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From a bullfrog, Rana catesbiana , the upper portion of the head is removed following the procedures described in previous work , by cutting with scissors through from the junction of the posterior pharynx and esophagus out to the skin of the back. This procedure was carried out after lowering the body temperature of the frog for 30 – 60 minutes inside a refrigerator to abolish pain sensations. The palate was examined for macroscopic lesions, such as ulcers, petechia or redness as evidence of inflammation. Only palates free of inflammatory indicators were included in this study. Any blood remaining in the epithelial surface was carefully washed away, then the excised head was placed palate side facing upwards on a piece of gauze saturated with frog Ringer solution (FRS) in a Petri dish. The experimental procedures involving animals were approved by the Health Sciences Animal Policy and Welfare Committee, University of Alberta.
|
15357881_p5
|
15357881
|
Frog palate preparation
| 4.122009 |
biomedical
|
Study
|
[
0.9993889331817627,
0.00024933842360042036,
0.00036167155485600233
] |
[
0.998138427734375,
0.001517435652203858,
0.0002359608479309827,
0.00010813712287927046
] |
en
| 0.999997 |
The FRS was prepared by mixing standard Ringer injection with sterile water (2:1). The composition of standard frog Ringer (in mmol/l) is 90 NaCl, 3 KCl, 2 CaCl 2 , and 15 NaHCO 3 (220 mosm/l). The palate was placed inside the frog chamber, a wooden box with a glass top and fitted glass front, and manipulated trough glove openings. The humidity inside the box is maintained at 100% using an ultrasonic Pari nebulizer and the temperature is kept between 22° to 24°C by a rheostat-controlled, externally mounted light source. Before carrying out any measurement, the palate was allowed to stabilize inside the box for 15 minutes before testing.
|
15357881_p6
|
15357881
|
Frog palate preparation
| 4.106594 |
biomedical
|
Study
|
[
0.9994045495986938,
0.0002570378128439188,
0.00033844512654468417
] |
[
0.9905518293380737,
0.008896213956177235,
0.0003782866697292775,
0.00017356546595692635
] |
en
| 0.999997 |
The exposure chamber with a volume ~10 liters had two inlets: one connected to an ultrasonic Pari jet nebulizer system set at 8 L/min measured by a Puritan flow meter to maintain the chamber near 100 % humidity. The other inlet was linked to a burning chamber. The latter, which contained a burning cigarette, was slightly pressurized with air flowing into the chamber at a rate of 2 L/min to promote cigarette combustion. Positive ventilation inside the burning chamber pushed the side stream smoke into the covered but not sealed exposure chamber, which was exhausted into a fume hood. Temperature inside the chamber was maintained to 22°C. and monitored through a thermocouple and digital-display thermometer. The palate was placed inside with the palate side upwards on a piece of gauze saturated with FRS in a glass dish at about five centimeters above the bottom of the chamber.
|
15357881_p7
|
15357881
|
Exposure chamber
| 4.103473 |
biomedical
|
Study
|
[
0.9990229606628418,
0.00034355249954387546,
0.0006334935897029936
] |
[
0.9963616728782654,
0.0033222141209989786,
0.00023229613725561649,
0.00008377804624615237
] |
en
| 0.999996 |
The exposure chamber was designed to allow a steady flow of side stream tobacco smoke to reach the epithelial tissue. The concentration of cigarette smoke inside the exposure chamber was maintained constant throughout the experiment by the presence of a mixing baffle on the outflow of the chamber. The concentration of tobacco smoke inside the chamber was not directly measured, but is estimated that the half palate was exposed to the smoke of each cigarette delivered, diluted in 180 liters of fresh air. As much as possible, the conditions (humidity, type of solution, temperature, physical manipulation and airflow in and out) in the frog chamber and in the exposure chamber were maintained similar, with cigarette smoke being the independent variable.
|
15357881_p8
|
15357881
|
Exposure chamber
| 4.085402 |
biomedical
|
Study
|
[
0.9993287324905396,
0.00024186163500417024,
0.00042945699533447623
] |
[
0.9989479184150696,
0.0008406149572692811,
0.00015963215264491737,
0.000051790142606478184
] |
en
| 0.999996 |
The palate was divided longitudinally in two halves along the midline as shown in Figure 2 , cutting the epithelium with a scalpel to minimize damage. After five minutes the mucus transport was measured in both halves, left and right, to confirm that both half palates were functioning normally. One side was used as control and the other half was exposed to tobacco smoke. The control half of the palate was left in the frog chamber while the other half was placed in the exposure chamber maintained at similar conditions of 100 % humidity and room temperature. If any or both halves showed a variation in mucus transport greater than 30 % from the baseline, the experiment was aborted.
|
15357881_p9
|
15357881
|
Frog palate exposure model preparation
| 4.106613 |
biomedical
|
Study
|
[
0.9993489384651184,
0.0003763390122912824,
0.0002746984246186912
] |
[
0.9988320469856262,
0.0008189881918951869,
0.0002593076787889004,
0.00008962715219240636
] |
en
| 0.999997 |
The palate was placed under a dissecting stereomicroscope provided with a reticulated eyepiece. Mucociliary clearance was determined by observing the movement of particles of charcoal powder gently deposited on a sample of mucus on the palate surface; its clearance was visually monitored and MTV determined. The displacement of 3 – 5 μL of endogenous frog mucus sample was calculated by dividing the distance traveled by the transit time across the 0.3 inch (7.62 mm) segment marked between 0.1 and 0.4 inches in the graduated eyepiece. At least five measurements of the time required for the mucus sample to travel the defined distance were made every time to obtain control and smoke exposure mucus transport velocity.
