined with LC/MS-MS with a limit of quantitation of 0.50 to 2.00 μg/mL (17, 18). GRN1005 (MW of 5,109.14 Da) was extracted by protein precipitation and quantified by peak area ratio. A weighed 1/X2 linear regression was carried out to determine the concentration of GRN1005. Concentration of free paclitaxel was determined with LC/MS-MS with a limit of quantitation of 100 ng/mL. Paclitaxel (MW of 853.9 Da) was extracted from an aliquot of human EDTA plasma containing GRN1005 using an automated liquid–liquid extraction, then injected into a liquid chromatograph equipped with a tandem mass spectrometry detector and quantified by peak area ratio. A weighed 1/X2 linear regression was carried out to determine the concentration of paclitaxel. Evaluation of efficacy Treatment efficacy was evaluated by CT or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 (19) in all organs in which disease was present, including brain, before treatment, and every 6 weeks thereafter. Briefly, complete response was disappearance of all lesions; partial response was 30% or more reduction in the sum of the longest diameters of the lesions; stable disease was sum of longest diameters not decreased more than 30% and not increased more than 20%; and progressive disease was 20% or more increase in the sum of the longest diameters of the lesions. Overall response was determined by the primary physician; scans from patients dosed more than 300 mg/m2 and who experienced tumor shrinkage per RECIST were later sent to an independent radiologist for examination of lesion response per organ system. Descriptive statistics are provided for demographic, safety, pharmacokinetics, and efficacy data. Categorical data are summarized by frequency and percentages; continuous data are summarized by mean and SD, or median and range, as appropriate. Changes from baseline in neurocognitive test results were assessed using paired t tests. Patient characteristics Fifty-six patients were enrolled across 3 study centers in the United States (University of Texas MD Anderson Cancer Center, Houston, TX; Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, San Antonio, TX; and Gabrail Cancer Center, Canton, OH). A total of 160 doses of GRN1005 were administered, for a median of 2 doses per patient (range: 1–11). All 56 patients were included in safety and efficacy evaluations. Demographics and clinical characteristics at study entry are summarized in Table 1. Forty-one patients (73%) had brain metastases at the time of enrollment, including both patients who had and had not received prior brain radiation and patients treated with steroids, including while receiving GRN1005. The median number of prior therapies was 4 (range: 0–22). Patient demographics Reasons for study withdrawal were: disease progression (n = 33), adverse events (all causalities including not related to drug; n = 12), investigator decision (n = 4), consent withdrawal (n = 6), and death (n = 1). Dose escalation Patients were enrolled sequentially into the following dose cohorts: 30, 60, 120, 200, 300, 420, 500, 550, 650, and 700 mg/m2. At the 60 mg/m2 dose, grade 2 neutropenia and anemia occurred, and the dose level and subsequent dose-escalation cohorts were expanded to include 3 to 6 patients. At the 500 mg/m2 dose, the study sites noticed that the dosing solution was turning cloudy during the infusion period. On the basis of reported adverse events, the cloudy solutions did not jeopardize patient safety; enrollment was nevertheless temporarily interrupted to investigate the formulation. Analyses determined that at higher concentrations, GRN1005 was precipitating out of solution; this did not affect the purity of GRN1005 but did influence its potency. These patients were still included in safety and efficacy evaluations. A modified dilution process was subsequently implemented and dosing was repeated as of the 300 mg/m2 dose level in the interest of rigor. These findings were reported to the Institutional Review Boards and the U.S. Food and Drug Administration. DTLs and MTD No DLTs were reported at doses 550 mg/m2 or less. The first DLT (febrile neutropenia) was reported in one of 3 patients initially enrolled at 650 mg/m2. This patient was treated with filgrastim and intravenous antibiotics, and febrile neutropenia resolved in 2 days. Dose escalation continued after no DLTs were observed in the additional 3 patients enrolled at this dose level. A DLT occurred in 2 of 6 patients enrolled at the next dose level (700 mg/m2). One patient experienced grade 4 thrombocytopenia that was treated with a platelet transfusion to resolution the same day. Another patient with metastatic breast cancer to the bone, brain, liver, and lung experienced grade 3 hypotension accompanied by multiorgan failure within 6 days of the first infusion. Relationship to GRN1005 could not be ruled out because of the temporal relationship between events, although disease state could have also been a cause. Because criteria for MTD were exceeded at 700 mg/m2, the 650 mg/m2 dose was determined to be the MTD for GRN1005 and the dose cohort was expanded to 20 patients, including 16 with brain metastases. Among the 20 patients treated at 650 mg/m2, 5 patients experienced DLTs in the first cycle: febrile neutropenia (n = 2), dehydration with stomatitis (n = 1), neuropathy (n = 1), and pneumonia (n = 1). All 56 patients received at least one dose of GRN1005 and were evaluated for safety and tolerability. Dose reductions were required in 11 patients (20%). Myelosuppression was the major toxicity (Table 2) although most incidences were manageable and reversible with standard treatments. Dose-limiting neutropenia and febrile neutropenia was managed by the addition of granulocyte colony-stimulating factor (G-CSF), dose reduction, or both. Peripheral neuropathy was reported only at doses 420 mg/m2 or more; it occurred in 21.5% of patients (≥ grade 2 in 12.5% of patients). Infusion reactions were observed in 9% of patients (≥ grade 3 in 3.5% of patients); they occurred at doses ranging from 200 to 650 mg/m2. Symptoms included facial flushing, bradycardia, hypotension, and dyspnea; they occurred sporadically and despite premedication with acetylsalicylic acid, hydrocortisone, ranitidine, and diphenhydramine in one patient. Rash (≤ grade 2 in all cases) was reported only at 650 mg/m2; it occurred in 9% of patients. Rash, typically erythema, was not associated with infusion reaction except in one patient. Adverse events ≥ possibly related to GRN1005 One hundred and fifty-five samples from 45 patients were analyzed for presence of anti-GRN1005 antibodies. No antibodies were detected, even in patients who received up to 11 treatment cycles and/or patients who reported infusion reactions and/or rashes. Twenty patients carried out at least one posttreatment neurocognitive test battery and were included in the analysis. Results revealed no evidence that GRN1005 causes central nervous system (CNS) toxicity. One patient who experienced stable disease for more than 7.5 months showed significant improvement in memory, processing speed, and executive function after 6, 12, 18, and 24 weeks of therapy. Radiographic images of the patient's brain lesion showed changes in tumor size from baseline of −9%, +3%, −6%, and −3% at 6, 12, 18, and 24 weeks, respectively. Fifty-five patients had at least one posttreatment pharmacokinetics sample drawn and were included in the analysis. The pharmacokinetics of GRN1005 seemed to be dose proportional. After single dose intravenous infusion, GRN1005 showed an overall mean time to maximum observed plasma concentration (Tmax) ranging from 0 to 0.5 hours after infusion (Table 3). The mean terminal-phase elimination half-life (t1/2) was approximately 3.6 hours. Plasma concentrations of GRN1005 during and after cycle 1 infusion are shown in Fig. 1A. No evidence of accumulation was observed after repeat dosing, as indicated by comparable mean maximum concentration (Cmax) and area under the concentration–time curve to infinity (AUCinf) values at cycles 1 and 3 (Fig. 1B). Plasma concentrations of free paclitaxel measured at the MTD (650 mg/m2) revealed that most paclitaxel in plasma remained associated with angiopep-2 over the time course analyzed (Fig. 1C). Pharmacokinetic measures of paclitaxel exposure (Cmax and AUClast) showed that free paclitaxel exposures were approximately 14- to 15-fold lower than those of ANG1005-associated paclitaxel in plasma during both cycles (AUC = 1,447 μmol/L for GRN1005 versus 101 μmol/L for paclitaxel and Cmax = 1,187 μmol/L for GRN1005 versus 13 μmol/L for paclitaxel). There was no evidence of accumulation of unconjugated paclitaxel based on pharmacokinetics analyses for cycle 1 versus cycle 3. A, mean (±SEM) plasma concentrations of GRN1005 during and after infusion at cycle 1 (n = 3–20). B, mean plasma concentrations of GRN1005 in the MTD group (n = 8) at cycles 1 and 3. C, mean (±SEM) paclitaxel concentrations (free and associated with angiopep-2 expressed as paclitaxel-equivalent GRN1005) during cycle 1 in the MTD Group (n = 16). Pharmacokinetic data for GRN1005 All 56 patients were included in the efficacy evaluation. Response data were available for 43 patients: 39 patients had at least one posttreatment evaluation and 4 patients came off study early for clinical progression. The remaining 13 patients were not reevaluated posttreatment for the following reasons: consent withdrawal (n = 5), adverse events (n = 4), investigator decision (n = 3), and death (n = 1); these patients were considered treatment failures. Best overall responses (n = 43) are shown in Fig. 2A and Table 4. Five patients (9%) achieved a partial response (breast cancer, n = 2; non–small cell lung cancer (NSCLC), n = 2, 1 unconfirmed; and ovarian cancer, n = 1). All partial responses were observed at the 650 mg/m2 dose (MTD; Table 4). Among the 5 patients achieving partial response, all also experienced shrinkages in their brain lesions (Fig. 2B and C) as assessed by an independent radiologist; brain responses ranged from −17% to −50%. Furthermore, 3 of these patients had failed prior taxane therapy. No patients in Fig. 2B who had increase in brain lesions achieved partial response or stable disease for 4 months or more. A, best response in 43 of 56 patients treated. Patients with early clinical progression or new lesions are indicated on the graph as +21% and marked with an asterisk. Thirteen patients were not reevaluated posttreatment because of consent withdrawal (n = 5), adverse events (n = 4), investigator decision (n = 3), and death (n = 1). All these patients are considered treatment failures. B, brain responses in patients were assessed for nonprogressing patients who received doses from 420 mg/m2 and higher, including all patients who were treated at the MTD. C, radiographic images of the brain of 3 patients treated at the MTD (650 mg/m2) who achieved an overall best response of partial response: i, 45-year-old woman with breast cancer; ii, 73-year-old woman with ovarian cancer; and iii, 38-year-old woman with breast cancer. Overall best response by dose cohort The median duration of partial response was 1.5 months (range: 1–5 months). The greatest overall tumor reduction was observed in a 45-year-old woman with breast cancer metastasized to the brain, liver, lung, and lymph nodes who was treated at 650 mg/m2 for 5 cycles then 420 mg/m2 for 2 cycles. The patient achieved a partial response (−60%) after 1.5 months of GRN1005. Measurement of her brain lesions by an independent radiologist showed shrinkage of −48% after 4.5 months of treatment [Fig. 2C (i)]. The patient withdrew from the study after approximately 6.5 months due to neuropathy. In addition to the 5 patients with partial response, 6 patients (11%) had stable disease for 4 months or more, with the longest duration being 8 months (a patient with NSCLC and brain metastasis dosed at 420 mg/m2). GRN1005 administered as monotherapy by intravenous infusion once every 3 weeks was well tolerated up to 650 mg/m2. The most common DLT was febrile neutropenia. The most frequently observed toxicity was myelosuppression, which was generally manageable and reversible with standard treatments. Adverse events such as peripheral neuropathy, infusion reactions, and rashes were seen in a minority of patients, and no CNS toxicity was revealed by neurocognitive testing and neurologic examination. Reversal of neurologic deficits after treatment with GRN1005 was observed in one patient who showed marked improvements in memory, processing speed, and executive function after only 6 weeks of therapy; these improvements were accompanied by a 9% shrinkage of brain metastases. The pharmacokinetics of GRN1005 showed dose proportional increases in Cmax and AUCinf at doses ranging from 30 to 700 mg/m2. The mean t1/2 was 3.6 hours; in contrast, the t1/2 for nab-paclitaxel is 21.6 hours and 20.5 hours for paclitaxel (20). Repeat dosing revealed no evidence of accumulation, lending evidence to support the safety of long-term GRN1005 use. Analyses at the MTD showed that most paclitaxel in plasma remains associated with the angiopep-2 peptide over a period of at least 24 hours postinfusion. The Cmax for GRN1005 at the MTD was 3,06,000 ng/mL versus 22,968 and 3,543 μg/mL for nab-paclitaxel and paclitaxel, respectively, at doses of 260 and 175 mg/m2 (which are their MTDs; ref. 20). This supports preclinical testing results and correlates well with the favorable safety profile observed in patients to date. Although GRN1005 has a peptide backbone, no anti-GRN1005 antibodies were detected even after repeat dosing and in cases where infusion reactions and rashes were observed. These results suggest that GRN1005 does not elicit an antibody response. In this heavily pretreated patient population, treatment with GRN1005 showed evidence of efficacy with tumor stabilization and several cases of significant reductions in tumor size. While paclitaxel is efficacious against various cancers, the clinical use of paclitaxel to treat brain cancer has been hampered by the inability of molecule to cross the blood–brain barrier and reach the tumor. In this study, 5 of 20 patients (25%) dosed at the MTD (650 mg/m2) achieved an overall partial response; in each of these patients, there was also shrinkage in brain metastases by RECIST criteria (−17% to −50%). Three of these patients had failed prior taxane therapy. Future phase II studies could also evaluate brain response by Macdonald and RANO criteria (21, 22). The receptor that facilitates GRN1005's penetration of the brain, LRP-1, is not only highly expressed on the surface of the blood–brain barrier, it is also upregulated in various cancer cell types (23). Lesion response by organ system was therefore assessed by an independent radiologist in patients dosed more than 300 mg/m2 and who experienced tumor shrinkage per RECIST (data not shown). Interesting antitumor effects were observed in metastatic locations including the liver, lungs, lymph nodes, and bones. Notably, 7 of 8 patients with liver metastases showed shrinkage in their liver lesions (maximum = −100%) and all 9 patients with lung lesions had tumor shrinkage within the lung (maximum = −100%). Lung metastases and liver lesion shrinkage occurred even in patients who did not have an overall response of partial response, including one patient with a complete response in liver lesions and one patient who achieved a partial response in the lung. In addition, one patient who did not achieve an overall partial response had a partial response in her brain lesions. These data points to a possible distinct ability of GRN1005 to effectively treat patients with brain metastases as well as active systemic disease. In summary, GRN1005 is a new chemical entity with a unique targeting mechanism. It was well tolerated and showed evidence of activity in patients with advanced solid tumors and brain metastases. These results suggest that GRN1005 is able to penetrate the blood–brain barrier and has activity in both the brain and other metastatic sites, despite failure of multiple previous lines of therapy including taxanes. Further study of this molecule at the recommended phase II starting dose of 650 mg/m2 given intravenously once every 3 weeks is warranted and studies in patients with breast and NSCLC with brain metastases are planned. K. Elian was employed by Angiochem Inc. at the time the research was conducted. R. Kurzrock received commercial research support from Angiochem Inc. No potential conflicts of interest were disclosed by the other authors. This study was supported by Angiochem Inc., Montreal (Québec), Canada, and the Institute for Drug Development, Cancer Therapy, and Research Center at University of Texas Health Science Center San Antonio: Cancer Center Support Grant (P30CA054174). The authors thank the patients and their families for their participation; Zhong Guo for study conduct at MDACC; Sonia-Morgan-Linnell for assisting with manuscript preparation; Cherie Noles for study conduct at CTRC; and Christina Meyers, Jean-Paul Castaigne, Betty Lawrence, Wendy Churchill, Paula Bento, Bruno Fraitag, Dimitri Fitsialos, and Ann Neale for their contributions. Note: This study was presented in part at the European Organization for Research and Treatment of Cancer (EORTC)/National Cancer Institute (NCI)/American Association for Cancer Research (AACR) Meeting, Geneva, Switzerland, October 20–24, 2008; Society for NeuroOncology (SNO) Annual Meeting, Lake Las Vegas, NV, November 20–23, 2008; 15th Annual Blood-Brain Barrier Consortium Meeting in collaboration with The International Brain Barriers Society, Gleneden Beach, OR, March 19–20, 2009; American Association for Cancer Research (AACR) Annual Meeting, Denver, CO, April 18–22, 2009; Society for Neuroscience (SfN) Annual Meeting, Chicago, IL, October 17–21, 2009; Joint meeting of the Society for Neuro-Oncology (SNO)/American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS), New Orleans, LA, October 22–24, 2009; American Association for Cancer Research (AACR)/National Cancer Institute (NCI)/European Organization for Research and Treatment of Cancer (EORTC) International Meeting, Boston, MA, November 15–19, 2009; American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 4–8, 2010. 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Regina A, Demeule M, Che C, Lavallee I, Poirier J, Gabathuler R, Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol 2008;155:185–97. [PACKAGE INSERT DATA]: TAXOL (paclitaxel) INJECTION, solution. Princeton, NJ: Bristol-Myers Squibb Co.; 2010. Rev 2007 July. Gelderblom H, Verweij J, Nooter K, Sparreboom A . Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 2001;37:1590–8. Thomas FC, Taskar K, Rudraraju V, Goda S, Thorsheim HR, Gaasch JA, Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res 2009;26:2486–94. Fellner S, Bauer B, Miller DS, Schaffrik M, Fankhanel M, Spruss T, Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo . J Clin Invest 2002;110:1309–18. Heimans JJ, Vermorken JB, Wolbers JG, Eeltink CM, Meijer OW, Taphoorn MJ, Paclitaxel (Taxol) concentrations in brain tumor tissue. Ann Oncol 1994;5:951–3. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC . Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 1997;89:1138–47. Meyers CA, Brown PD . Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol 2006;24:1305–9. Smith JA, Bezjak A, Liebmann J, Illidge T, Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 2004;22:157–65. Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Maia M, Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods 2004;289:1–16. A direct enzyme-linked immunosorbent assay (ELISA) to detect human antibodies against ANG1005 in human serum. Billerica, MA: Millipore Drug Discovery Project; 2008. Number 07-048. Validation of a high performance liquid chromatographic method using tandem mass spectrometry detection for the determination of ANG1005 in human EDTA plasma. Montreal, Canada: Anapharm Project; 2009. Number 77074QSI. Non-GLP determination of paclitaxel in human EDTA plasma for study samples containing ANG1005 using a high performance liquid chromatographic method with tandem mass spectrometry detection. Montreal, Canada: Anapharm Project; 2009. Number 77075QSR. Therasse P, Eisenhauer EA, Wanders J, Kaplan RS, New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.J Natl Cancer Inst 2000;92:205–16. Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res 2005;11:4136–43. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963–72. van den Bent MJ, Wefel JS, Schiff D, Jaeckle K, Junck L, Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 2011;12:583–93. Song H, Li Y, Lee J, Schwartz AL, Bu G . Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 2009;69:879–86. You are going to email the following Safety, Pharmacokinetics, and Activity of GRN1005, a Novel Conjugate of Angiopep-2, a Peptide Facilitating Brain Penetration, and Paclitaxel, in Patients with Advanced Solid Tumors Ligand Systemic Targeting of the Grp78 Promoter Sorafenib Targets VCP in Hepatocellular Cancer Cells RSK2 as Therapeutic Target for Myeloma Show more Therapeutic Discovery
Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts Myriam Alexander1, A. Katrina Loomis2, Johan van der Lei3, Talita Duarte-Salles4, Daniel Prieto-Alhambra5, David Ansell6, Alessandro Pasqua7, Francesco Lapi7, Peter Rijnbeek3, Mees Mosseveld3, Dawn M. Waterworth8, Stuart Kendrick9, Naveed Sattar10 na1 & William Alazawi ORCID: orcid.org/0000-0002-3891-591411 na1 Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 "non-NAFLD" patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43–9.19) and for HCC, 3.51 (95% CI 1.72–7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. NAFLD represents a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis [1]. The numbers of individuals presenting with end-stage complications of NASH, namely decompensated cirrhosis and hepatocellular carcinoma (HCC), are rising [2, 3], and NASH is rapidly becoming the most common indication for liver transplantation [4]. Yet not all patients within the NAFLD spectrum progress, and for the majority, NAFLD is a benign condition [1]. A key clinical challenge is to identify the proportion of patients who are at high risk of developing advanced liver disease, so that interventions, including the many novel therapies in development, can be targeted to those at greatest need. Our current understanding of NAFLD epidemiology and progression largely derives from single-centre studies of small- or medium-sized cohorts and meta-analyses of these [5,6,7]. These studies, together with emerging data from placebo arms of therapeutic trials [8], have taught us that patients with existing evidence of progressive disease (e.g., fibrosis) are at risk of further progression to HCC and decompensated cirrhosis, albeit this may reflect a degree of lead-time bias. Such studies often involve formal assessment of well-phenotyped patients at inclusion but are, by design, selective and may not represent the 'real-world' situation for the majority of patients with NAFLD. Paired biopsy data have been reported, although the second biopsy is often performed because of clinical suspicion and not per study protocol, which may bias estimates of progression [9]. Real-world patients are socially and ethnically diverse, have comorbidities and concomitant medications or simply cannot commit to long-term studies or trials and therefore may not be represented by any of these study designs. Increasingly, real-world data derived from primary care electronic health records (EHR) of a sizeable proportion of the general population [10, 11] are being used to address these issues. In many European countries, where healthcare is largely state-funded and there are low or absent primary care co-payments, the population has unrestricted access to healthcare via primary care physicians who act as gatekeepers for referral to secondary care [12]. People register with primary care centres at birth or when they move to an area in order to access healthcare; therefore, primary care EHR represent data that are as close to the 'general' population as possible. If a practice joins the database, all the patients at that practice are registered in the database and, although there is an option for individual patients to opt out, this is minimal (< 1%). In order to gain insights into the NAFLD spectrum of diseases in real-world patients, we extracted data from four large European primary care databases and identified a cohort of patients with a diagnosis of NAFLD or of NASH. Our aim in this study was to estimate the risk for patients with diagnoses of NAFLD or NASH to acquire a new diagnosis of cirrhosis and HCC and to understand the main predictors for this. Databases were accessed via the European Medical Information Framework (EMIF) network: The Health Search Database (HSD) in Italy [13], The Integrated Primary Care Information (IPCI) in the Netherlands [14], the Information System for the Development of Research in Primary Care (SIDIAP) in Spain [15] and The Health Information Network (THIN) in the UK [16] (Additional file 1: Table S1). HSD collects electronic medical record data from a network of over 800 Italian GPs who are members of the Italian College of General Practitioners. IPCI is a longitudinal collection of electronic patient records from over 750 Dutch general practitioners, containing data from over 2 million patients. SIDIAP collects data from 274 primary care practices comprising 3414 basic care units [17], and THIN contains the electronic medical records of 11.1 million patients from 562 general practices in the UK, covering 6.2% of the UK population [18]. The data custodians for each database provided approval that the protocol of the study complied with local privacy laws. Anonymised data were extracted locally by each data custodian liaising with the EMIF Platform and using a data transformation tool called Jerboa Reloaded [10]. The data were then uploaded onto a secure remote server maintained by an independent academic centre (Erasmus Medical Centre Private Research Environment, Netherlands) and analysed centrally. We conducted a matched cohort study. All patients with a diagnosis of NAFLD or NASH (termed NAFLD/NASH) prior to 01/01/2016 were identified in the four databases using harmonisation methods previously described [10]. Patients were included in the analysis if they were aged ≥ 18 at diagnosis and had medical records available for ≥ 12 months from registration with the practice. Exclusion criteria were missing information on age and sex, a record of alcohol abuse at any time prior to diagnosis and a history of liver morbidity within the 12 months prior to diagnosis [10] (see Additional file 1: Supplementary Methods for exclusion diagnoses). Each NAFLD/NASH patient was matched with up to 100 'non-exposed' controls who did not have a NAFLD or NASH diagnosis at or prior to the index date (defined as the date of diagnosis of the matched NAFLD/NASH patient). Matching was done by practice site, age at index date ± 5 years, sex and a visit at the practice within ± 6 months of the index date. In the THIN and SIDIAP databases, the terminology of the database (Read code and International Classification of Disease version 10, ICD10, respectively) allowed NAFLD and NASH diagnoses to be distinguished from each other. Therefore, in these databases, a matched control cohort was constructed for each of the diagnoses: NAFLD, NASH and, to enable comparison between all databases, NAFLD/NASH. If a patient had both NAFLD and NASH diagnoses recorded, the earliest event was used to define index date of NAFLD/NASH diagnosis, and the NASH diagnosis deemed an incident event. In HSD (ICD 9) and IPCI (IPCI Dutch), where NAFLD and NASH could not be distinguished, only one cohort (NAFLD/NASH) was defined and controls matched to this. Patients were followed up from the index date until the earliest of occurrence of cirrhosis, hepatocellular carcinoma or NASH (where this could be identified), end of the study period (31/12/2015) and loss of follow-up due to exit out of the database or death. Events of interest were incident diagnosis of cirrhosis, hepatocellular carcinoma or NASH, where this could be identified. See Additional file 1: Supplementary Methods for variable extraction and data analysis. Out of 18,782,281 eligible individuals in the four databases, we identified 136,703 (0.7%) who had a recorded diagnosis of either NAFLD or NASH (coded NAFLD/NASH) and who met the inclusion criteria (Additional file 1: Table S1). The Spanish (SIDIAP) and UK (THIN) databases contributed 71% of all cases; the remaining 29% of coded NAFLD/NASH cases were from the Dutch (IPCI) and Italian (HSD) databases. In SIDIAP, 2.5% of all coded NAFLD/NASH patients (n = 1880) had NASH, and in THIN, this was 4.7% (n = 1212). Due to the coding, NAFLD and NASH could not be distinguished in IPCI and HSD. Therefore, in the initial phase of analysis, we combined all NAFLD and NASH codes from all four databases as coded NAFLD/NASH. Comparing coded NAFLD/NASH patients across the four databases, there were minor differences between databases in mean age, BMI and proportion with diabetes (Table 1 and Additional file 1: Table S2). BMI data were available in 64.6% of patients with coded NAFLD/NASH and in 45.9% of matched controls (Additional file 1: Table S3). In the subset of patients for whom data were available, ALT and AST values were highest in THIN, and the proportion of obese patients highest in SIDIAP. Sufficient data were available to calculate the non-invasive fibrosis Fib-4 score (age, AST, ALT and platelets) in 46.7% of patients (range 12.6–62.6%, Table 2). THIN (UK) had the smallest proportion of patients with Fib-4 data (12.6%), in whom the proportion of patients with high-risk scores was 10.5%, highest among the four databases. Table 1 Descriptive characteristics of coded NAFLD/NASH patients and matched unexposed cohorts Table 2 Distribution of Fib-4 scores in coded NAFLD/NASH patients shown for each country database Patients with a coded diagnosis of NAFLD/NASH had comparable age and sex distribution, smoking rates and duration of follow-up as matched controls (Table 1). As expected, however, controls had lower BMI; lower rates of obesity, hypertension or diabetes; and lower serum levels of ALT and AST. Risk of incident cirrhosis and HCC is higher in NAFLD/NASH patients compared to controls Combining all four databases, the median duration of follow-up was 3.3 years (IQR 1.8–5.3) totalling 531,452 person-years for patients with coded NAFLD/NASH and 43,385,495 person-years for controls. Among all coded NAFLD/NASH patients, the incidence of cirrhosis diagnosis was 0.76 per 1000 person-years, (95% confidence interval (CI) 0.46 to 2.32), and the incidence of hepatocellular carcinoma diagnosis was 0.3 per 1000 person-years, (0.26 to 0.60; Additional file 1: Table S4). Patients with coded NAFLD/NASH were at significantly higher risk of acquiring a new diagnosis of cirrhosis compared to controls with a pooled HR of 4.73 (95%CI 2.43–9.19) after adjustment for age, smoking status and BMI (Fig. 1). Association of coded NAFLD/NASH, NAFLD and NASH with cirrhosis. Hazard ratios and 95% confidence interval for acquiring a new diagnosis of cirrhosis in each database and combined across databases (subtotal) Similarly, the risk of incident HCC diagnosis was significantly higher in coded NAFLD/NASH patients compared to controls. The pooled HR across the four databases for an incident diagnosis of HCC was 3.51 (95%CI 1.72–7.16 Fig. 2). There were no significant differences in the HRs when categorising patients into those with and without obesity, smoking, diabetes or hypertension; male sex and older age (Additional file 1: Figure S1). There were no significant differences in the HRs for cirrhosis and HCC diagnoses following adjustment for age and smoking alone in all coded NAFLD/NASH patients compared to patients with available BMI data (Additional file 1: Figures S2 and S3). This is despite the fact that patients with BMI data were more likely to be smokers (19.5% vs 11.2%), diabetic (26.9% vs 7.0%) and hypertensive (50.1% vs 27.9%, Additional file 1: Table S5). Association of coded NAFLD/NASH, NAFLD and NASH with hepatocellular carcinoma (HCC). Hazard ratios and 95% confidence interval for acquiring a new diagnosis of HCC in each database and combined across databases (subtotal) Fib-4 predicts disease progression in patients with NAFLD/NASH In the subset of coded NAFLD/NASH patients in whom we could calculate Fib-4 (n = 63,971, Additional file 1: Table S3), the incidence of a new diagnosis of cirrhosis was significantly higher for the high-risk compared to low-risk category (HR 33.24, 95%CI 8.82–125.34), adjusting for age and smoking status and more modest, albeit still significant, for the intermediate compared to low-risk group (HR 5.04, 95%CI 2.30–11.04 Additional file 1: Figure S4A). Similarly, compared to patients with low-risk scores, the incidence of an HCC diagnosis was higher in patients with indeterminate (HR 3.74, 95%CI 1.76–7.96) or high-risk scores (HR 25.2, 95%CI 7.83–80.66, Additional file 1: Figure S4B). Distinguishing NAFLD from NASH diagnoses when estimating risk of cirrhosis and HCC The pooled HR for incident NASH diagnosis in patients with a coded diagnosis of NAFLD compared to controls was 7.75 (95%CI 2.56–23.51, p = 0.008) although this estimate is based on a very small number of individuals (n = 130 of whom only seven were in SIDIAP, Additional file 1: Figure S5). In the subset of patients with a coded diagnosis of NASH, the incidence of diagnoses of liver outcomes was higher than in those with NAFLD albeit confidence intervals overlapped: 3.25 per 1000 person-years (95%CI 2.41–4.10) for cirrhosis and 1.16 per 1000 person-years (95%CI 0.67–1.65) for HCC (Figs. 1 and 2). Short time interval to cirrhosis diagnosis in patients with NAFLD and NASH In SIDIAP, 174 out of 75,415 patients with coded NAFLD were coded as having cirrhosis (incidence rate 0.66 per 1000 person-years (95%CI 0.56–0.76) with a median time to the new diagnosis of 2.9 years whereas 38 out of 1880 patients with NASH acquired a diagnosis of cirrhosis (incidence rate 2.83 per 1000 person-years (95%CI 2.0–3.88, Additional file 1: Table S4) with a similar median time to diagnosis of 3.0 years (Additional file 1: Table S6). In THIN, the incidence of cirrhosis was higher and the interval between diagnoses was shorter for both stages of disease. One hundred three out of 24,743 patients with coded NAFLD acquired a cirrhosis diagnostic code (incidence rate 2.17 per 1000 person-years (95%CI 1.86–2.51) with median time to diagnosis of 2.0 years, compared to 26 out of 1212 patients with coded NASH (incidence rate 5.81 per 1000 person-years (95% CI 3.8–8.52) with median time to diagnosis of 0.5 years. Diabetes predicts disease progression In coded NAFLD/NASH patients, the strongest association with incident liver outcomes was observed in patients who also had a past diagnosis of diabetes at baseline (HR 2.3, 95% CI 1.9–2.78). In matched controls without coded NAFLD/NASH, smoking was also associated with liver outcome (HR 1.5, 95% CI 1.41–1.6) in addition to the independent risk attributed to diabetes, which was higher than in patients with coded NAFLD/NASH (HR 2.92, 95% CI 2.76–3.08, Table 3). Table 3 Association between covariates and risk of liver outcomes: cirrhosis or hepatocellular carcinoma. Using a 1-step Cox model stratified by database To our knowledge, this is the largest study to date that has used EHR data to investigate rates of new diagnoses of advanced liver disease in patients with NAFLD. Our patients were well-matched to a very large number of controls according to sex, age, GP practice and most recent visit, thus limiting bias due to geographical and socioeconomic diversity and behaviours relating to health service utilisation. Patients with coded NAFLD/NASH are at significantly increased risk of acquiring a diagnosis of cirrhosis or HCC, compared to matched controls. The risk is greater in patients with a coded diagnosis of NASH compared to NAFLD and in those with high-risk Fib-4 fibrosis scores compared to indeterminate or low-risk scores. Diabetes is an independent risk factor for progression to either HCC or cirrhosis diagnoses in both coded NAFLD/NASH patients and matched controls. We applied minimal selection criteria and therefore were able to include over 78% of all adults registered in the databases, hence the 'real-world' nature of the study. The overall proportion of people with coded NAFLD/NASH diagnoses is lower than expected as reported previously [10], is in keeping with other primary care work [19] and may reflect levels of awareness of NAFLD/NASH in primary care [20, 21]. Hence, our data, by definition, can only represent the visible part of the clinical iceberg. Despite this, we find that patients with coded NAFLD/NASH acquire diagnoses of life-threatening liver disease within a relatively short follow-up period (median 3.3 years). It is not feasible that the short time intervals between coded diagnosis of NAFLD/NASH and advanced liver disease reflect true rates of disease progression, estimated to be one fibrosis stage per 7 years [22]. The acquisition of a new code in the healthcare record does not necessarily mean that pathological progression has occurred at that time, nor that the stage did not exist at baseline. Our interpretation of these data is that patients in Europe are being diagnosed at the later stages of disease, which are associated with greater risk of liver-related mortality [23,24,25]. Less than 50% of patients had sufficient data to calculate Fib-4, the components of which are also needed to calculate many other non-invasive fibrosis scores [26]. There was marked national variation in fibrosis assessment; 73.1% of patients in whom we could calculate Fib-4 were from the Spanish database. We have no way of determining whether these scores were actually calculated by clinicians and whether they influenced decision-making. This is despite the fact that such risk stratification is central to most guidelines [27,28,29], used to determine clinical management, select patients for clinical trials and probably triage patients for future therapy. In the databases where NAFLD/NASH codes could not be distinguished (HSD and IPCI), even those with low-risk Fib-4 scores were at increased risk of cirrhosis and HCC compared to controls. This further suggests that primary care records under-estimate disease severity and that some patients with NAFLD/NASH diagnoses actually have advanced fibrosis or cirrhosis already. Apart from a diagnosis of NAFLD/NASH, diabetes was the strongest independent risk factor for acquiring a diagnosis of cirrhosis or HCC. In the matched control population, the HR for diabetes was even higher than the coded NAFLD/NASH cohort, which may reflect a significant number of individuals with undiagnosed NAFLD/NASH among the controls. The importance of diabetes is consistent with a review of patients who had undergone more than one biopsy in the course of their routine clinical care in the UK, which showed that diabetes was a risk factor for progression of fibrosis [9]. Obesity is an important risk factor for many cancers including HCC [30], but we did not find that in our study. If patients are diagnosed late in the disease spectrum, it is unlikely that patients will have undergone surveillance and HCC may be diagnosed at late stages when symptoms including weight loss are manifest. Taken together, these findings emphasise the need to recognise risk factors for progressive disease and to detect disease at early stages when interventions can be more effective. This study is subject to limitations. The nature of real-world data is such that we cannot ascertain the origin of codes nor the motivation for adding diagnoses to the patient record. Although the study is based in primary care, it is likely that a large proportion of diagnoses will have been made with some involvement of secondary care. It would be inaccurate to assume that all patients who carry the code 'NASH' have had a liver biopsy and histological assessment and it might be that the diagnosis was assumed and recorded based on, for example, ultrasound evidence of fatty liver and elevated serum transaminases or increased stiffness on transient elastography. Similarly, it was not possible to confirm that the matched controls did not have NAFLD/NASH. However, the clinical features of patients with coded NAFLD/NASH are consistent with the diagnostic codes, although if patients with NAFLD/NASH do exist in the control group then the effect sizes reported here are underestimates of the real risk. This means that there are individuals living with diabetes in primary care who have not been diagnosed with NAFLD/NASH but are at significantly increased risk of developing liver cirrhosis and cancer. The estimated size of the NAFLD problem has raised fears of large unmanageable patient numbers who are not at immediate threat of disease. Notwithstanding our expectation that many cases have not been identified in this study, we have shown that 0.6% of patients with an existing coded diagnosis of NAFLD/NASH acquire a diagnosis of cirrhosis and/or HCC within a 3-year follow-up period. This gives us insight into the rate at which advanced disease is discovered, even if this is not the natural history in the general population. The clinical impact of our data is that they highlight the large gaps in diagnosis and risk assessment of NAFLD and NASH with variable rates of risk stratification, staging of disease and seemingly late diagnosis. Our knowledge of NAFLD/NASH is being based on small, highly selected cohort studies. These have been accurate in telling us the potential scale of the prevalence and progression of disease, but the reality for many in the general population is some way from that. In order to affect population health and make an impact on the overall health burden of advanced liver disease, we cannot simply rely on introducing effective therapies to the small number of people with established diagnoses. The current approach to opportunistically investigate those in whom abnormalities in liver tests arise is clearly not working. While better biomarkers are needed that identify those at risk more precisely, the current tools are not being used, leaving many patients unclear as to the stage of their disease and its significance to their health. Therefore, making an impact on advanced liver disease will need co-ordinated efforts to identify those with NAFLD, to stage their disease and target those at risk of progression. AST: Aspartate transaminase CI: EHR: EMIF: European Medical Information Framework HCC: HSD: Health Search Database IPCI: Information System for Research in Primary Care LFT: NAFLD: Non-alcoholic fatty liver disease NASH: Non-alcoholic steatohepatitis SIDIAP: THIN: The Health Improvement Network Friedman SL, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22. Dyson J, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol. 2014;60(1):110–7. Mittal S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31 e1. Wong RJ, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55. Koehler EM, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol. 2012;57(6):1305–11. Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595–602. Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. Nunez, D.J., et al., Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol. 2019;316(3):G372–86. McPherson S, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55. Alexander M, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16(1):130. Vargas-Santos AB, et al. Association of Chronic Kidney Disease with Allopurinol use in gout treatment. JAMA Intern Med. 2018;178(11):1526–33. Kringos D, et al. The strength of primary care in Europe: an international comparative study. Br J Gen Pract. 2013;63(616):e742–50. Gini R, et al. Chronic disease prevalence from Italian administrative databases in the VALORE project: a validation through comparison of population estimates with general practice databases and national survey. BMC Public Health. 2013;13:15. Vlug AE, et al. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med. 1999;38(4–5):339–44. Garcia-Gil Mdel M, et al. Construction and validation of a scoring system for the selection of high-quality data in a Spanish population primary care database (SIDIAP). Inform Prim Care. 2011;19(3):135–45. Blak BT, et al. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care. 2011;19(4):251–5. Filippi A, et al. Computerized general practice databases provide quick and cost-effective information on the prevalence of angina pectoris. Ital Heart J. 2005;6(1):49–51. IQVIA. The Health Improvement Network. 18th March, 2019]; Available from: https://www.iqvia.com/locations/uk-and-ireland/thin-hes-data. Accessed 30 Apr 2019. Alazawi W, et al. Ethnicity and the diagnosis gap in liver disease: a population-based study. Br J Gen Pract. 2014;64(628):e694–702. Patel PJ, et al. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis. Intern Med J. 2018;48(2):144–51. Standing HC, et al. GPs' experiences and perceptions of early detection of liver disease: a qualitative study in primary care. Br J Gen Pract. 2018;68(676):e743–9. Singh S, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643–54 e9. Boursier J, et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol. 2016;65(3):570–8. Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–54. Younossi ZM, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. Hepatol Commun. 2017;1(5):421–8. De Silva S, et al. Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of south Asian descent. Frontline Gastroenterol. 2018;9(2):115–21. Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. European Association for the Study of the Liver European Association for the Study of Diabetes European Association for the Study of, O. EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402. Newsome PN, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6–19. Hassan MM, et al. Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma. Gastroenterology. 2015;149(1):119–29. The European Medical Information Framework (EMIF) is a collaboration between industry and academic partners that aims to develop common technical and governance solutions to facilitate access to diverse electronic medical and research data sources. These analyses were supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The authors would like to acknowledge Nicholas Galwey for his advice on the statistical methods, Alba Jene for her administrative support and support during submission to ethical review boards and Derek Nunez for support early on a protocol design stage. FP7 Ideas: European Research Council Award Number 115372. ERC had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. DPA is funded by a National Institute for Health Research Clinician Scientist award (CS-2013-13-012). This article presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. This work was partially supported by the NIHR Biomedical Research Centre, Oxford. WA is in receipt of a Medical Research Council New Investigator Award. This work uses data provided by patients and collected by the different healthcare systems involved as port of their care and support. All data relevant to the study purpose are within the paper and its Supporting Information files. Original, individual-level data are in custody to local partners, and the possibility to access them may vary depending on local governance rules. Local restrictions on publicly sharing original study data may vary on a case-by-case basis and depend on institutional review board, ethics committee or law. Further information on data request and access should be sent individually to the authors of this paper responsible for the data provided by the relevant organisations: SIDIAP ([email protected]), HSD ([email protected]), THIN ([email protected]), IPCI ([email protected]). Naveed Sattar and William Alazawi contributed equally to this work. Real World Data, GlaxoSmithKline, Uxbridge, UK Myriam Alexander Worldwide Research and Development, Pfizer, Genome Sciences and Technologies, New York, USA A. Katrina Loomis Erasmus Universitair Medisch Centrum, Rotterdam, Netherlands Johan van der Lei , Peter Rijnbeek & Mees Mosseveld Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spain Talita Duarte-Salles Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK Daniel Prieto-Alhambra Quintile IMS, London, UK David Ansell Health Search, Italian College of General Practitioners and Primary Care, Firenze, Italy Alessandro Pasqua & Francesco Lapi Genetics, GlaxoSmithKline, Collegeville, PA, USA Dawn M. Waterworth GlaxoSmithKline, Medicines Research Centre, Cambridge, UK Stuart Kendrick University of Glasgow, Glasgow, UK Naveed Sattar Barts Liver Centre, Blizard Institute, Queen Mary, University of London, London, UK William Alazawi Search for Myriam Alexander in: Search for A. Katrina Loomis in: Search for Johan van der Lei in: Search for Talita Duarte-Salles in: Search for Daniel Prieto-Alhambra in: Search for David Ansell in: Search for Alessandro Pasqua in: Search for Francesco Lapi in: Search for Peter Rijnbeek in: Search for Mees Mosseveld in: Search for Dawn M. Waterworth in: Search for Stuart Kendrick in: Search for Naveed Sattar in: Search for William Alazawi in: MA, AKL, JvdL, PR, DW, SK, NS and WA contributed to the study design. TDS, DP-A, DA, AP, FL, PR (data transformation and federated data analysis) and MM extracted the data. MA analysed the data. All authors interpreted the results. MA, NS and WA wrote the manuscript. All authors edited the manuscript. All authors read and approved the final manuscript for submission. Correspondence to William Alazawi. We followed local data laws in all four territories from which data were obtained, and in all countries, specific ethical approval was not required for this study that used anonymised data. However, approval was sought and obtained from the scientific research committee for THIN, the IPCI Governing Board (ref 2015/18) and the IDIAP Ethics Committee (Reference P15/167) and the scientific committee of the Italian College of General Practitioners and Primary Care. MA was contracted to work at and SK and DMW are employees of GlaxoSmithKline which has conducted clinical research including trials of therapeutic agents in NAFLD. AKL is an employee of Pfizer which is conducting clinical research including trials of therapeutic agents in NAFLD. TDS: none to declare. DP-A: unrestricted research grants from UCB, Amgen, Servier, and consultancy fees (paid to his department/research group) from UCB Pharma. DA: consultancy and advice to many pharmaceutical companies on undertaking outcomes studies using real-world evidence. FL: consultancy for AlfaSigma, Bayer and Abbvie. SK: Employee and stock holder, GlaxoSmithKline. NS: consulted for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Janssen, and grants from Astrazeneca and BI. WA: Consultant and sponsored lectures: UCB Pharma, Gilead, Intercept and Medimmune. Supplementary Methods. Table S1. Attrition table showing patients with recorded diagnoses of NAFLD or NASH and matched unexposed controls. Table S2. Descriptive characteristics of coded NAFLD or NASH patients and matched unexposed cohorts in SIDIAP and THIN. Table S3. Number of patients with data available in coded NAFLD/NASH and matched unexposed cohorts. Table S4. Incidence rate of liver outcomes in four primary care databases. Table S5. Descriptive characteristics of coded NAFLD/NASH patients and matched non-NAFLD/NASH in a sample of patients with and without BMI data available, all datasets combined. Table S6. Median and interquartile range (in years) for time to event in coded NAFLD and matched non-NAFLD who experience a cirrhosis or hepatocellular carcinoma event during follow-up. Figure S1. Subgroup analysis of the association between coded NAFLD/NASH and incident (A) cirrhosis and (B) hepatocellular carcinoma events by medical history and demographics. Figure S2. Hazard ratio (HR) for cirrhosis (A) adjusted for age and smoking in all patients and (B) adjusted for age and smoking in patients with BMI. Figure S3. Hazard ratio (HR) for HCC (A) adjusted for age and smoking in all patients and (B) adjusted for age and smoking in patients with BMI. Figure S4. Fib-4 Association with (A) cirrhosis or (B) HCC. Figure S5. Risk of coded NASH in patients with coded NAFLD. (DOCX 540 kb) Alexander, M., Loomis, A.K., van der Lei, J. et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med 17, 95 (2019) doi:10.1186/s12916-019-1321-x Hepatocellular cancer NAFLD
According to the March of Dimes, each year more than half a million babies are born too soon in the United States. The nation's premature birth rate has risen by 36 percent over the last 25 years. Premature birth, when a baby is born more than three weeks early, costs us more than $26 billion a year. Even when infants survive prematurity, they are at risk of severe health problems and lifelong disabilities. Just this week, another baby in Milwaukee died as a result of unsafe sleeping. As a mother, I'm heartbroken for this family. The public concern and grief is justified, but the story is incomplete. Despite our increased awareness of and attention to what are often termed "co-sleeping deaths," it is premature births that are the cause of most newborn deaths. In Milwaukee, nearly half of the infants that do not reach their first birthday die as a result of prematurity. African American women bear the highest burden. In 2011, 10.4 percent of live births in Wisconsin were born preterm or less than 37 weeks gestational age. However, rates of preterm birth were 16 percent among births to Black mothers, significantly higher than both state and national averages. Research indicates that there are multiple risk factors that may lead to premature labor and delivery, including a history of preterm birth, expecting more than one baby, and uterine and/or cervical abnormalities. Other risk factors include: diabetes mellitus, hypertension, inadequate prenatal care, smoking, and alcohol/drug use. The positive news is that many of these factors can be changed, even preventable. November is Prematurity Awareness Month. You will hear about tremendous local efforts, many being led by the Wisconsin Chapter of the March of Dimes, that are addressing this crisis. In fact, Milwaukee is currently engaged in substantive collaboration to reduce the overall infant mortality rates, rates of prematurity, and, in particular, the disparity between white birth outcomes and those of non-whites. United Way of Greater Milwaukee is mobilizing its resources—human and financial—to impact this issue, and has made Healthy Birth Outcomes a priority. Our goal is that all of our community's babies are born ready to thrive. Within this initiative, we engage in two core strategies: Teen Pregnancy Prevention and Infant Mortality Reduction. Two weeks ago, we were proud to stand with the City of Milwaukee and announce that Milwaukee's teen birth rates, long among the highest in the nation, had fallen over 50 pecent in 6 years. With similar vigor and breadth, we will address the issue of prematurity and infant mortality. We want every baby born in Milwaukee to blow out that first birthday candle. *Special thanks to the March of Dimes for providing data and their work on this important community issue.
AveXis is a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases. The company's initial proprietary gene therapy candidate, AVXS-101, is in the pivotal phase of study for the treatment of spinal muscular atrophy (SMA) Type 1. The company also intends to expand the study of gene therapy into other types of SMA and two additional rare neurological monogenic disorders: Rett syndrome (RTT) and a genetic form of amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene.
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They are promising, scary, and--so far--premature. Early Detection of Alzheimer's through Retinal Scan The burden of Alzheimer's disease (AD) goes far beyond the afflicted patient, affecting family, friends, and a significant portion of the healthcare system. Currently, there are more than 5 million individuals living with AD in the U.S., incurring $259 billion in healthcare costs. With costs estimated to rise to $1.1 trillion by 2050 as the number of AD cases could surpass 16 million, it is imperative that diagnostic tests be developed to detect early warning signs that signal the onset of the disease—at the very least to allow patients and their family time to prepare for various eventualities. Glen Campbell's last song chronicled his struggle with Alzheimer's disease: VIDEO Singer Glen Campbell performs on stage in 2011 at Club Nokia in Los Angeles, California, as part of a farewell concert tour following his diagnosis with Alzheimer's disease. Campbell has died at age 81. REUTERS/Jonathan Alcorn/File Photo Glen Campbell, the "Rhinestone Cowboy," country music legend, hitmaker, and TV star, is dead at 81. Scientists Aim For Better, Cheaper Tests For Alzheimer's Finding some change in the blood of an Alzheimer's patient that accurately reflects the damaging changes in the brain has been tough. utah778//iStockphoto/Getty Images Efforts to develop a treatment that stalls the memory-robbing devastation of Alzheimer's disease have so far been unsuccessful, but scientists are making strides in another important area: the development of better tests to tell who has the condition.
Home > Vol. 4, No. 4, Dec 2015 > Enakpene Dysmenorrhea as a Risk Factor for Hyperemesis Gravidarum Christopher Atsaboghena Enakpene, Mudar Dalloul, Carla Petterkin-Caldwell, Jenny Anopa, Ozgul Muneyyirci-Delale Background: The aims of the study were to assess the association of dysmenorrhea and hyperemesis gravidarum (HG) and to determine other factors that may influence its onset and severity. Methods: This is a prospective case-control IRB approved study of 344 consecutive singleton pregnant women with and without hyperemesis gravidarum in pregnancy from February 2011 to April 2012. The association between HG and dysmenorrhea in adolescent and adult was examined using Pearson's Chi-square with Yates correlation, Student's t-test and Mann-Whitney U test. Bivariate analysis and odd ratios (ORs) were calculated to evaluate the strength of their association, and multivariate logistic regression analysis while correcting for confounders. P-value of 0.05 was considered statistically significant. Results: A total of 344 consecutive singleton pregnant women were recruited. Significant association was found between HG and adolescent dysmenorrhea: 77.8% versus 43.4% of controls (P < 0.0001, OR: 4.6, 95% CI: 2.3 - 8.9). Also, there was a significant association between HG and adult dysmenorrhea: 76.4% versus 38.1% controls (P < 0.0001, OR: 5.3, 95% CI: 2.7 - 10.2). The association of severe adolescent and adult dysmenorrhea with HG was stronger (P < 0.0001, OR: 8.8, 95% CI: 3.9 - 19.9 and P < 0.0001, OR: 12.2, 95% CI: 5.0 - 29.7 respectively). There was a modest association with moderate dysmenorrhea (P = 0.004, OR: 3.1, 95% CI: 1.4 - 6.9) which was not sustained but no associations were found between HG and all mild dysmenorrhea of both adolescent and adult. Conclusion: This study found an association between adolescent and adult dysmenorrhea and HG. These associations were stronger with severe dysmenorrhea. doi: http://dx.doi.org/10.14740/jcgo356w Dysmenorrhea; Hyperemesis gravidarum; Adolescent; Adult; Onset; Severity
Paola Binda, Jessica Thomas, Geoffrey M. Boynton, Ione Fine; Avoiding biases in estimating cortical reorganization using fMRI population receptive field mapping. Journal of Vision 2012;12(9):1121. doi: 10.1167/12.9.1121. Purpose: The population receptive field approach (pRF) 1 provides an estimate of the region of visual space that best excites each fMRI voxel. Recently there has been increasing interest in using the pRF method to examine cortical reorganization resulting from vision loss2. Here, we tested the validity of the pRF method in four normally sighted subjects under conditions that simulated a retinal lesion. Methods: We measured BOLD responses to bars drifting in random directions stimulating the central 15 deg of the visual field1 or with the central 3 deg masked, simulating a foveal scotoma. We analyzed the data in two ways. In the 'full visual stimulus' condition we used the full unmasked stimulus as the input into the pRF model, as is currently the standard procedure. In the 'retinal lesion stimulus' condition we used the masked stimulus as input into the pRF model. Results: Using the 'full visual stimulus' analysis method, voxels with pRFs that fell within or near the edge of the scotoma were shifted peripherally, even in voxels with relatively low fit errors (there was no systematic bias in receptive field size). However, this 'apparent rapid re-organization' completely disappeared when analyzing the same data using the 'retinal lesion stimulus' method. A model simulation similarly found that the peripheral shifts observed with the 'full visual stimulus' analysis can be explained purely in terms of biases in the pRF fits, without any underlying cortical reorganization. Conclusion: It is possible to accurately measure pRFs under condition of vision loss, if and only if pre-cortical visual losses are taken into account. 1Dumoulin SO, Wandell BA. NeuroImage. 39(2): 647-660 (2008). 2Baseler HA et al. Nature Neuroscience. 14: 649–655 (2011).
What still is not clear to drug regulators and medical researchers about the drug safety issue of lower limb amputations linked to Invokana and Invokamet use is the so-called "mechanism of injury". Put otherwise, they are still searching for an explanation as to how and why there is an increased risk of lower limb amputations for patients using Invokana. Further, it remains uncertain whether this serious side effect may be associated with Farxiga, Jardiance, and other diabetes drugs known as Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors. Since the US Food and Drug Administration announced its black-box warning earlier this year for [Invokana (canagliflozin)], many of us have been concerned about the amputation risk observed with this drug in the CANVAS trial (hazard ratio [HR], 1.97 compared with placebo). Despite the overall positive cardiovascular, heart failure, and kidney disease-related benefits seen with canagliflozin, a key clinical concern among prescribing clinicians such as me relates to predictive factors for amputations, and whether this risk correlates with the other treatment-related adverse effects observed (eg, volume depletion and hemoconcentration). I expected further data clarifications surrounding this issue at the 1-hour CANVAS session at the European Association for the Study of Diabetes (EASD) 2017 meeting, held in September in Lisbon. But I was disappointed; no new data related to amputations from the CANVAS program were shared. Moreover, to clarify whether the amputation harm could be a class effect of SGLT2 inhibitors, a thorough collection of prospective data on amputations and other foot-related complications should be required of all ongoing and future long-term trials within the class (eg, DAPA-CKD, DAPA-HF, and DECLARE with [Farxiga (dapagliflozin)]; EMPEROR-Preserved and EMPEROR-Reduced with [Jardiance (empagliflozin)]; and VERTIS CV with ertugliflozin [a SGLT2 inhibitor which has not been approved by the FDA, yet]). Of course, we will continue to monitor the medical literature to learn more about how and why there is an increased risk of amputations involving toes, feet, and legs in patients using Invokana or Invokamet– and perhaps Farxiga, Jardiance, and other SGLT2 inhibitors used as diabetes drugs.
Understanding closed system transfer devices Published on 9 May 2017 No gain from clodronate Voice picking improves multiple warehouse operations Drug information for mental illness sufferers Man died after prescription error Antifungal drug may cause birth defects Containment of hazardous drug vapour by closed system transfer devices is critical; new test methods are providing valuable insights into the performance of these devices and recent studies are suggesting new potential applications Christine Clark Freelance Medical Writer The use of closed system transfer devices (CSTDs) should be obligatory whenever cytotoxic or other hazardous drugs are prepared, administered or disposed of, according to Paul Sessink (Managing Director, Exposure Control, Sweden). This is because occupational exposure to cytotoxic drugs poses recognised risks of mutagenicity, carcinogenicity and reproductive toxicity. However, engineering controls, such as biological safety cabinets, do not always provide adequate protection for workers. Studies with CSTDs show substantial reductions of environmental contamination with cytotoxic drugs when the devices are used – and this should reduce potential adverse health effects. A further point to note is that CSTDs are containment devices and the use of such devices has a higher priority in the hierarchy of protection measures than engineering controls, administrative controls and personal protective equipment. Dr Sessink drew attention to a recent publication of the European Biosafety Network, which calls for a common (European) definition of CSTDs, including the technical specifications to be met by a medication transfer system to be considered as a closed system, and harmonised protocols for testing CSTDs.1 Dr Paul Sessink Challenges in selecting a CSTD Selecting a suitable CSTD is not always a straightforward process, explained Jay Brown (Director of Pharmacy Oncology, Specialty and Infusion Services, Novant Health Oncology Specialists, Winston-Salem, North Carolina, US). An ASHP survey published in 2012 showed that only 21% of health institutions had previously used CSTDs.2 The available CSTDs are based on several different mechanisms to achieve 'closedness' and may not be directly comparable. For example, some rely on a physical barrier or expansion balloon to contain drug vapours or aerosols and others use filtration or air cleaning systems. In addition, different methods of assessment have been used to support claims of being 'closed systems'. The decision about which CSTD to use may also be driven by outside influences such as the nursing leaders' views and costs to the institution, he added. Dr Jay Brown United States Pharmacopeia (USP) General Chapter 800 provides standards for safe handling of hazardous drugs to minimise the risk of exposure to healthcare personnel, patients and the environment. It recommends evaluation of existing CSTDs based on published, peer-reviewed data and containment studies. It also requires the use of a CTSD in hazardous drug administration, emphasised Dr Brown. However, it does not require the use of CSTD in compounding of hazardous drugs and it does not guarantee 100% hazardous drug containment through the use of CSTDs. In 2014 the Food and Drug Administration (FDA) created a product code specifically for CSTDs (the FDA ONB code). This defines as CSTD as: "a product that reconstitutes and transfers antineoplastic and other hazardous drugs in the healthcare setting, and is indicated to reduce the exposure of healthcare personnel to chemotherapy agents in healthcare settings".3 The National Institute for Occupational Safety and Health (NIOSH) (in the US) defines as CSTD as, "a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system."4 This is a performance standard rather than a technical specification, noted Dr Brown. Evaluation of CSTDs Testing the efficacy of a CSTD depends on the type of CSTD and its intended purpose – whether it is for use in injection preparation, administration or for waste disposal of cytotoxic drugs. One thing that is very important is that real drugs should be used in the testing process and not surrogate agents that could behave differently, said Dr Sessink. Another danger is that surrogates might damage the integrity of the CSTD and lead to false positive results, he warned. Testing should be undertaken initially under laboratory conditions but devices should also be evaluated in the 'in use' situation to reflect normal practice. One way of assessing the performance of a CSTD is by measuring the amount of drug that is released into the environment. In practice this can involve wipe-sampling of surfaces, air sampling to check for release of particles and analysis of absorbent mats (if used). Sampling of gloves is important because they can be a route for skin contamination and absorption. Finally, urine analysis provides definite evidence of exposure, although not the route of exposure, said Dr Sessink. Pitfalls of testing "No CSTD system is 100% closed and much depends on the test process", Alan Wilkinson (Managing Director, Biopharma Stability Testing Laboratory (BSTL) Ltd, Nottingham UK) told the audience. The challenge agent used in the test procedure should be chemically inert and in other respects behave in a "drug-like" way, he continued. Highly reactive chemicals, such as titanium tetrachloride are therefore not suitable. Isopropyl alcohol (IPA) was originally proposed by NIOSH as a challenge agent. Dr Alan Wilkinson It is inert but has a very high vapour pressure, unlike most injectable drugs. When used in vapour-containment tests, it can be shown that all CSTDs leak IPA, if a suitably sensitive detector is used. Fluorescent dye (fluorescein) has previously been suggested as a way to assess leakage of liquid droplets but Dr Wilkinson questioned the scientific validity of the test methodology. In practice, it is almost impossible to distinguish between light emission from liquid on the surface of the container and liquid inside the CSTD-drug vial assembly. Other factors, such as the intensity and bandwidth of the light excitation source, can dramatically alter the results obtained. NIOSH protocol In 2015, NIOSH published a draft protocol for testing the vapour containment performance of physical barrier CSTDs (but not for the air cleaning/filtration type) in which the challenge agent was 70% IPA, Ian Pengelly (Principal Chemist, Analytical Chemistry Team at the Health and Safety Laboratory of the United Kingdom Health and Safety Executive) explained. The idea behind it was that pharmacists would build their own apparatus and carry out testing – a scenario that Dr Pengelly described as being "unlikely". After consultation a new draft universal test protocol was published in 2016. This included nine potential surrogate compounds for use as challenge agents and used thermal desorption followed by gas chromatography and mass spectrometry (TD-GC-MS) for detection. This is a method that is capable of detecting parts per billion, in contrast to the infra-red detection method in the original protocol that can only detect parts per million. The new procedure is designed for use in accredited testing laboratories rather than pharmacies, noted Dr Pengelly. Dr Ian Pengelly The principle of the new, universal protocol is that manipulation of, for example, a cytotoxic drug, is carried out in a sealed chamber so that leakages can be detected. Two air sampling devices containing a sorbent (Tenax) are positioned inside the chamber and used to collect air samples. Results are generated by a process of thermal desorption followed by gas chromatographic separation and mass spectrometry (TD-GC-MS). So far, more than 250 separate tests on three different CSTDs, using 2.5% solution of 2-phenoxyethanol (2-POE) as the challenge agent (following the universal protocol), have been carried out at an independent laboratory in the UK (BSTL). The popular perception is that physical barrier type CSTDs are superior to air cleaning/filtration types but the results show that both Tevadaptor (filtration type) and BD-PhaSeal (barrier type) release less than 0.71ppb (the limit of quantitation). In contrast, the Chemoclave released 2.7–7.3 ppb and the needle and syringe (open) method released more than 4.00 ppb. This difference can be attributed to the use of double-membrane connectors between vial and syringe adaptors the rather than Luer locks, said Dr Wilkinson. "The data presented clearly show the Luer lock connection provides a health worker with less protection than the open system using a needle and syringe", he added. NIOSH has proposed nine potential surrogate compounds, including 2-POE, for use as challenge agents. Isopropyl alcohol has a vapour pressure of 4400 Pascals (Pa) whereas commonly-used cytotoxic drugs, including cyclophosphamide and fluorouracil have vapour pressures of less than 0.01 Pa. "IPA is a solvent and does not behave like any hazardous drug", said Dr Wilkinson. He concluded that 2-POE is a safe and suitable challenge agent for testing the containment performance of all CSTDs, regardless of what technology they employ. The BSTL environmental test chamber as used to replicate the NIOSH test protocol for assessment of CSTD systems. Tevadaptor performance The next step was to test the ability of a CSTD to contain hazardous drug vapour, rather than a surrogate substance. Dr Wilkinson described a study that had been carried out in his laboratory in the UK. A CSTD (OnGuard/Tevadaptor) was used to reconstitute a vial of cyclophosphamide, as it would be when in routine use. The cyclophosphamide vial was placed in a water bath at 50°C inside a sealed glass chamber. This increases the vapour pressure of the drug above the normal (room temperature) value and provides a "really serious challenge to the OnGuard (Tevadaptor) technology and specifically the ToxiGuard vapour capture system", said Dr Wilkinson. Nitrogen was fed into the vial at a rate of 300ml/min, via a 21-gauge needle inserted through the adaptor. The tip of the cannula was above the surface of the drug solution. "This experimental design follows a method described in a published protocol", commented Dr Wilkinson. The effect of the nitrogen flow is to present constantly saturated cyclophosphamide vapour to the ToxiGuard filtration system of the Tevadaptor CSTD. If the CSTD system remains effective then nitrogen gas will flow through the 0.2 micron filter and the ToxiGuard activated carbon membrane, providing pressure equalisation at all times, but the drug will be retained. The exit tube from the apparatus (carrying the exhaust nitrogen) goes to a cold trap (at -90°C) so that all of the vapour that is released by the system is captured. In addition, the rinsate from the trap plus washings from the internal surfaces of the apparatus was analysed using liquid chromatography with tandem mass spectrometry (LC-MS/MS) equipment capable of detecting as little as 10 picograms of cyclophosphamide. The activated charcoal membrane was being challenged with cyclophosphamide vapour – one of the most volatile hazardous drugs in existence – at 50°C at a flow rate of 300ml/minute for 24 hours, and even under these stringent test conditions, the results consistently showed that the amounts of cyclophosphamide that escaped was below the limit of quantitation, suggesting that the ToxiGuard filter was capturing all of the drug, said Dr Wilkinson. The ToxiGuard filters were later removed and extracted to determine the amounts of cyclophosphamide trapped. The results showed that in two (out of five replicates) the amount of cyclophosphamide detected exceeded 10,000 nanograms. "This study provided two robust pieces of evidence – first, there was no cyclophosphamide outside the Tevadaptor CSTD/drug vial assembly and, second, the ToxiGuard filter captured and retained 100% of the cyclophosphamide vapour. A flow rate of 300 ml/hour for 24 hours means that the CSTD was challenged with 432 litres of cyclophosphamide-containing vapour, whereas in normal use a volume of 100ml might be pushed through a CSTD – so we conclude that OnGuard/Tevadaptor is 100% effective", said Dr Wilkinson. Exposure to antibiotics Occupational exposure to antibiotics can be a serious hazard, according to Dr Sessink, with effects ranging from hypersensitivity and allergies to anaphylactic shock. In addition, health care staff can harbour resistant organisms as a result of frequent exposure. Nurses have reported seeing splashes and leakages during preparation of injections and experiencing a bitter taste. The Swedish Work Environment Authority has recently established a maximum limit for penicillin of 0.1mg/m3 as inhalable dust. Pilot studies in Sweden and Hungary assessed the effectiveness of the Tevadaptor CSTD to reduce environmental contamination with antibiotics (vancomycin, Augmentin, ceftriaxone and meropenem in Hungary, and cefotaxime, piperacillin, benzylpenicillin, vancomycin, ceftriaxone and meropenem in Sweden). Baseline studies showed that the needle and syringe method of preparation was associated with widespread contamination. The introduction of the CSTD resulted in substantial, statistically significant reductions in the levels of contamination with all antibiotics in Hungary, and with four out of six in Sweden. There were no reduction in the levels of ceftriaxone and meropenem in some positions and the reasons for this are not clear, said Dr Sessink. The satellite symposium, Containing hazardous drugs with CSTDs: Understand the evidence and requirements from USP 800 to the NIOSH Universal Testing Protocol was held during the ASHP Midyear Clinical Meeting, Las Vegas USA in December 2016. The symposium was sponsored by B Braun USA, which markets OnGuard /Tevadaptor in the US. Closed system transfer devices (CSTDs) should be tested for vapour containment using suitable surrogate agents and with actual hazardous drugs. 2-Phenoxyethanol 2.5% is a safe and suitable surrogate agent for vapour-containment testing. Both Tevadaptor (filtration-type) and BD-PhaSeal (barrier-type) CSTDs contain vapour effectively when tested using the NIOSH protocol. Rigorous testing of the Tevadaptor shows that it is 100% effective at containing cyclophosphamide vapour. Preventing occupational exposure to cytotoxic drugs. Sessink PJM, Sewell G, Vandenbroucke J (eds). www.europeanbiosafetynetwork.eu/preventing-occupational-exposure-to-cytotoxic-drugs/ (accessed April 2017). Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration 2011. Am J Health Syst Pharm 2012;69:768–85. US Department of Health and Human Services. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm?ID=ONB. Nygren O et al. NIOSH Definition of closed-system drug-transfer devices. Ann Occup Hyg 2009;53:549. AllergoOncology an "established field" Nonsmall-cell lung cancer management Doctors downplay bird flu risk Halaven® available in Italy for breast cancer Osteoporosis drug begins trials in humans