|
15357881_p10
|
15357881
|
Mucus transport velocity (MTV) determination
| 4.143163 |
biomedical
|
Study
|
[
0.9993951320648193,
0.00039050879422575235,
0.0002143308229278773
] |
[
0.9990472197532654,
0.0005571389920078218,
0.0003100701724179089,
0.0000855002217576839
] |
en
| 0.999997 |
We used cigarettes regularly available at commercial outlets of a representative brand in terms of customer preference and toxic emissions: nicotine 0.5 – 2.1 mg, tar 4 – 24 mg, carbon monoxide 5 – 25 mg, hydrogen cyanide 0.04 – 0.21 mg, benzene 0.025 – 0.069 mg, formaldehyde 0.018 – 0.1 mg. One cigarette took 17 minutes on average to burn completely in this preparation.
|
15357881_p11
|
15357881
|
Mucus transport velocity (MTV) determination
| 2.394354 |
biomedical
|
Study
|
[
0.9699885845184326,
0.000963355996645987,
0.02904803678393364
] |
[
0.7040844559669495,
0.29436174035072327,
0.0008455812348984182,
0.0007082250085659325
] |
en
| 0.999996 |
After being exposed to one cigarette, the half palate was brought back to the frog chamber and MTV was measured in both control and exposed halves. A sample of mucus was collected from each half, and placed in separate containers and frozen at -80°C in liquid nitrogen followed by storage in a -80° freezer until analysis. The exposed half, brought back to the exposure chamber was further exposed to 3 more cigarettes (51 additional minutes of exposure). Following tobacco exposure, the half palate was again brought back to the frog chamber to measure mucus transport and collect tissue and mucus sample in both halves, control and exposed. One set of half palates (control and exposed to four cigarettes) was stored at 4°C overnight, and transport of mucus was reassessed the next day.
|
15357881_p12
|
15357881
|
Measurements and mucus samples collection
| 4.074909 |
biomedical
|
Study
|
[
0.9993417859077454,
0.00033808936132118106,
0.0003201310464646667
] |
[
0.999338686466217,
0.000400483695557341,
0.00020017607312183827,
0.00006068484071874991
] |
en
| 0.999996 |
Sample of mucus from both halves were immersed in glutaraldehyde 2.5%, and placed in properly identified separate containers for storage at 4°C for later Scanning Electron Microscope (SEM) studies. The epithelial tissue was carefully dissected and separated from the palate musculature. Samples of the palate tissue from each half were sectioned, frozen in liquid nitrogen and stored at -80°C for gelatinase zymography studies.
|
15357881_p13
|
15357881
|
Tissue and mucus samples collection
| 4.104688 |
biomedical
|
Study
|
[
0.9995524287223816,
0.00022828673536423594,
0.0002193005639128387
] |
[
0.9955689311027527,
0.003882448887452483,
0.0004108856664970517,
0.00013776923879049718
] |
en
| 0.999996 |
Samples of tissue, as well as mucus, were taken out of the freezer and ground to a powder in a mortar and pestal. Liquid nitrogen was added to keep the samples frozen. Homogenizing buffer (KCl 100 mM, ZnCl 2 0.5 mM, EDTA 10 mM, Tris-HCl 1 M, pH 6.8) was added to the ground samples (approximately 500 ul buffer per 10 mg tissue sample, 200 buffer per 10 mg mucus sample) that were sonicated for 30 seconds on ice and then centrifuged at 8000 rpm for 5 minutes at 4°C. The supernatant was collected for protein assay (BCA protein assay kit, Pierce). Normalizing the protein content as 5 μg, different amount of samples were loaded into the 7.5% separating zymography gel (30% acrylamide/ 0.8% bisacrylamide 3.75 ml, 4 × Tris-Cl/ SDS, pH 8.8 3.75 ml, H 2 O 6 ml, 2% gelatin A 1.5 ml, 10% ammonium persulfate 0.1 ml, TEMED 0.01 ml, for 4 gels) and were run at 100 volts for 20 minutes, 150 volts for 40 minutes. After electrophoresis, the gel was washed 3 times (20 minutes per a time) in 2.5% Triton X-100 at room temperature followed by incubation for 96 hours in zymography development buffer (0.15 M NaCl, 5 mM CaCl 2 , 0.05% Azide NaN 3 , 50 mM Tris-HCl pH 7.6). The gel was then stained for 2 hours with stain solution (Coomassie brilliant blue R-250 1 g/L, methanol: acetic acid: H 2 O= 2.5: 1: 6.5) followed by de-staining (ethanol: acetic acid: H 2 O= 1: 2: 22) overnight. The expression of the gelatinases was shown on the gel as clear bands against the dark background stained with Coomassie blue. The bands were compared with the gelatinase standards for MMP 2 and 9 running in the first lane of each gel. The density of the gels was measured in the Bio-Rad scanning densitometer.
|
15357881_p14
|
15357881
|
Zymography
| 4.194807 |
biomedical
|
Study
|
[
0.9994605183601379,
0.00035118087544105947,
0.00018824175640475005
] |
[
0.9982072114944458,
0.0012063647154718637,
0.00048104222514666617,
0.00010530115105211735
] |
en
| 0.999998 |
Samples of mucus and tissue were placed in 2.5 % glutaraldehyde solution immediately after collection and stored at 4°C until processing. The samples were post-fixed in 1 % osmium tetraoxide in Milonig's buffer at room temperature for one hour. They were then washed in a series of ethanol (50 – 100 %), ten minutes at each step, followed by two additional periods of absolute ethanol (10 minutes each). The samples were further dehydrated by critical point drying at 31°C for 5 – 10 minutes, then mounted on a specimen holder for SEM and dried overnight in vacuum desiccators. In the final stage of preparation for viewing, the samples were sputter coated with gold (Edwards, model S150B Sputter Coater). Samples were viewed using SEM . Images were scanned directly to a computer and stored as image files for subsequent viewing and analysis.