Continental-scale changes in woody plant cover have been mapped for forests >5 m in height1, indicating an overwhelming deforestation trend induced by human land use2. A less well-known, yet equally important global trend is gradual woody plant encroachment (WPE), occurring in non-forest biomes3. In Africa, WPE has been identified as a concern for rangeland management since the early 20th century, and has the potential to reduce rangeland carrying capacities of wild and domestic grazers through the displacement of herbaceous forage by trees and shrubs. On the other hand, WPE may significantly contribute to forage for wild and domestic browsers, household fuel-wood provision, and may lead to increased carbon sequestration, with consequences for global carbon budgets and climate change4. In order to manage the effects of WPE on these diverse local and global ecosystem services, we need to understand what is driving it. The drivers of WPE are poorly understood compared to those of deforestation where human-induced clearing is dominant. Rising atmospheric CO25,6 and associated climatic changes, coupled with changing fire and herbivore management regimes, have been proposed as dominant drivers3,4,7,8. While homogenous global CO2 enrichment may enhance tree growth9, the trends in WPE are spatially variable, suggesting other local- or regional-scale drivers. For example, increases in rainfall have been shown to correlate with WPE, while the influences of trends in temperature are less clear10. Agriculturally induced transformation of Africa's unique set of functional herbivore guilds11, and the alteration of fire regimes12 may shift systems into tree-dominated states at the local scale. However, quantifying these drivers at continental scales has been limited by the paucity of local-scale studies3 or continental analyses relying on low-resolution remotely sensed data10. The lack of spatially explicit measures of the magnitude and scale of WPE has made it difficult to draw generalised conclusions about its causes, and to identify the potential for the use of local drivers (i.e. fire, herbivory and human disturbance) as management tools to mitigate the putative effects of global (i.e. climatic) drivers on WPE. We mapped change in woody plant cover excluding closed forest (more than 40% cover by trees taller than 5 m) at 30 m resolution for Africa over the past three decades. We considered a suite of potential drivers to explain this change, including CO2 as a global driver and other local- or regional-scale drivers that have received less attention (Supplementary Fig. 1). We report that non-forest biomes in Africa have undergone a net 8% increase in woody plant cover over the past three decades, although the magnitude and direction of this trend was spatially variable. During the same period there have been significant increases in CO2, rainfall and herbivory, and reductions in burned area. We develop a machine learning model to elucidate these complex correlations and find that a diversity of drivers other than atmospheric CO2 are able to explain 78% of the spatial variation in African woody cover change. WPE has been exacerbated by warming and wetting climates associated with global climate change, but local changes in fire, herbivory and direct anthropogenic disturbance (e.g. deforestation) predominate. Altering fire and herbivory management regimes thus has the potential to mitigate WPE. Over the past three decades, 7.5 million km2 (55%) of non-forest biomes (see data mask in Supplementary Fig. 2) in sub-Saharan Africa underwent significant net gains in woody plant cover (Figs. 1, 2a, and Supplementary Fig. 3). This is more than triple the 2.2 million km2 (16%) significant decrease in woody plant cover, confirming local-scale studies indicating increases in WPE over the last century3. Woody cover loss was prevalent in parts of the Sahel, East Africa and much of Madagascar, but WPE dominated the central-interior of Africa. Countries exhibiting a mean fractional increase >30% were Cameroon, Central African Republic, South Sudan, and Uganda (Supplementary Table 1). Almost all other counties experienced net encroachment, with only Congo, Kenya, Madagascar, Niger and Somalia undergoing a net decline in woody cover. The highest rates of encroachment occurred in areas with moderate initial woody cover (i.e. 30–60%) in 1986 (Supplementary Fig. 4). Areas with more than 75% initial cover experienced highest rates of loss, probably due to human-induced clearing (e.g. Supplementary Fig. 3). There was little difference between WPE inside (13.9%) and outside of (12.5%) protected areas. Encroachment trends were lowest in shrublands (3.5 ± 0.4% increase) and highest in Caesalpinioid savannas (20 ± 0.4% increase), but were pronounced across all vegetation types (Supplementary Fig. 5), indicating that the drivers of this change are globally available, but act regionally allowing WPE in some areas and deforestation in others. The widespread trend in WPE correlates with a significant rise in atmospheric CO2 and rainfall (Fig. 2b, d), but also a significant increase in herbivore densities and decline in burned area (Fig. 2c, e). To avoid drawing conclusions about drivers of WPE from such continental-scale correlations (Fig. 2) without acknowledging the spatial variation in trends (i.e. some areas have increased in rainfall or woody cover while others have decreased), we employed the established machine learning technique of boosted regression tree (BRT) modelling13,14 to investigate the relative importance of and interactions between a set of >60 explanatory variables (climatic, edaphic and disturbance) and woody cover change. Our final model explained 78% of the deviance in spatially explicit woody cover trends. WPE expresses a hump-shaped response to human population growth (Fig. 3a). At high population growth rates, WPE was inhibited, presumably due to clearing, emphasising that deforestation trends1 are not limited to the forest biome. Low population growth rates had a negligible effect on curbing WPE, potentially due to a covariance with human-induced landscape fragmentation and the subsequent reduction in fire spread12. Local disturbances by fire and herbivory are known to maintain open savannas in areas that could climatically support closed-canopy forest15. Our analysis confirms that local disturbance patterns can have continental consequences for WPE and are of equal importance to edaphic and climatic variables in explaining the spatial variation in woody cover change (Supplementary Figs. 6 and 7). Large reductions in burned area in Africa, consistent with the global trend16, have driven larger WPE rates (Fig. 3e). Decreases in fire reduces tree mortality and consequently reduces competition from the grass layer and facilitates tree recruitment which further reduces the grass fuel load for fires, creating a negative feedback loop17. The bulk of the data for trends in herbivory suggest that increasing herbivore intensity exacerbates WPE (shaded area in Fig. 3c). Grazing herbivores, which dominate most African rangelands18,19, reduce grass competition with woody plants and reduce fuel loads for fires, thereby releasing woody plants from the fire trap8,20. However, WPE might also be facilitated in areas with large declines in herbivory (Fig. 3c). These contradictory herbivore-induced effects on WPE are likely due to differing livestock management contexts coupled with the widespread loss of mid-Holocene herbivore functional guilds, such as browsers18,21. Browsers play an important role in regulating woody plant populations through direct mortality (e.g. elephant impact11,22,23,24) or by inhibiting shrub and tree growth rates and thereby increasing vulnerability to fire17,25. Indeed, we found that areas with high browser densities experienced lower encroachment rates (Supplementary Fig. 8a). In contrast, grazers reduce fuel loads for fire and thus enhance WPE17; however, we found that extreme grazer densities may inhibit WPE (Supplementary Fig. 8b). One possible way that high grazer densities may reduce WPE is through consumption and trampling of coppicing and young woody plants. Areas experiencing increases in rainfall underwent greater WPE than those where rainfall has decreased (Fig. 3d), confirming rainfall as a potent determinant of tree cover26,27. Although rises in temperature have been shown to enhance WPE at local scales through declines in frost-induced tree mortality, the regional-scale interaction between changes in temperature and woody cover are less well understood for Africa8. Here we show that changes in WPE with rising temperatures mirrored the effect of increases in rainfall (Fig. 3b), suggesting that WPE may be set to continue under global warming scenarios. The detrimental effects of increased transpiration and drought stress under warmer temperatures may be mitigated by wetter climates and enhanced water use efficiency induced by rising atmospheric CO27,28. Experimental evidence also exists for increased seedling establishment under warmer climates for some savanna woody species29. Apart from the interactive effect with temperature and water use efficiency, rising atmospheric CO2 levels might contribute to continental WPE through enhanced C3 woody plant photosynthetic rates and post-fire resprouting capabilities, relative to C4 grasses30,31. The lack of spatial variability in atmospheric CO2 trends precluded it from being incorporated into our model. Notwithstanding, the changes we observe between 1986 and 2016 might reflect the legacy effects of post-industrial revolution CO2 trends, although the shape of continental trend lines suggests that the temporal variation in WPE rate is not directly linked to that of CO2 (Fig. 2a, b). While experimental studies have noted a positive growth response in trees to elevated CO29,32, the strength of this response relative to herbaceous plants is variable, especially when considered in isolation from nutrient limitations and competitive interactions present in natural systems but commonly absent in experimental set-ups33,34. While CO2 may contribute to WPE, the global trend in atmospheric CO2 has not led to homogenous trends in WPE (Fig. 1b). Thus the other climatic and disturbance drivers assessed here are important in determining the direction of vegetation change and determining the magnitude of WPE. The widespread continental increase in woody plants shown here corroborates global trends of increasing leaf area index35 and vegetation greenness36 in semi-arid areas, thereby challenging the long-held desertification narrative37. The inclusion of spatially explicit greening trends into global carbon budgets have previously relied on low resolution (>250 m) estimates of net primary productivity in semi-arid areas38. The present dataset of decadal woody cover change might aid in more accurately quantifying the extent to which WPE contributes to the global carbon sink, potentially offsetting the carbon losses from deforestation. Despite the potential benefits to the global carbon budget, the local-scale disadvantages (e.g. reduced grazing capacity) and their effects on rural livelihoods has motivated substantial governmental investment into clearing alien and native invasive woody plants (e.g. ca.100 million US$ per annum in South Africa)39. Initial indications from our models suggest that WPE management interventions will be most needed in areas that are expected to increase in temperature and rainfall under future climate change scenarios. More importantly, manipulating local disturbance patterns has the potential to override climatic effects and significantly mitigate WPE. Management interventions may include increasing fire using heterogenous management regimes40, or through rewilding savannas with historical herbivory pressures11,21, and diversifying herbivore functional guilds by incorporating more browsers18. Thus, while global drivers such as climate and CO2 may enhance the risk of WPE, the realisation of WPE is largely dependent on management decisions. The study area included sub-Saharan Africa, totalling 20.5 M km2, equivalent to 22.8 billion Landsat pixels. Woody plant cover was defined as fractional woody cover of 30 × 30 m squares, defined by the Landsat pixel grid. The dynamics of tree cover change have been comprehensively explored using remote sensing techniques for forest biomes1. Given that the potential for WPE to occur in areas already saturated with tree cover is negligible and that our aim was to investigate WPE and its drivers, we excluded the forest biome from our analysis. Pixels with >40% cover by trees of >5 m in height were considered as closed forest41,42 and excluded using data from the Global Land Cover Facility43. Tree cover may be unable to fully distinguish forests from densely wooded savannas44; however, these ecotonal boundary areas are relatively small compared to the total area occupied by true non-forest biomes. Thus, the erroneous masking of densely wooded savannas was expected to have little effect on the continent-wide analysis. Forestry areas were defined as pixels that have both lost and gained woody cover between 2000 and 2015 using global forest cover change data derived from Hansen et al. 20131 and were excluded from our analysis. Urban surfaces, water, wetland, cropland, and natural-cropland mosaics were also excluded from the analysis using the MODIS landcover product45. This combined pixel mask (Supplementary Fig. 2) was applied to all Landsat- and MODIS-derived data in this analysis. The remote sensing analysis was performed using the Google Earth Engine cloud computing platform for earth observation and data analysis46. The near-complete set of Landsat surface reflectance data available for Africa (1986–2016) from the USGS Earth Resources Observation and Science archive47 were analysed to identify change in fractional woody cover. We analysed 6 epochs of Landsat data between 1986 and 2016 (Supplementary Fig. 1). Landsat 5 Thematic Mapper (TM) was used for the 1986–1991, 1991–1996 and 1996–2001 epochs. Landsat 7 Enhanced Thematic Mapper Plus (ETM+) was used for the 2001–2006, 2006–2011 and 2011–2016 epochs. Data gaps in the 2011–2016 epoch were filled by merging the Landsat 7 ETM+collection with the Landsat 8 Operational Land Imager (OLI) collection using published cross-calibration coefficients for surface reflectance48. A cloud mask and confidence quality assessment data were used to create cloud-free image collections, which were used to derive per-pixel time-series spectral metrics for each epoch. Temporal reflectance data were derived from visible, near infrared, and shortwave infrared bands, as well as three vegetation indices, namely normalised difference vegetation index49, soil-adjusted vegetation index50, and enhanced vegetation index51. Vegetation indices have been used extensively in vegetation cover mapping and landcover classification52. Time-series metrics derived from these included the minimum, maximum and selected percentile values (10, 25, 50, 75 and 90% percentiles) and the mean reflectance values for observations between selected percentiles (10–25%, 25–50%, 50–75%, 75–90% and 25–75%). Similar time-series metrics have been successfully used in forest cover mapping using Landsat data1,53,54. To further assist in differentiating between woody and herbaceous cover, which have different phenological metrics55, we derived the variance and range in vegetation indices over time for each epoch. Time-series metric data were used to train a Random Forest (RF) regression model to predict fractional woody plant cover for each 5-year epoch (Supplementary Fig. 1). RF is a supervised classification and prediction tool has that has been extensively used because it avoids overfitting and can incorporate non-parametric data56. Training data were derived from image interpretation methods using very high spatial resolution images derived from Google Earth. We generated 4000 randomly scattered 30 × 30 m sampling quadrats, aligning with the Landsat pixel grid, within the unmasked areas for the given Landsat epoch collection. We manually classified the fractional woody plant cover of each sampling quadrat by identifying woody plant canopies using texture, colour and canopy shadows as identification cues (Supplementary Fig. 9). We estimated the woody plant cover to the closest percentile class (0, 0.25, 0.5, 0.75, 1). Sampling quadrats were excluded if the image acquisition date fell outside of the epoch date range or if there was any uncertainty in designating a fractional woody plant cover value. A separate RF classifier was trained for Landsat 5 TM, Landsat 7 ETM+, and gap-filled Landsat 7 ETM+ with Landsat 8 OLI collections. RF accuracy assessment traditionally employs internal cross-validation between in-bag samples used to train the trees, and out-of-bag samples used for model validation57. However, recent literature suggests internal cross-validation may over-estimate model accuracy, and suggest validation against an testing dataset independent from that used in model construction56,58. Our RF regression models produced high accuracies when using both internal and independent hold-out datasets for validation (Supplementary Table 2). The RF models were used to predict fractional woody plant cover across Africa at 30 m resolution for each epoch. Pixel-level change was defined by the slope of the linear regression between fractional woody cover and year. This is the same metric of change employed by other remote sensing analyses of forest cover change1. Although the response variable in the linear regression was bounded (i.e. proportional woody cover), the model assumptions were checked and satisfied, thus data were not transformed prior to fitting the model. Nevertheless, the analysis of drivers of woody cover change was performed on both untransformed and logit-transformed woody cover data, and both yielded similar results. Estimates of data quality were calculated for each pixel based on the number of available Landsat timepoints for the linear regression, and the total number of pixels used to derive time-series metrics (Supplementary Fig. 10). To explain the change in fractional woody cover we obtained a broad set of climatic, edaphic, biotic, and demographic explanatory variables (Supplementary Figs. 6 and 7). All variables were sourced and analysed within the Google Earth Engine platform, except for herbivore density, protected area status and soils data, which were obtained from sources documented below and analysed within R59 and QGIS60. High temporal resolution climatic data were obtained from the Global Land Data Assimilation System (GLDAS) produced by NASA at 0.25° every 3 h between 1986 and 201661. Variables included were surface temperature, air temperature, rainfall, potential evaporation rate, soil moisture and wind speed. Additional rainfall data were obtained from the Tropical Rainfall Measuring Mission62 and Climate Hazards Group (CHIRPS)63 for comparison with GLDAS. Annual counts of extreme rainfall events, defined as any 5-day rainfall amount that exceeded the 95th percentile of all measurements for that gird cell64, were calculated. Rainfall variability was calculated as the standard deviation across both yearly and 5-hourly time series. The extent to which rainfall is evenly distributed though the year was calculated as the precipitation concentration index65 using data from the CHIRPS dataset. For each variable, we calculated the long-term average and the slope of the linear trend over time. WorldClim rainfall and temperature min, max, mean values for the driest, wettest, warmest and coldest quarters, and seasonality were also included66. Mid-troposphere daily CO2 concentration data at 2 × 2.5° resolution were obtained from Atmospheric Infrared Sounder between 2010 and 201767. The means and trends were calculated per grid cell, but after consideration were not included in the modelling procedure for the following reasons: the data were collected at lower spatial resolution than all other explanatory variables; they were collected for the mid-troposphere and thus the relevance to ambient ground-level CO2 was questionable; and, unlike other bio-climatic variables, the range in the means (2 ppm) and temporal trends in CO2 (0.35 ppm yr−1) concentrations were very small (Supplementary Fig. 11) in comparison to the CO2 enrichment values necessary (>160 ppm) to induce significant changes in woody plant growth34. An attempt was also made to include the long-term CO2 trend in the model, however, because this is spatially homogenous it had very low explanatory power and was thus excluded. Edaphic data were derived from the 'SoilsGrid 1 km' global dataset68. These included depth to bedrock (R horizon); bulk density (kg m3); cation exchange capacity (cmol kg−1); clay and sand content (% gravimetric); soil organic carbon content (g kg−1) and pH (in H2O). The data for six soil depths were aggregated by depth-weighted averaging (i.e. averaged by weighting values for each depth-interval). Digital elevation at 30 m resolution from the Shuttle Radar Topography Mission69 was used to calculate a terrain ruggedness index70, which measures the sum change in elevation between a pixel and its eight neighbouring pixels. Herbivory data were supplied by Archibald and Hempson71 at quarter degree resolution. These included modelled grazer, browser, mixed feeder and total herbivore densities using the FOA livestock data19 and indigenous wildlife census data from reserves across Africa. To obtain a change layer for herbivore density, we constructed a BRT model (see methods in following section) to hind- and fore-cast herbivore densities. The FAO reference year used in the dataset was 2005, thus the 2001–2006 epoch was used as the starting point for hind- and fore-casting. The model was able to explain 72% of the total deviance in herbivore density. Explanatory variables included population density, normalised difference vegetation index, longitude, latitude, temperature, and rainfall which contributed 25, 24, 22, 21, 5, and 3% to the explanatory power of the model, respectively. The slope of the linear trend in modelled herbivore density was calculated for each 0.5° square. Despite the uncertainty in deriving herbivory trends, we found that its removal/addition in woody cover change models did not unduly influence model explanatory power. Removing change in herbivory from the model presented in Fig. 3 reduced the explanatory power by only 4%. Fire data from the MODIS (MCD45A1.051) burned area monthly product at 500 m resolution72 were used to derive the annual average and annual trend in mean annual burned area, fire frequency, and burn date per 0.5 × 0.5° square between 2000 and 2017. Due to technical problems on the MODIS satellite experienced during 200173, we decided to exclude burned area for 2001 in our analysis. To derive trends in fire data that are representative of the study period (1986–2016), we followed the same approach as with herbivory and hind-cast fire data using a BRT model. The model, trained on the mean fire data between 2000 and 2017, was able to explain 70% of total deviance. For further validation, a separate model, trained on 2006–2011 mean data, was used to predict burned area for 2001–2006 and 2011–2016 mean data. The adjusted R2 of the linear regression between observed and predicted burned area for 2001–2006 and 2011–2016 was 0.66 and 0.72, respectively, thus corroborating the predictive capability of the model used for hindcasting. Explanatory variables included in the model were latitude, normalised difference vegetation index, population density, longitude, rainfall, and temperature, which contributed 24, 22, 17, 15, 14, and 8% to the explanatory power of the model, respectively. The equivalent analyses were conducted on fire intensity data from the Fire Information for Resource Management System dataset74. All fires that fell within the data mask (Supplementary Fig. 1) used in the woody plant cover analysis were excluded. We determined the proportion of each 0.5° square covered by protected areas using data from Protected Planet (www.wdpa.org)75. Quarter degree squares were classified into vegetation type76, ecoregion and biome77 based on the centroid of each grid cell. The average and trend in African population density between 2000 and 2015 at 1 km resolution was obtained from the Gridded Population of the World, Version 4 (GPWv4) dataset78. To assess the interactions between explanatory variables and fractional woody cover change, we used BRTs (Supplementary Fig. 1) which have been used extensively in ecological studies to analyse complex systems, including drivers of woody plant cover26. BRTs are an advanced form of machine learning that iteratively fit and combine multiple regression tree models to improve predictive performance13. An advantage of BRTs is their ability to ingest explanatory variables of multiple classes to model complex interactions with a given response without making assumptions about variable interactions, as is often the case with other forms of linear and non-linear modelling13. All BRTs were fitted in R59, using the 'dismo' library following the procedure outlined by Elith et al.13. Variables used in the modelling exercise were aggregated up to a common spatial resolution of 0.5°. Raw data with a resolution >500 m were resampled to 0.5° using bilinear resampling, and those with a resolution ≤500 m were reduced to the mean value per 0.5° grid cell. Data points were assigned a quality weighting based on the 30 m per-pixel quality layers (Supplementary Fig. 10) and the number of unmasked pixels per 0.5° cell. This was used as a weighting variable by assigning it to the "site.weights" call in the BRT model to prevent low quality data with small samples sizes from having an undue influence on the model fitting and prediction. Data with a quality score less than the 0.25 percentile value were excluded from the BRT analysis. Combined and separate models were fitted with explanatory variables termed "drivers" and "facilitators" of woody cover change. We distinguished between explanatory variables with a temporal component (e.g. slope of linear trend in precipitation) and called these drivers, and those without a temporal component (e.g. average precipitation) and called these facilitators of WPE. Prior to fitting the models, we identified a limited set of strongly collinear variable groups with an r>0.779 (Supplementary Fig. 12) and removed variables within these groups that were deemed less likely to be influential for woody cover change. Nevertheless, the excluded collinear variables were kept in mind during the analysis of model results. Further, no trend variables were collinear, making interpretation of the model with drivers of woody cover change (i.e. Fig. 3) simpler. Following parameter optimisation, we used family = Gaussian, tree complexity = 5, learning rate = 0.01, bag fraction = 0.5 and cross-fold validation = 10 as model parameters. The initial BRT models were simplified using procedures described by Elith et al.13, and only the variables with the highest explanatory power were included and analysed for interactions with change in fractional woody cover. To ensure that the BRT results were not a product of chance, we randomly assigned woody cover change values for all 0.5° grid cells and re-ran the model. The model failed to resolve, thus confirming the initial results were not a product of chance. The relative importance of predictors was determined based on the number of times it was selected for splitting, weighted by the squared improvements to the model, averaged over all trees80. Our final models for the simplified set of 31 combined, 25 facilitator (Supplementary Fig. 6) and 12 driver (Supplementary Fig. 7) explanatory variables explained 78%, 75% and 51% of the total deviance in woody cover change, respectively. 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We thank GreenMatter and the Oppenheimer Memorial Trust for their support to Z.V. and the Red Meat Producers Organization and Cape Wools SA for their support to all the authors on the Holistic Planned Grazing project. Z.V. led the data analysis and writing under the supervision of M.D.C. and H.-J.H. All authors discussed the results and contributed to the writing and intellectual development of the manuscript. Correspondence to Z. S. Venter.
Søren Riis Paludan's laboratory focuses on how the immune system recognizes virus infections and how this leads to an immune response. They aim to improve understanding of how the immune system works and interacts with viruses, and how this impacts on the pathogenesis of viral infections. Such work may lead to better understanding of viral diseases and could have implications for future development of improved vaccines, antiviral therapeutics, and diagnostic tools. The main areas of work focus on: mechanisms of viral detection by the innate immune system and viral means to evade these processes; interactions between the innate immune system and basic cellular processes, and the impact on host defense and development of disease; mechanisms of host defense in animal models for human diseases.
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Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.) Kreissman, Susan Gail Yu, AL; Gilman, AL; Ozkaynak, MF; London, WB; Kreissman, SG; Chen, HX; Smith, M; Anderson, B; Villablanca, JG; Matthay, KK; Shimada, H; Grupp, SA; Seeger, R; Reynolds, CP; Buxton, A; Reisfeld, RA; Gillies, SD; Cohn, SL; Maris, JM; Sondel, PM; Children's Oncology Group, 10.1056/NEJMoa0911123 Antibodies, Monoclonal Gangliosides Granulocyte-Macrophage Colony-Stimulating Factor Intention to Treat Analysis
Experience our REJUVENATING organic Argan oil blend, designed to restore the skin and relieve body tension and stress. CBD's anti-inflammatory healing properties can assist in physical aches and pain, sore joints and muscles, promote better sleep and stabilize mood for a body in balance. Contains no THC. Infused with a blend of lavender, peppermint, eucalyptus and grapefruit oil. Our CBD is organically and sustainably sourced from California. Handcrafted in small batches to maintain quality and integrity. Free of chemical additives, parabens and sulfates. All natural and cruelty-free. Organic argan oil, CBD (500mg), organic lavender oil, organic eucalyptus oil, organic peppermint oil, organic grapefruit oil. Argan Oil: Argan oil hydrates and tones the skin, is fast absorbing and leaves no oily residue. It naturally contains Vitamin A and E, improves elasticity and is used as an acne remedy for oily skin. CBD: We source high quality CBD from Northern California, a non-psychoactive compound extracted from the hemp plant and studied for its various healing properties. CBD is naturally anti-inflammatory offering relief from physical aches and pains, stress and anxiety. Lavender Oil: has a calming gentle effect and is widely used for many purposes. It can be used to reduce anxiety and stress and alleviate headaches and improve mood. Peppermint Oil: is known for its respiratory benefits, sinus and headache relief and soothes muscle and joint pain. Eucalyptus Oil: is known for its respiratory benefits, headache relief and soothes pain and inflammation. Grapefruit Oil: is uplifting and is naturally anti-bacterial and anti-inflammatory. It can stimulate circulation and blood flow and soothe menstrual cramps and PMS. Apply topically. Massage on affected area or throughout the whole body for relief. Can be used pre and post-workouts and before going to sleep. *For external use only. Avoid contact with eyes. If any adverse reaction occurs, stop use and contact your physician.
Rosgosstrakh, Russia's largest insurance company, offers you health insurance during your stay in Russia. The insurance covers a full range of medical treatment options including: - initial consultation of the Insured Person for urgent medical indications, to be provided by internist, surgeon, gynecologist, urologist, traumatologist, neurologist, otolaryngologist, ophthalmologist and other specialists, as necessary to provide medical care. - instrumental diagnostics: X-ray, ultrasonic and functional diagnostics (ECG) - laboratory tests: general clinical and biochemical - emergency primary care - hospitalization - dental X-ray imaging - dental surgery: simple and complex tooth extraction - repatriation of mortal remains. Medical care shall be provided at the Volga District Medical Center, which is a major medical institution in Nizhny Novgorod. The Center provides a full range of medical services, including diagnostics, surgery and hospitalization.
Getting enough quality sleep can help protect people against stress, infections and multiple diseases, such as heart and kidney disease, high blood pressure and diabetes, researchers said. There are around 10 per cent of patients who are below 30 and about 15 patients are between 30 and 40 years of age. Hypertension, stress, lack of physical activity, long working hours and no proper balanced diet are the reasons for the increasing heart problems. The study found that people with healthier gums had lower BP and responded better to blood pressure-lowering medications, compared to individuals who had gum disease, a condition known as periodontitis. Suffering from pre-eclampsia increases the risk of vascular dementia by almost double and the risk is even higher for women over the age of 65. Researchers have developed a wearable off-the-shelf and machine learning technology that can predict an individual's blood pressure and provide personalised recommendations to lower it. The new ultrasound patch can continuously monitor central blood pressure in major arteries as deep as four centimeters below the skin. The technology would be useful in various inpatient procedures, researchers said. A new study states that women with mild sleeping problems such as those who have trouble falling asleep can have high blood pressure. Even those women who sleep for about seven to nine hours are more likely to have elevated blood pressure. In adolescents, both quantity and quality of sleep had significant effects on aspects of cardiovascular health such as blood pressure, cholesterol levels and fat deposition. Longer sleep duration were associated with reduced cardiometabolic risk. A high blood pressure level but still below the usual threshold for treating hypertension can put 50-year-olds at increased risk of developing dementia later. Normal blood pressure is below 120/80 mmHg.
The hemostatic system has evolved to prevent the loss of blood at the site of vascular injury. The response is rapid to limit bleeding and is regulated to prevent excessive clotting that can limit flow. The processes that are involved in the assembly of a thrombus (blood clot) include complex interactions among multiple molecular and cellular components in the blood and vessel wall occurring under fluid flow. Formation of a thrombus (thrombogenesis) involves the close interplay between many processes that occur at different scales (subcellular, cellular and multicellular). In the past, these processes have been studied separately. In this talk an extended multi-scale model will be described for studying the formation of platelet thrombi in blood vessels. The model describes the interplay between viscous, incompressible blood plasma, activated and non-activated platelets, as well as other blood cells, activating chemicals, fibrinogen and vessel walls. The macroscale dynamics of the blood flow is represented by the continuous submodel in the form of the Navier-Stokes equations. The microscale cell-cell interactions are described by extended stochastic lattice and off-lattice models. Simulations indicate that increase in flow rates leads to greater structural heterogeneity of the clot. As heterogeneous structural domains within the clot affect thrombus stability, understanding the factors influencing thrombus structure is of significant biomedical importance. Xu, Z., Chen, N., , Kamocka, M.M., Rosen, E.D., and M.S. Alber , Multiscale Model of Thrombus Development, Journal of the Royal Society Interface 5 705-722. Xu, Z., Chen, N., Shadden, S., Marsden, J.E., Kamocka, M.M., Rosen, E.D., and M.S. Alber, Study of Blood Flow Impact on Growth of Thrombi Using a Multiscale Model, Soft Matter DOI:10.1039/b300001a (to appear).
PCR, primers, cloning, Northern blotting SDS-PAGE, Western blotting Chemotaxis Data bank analyses Identification of a novel splice variant of CXCR3 Analyses of cells transfected with CXCR3-alt Analysis of mRNA expression by Northern blotting and RT-PCR Analysis of protein expression by Western blotting Analysis of surface expression of CXCR3 isoforms by immunofluorescence Analysis of chemotactic responsiveness of CXCR3-alt-expressing cells toward CXCL11, CXCL10, and CXCL9 Research Article| November 15 2004 Identification and Partial Characterization of a Variant of Human CXCR3 Generated by Posttranscriptional Exon Skipping1 Jan Erik Ehlert; Jan Erik Ehlert *Proqinase GmbH, Freiburg, Germany; Christina A. Addison; Christina A. Addison †Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada; Marie D. Burdick; Marie D. Burdick ‡Departments of Medicine, Pathology, Pediatrics, Division of Pulmonary Critical Care, David Geffen School of Medicine, University of California, Los Angeles, CA 90024; and Steven L. Kunkel; Steven L. Kunkel §Department of Pathology, University of Michigan, Ann Arbor, MI 48109 Robert M. Strieter Address correspondence and reprint requests to Dr. Robert M Strieter, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, 900 Veteran Avenue, 14-154 Warren Hall, Box 711922, Los Angeles, CA 90024-1922. E-mail address: [email protected] Received: March 29 2004 Jan Erik Ehlert, Christina A. Addison, Marie D. Burdick, Steven L. Kunkel, Robert M. Strieter; Identification and Partial Characterization of a Variant of Human CXCR3 Generated by Posttranscriptional Exon Skipping1. J Immunol 15 November 2004; 173 (10): 6234–6240. https://doi.org/10.4049/jimmunol.173.10.6234 Chemokines are recognized as functionally important in many pathological disorders, which has led to increased interest in mechanisms related to the regulation of chemokine receptor (CKR) expression. Known mechanisms for regulating CKR activity are changes in gene expression or posttranslational modifications. However, little is known about CKR with respect to a third regulatory mechanism, which is observed among other seven-transmembrane receptor subfamilies, the concept of differential splicing or processing of heteronuclear RNA. We now report on the discovery of a variant human CKR, CXCR3, resulting from alternative splicing via exon skipping. The observed RNA processing entails a drastically altered C-terminal protein sequence with a predicted four- or five-transmembrane domain structure, differing from all known functional CKR. However, our data indicate that that this splice variant, which we termed CXCR3-alt, despite its severe structural changes still localizes to the cell surface and mediates functional activity of CXCL11. Chemokines are small molecules of 7–10 kDa that form a large cytokine family composed of ∼50 members in the human system. These polypeptides influence very different cellular activities such as chemotaxis, adhesion, angiogenesis, and proliferation. Approximately 16 different chemokine receptors (CKR),3 all belonging to the large family of seven-transmembrane domain (7TMD) receptors, have been identified as mediators of chemokine activities. The fact that chemokines are recognized as functionally important for progression of many pathological phenomena such as asthma, arthritis, multiple sclerosis, or cancer, has led to increased research interest in the modes of CKR regulation. Important, relatively well-explored regulatory mechanisms of CKR activity are changes in gene expression or posttranslational modifications such as phosphorylation. However, very little is known about CKR with respect to a third regulatory mechanism that has the potential to drastically alter a receptor's structure and that is often observed among other 7TMD receptor subfamilies (1), i.e., differential splicing or processing of heteronuclear RNA. Evidence exists that such regulation might also be important in CKR biology. Differentially processed mRNA messages have indeed been observed for CXCR4 (CXCR4 and CXCR4-Lo) (2), CCR9 (A and B) (3), and CCR2 (A and B) (4). We now report on the discovery of a posttranscriptionally altered variant of human CXCR3, the designated receptor for non-ELR-CXC-chemokines IFN-inducible protein 10/CXCL10, monokine induced by IFN-γ/CXCL9 (5), and IFN-inducible T cell α chemoattractant/CXCL11 (6). In contrast to the most recently reported CXCR3 splice variant CXCR3-B (7), we find alternative splicing of the CXCR3 message via exon skipping that entails a drastically altered C-terminal protein sequence of CXCR3, resulting in a predicted four- or five-transmembrane receptor structure. Our data indicate that this splice variant, which we termed CXCR3-alt, despite its severe structural changes still localizes to the cell surface and mediates functional activity of CXCL11. Human CXCL11, CXCL9, and CXCL10 were obtained from PeproTech (Rocky Hill, NJ). A mAb (clone 1C6) directed against the 37 N-terminal amino acid residues of human CXCR3 (obtained from BD Pharmingen, San Diego, CA) was used for Western blotting (1 μg/ml) and FACS (5 μg/ml) analyses. CXCR3-expressing primary cells were generated by stimulation of PBMC prepared from heparinized peripheral blood from healthy donors in a manner similar to that described by Cole et al. (6). Briefly, whole blood was mixed 1:1 with physiological saline and separated by differential centrifugation using Ficoll. The cells from the PBMC-representing band were diluted in ice-cold culture medium (RPMI 1640, 10% FCS, 100 U/ml penicillin, 100 μg/ml streptomycin, 10 mM HEPES, 2 mM l-glutamine) and washed three times. A total of 2 × 106 cells/ml was stimulated 3 days with 5 μg/ml PHA (Sigma-Aldrich, St.Louis, MO) at 37°C and 5% CO2. Subsequently, cells were stimulated for 9 days with 50 U of IL-2 (R&D Systems, Minneapolis, MN), at which point cells mainly represented T cells, expressing CD3 by >99% as assessed by FACS analyses (data not shown). Human embryonal kidney 293 (HEK) cells (kind gift of P. Graham, Hamilton, CA) were cultured in Eagle's MEM medium (Cambrex, Cambridge, MD) containing 10% FCS, 100 U/ml penicillin, 100 μg/ml streptomycin, 10 mM HEPES, 2 mM l-glutamine, and Fungizone (10 μg/ml; Cambrex). HEK stably transfected with pTarget-derived plasmids were selected in the presence of 400 μg/ml G418 (Sigma-Aldrich). PCRs were performed as described previously (8). Poly(A) RNA was purified from the different cell sources by oligo(dT) Dynabeads (Dynal, Oslo, Norway) according to the manufacturer's manual. The cDNA was prepared by reverse transcription with oligo(dT) using the Superscript kit (Invitrogen Life Technologies, Carlsbad, CA). The PCR primers (5′ to 3′), with their positions on the CXCR3 cDNA sequence (accession no. X95876), are listed as follows (the respective orientation is indicated by S for sense and A for antisense): PRI1-S (positions 8–27), GCGAATTCAAGCACCAAAGCAGAGGGG; PRI1-A (positions 1204–1186), GCTCTAGATGGGCGAAAGGGGAGCCCG; PRI2-S (positions 92–111), CCAAGTGCTAAATGACGCCG; PRI2-A (positions 1052–1071), GCAAGAGCAGCATCCACATC; PRI3-A (positions 838–861), CAAAGGCCACCACGACCACCACCA; PRI4-A (positions 692–695 and 1032–1049), CTCCCGGAACTTGACCCCTGTG. Northern blotting and DNA sequencing were performed using standard techniques. As Northern probes, PCR products generated with primers PRI1-S+A were digoxigenin (DIG) labeled. Labeling and detection of these probes was performed using the PCR DIG probe synthesis kit (Roche, Indianapolis, IN) according to the manufacturer's manual. For sequencing of CXCR3-related inserts within the plasmid pTarget, the following primers were used: sense, ptarget2, CGGCCAGAGAATTATAATACGACT; pri-1802, CTGCATCAGCTTTGACCGCT; pri-2053, AGCTGGTGGCTGGCTTTCTG; antisense, ptarget1, TTACGCCAAGTTATTTAGGTGACA. Sequencing reaction was performed using the Thermo Sequenase radiolabeled terminator cycle sequencing kit (Amersham Biosciences, Piscataway, NJ). Cloning of CXCR3 variants coding sequences was performed from PCR products using PRI1-S and PRI1-A as primers. PCR products were ligated into the T-overhang plasmid pTarget (Promega, Madison, WI) according to the manufacturer's directions. pTarget provides the human CMV promoter to allow insert transcription and bears the neomycin resistance gene. Resulting plasmids pTar-CXCR3-fs and pTar-CXCR3-alt were insert-specifically sequenced and subsequently used for transfection experiments of HEK cells. Transfections were performed by standard calcium phosphate precipitation using 20 μg of plasmid DNA. Transfection efficiencies were ∼90–100%. Subsequently, cells were either analyzed 48 h later for CXCR3 expression by flow cytometry or cultured under G418 selection to generate stably transfected cell lines as described previously (9). G418 resistant colonies were expanded and further analyzed for CXCR3 expression. To analyze protein expression of CXCR3 isoforms, lysates of stably transfected HEK cells were separated by 10% SDS-PAGE followed by