|
15357881_p15
|
15357881
|
Scanning electron microscopy
| 4.141361 |
biomedical
|
Study
|
[
0.9991230368614197,
0.0005580328870564699,
0.0003189670678693801
] |
[
0.9450006484985352,
0.05254151672124863,
0.0018311060266569257,
0.0006267543649300933
] |
en
| 0.999997 |
Data are expressed as mean ± standard deviation unless otherwise stated. A paired Student-T test was used for simple comparison. The level of significance was set at 5 %.
|
15357881_p16
|
15357881
|
Statistical analysis
| 2.513731 |
biomedical
|
Study
|
[
0.9974426031112671,
0.0004761941381730139,
0.0020812370348721743
] |
[
0.6739775538444519,
0.32245638966560364,
0.0024498142302036285,
0.0011162509908899665
] |
en
| 0.999996 |
The modified fresh frog palate exposure model was relatively easy to prepare and practical to handle. On gross examination, the surface of the palate exposed to side stream tobacco smoke did not show any macroscopic change in appearance after cigarette smoke exposure (CSE) compared to the control halves maintained in the normal chamber.
|
15357881_p17
|
15357881
|
Results
| 2.783902 |
biomedical
|
Study
|
[
0.9959872364997864,
0.0007094114553183317,
0.0033032787032425404
] |
[
0.9663054943084717,
0.03264116123318672,
0.0005660598981194198,
0.0004873509460594505
] |
en
| 0.999999 |
One half of the palate was used as a control and the other half was exposed to cigarette smoke. Baseline mucus transport velocity( MTV ) was measured in both half palates prior to exposure of one half palate to cigarette smoke, and were identical (19.5 ± .03 mm/sec). Two additional MTV determinations were carried out in the control half after one and four cigarettes and after 24 h period of recovery during which time the palate was kept at 4°C. A paired T-test showed no statistical difference in mucus transport velocity among the control measurements during the entire experiment .
|
15357881_p18
|
15357881
|
Results
| 4.129352 |
biomedical
|
Study
|
[
0.9992523789405823,
0.0003808814799413085,
0.00036682147765532136
] |
[
0.999477207660675,
0.0002114174421876669,
0.00025675856159068644,
0.000054625572374789044
] |
en
| 0.999997 |
A paired T-test of MTV on the control half compared to the exposed half showed that mucus transport velocity in the exposed half palate was reduced (p < 0.03) immediately after exposure to the side stream smoke of one cigarette compared with the non-exposed half palate. Further exposure to the side stream smoke of three more cigarettes (4 in total) significantly reduced MTV (p < 0.001), with no signs of recovery after 24 hours.
|
15357881_p19
|
15357881
|
Results
| 4.107984 |
biomedical
|
Study
|
[
0.9992683529853821,
0.00043616117909550667,
0.0002954920055344701
] |
[
0.9993529915809631,
0.0002566955517977476,
0.0003230648871976882,
0.00006717725045746192
] |
en
| 0.999997 |
We obtained a sample of mucus from the half palate exposed to four cigarettes and used it on the control half palate to measure MTV. Clearance was within the normal range. Immediately after, the same sample of mucus was tested on the exposed half palate and mucus clearance was again seen to be very slow. Mucus transport had basically ceased in some areas of the tobacco-smoke exposed palate.
|
15357881_p20
|
15357881
|
Results
| 3.58512 |
biomedical
|
Study
|
[
0.9987640380859375,
0.0006578314932994545,
0.0005781325744464993
] |
[
0.9946714043617249,
0.004667829722166061,
0.00029602317954413593,
0.0003646620607469231
] |
en
| 0.999998 |
Scanning electron microscopy (SEM) studies to assess the integrity of the epithelium after exposure to side stream smoke of one cigarette showed areas where the layer of cilia looked disordered. However, we did not see loss of cilia or exfoliation of ciliated epithelial cells after careful examination under the SEM in lower and high power of the entire surface of the sample after this level of exposure.
|
15357881_p21
|
15357881
|
Results
| 3.798206 |
biomedical
|
Study
|
[
0.9992846846580505,
0.0002625372726470232,
0.0004528476274572313
] |
[
0.9936137795448303,
0.005860847886651754,
0.0003031152591574937,
0.00022223408450372517
] |
en
| 0.999999 |
In Figure 4 , SEM images from palates exposed to the smoke of four cigarettes showed greater epithelial tissue disruption (panels 2 and 3) compared to a control palate (panel 1). Large areas of deciliated cells were observed, as well as exfoliation of intact ciliated cells. Examples of exfoliated cells found on the surface of the epithelium in the representative SEMs are indicated with black arrows. Morphometric analysis of the area of cilia loss from 3 paired palates exposed to four cigarettes, evaluating 12 different areas randomly selected in each palate, showed cilia loss of 51 ± 14 % compared to < 2 % on control palates.
|
15357881_p22
|
15357881
|
Results
| 4.1287 |
biomedical
|
Study
|
[
0.9993758797645569,
0.0003878377901855856,
0.00023638049606233835
] |
[
0.9994021654129028,
0.0002336665929760784,
0.00028687427402473986,
0.0000772319981479086
] |
en
| 0.999995 |
Gelatinase zymography showed increased activity of MMP-9 in mucus collected from the palates exposed to tobacco smoke of four cigarettes compared to mucus from control palates as shown in Figure 5 . MMP2 activity was not different in mucus samples obtained from palates exposed, or not to cigarette smoke, but these results are inconclusive.