Western blotting performed as described previously (8). Protein concentration of lysates was determined according to the Bradford method using Coomassie protein assay kit (Pierce, Rockford, IL). For decent SDS-PAGE separation of the full-size CXCR3 protein, it was essential not to boil SDS-PAGE samples but to perform mild reduction at 37°C for 1 h. Samples were separated by 10% SDS-PAGE, run in comparison to a molecular mass marker (Rainbow Marker; Amersham Biosciences). For analyses of CXCR3 surface expression, transfected HEK cells (1 × 106 cells) were treated on ice for 1 h with murine anti-human CXCR3 mAb clone 1C6 (see above) at 5 μg/ml in PBS/0.1% BSA. After removal of excess Ab, cells were subsequently treated with 1/200-diluted biotin-labeled goat anti-mouse antiserum (DakoCytomation, Hamburg, Germany) for 30 min. Finally, RPE-labeled streptavidin at a dilution of 1/50 (DakoCytomation) was added. Dye-labeled cells were finally assessed on an FACSCalibur flow cytometer (BD Biosciences, Heidelberg, Germany). Data were analyzed using CellQuest software (BD Biosciences). Stably transfected HEK cells were analyzed for chemotactic responses using modified 12-well Boyden chambers (Neuroprobe, Gaithersburg, MD). A volume of 160 μl of stimulus diluted in Eagle's MEM medium containing 100 U/ml penicillin, 100 μg/ml streptomycin, 10 mM HEPES, 2 mM l-glutamine, Fungizone, and 0.1% BSA was added to the lower compartments, which were covered with polycarbonate membranes (10-μm pore size; Osmonics, Minnetonka, MN) pretreated overnight with collagen IV (Invitrogen Life Technologies) at 10 μg/ml in 0.5 M AcOH. Subsequently, a 100-μl cell suspension (1 × 106/ml in the same buffer) was added to the upper compartment, and the chambers were incubated 4 h at 37°C and 5% CO2. Finally, cells migrated to the lower side of the membrane were stained using the Diff-Quick kit (Baxter Diagnostics, Cambridge, MA) according to the manufacturer's directions. Each stimulus concentration was tested in triplicate. In each well of the triplicates, the number of cells observed in three high-powered fields (HPFs) (×100 magnification, HPF) was counted. The number of cells counted in nine HPFs per stimulus-concentration was averaged. The chemotactic index (CI) was calculated from the ratio of the number of migrated cells in the presence of a stimulus vs in the absence of a stimulus. The different cell lines tested showed similar background migration in the absence of a stimulus. Alternatively, cells were preincubated in 2.5 mM pertussis toxin (Ptx; Sigma-Aldrich) at 37°C for 1 h. Following preincubation, chemotaxis was performed as described above. Six individual chemotaxis assays were performed under each of the above conditions. Statistics were performed applying the independent Student t test using the program Origin 3.2 (Microcal Software, Northhampton, MA). Statistical significances with an error of p < 0.05, 0.01, and 0.001 are expressed as ∗, ∗∗, and ∗∗∗, respectively. Transmembrane regions were analyzed by the programs SPLIT (http://pref.etfos.hr/split/) (10) and TMpred (ch.embnet.org/software/TMPRED_form.html) (11). Analyzing the expression of CXCR3 by PHA/IL-2-stimulated PBMC by RT-PCR, we surprisingly observed two instead of one product using the primer set PRI2-S and PRI2-A (Fig. 1). Apart from a 980-bp signal, which was expected from the published CXCR3 cDNA sequence (accession no. X95876), we observed another signal at ∼650 bp. Both PCR products were observed at very stringent annealing temperatures (up to 67°C), using different open reading frame-enclosing primers (e.g., PRI1-S and PRI1-A, Fig. 1), and was absent when using genomic DNA as template (data not shown), indicating that we were not seeing a PCR artifact. Identification of a mRNA splice variant of CXCR3. A, Schematic illustration of the position of the alternative intron (light box) within the CXCR3 cDNA and of the different primers used. Small letters represent intronic donor and acceptor nucleotide motifs. Numbers below primer names represent respective hybridization sites on CXCR3 cDNA. The symbols (○, •, ▵, ▴) designate the individual PCR products: CXCR3 isoform (○, • = product derived from full-size (fs) isoform; ▵, ▴ = product derived from alternatively (alt) spliced isoform). B, Simultaneous as well as separate detection of the CXCR3 full-size transcript and the splice variant by RT-PCR using different primers. PCR was performed using cDNA from PHA/IL-2-stimulated PBMC as template. The symbols (○, •, ▵, ▴) designate the individual PCR products: CXCR3 isoform (○, • = product derived from full-size (fs) isoform; ▵, ▴ = product derived from alternatively (alt) spliced isoform). Cloning of the whole open reading frame of the novel CXCR3 message into the TA-overhang plasmid pTarget and subsequent sequencing revealed a variant in which the nucleotide sequence was identical with that of CXCR3 except for missing bases 696-1032. We called this variant CXCR3-alt. Subsequently, constructed PCR antisense primers 3-A and 4-A allowed for isoform-specific detection of the two CXCR3 messages. Primer 3-A was designed complementary to the sequence missing in the CXCR3-alt message and should thus specifically detect cDNA coding for full-size CXCR3. In contrast, primer 4-A was designed to hybridize to the CXCR3-alt-specific sequence that arises from joining bases on positions 695 and 1033. As shown in Fig. 1, both primers 3-A and 4-A in combination with the common sense primer 2-S yielded only a single band of the expected size of 622 and 770 bp, respectively. The bands in between the fs and the splice product (alt) were identified. Excision of this band and subsequent PCR reamplification always resulted in the same band pattern as in Fig. 1 B, lane 1 or 2, respectively. This suggests that these bands are double-strand artifacts, comprised of one single strand of the fs PCR product and one single strand of the splice (alt) PCR product. These analyses confirmed the existence of two distinct CXCR3 variants. Posttranscriptional excision of bases 696-1032 within the CXCR3 message entails severe changes for the receptor's predicted protein structure. Because such splicing not only removes a coding mRNA fragment but also causes a frame shift, CXCR3-alt on a protein level is identical with full-size CXCR3 only up to the amino acid glutamine (Q) on position 209 within the second extracellular loop (Fig. 2). The following stretch of 58 amino acid residues in CXCR3-alt has no sequence homology to the remaining 158 residues in the original CXCR3 (Fig. 2), and no or one TMD (TMD prediction programs SPLIT and TMpred, respectively; see Materials and Methods). These analyses indicate that, with CXCR3-alt, we have discovered an isoform of CXCR3 bearing a structure that has not been associated with a functional CKR so far. Therefore, we were interested in the functional and biochemical properties of CXCR3-alt compared with full-size CXCR3. Hence, we stably transfected human embryonic kidney cells with pTar-CXCR3-alt (HEK-alt), or with pTar-CXCR3-full-size (HEK-fs). Comparison of amino acid sequences of splice variant CXCR3-alt and CXCR3-full-size (fs). Dashes indicate sequence identical with CXCR3-fs. Bold letters show the novel sequence in CXCR3-alt. Gray boxes surround predicted transmembrane regions according to the program TMpred. Northern blot analyses of RNA from HEK-alt cells showed only a single band that was migrating faster than the major band observed with RNA from HEK-fs cells (Fig. 3,A). Additionally, analyses of the latter RNA revealed a fainter band comigrating with the single band seen with HEK-alt RNA, which might represent the alternatively spliced message (compare arrow-marked band in lane 3 in Fig. 3,A). Interestingly, such an additional fainter, faster-migrating band could also be observed in analyses of RNA obtained from stimulated PBMC (Fig. 3,A, lane 8). These observations indicate that cells expressing full-size CXCR3, i.e., HEK-fs and stimulated PBMC, also bear the splice variant's message, although at a lower level. We also noticed that the CXCR3-specific signal intensity obtained from HEK-alt mRNA was generally ∼10-fold lower than that obtained from HEK-fs (compare Fig. 3,A). This held true for different HEK-fs and HEK-alt clones (data not shown). Because the probe was generated to bind RNA from both isoforms, this observation suggested that, under similar conditions, lower message levels were reached with the splice variant compared with the full-size variant, possibly due to reduced mRNA stability. Moreover, conventional RT-PCR of the CXCR3-alt using specific primer sets are shown in Fig. 3 B. The full-size-specific primer combination PRI 1-S/3-A reacts only with the HEK fs-cDNA, whereas the splice-specific primer combination PRI 1-S/4-A generates a signal from the cDNA of both, HEK-fs as well as HEK-alt. This supports the view that the splice product is always present in cells expressing the full-size product. Biochemical analyses of HEK cells transfected with pTar-CXCR3-alt (HEK-alt), pTar-CXCR3-fs (HEK-fs), and the pTarget-plasmid alone (HEK-c). A, Analyses of stably transfected HEK cells on mRNA level. Shown is a Northern blot probed with a DIG-labeled PCR product complementary to both CXCR3 variants. Indicated amounts of RNA were applied. For comparison, RNA from unstimulated or PHA/IL-2-stimulated PBMC (refer to Materials and Methods) was analyzed. Arrows point out potential splice-variant RNA in Northern blot of cells expressing full-size-CXCR3. B, Conventional RT-PCR of the CXCR3-alt using specific primer sets. The full-size-specific primer combination PRI 1-S/3-A only reacts with the HEK fs-cDNA, whereas the splice-specific primer combination PRI 1-S/4-A generates a signal from the cDNA of both, HEK-fs as well as HEK-alt. C, Analyses of stably transfected HEK cells on protein level. Lysates of transfectants and, for comparison, of PHA/IL-2-stimulated PBMC, were separated by 10% SDS-PAGE and blotted. Blots were developed using anti-human CXCR3 mAb 1C6. D, Analyses of surface-expressed CXCR3 isoforms on transfected HEK cells. Cells were transfected with pTarget (pTar), pTar-CXCR3-alt, and pTar-CXCR3-fs, and after 48 h, were harvested using citric saline. Subsequently, surface-expressed receptor was detected with mAb 1C6. Via biotinylated secondary antiserum and RPE-labeled streptavidin, CXCR3-expressing cells are labeled with RPE. One of two experiments with similar outcome is shown. We were interested in whether the dramatically altered CXCR3-alt isoform was expressed and stable on the protein level. For that purpose, we analyzed lysates of HEK-alt and HEK-fs cells by SDS-PAGE and subsequent Western blotting for the presence of the respective isoform. Using an Ab directed against the N terminus of CXCR3 (see Materials and Methods), we found CXCR3-alt protein indeed being expressed (Fig. 3,C, lane 3). However, CXCR3-alt was detected at much lower levels than full-size CXCR3 (Fig. 3 C, compare lanes 1 and 3), although the Ab's epitope should not be affected by the alternative splicing. These data indicate that CXCR3-alt protein is in fact being expressed albeit in lower amounts than full-size CXCR3. It appears noteworthy that both molecules differed strikingly in their electrophoretic migration behavior. Blot analyses of HEK-alt lysates revealed a well-focusing band at ∼33 kDa, corresponding quite well with the predicted size of 28,715 Da for the 267 residues containing CXCR3-alt, taking into account potential N-glycosylation on the extracellular parts of the receptor. In contrast, the 368 residues containing full-size CXCR3 with a predicted molecular mass of 40,659 Da did not give a well-focusing band. Instead, it appeared as a broad signal between 33 and 75 kDa when SDS-PAGE samples were mildly reduced at 37°C. Boiling, in contrast, led to shift of the CXCR3-fs but not the CXCR3-alt signal to an apparent molecular mass of ∼250 kDa. These observations indicate that alternative splicing entails further biochemical differences besides reduction in size. The drastic structural changes observed with the CXCR3 splice variant could result in defects in intracellular trafficking and surface expression. To elucidate this question, we performed CXCR3-specific FACS analysis of stably transfected HEK cell lines. Although full-size CXCR3-expressing HEK-fs cells displayed 7-fold increased median fluorescence compared with the mock-transfected HEK cells, HEK-alt cells expressing the splice variant showed only slightly increased surface immunoreactivity that was not significant (data not shown). This observation indicated that more sensitive detection could be required for CXCR3-alt detection. Therefore, we analyzed HEK cells after transient transfection with CXCR3 isoform constructs, which would result in high uptake of plasmid DNA and entail enhanced expression of the respective CXCR3 isoform. In fact, cells transiently transfected with CXCR3 full-size encoding plasmid pTar-CXCR3-fs showed 19-fold higher CXCR3-specific median fluorescence (e.g., 365 arbitrary units (a.u.)) than the background signal of mock-transfected cells (e.g., 19 a.u.) (compare Fig. 3,D). Most interestingly, cells transfected with the splice variant encoding construct pTar-CXCR3-alt also showed clearly detectable CXCR-3-alt expression with a median fluorescence (e.g., 36 a.u.) 2-fold above background (compare Fig. 3 D). These data show that CXCR3-alt does indeed localize to the cell surface and might thus be functional as ligand receptor. To assess whether the CXCR3 splice variant was functional as receptor, we compared HEK cells stably transfected with the CXCR3 isoforms with respect to their capacity to chemotactically migrate in response to CXCR3 ligands IFN-inducible T cell α chemoattractant/CXCL11, IFN-inducible protein 10/CXCL10, and monokine induced by IFN-γ/CXCL9. As shown in Fig. 4, we found that HEK-fs cells expressing the full-size receptor showed a pronounced chemotactic response toward CXCL11 already at a concentration of 1 nM (CI, ∼6), whereas higher CXCL11 concentrations hardly increased the CI. In contrast, whereas CXCL10 and CXCL9 caused chemotactic activation of the HEK-fs cells, the effect was less than CXCL11 at 100 nM (Fig. 4,A). Mock-transfected cells HEK-c, on the contrary, did not respond to the CXCR3 ligands. The observation that, on transfected HEK cells, CXCL11 was functionally more potent than CXCL10 or CXCL9 corresponds to data obtained for CXCR3 expressed on other cells types (6, 12). Most interestingly, we found that HEK-alt cells expressing the CXCR3 splice variant also showed chemotactic responses toward CXCL11. However, the CIs of HEK-alt cells were considerably lower. The strongest and most significant response (CI, 3.3) was observed at the highest CXCL11 concentration tested (100 nM) (Fig. 4,A). We did not observe induction of chemotactic activity in HEK-alt cells by either CXCL10 or CXCL9, which could be due to lack of sensitivity of the assay. To further assess the proximal G-protein coupling of CXCR3-alt, we next assessed the effect of Ptx on the chemotactic response of HEK-fs and HEK-alt cells to CXCR3 ligands (Fig. 4,B). We found that Ptx inhibited the chemotactic response of HEK-fs to all three CXCR3 ligands (Fig. 4 B). Furthermore, we determined that Ptx inhibited the chemotactic response of CXCL11 on HEK-alt cells. A, Functional analyses of HEK cells stably transfected with pTar-CXCR3-alt (HEK-alt), pTar-CXCR3-fs (HEK-fs), and the pTarget-plasmid alone (HEK-c). Cells were analyzed in a modified Boyden chamber for their chemotactic response toward indicated concentrations of chemokines CXCL11, CXCL9, and CXCL10. B, The effect of Ptx on the chemotactic response of HEK-fs and HEK-alt cells to CXCR3 ligands. The cellular responses are shown as CIs indicating the ratio of migrated cells in the presence of a stimulus compared with migrated cells in the absence of a stimulus. Given are the mean values of six independent experiments ± SD. Statistical significances with an error of p < 0.05, 0.01, and 0.001, are indicated with ∗, ∗∗, and ∗∗∗, respectively. We report on the discovery, identification, and partial characterization of an alternatively spliced isoform of CXCR3, which we termed CXCR3-alt. Differentially processed mRNA messages have previously been observed for CKR such as CXCR4 (2), CCR9 (3), and CCR2 (4). CXCR4 polymorphism has been shown to be due to intron retention, whereas alternative splicing is responsible for the different CKR transcripts. Recently, first data have been published, indicating that differential mRNA processing is an important issue for CXCR3 biology as well. Lasagni et al. (7) identified a novel exon region within the CXCR3 gene, which is included into the CXCR3 mRNA in certain cell types only. Such alternative splicing produces the CXCR3 isoform CXCR3-B, which not only binds CXCL9, CXCL10, and CXCL11, but also PF-4/CXCL4. CXCR3-B is structurally very similar to the original CXCR3, differing only in the presence of an extended N terminus. We now present a completely different CXCR3 splice product, CXCR3-alt. Our data show that the coding sequence for this splice variant is the result of exon skipping in the context of alternative splicing, where within the original CXCR3 open reading frame (composed of at least three exons: I = …-bp 695; II = bp 696-1032; III = bp 1033-…), exon II is left out (Fig. 1). This observation implies that, whenever the message for the original full-size CXCR3 is recombinantly constructed, introduced into cells, and then transcribed, the CXCR3-alt message is also generated. In fact, in HEK cells recombinantly expressing full-size CXCR3, by PCR, we always observe a message for CXCR3-alt (data not shown). Hence, functional effects observed with cells recombinantly expressing full-size CXCR3 may reflect a mixture of effects caused by the different splice variants CXCR3-fs and CXCR3-alt. Alternative splicing is associated with drastic structural alterations of the receptor protein. Due to a frameshift, the splicing process leads to a change in sequence after amino acid Q209 within the second extracellular loop of the full-size CXCR3 protein, from which, instead of 159 aa, only 58 aa follow (Fig. 2). Due to this changed sequence, CXCR3-alt is predicted to have only four or five TMDs, depending on the TMD prediction program used (see Data bank analyses in Materials and Methods). This structural impact is more severe than those observed with so-far-known CKR and splice variants that showed rather moderate N- or C-terminal modulations (2, 3, 4, 7). The CKR splice variant that, with respect to structure, most closely resembles CXCR3-alt is the genomic mutant of CCR5, CCR5Δ32 (13). CCR5Δ32 lacks the final three TMDs of the original 7TMD receptor and is considered either not to be translated into protein (13), or, if so, not to be transported to the cell surface (14), resulting in lack of biological activity. Using sensitive detection methods, we could show that these properties are not true for CXCR3-alt. Although several lines of evidence show that CXCR3-alt is expressed at considerably (∼15-fold) lower levels than the full-size receptor, CXCR3-alt is clearly expressed as protein and appears to traffic as functional receptor to the cell surface (Fig. 3). Possibly the same is the case for the CCR5 mutant CCR5Δ32, and more sensitive methods might be required for its detection. Facing the low mRNA and protein expression levels of CXCR3-alt in comparison to full-size CXCR3 (Fig. 3), one may doubt a functional relevance of the presence of the CXCR3-alt splice variant. However, it has to be kept in mind that the CXCR3-B isoform shows low expression levels as well (7), indicating that reduced expression may be a general phenomenon of CXCR3 splice variants and also low amounts of such variants can well be of functional importance. In fact, we could show that, despite its structural changes, CXCR3-alt surprisingly still possesses, albeit reduced, functional activity mediating chemotactic effects induced by CXCL11 (Fig. 4). In addition, the chemotactic activity of CXCL11 through CXCR3-alt is Ptx sensitive, supporting the notion that proximal G-protein coupling is intact and Giα dependent. Apparently, CXCL11 can still interact with the CXCR3 variant lacking the third and most of the second extracellular loop. This finding is corroborated by literature data indicating that especially the N terminus and first extracellular loop of CXCR3 contribute to the interaction of CXCL11 with CXCR3 (12). A major reason for reduced chemotactic activity of CXCL11 may be the reduced surface expression of CXCR3-alt protein compared with that of the full-size receptor (Fig. 3). Due to the lack of receptor binding experiments, which were not within the scope of this study, we cannot estimate how far reduced CXCL11 activity is also due to reduced ligand affinity. The questions of affinity and quality of interaction will have to be addressed in an independent study. Such a study may also clarify the way in which glycosaminoglycans are involved in the binding of IFN-inducible non-ELR chemokines to CXCR3. Interestingly, full-size CXCR3 as the only CKR contains a potential recognition site for the attachment of glycosaminoglycans (S304-G307) (15), which has been conserved in slightly modified form in the CXCR3-alt protein (S213-G215). It remains to be shown, however, whether these sites have any functional relevance. The physiological function of CXCR3-alt, however, remains unclear. Possibly alternative splicing of CXCR3 is just a way to regulate the number of the full-size and fully active receptor on the transcriptional level. In contrast, CXCR3-alt might regulate CXCR3 activity on a cotranslational level, e.g., by heterodimerization, a mechanism by which CCR5Δ32 was postulated to modulate the full-size CCR5's function (14). Under different PBMC stimulation conditions using PHA, IL-2, IL-4, IL-12, or IFN-γ, we could, however, not see a regulation in the ratio of the CXCR3-alt to the CXCR3-fs message. Whenever we observe a CXCR3-fs message, we also detect the splice variant's message (data not shown). Perhaps the CXCR3-alt message is an always-occurring side product of the full-size message and can per se not be regulated. So, very different scenarios are possible for CXCR3-alt function, ranging from accidental irrelevant side product on the one hand to being required for correct CXCR3-full-size function, which has by the way never been shown to be active without CXCR3-alt, in contrast. Further studies focusing on physiological CXCR3 functions in inflammation (5), diseases of lung (16), kidney (17), and CNS (18), and angiostasis and cell proliferation (19, 20), will have to scrutinize which functional relevance this novel CXCR3 isoform indeed has. Funding for this work was provided by National Institutes of Health Grants CA87879, HL66027, P50HL67665, and P50CA90388 (to R.M.S.). J.E.E. was supported by Grant Eh188/1-1 of the German Research Foundation, Deutsche Forschungsgemeinschaft. Abbreviations used in this paper: CKR, chemokine receptor; DIG, digoxigenin; HPF, high-powered field; CI, chemotactic index; Ptx, pertussis toxin; TMD, transmembrane domain; a.u., arbitrary unit. Kilpatrick, G. J., F. M. Dautzenberg, G. R. Martin, R. M. Eglen. . 7TM receptors: the splicing on the cake. Trends Pharmacol. Sci. Gupta, S. K., K. Pillarisetti. . Cutting edge: CXCR4-Lo: molecular cloning and functional expression of a novel human CXCR4 splice variant. Yu, C. R., K. W. Peden, M. B. Zaitseva, H. Golding, J. M. Farber. . CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ckβ-15 that differ in their sensitivities to ligand. Wong, L. M., S. J. Myers, C. L. Tsou, J. Gosling, H. Arai, I. F. Charo. . Organization and differential expression of the human monocyte chemoattractant protein 1 receptor gene: evidence for the role of the carboxyl-terminal tail in receptor trafficking. Loetscher, M., B. Gerber, P. Loetscher, S. A. Jones, L. Piali, I. Clark-Lewis, M. Baggiolini, B. Moser. . Chemokine receptor specific for IP10 and Mig: structure, function, and expression in activated T-lymphocytes. Cole, K. E., C. A. Strick, T. J. Paradis, K. T. Ogborne, M. Loetscher, R. P. Gladue, W. Lin, J. G. Boyd, B. Moser, D. E. Wood, et al . Interferon-inducible T cell α chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. Lasagni, L., M. Francalanci, F. Annunziato, E. Lazzeri, S. Giannini, L. Cosmi, C. Sagrinati, B. Mazzinghi, C. Orlando, E. Maggi, et al . An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. Ehlert, J. E., F. Petersen, M. H. G. Kubbutat, J. Gerdes, H.-D. Flad, E. Brandt. . Limited and defined truncation at the C-terminus enhances receptor binding and degranulation activity of the neutrophil-activating peptide 2 (NAP-2). Addison, C. L., T. O. Daniel, M. D. Burdick, H. Liu, J. E. Ehlert, Y. Y. Xue, L. Buechi, A. Walz, A. Richmond, R. M. Strieter. . The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. Juretic, D., A. Lucin. . The preference functions method for predicting protein helical turns with membrane propensity. J. Chem. Inf. Comput. Sci. Hofmann, K., W. Stoffel. . TMbase: a database of membrane spanning proteins segments. Biol. Chem. Hoppe-Seyler Xanthou, G., T. J. Williams, J. E. Pease. . Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi-step model of ligand binding and receptor activation. Liu, R., W. A. Paxton, S. Choe, D. Ceradini, S. R. Martin, R. Horuk, M. E. MacDonald, H. Stuhlmann, R. A. Koup, N. R. Landau. . Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply exposed individuals to HIV-1 infection. Benkirane, M., D. Y. Jin, R. F. Chun, R. A. Koup, K. T. Jeang. . Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32. Bourdon, M. A., T. Krusius, S. Campbell, N. B. Schwartz, E. Ruoslahti. . Identification and synthesis of a recognition signal for the attachment of glycosaminoglycans to proteins. Belperio, J. A., M. P. Keane, M. D. Burdick, J. P. Lynch, III, Y. Y. Xue, K. Li, D. J. Ross, R. M. Strieter. . Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome. Bek, M. J., H. C. Reinhardt, K. G. Fischer, J. R. Hirsch, C. Hupfer, E. Dayal, H. Pavenstadt. . Up-regulation of early growth response gene-1 via the CXCR3 receptor induces reactive oxygen species and inhibits Na+/K+-ATPase activity in an immortalized human proximal tubule cell line. Sorensen, T. L., C. Trebst, P. Kivisakk, K. L. Klaege, A. Majmudar, R. Ravid, H. Lassmann, D. B. Olsen, R. M. Strieter, R. M. Ransohoff, F. Sellebjerg. . Multiple sclerosis: a study of CXCL10 and CXCR3 colocalization in the inflamed central nervous system. J. Neuroimmunol. Arenberg, D. A., S. L. Kunkel, P. J. Polverini, S. B. Morris, M. D. Burdick, M. C. Glass, D. T. Taub, M. D. Iannettoni, R. I. Whyte, R. M. Strieter. . Interferon-γ-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. Romagnani, P., F. Annunziato, L. Lasagni, E. Lazzeri, C. Beltrame, M. Francalanci, M. Uguccioni, G. Galli, L. Cosmi, L. Maurenzig, et al . Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity.
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Findings from RCT Grants Positive impacts on bachelor's degree receipt in a randomized controlled trial of Bottom Line – a program providing one-on-one guidance to help low-income students get into and graduate from college This well-conducted RCT found that Bottom Line increased the likelihood of earning a bachelor's degree by approximately 8 percentage points in the sixth year after random assignment (i.e. five years after expected high school graduation). We fund RCTs across the spectrum of social policy. Read a one-page summary of each completed study, including the program evaluated, the key study findings, and a link to the full study report. Grantee: Bottom Line. The study's publicly-available report is posted here. Description of the Intervention: This project was a randomized controlled trial (RCT) of Bottom Line, a program that provides one-on-one guidance to help low-income students get into and graduate from college. The program serves students beginning in their senior year of high school and continuing for up to six years of college. Full-time trained advisors help students identify colleges where they are likely to be successful, apply to those schools, complete financial aid applications, and select a college or university that best meets their needs. Once enrolled in college, students who attend a college affiliated with Bottom Line are offered ongoing support from campus-based advisors in several areas including course selection, adjusting to college social life, and managing financial aid. The program costs approximately $4,000 per student. Study Design: The study randomly assigned 2,422 students at three sites — Boston, MA; Worcester, MA; and New York City, NY — to a treatment group that was offered Bottom Line or a control group that was not (but had access to usual school and community services). Seventy percent of sample members were female and 64% were Black or Hispanic. At the start of the study, 81% of the sample were children of parents who did not attend college, and the average household income for students in the sample was approximately $23,000. The study is measuring college enrollment, persistence, and completion outcomes over a seven-year period, using administrative data from the National Student Clearinghouse. The report discussed in this summary presents findings for the full sample for whom six-year outcome data are currently available. Impact on the Primary Outcome: On the study's pre-registered primary outcome, the analysis found that Bottom Line produced a sizable increase of 8 percentage points in the likelihood of earning a bachelor's degree six years after random assignment (i.e. five years after expected high school graduation). Specifically, 55% of the Bottom Line group had received a bachelor's degree vs. 47% of the control group. This effect was statistically significant in the full sample (p<0.01), and consistent across the study's three implementation sites.1 Over the same period, Bottom Line also produced a 5 percentage point increase in any college enrollment (87% of the Bottom Line group had enrolled in any college vs. 82% of the control group) and a 9 percentage point increase in enrollment in a four-year college (79% of the Bottom Line group had enrolled in a four-year college vs. 70% of the control group). Both effects were statistically significant (p<0.01).2 Study Quality: Based on a careful review, we believe this study is well-conducted, and that the findings are valid.3 The effects were between 7 and 8 percentage points at each site and statistically significant (p<0.05) at two of the three sites (Boston and New York). The effect at the third site (Worcester) did not reach statistical significance, because it had a smaller sample of youth than the other sites. These site-specific impacts were requested directly from the study authors for the purposes of this summary. ↩︎ Bottom Line produced statistically significant reductions in (i) enrollment in two-year degree programs (9% of the Bottom Line group had ever enrolled in a two-year degree program vs. 13% of the control group), and (ii) receipt of an associate's degree (10% of the Bottom Line group earned an associate's degree vs. 13% of the control group). Taken as a whole, the study's findings suggest that Bottom Line may have shifted some students into four-year degree programs who otherwise would have pursued two-year degree programs. For example, the study had successful random assignment (as evidenced by highly similar treatment and control groups), no sample attrition, and valid analyses that were publicly pre-registered.
Australia has the highest prevalence of skin cancer in the world. People with albinism are at high risk and the prevalence of skin cancer among Australian affected by albinism is nearly 100 %. The number of persons affected by albinism in the Victoria area is between 500 and 1000. Since the end of 2017, Sinclair Dermatology Clinic and the team of dermatologists set up a partnership with the Albinism Fellowship of Australia in order to offer free skin checks for individuals with albinism. Skin checks include full body skin imaging with an advanced skin cancer surveillance system. 50 persons are already included in this program and 12 skin cancers have been detected. The objective of the project is to increase the number of skin checks – up to 500 patients – and to offer free skin cancer surgery in case of diagnosis of skin cancer with operating facility, instruments, surgical and nursing staff.
Measuring changes in breathing rate can lead to the early detection of disease (1) and is key in evaluating the safety profile of novel therapeutics (2), (3). A range of conditions including exercise, stress, lung disorders, cardiovascular disease, metabolic acidosis, drug overdose, and central nervous system abnormalities can all manifest in detectable alterations in breathing rate (1), (3-5). The Vium Breathing Rate™ (breaths per minute) is derived from continuous video streams of animals in Vium Smart Housing. Computer vision algorithms search for regions of time when animals are stationary, and identify periodic motion that falls within a frequency band containing known rodent breathing rates (6). The peak root mean square (RMS) power is compared to a threshold to determine whether the periodic motion is significant. The Vium Breathing Rate™ was compared to breathing rate measured by conventional whole-body plethysmography of awake mice with known differences in baseline breathing rate (3). Six-week old male C57BL/6J and C3H/HeJ mice were acclimated to the Vium Digital Vivarium™ for a total of one week prior to commencing the study. Animals were singly housed three days prior to study start. Unrestrained animals were placed in a whole-body plethysmograph (EMKA technologies), and breathing rate was simultaneously collected via plethysmograph and the Vium Breathing Rate algorithm. Our breathing metric was compared to breathing rate measured by the plethysmograph (Fig. 2, R2 = 0.981; RMS error = 3.7%). In this validation, we demonstrated that the Vium Breathing Rate has a 95% confidence interval of -2.9% to +8% of the breathing rate observed by plethysmograph. Consistent with the literature6 we observed that C3H/HeJ mice had a significantly lower breathing rate (136.3 +/- 3.2) than C57BL/6J animals (180.7 +/- 3.7) [ANOVA: F(1,27) = 65.99; p < 0.0001]. We have successfully demonstrated that the Vium breathing metric accurately measures breathing rate. The Vium Digital Vivarium provides an unprecedented opportunity to obtain continuous real, in cage, breathing rate data, over the course of a study, without the need for human intervention. Removing the human intervention eliminates the introduction of variables associated with stress and anxiety, known to affect animal physiology. This results in more reliable and reproducible data from which scientists can glean valuable information on drug safety and efficacy and provides data not often assessed due to the laborious and notoriously unreliable conventional methods of collection. 1. Braun SR. Respiratory Rate and Pattern. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 43. 2. Pugsley MK, Authier S, Curtis MJ. Principles of safety pharmacology. Br J Pharmacol. 2008 Aug;154(7):1382-99. 3. Murphy DJ. Assessment of respiratory function in safety pharmacology. Fundam Clin Pharmacol. 2002 Jun;16(3):183-96. 5. Jerath R, Barnes VA, Crawford MW. Mind-body response and neurophysiological changes during stress and meditation: central role of homeostasis. J Biol Regul Homeost Agents. 2014 OctDec;28(4):545-54.
> Hip fractures occur almost exclusively in older adults; plain radiographs are the appropriate initial imaging test, with a sensitivity of 90% – 98%. What is the sensitivity of CT for radiograph-occult hip fractures? Of MRI? > CT has a 58% – 80% sensitivity for radiograph-occult hip fractures; MRI has a sensitivity of 99% – 100% (Annals of EM, epub, 10/2/18).
It is a fact that the state of your dental health is an indicator of your overall health status. Healthy teeth and gums are directly linked to having a healthy cardiovascular system. At Cranberry Endodontics we understand your fear of the dentist and it is our goal to help you feel comfortable and relaxed at every stage of your dental care. Our friendly office prides itself on providing the best dental care in the most comfortable environment possible. Digital x-rays produce an incredibly low dose of radiation and are perfectly safe and should be a part of your routine dental care. The risk of forgoing x-rays is greater than skipping them completely. Chewing gum with xylitol has been proven to prevent cavities. Chew a piece after every meal and occasionally between meals as well for optimal protection. At the first sight of bleeding gums, a call to the dental center should be made. Gum disease is a serious condition and bleeding gums are often the first symptom. Regular cleanings and check ups at the dental center will ensure that your mouth is healthy and there are no problems brewing. The ingredients in soft drinks work together to erode tooth enamel and weaken teeth. It is best to avoid soda, but if you must drink one, rinse and brush shortly after consuming. It is important to floss at least once every day to remove food particles and plaque build up between teeth. When children learn to brush properly at a young age, their teeth are healthier for it. The staff at Cranberry Endodontics is happy to give brushing demonstrations. Eating a healthy diet rich in whole grains and fiber-filled fruits and vegetables will keep teeth healthy and strong. Our state of the art dental center is available to meet all of your dental needs. Call Cranberry Endodontics at (724) 452-7080 today to schedule an appointment.
Psoriasis is a major skin disease in which huge abnormal patches appear on the skin. These patches are red in color and feel itchy and scaly. Immediate medication is required if you are experiencing symptoms of psoriasis. Although no scientific theory proves that certain foods controls or shows positive effects in curing psoriasis, weight loss is the key to treat psoriasis, according to the experts. Hence, experts suggest few foods to cure psoriasis. Experts also say that weight loss not only helps in curing various disorders, but it also helps in curing diabetes, heart diseases as well as strokes, which are found on high scales in people suffering with psoriasis. According to the nutritionists, healthy diet includes, low-fat dairy products, lean protein, fruits and vegetables and whole grains. We have brought you a list of few best foods, which has been recommended by the experts, to cure a dangerous skin disorder of psoriasis. According to many nutritionists, diet rich in proportion of fruits and vegetables may show positive results against inflammatory disorders. As I have already said that there are no scientific backing for the theory that certain foods controls the effects of psoriasis, we know that psoriasis is a condition occurs due to specific inflammatory conditions. Hence, it is required to have foods and vegetables,which have anti-inflammatory properties for the patients who are suffering from psoriasis. Among the best fruits and vegetables with anti-inflammatory properties, carrots, sweet potatoes, squash, kale, broccoli and spinach are ranked higher. Seafood which are high in omega-3 fatty acids, which can be found in salmon, mackerel, albacore tuna and sardines, are highly helpful in preventing heart diseases. Additionally,this fish oil is also helpful in lowering down the inflammation and strengthening the immune system, which is found to be negatively affected in the patients with psoriasis. Considering the fact that psoriasis can also cause stroke as well as heart attack, experts suggest to eat fish twice every week. Grains have always been considered as the major factor balanced diet. Grains such as cereals, pasta, oatmeal and brown rice, just like fruits and vegetables, contain anti-inflammatory properties and are highly effective in blood sugar regulation. These grains along with legumes, beans and lentils are rich in fiber as well as antioxidants, which are helpful in full body development. Again,meat is also not considered as the best on psoriasis. However, consumption of lean meats such as white-meat chicken and turkey helps in controlling effects of it. Experts suggest that various patients have shown recoveries after limiting their consumption of red meat. According to the nutritionists, intake of fatty red meat results in inflammation in the body, which can cause psoriasis. However, eating red meat occasionally with less fatty cuts such as lean flank steak as well as sirloin, is permitted. Fats have always been considered as bad in maintaining health. However, very few people know that there are few fat types which are actually very helpful in getting fit. These fats are known as polyunsaturated fats, which are found in high proportions in vegetable oils, avocados and nuts. Other beneficial fat type, monounsaturated fats are found in walnuts, soybean oil and flaxseed as well as certain fishes. Intake of these fats, however, should under moderation, according to the experts. Nutritionists also suggest to stay away from saturated as well as trans fats,which may trigger inflammation in the body.