|
15357881_p23
|
15357881
|
Results
| 4.008997 |
biomedical
|
Study
|
[
0.9995044469833374,
0.0002017239312408492,
0.00029386705136857927
] |
[
0.9993177652359009,
0.0004348198417574167,
0.00018699256179388613,
0.00006036644845153205
] |
en
| 0.999997 |
Major findings in this study include: a) our amphibian mucociliary clearance model appears to be appropriate to study the early effects of tobacco smoke exposure; b) the clearance of mucus is significantly reduced after exposure to side stream tobacco smoke associated to dose response; c) ciliated cells are anatomically and physiologically acutely affected therefore drastically impairing mucus clearance. Acute irritation and inflammation of cilia due to exposure to tobacco smoke could explain this alteration; d) mucus seems to not be physiologically affected at this stage; and e) tobacco smoke triggers an increased activity of matrix metalloproteinases (in particular MMP9) associated with disruption of the extracellular matrix, most likely affecting cellular attachments to the basal membrane generating a substantial exfoliation of the ciliated cells.
|
15357881_p24
|
15357881
|
Discussion
| 4.209503 |
biomedical
|
Study
|
[
0.9995054006576538,
0.00028453004779294133,
0.00021009163174312562
] |
[
0.9993183612823486,
0.0001839993492467329,
0.00043322794954292476,
0.0000644213505438529
] |
en
| 0.999998 |
These findings might assist us in enhancing the knowledge of the changes in the mucociliary apparatus that occur early after exposure to environmental tobacco products, with the goal to understand how these changes relate to the development of chronic airway pathologies in humans.
|
15357881_p25
|
15357881
|
Discussion
| 3.243414 |
biomedical
|
Study
|
[
0.9987407326698303,
0.0002503868017811328,
0.0010088629787787795
] |
[
0.672748327255249,
0.3177761435508728,
0.008448920212686062,
0.0010265731252729893
] |
en
| 0.999998 |
The frog palate has been used for several decades as a model to assess mucociliary clearance . Different species of frogs have also been used, as well as a variety of study designs. Researchers had to deal with several sources of variability, making it difficult to standardize a widely acceptable model. There are disadvantages in our model such that it pertains to a non-mammalian species, in addition that the epithelial tissue is non-respiratory. However as a model it has advantages over some mammalian models like rodents in that the ciliated epithelium has a well developed mucus blanket that work in coordination with cilia similar to the human situation.
|
15357881_p26
|
15357881
|
Discussion
| 3.757787 |
biomedical
|
Study
|
[
0.9989603757858276,
0.00012629498087335378,
0.0009132968843914568
] |
[
0.875471830368042,
0.09414030611515045,
0.02992110513150692,
0.0004668035835493356
] |
en
| 0.999995 |
This exposure model is an isolated system, theoretically free of interferences from other agents or systemic physiological responses resulting from other internal or external influences. In this injury model we randomly exposed either half palate to side stream tobacco smoke and used the opposite half palate as the control (internal control). Since there was no statistical difference in mucus transport between them, previously established in different sets of pairs of palates, one side was arbitrarily selected for control and the opposite half for exposure to tobacco smoke. This study follows an approach utilized previously by Zayas et al that compared samples of mucus obtained from both mainstem bronchi in smokers and in nonsmokers.
|
15357881_p27
|
15357881
|
Discussion
| 4.044037 |
biomedical
|
Study
|
[
0.9994155168533325,
0.0002117548865498975,
0.000372772483387962
] |
[
0.999546229839325,
0.00022229492606129497,
0.00018762021500151604,
0.0000437431299360469
] |
en
| 0.999998 |
In assessing the mucus transport rate in both half palates before any experimental procedure and to insure that they functioned identically, we established baseline data for our experiment. This helped to reduce error variability due to sex, weight, age, as well as control for any seasonal effect on the mucus transport rate in the frog palates as demonstrated by Rubin et al .
|
15357881_p28
|
15357881
|
Discussion
| 3.802052 |
biomedical
|
Study
|
[
0.9991162419319153,
0.00019481670460663736,
0.0006889560609124601
] |
[
0.9983240962028503,
0.0013637450756505132,
0.00024953519459813833,
0.00006261679664021358
] |
en
| 0.999996 |
Since the palate is excised from the frog we may assume that any observed effect or response is a local and direct effect of exposure to side stream tobacco smoke, which is an advantage of our model. From the data obtained, we would conclude that our frog palate exposure model is suitable to study the acute effects of second hand tobacco smoke.
|
15357881_p29
|
15357881
|
Discussion
| 2.731903 |
biomedical
|
Study
|
[
0.9945970773696899,
0.00044747497304342687,
0.004955409560352564
] |
[
0.9541812539100647,
0.044584792107343674,
0.0008498241077177227,
0.0003842201258521527
] |
en
| 0.999997 |
We may also conclude that clearability of mucus seems not to be altered at this stage, at this level of exposure and in this particular exposure preparation or design. Therefore, at this stage mucus transport seems not to be functionally affected for being cleared in a normal fashion by non-exposed cilia. However, after more prolonged tobacco exposure there will be modifications in mucus properties, as seen and measured in smoking dogs where after two months of tobacco exposure, the galactose content and the viscoelastic properties of mucus were observed to present alterations. After further exposure the viscosity and elasticity properties of mucus were reversed to quasi-normal levels, but galactose content did not . Hence the model makes it very useful for differentiation of cilia-related effects versus mucus-related effects on mucociliary clearance after acute tobacco exposure.