Home » Obesity » NIH Guidelines Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults by National Hearth Lung and Blood Institute Excerpt from NIH PDF file: An estimated 97 million adults in the United States are overweight or obese, a condition that substantially raises their risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and endometrial, breast, prostate, and colon cancers. Higher body weights are also associated with increases in all-cause mortality. Obese individuals may also suffer from social stigmatization and discrimination. As a major contributor to preventive death in the United States today, overweight and obesity pose a major public health challenge. Overweight is here defined as a body mass index (BMI) of 25 to 29.9 kg/m2 and obesity as a BMI of ≥ 30 kg/m2. However, overweight and obesity are not mutually exclusive, since obese persons are also overweight. A BMI of 30 is about 30 lb overweight and equivalent to 221 lb in a 6'0″ person and to 186 lb in one 5'6″. The number of overweight and obese men and women has risen since 1960; in the last decade the percentage of people in these categories has increased to 54.9 percent of adults age 20 years or older. Overweight and obesity are especially evident in some minority groups, as well as in those with lower incomes and less education. Obesity is a complex multifactorial chronic disease that develops from an interaction of genotype and the environment. Our understanding of how and why obesity develops is incomplete, but involves the integration of social, behavioral, cultural, physiological, metabolic and genetic factors. While there is agreement about the health risks of overweight and obesity, there is less agreement about their management. Some have argued against treating obesity because of the difficulty in maintaining long-term weight loss and of potentially negative consequences of the frequently seen pattern of weight cycling in obese subjects. Others argue that the potential hazards of treatment do not outweigh the known hazards of being obese. The intent of these guidelines is to provide evidence for the effects of treatment on overweight and obesity. The guidelines focus on the role of the primary care practitioner in treating overweight and obesity. Evidence-Based Guidelines To evaluate published information and to determine the most appropriate treatment strategies that would constitute evidence-based clinical guidelines on overweight and obesity for physicians and associated health professionals in clinical practice, health care policy makers, and clinical investigators, the National Heart, Lung, and Blood Institute's Obesity Education Initiative in cooperation with the National Institute of Diabetes and Digestive and Kidney Diseases convened the Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults in May 1995. The guidelines are based on a systematic review of the published scientific literature found in MEDLINE from January 1980 to September 1997 of topics identified by the panel as key to extrapolating the data related to the obesity evidence model. Evidence from approximately 394 randomized controlled trials (RCTs) was considered by the panel. The panel is comprised of 24 members, 8 ex-officio members, and a methodologist consultant. Areas of expertise contributed to by panel members included primary care, epidemiology, clinical nutrition, exercise physiology, psychology, physiology, and pulmonary disease. There were five meetings of the full panel and two additional meetings of the executive committee comprised of the panel chair and four panel members. The San Antonio Cochrane Center assisted the panel in the literature abstraction and in organizing the data into appropriate evidence tables. The center pretested and used a standardized 25-page form or "Critical Review Status Sheet" for the literature abstraction. Ultimately, 236 RCT articles were abstracted and the data were then compiled into individual evidence tables developed for each RCT. The data from these RCTs served as the basis for many of the recommendations contained in the guidelines. The panel determined the criteria for deciding on the appropriateness of an article. At a minimum, studies had to have a time frame from start to finish of at least 4 months. The only exceptions were a few 3-month studies related to dietary therapy and pharmacotherapy. To consider the question of long-term maintenance, studies with outcome data provided at approximately 1 year or longer were examined. Excluded were studies in which self-reported weights by subjects were the only indicators used to measure weight loss. No exclusions of studies were made by study size. The panel weighed the evidence based on a thorough examination of the threshold or magnitude of the treatment effect. Each evidence statement (other than those with no available evidence) and each recommendation is categorized by a level of evidence which ranges from A to D. Table ES-1 summarizes the categories of evidence by their source and provides a definition for each category. Who is at Risk? All overweight and obese adults (age 18 years of age or older) with a BMI of ≥25 are considered at risk for developing associated morbidities or diseases such as hypertension, high blood cholesterol, type 2 diabetes, coronary heart disease, and other diseases. Individuals with a BMI of 25 to 29.9 are considered overweight, while individuals with a BMI ≥30 are considered obese. Treatment of overweight is recommended only when patients have two or more risk factors or a high waist circumference. It should focus on altering dietary and physical activity patterns to prevent development of obesity and to produce moderate weight loss. Treatment of obesity should focus on producing substantial weight loss over a prolonged period. The presence of comorbidities in overweight and obese patients should be considered when deciding on treatment options. Why Treat Overweight and Obesity? Obesity is clearly associated with increased morbidity and mortality. There is strong evidence that weight loss in overweight and obese individuals reduces risk factors for diabetes and cardiovascular disease (CVD). Strong evidence exists that weight loss reduces blood pressure in both overweight hypertensive and non-hypertensive individuals; reduces serum triglycerides and increases high-density lipoprotein (HDL)-cholesterol; and generally produces some reduction in total serum cholesterol and low-density lipoprotein (LDL)-cholesterol. Weight loss reduces blood glucose levels in overweight and obese persons without diabetes; and weight loss also reduces blood glucose levels and HbA1c in some patients with type 2 diabetes. Although there have been no prospective trials to show changes in mortality with weight loss in obese patients, reductions in risk factors would suggest that development of type 2 diabetes and CVD would be reduced with weight loss.
The ICT Procurement Team is currently supporting the Client's CX Program with a number of existing procurement activities and two further major procurement activities are planned for 2019. To date, the ICT Procurement Team has worked closely with the CX Program team to plan and execute these procurement activities and to provide guidance in relation to evaluation of offers and negotiation of contract arrangements, primarily in an advisory capacity only. The CX Program has expressed interest in a greater level of assistance which would enable a more active role for procurement in the preparation of procurement planning documentation, evaluation of offers and contract negotiations. Given the current workload of the ICT Procurement team and the strategic importance and accelerated delivery timeframes for the CX Program, it is proposed that an additional procurement specialist be recruited to join the ICT Procurement team for a 6 month period to enable dedicated support of the CX Program procurements. • Contribute effectively to all aspects of ICT procurement including procurement plans, specification / tender development, management and evaluation, with a particular focus on facilitating procurements for marketing technology solutions and services associated with the client's CX Program of work. • Contribute effectively to all aspects of supplier negotiations, including commercial and contract negotiation. • Independently prepare ICT procurement contracts based on client's specifications and approved template terms and manage the execution of ICT contracts in accordance with client's Delegations Policy. • Liaise with Client's Legal Services in relation to identified legal risks associated with ICT procurement activities. • Support IT Managers in following appropriate recruitment and procurement processes to engage resources for project activities. • Support IT Managers by providing technical writing support. • Provide a high level of customer service and advice to Client's ICT purchasers in a relevant, timely and accurate manner on matters relating to procurement policy and procedures. • Publish tenders on the Queensland Government's Qtenders website and monitor and update as necessary. • Contribute to the development, implementation and review of ICT procurement strategies and policies and support the Category Manager (ICT) and ICT sub-category managers in the preparation of the ICT Category Management Plan, through spend analysis, demand analysis, market analysis and stakeholder engagement. • Contribute to the development, implementation and review of ICT procurement guidelines, templates, website and procurement system, consistent with the requirements of the client's Procurement Policy and procurement best practice. • A degree (preferably in Information Technology, Law, Commerce or Business) with subsequent relevant experience working in or supporting a large IT department; or extensive experience and specialist expertise in IT Procurement for large organisations; or an equivalent combination of relevant experience and/or education/training. • Knowledge of procurement policy and procedures as they apply to IT procurement in a large public sector or commercial organisation. • Experience in leading and advising on significant procurement activities from planning, risk management, and development of tender documentation through to vendor negotiation and contract delivery. • Excellent interpersonal, written and verbal communication skills, including demonstrated negotiation abilities, with experience in consulting with and influencing stakeholders to deliver outcomes within a large environment, preferably at a University. • High level analytical skills and ability sufficient to assess problems, articulate trends and strategies based on that analysis, and propose appropriate solutions and provide concise reports against indicators for management. • A proven ability to be highly organised and self-managing, with the ability to meet tight deadlines, manage conflicting priorities and set realistic goals with minimal supervision or direction. • Experience in managing end to end procurement processes for the procurement of marketing technology solutions and services and associated CX change projects. • Sound knowledge of the client's policies, procedures and documentation, or the ability to acquire this knowledge rapidly. • Knowledge and understanding of current State Government legislation with regards to procurement, or the ability to acquire this knowledge rapidly.
We have a wide range of learning opportunities in the exhibition hall and in dedicated sessions delivered by healthcare companies and charities keen to interact with the primary care audience and help develop their products and services for the benefit of patients. Please note: All sponsored sessions at the Annual Conference are the views of the responsible organisation, not the RCGP, and have not been accredited for CPD by the RCGP. See full sponsorship guidelines here: The RCGP guidelines for sponsorship and funding Thursday 24 October: 13:00 Symposium sponsored by Nutricia Advanced Medical Nutrition Malnutrition to improve lives and save money This session will review the importance of considering nutrition across the spectrum of primary care. It will highlight the importance of identifying and managing malnutrition, especially in frail older patients. It will look at the clinical and financial consequences of malnutrition and the effects on outcomes. The session will review the evidence and give practical advice and tools on identifying and managing malnutrition in a cost effective way. Dr Trevor Smith, Consultant Gastroenterologist at University Hospital Southampton NHS Foundation Trust. He has a specialist interest in the care of patients who have inflammatory and other complex gut disorders, particularly those who require long term artificial nutrition support. He has several leadership roles in Southampton as Director of the supra-regional Intestinal Failure service and Clinical Director for Specialist and in-patient Medicine. Trevor has been President of the British Association of Parenteral and Enteral Nutrition (BAPEN) since November 2018; prior to this he was a member of the BAPEN executive team and Council for several years. He also chaired the British Artificial Nutrition Survey (BANS) and led the introduction of a national Intestinal Failure patient registry. He has an active research interest in clinical nutrition and has published a number of papers in this area. Find out more about Nutricia Advanced Medical Nutrition Symposium sponsored by LIVI Thursday, 24 October Mini Theatre 2 Webside manner: Lessons in how to deliver care in a digital age Dr Harriet Bradley Find out more about LIVI Symposium sponsored by NHS Scotland 11 b&c "What matters to you?" The Scottish approach to GP recruitment and retention Join us for an informal and interactive discussion to hear directly from GP's about the values driven approach we are taking to GP recruitment and retention in Scotland. Taking time to really listen to GP's at all stages of their career, and using what we have heard to help shape sustainable GP and portfolio careers that matter to you, we will share our journey so far- the joys and the challenges! Dr. Michelle Watts Dr. Sian Tucker Dr. Shawkat Hasan Find out more bout NHS Scotland Symposium sponsored by Novo Nordisk When is the right time to start GLP1-RA treatment in people living with type 2 diabetes – Dr Nithya Nanda Many people living with type 2 diabetes are escalated from oral therapies to basal insulin. Approximately 87% of patients starting on basal insulin skipped the GLP-1 RA* class altogether 1 without trying a GLP-1 RA class first. GLP-1 RA therapies offer glycaemic control, have a lower risk of hypoglycaemia and are associated with reductions in body weight compared with weight gain with insulin, with the added benefit of some GLP-1 RAs allowing for once weekly injections, as opposed to daily for insulin. 2,3. Based on these considerations, international guidelines suggest to consider a GLP-1 RA before trying basal insulin for patients with type 2 diabetes who are not meeting desired targets with oral therapies. 4,5 In this symposium we shall explore the: extent of the burden of T2D on the NHS latest evidence-based recommendations in managing T2D the role of GLP-1 RA therapy in the multi-modal treatment of T2D considerations when choosing GLP-1 RA or basal insulin Find out more about Novo Nordisk Symposium sponsored by Prostate Cancer UK PSA: Best Practice This session will give a brief overview of the prostate cancer diagnostic pathway and provide an explanation of procedures for managing raised PSA Professor Michael Kirby FRCP, Editor Trends in Urology & Men's Health Find out more about Prostate Cancer UK Symposium sponsored by L'Oreal Diagnosis and Management of Venous Eczema Venous eczema is a common chronic condition which affects approximately 20% of adults over the age of 70. It has a significant impact on healthcare resources, particularly those in the community, and is often misdiagnosed and mismanaged. The points below will be addressed to try to decrease the sequelae that occur without good effective management. Key learning points will be: Pitfalls of treatment Sequelae Dr Kate London Find out more about CeraVe PSA: When the guidelines aren't enough This session will cover those difficult PSA situations, which fall out of current guidelines. What would you do with a well 75 year old man…Test or not to test, that is the question? Symposium sponsored by Public Health England GPs helping patients to remain in /return to work – why does it matter? This presentation provides an overview of the national health and work agenda and provides GPs with practical information on how to support their patients to remain in and return to work. Dr Rob Hampton, GP Partner for 15 years before becoming freelance in 2012. Find out more about Public Health England Friday 25 October - 10:35 Acne management in the era of antimicrobial stewardship This presentation outlines the recognition of the sub-types of acne and lesion recognition in order to treat appropriately in the era of antibiotic resistance avoidance. Cases will be discussed with participation from the audience on how best to treat the different presentations of acne with relevance to primary care guidelines. Dr Aysha Javed Find out more about La Roche-Posay Friday, 25 October Symposium sponsored by Hologic How can we best help women with heavy menstrual bleeding (HMB) How HMB impacts women. Applying NICE guidance. Ensuring informed choice. Dr Anne Connolly, GPSI gynaecologist in Bradford, chair of the Primary Care Women's Health Forum (PCWHF) and RCGP Clinical Champion for women's health Find out more about Hologic Safeguarding men with a raised PSA who have been ruled out of biopsy With the addition of mpMRI to the prostate cancer diagnostic pathway many men do not go on to have a biopsy when the mpMRI rules out a diagnosis. But how can we manage care for men who have a raised PSA and no diagnosis? This session will look at the guidelines produced by NICE and the ongoing work to determine how we can best safeguard men ruled out of biopsy on the prostate cancer diagnostic pathway. Mr William (Bill) Cross, Consultant Urological Surgeon, Leeds Teaching Hospitals NHS Trust Symposium sponsored by Chiesi COPD – Making it Personal What's new in the management of COPD. Update on latest guidelines. Personalising management of COPD. Dr Stephen Gaduzo – Stephen, who has recently retired after 30 years as a partner at the Cheadle Medical Practice in Stockport, has had an interest in respiratory medicine since becoming a junior doctor. This interest led Stephen to be a Clinical Assistant at a chest clinic for 18 years. He assisted with the initiation of the Stockport COPD Community Multidisciplinary Service and has worked as a respiratory GPwSI for the last 15 years. In addition to being a member of the PCRS for 25 years, Stephen was Chair from 2013 to 2016 and remains Chair of the Respiratory Leadership Programme. Find out more about Chiesi Mini Theatre 1, Exhibition Hall
SubjectsFoxp3 (3)inflammation (2)NF-κB (2)regulatory T cells (2)Th17 (2)View MoreJournalPloS one (4)European journal of immunology (3)Frontiers in immunology (3)The Journal of experimental medicine (3)Cell death & disease (2)View MoreAuthorsHuehn, Jochen (37)Floess, Stefan (17)Schmitz, Ingo (14)Huehn, Jochen (10) Schmitz, Ingo (9) View MoreYear (Issue Date)2017 (16)2019 (11)2018 (8)2013 (7)2014 (7)TypesArticle (61)Journal Article (1)Other (1) Generation of Foxp3CD25 Regulatory T-Cell Precursors Requires c-Rel and IκB. Schuster, Marc; Plaza-Sirvent, Carlos; Visekruna, Alexander; Huehn, Jochen; Schmitz, Ingo (Frontiers, 2019-01-01) Next to the classical developmental route, in which first CD25 and subsequently Foxp3 are induced to generate thymic regulatory T (Treg) cells, an alternative route has been described. This alternative route is characterized by reciprocal induction of Foxp3 and CD25, with CD25 induction being required to rescue developing Treg cells from Foxp3-induced apoptosis. NF-κB has been demonstrated to be crucial for the development of thymic Treg cells via the classical route. However, its impact on the alternative route is poorly characterized. Using single and double deficient mice for key regulators of the classical route, c-Rel and IκBNS, we here demonstrate that NF-κB is essential for the generation of alternative CD25-Foxp3+ precursors, as well. Thus, c-Rel and IκBNS govern both routes of thymic Treg cell development. Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells. Sosna, Justyna; Philipp, Stephan; Fuchslocher Chico, Johaiber; Saggau, Carina; Fritsch, Jürgen; Föll, Alexandra; Plenge, Johannes; Arenz, Christoph; Pinkert, Thomas; Kalthoff, Holger; et al. (2016-10-15) Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H(+)-ATPase. Notably, executive mechanisms of both TRAIL- and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38α increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF- and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches. A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. Zhao, Gang; Wirth, Dagmar; Schmitz, Ingo; Meyer-Hermann, Michael (2017-11-08) Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field. IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes. Prajeeth, Chittappen K; Dittrich-Breiholz, Oliver; Talbot, Steven R; Robert, Philippe A; Huehn, Jochen; Stangel, Martin (2018-01-01) Autoreactive T cells that infiltrate into the central nervous system (CNS) are believed to have a significant role in mediating the pathology of neuroinflammatory diseases like multiple sclerosis. Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes. Our previous work demonstrated that effectors secreted by Th1 and Th17 cells have different capacities to influence the phenotype and function of glial cells. We have shown that Th1-derived effectors altered the phenotype and function of both microglia and astrocytes whereas Th17-derived effectors induced direct effects only on astrocytes but not on microglia. Here we investigated if effector molecules associated with IFN-γ producing Th1 cells induced different gene expression profiles in microglia and astrocytes. We performed a microarray analysis of RNA isolated from microglia and astrocytes treated with medium and Th-derived culture supernatants and compared the gene expression data. By using the criteria of 2-fold change and a false discovery rate of 0.01 (corrected Atypical IκB proteins - nuclear modulators of NF-κB signaling. Schuster, Marc; Annemann, Michaela; Plaza-Sirvent, Carlos; Schmitz, Ingo (2013) Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning. Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice. Ewald, F; Annemann, M; Pils, M C; Plaza-Sirvent, C; Neff, F; Erck, C; Reinhold, D; Schmitz, I (2014) Death receptor-mediated apoptosis is a key mechanism for the control of immune responses and dysregulation of this pathway may lead to autoimmunity. Cellular FLICE-inhibitory proteins (c-FLIPs) are known as inhibitors of death receptor-mediated apoptosis. The only short murine c-FLIP splice variant is c-FLIPRaji (c-FLIPR). To investigate the functional role of c-FLIPR in the immune system, we used the vavFLIPR mouse model constitutively expressing murine c-FLIPR in all hematopoietic compartments. Lymphocytes from these mice are protected against CD95-mediated apoptosis and activation-induced cell death. Young vavFLIPR mice display normal lymphocyte compartments, but the lymphocyte populations alter with age. We identified reduced levels of T cells and slightly higher levels of B cells in 1-year-old vavFLIPR mice compared with wild-type (WT) littermates. Moreover, both B and T cells from aged vavFLIPR animals show activated phenotypes. Sera from 1-year-old WT and transgenic animals were analysed for anti-nuclear antibodies. Notably, elevated titres of these autoantibodies were detected in vavFLIPR sera. Furthermore, tissue damage in kidneys and lungs from aged vavFLIPR animals was observed, indicating that vavFLIPR mice develop a systemic lupus erythematosus-like phenotype with age. Taken together, these data suggest that c-FLIPR is an important modulator of apoptosis and enforced expression leads to autoimmunity. Ewald, F; Ueffing, N; Brockmann, L; Hader, C; Telieps, T; Schuster, M; Schulz, W A; Schmitz, I (2011) c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma. Luebke, Tobias; Schwarz, Lisa; Beer, Yan Yan; Schumann, Sabrina; Misterek, Maria; Sander, Frida Ewald; Plaza-Sirvent, Carlos; Schmitz, Ingo (Springer-Nature, 2019-05-16) Clear cell renal cell carcinoma (ccRCC) is the most-prominent tumor type of kidney cancers. Resistance of renal cell carcinoma (RCC) against tumor therapy is often owing to apoptosis resistance, e.g., by overexpression of anti-apoptotic proteins. However, little is known about the role of the apoptosis inhibitor c-FLIP and its potential impact on death receptor-induced apoptosis in ccRCC cells. In this study, we demonstrate that c-FLIP is crucial for resistance against CD95L-induced apoptosis in four ccRCC cell lines. Strikingly, downregulation of c-FLIP expression by short hairpin RNA (shRNA)interference led to spontaneous caspase activation and apoptotic cell death. Of note, knockdown of all c-FLIP splice variants was required to induce apoptosis. Stimulation of ccRCC cells with CD95L induced NF-κB and MAP kinase survival pathways as revealed by phosphorylation of RelA/p65 and Erk1/2. Interestingly, CD95L surface expression was high in all cell lines analyzed, and CD95 but not TNF-R1 clustered at cell contact sites. Downstream of CD95, inhibition of the NF-κB pathway led to spontaneous cell death. Surprisingly, knockdown experiments revealed that c-FLIP inhibits NF-κB activation in the context of CD95 signaling. Thus, c-FLIP inhibits apoptosis and dampens NF-κB downstream of CD95 but allows NF-κB activation to a level sufficient for ccRCC cell survival. In summary, we demonstrate a complex CD95-FLIP-NF-κB-signaling circuit, in which CD95-CD95L interactions mediate a paracrine survival signal in ccRCC cells with c-FLIP and NF-κB both being required for inhibiting cell death and ensuring survival. Our findings might lead to novel therapeutic approaches of RCC by circumventing apoptosis resistance. Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. Keil, E; Höcker, R; Schuster, M; Essmann, F; Ueffing, N; Hoffman, B; Liebermann, D A; Pfeffer, K; Schulze-Osthoff, K; Schmitz, I (2013-02) Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45β-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45β/MEKK4 negatively regulates the autophagic process. Gadd45 proteins in immunity. Schmitz, Ingo (2013) The vertebrate immune system protects the host against invading pathogens such as viruses, bacteria and parasites. It consists of an innate branch and an adaptive branch that provide immediate and long-lasting protection, respectively. As the immune system is composed of different cell types and distributed throughout the whole body, immune cells need to communicate with each other. Intercellular communication in the immune system is mediated by cytokines, which bind to specific receptors on the cell surface and activate intracellular signalling networks. Growth arrest and DNA damage-inducible 45 (Gadd45) proteins are important components of these intracellular signalling networks. They are induced by a number of cytokines and by bacterial lipopolysaccharide. Within the innate immune system, Gadd45 proteins are crucial for the differentiation of myeloid cells as well as for the function of granulocytes and macrophages. Moreover, Gadd45β regulates autophagy, a catabolic pathway that also degrades intracellular pathogens. Regarding adaptive immunity, Gadd45 proteins are especially well characterized in T cells. For instance, Gadd45β and Gadd45γ regulate cytokine expression and Th1 differentiation, while Gadd45α inhibits p38 kinase activation downstream of the T cell receptor. Due to their many functions in the immune system, deficiency in Gadd45 proteins causes autoimmune diseases and less efficient tumour immunosurveillance.
BACKGROUND: Frequent chronic obstructive pulmonary disease (COPD) exacerbation is a major cause of hospital admission and mortality. It has been reported that Traditional Chinese Medicine (TCM) may relieve COPD symptoms and reduce the incidence of COPD exacerbations, thus improving life quality of COPD patients. The acute exacerbation of COPD risk-window (AECOPD-RW) is the period after an exacerbation and before the patient returns to baseline. In the AECOPD-RW, patients are usually at increased risk of a second exacerbation, which may lead to hospital admission and high mortality. BACKGROUND: Chronic obstructive pulmonary disease (COPD) has become a major public health problem worldwide because of its high and increasing prevalence, morbidity, and mortality. Little attention has been paid to earlier stages of COPD or before it has developed. Reportedly, TCM may have some advantages in relieving symptoms and reducing the incidence of COPD exacerbations. We postulate that patients with COPD will benefit from therapy with TCM treatment according to syndrome differentiation. OBJECTIVE: To evaluate the influence and long-term effects on systemic and local inflammation responses in rat with stable chronic obstructive pulmonary disease (COPD) treated with traditional Chinese medicine (TCM) for regulating and invigorating the lung and kidney, including invigorating the lung and spleen (Bufei Jianpi) therapy, supplementing the lung and kidney (Bufei Yishen) therapy, and nourishing qi and kidney (Yiqi Zishen) therapy. METHODS: Rats were randomly divided into six groups: control, model, aminophyline, Bufei Jianpi, Bufei Yishen and Yiqi Zishen groups. BACKGROUND: Traditional Chinese medicine (TCM) has been used to treat chronic obstructive pulmonary disease (COPD) for many years. This study aimed to evaluate the efficacy and safety of the comprehensive therapy based on the three common TCM patterns in stable COPD patients. METHODS: A four-center, open-label randomized controlled method was conducted. OBJECTIVE: To evaluate the efficacy of Jianpi therapy in Traditional Chinese Medicine (TCM) for treatment of chronic obstructive pulmonary disease (COPD) in stable phase by performing a systematic review and meta-analysis. OBJECTIVE: To study the therapeutic effect Bufei granule, which is a traditional Chinese drug that can enhance the immune function of the lung, on patients with stable chronic obstructive pulmonary disease (COPD). METHODS: This is a randomized, double blinded, placebo-controlled, and multicenter clinical study. Three medical centers in Tianjin, China, participated in the trial. A total of 140 patients with stable COPD were enrolled and randomized into two groups, with 70 patients in each. The treatment group was treated with Bufei granule, while the control group received Bufei placebo. PURPOSE: This paper evaluates the effectiveness of a 3-month Tai chi Qigong (TCQ) program in promoting the psychosocial functional health of clients with chronic obstructive pulmonary disease (COPD) in Hong Kong. METHODS: This study employed a single-blind, randomized controlled trial. Two hundred and six COPD clients were randomly assigned into three groups, namely, TCQ group, exercise group, and control group. Subjects in the TCQ group received a TCQ program, consisting of two 60-min sessions each week for 3 months. OBJECTIVE: To determine the feasibility of a randomized controlled trial of the effect of a tai chi program on quality of life and exercise capacity in patients with COPD. METHODS: We randomized 10 patients with moderate to severe COPD to 12 weeks of tai chi plus usual care (n = 5) or usual care alone (n = 5). The tai chi training consisted of a 1-hour class, twice weekly, that emphasized gentle movement, relaxation, meditation, and breathing techniques. The effectiveness of exercise training in people with COPD is well established. However, alternative methods of training such as Tai Chi have not been widely evaluated. This paper describes the study design of a clinical trial which aims to determine if short form Sun-style Tai Chi improves exercise capacity and quality of life in people with COPD. METHOD: This randomised controlled trial will be conducted with concealed allocation and blinded outcome assessment. Participants will be recruited from Concord Repatriation General Hospital, Sydney. OBJECTIVE: To evaluate the effectiveness of a Tai chi Qigong (TCQ) program in enhancing respiratory functions and activity tolerance in clients with chronic obstructive pulmonary disease (COPD). DESIGN: A single-blind, randomized controlled trial. SETTING: Five general outpatient clinics in Hong Kong. INTERVENTION: In total, 206 COPD clients were randomly assigned into one of the three groups, namely, TCQ, exercise, and control group. Subjects in the TCQ group received a TCQ program consisting of two 60-min sessions each week for three months.
Effects of age and ischemic times on biochemical evidence of myocardial injury after pediatric cardiac operations. Taggart DP., Hadjinikolas L., Hooper J., Albert J., Kemp M., Hue D., Yacoub M., Lincoln JC. INTRODUCTION: The vulnerability of pediatric myocardium to ischemia is poorly documented in the clinical setting. METHODS: Serial measurements of serum concentrations of myoglobin, the MB isoenzyme of creatine kinase, and cardiac troponins T and I and their respective areas under the curve were obtained, with particular reference to age and ischemic time, in 80 children undergoing cardiac operations. Sixteen (the control group) did not require cardiopulmonary bypass and 64 did. RESULTS: In the control group there were increases (p < 0.01) in myoglobin and creatine kinase MB isoenzyme but no increase in cardiac troponin T or I; by contrast, the group treated with cardiopulmonary bypass had significant increases in all four markers but with differing temporal patterns. Younger age (especially < 12 months) was a highly significant explanatory variable only for the release of cardiac troponins T and I, and ischemic time was a significant explanatory variable for the release of creatine kinase MB isoenzyme, cardiac troponins T and I, but not myoglobin. In comparison with previous studies in adults, creatine kinase MB and cardiac troponin T concentrations were three times greater in children than in adults. CONCLUSIONS: This study supports the specificity of cardiac troponins T and I as markers of myocardial injury after pediatric cardiac operations and defines the importance of age and ischemic time in determining their release. In comparison with previous data in adults, our results raise the possibility that the pediatric heart may be more vulnerable to the effects of ischemia and reperfusion. Cardiac troponins will permit comparison of new myocardial protective strategies or other potentially therapeutic myocardial interventions. Adult, Age Factors, Biomarkers, Cardiopulmonary Bypass, Child, Preschool, Creatine Kinase, Heart Defects, Congenital, Humans, Infant, Isoenzymes, Myocardial Ischemia, Myocardial Reperfusion Injury, Myoglobin, Reproducibility of Results, Sensitivity and Specificity, Time Factors, Troponin
Are you a runner, an after-work softball star, or a weekend warrior who loves to push yourself to the limit? If you've been noticing pain along the back of your leg and near your heel, it may be a sign of Achilles tendonitis or inflammation in the body's largest tendon. Achilles tendonitis is an extremely common condition. More than 200,000 new cases are reported each year. The pain can go away after a few days' rest, but if it persists and you begin to notice tenderness or stiffness in the morning, it might be time to check with your doctor. On your way to that check-up, here's what might have caused the condition and what you can do to treat it. The Achilles tendon connects your calf muscles to your heel bone, enabling you to walk, run, jump, and walk on your toes. Achilles tendonitis inflammation comes from repetitive movements or excessive strain, similar to forms of tendonitis that appear elsewhere in the body. "Weekend warriors and those who decide to take up a new training regimen without easing into it are especially at risk for Achilles tendonitis. If the tendon isn't strong or flexible enough for the activity you've chosen, it will flare up. In addition to lifestyle factors, men are more prone to the condition than women. It also becomes more common as you age. If you have a history of Achilles tendonitis and want to prevent a flare-up, it's important to stretch often, especially before or after a workout. If you're beginning a new sport or activity, remember to ease into it and increase intensity gradually. Maintaining a varied workout will also help you to not put too much strain on the tendon. In most cases, improving your workout habits will relieve symptoms of Achilles tendonitis. Trying different exercises throughout the week, leaving time for cross-training and resting tired muscles can help you avoid inflammation and pain. If you're looking for an at-home fix, try icing your heel, wearing compression socks, or elevating your foot after an intense workout or game to reduce inflammation. However, if pain continues or worsens, you may want to see your doctor. Most doctors will recommend an over-the-counter pain reliever, such as ibuprofen or naproxen, for tendonitis, but may consider prescription medications or physical therapy if the inflammation is severe. If your doctor does recommend physical therapy, you can expect to do exercises focusing on strengthening the foot, leg, and calf. These will ensure that joints and muscles around the Achilles tendon are providing enough support and reducing strain. Regular guided stretching will also improve the flexibility and elasticity of the muscle, making it less prone to inflammation. A physical therapist may also recommend orthotic solutions like heel wedges or specialized shoes. In the unlikely event that your pain continues to be severe and resistant to non-surgical treatment, your doctor may recommend an MRI and eventual surgery to repair the tendon. Dr. Aaron Dawes is a Geisinger fellowship-trained family and sports medicine physician.
The Federal Aviation Administration (FAA) has experienced decreased return on investment caused by hiring too many air traffic controller specialists (ATCSs) who performed poorly in field training, thus failing to become certified professional controllers (CPCs). Based on Schmidt and Hunter's theory of job performance and biodata theory, this quantitative, archival study examined whether factors of cognitive ability and biodata could predict job performance status of 2 generations of ATCSs, poststrike (PS) and next generation (NG) controllers. For each generation of controllers, binary logistic regression analysis was conducted to determine if any of the independent variables---transmuted composite (TMC) score for PS controllers, Air Traffic and Selection and Training (AT-SAT) test score for NG controllers, average of high school arithmetic/math letter grade, overall high school average letter grade, self-estimation of time to become fully effective in the ATCS role, self-estimation of percentile ranking in the FAA program relative to the class, size of neighborhood raised, or socioeconomic status---are significant predictors of job performance status for controllers as measured by whether they pass the field OJT (i.e., certified or still in training, or failed certification or left training). The regression results for the PS and NG controllers were found to be statistically significant (chi2 (23) = 68.377, p < .001) and (chi 2 (17) = 99.496, p < .001), respectively. Findings that overall high school grade point average and socioeconomic status significantly predicted ATCS job performance for both PS and NG controllers could influence the FAA's use of revised biodata to better predict ATCS job performance. Further research should include studies of socioeconomic status, gender, and race to address new evidence that the AT-SAT has adverse impact.
It this article about failure of amalgam restorations, we will explain the etiology of the amalgam restored tooth fracture, clinical picture, causes, etiology and methods of treatment. Fractured cusp or ridge under functional forces due to lack of support and reinforcement in the restored tooth. Amalgam lacks sufficient tensile strength to support remaining tooth substance and much less able to re-enforce weak cusps and ridges. Thus it leads to a worst outcome if the restoration is relatively large leading to less support of remaining tooth structure. Eliminate all undermined enamel as well as weak cusps and ridges. Ensure wide distribution of stresses. Reinforce weak cusps and ridges using inlays, onlays or full coverage.
Project outline © greensahara 2016 Demographic modelling. We have developed a technique (Shennan et al. 2013; Manning and Timpson 2014), which allows us to investigate changes in human demography using a Monte Carlo Summed Probability Distribution (MCSPD) method, which assesses the density of 14C dates as a proxy for relative population size. We have recently demonstrated a major and rapid demographic increase between 10,500 and 5500 BP (Manning and Timpson 2014), which clearly corresponds to the Holocene AHP. Building on this, we will undertake a systematic collection of all 14C dates, combined with the proposed programme of compound-specific 14C dates, which will increase the number of existing Saharan Holocene radiocarbon dates by nearly 20%, in order to increase the resolution of our demographic proxy and to investigate key events highlighted in the pilot study. For example, our initial study revealed an apparent fall and rise in population levels between 7500 and 6500 BP, which we hypothesised may relate to a replacement of early Holocene hunter-gatherer-fisher groups, with later Holocene pastoral populations deriving from the eastern Sahara. Spatial analysis of the 14C dates will test this by estimating temporal fluctuations in the total area covered (both at the macro scale, and within regions), and temporal fluctuations in clustering patterns. In particular we will calculate regional variations in the timing of population increase and decrease, and investigate the evidence for population displacement between neighbouring regions. By providing a high temporal resolution proxy for effective carrying capacity our demographic curve also offers an independent estimate of environmental change in northern Africa, indicating a temporal delay in the terrestrial response to atmospheric climate change. These results highlight the degree to which human demography is a function of environment at the appropriate scale of observation in both time and space and provides strong support for the efficacy of this method in the context of North Africa.​​ Demography and Human Adaptation Figure 1. Demographic proxy based on a Monte-Carlo Summed Probability Distribution of radiocarbon dates from Neolithic Saharan sites (Manning and Timpson 2014) Identification of biomarkers for the processing of aquatic commodities, animal fats and plant resources. An important methodological component of our work will be to detect specific marker compounds for the processing of fish and other aquatic products to assess the role of freshwater resources in the diet of early Holocene Saharan populations, i.e. testing the "Aqualithic" hypothesis. Our recent identification of stable compounds formed from the transformation during cooking of diagnostic aquatic lipids, including dihydroxy acids (DHYAs), isoprenoid acids (IPAs) and ω-(o-alkylphenyl) alkanoic acids (APAAs), offers the possibility for highly sensitive and large-scale detection of aquatic product processing in archeological pottery (Cramp and Evershed 2014). Figure 2. Encrusted ceramic residue © Julie Dunne Figure 3. Partial gas chromatograms of trimethylsilylated total lipid extracts (TLEs) from potsherds excavated from Takarkori rock shelter showing leaf wax n-alkanes and plant fatty acids. Biomolecular and carbon isotopic analysis of food residues to determine modes of animal exploitation. Recent work by Dunne et al. (2012) demonstrates the potential for applying biomolecular techniques in the context of Saharan prehistory, most notably in providing evidence for the adoption of dairying by Libyan Saharan pastoralists by at least 6500 BP. We will use the compound-specific stable carbon isotope approach to individual fatty acids to identify the major classes of domesticates, ruminants and non-ruminants, together with dairy fats (see Palaeoenvironment page). The signals will be used, in conjunction with the palaeohydrological results, to map spatial and temporal trends in the adoption of domesticates and development of dairying economies across the Sahara.
One of the main complications caused by diabetes mellitus is the development of diabetic foot, which in turn, can lead to ulcerations. Because ulceration risks are linked to an increase in plantar temperatures, recent approaches analyze thermal changes. These approaches try to identify spatial patterns of temperature that could be characteristic of a diabetic group. However, this is a difficult task since thermal patterns have wide variations resulting on complex classification. Moreover, the measurement of contralateral plantar temperatures is important to determine whether there is an abnormal difference but, this only provides information when thermal changes are asymmetric and in absence of ulceration or amputation. Therefore, in this work is proposed a quantitative index for measuring the thermal change in the plantar region of participants diagnosed diabetes mellitus regards to a reliable reference (control) or regards to the contralateral foot (as usual). Also, a classification of the thermal changes based on a quantitative index is proposed. Such classification demonstrate the wide diversity of spatial distributions in the diabetic foot but also demonstrate that it is possible to identify common characteristics. An automatic process, based on the analysis of plantar angiosomes and image processing, is presented to quantify these thermal changes and to provide valuable information to the medical expert. Puzzle based secure data transmission scheme to avoid intruders.