|
15357881_p30
|
15357881
|
Discussion
| 4.160177 |
biomedical
|
Study
|
[
0.9996011853218079,
0.0001784285850590095,
0.00022047765378374606
] |
[
0.9987096786499023,
0.00042056143865920603,
0.0008029852178879082,
0.00006670806760666892
] |
en
| 0.999995 |
Mucus clearance is a function of cilia beat frequency and mucus viscoelastic properties. A change in mucus clearance may be due to one or the other component or both. In future studies, incorporating high speed digital imaging of the palate surface to determine cilia beat frequency will allow us to further differentiate between cilia related effects versus mucus related effects.
|
15357881_p31
|
15357881
|
Discussion
| 3.702006 |
biomedical
|
Study
|
[
0.9989084005355835,
0.0001902763469843194,
0.0009013164672069252
] |
[
0.8077024817466736,
0.18483765423297882,
0.0069794608280062675,
0.0004804600030183792
] |
en
| 0.999995 |
Exposure to tobacco smoke with all its noxious agents and components will possibly allow us to separate and study in detail, the timing and appearance of different phases of the organism response. Our exposure model may allow us to individualize and study the inflammation phase resulting from the tobacco exposure. We can then focus on the injury phase occurring in the mucociliary system. Later we will explore mechanisms involved in the healing process. The remodeling of the ciliated epithelium following acute injury will be an important component of our studies and particularly how the remodeling is mediated. The time frame of the injury and recovery phases needs to be determined.
|
15357881_p32
|
15357881
|
Discussion
| 3.994411 |
biomedical
|
Study
|
[
0.999505877494812,
0.0001291152002522722,
0.00036499122506938875
] |
[
0.9955011010169983,
0.0037950663827359676,
0.0006221531657502055,
0.00008159448771039024
] |
en
| 0.999996 |
Cilia do not work alone, but in association with other cilia to produce metachronal waves. Several metachronal waves may contribute to the propulsion of the mucus layer to flow over irregularities or non-ciliated areas. Our data indicates that acute tobacco exposure may have an initial and early irritation effect, possibly mediated by an unknown mechanism on the exposed palate that leads to inhibition of ciliary beat frequency or discoordination of metachronal waves. Such factors adversely affect clearance by imposing stasis or local eddies resulting in erratic clearance that may be the reason why scanning electron micrographs of palates after one cigarette showed cilia somewhat disordered, but not visibly disrupted.
|
15357881_p33
|
15357881
|
Discussion
| 4.193348 |
biomedical
|
Study
|
[
0.9995251893997192,
0.00023127227905206382,
0.00024354342895094305
] |
[
0.9990390539169312,
0.0006093090050853789,
0.0002620965533424169,
0.00008958385296864435
] |
en
| 0.999998 |
We have shown that tobacco smoke exposure interferes with mucociliary clearance. Sustained exposure may lead to loss of ciliated epithelium associated with activation of matrix metalloproteinases. Significant loss of cilia or ciliated epithelial cells results in disruption or even cessation of mucociliary clearance. Matrix metalloproteinases may be implicated in this injury through disruption of epithelial cell-to-cell or cell-to-basement membrane connections. Further clarification of the mechanisms involved will be undertaken in subsequent studies.
|
15357881_p34
|
15357881
|
Discussion
| 4.101891 |
biomedical
|
Study
|
[
0.9995790123939514,
0.00020373117877170444,
0.00021722196834161878
] |
[
0.9984778761863708,
0.0008700137259438634,
0.000558702100533992,
0.00009341417899122462
] |
en
| 0.999999 |
Our exposure model can assess physiological, ultrastructural and molecular parameters in response to the initial deleterious effects of acute exposure to side stream tobacco smoke in an epithelial model homologous to the human airways. In these preliminary studies we did not attempt to mimic "human smoking conditions". However, our results show that MTV is affected even after exposure to one cigarette. Although concentration of smoke used in the present study is higher than likely encountered in typical environmental tobacco exposures, they are within an order of magnitude of those computed for exposure in poorly ventilated cars or homes. Future studies will try to replicate real conditions faced by non-smokers exposed to environmental tobacco smoke and to characterize the mediation and effectors of this acute injury.
|
15357881_p35
|
15357881
|
Discussion
| 4.065843 |
biomedical
|
Study
|
[
0.9995786547660828,
0.00018504535546526313,
0.0002362576051382348
] |
[
0.9994258880615234,
0.00023671446251682937,
0.00028978975024074316,
0.000047643141442677006
] |
en
| 0.999997 |
Cervical carcinoma is a leading cause of death in women of reproductive age worldwide, particularly in developing countries. While curable in early stages, the treatment results of locally advanced disease are unsatisfactory. The current standard of treatment -cisplatin-based chemoradiation- fails to cure at least 15% to 45% of bulky IB to IIIB patients, and in addition, multimodality treatment incorporating chemotherapy, surgery and radiation at its best is unlikely to substantially increase the cure rate. Because of this, the logical step to follow is the testing of molecular targeted therapies trying to improve the prognosis of cervical cancer patients .