Quality of life and memory performance in patients with temporal lobe epilepsy Anna Rita Giovagnoli, G. Avanzini Fondazione IRCCS Istituto Neurologico "C. Besta" Objective - To explore the contribution of memory performance to quality of life (QOL) in patients with left or right temporal lobe epilepsy (TLE). Subjects and methods - Sixty-five patients with left or right TLE compiled the QOL in Epilepsy-89 Inventory (QOLIE-89), the State-Trait Anxiety Inventory (STAI) and the Hopelessness Scale (BDI) for self-evaluation of QOL and mood. Memory was assessed by tests of verbal and non-verbal memory and the Questionnaire of Memory Efficiency (QME). A neuropsychological battery was also administered to assess general intelligence, attention, visual perception, language, set shifting, word fluency and conceptual-motor tracking. Results - On factor analysis, the neuropsychological battery and mood scales consisted of six factors (Memory, Mental Speed, Mood, Praxis, Sorting and Perception), while the QOLIE-89 consisted of five factors (Psychosocial Satisfaction, Epilepsy-Related Effects, Role, Physical Performance, Cognition). On regression analysis, overall QOLIE-89 score was predicted by the factor Mood and QME score. The QOLIE-89 factor Cognition was predicted by QME score and the Memory, Mental Speed, Perception and Praxis factors of the neuropsychological battery. Conclusion - In TLE patients self- reported memory, as assessed by QME, is an important predictor of QOL, and also correlates with performance on memory tests. This suggests that memory improvement by specific training may help to improve QOL in these patients. Acta Neurologica Scandinavica https://doi.org/10.1034/j.1600-0404.2000.90257A.x Diagnostic Self Evaluation Giovagnoli, A. R., & Avanzini, G. (2000). Quality of life and memory performance in patients with temporal lobe epilepsy. Acta Neurologica Scandinavica, 101(5), 295-300. https://doi.org/10.1034/j.1600-0404.2000.90257A.x Quality of life and memory performance in patients with temporal lobe epilepsy. / Giovagnoli, Anna Rita; Avanzini, G. In: Acta Neurologica Scandinavica, Vol. 101, No. 5, 2000, p. 295-300. Giovagnoli, AR & Avanzini, G 2000, 'Quality of life and memory performance in patients with temporal lobe epilepsy', Acta Neurologica Scandinavica, vol. 101, no. 5, pp. 295-300. https://doi.org/10.1034/j.1600-0404.2000.90257A.x Giovagnoli AR, Avanzini G. Quality of life and memory performance in patients with temporal lobe epilepsy. Acta Neurologica Scandinavica. 2000;101(5):295-300. https://doi.org/10.1034/j.1600-0404.2000.90257A.x Giovagnoli, Anna Rita ; Avanzini, G. / Quality of life and memory performance in patients with temporal lobe epilepsy. In: Acta Neurologica Scandinavica. 2000 ; Vol. 101, No. 5. pp. 295-300. @article{a46e3794e8194a5fb9093c4f473a37f3, title = "Quality of life and memory performance in patients with temporal lobe epilepsy", abstract = "Objective - To explore the contribution of memory performance to quality of life (QOL) in patients with left or right temporal lobe epilepsy (TLE). Subjects and methods - Sixty-five patients with left or right TLE compiled the QOL in Epilepsy-89 Inventory (QOLIE-89), the State-Trait Anxiety Inventory (STAI) and the Hopelessness Scale (BDI) for self-evaluation of QOL and mood. Memory was assessed by tests of verbal and non-verbal memory and the Questionnaire of Memory Efficiency (QME). A neuropsychological battery was also administered to assess general intelligence, attention, visual perception, language, set shifting, word fluency and conceptual-motor tracking. Results - On factor analysis, the neuropsychological battery and mood scales consisted of six factors (Memory, Mental Speed, Mood, Praxis, Sorting and Perception), while the QOLIE-89 consisted of five factors (Psychosocial Satisfaction, Epilepsy-Related Effects, Role, Physical Performance, Cognition). On regression analysis, overall QOLIE-89 score was predicted by the factor Mood and QME score. The QOLIE-89 factor Cognition was predicted by QME score and the Memory, Mental Speed, Perception and Praxis factors of the neuropsychological battery. Conclusion - In TLE patients self- reported memory, as assessed by QME, is an important predictor of QOL, and also correlates with performance on memory tests. This suggests that memory improvement by specific training may help to improve QOL in these patients.", keywords = "Memory performance, Quality of life, Temporal lobe epilepsy", author = "Giovagnoli, {Anna Rita} and G. Avanzini", doi = "10.1034/j.1600-0404.2000.90257A.x", journal = "Acta Neurologica Scandinavica", publisher = "Wiley Blackwell", T1 - Quality of life and memory performance in patients with temporal lobe epilepsy AU - Giovagnoli, Anna Rita AU - Avanzini, G. N2 - Objective - To explore the contribution of memory performance to quality of life (QOL) in patients with left or right temporal lobe epilepsy (TLE). Subjects and methods - Sixty-five patients with left or right TLE compiled the QOL in Epilepsy-89 Inventory (QOLIE-89), the State-Trait Anxiety Inventory (STAI) and the Hopelessness Scale (BDI) for self-evaluation of QOL and mood. Memory was assessed by tests of verbal and non-verbal memory and the Questionnaire of Memory Efficiency (QME). A neuropsychological battery was also administered to assess general intelligence, attention, visual perception, language, set shifting, word fluency and conceptual-motor tracking. Results - On factor analysis, the neuropsychological battery and mood scales consisted of six factors (Memory, Mental Speed, Mood, Praxis, Sorting and Perception), while the QOLIE-89 consisted of five factors (Psychosocial Satisfaction, Epilepsy-Related Effects, Role, Physical Performance, Cognition). On regression analysis, overall QOLIE-89 score was predicted by the factor Mood and QME score. The QOLIE-89 factor Cognition was predicted by QME score and the Memory, Mental Speed, Perception and Praxis factors of the neuropsychological battery. Conclusion - In TLE patients self- reported memory, as assessed by QME, is an important predictor of QOL, and also correlates with performance on memory tests. This suggests that memory improvement by specific training may help to improve QOL in these patients. AB - Objective - To explore the contribution of memory performance to quality of life (QOL) in patients with left or right temporal lobe epilepsy (TLE). Subjects and methods - Sixty-five patients with left or right TLE compiled the QOL in Epilepsy-89 Inventory (QOLIE-89), the State-Trait Anxiety Inventory (STAI) and the Hopelessness Scale (BDI) for self-evaluation of QOL and mood. Memory was assessed by tests of verbal and non-verbal memory and the Questionnaire of Memory Efficiency (QME). A neuropsychological battery was also administered to assess general intelligence, attention, visual perception, language, set shifting, word fluency and conceptual-motor tracking. Results - On factor analysis, the neuropsychological battery and mood scales consisted of six factors (Memory, Mental Speed, Mood, Praxis, Sorting and Perception), while the QOLIE-89 consisted of five factors (Psychosocial Satisfaction, Epilepsy-Related Effects, Role, Physical Performance, Cognition). On regression analysis, overall QOLIE-89 score was predicted by the factor Mood and QME score. The QOLIE-89 factor Cognition was predicted by QME score and the Memory, Mental Speed, Perception and Praxis factors of the neuropsychological battery. Conclusion - In TLE patients self- reported memory, as assessed by QME, is an important predictor of QOL, and also correlates with performance on memory tests. This suggests that memory improvement by specific training may help to improve QOL in these patients. KW - Memory performance KW - Quality of life KW - Temporal lobe epilepsy U2 - 10.1034/j.1600-0404.2000.90257A.x DO - 10.1034/j.1600-0404.2000.90257A.x JO - Acta Neurologica Scandinavica JF - Acta Neurologica Scandinavica 10.1034/j.1600-0404.2000.90257A.x
News Release 26-Nov-2019 Minimally invasive procedure relieves tremors in Parkinson's patients IMAGE: This is a bar graph showing evaluation of the patients' quality of life (QUEST score). view more Credit: Study author and RSNA CHICAGO - A procedure that applies pulses of focused ultrasound to the brain is safe and effective for reducing tremors and improving quality of life in people with essential tremor (ET) or Parkinson's disease (PD) tremor, according to a new study being presented next week at the annual meeting of the Radiological Society of North America (RSNA). Tremors are rhythmic, involuntary muscle movements that cause shaking in one or more parts of the body, usually in the hands. They are characteristic of movement disorders like ET and PD, two progressive conditions that affect millions of people worldwide. Previous treatment options for reducing tremors in patients who have not responded to medical therapy include deep brain stimulation, a surgical procedure that involves implanting a small electrode in the brain connected to a pulse generator that is implanted in the chest like a pacemaker. A more recently available option is magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy, an incisionless interventional radiology procedure in which focused beams of sound energy are used to heat and destroy a small part of a structure in the brain called the thalamus. The procedure gives relief to the opposite side of the body, meaning that treatment to the right side of the brain would relieve tremors on the left side of the body, and vice versa. As a minimally invasive approach, focused ultrasound has advantages over deep brain stimulation, including a reduced risk of complications from bleeding and infections, according to study lead author Federico Bruno, M.D., a radiologist in the Department of Biotechnological and Applied Clinical Sciences at the University of L'Aquila in L'Aquila, Italy. "Another advantage is the immediate effect this treatment provides, unlike deep brain stimulation which requires a break-in period for the electrostimulation," he said. "Additionally, treatment with MRgFUS requires shorter hospitalization and is a fairly well-tolerated procedure even by more fragile patients." For the new study, Dr. Bruno and colleagues enrolled 39 patients, average age 64.5 years, with disabling tremors that had not responded to treatment. The people in the study group, including 18 with ET and 21 with PD, had experienced symptoms for an average of more than 10 years. The researchers evaluated the patients for tremor severity and quality of life before MRgFUS thalamotomy, immediately after treatment and over the course of the ensuing year. They found that 37 of 39 patients, or 95%, had substantial and immediate reduction of tremor. These reductions in tremor were sustained in follow-up evaluations. Quality of life evaluation showed substantial improvement in both the ET and PD groups. "The study we present reports our experience of over a year in the treatment of tremor by thalamotomy with focused ultrasound," Dr. Bruno said. "It is worth noting that we had a high number of patients with Parkinson's disease in our series, compared to previously published data, where the procedure was used mainly in the treatment of essential tremor patients." Currently, MRgFUS thalamotomy is only available at a limited number of sites worldwide, Dr. Bruno said, but may become more widespread as research findings supporting its use are published. Improvements in neuroimaging techniques that allow for greater precision and detail in planning, implementation and monitoring over time of the treatment should also expand its availability. "The clinical application of this technique for neurological diseases is an absolute novelty--the clinical use was approved by the FDA less than three years ago," Dr. Bruno said. "Few patients know of this treatment option so far, and there are not many specialized centers equipped with the required technology." Future research in this area includes the possibility of treating both sides of the thalamus. MRgFUS is also being explored in areas beyond movement disorders, Dr. Bruno said. Several preclinical studies and clinical trials are looking at the technique for the treatment of other neurological conditions like neuropathic pain, epilepsy and obsessive-compulsive disorders, as well as for treatment of brain tumors. Co-authors are Luca Panebianco, M.D., Maria Valeria Marcella Micelli, M.D., Antonella Corridore, M.D., Milvia Martino, M.D., Silvia Torlone, M.D., Marco Varrassi, M.D., Alessia Catalucci, M.D., Francesco Arrigoni, M.D., Alessandra Splendiani, M.D., and Carlo Masciocchi, M.D. Note: Copies of RSNA 2019 news releases and electronic images will be available online at RSNA.org/press19 beginning Monday, Nov. 25. RSNA is an association of over 53,400 radiologists, radiation oncologists, medical physicists and related scientists, promoting excellence in patient care and health care delivery through education, research and technologic innovation. The Society is based in Oak Brook, Ill. (RSNA.org) Editor's note: The data in these releases may differ from those in the published abstract and those actually presented at the meeting, as researchers continue to update their data right up until the meeting. For patient-friendly information on ultrasound and interventional radiology, visit RadiologyInfo.org. Linda Brooks [email protected] @rsna http://www.rsna.org 105th Scientific Assembly and Annual Meeting of the Radiological Society of North America-RSNA 2019 Minimally Invasive Procedure Relieves Tremors in Parkinson's Patients (IMAGE) Engagement and education key to changing attitudes towards virginity testing Boston University School of Medicine IKBFU scientists developed capsule composition for enzyme against intellectual disability Immanuel Kant Baltic Federal University Antiviral compound offers hope against deadly flu Michigan Medicine - University of Michigan Zebrafish teach researchers more about atrial fibrillation University of Copenhagen The Faculty of Health and Medical Sciences
Background 28 Sep 2017 last update:6 Nov 2017 When cows are sick: Feed accordingly A number of feeding management strategies can be used as a supportive treatment of various metabolic and infectious diseases in cows. What can be done to reduce the impact of sickness on the profitability of farm operations? Metabolic and infectious diseases in cows range from grain bloat to acidosis and parasitic infections. Grain bloat elimination With high grain feeding for example, large amounts of acids are produced in the rumen. This may reduce rumen motility and hence contribute further to the development of grain bloat. The changes associated with the high-grain feeding depend largely on the physical form of the diet. In a study with identical twin cows, the diet with a fine particle size (388 micrometers) provoked more bloat than the one with coarse particles (715 micrometers) and caused serious bloat losses. Once grain bloat has occurred, feeding equal parts of concentrates and hay will not reduce bloat severity even by feeding hay up to 50% of the diet. Bloat then can be eliminated only by removing more than 50% of the grain for four to six weeks. If bloating animals are fed high-roughage diet for only one week and then high-grain diet, they will start bloating in one to 2 days. The high-roughage diet should, therefore, be fed over a sufficient period of time in order to allow it to remove the slime from the rumen wall and suppress growth and ­multiplication of the slime-producing organisms. Ketosis is a common disease of adult cattle, typically occurring in dairy cows in early lactation and rarely in late gestation. Photo: Robin Britstra The effect of parasites The grazing animals are always exposed to parasites and are thus constantly re-infected in chain reaction mode. Anti-parasitic drugs are effective to minimise the internal parasites in grazing herds, but they cannot provide a long-term solution. Therefore, integrated feeding strategies become obligatory to control internal parasites and hence improve the productivity of the grazing herds and minimise the economic losses associated with the parasite infestation. Animals on low protein diets are more susceptible to parasite infection because they produce less immunoglobulin IgA. Protein supplement should, therefore, be considered particularly for the young susceptible animal for improving resistance to parasites. Animals infected with parasites also exhibit reduced utilisation of calcium and phosphorus. Parasitic animals should, therefore, get an adequate supply of calcium and phosphorus to compensate for the deficiency. The provision of trace minerals such as zinc, iron, and cobalt and vitamin A is also important for immunity and intestinal epithelial integrity. Too much grain and acidosis Diets with high-grain and low-fibre contents are more digestible and ferment faster, so the animal is provided with nutrients at a faster rate and can thus grow faster. Also, cattle fed on high-grain diets provide nicely marbled beef compared to those fed on low-grain diets. The low-fibre diets, however, can be very stressful for animals because they allow fermentation acids to accumulate in the rumen. Acid build-up can cause ulcers in animals consuming too much grain with little fibre. The infective bacteria then come from the rumen through the ulcers into the bloodstream and finally into the liver, where they cause abscesses. Grains can also accumulate in the animal's intestines because they lack the starch digesting enzymes. Thus, the high grain diets can promote an overgrowth of Clostridium perfringens, bacteria associated with the sudden death syndrome in feedlot cattle. These diets may further promote E. coli within the digestive tract of cattle and hence cause harm to the animal. These problems can be controlled with the gradual inclusion of grain in the diet (Table 1). It is recommended therefore to begin with the inclusion of starch sources such as corn, sorghum, and oats, which are slowly fermented compared to the other sources such as wheat and barley. It is also recommended to increase the proportion of the forage fed during particularly cold weather, as the effects of acidosis are worsened if the animal is also suffering from cold stress. The use of a feed additive may further help to reduce the risk of acidosis. Dealing with ketosis Ketosis is a common disease of adult cattle, typically occurring in dairy cows in early lactation and rarely in late gestation. It is most consistently characterised by partial anorexia and depression. In addition, signs of nervous dysfunction, including pica, abnormal licking, incoordination and abnormal gait, bellowing, and aggression are occasionally seen. The condition is worldwide in distribution but is most common where dairy cows are bred and managed for high production. Ketosis can be managed through nutrition, especially in the dry period. There should always be adequate protein and carbohydrate in the diet of the dry cow, but even more important is an ample supply of fibre, preferably in the form of good hay. That is because the bulk of the energy is produced in the cow's first stomach and the fibre is, therefore, needed to keep the concentrates in the rumen long enough to allow the breakdown of the feed to fatty acids. Silage may also provide sufficient fibre, but care must be taken in this case to ensure palatability and quality of the silage. For instance, silage which has been badly made containing a high concentration of butyrate is not only unpalatable but also lacks glucogenic precursors and leads directly to ketone production. Some feed additives, including niacin, calcium propionate, sodium propionate, propylene glycol, and rumen-protected choline, may help prevent and manage ketosis. To be effective, these supplements should be fed in the last two to three weeks of gestation, as well as during the period of ketosis susceptibility. Form protective layer on the mucosal surface of the intestines and reduce the severity of diarrhoea. Regulate the peristaltic movement of the intestines. Provide a healthy environment for growth and multiplication of micro-flora.G23 Diarrhoea and importance of colostrum Calf diarrhoea and subsequent dehydration are the number one cause of calf mortality prior to weaning. Calf diarrhoea can be due to infection in the intestine by viruses, bacteria, and protozoa. It can also be caused by inadequacies in the feeding programme including poor sanitation, failure of passive transfer (feeding insufficient quantity and/or quality of colostrum), inconsistent delivery of milk or milk replacer, and poor housing conditions. When scouring, calves lose a considerable amount of water and electrolytes (minerals such as sodium, phosphorous, potassium, chloride, and others). The calf is born without diarrhoea-fighting antibodies. It will acquire these antibodies only by nursing colostrum early in life. Colostrum should be fed in adequate amounts (10% of calf body weight) within the first 24 hours after birth. After providing adequate colostrum on day one, a second dose should be fed (especially useful in stressed calves). The immunoglobulins in colostrum will coat the small intestine and prevent attachment and colonisation by pathogens. Additionally, colostrum provides an excellent source of energy and contains compounds such as lactoferrin and fatty acids that benefit the calf. The use of feed additives in milk replacer in a later stage of feeding should be considered for promoting gut health. If the diarrhoea is not severe and the animal is not dehydrating it is better to treat diarrhoea with herbal remedies. There are varieties of herbal species commonly used in most Asian countries for this purpose (Table 2). Limewater, tannic acid or commercial diarrhoea remedies could be used to treat diarrhoea if the animal is in danger of dehydration. Also, administration of clean water or barley water at intervals of two to three hours helps to compensate for the loss of body fluids. References are available from the author upon request ([email protected]). Dr Salah Hamed Esmail Independent freelance journalist Feed Grains To comment, register here Or register to be able to comment. Reducing the impact of summer on birds Half of the birds reared worldwide are estimated to suffer from the consequences of heat stress during the... On 15 Apr 2019 In Health Interview: What makes a good sensor? We are learning fast when it comes to sensors for dairy cows. But what are the latest innovations and insights?... On 30 Aug 2018 In Smart farming
Behind the Paper, Journal club Fully remote clinical trials – The dawn of a new era We implemented a fully randomized controlled trial of patients with COVID-19 with cardiac monitoring using a mobile six-lead electrocardiogram. Our study represents the first successful implementation of digital technologies to conduct a fully remote clinical trial with QT interval monitoring. Vidhushei Yogeswaran and 2 others View all Cardiology Fellow, University of Washington Vidhushei Yogeswaran Jacob Mayfield Arun R Sridhar Cardiologist and Cardiac Electrophysiologist, University of Washington, Seattle Clinical trials have traditionally been conducted at research institutions that require travel for treatment and safety monitoring. The execution of a proper clinical trial requires selecting an appropriate study population and can be limited by volunteer bias due to geographic distance from study site, education, and socioeconomic status limiting enrollment[1]. Safety monitoring during clinical trials is the primary focus of the US Food and Drug Administration during drug development,[2] a key component of which is surveillance for cardiovascular toxicity[3]. COVID-19, which remains a critical public health issue,[4] has spurred unprecedented advances in vaccine developments and digital health[5]. As with the shift towards remote schooling and remote work, many aspects of life have undergone dramatic digitization. When we set out to design this study, we were faced with the need to minimize contact between participants and the wider world, including the research team. To overcome this hurdle, we designed a fully remote randomized controlled clinical trial. Given the concern for potential cardiovascular toxicity related to hydroxychloroquine and azithromycin, this study was specifically designed to evaluate QT prolongation [6, 7]. In this trial, we randomized patients age 18-80 at who tested positive for SARS-CoV-2 virus, as previously described[8]. The entire trial was conducted remotely and each participant was delivered a self-monitoring kit, which included a 6-lead ECG monitor (KardiaMobile 6L, AliveCor Inc.). In our paper, Implementation of a fully remote randomized clinical trial with cardiac monitoring, we describe the steps we took to implement internet-based recruitment, patient enrollment, data storage, rapid machine-assisted data analysis, and interfacility collaboration. Although we now know that these agents are not effective for the treatment of COVID-19, our trial is a proof-of-concept demonstrating that QT-related cardiac toxicity monitoring in clinical trials can be executed remotely. Given the traditional barriers to clinical trial enrollment, this may improve access for patients and improve diversity and equity in research – our study population was more diverse population than average US demographics. Of the participants who met our inclusion criteria, we had a lower percentage of patients who self-identified as white, compared to the general population[9]. Additionally, our participants had great adherence to our ECG testing protocol, indicating reproducibility with future trials. While there is concern that technological advancements and remote testing may contribute to future disparities in care, we did not find a digital divide with our cohort of patients. While there was varying skill level in the technological skill of our patients, after proper guidance there was no trouble with participating in or completing our trial. While there have been several studies showing that remote cardiac monitoring can be useful in arrhythmia detection, our work demonstrates that these tools can also be utilized to safely and remotely monitor cardiac toxicity in clinical trials[10]. With the rise of digital health, ECG monitoring devices are an important tool we can leverage to further assess the cardiac safety profiles for drugs in clinical trials. We showed a proof of concept by being able to study the efficacy and safety of a medication using a low-cost device. As medical innovation continues to advance, we hope to see a rise of cardiac monitoring devices, including low-cost ECG monitors and ultrasounds, that can be used to study research questions across different populations. The future of clinical trials is inclusive, cost-effective and unbound by geography Although developing countries represent the majority of the global population, they remain underrepresented in research and in clinical trials [11]. Access to research materials through low-cost devices, research infrastructure through a core-central laboratory, and remote research training and monitoring may remove some of the traditional barriers to clinical trials in developing countries. We hope that the advances in medical technology and the growing digitalization of research will contribute to a new future where we can ethnically test the safety and efficacy of medications across a wide range of populations to truly have diversity in clinical trials. Read the article published in Nature Communications Medicine at https://www.nature.com/articles/s43856-021-00052-w Umscheid, C.A., D.J. Margolis, and C.E. Grossman, Key concepts of clinical trials: a narrative review. Postgraduate medicine, 2011. 123(5): p. 194-204. Yao, B., et al., Safety monitoring in clinical trials. Pharmaceutics, 2013. 5(1): p. 94-106. Seltzer, J.H., et al., Assessing cardiac safety in oncology drug development. Am Heart J, 2019. 214: p. 125-133. Dong, E., H. Du, and L. Gardner, An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis, 2020. 20(5): p. 533-534. Slaoui, M., S.E. Greene, and J. Woodcock, Bridging the Gap at Warp Speed - Delivering Options for Preventing and Treating Covid-19. N Engl J Med, 2020. 383(20): p. 1899-1901. Chatre, C., et al., Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf, 2018. 41(10): p. 919-931. Ray, W.A., et al., Azithromycin and the Risk of Cardiovascular Death. New England Journal of Medicine, 2012. 366(20): p. 1881-1890. Johnston, C., et al., Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial. EClinicalMedicine, 2021. 33: p. 100773. U.S. Census Bureau QuickFacts: United States. p.https://www.census.gov/quickfacts/fact/table/US/PST045219. Perez, M.V., et al., Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. New England Journal of Medicine, 2019. 381(20): p. 1909-1917. Alemayehu C, Mitchell G, Nikles J. Barriers for conducting clinical trials in developing countries- a systematic review. Int J Equity Health. 2018;17(1):37.
Antibacterial Activity of an Effective Spice Essential Oil Formulated in Foot Deodorant Gel against Bacillus subtilis Pilanthana Lertsatitthanakorn and Bhuddhipong Satayavongthip Skin bacterial flora, namely Staphylococcus epidermidis, are able to metabolise sweat that hence leads to foot odor. Moreover, Bacillus subtilis was found in the plantar skin of subjects possessing strong foot odor. The synthetic antibacterial agent generally used in various foot deodorant formulations is triclosan which tends to cause bacterial tolerance. To avoid that shortcoming, researchers in this study developed a natural foot deodorant gel from essential oils. Previous research of our group revealed that cinnamon oil showed a higher antibacterial activity against S. epidermidis than the essential oils obtained from kaffir lime, lemongrass, sweet basil, galanga and ginger. In the present study, the susceptibility of B. subtilis to the mentioned essential oils was determined and the results showed that cinnamon oil possessed the highest activity. Foot deodorant gel containing cinnamon oil was formulated and studied for its biological stability for 90 days at accelerated conditions. The lethal effect of the cinnamon oil gel exposed to B. subtilis for 1 h, was studied at day 0, 15, 30, 60 and 90. It was found that on all sampling days, cinnamon oil gel could decrease by at least 90% the initial bacterial population after 1 h of contact time. In conclusion, cinnamon oil foot deodorant gel demonstrated a good ability to decrease the bacteria involved in strong foot odor. The cinnamon oil foot deodorant gel might be an alternative cosmetic for people who have strong foot odor. Pilanthana Lertsatitthanakorn and Bhuddhipong Satayavongthip, 2012. Antibacterial Activity of an Effective Spice Essential Oil Formulated in Foot Deodorant Gel against Bacillus subtilis. Journal of Biological Sciences, 12: 315-320. DOI: 10.3923/jbs.2012.315.320 URL: https://scialert.net/abstract/?doi=jbs.2012.315.320 Received: March 15, 2012; Accepted: July 13, 2012; Published: September 06, 2012 Foot odor has been characterized as a health problem. Its etiology attributes to degradation of the leucine found in sweat by the skin's normal bacteria flora, namely, Staphylococcus epidermidis which is the most Staphylococcal species investigated on glabrous skin (Rath et al., 2001; Troccaz et al., 2009). The major produced metabolites are short chain fatty acids including isovaleric acid, acetic acid, butyric acid and isobutyric acid which derived to foot odor (Ara et al., 2006; Caroprese et al., 2009). Moreover, Bacillus subtilis is also found in the plantar skin of people having strong foot odor (Ara et al., 2006). Some of these people rely on deodorant to eliminate body odors such as axillary and foot odor. Deodorant is a type of cosmetic used to eliminate these body odors. Numerous dosage forms of foot deodorant have been distributed to the marketplace such as sprays (Kalavala et al., 2007) and creams (Caroprese et al., 2009). The antibacterial agent widely used in these various types of antibacterial cosmetics is triclosan. However, triclosan is a synthetic biocide which tends to cause bacterial tolerance (Cottell et al., 2009). As an alternative, researchers have explored natural antibacterials and subsequently reported on the antibacterial activity of essential oils from Citrus hystrix DC. (kaffir lime) fruit peel, Cymbopogon citratus Stapf. (lemongrass) grass, Cinnamomum zeylanicum Nees (cinnamon) bark, Ocimum basilicum L. (sweet basil) leaves, Alpinia galanga (L.) Willd. (galanga) and Zingiber officinale Rosc (ginger) rhizome (Inouye et al., 2001; Lertsatitthanakorn et al., 2006; Luangnarumitchai et al., 2007; Chanthaphon et al., 2008; Wannissorn et al., 2009). In our previous study, the susceptibility of S. epidermidis to these mentioned essential oils was determined. It was found that cinnamon oil showed the highest activity against S. epidermidis while kaffir lime oil and lemongrass oil revealed the second and third highest potencies, respectively (Chimmalee and Lertsatitthanakorn, 2010). The purpose of this study is to determine the antibacterial activity of these essential oils against B. subtilis by the broth microdilution method. Foot deodorant gel containing the oil most active against both B. subtilis and S. epidermidis was formulated and studied for its biological stability for 90 days. Hopefully, this cosmetic preparation might serve as an alternative foot deodorant for people with strong foot odor. Materials: Essential oils from Citrus hystrix DC. (kaffir lime) fruit peel, Cymbopogon citratus Stapf. (lemongrass) grass, Cinnamomum zeylanicum Nees (cinnamon) bark, Ocimum basilicum L. (sweet basil) leaves, Alpinia galanga (L.) Willd. (galanga) and Zingiber officinale Rosc (ginger) rhizome were purchased from Thai China Flavors and Fragrances Industry Co. (Thailand). Mueller-Hinton agar and Mueller-Hinton broth were provided by Himedia (India). Dimethyl sulfoxide was purchased from Analar (UK). Glycerin, carbomer 937, sodium chloride, propylene glycol, triethanolamine, polysorbate 80, methyl paraben, propyl paraben and lavender oil were purchased from local suppliers in Thailand. Culture and growth condition: B. subtilis DMST 15896 strain was obtained from the Department of Medical Science, Ministry of Public Health, Thailand. A culture was maintained and grown in Mueller-Hinton broth at 37°C. Determination of MIC and MBC values of the six essential oils against B. subtilis: A broth microdilution method was used to determine the Minimum Inhibitory Concentrations (MICs) and Minimum Bactericidal Concentrations (MBCs) of the six essential oils in the same manner of the methods used by Lertsatitthanakorn et al. (2006) and Tarawneh et al. (2010). Muller-Hilton broth was added with 10% dimethyl sulfoxide to dissolve the oils. Fifty microliters of two folded dilutions of each oil sample were prepared in a 96-well plate. Fifty microliters of B. subtilis culture were added to each well to make a final concentration of approximately 108 CFU mL-1. In each test, B. subtilis in Mueller-Hinton broth and Mueller-Hinton broth alone were used as a positive and negative growth control, respectively. The plates were then incubated at 37°C for 24 h before the MICs were determined. The MIC value was defined as the lowest concentration of the oil inhibiting visible growth of bacteria. Ten microliters of broth were removed from each well and spotted onto Mueller-Hinton agar to determine the MBC value. After incubation at 37°C for 24 h, the number of surviving B. subtilis was counted. The lowest concentration, where less than 0.1% of the initial inoculum survived, was defined as the MBC value. Each experiment was performed in triplicate. Determination of the lethal effect of the selected essential oil against B. subtilis: The lethal effect determination was modified from the method previously described by Lertsatitthanakorn et al. (2010). A suspension of 0.1 mL of B. subtilis, approximately 108 CFU mL-1, was added to 0.9 mL solution of the selected essential oil. The oil solution was composed of 10% dimethyl sulfoxide in Mueller-Hinton broth mixed with the selected oil to give the two desired concentrations of the oil. A 0.9 mL solution of 10% dimethyl sulfoxide in Mueller-Hinton broth mixed with a 0.1 mL suspension of B. subtilis, approximately 108 CFU mL-1, was used as control. Two 0.1 mL samples and one 0.1 mL control were stirred carefully and transferred to three separate 0.9 mL tubes of normal saline solution at 0, 10, 20, 30 and 60 min. The samples were serially 10-fold diluted in normal saline solution and 100 μL of each sample were spread on Mueller-Hinton agar for viable counting. The experiment was performed in triplicate. Results are presented as time-log survivor's curves with bars representing the standard deviation. Formulation of foot deodorant gel containing the selected essential oil: Various formulations of hydrogel containing a suitable concentration of the selected oil were prepared using carbomer as a gelling agent. To overcome the spicy odor of the selected essential oil, various perfume oils such as lavender and jasmine were added to the preparation. The foot deodorant gel with the best odor was chosen for determination of its physical stability using the freeze-thaw cycling method. The freeze-thaw cycling method consisted of keeping the selected deodorant at 4°C for 24 h and at 45°C for 24 h. The time frame for one complete cycle was two days; ten days was allocated for 5 cycles. Color, odor, pH and feeling, after applying deodorant gel on the foot, were recorded before the first cycle and after the fifth cycle. The deodorant gel (Table 3) that was selected was determined following the steps outlined in the next section. Biological stability study of foot deodorant gel containing the selected essential oil against B. subtilis: The developed deodorant gel was stored in two separate environments for 90 days: room temperature with natural light and 45°C without light. At day 0, 15, 30, 60 and 90, the biological stability of the deodorant gel was studied by lethal effect determination as previously described by Lertsatitthanakorn et al. (2008). A bacterial suspension of 0.1 mL (approximately 108 CFU mL-1) was added to 0.9 mL of the deodorant gel and mixed well in a vortex mixer. The samples were kept at 37°C. A sample of 0.1 mL was collected for serial 10-fold dilution at 0 and 1 h of contact time. The sample was then placed on Mueller-Hinton agar and counted for survival bacteria after 24 h incubation. The results were presented as log reduction of bacteria after 1 h exposure (log survivors of bacteria at 0 min contact time - log survivors of bacteria at 1 h contact time) and the storage time. Data analysis: SPSS 11.5 for windows was used to perform statistical analysis. The statistical difference of the biological stability, in term of B. subtilis reduction ability, between the foot deodorant gel containing the selected oil stored at room temperature with natural light and the one kept at 45°C without light was analyzed by Student t-test. The p-value of less than 0.05 was considered statistically significant. Susceptibility of B. subtilis to six essential oils: MIC and MBC values of six essential oils against B. subtilis are shown in Table 1. Cinnamon oil exhibited the highest antibacterial activity to B. subtilis with the lowest minimum inhibitory concentration (MIC) at 0.049 μL mL-1. However, the Minimum Bactericidal Concentration (MBC) of all tested oils to B. subtilis was 100 or more than 100 μL mL-1. Lemongrass and kaffir lime oils showed the second and third highest activity to B. subtilis, respectively. Therefore, the susceptibility of B. subtilis to the six essential oils showed a similar pattern as that of S. epidermidis obtained from our previous study. In that study, among the six essential oils, cinnamon oil exhibited the lowest MIC and MBC against S. epidermidis at the same range of 0.391-1.562 μL mL-1 (Chimmalee and Lertsatitthanakorn, 2010). Notably, cinnamon oil was the most active oil against both bacterial strains involved in foot odor and it will be scrutinized in the following section. The lethal effect of cinnamon oil against B. subtilis: The lethal effect of cinnamon oil against the tested bacteria was measured to determine a suitable concentration of oil for foot deodorant preparation. Table 1: MIC and MBC values of six essential oils against B. subtilis According to our previous work, 3.125 and 9.375 μL mL-1 of cinnamon oil could decrease 1.5 log and 3 log of initial S. epidermidis population within 1 h, respectively (Chimmalee and Lertsatitthanakorn, 2010). Therefore, the desired concentrations for studying the lethal effect of cinnamon oil against B. subtilis were 3.125 and 9.375 μL mL-1. As shown in Figure 1 and Table 2, both concentrations of cinnamon oil were able to reduce B. subtilis population rapidly. Because, the initial bacterial count was approximate 108 CFU mL-1 and reduced to less than 102 CFU mL-1 within 10 min after cinnamon oil exposure. By contrast, the solvent could not decrease B. subtilis population and contributed to the "control" curve in Fig. 1. Therefore, both concentrations of cinnamon oil were able to decrease at least 6 log of the initial population of B. subtilis within 10 min and this lethal effect was constant for 1 h of contact time. Therefore, 3.125 and 9.375 μL mL-1 of cinnamon oil were selected as suitable concentrations to decrease the population of B. subtilis. The gel base however, retards the release of the essential oil, so the higher concentration (9.375 μL mL-1) was chosen to incorporate into a suitable gel base. Formulation of foot deodorant gel containing cinnamon oil: An amount of 9.375 μL mL-1 of cinnamon oil was incorporated into a suitable hydrogel base for foot application. Cinnamon oil foot deodorant gel using lavender oil as a perfume produced the most favorable odor and was chosen for further study (Table 3). Fig. 1: Time-killing curves of cinnamon oil on B. subtilis Mean±SD, n = 3 Table 2: Log reduction of initial B. subtilis population after 1 h exposure with cinnamon oil Table 3: Ingredients of the selected cinnamon oil foot deodorant gel *Paraben concentrated consisted of 10 g methyl paraben and 2 g propyl paraben dissolved in 100 mL propylene glycol Table 4: Physical properties of the selected cinnamon oil foot deodorant gel before the first cycle and after the fifth cycle of freeze-thaw cycling storage *pH of the foot deodorant gel was measured in triplicate by pH meter Fig. 2: Biological stability of cinnamon oil foot deodorant gel expressed as log reduction of B. subtilis after 1 h exposure with the gel, Mean±SD, n = 3 To prepare the gel, 2 g of carbomer 937 was dispersed in 80 mL of deionized water and continuously stirred. 