|
15341668_p0
|
15341668
|
Background
| 3.976802 |
biomedical
|
Review
|
[
0.9964809417724609,
0.0022902279160916805,
0.001228770473971963
] |
[
0.0315023809671402,
0.0220605731010437,
0.9457168579101562,
0.0007202525739558041
] |
en
| 0.999996 |
Human papillomavirus infection is recognized as the stronger etiological factor for the development of this tumor; however, overexpression of the epidermal growth factor receptor family members is also common and seems to play an important oncogenic role . HER2 (also known as c-erbB-2) is a transmembrane receptor protein with tyrosine kinase activity that belongs to this family and it is overexpressed in a number of solid tumors. Its overexpression and prognostic significance in breast cancer led to the development and approval of the use of trastuzumab (Trastuzumab, Genentech, South San Francisco, CA), a recombinant monoclonal antibody to HER2, for the treatment of patients with metastatic breast carcinomas overexpressing HER2 .
|
15341668_p1
|
15341668
|
Background
| 4.174032 |
biomedical
|
Review
|
[
0.9991497993469238,
0.0005417127395048738,
0.0003085267962887883
] |
[
0.33988091349601746,
0.017687469720840454,
0.6411653757095337,
0.0012662559747695923
] |
en
| 0.999995 |
Until more recently, poor standardization in HER2 status evaluation precluded reliable comparison of overexpression rates in different tumors. A source of variability in results not only comes from methodological variations in tissue processing (time to fixation, duration of fixation, denaturation, heating, antigen retrieval, the staining procedure) and grading scores but also from the antibody used. This issue was addressed by Press et al., who showed extremely variable results in 187 breast cancer specimens evaluated with 7 polyclonal and 21 monoclonal antibodies . However, standardized methodologies have been introduced recently for these analyses, and have identified frequencies of 51%, 44%, 26% and 25% in Wilm's tumor, bladder, pancreatic and breast carcinoma, respectively. Other tumors tested had frequencies below 20% .
|
15341668_p2
|
15341668
|
Background
| 4.093881 |
biomedical
|
Study
|
[
0.9995396137237549,
0.00019521139620337635,
0.0002652622351888567
] |
[
0.9834254384040833,
0.00043843407183885574,
0.016022324562072754,
0.00011388562415959314
] |
en
| 0.999998 |
Before the introduction of the Hercep Test, it was known that a variable subset of cervical carcinomas ranging from 8% to 77% express HER2 as evaluated by diverse methods and that in some studies its overexpression has shown to confer a worse prognosis . Because these results on HER2 expression in cervical cancer were obtained before the standardization required in breast cancer, we wanted to investigate the expression status of HER2 using the Hercep Test in a series of cervical carcinoma cell lines, primary tumors of locally advanced cervical cancer cases and in four recurrent tumors of these patients.
|
15341668_p3
|
15341668
|
Background
| 4.067894 |
biomedical
|
Study
|
[
0.9995222091674805,
0.00026981407427228987,
0.00020805897656828165
] |
[
0.9993919134140015,
0.00023163497098721564,
0.00031502865022048354,
0.00006144398503238335
] |
en
| 0.999998 |
Thirty-five paraffin-embedded tumor tissues from patients FIGO staged as IB2 to IIIB, treated with standard radiation concurrent with weekly cisplatin. Diagnosis was made on the basis of routine hematoxilin-eosin examination under light microscopy according to the World Health Organization criteria. Tumor specimens at diagnosis were taken before any treatment was instituted whereas the tumors samples from the four recurrent cases were also taken before patients received any second line therapy.
|
15341668_p4
|
15341668
|
Tumor specimens
| 3.942102 |
biomedical
|
Study
|
[
0.9961780309677124,
0.00351890129968524,
0.00030308999703265727
] |
[
0.9967328310012817,
0.002439936390146613,
0.00033532315865159035,
0.0004919846542179585
] |
en
| 0.999997 |
DMEM culture media and Fetal Calf Serum were purchased from Gibco BRL Life Technologies (Grand Island, New York). HeLa, CasKi, SiHa and C33A carcinoma cell lines were obtained from the ATCC. The cell line ViBo established from a Mexican patient with cervical cancer was kindly provided by Dr. Monroy (FES Zaragoza, UNAM, Mexico City). Cells were grown in DMEM supplemented with 10% FCS at 37°C and 5% CO 2 . Cell lines were grown on two-chamber polysterene vessel Falcon ® (Becton Dickinson, NJ.) and subsequently formalin-fixed for 24 hrs at room temperature, then rehydrated in graded ethanol. Afterwards immunochemistry was performed as below described.
|
15341668_p5
|
15341668
|
Cell lines and reagents
| 4.033454 |
biomedical
|
Study
|
[
0.999601423740387,
0.0001553682523081079,
0.00024323217803612351
] |
[
0.9941278696060181,
0.005250699818134308,
0.0004763497272506356,
0.00014506440493278205
] |
en
| 0.999997 |
Hercep Test was performed following the manufacturer's guidelines of HER2 protein expression as follows. Sections were deparaffinized in xylene and rehydrated through graded ethanols to distilled water. The sections were immersed in Dako Epitope Retrieval Solution (10 mM citrate buffer, pH6) that had been preheated to 95°C in a water bath and then heat-treated at 95°C for 40 min. After a 20-minute cooldown period at room temperature, the sections were washed with Dako Wash Buffer, a procedure that followed every subsequent incubation. Endogenous peroxidase was blocked with Dako Blocking Buffer (0.3% hydrogen peroxide containing 15 mM sodium azide) for 5 min at room temperature. The sections were incubated with the primary polyclonal antibody, an affinity-purified rabbit antihuman HER2 antibody supplied in the kit, for 30 min at room temperature. Bound primary antibody was labeled by incubating the slides with the Dako Visualization reagent (horseradish peroxidase-labeled dextran polymer conjugated to affinity-purified goat antirabbit immunoglobulins in Tris-HCl) for 30 min. Color development was achieved with 3,3'-diaminobenzidine (DAB) for 10 min. The sections were counterstained with hematoxylin and eosin. To confirm validation of the staining run, control cell slides, which were provided in the kit and consisted of three pelleted, formalin-fixed, paraffin-embedded human breast cell lines with known HER2 positivity (MDA-231: 0; MDA-175: 1+; SK-BR-3: 3+), were also stained simultaneously. In the negative controls, the primary antibody was replaced by normal rabbit serum (Dako Negative Control Reagent) for the HER2 primary antibody. The antibody used in Hercep Test did not exhibit cross-reactivity to HER3 and HER4 in western blot analysis.