0.12 g of triethanolamine was used to neutralize carbomer until a clear gel base was achieved. Glycerin (4 g), polysorbate 80 (2 g) and 937.5 μL of cinnamon oil were then added and mixed. Paraben concentrated (1 g) and lavender oil (0.44 g) were added and mixed well. Finally, the volume of the gel was adjusted to 100 mL with deionized water. The physical stability of the cinnamon oil deodorant gel was studied using a freeze-thaw cycling method. The results in Table 4 revealed that the selected cinnamon oil foot deodorant gel possessed a physical stability. Because, the physical properties of the gel including color, odor and feeling after applying on the foot, did not change after the fifth cycle of freeze-thaw cycling storage. On the one hand, the pH of the gel was rather constant due to a minute changing from 5.04 (before the first cycle) to 5.02 (after the fifth cycle). Biological stability study of the selected cinnamon oil foot deodorant gel against B. subtilis: As shown in Fig. 2, the log reduction of the tested bacteria exposed to cinnamon oil deodorant gel was more than 90% (1 log) for all sampling times. The bacterial reduction ability between the gel kept at room temperature with natural light and the gel kept at 45°C without light was not statistically significant different (p>0.05). Cinnamon oil exhibited the highest antibacterial activity against the bacteria (B. subtilis) found in the plantar skin of subjects having strong foot odor. The MIC value of cinnamon oil to B. subtilis was rather low and compared well with the work of Prabuseenivasan et al. (2006). In our previous research, the major components in cinnamon oil, determined by Gas Chromatography-Mass Spectrometry, were cinnamaldehyde (32.66%) and eugenol (36.49%) respectively (Chimmalee and Lertsatitthanakorn, 2010). In the present research, it was suggested that the prominent antibacterial activity of cinnamon oil against B. subtilis might be attributable to both of these major constituents. The previous antibacterial activity study of cinnamon leaf and bark essential oils and their components clearly supported our results. Since, Singh et al. (2007) found that E-cinnamaldehyde and eugenol were the main components of cinnamon bark oil and cinnamon leaf oil, respectively. They determined antibacterial activity of these chemicals against six pathogenic bacteria including B. subtilis by agar well diffusion method. The results of anti- B. subtilis demonstrated that E-cinnamaldehyde showed a comparable inhibition zone with that of cinnamon bark oil at the same concentration. On the one hand, eugenol revealed a comparable zone with that of cinnamon leaf oil. Lu et al. (2011) found that cinnamon bark oil, rich in trans-cinnamaldehyde, showed a strong antibacterial activity against B. subtilis with the low MIC of 0.2 μL mL-1. The essential oil of Ocimum basilicum (basil) containing 62.60% of eugenol also showed antibacterial activity against B. subtilis with the low MIC of 0.625 μL mL-1 (Lv et al., 2011). Cinnamaldehyde revealed a prominent antibacterial activity against B. subtilis by disc diffusion method and it showed a higher activity than benzoic acid at the same concentration (Wei et al., 2011). Moreover, cinnamaldehyde and eugenol revealed a potent antimicrobial activity to Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Staphylococcus aureus, Helicobacter pylori and Escherichia coli (Ali et al., 2005; Baskaran et al., 2009; Pei et al., 2009). Matan (2007) also found that cinnamaldehyde and eugenol possessed antifungal activity against Aspergillus niger by disc diffusion assay. In addition, when using various skin sensitization potency assay methods, cinnamaldehyde was classified as a mild to moderate contact allergen while eugenol was classified as a mild allergen (Kimber et al., 2003). Therefore, the low concentration of 9.375 μL mL-1 of cinnamon oil added to the deodorant gel in the present study translates into a safe non-irritant concentration of cinnamaldehyde and eugenol. Cinnamon oil foot deodorant gel stored at both accelerated conditions showed less B. subtilis reduction than pure cinnamon oil. A time killing assay of pure cinnamon oil revealed that the oil was able to reduce B. subtilis population rapidly, at least 6 log of the initial population, within 1 h. By contrast, the B. subtilis reduction ability of cinnamon oil foot deodorant gel ranged between 1-4 log of the initial population after 1 h exposure. This diminution in the ability of the cinnamon oil deodorant gel to reduce the B. subtilis population might be attributed to the cinnamon oil deodorant gel's exposure to natural light and high temperature. The same phenomenon was occurred with citronella oil oleogel, an anti-acne preparation, performed in our previous researches. The oleogel containing 6.5% v/w of citronella oil which kept at 40°C for 120 days, could reduce less than 1.5 log of the initial Propionibacterium acnes population after 12 h exposure (Lertsatitthanakorn et al., 2008). By contrast, 5% v/v citronella oil could decrease about 6.5 log of the initial P. acnes population within 6 h (Lertsatitthanakorn et al., 2010). In addition, the retard effect of the gel base might lead to a slow release of cinnamon oil from the gel even before it is exposed to bacteria. Nevertheless, cinnamon oil foot deodorant gel still possesses satisfactory biological stability due to its ability to decrease at least 1 log (90%) of B. subtilis population over a 90 days storage period. To prove a foot malodor relief efficacy of the developed gel, clinical trial should be studied in people who possessing strong foot odor in the future. Cinnamon oil demonstrated the highest antibacterial activity to B. subtilis, the skin bacteria involved in strong foot odor. Therefore, cinnamon oil was suitable to use as an antibacterial agent in foot deodorant preparations. The developed cinnamon oil foot deodorant gel possessed a good ability to decrease B. subtilis population throughout the gels' 90 days storage period at accelerated conditions. To extend its shelf-life and bacterial reduction ability, cinnamon oil gel should be protected from light and exposure to high temperature. The cinnamon oil foot deodorant gel can be developed as an alternative cosmetic for people who have strong foot odor. One of the authors (Pilanthana Lertsatitthanakorn) would like to kindly thank Mahasarakham University Development Fund and Faculty of Pharmacy, Mahasarakham University for financial support in presenting a part of this research as a poster at the 1st International Conference on Antimicrobial Research, Valladolid, Spain during 3-5 November 2010. In addition, we would like to thank Mahasarakham University for providing a research grant, fiscal year 2009, to this project. 1: Ali, S.M., A.A. Khan, I. Ahmed, M. Musaddiq and K.S. Ahmed et al., 2005. Antimicrobial activities of eugenol and cinnamaldehyde against the human gastric pathogen Helicobacter pylori. Ann. Clin. Microbiol. Antimicrob., Vol. 4 10.1186/1476-0711-4-20 2: Ara, K., M. Hama, S. Akiba, K. Koike and K. Okisaka et al., 2006. Foot odor due to microbial metabolism and its control. Can. J. 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Antibacterial effect of cinnamon oil combined with thyme or clove oil. Agric. Sci. China, 10: 1482-1487. CrossRef | Direct Link | 8: Inouye, S., T. Takizawa and H. Yamaguchi, 2001. Antibacterial activity of essential oils and their major constituents against respiratory tract pathogens by gaseous contact. J. Antimicrobiol. Chemother., 47: 565-573. CrossRef | PubMed | Direct Link | 9: Kalavala, M., T.M. Hughes, R.G. Goodwin, A.V. Anstey and N.M. Stone, 2007. Allergic contact dermatitis to peppermint foot spray. Contact Dermatitis, 57: 57-58. 10: Kimber, I., D.A. Basketter, M. Butler, A. Gamer and J.L. Garrigue et al., 2003. Classification of contact allergens according to potency: Proposals. Food Chem. Toxicol., 41: 1799-1809. 11: Lertsatitthanakorn, P., S. Taweechaisupapong, C. Aromdee and W. Khunkitti, 2006. In vitro bioactivities of essential oils used for acne control. Int. J. Aromather., 16: 43-49. 12: Lertsatitthanakorn, P., S. Taweechaisupapong, C. Aromdee and W. Khunkitti, 2008. Antibacterial activity of citronella oil solid lipid particles in oleogel against Int. J. Essent. Oil Ther., 2: 167-171. 13: Lertsatitthanakorn, P., S. Taweechaisupapong, C. Arunyanart, C. Aromdee and W. Khunkitti, 2010. Effect of citronella cil on time kill profile, leakage and morphological changes of Propionibacterium acnes. J. Essent. Oil Res., 22: 270-274. 14: Luangnarumitchai, S., S. Lamlertthon and W. Tiyaboonchai, 2007. Antimicrobial activity of essential oils against five strains of Propionibacterium acnes. Mahidol Univ. J. Pharm. Sci., 34: 61-64. 15: Lv, F., H. Liang, Q. Yuan and C. Li, 2011. In vitro antimicrobial effects and mechanism of action of selected plant essential oil combinations against four food-related microorganisms. Food Res. Int., 44: 3057-3064. 16: Matan, N., 2007. Growth inhibition of Aspergillus niger by cinnamaldehyde and eugenol. Walailak J. Sci. Tech., 4: 41-51. 17: Pei, R.S., F. Zhou, B.P. Ji and J. Xu, 2009. Evaluation of combined antibacterial effects of eugenol, cinnamaldehyde, thymol, and carvacrol against E. coli with an improved method. J. Food Sci., 74: M379-M383. 18: Prabuseenivasan, S., M. Jayakumar and S. Ignacimuthu, 2006. In vitro antibacterial activity of some plant essential oil. BMC Complement. Altern. Med., Vol. 6. 10.1186/1472-6882-6-39 19: Rath, P.M., M. Knippschild and R. Ansorg, 2001. Diversity and persistence of Staphylococcus epidermidis strains that colonize the skin of healthy individuals. Eur. J. Clin. Microbiol. Infect. Dis., 20: 517-519. CrossRef | PubMed | 20: Chanthaphon, S., S. Chanthachum and T. Hongpattarakere, 2008. Antimicrobial activity of essential oils and crude extract from tropical Citrus spp. against food-related microorganisms. Songklanakarin J. Sci. Technol., 30: 125-131. 21: Singh, G., S. Maurya, M.P. de Lampasona and C.A.N. Catalan, 2007. A comparison of chemical, antioxidant and antimicrobial studies of cinnamon leaf and bark volatile oils, oleoresins and their constituents. Food Chem. Toxicol., 45: 1650-1661. 22: Tarawneh, K.A., F. Irshaid, A.S. Jaran, M. Ezealarab and K.M. Khleifat, 2010. Evaluation of antibacterial and antioxidant activities of methanolic extracts of some medicinal plants in northern part of Jordan. J. Biol. Sci., 10: 325-332. 23: Troccaz, M., G. Borchard, C. Vuilleumier, S. Raviot-Derrien, Y. Niclass, S. Beccucci and C. Starkenmann, 2009. Gender-specific differences between the concentrations of nonvolatile (R)/(S)-3-methyl-3-sulfanylhexan-1-ol and (R)/(S)-3-hydroxy-3-methyl-hexanoic acid odor precursors in axillary secretions. Chem. Senses, 34: 203-210. 24: Wannissorn, B., P. Maneesin, S. Tubtimted and G. Wangchanachai, 2009. Antimicrobial activity of essential oils extracted from Thai herbs and spices. Asian J. Food Agro Ind., 2: 677-689. 25: Wei, Q.Y., J.J. Xiong, H., Jiang, C. Zhang and W. Ye, 2011. The antimicrobial activities of the cinnamaldehyde adducts with amino acids. Int. J. Food Microbiol., 150: 164-170. PubMed |
"Life is a process of being an organising whole" – Mae Wan Ho: The Rainbow and the Worm. The physics of Organisms. Every cell in the body is utterly dependent upon oxygen. Without oxygen, no cell can continue to live for more than a few minutes. Furthermore, if a cell is receiving just enough oxygen to stay alive, but not enough to thrive its function declines markedly. When it happens to muscle tissue cells, they hurt. When it happens to brain cells, it causes a feeling of emotional distress. Conversely, if the cells of the body and brain are receiving an abundant supply of oxygen, this oxygen confers feelings of energy and optimal mood. On inhalation, Oxygen enters the bloodstream in the lungs, through the alveolar sacs, and attaches to the haemoglobin of red blood cells, which carry it throughout the body. When a cell receives oxygen from a capillary, it exchanges an approximately equal amount of the gaseous waste carbon dioxide, which is carried back to the lungs and expelled through exhalation. This energy exchange occurs every moment of your life. Inhalation occurs by contraction of the three diaphragm muscles, chiefly the large diaphragm muscle at the base of the lungs. The contraction of the diaphragm, and the associated expansion of the lungs, exerts a number of critically important functions. * Stimulation of blood circulation. Blood circulation is the prime physical nourisher of the body and brain, and the mechanism for cellular disposal. Blood circulation is also enhanced by the effect of the lungs on the liver. When breathing is shallow or irregular, blood accumulates in the liver, causing swelling. This decreases blood flow to the alimentary canal causing digestive problems. * Toning of the Nervous System including the peripheral nerves. * Direct cleansing of the lungs. Deep powerful breaths eliminate a great deal of toxic and noxious debris. It can help prevent respiratory infections. Breathing exercises also confer a high degree of immunity to tuberculosis. * Mood regulation. Conscious breathing is one of the best ways to calm oneself and reduce or change the feelings of fear, anger and pain. Breathing deeply has an impact upon a part of the brain known as the peri-aqueductal grey area. (PAG). This is an important nodal point where many nerves come together. This nodal point is the site of the body's largest supply of opiate receptors, which can help to decrease uncomfortable emotional feelings and help control anger and fear and pain. This relief from pain, anger and fear is also a powerful boost to healing. New research has shown consistent, powerful, positive shifts in mood when the correct type of breathing is used in a walking meditation programme. Moreover, energy levels are rapidly elevated while chronic pain is diminished. Healing occurs in the sacred space of calmness and confidence, not amid the turmoil of fear, anger and pain. All this can be overcome with proper healthy breathing. Whenever you get the chance, stop, inhale deeply, bring the energy up, and then exhale again through the nose. This will keep you calm, centred, relaxed and at peace. There are many breathing techniques one can learn in order to cope with specific situations. Breath you are Alive. Thich Nhat Hanh. Breath by Breath – Larry Rosenberg.
If you have been advised by your physician or dentist to take antibiotic premedication because of joint replacement or for any other reason, please follow their recommendation. If there is a question, please call our office prior to your appointment. What Should I Do About Pain After Treatment? It is not uncommon to have some discomfort following root canal therapy. Not all teeth are created equal and some conditions are more prone to pain following treatment than others. Studies have shown that the biggest predictor of pain following root canal therapy is pain before treatment. Often there is damage in the bone around the tooth and this takes time to heal. Most patients respond well to a combination of acetaminophen (Tylenol) and ibuprofen (Advil). We would recommend starting with 600mg (that would be 3 over the counter pills which are usually 200mg each) of Advil after the procedure and then two extra-strength Tylenol (500 mg each) about three hours later. You can continue to alternate these two medications every 3 hours for the first day. It is normal to experience tenderness and biting sensitivity for 2-3 days after your appointment, even if you didn't have any discomfort before you came to you appointment. Ibuprofen is ideal for dealing with pain. If you don't have problems taking Ibuprofen, you can take 2-3 tablets (200mg each; 400-600mg total) every 6 hours. If taken regularly rather than when the pain is felt, it will help to prevent the pain from coming. This is the best medicine for helping the swelling because it is an anti-inflammatory. If you cannot take Ibuprofen, please let us know and we will prescribe a different medication. You can also take the prescribed pain medication with the Ibuprofen if needed. Avoid strenuous activity for the remainder of the day. Apply an ice bag or cold compress to the outside of the face, over the operated area for 20 minutes on and 20 minutes off for the remainder of the day. This will help keep swelling and discoloration to a minimum. Eat only soft foods for the first 24 hours; avoid chewing in the operated area until the sutures are removed or you have had a follow-up appointment. Do not brush the area for the first 24 hours; after 24 hours gently brush the teeth alone (avoiding the gums in the operated area). Do not floss the area until the sutures are removed.
Nelarabine, sold under the brand names Arranon (US) and Atriance (EU), is a chemotherapy medication used for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Nelarabine is a prodrug of arabinosylguanine nucleotide triphosphate (araGTP), a type of purine nucleoside analog, which causes inhibition of DNA synthesis and cytotoxicity. Pre-clinical studies suggest that T-cells are particularly sensitive to nelarabine. In October 2005, it was approved by the FDA for acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma that has not responded to or has relapsed following treatment with at least two chemotherapy regimens. It was later approved in the European Union in October 2005. It is available as a generic medication. References External links Purine antagonists Nucleosides Purines Arabinosides Hydroxymethyl compounds
ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUuc3RhZ2luZy5tZWRzY2FwZS5jb20vYXJ0aWNsZS8xMTc4MjgzLXdvcmt1cA==\nDrugs & Diseases > Neurology\nNeurofibromatosis Type 2 Workup\nAuthor: David T Hsieh, MD, FAAP; Chief Editor: George I Jallo, MD more...\nNeurofibromatosis Type 2\nSections Neurofibromatosis Type 2\nGenetic Studies\nAuditory Evaluation\nOphthalmic Examination\nRadiation Treatment and Chemotherapy\nTumor Resection and Radiosurgery\nAuditory Brainstem Implants\nGenetic analysis for disease-causing mutations of neurofibromatosis type 2 (NF2) is clinicially available. Detection rates for molecular-based testing approaches 72% in simplex cases; therefore, such testing has some inherent limitations when trying to confirm a diagnosis of NF2. However, for a patient with suspected NF2 who is still young, has a negative family history, and may eventually develop additional criteria, the identification of a specific mutation may be very helpful.\nIn light of the high rate of somatic mosaicism in sporadic cases of NF2 (perhaps as many as 25%), molecular testing of tumor tissue may augment traditional molecular studies when analysis of deoxyribonucleic acid (DNA) obtained from blood lymphocytes is nondiagnostic.\nThe UK NF2 Genetic Severity Score (GSS) provides useful genetic-phenotype correlations with potential for further clinical use: [24, 25]\nType 1: Mild: mosaic for mutations only found in tumor, not blood\nType 2a: Mild: missense variants, exon 1 and 13/14 truncating, splicing 7-15, mosaic for variants except in 2b in blood\nType 2b: Moderately severe: large deletions, splicing variants exons 1-6, mosaic for truncating variants (exon 2-13) in blood\nType 3: Severe: truncating mutations exons 2-13\nType 3 is the most severe gradation, with early childhood onset, a high frequency of meningiomas, and early mortality. [24, 25] In addition, a higher growth rate of vestibular schwannomas is associated with higher gradation. [26]\nImaging studies and auditory, ophthalmic, and histologic examinations are also important in the diagnosis and management of NF2.\nAttempts to increase the detection rate of NF2 mutations have met with some success by using a variety of technologies. Denaturing high-performance liquid chromatography has shown promise in identifying more point mutations in affected individuals, and, when used in conjunction with multiplex ligation-dependent probe amplification, may uncover NF2 gene rearrangements. The addition of a third technique, high-resolution melting analysis, rounds out the new molecular armamentarium, which enables exons to be more efficiently scanned, thereby further improving the detection rate by uncovering additional point mutations. [27]\nFor families with asymptomatic, at-risk members, the application of molecular testing is viewed from a slightly different perspective. Once the clinical diagnosis has been established unequivocally in a given individual, he or she could be offered direct molecular analysis to see if a mutation can be identified. If a mutation were found, then other asymptomatic family members might benefit from presymptomatic testing to see who would and who would not develop neurofibromatosis type 2 (NF2). Screening and surveillance recommendations would then be based on the results of this testing and, if a sibling or child of an affected person were found not to carry the mutation, he or she would need not be concerned about developing NF2 in the future.\nFor families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. However, this requires cooperation on the part of the family, as well as DNA samples from multiple affected and unaffected individuals. Even utilizing the best technology available, diagnostic uncertainty may remain, depending on the geographical relationship between the genetic markers and the disease-causing gene. On the other hand, with advances that have taken place in genetic mapping and the likelihood of finding informative markers close to or within the gene itself, linkage analysis remains an excellent choice for determining risk from a molecular standpoint.\nFor a parent who has NF2, prenatal testing can be done on amniocytes or chorionic villi, either through direct gene mutation analysis when such a change has been identified or through linkage analysis. Prenatal testing may not be possible if the affected parent is the first affected person in the family and a mutation cannot be found. For an affected parent with a known mutation, preimplantation genetic diagnosis may be possible if the couple is willing to undergo in vitro fertilization with transfer of unaffected embryos.\nOne note of caution must be made in light of advances in molecular genetic technology. Presymptomatic testing of at-risk family members requires a vigorous informed consent process and might best be done during a genetic counseling session at a cancer, genetic, or neurofibromatosis center that specializes in such matters. This is of even greater concern when considering testing of minors, in whom the potential harm must be weighed against medical benefit.\nSince aggressive medical surveillance can still be implemented in the absence of a definitive diagnosis and no preventive or curative measures are currently available, the decision to undergo presymptomatic testing for this adult-onset disease is a personal one that must be made after a frank and complete discussion with health professionals.\nPlain films of the spine may be helpful in evaluating scoliosis but are of limited value in looking for spinal cord tumors that may occur in NF2.\nMagnetic resonance imaging (MRI) remains the mainstay for diagnosis and screening of CNS, cranial nerve, and spinal cord tumors (see the images below). At-risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRI scans of the head performed through their late 50s. Clear molecular diagnosis may help to modify risks for family members and prevent unnecessary testing for asymptomatic individuals who are found not to carry a gene mutation.\nMeningioma to the left of midline in a patient with neurofibromatosis type 2.\nMultiple meningiomas (on the left) on the surface of the brain in a patient with neurofibromatosis type 2.\nBilateral acoustic neuromas in a patient with neurofibromatosis type 2.\nBilateral acoustic neuromas and a left-sided meningioma in a patient with neurofibromatosis type 2.\nSmall ependymoma in a patient with neurofibromatosis type 2.\nMultiple meningiomas in a patient with neurofibromatosis type 2.\nMRI using 3-dimensional (3D) volumetrics is now the preferred method for following vestibular schwannoma growth over time. [2]\nMRI of the spine is indicated diagnostically when an individual presents with motor or sensory changes suggestive of a spinal cord lesion or lesions. The key point here is early detection, which may result in prompt action and provide a better outcome. However, routine MRI imaging of the spinal cord probably is not indicated for asymptomatic affected or at-risk individuals.\nAlthough whole body MRI is often utilized within clinical trials, its use within clinical practice is still being defined. Short-tau inversion recovery (STIR) sequences have been particularly useful for the detection of whole body tumor burden. [28]\nHearing evaluations, including brainstem auditory-evoked response (BAER), are important in the identification of early hearing loss and may demonstrate latency abnormalities before a mass is detectable on MRI. In light of this, auditory screening on an annual basis may be quite useful in asymptomatic or presymptomatic individuals.\nOnce a vestibular schwannoma is identified, full audiometry testing, including acoustic reflex testing as well as BAER, is useful as a means of monitoring disease progression. Clinical experience clearly indicates that the size of the vestibular tumor often does not correlate with the degree of hearing loss. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) found the Self-Assessment of Communication adult and adolescent forms for the assessment of patient-reported hearing function and quailty of life to be the most useful and recommends them for use in NF2 clinical trials. [29]\nDilated eye examinations are an important part of the care of affected individuals because they are at a risk for developing visually significant cataracts or retinal lesions. As a diagnostic test, an eye examination for lens opacities, retinal hamartomas, or epiretinal membranes may be quite useful even in a child at risk for neurofibromatosis type 2 (NF2). In fact, juvenile cataracts, as the name implies, frequently occur in children and may be seen long before there is any evidence of vestibular schwannomas.\nFor children and adults with NF2, annual eye examinations are recommended, since unrecognized visual impairment can further interfere with activities of daily living, especially in an individual with concomitant hearing loss.\nUnlike the tumors associated with neurofibromatosis type 1 (NF1), those found in neurofibromatosis type 2 (NF2) are usually made up of 1 of 3 cell types—Schwann cells, glial cells, or meningeal cells. Although the tumors in NF2 can be locally invasive and cause significant morbidity as a result of their growth properties, they rarely, if ever, undergo malignant transformation. This is somewhat different than in NF1, in which plexiform neurofibromas occasionally develop into neurosarcomas.\nHowever, vestibular schwannomas and meningiomas in NF2 tend to be more aggressive than they are in cases of sporadic tumors (ie, those not related to NF2), with a tendency for more extensive local invasion and with histologic evidence of increased mitoses.\nTreatment & Management\nEvans DG. Neurofibromatosis 2. Genet Med. 2009. 11:599-610. [QxMD MEDLINE Link].\nHarris GJ, Plotkin SR, Maccollin M, et al. Three-dimensional volumetrics for tracking vestibular schwannoma growth in neurofibromatosis type II. Neurosurgery. 2008 Jun. 62(6):1314-9; discussion 1319-20. [QxMD MEDLINE Link].\nAboukais R, Baroncini M, Zairi F, Bonne NX, Schapira S, Vincent C, et al. Prognostic value and management of spinal tumors in neurofibromatosis type 2 patients. Acta Neurochir (Wien). 2013 May. 155(5):771-7. 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[QxMD MEDLINE Link].\nGugel I, Grimm F, Teuber C, Zipfel J, Tatagiba M, Mautner VF, et al. Presenting symptoms in children with neurofibromatosis type 2. Childs Nerv Syst. 2020 Oct. 36 (10):2463-2470. [QxMD MEDLINE Link].\nGaudioso C, Listernick R, Fisher MJ, Campen CJ, Paz A, Gutmann DH. Neurofibromatosis 2 in children presenting during the first decade of life. Neurology. 2019 Sep 3. 93 (10):e964-e967. [QxMD MEDLINE Link].\nSmith MJ, Bowers NL, Bulman M, et al. Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology. 2017 Jan 3. 88 (1):87-92. [QxMD MEDLINE Link].\nEvans DG, Freeman S, Gokhale C, et al. Bilateral vestibular schwannomas in older patients: NF2 or chance?. J Med Genet. 2015 Jun. 52 (6):422-4. [QxMD MEDLINE Link].\nLee HBH, Garrity JA, Cameron JD, Strianese D, Bonavolonta G, Patrinely JR. Primary optic nerve sheath meningioma in children. Surv Ophthalmol. 2008. 53:543-58.\nBettegowda C, Upadhayaya M, Evans DG, Kim A, Mathios D, Hanemann CO, et al. Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical Use. Neurology. 2021 Aug 17. 97 (7 Suppl 1):S91-S98. [QxMD MEDLINE Link].\nHalliday D, Emmanouil B, Pretorius P, MacKeith S, Painter S, Tomkins H, et al. Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 2017 Oct. 54 (10):657-664. [QxMD MEDLINE Link].\nMoualed D, Wong J, Thomas O, Heal C, Saqib R, Choi C, et al. Prevalence and natural history of schwannomas in neurofibromatosis type 2 (NF2): the influence of pathogenic variants. Eur J Hum Genet. 2022 Jan 24. [QxMD MEDLINE Link].\nSestini R, Provenzano A, Bacci C, et al. NF2 mutation screening by denaturing high-performance liquid chromatography and high-resolution melting analysis. Genet Test. 2008 Jun. 12(2):311-8. [QxMD MEDLINE Link].\nAhlawat S, Fayad LM, Khan MS, et al. Current whole-body MRI applications in the neurofibromatoses: NF1, NF2, and schwannomatosis. Neurology. 2016 Aug 16. 87 (7 Suppl 1):S31-9. [QxMD MEDLINE Link].\nThompson HL, Blanton A, Franklin B, Merker VL, Franck KH, Welling DB, et al. Patient Report of Hearing in Neurofibromatosis Type 2: Recommendations for Clinical Trials. Neurology. 2021 Aug 17. 97 (7 Suppl 1):S64-S72. [QxMD MEDLINE Link].\nOtto SR, Brackmann DE, Hitselberger W. Auditory brainstem implantation in 12- to 18-year-olds. Arch Otolaryngol Head Neck Surg. 2004 May. 130(5):656-9. [QxMD MEDLINE Link].\nKanowitz SJ, Shapiro WH, Golfinos JG, et al. Auditory brainstem implantation in patients with neurofibromatosis type 2. Laryngoscope. 2004 Dec. 114(12):2135-46. [QxMD MEDLINE Link].\nPlotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009 Jul 23. 361(4):358-67. [QxMD MEDLINE Link].\nGugel I, Zipfel J, Hartjen P, Kluwe L, Tatagiba M, Mautner VF, et al. Managing NF2-associated vestibular schwannomas in children and young adults: review of an institutional series regarding effects of surgery and bevacizumab on growth rates, tumor volume, and hearing quality. Childs Nerv Syst. 2020 Oct. 36 (10):2471-2480. [QxMD MEDLINE Link].\nKarajannis MA, Legault G, Hagiwara M, Ballas MS, Brown K, Nusbaum AO, et al. Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2012 Sep. 14 (9):1163-70. [QxMD MEDLINE Link].\nOsorio DS, Hu J, Mitchell C, Allen JC, Stanek J, Hagiwara M, et al. Effect of lapatinib on meningioma growth in adults with neurofibromatosis type 2. J Neurooncol. 2018 Sep. 139 (3):749-755. [QxMD MEDLINE Link].\nvon Eckardstein KL, Beatty CW, Driscoll CL, Link MJ. Spontaneous regression of vestibular schwannomas after resection of contralateral tumor in neurofibromatosis Type 2. J Neurosurg. 2010 Jan. 112(1):158-62. [QxMD MEDLINE Link]. [Full Text].\nGerszten PC, Burton SA, Ozhasoglu C, McCue KJ, Quinn AE. Radiosurgery for benign intradural spinal tumors. Neurosurgery. 2008 Apr. 62(4):887-95; discussion 895-6. [QxMD MEDLINE Link].\nColletti V, Shannon R, Carner M, Veronese S, Colletti L. Outcomes in nontumor adults fitted with the auditory brainstem implant: 10 years' experience. Otol Neurotol. 2009 Aug. 30(5):614-8. [QxMD MEDLINE Link].\nSubcutaneous and cutaneous lesions in a young man with neurofibromatosis type 2; note paucity of cafe-au-lait spots.\nRight neck mass in a patient with neurofibromatosis type 2.\nFacial asymmetry, OS proptosis, and exotropia, as well as several subcutaneous lesions on the forehead and face, in a 20-year-old man with neurofibromatosis type 2.\nPosterior cervical scar from cord lesion resection, thoracic scoliosis, and subcutaneous masses in a young adult with neurofibromatosis type 2.\nDavid T Hsieh, MD, FAAP Associate Professor of Pediatrics and Neurology, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Chief, Physician Education, Joint Base San Antonio (JBSA)\nDavid T Hsieh, MD, FAAP is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, Child Neurology Society\nLuis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio\nLuis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics\nGeorge I Jallo, MD Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine\nGeorge I Jallo, MD is a member of the following medical societies: American Association of Neurological Surgeons, American Medical Association, American Society of Pediatric Neurosurgeons\nThe view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, Department of Defense or the U.S. Government.\nDavid A Griesemer, MD Professor, Departments of Neuroscience and Pediatrics, Medical University of South Carolina\nDavid A Griesemer, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Epilepsy Society, Child Neurology Society, and Society for Neuroscience\nBeth A Pletcher, MD Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey\nBeth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics\nencoded search term (Neurofibromatosis Type 2) and Neurofibromatosis Type 2\nNeurofibromatosis Type 2 Imaging\nGenetics of Neurofibromatosis Type 1 and Type 2\nDermatologic Manifestations of Neurofibromatosis Type 1\nOral Neurofibroma\nCafe Au Lait Spots\nClinical, Imaging and Biochemical Presentation of Cystic Pheochromocytomas\nThe Role of Hemodynamic Shear Stress in Healing Chronic Wounds\nClonidine Suppression Test for a Reliable Diagnosis of Pheochromocytoma\nCentral Vertigo: Identifying the Hidden Cause\nDiseases & Conditions Neurofibromatosis Type 2\nUnderstanding the Biology and Addressing the Management Challenges of Cytopenic Myelofibrosis 1.25 CME / CE / ABIM MOC Credits\nUnderstanding the Biology and Addressing the Management Challenges of Cytopenic Myelofibrosis\nDiseases & Conditions Genetics of Neurofibromatosis Type 1 and Type 2\nDiseases & Conditions Neurofibromatosis Type 2 Imaging"
Corrections (1) Jeffrey L. Brodsky Protein quality control in the secretory pathway Zhihao Sun, Jeffrey L. Brodsky J Cell Biol (2019) 218 (10): 3171–3187. DOI: https://doi.org/10.1083/jcb.201906047 Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation Atin K. Mandal, Paul Lee, Jennifer A. Chen, Nadinath Nillegoda, Alana Heller, Susan DiStasio, Handy Oen, Jacob Victor, Devi M. Nair, Jeffrey L. Brodsky, Avrom J. Caplan Cdc37 is a molecular chaperone that functions with Hsp90 to promote protein kinase folding. Analysis of 65 Saccharomyces cerevisiae protein kinases (∼50% of the kinome) in a cdc37 mutant strain showed that 51 had decreased abundance compared with levels in the wild-type strain. Several lipid kinases also accumulated in reduced amounts in the cdc37 mutant strain. Results from our pulse-labeling studies showed that Cdc37 protects nascent kinase chains from rapid degradation shortly after synthesis. This degradation phenotype was suppressed when cdc37 mutant cells were grown at reduced temperatures, although this did not lead to a full restoration of kinase activity. We propose that Cdc37 functions at distinct steps in kinase biogenesis that involves protecting nascent chains from rapid degradation followed by its folding function in association with Hsp90. Our studies demonstrate that Cdc37 has a general role in kinome biogenesis. Correction: The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum Nathan N. Alder, Ying Shen, Jeffrey L. Brodsky, Linda M. Hendershot, Arthur E. Johnson J Cell Biol (2005) 169 (1): 203. DOI: https://doi.org/10.1083/jcb.200409174042905c The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum The Sec61 translocon of the endoplasmic reticulum membrane forms an aqueous pore that is gated by the lumenal Hsp70 chaperone BiP. We have explored the molecular mechanisms governing BiP-mediated gating activity, including the coupling between gating and the BiP ATPase cycle, and the involvement of the substrate-binding and J domain–binding regions of BiP. Translocon gating was assayed by measuring the collisional quenching of fluorescent probes incorporated into nascent chains of translocation intermediates engaged with microsomes containing various BiP mutants and BiP substrate. Our results indicate that BiP must assume the ADP-bound conformation to seal the translocon, and that the reopening of the pore requires an ATP binding–induced conformational change. Further, pore closure requires functional interactions between both the substrate-binding region and the J domain–binding region of BiP and membrane proteins. The mechanism by which BiP mediates translocon pore closure and opening is therefore similar to that in which Hsp70 chaperones associate with and dissociate from substrates. Molecular Chaperones in the Yeast Endoplasmic Reticulum Maintain the Solubility of Proteins for Retrotranslocation and Degradation Shuh-ichi Nishikawa, Sheara W. Fewell, Yoshihito Kato, Jeffrey L. Brodsky, Toshiya Endo Endoplasmic reticulum (ER)-associated degradation (ERAD) is the process by which aberrant proteins in the ER lumen are exported back to the cytosol and degraded by the proteasome. Although ER molecular chaperones are required for ERAD, their specific role(s) in this process have been ill defined. To understand how one group of interacting lumenal chaperones facilitates ERAD, the fates of pro–α-factor and a mutant form of carboxypeptidase Y were examined both in vivo and in vitro. We found that these ERAD substrates are stabilized and aggregate in the ER at elevated temperatures when BiP, the lumenal Hsp70 molecular chaperone, is mutated, or when the genes encoding the J domain–containing proteins Jem1p and Scj1p are deleted. In contrast, deletion of JEM1 and SCJ1 had little effect on the ERAD of a membrane protein. These results suggest that one role of the BiP, Jem1p, and Scj1p chaperones is to maintain lumenal ERAD substrates in a retrotranslocation-competent state.