|
15341668_p6
|
15341668
|
Hercep test
| 4.23633 |
biomedical
|
Study
|
[
0.9981465339660645,
0.0015937266871333122,
0.0002597497368697077
] |
[
0.9820176362991333,
0.01605101488530636,
0.0013040915364399552,
0.0006272364407777786
] |
en
| 0.999997 |
Following the FDA scoring guidelines for breast carcinomas, only membrane staining intensity and pattern were evaluated using the 0–3+ scale as illustrated in the Hercep Test kit scoring guidelines (0 for no staining at all or membrane staining in less than 10% of the tumor cells; 1+ for only partial, weak staining of the cell membrane of more than 10% of the tumor cells; 2+ for moderate staining of the complete cell membrane in more than 10% of the tumor cells; 3+ for intense staining of the complete membrane in more than 10% of the tumor cells). The analysis was performed by a pathologist (VP-S) familiarized in the use of Hercep Test for breast cancer patients. In accordance with the Hercep Test kit guide, HER2 overexpression was assessed as negative for scores of 0 or 1+ and positive for scores of 2+ and 3+.
|
15341668_p7
|
15341668
|
Hercep test
| 4.090865 |
biomedical
|
Study
|
[
0.999131977558136,
0.0007140259840525687,
0.00015404415898956358
] |
[
0.9941752552986145,
0.004663666244596243,
0.0009453939856030047,
0.00021570714307017624
] |
en
| 0.999997 |
Amplification of Her-2/neu was evaluated using the Path-Vysion DNA Probe Kit (Vysis), which uses a dual-color probe for determining the number of copies of both Her-2/neu (orange) and the chromosome 17 centromeres (green). The kit was used following the manufacturer's instructions with a few minor modifications. Slides containing 5μ thick paraffin-embedded tissue sections of studied cervical tumor cases and a known Her-2/neu amplified breast tumor were placed on a slide warmer overnight at 58°C, followed by deparaffinization in Xilol, dehydration in 100 ethanol, and drying on a slide warmer at 45 to 50°C. Slides were then pretreated with 0.2 N hydrochloric acid for 20 minutes, followed by washes in purified water and immersion in Vysis wash buffer. They were subsequently immersed in Vysis protease solution at 37°C for 10 minutes, washed in Vysis wash buffer, and dried on the slide warmer. The slides were then immersed in 10% buffered formalin at room temperature for 10 minutes, immersed in Vysis wash buffer, and dried on the slide warmer. Sections were denatured by placing the slides in formamide for 5 minutes at 72°C followed by dehydration in 70, 85 and then 100% ethanol. Slides were then dried on a slide warmer, and 10 μl of probe was applied. They were then coverslipped, sealed and placed in a prewarmed humid incubation chamber at 37°C for 21 hours. This was followed by immersion in prewarmed postwash solution at 72°C for 2 minutes. The slides were air-dried, and a 4',6-diamidino-2-phenylindole (DAPI) counterstain was applied.
|
15341668_p8
|
15341668
|
FISH in the four recurrent cases
| 4.188051 |
biomedical
|
Study
|
[
0.9985353946685791,
0.0011606959160417318,
0.0003039338917005807
] |
[
0.9329533576965332,
0.06417615711688995,
0.0019171102903783321,
0.0009533576085232198
] |
en
| 0.999996 |
The scoring system used is described in detail in the manufacturer's instruction. A minimum of 60 nuclei were scored by each of 2 observers using a Zeiss Axioskop-2 fluorescent microscope with V.2 filter. The ratio of Her-2/neu signals (orange) to chromosome 17 centromere signals (green) was determined with ratios of <2.0 considered nonamplified and those ≥ 2.0 amplified.
|
15341668_p9
|
15341668
|
FISH in the four recurrent cases
| 4.052402 |
biomedical
|
Study
|
[
0.9994847774505615,
0.0003412506193853915,
0.00017397956980857998
] |
[
0.9943287968635559,
0.004945116117596626,
0.0005396112101152539,
0.0001865461963461712
] |
en
| 0.999997 |
The immunohistochemical expression of HER2 in the primary tumors of 35 patients at diagnosis was evaluated. Accordingly, these patients had no received any previous anticancer therapy; their mean age was 40.8 years; 5 were staged as IB2-IIA, 14 as IIB and 16 as IIIB; 31 and 4 were histologically classified as squamous and adeno/adenosquamous respectively. Overexpression of HER2 was demonstrated in only one out of 35 cases, which had a score of 3+ (not shown). The remaining cases were interpreted as negative [score of 0]. The case with HER2 overexpression at diagnosis was a 56-year old woman diagnosed with a FIGO stage IIB large cell poorly differentiated squamous cell carcinoma, who received treatment with 6 weekly courses of cisplatin concurrent with external beam radiation and brachytherapy. She is currently free of disease at 44 months of follow-up. At a median follow-up time 40 months, seven patients have relapsed.