Computational and Mathematical Methods in Medicine Computational and Mathematical Methods in Medicine / 2012 / Article AbstractIntroductionMaterialsResultsConclusionAcknowledgmentsReferencesCopyright Cardiovascular System Modeling View this Special Issue Research Article | Open Access Volume 2012 |Article ID 948781 | https://doi.org/10.1155/2012/948781 Jianhong Dou, Ling Xia, Dongdong Deng, Yunliang Zang, Guofa Shou, Cesar Bustos, Weifeng Tu, Feng Liu, Stuart Crozier, "A Study of Mechanical Optimization Strategy for Cardiac Resynchronization Therapy Based on an Electromechanical Model", Computational and Mathematical Methods in Medicine, vol. 2012, Article ID 948781, 13 pages, 2012. https://doi.org/10.1155/2012/948781 A Study of Mechanical Optimization Strategy for Cardiac Resynchronization Therapy Based on an Electromechanical Model Jianhong Dou,1,2 Ling Xia,2 Dongdong Deng,2 Yunliang Zang,2 Guofa Shou,2 Cesar Bustos,2 Weifeng Tu,1 Feng Liu,3 and Stuart Crozier3 1Department of Anesthesiology, General Hospital of Guangzhou Military Command, Guangzhou 510010, China 2Key Lab of Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China 3The School of Information Technology & Electrical Engineering, The University of Queensland, Brisbane, QLD 4072, Australia Academic Editor: Dingchang Zheng Received21 Jun 2012 Accepted10 Sep 2012 Published16 Oct 2012 An optimal electrode position and interventricular (VV) delay in cardiac resynchronization therapy (CRT) improves its success. However, the precise quantification of cardiac dyssynchrony and magnitude of resynchronization achieved by biventricular (BiV) pacing therapy with mechanical optimization strategies based on computational models remain scant. The maximum circumferential uniformity ratio estimate (CURE) was used here as mechanical optimization index, which was automatically computed for 6 different electrode positions based on a three-dimensional electromechanical canine model of heart failure (HF) caused by complete left bundle branch block (CLBBB). VV delay timing was adjusted accordingly. The heart excitation propagation was simulated with a monodomain model. The quantification of mechanical intra- and interventricular asynchrony was then investigated with eight-node isoparametric element method. The results showed that (i) the optimal pacing location from maximal CURE of 0.8516 was found at the left ventricle (LV) lateral wall near the equator site with a VV delay of 60 ms, in accordance with current clinical studies, (ii) compared with electrical optimization strategy of , the LV synchronous contraction and the hemodynamics improved more with mechanical optimization strategy. Therefore, measures of mechanical dyssynchrony improve the sensitivity and specificity of predicting responders more. The model was subject to validation in future clinical studies. Congestive heart failure (CHF) is a common heart disease caused by dilated cardiomyopathy or damage to the excitation conduction system. Biventricular pacing (BiVP), or cardiac resynchronization therapy (CRT), was a major breakthrough in the treatment for patients with advanced CHF complicated by discoordinate contractions caused by inter- or intraventricular conduction delays [1]. CRT has the potential to improve the quality of life and functional capacity, promote left ventricle (LV) reverse remodeling, and reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association class III or IV CHF [2–6]. However, up to 20–30% of patients do not respond favourably to CRT using standard clinical selection criteria [7], and a critical analysis of the data suggests the true nonresponder rate can be estimated at perhaps 40–50% [8]. Data indicate that factors associated with a poor outcome are multifactorial and that inappropriate patient selection, left ventricular pacing site, and inadequate device programming are likely to be important [9]. Therefore, an individual optimal electrode position, atrio-ventricular delay (AV delay, AVD), or interventricular delay (VV delay, VVD) in CRT are needed to improve its success [10, 11]. However, left ventricular lead placement and timing delays continue to pose a number of challenges regarding the delivery of an effective CRT. Over the past decade, many studies have examined the pathophysiology of cardiac dyssynchrony and tested the effect of cardiac resynchronization on heart functions and the efficacy of symptoms enhancements. Most of these researches have focused on the ECG characteristic of distinct responders versus nonresponders to CRT. For example, left and right ventricular leads were placed in different locations to attain the shortest QRS duration during biventricular stimulation. Presently, the optimal electrode setups and timing delays are also determined by measuring the cardiac index using magnetic resonance tagging (MR tagging), nuclear imaging (NI) or Doppler flow imaging and so on [12–15], most of which relate to the measurement of interventricular asynchrony (interVA) or intraventricular asynchrony (intraVA). However, it may be not sufficient for clinicians to formulate a scientific and reasonable treatment scheme for CRT optimization with only physical examination of ECG or medical imaging. Quantitative information and precise programming of the optimal stimulation delays and lead positioning accordant with the physiological function are needed. For example, although it is generally accepted that the posterior-lateral wall is the preferred location for LV lead location in CRT, other LV pacing sites have also been shown to offer superior benefits for selected patient population. In other words, there is no universally accepted best LV pacing site, nor the best V-V interval. Therefore, patient-specific CRT optimization is needed. There are both intersubject variability and intrasubject variability (e.g., compare resting versus exercise conditions). Modeling of heart can provide a useful supplementary tool to investigate the dynamical behaviour of heart quantitatively and thus enhance our understanding of the cardiac electrophysiological and mechanical properties under physical and pathological conditions. Consequently, the computer modeling of a patient-specific heart appears to be a reasonable solution for solving this problem, which can determine the optimal AV and VV timing pre- or postoperatively with respect to the lead positions in patients undergoing CRT. Many scientists have concentrated on the study of individual optimization of lead position and pacing delays of CRT by means of heart modeling and simulation with the progress of mathematical modeling techniques. The electrical-based optimization approach, for example, minimizing the QRS duration, has been widely accepted due to its simplicity. Therefore, most of researches have concentrated on the electrical strategies of optimizing parameters in CRT. Reumann et al. simulated an atrio-ventricular (AV) and a left bundle branch block (LBBB) with different reductions in the interventricular conduction velocity based on computer models of the Visible Man and a patient's heart [16]. They assumed that the ideal cardiac function is achieved if the excitation of the ventricles is as close as possible to the physiological rhythm. Consequently, the minimum error between the physiological excitation and pathology/therapy, that is, the root mean square error , was used as an optimization assessment index and automatically computed for 12 different electrode positions with different AV and VV intervals. Their results showed the importance of individually adjusting the electrode position, beside the timing delays, to the patient's anatomy and pathology in accordance with current clinical studies. Mohindra et al. recorded 120-electrode body-surface potential mapping (BSPM) data and calculated the epicardial potentials and isochrones of activation for different V-V intervals by means of an electrocardiographic inverse solution based on a ventricular computer model [17]. They used the area between the LV and RV percentage surface-activated curves as a measure of interventricular synchrony for a variety of V-V settings. Their results demonstrated that an optimal CRT pacing V-V interval can be selected by aiming to minimize the dyssynchrony in the ventricular activation patterns. However, they found that it was difficult to correlate the heart model results with the clinical recordings and moreover, the BSPM did not provide any information about how these patterns improved the cardiac output. To some extent, these mathematical models carried out well the adjustment of the optimization parameters of CRT. Yet, because the optimization procedure was based on the electrical criterion that was not necessarily equal to the electromechanical coupling [15], the simulations in these works might be wrong if the mechanical activation followed the electrical activation with an unfixed delay, that is,the electromechanical dissociation in the cardiopulmonary resuscitation (CPR) [18]. Thus, we doubt the soundness of the electrical optimization strategy for predicting effect of CRT. A relationship between electrical dyssynchrony and mechanical performance needs to be established. Nowadays, the importance of correcting mechanical dyssynchrony has been more and more realized in the field of CRT optimization. For example, most echo-based CRT optimization approaches target the mechanical synchrony, not the electrical synchrony. Unfortunately, the mechanical optimization strategy for CRT has seldom been investigated in the previous computational models. Compared with previous electrophysiological models for CRT optimization, the present heart model in this paper is extended to include a mechanical contraction model for the optimization of the pacing lead locations and the interventricular delays (VVds) of CRT. Since the spatial distribution of local wall mechanics was very sensitive to the choice of myofiber orientations, specific data of real fiber orientations were used for true description of cardiac deformation in this study. The ventricular mechanical dyssynchrony is evaluated by the assessment of a circumferential uniformity ratio estimate (CURE) [15, 19]. The aim of this study is to validate the feasibility of CRT optimization with mechanical predictors (CURE) and to make a contrast analysis of cardiac function improvement between mechanical (CURE) and electrical () optimization strategy for CRT. The present study resolves this question through the simulation of the cardiac electrical activation spread and the mechanical strain maps based on our previous electromechanical canine model of HF combined with a complete LBBB (CLBBB) [20]. 2.1. Heart Model of CHF with CLBBB 2.1.1. Heart Anatomical Model The anatomical canine heart model used in this study was reconstructed from the MR scans of an intact dog heart derived at the Duke University Medical Center for In Vivo Microscopy, Durham, NC, USA (Figures 1(a), 1(b), 1(c), and 1(d)). The spatial discrete matrix size of the original data was , corresponding to a pixel size of mm. Myocardial fiber orientations were obtained from diffusion tensor MR imaging (DT-MRI) in a 7.1 T MRI scanner (Figures 1(e), 1(f)) and different tissues were manually segmented into functional modules, including papillary muscles and Purkinje fiber networks (Figures 1(g), 1(h)). Full details of this model can be found in [20]. Note that papillary muscles are not used in the simulation. 3D view of the canine ventricular anatomical model. The left panel ((a), (b)) shows anatomical geometry from original datasets. (c) and (d) display 3D view of the whole ventricles scanned from DT-MRI at Duke University Center visualized by Volview 2.0. (e) and (f) display distribution of 3-D fiber angles in the space. (g) and (h) display the reconstructed canine heart model. 2.1.2. Heart Electrophysiological Properties To model electrical propagation in a dilated failing heart with CLBBB, an initial stimulus current with a magnitude of 100 μA/cm2 and duration of 0.5 ms was added to the right bundle branch while blocking the conduction of the left bundle branch, leaving the rest of the conduction tree intact. Latest depolarization time in LBBB simulations occurred at 108 ms (see Figure 2). After these cardiac electrical excitation sequences were obtained, the active forces of myocardium can be calculated. 3D maps of simulated complete LBBB activation of the canine ventricles in different views. Ventricular Cell Model The dynamic ionic cell model developed by Winslow et al. [21] was used to simulate the electrophysiology of a single ventricular cell. The cell model with different ionic channel currents could be described by the following differential equations: where is the transmembrane potential, is the membrane capacitance, is the current flow through the ion channel is the conductance of the channel, and is the reversal potential for the channel [20]. Reaction-Diffusion Equations The asynchronous excitation propagation and intraventricular conduction in the LBBB were simulated based on solutions of reaction-diffusion equations of the monodomain model as shown in the following with a strategy of parallel computation: where is the sum of all transmembrane ionic currents, is the transmembrane stimulating current density, and represents the diffusion coefficient. In order to solve the monodomain equations, an initial equation (3) as well as boundary condition (4) were required: 2.1.3. Electromechanical Coupling In this study, we have modeled the electrical excitation and mechanical contraction as two separate processes weakly coupled together through the use of the excitation wavefront to drive the active tension development. Myocardium Mechanical Properties After the cardiac electrical excitation sequences were determined by an excitation propagation algorithm in the electrical simulation, the resultant active forces of the myocardium were calculated. The active stress development in the myofibers depended on the time and sarcomere length and was initiated at the timing of the depolarization, as Kerekhoffs et al. [22–24] did. Then the active force along the fiber was calculated. Finite Element Method (FEM) In this work, the ventricular walls were divided into 14 layers from apex to base along the long axis of the LV (see Figure 3). There are in total 2,269 hexahedral elements and 8,736 degrees of freedom. A 3D 8-node isoparametric element is used as the basic element. Notice that the original reference heart geometry corresponds to the end-diastolic state of a dog heart. Also, muscle alike restriction was added to ventricular base elements due to the constraint of pleura. Schematic for layer display. (a) Four short slices near the equator site (layer 6 to layer 9) for calculation of CURE. (b) The finite element meshes of biventricular mechanical model of canine. (c) The coordinate system of biventricular mechanical model of canine. To analyze the motion of ventricles, the following equation at time need to be computed: where is the total stiffness matrix, is the volume vector of nodal displacement, and is the total vector of the active forces: where is the nodal force vector of an element described above, and is the stiffness matrix of an element with the following expression: where is the elasticity matrix of layer and segment denotes the number/total numbers of segments in layer in the circumferential direction, respectively. In the fiber-coordinate system, the nodal force vector of each element in the direction of fiber can be calculated as shown in the following: where [] is the geometric matrix of an element, is the active myofiber stress as a function of time after onset of contraction and sarcomere length history, is the determinant of the Jacobin matrix, the local coordinate system with the magnitudes ranging from −1 to 1, and are the number and total number of layers in an element, respectively, and is the transformation matrix between the fiber coordinate and global coordinate (see Appendix A). These constitutive relations for the cardiac mechanics were then incorporated into a continuum electromechanical model of biventricles to predict the displacement and deformation. From (5) to (7), we can calculate displacement . The equations related to mechanics are solved with eight-node isoparametric element method. Local myocardial circumferential strain of the biventricles is then calculated during the systole phase. As far as mechanical properties are concerned, the material was considered as transversely isotropic at any point in the myocardium. The in-vitro stiffness parameters and material constants were used as before [20]. 2.2. Optimization Strategies 2.2.1. Mechanical Index Mechanical dyssynchrony is a potential indicator for predicting responses to CRT. For example, novel echocardiographic image speckle tracking applied to routine midventricular short-axis images can quantify dyssynchrony by calculating the radial strain from the multiple circumferential points averaged to several standard segments and thus predict the response to CRT [25]. Dyssynchrony for the study was usually defined as the difference in the timing of the peak strain from the earliest to latest segment. However, most clinicians prefer to use the circumferential uniformity ratio estimate (CURE) as the assessment of the mechanical dyssynchrony in the practice of CRT [15, 26, 27]. Therefore, in this study, the CURE is used to index the mechanical dyssynchrony. According to the report [15], short-axis slices motion near the equator can reflect the actual synchronous systolic process of the ventricular wall; thus, in this study, we chose four short-axis slices near the equator site (layers 6 to 9 in our heart model) to calculate CURE, excluding the most apical and basal regions (Figures 3(a), 3(b)). The coordinate system of biventricular mechanical model of canine was shown in Figure 3(c). The algorithm are as follows. Step 1. Compute circumferential strain over the entire LV-midwall (-axis) at 30 circumferentially-distributed locations around each short-axis section (-axis), and plot versus spatial position for each time-frame. The more oscillatory the plot, the greater was the dyssynchrony among the segments around the short axis. To explain this, we can plot circumferential strain versus spatial location of the segment as Figure 4 showed. Then, from the data, zero-order S0 and first-order S1 terms can be obtained by Fourier series decomposition. A perfectly synchronous heart appeared as a straight line (solely S0 term), whereas one that was perfectly dyssynchronous would appear as a sinusoid (S1 term) (Figure 4). Circumferential strain plotted as a function of spatial location of heart segment at a given time. Data were first processed by Fourier series decomposition. The zero-order (S0) and first-order (S1) terms shown plotted versus spatial position. Step 2. Plots for the four mid-wall short-axis slices are then subjected to Fourier analysis with a function of fft() in Matlab7.0.1, and the results are averaged over space and time to yield where and are the spatial and temporal sums of the zero- and first-order power terms, respectively. The ratio of mean to "mean plus first-order power" provides the CURE index, and the maximal value for CURE is 1 with all segments contracting synchronously; whereas symmetrically dyssynchronous contractions produce a CURE = 0 [15, 26, 27]. A further description of calculating zero and first-order power terms of layer 6 to 9 around equator sites at a given time was given in Appendix B. Then with (9), CURE can be obtained. Step 3. Compute the CURE for each electrode pair and each VVD and choose maximum CURE as optimal result of CRT. Because the left ventricular dyssynchrony is an important determinant of CRT response, the CURE calculated from LV and septum is chosen alternatively as the criterion for predicting the response to CRT in the simulation. The optimization method was then applied to the electromechanical canine heart model of LBBB. The optimization parameter of the CURE was sequentially calculated for each combination of the pacing location and VVD. The optimal result of CRT can be determined by the combination that provided the maximum CURE. 2.2.2. Electrical Index The description of the electrical optimization strategy with can be found in many published reports. Briefly, it is assumed that the optimal cardiac output is to be achieved through the sinus rhythm and the normal electrophysiological parameters [16]. Therefore, the aim of the pacing therapy is to restore an electrophysiological status as close as possible to the physiological electromechanical coupling. Here, we calculate the root mean square error between the physiological excitation during the sinus rhythm and pathological excitation as below: where is the whole number of voxel elements, dedicates the activation time of voxel under the sinus rhythm, and is the activation time of voxel under the pathological condition. Thus, by minimizing the , the activation of the heart will be as close as possible to the healthy activation and will provide an optimal combination of the pacing site and timing delay in CRT. 2.3. Objective Function of the Optimization Problem In order to make a contrast analysis of cardiac function improvement between mechanical (CURE) and electrical () optimization strategy for CRT, two objective function are defined as below. 2.3.1. Dyssynchrony Index (DI) Dyssynchrony for the study was usually defined as the difference in the timing of the peak strain from the earliest to latest segment, as represented by DI, which can be used to describe the contraction synchrony of biventricles. In the clinic research, the radial strain was usually used to substitute for the maximum principal strain. However, they all indicated a thickening of cardiac walls. 2.3.2. Ejection Fraction (EF) The hemodynamic parameter of EF, which is the percentage of blood ejected from the ventricle with each heartbeat, can determine the cardiac function. Since LV is the heart's main pumping chamber, EF is usually measured only in the LV. A measure of the function of LV, also called left ventricular ejection fraction (LVEF), can help determine the cardiac hemodynamics effect. LVEF is defined as where EDV means LV volume of end-diastole while ESV represents the LV volume of end-systole. 2.4. Pacing Site and VVD 2.4.1. Pacing Site In this study, BiVP was chosen for CRT simulations. In clinic, doctors often choose the branches of coronary sinus as the LV pacing lead site as shown in Figure 5(a). Here, the anterior, lateral, and posterior branches of the coronary sinus were plotted according to the original anatomical data as shown in Figures 1(c), 1(d). Moreover, to better contrast the influence of the different LV pacing lead positions to the response of CRT, theoptional LVpacing sites were chosen at the base and equator sites of the LV along the branches of the blood coronary veins, as shown in Figure 5(b). The pacing lead positions on the transverse plane are shown in Figure 5(c). The right ventricular apex (RVA) of the endocardium, point RVA (36, 79, 49), was chosen as the position of RV pacing lead. The LV electrodes were placed in the anterior and posterior wall of the LV in addition to the LV free wall (LVFW) as followed, POST-B (77, 98, 89) at the posterior base, POST-E (79, 94, 57) at the posterior equator, LAT-B (114, 62, 89) at the lateral base, LAT-E (108, 53, 57) at the lateral equator, ANT-B (90, 15, 89) at the anterior base, and ANT-E (67, 20, 57) at the anterior equator. Then, pacing was performed for each pair of right and left ventricular pacing positions yielding six electrode setups for the CLBBB model to investigate the influence of the electrode position on the response to CRT. A diagram of the electrode positions of pacing leads. (a) Reconstructed LV, RV, blood coronary veins (blue) and blood coronary arteries (red) from USA VHP female dataset. (b) Three-dimensional display of LV and RV pacing lead positions. (c) Display of pacing lead positions on transverse plane. 2.4.2. Pacing Timing Delays Generally, the activation of the sinus node serves as the reference time for the AV delay. Several studies have pointed out that the VVD should be optimized according to the changes in the AV delay to obtain the maximum hemodynamic benefit [16]. However, because the original canine data did not include the atria, the construction of a whole heart model was infeasible and therefore the AV delay was kept constant in this research. Considering the special features of the canine activation period, we choose −72 ms, −60 ms, −48 ms, −36 ms, −24 ms, −12 ms, 0 ms, 12 ms, 24 ms, 36 ms, 48 ms, 60 ms, and 72 ms as the VVD timings. To contrast with clinic studies, the scope of VVD timings was enlarged to better investigate the influence of VVD on the optimal efficacy of CRT. Positive values indicated that the LV was the first ventricle stimulated and a negative VVD indicated a right-before-left ventricular stimulation. Therefore, there were 78 simulations in whole by multiplying pacing leads numbers and VVD numbers. So, an optimization can be achieved by maximizing the CURE or minimizing the through adjustment of the pacing location and VVD. 2.5. Numerical Solutions Simulation of the cardiac excitation anisotropic propagation throughout the ventricular myocardium is computationally very expensive. Thus, high-performance computing techniques should be used. By using an operator-splitting scheme, adaptive time step, and backward differentiation formulation techniques in a parallel implement, we solved the monodomain equations of the cardiac excitation anisotropic propagation successfully [28]. For a combination of the pacing location and VVD, the model of the electrical propagation ran for approximately 10 hours on a Dell computer with four 3.0 GHz Xeon processors running in parallel and with 4 GB of RAM. The computation of the CURE took approximately 190 MB of main memory and 1.5 hours on a Dell computer with a single 3.0 GHz Xeon processor. 3.1. The Optimal Result of CRT The maximal value of CURE was 0.8516, with pacing site at point LAT-E and a VVD of 60 ms (see Figure 6), which could be regarded as the optimal result for CRT. The calculated CURE value of the LBBB model was 0.67. According to clinical reports, cardiac mechanical synchrony was also less in patients with LBBB (CURE in one cardiac cycle: ) [27]. The value of the maximum CURE significantly increased after BiVP optimization, indicating that CRT could enhance the intrasynchrony of LV for CHF hearts with LBBB. A column map of CURE-VV delay time curve. With the electrical optimization strategy, an optimal pacing location and VVD were also found with a minimal error of 37.26 ms. The optimal stimulation site was also at point LAT-E, but with a VVD of 0 ms. To find the potential relationship between CURE and VVD, a diagram of the CURE-VV delay time column map was plotted in Figure 6. It was found that the values of CURE were larger when VVD ≥ 0 ms, which meant LV was the first stimulated. But for different LV pacing sites, CURE varied disorderly without a continued trend of ascending or descending with the change of VVD. It indicated that there existed a nonlinear relationship between CURE and VVD time. However, with the increasing of VVD, especially when VVD ≥ 48 ms, CURE varied little and the same thing happened when VVD ≤ −48 ms. For VVD ≥ 60 ms, CURE would not rise again. It was obvious that CURE was not the largest with VVD = 0 ms that commonly used in the previous VVD setup. Furthermore, CURE values of LV pacing sites near ventricular equator sites were all larger than those at base for VVD ≥ 12 ms. However, the CURE of LV pacing location near the lateral wall at equator site, that is, pacing location LAT-E, was always the largest. It can also be found that the CURE values were smaller when the pacing lead was at the anterior wall near base, that is, pacing location ANT-B and ANT-E. 3.2. Optimal Result Contrast of CRT between CURE and In order to better contrast with clinical findings, we divided the short-axis LV into four segments, named anterior wall, lateral wall, posterior wall, and septum (Figure 7). Then, the positive maximum principal strain (also called maximum strain) was calculated from the multiple circumferential points averaged to several standard segments near the equator sites (layer 7). Maximum strain was plotted against time under three conditions, including a CHF model with LBBB, a CRT optimization model with maximum CURE and a CRT optimization model with minimum (Figure 8), and thus predicted their responses to CRT [25]. The maximum strain,, was used to indicate thickening of the cardiac walls [20]. is the maximal eigenvalue of the Green Lagrange strain tensor with the expression of where represents the identity matrix and the superscript represents the matrix transpose, and deformation gradient tensor indicates both the rotation and the deformation around a point. Segments division of the short-axis LV, named anterior wall, lateral wall, posterior wall, and septum. An example of maximum principal strain-time curves. (a) a CHF study model with LBBB. (b) a CRT optimization model with maximum CURE. (c) a CRT optimization model with minimum . The curves are color-coded by the defined myocardial regions as depicted in the figure. An example of dys-synchrony is shown as the difference in the timing of the peak strain from earliest to latest segment (black arrow). (a) shows that DI equals to 60 ms. (b) shows that four segments arrive at the peak-of-strain almost at the same time. (c) shows that DI equals 30 ms. In the simulation of LBBB, as shown in Figure 8(a), DI equals 60 ms with septum the earliest to the peak strain while lateral and posterior wall the latest to the peak strain. LVEF in the simulation of LBBB is 22%. However, in the simulation of CRT with mechanical optimization strategy (CURE = 0.8516), the time for all four segments (anterior wall, lateral wall, posterior wall, and septum) to peak strain occurs almost simultaneously, as shown in Figure 8(b), and therefore DI equals 0 ms. LVEF in the simulation of BiVP is 35%, which means an enhancement of LV hemodynamic function after CRT optimization with mechanical strategy. The "Maximum Strain-Time" curve with the minimum (37.26 ms) was plotted as the optimal result of CRT from the electrical index (Figure 8(c)). Contrary to the LBBB result, lateral and posterior wall were the earliest to peak strain while septum was the latest to peak strain. The optimal pacing lead was located at the point LAT-E with a VVD of 0 ms. The calculated DI was 30 ms with a LVEF of 30%. 4. Discussions The clinical findings of CRT have demonstrated that the adjustment of pacing lead position and VVD were very important for an individual to get the best improvement in hemodynamics [29]. However, there still need more quantitative information for determining the optimal VV timing pre- or postoperatively with respect to the lead positions in patients undergoing CRT. Based on a coupled biventricular electromechanical model of the canine with CLBBB, the mechanical and electrical optimization strategies for predicting the effect of CRT were investigated. Unlike previous electrical optimization strategy of CRT (), we have adopted the mechanical optimization strategy CURE as the synchrony assessment index in the research. As we know, the main function of heart is to pump blood and exchange the metabolites. Therefore, the mechanical function of heart and the cardiac hemodynamics were the most basic characteristics and essential criteria for evaluating the cardiac function. The implantation location of LV pacing lead was proven to be very important for the improvement of the ventricular systolic synchrony [30]. From Figure 6, it indicated that the optimal pacing location was at the LV lateral wall (LVLW) near the equator site (point LAT-E) based on the mechanical index of CURE. It can also be found that a larger CURE could be obtained by placing stimuli at the posterior wall at base (point POST-B) or at the anterior wall near equator sites (point ANT-E). It was suggested by clinicians that the pacing lead should be implanted in the LV posterior or the lateral vein of the coronary sinus during the BiVP in accordance with our simulation results [30]. Thus, the mechanical synchronous contraction of the myocardium was forced to be better. According to clinical researches [31, 32], the left ventricular posterior wall (LVPW) and LVLW were often the latest activation sites in LBBB patients. In other words, we also validated that the latest activation or mechanical contracting site may be the optimal stimulating site, which was also validated by the mathematical model of Helm et al. [33]. Furthermore, Figure 6 also showed us that a better LV systolic synchrony (LVSS) could be achieved by placing pacing electrodes near the equator sites (points POST-E, LAT-E, and ANT-E) than near the base sites (point POST-B, LAT-B, and ANT-B). However, with the increasing of VVD, especially for VVD ≥ 48 ms, CURE varied little and the same thing happened when VVD ≤ −48 ms. For VVD ≥ 48 ms, LV was the first ventricle to be paced. However, when RV was paced, the intrinsic excitation or excitation from LV pacing lead had spread to the RV beforehand. Due to the influence of refractory period, the pacing lead of RV (point RVA) would not play a role. Therefore, CURE values make no variations when VVD was larger than a certain value. From Figure 6, it showed us that all maximal CURE values were larger than 0.8150 when VVD ≥ 0 ms. We could also find that a larger CURE may be obtained when the VVD equals 0 ms, especially for those with the LV pacing leads located at the equator sites. It has been observed by clinicians that a larger CURE might be obtained when the LV was first stimulated (VVD ≥ 0 ms) and about 28.4% of patients might get optimum hemodynamics when a VVD of 0 ms was offered [34]. Under pathological conditions of LBBB, normal rhythm was broken up and depolarization spread more slowly and less uniformly. Due to the spoiled excitation propagation, there was a profound abnormality of contraction sequences of both ventricles, which affected ventricular contractile activity and decreased the heart function. During simulation of LBBB (Figure 2), electrical and mechanical delay was evident in the LVFW segments, which suggested a severe interventricular dyssynchrony [20]. Therefore, LV needs to be paced first to get a coordinate contraction of whole heart during CRT. Before the invention of the second-generation dual-chamber pacemaker, the initial factory setting for the VVD was 0 ms. However, it could be found from our simulation results that the optimal VVD was not 0 ms but 60 ms, based on the mechanical strategy of predicting the response of CRT. Therefore, it will still be necessary for the optimization of VVD. To further observe the enhancement of LV synchronization after CRT optimization and to contrast the optimal result between mechanical (CURE) and electrical () strategy, Maximum Strain-Time curves were plotted in Figure 8. In the simulation of LBBB (see Figure 8(a)), the time to peak strain of all the ventricular segments had various degrees of delays in accordance with the clinic phenomenon [30], with a DI of 60 ms and a LVEF of 22%. Nevertheless, the optimal results with the CURE indicated that LV had a better synchrony (DI = 0 ms, meaning that all the LV segments contract almost simultaneously, as shown in Figure 8(b)) and a higher LVEF (35%), whereas the optimal result of CRT from the electrical criterion () had a worse synchrony (DI = 30 ms, meaning that the LV still has some dys-synchrony, as shown in Figure 8(c)) and a lower LVEF (30%). The results proved that mechanical index (CURE) used in this model was superior to the electrical index () for the optimal parameters of CRT. It also confirmed the fact that the CURE could better reflect the LV synchrony and hemodynamic result, although biventricles may not obtain the best electrical synchrony [25]. It has been proven by doctors that systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with LBBB [15]. Mechanical coordination plays the dominant role in the global systolic improvement with the BiVP approach. Besides, it may be easier for us to optimize the parameters of CRT using a mechanical criterion with clinic image methods, such as MRI, intracardiac ultrasound, and so on. Several studies have suggested that the measures of mechanical dys-synchrony by cardiac imaging were superior markers of the response to CRT, compared with the ECG QRS duration [25, 27, 33, 35]. In the practice of CRT optimization, clinicians often use the TDI to trace "tissue velocity-time" with the septal-to-lateral delay of the maximum velocity defined as the LV dyssynchrony, or use echocardiograph techniques to trace "radial strain-time" curves with ealiest to latest delay of peak strain defined as the LV dyssynchrony. The VVD that could produce the smallest septal-to-lateral delay and the maximum cardiac output (CO) would be selected as the optimal VVD of CRT, similar to our validation methods [25]. However, note that in this research, improved mechanical coordination and pump function may be observed in the optimal results (DI = 60 ms, LVEF = 22%) with both the CURE and as optimization strategy for CRT. The thickening of the cardiac walls also improved after CRT with the peak maximum principle strain (PMPS) increased from 0.70 in the LBBB model to 0.77 in CRT optimization model based on the CURE strategy as shown in Figure 8(c). However, the PMPS in CRT optimization model based on the strategy was larger, with a value of 0.98 as shown in Figure 8(c), indicating a better local myocardium contraction function. Previous electrical optimization procedures were based on the electrical isochrones, that is, the electrical activation of the cells, which did not necessarily equal the electromechanical coupling, that is, the phenomenon of the delayed electrical uncoupling. Assuming that the mechanical activation followed the electrical activation with a fixed delay, the results with the electrical optimization strategy of CRT might be valid, because the timing offset would be added to all cardiac cells. So long as the delay between the electrical and the mechanical activation per cell varied, the electrical optimization strategy of CRT might be not accurate, because of the pathological prolongation of the mechanical activation influenced by the delayed electrical uncoupling. Damage to the myocardium intercalated disks was another phenomenon of electromechanical dissociation. Because the conduction of the electrical excitation was accomplished by the intercellular "gap junctional communication", the path of the connection could be closed partly or completely when there was a very low blood calcium level or acidosis causing conduction disturbance in the damaged regions. For a heart with an electromechanical dissociation, the adjustment of the pacing location or VVD might produce profitable results, but the optimization of the pacing site and VVD of CRT with the electrical optimization strategy might be given a great discount [18]. Briefly, the electrical and mechanical activations were not completely equal to each other. However, with the mechanical criterion (CURE or other hemodynamical index) to optimize the parameters of CRT, the problem could be solved. Alternatively, an improved mechanical coordination and function may be inducible in the LBBB-CHF hearts without generating electrical synchrony. The difference of optimal delays and pacing sites was due to the difference of heart geometry, electrical and mechanical properties, and also the time regional differences in the time between electrical excitation and mechanical contraction at one part of the model versus another part. Therefore, clinicians would not always choose the lateral wall for the pacing locations. With the help of a patient-specific computation heart model, quantitative information will be obtained to enhance our understanding of cardiac dyssynchrony and decrease the blindness of CRT. In this study, however, there are still some defects in our optimization model of CRT. Because of the lack of the atria data, the construction of a whole heart model was not feasible and consequently, the adjustment of the AV delay has not been considered. Furthermore, the hemodynamics parameters should be taken into account in future modeling, such as the cardiac output and the (maximum value for the first derivative of the LV pressure (peak )) that were usually used as the optimal parameters of CRT in clinic [25, 36]. In addition, the heavy computation load might limit the clinical applications of the computation model. Another major limitation of this study is the use of a standard heart model. However, in clinical practice, there are numerous variations, for example, various geometry of the heart, various electrical properties of the heart (conduction velocities, conduction blocks, infarct zones, etc.), various mechanical properties of the heart, various autonomic tones, and so on. Therefore, the results of the single simulation study cannot be extrapolated to clinical patients now. By using a coupled biventricular electromechanical models of the canine heart, the optimization of the electrode positions and VV delay timings for CRT with the BiVP have been investigated, with both the mechanical criterion of CURE and electrical criterion of . We also demonstrated that the mechanical dyssynchrony measure was able to predicts well the effect of CRT, better than the electrical dyssynchrony measure. In comparison with other computational optimization models of CRT, the mechanical contraction and deformation was included in our model, and the mechanical index CURE was calculated. The results indicated that the LV pacing lead positioning was a very important factor that affecting the consequence of CRT and the hemodynamic changes. Also, the changes of VVD will lead to a variation in the mechanical synchrony and should be considered in the optimization of CRT. Therefore, it was very important for an individual to adjust the electrode position as well as the timing delays to the patient's anatomy and pathology, in accordance with current clinical studies [34, 37, 38]. In addition, we can conclude from simulation results that the site of the latest mechanical activation may be the optimal left ventricular lead position for the current LBBB-HF model, but it may be limited by the anatomy of the coronary vein. Compared with the electrical optimization strategy, the simulation results showed that the LV synchronous contraction and hemodynamics could be improved more with the mechanical optimization strategy for predicting the effect of CRT. Mechanical dyssynchrony, rather than the electrical dispersion, seems to be the more relevant. Therefore, mechanical dyssynchrony is a potential better means for predicting the response to CRT. However, it does point out that, to apply this modeling approach in clinical practice, patient-specific electromechanical heart model must be established [39]. A. Calculation of the Transformation Matrix between the Fiber Coordinate and Global Coordinate Since fiber orientations vary for different sublayers in an isoparametric element of hexahedron, the transformation between the fiber coordinate and the global coordinate is needed. As shown in Figure 9, we first need to transfer the fiber-coordinate system (--, one axis is chosen to coincide with the local muscle fiber direction , and another one is determined by the epicardium surface normal vector ) to the new surface-coordinate system (--, one axis is chosen to coincide with the epicardium surface normal vector , and another one is determined by the epicardium circumferential or tangential vector ), with the transformation matrix determined by the fiber direction angle of a single sublayer; then transfer the surface-coordinate system (--) to the global coordinate system (--), with the transformation matrix determined by the direction cosines between two doordinate systems. Cardiac walls coordinate systems. Finally, the transformation matrix between the fiber coordinate and the global coordinate is as follows: B. Calculation of Zero and First-Order Power Terms The codes for calculating zero and first-order power terms of layer 6 at a given time in Matlab7.0.1 are as follows: where are the circumferential strains over the entire LV-midwall at 30 circumferentially distributed locations in layer 6. From above, we can get the zero power term (s02_6) and first-order power term (s12_6) of layer 6 at a given time. Then the zero and first-order power terms of layer 7 to 9 during the cycle can be obtained in the same way. This project is supported by the National Natural Science Foundation of China (81171421, 31100671, 61101046), Guangzhou Zhujiang Scientific and Technological New Star Capitals (2011J2200001), and the Program for New Century Excellent Talents in University (NCET-04-0550). The authors would like to thank Prof. Edward W. Hsu, Department of Bioengineering, Duke University, for providing the dataset and technical discussions. S. Garrigue, P. Bordachar, S. Reuter, P. Jaïs, M. 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