|
15341668_p10
|
15341668
|
Results
| 4.06144 |
biomedical
|
Study
|
[
0.9859561920166016,
0.013761179521679878,
0.000282626278931275
] |
[
0.9932970404624939,
0.0025318143889307976,
0.0008797362679615617,
0.0032913496252149343
] |
en
| 0.999997 |
HER2 expression at recurrence could only be analyzed in four of these seven relapsed patients in whom whose recurrent disease was histopathologically confirmed. Two of these four tested positive with a staining intensity of 2+ and 3+ respectively, , both cases were squamous cell carcinomas and tested negative in the pretreatment surgical specimen
|
15341668_p11
|
15341668
|
Results
| 4.007003 |
biomedical
|
Study
|
[
0.9972526431083679,
0.002467841375619173,
0.00027949336799792945
] |
[
0.9982194304466248,
0.0011772923171520233,
0.00024377796216867864,
0.00035947325523011386
] |
en
| 0.999997 |
The five cervical cancer cell lines were negative.
|
15341668_p12
|
15341668
|
Results
| 2.141738 |
biomedical
|
Study
|
[
0.9898014664649963,
0.002755183493718505,
0.007443391717970371
] |
[
0.7237547039985657,
0.2691952884197235,
0.0034621800296008587,
0.0035878289490938187
] |
en
| 0.999997 |
None of the four recurrent cases tested by FISH were HER2 amplified .
|
15341668_p13
|
15341668
|
Results
| 2.685879 |
biomedical
|
Study
|
[
0.9904730916023254,
0.004764639772474766,
0.0047622364945709705
] |
[
0.9656822085380554,
0.03128764033317566,
0.001391743659041822,
0.001638371148146689
] |
en
| 0.999996 |
Molecular targeted therapies are currently being tested in a variety of tumor types with promising results. Because HER2 overexpression occurs and is related to a worse prognosis in cervical cancer, , its blockade with trastuzumab could potentially have therapeutic value. This monoclonal antibody is currently widely used in metastatic breast cancer and is being evaluated in an adjuvant setting as well as in a variety of tumor types , Based on the fact that the efficacy of this antibody is strongly associated to the level of HER2 expression in the primary tumor, the FDA approved the Hercep Test in the aim to grade the expression level so that only those patients whose tumors exhibit a 2+/3+ levels are candidates to trastuzumab therapy, though currently in most centers, tumors expression of 2+ is considered undeterminate therefore these cases are also evaluated by FISH analysis .
|
15341668_p14
|
15341668
|
Discussion
| 4.064247 |
biomedical
|
Review
|
[
0.9990532994270325,
0.0006435831310227513,
0.00030308860004879534
] |
[
0.4190211296081543,
0.0434064082801342,
0.5362651348114014,
0.0013073314912617207
] |
en
| 0.999995 |
Previous reports on cervical cancer using non-standardized methods for HER2 expression showed that up to 77% of cases express the receptor and that in general HER2 expression predominates in adenocarcinoma and adenosquamous carcinoma histologies In this work, using the Hercep Test with its corresponding guidelines for evaluation, we found contrastating results as none of the cell lines expressed HER2 and only a single tumor of squamous histology (1 out of 35) expresses this oncoprotein at a level of 3+. Such a discrepancy does not seem to be limited to this tumor type. For instances, in ovarian clear cell carcinoma a 43% of overexpression was reported utilizing systems other than Hercep Test , however, when evaluated with this standardized test, only 1 out of 17 tumors expressed 3+ . Likewise, the proportion of patients with 2+/3+ expression level of HER2 with the Hercep Test is uniformly low in tumor such as lung , colorectal carcinomas , gallbladder , and melanoma . A variety of factors such as the kind of antibody used, the technique per se, and scoring criteria may explain such phenomenon and its clarification requires further studies. A recent paper by Bellone et al., have reported that a substantially higher proportion of cervical cancer cells lines either established from fresh tumors or commercial ones (including CasKi, SiHa, HeLa and C33A which are negative by immunochemistry) express the receptor when evaluated by flow-cytometry and are growth inhibited when incubated with trastuzumab or trastuzumab plus IL-2 . These data led them to suggest the targeting the HER in cervical cancer could be more effective than the indicated by low immunohistochemical expression . However, it is largely known that in breast and more recently in lung cancer , tumor responses are almost confined to those with a 3+ level of expression. For instances, in a recent published study in 111 assessable breast cancer patients, the response rate to single agent trastuzumab for those expressing 3+ versus 2+ was 35% and 0% respectively , while in lung cancer, a phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive patients, yet there was not overall differences in response between both arms, the benefit was limited to those with 3+ of expression with the Hercep Test. Accordingly, five out of six patients with such level of expression receiving trastuzumab plus gemcitabine-cisplatin showed response . These data argue against the potential usefulness of trastuzumab in cervical cancer patients with HER expression that can only be detected by flow cytometry .
|
15341668_p15
|
15341668
|
Discussion
| 4.459792 |
biomedical
|
Study
|
[
0.9993230104446411,
0.000437404727563262,
0.0002396103518549353
] |
[
0.994466245174408,
0.0004339567094575614,
0.00492482865229249,
0.00017508272139821202
] |
en
| 0.999998 |
On the other hand, the HER2 expression in breast cancer is relatively stable, with 95% concordance between the HER2 status of primary and metastatic lesions, being rare a shift from positivity in the primary to negativity in the metastases . Conversely, 6% of breast cancer patients whose primary tumors are HER2 negative, convert to high expression (Hercep Test 3+) in their metastases . Such behavior is in line with experimental observations that receptor activation potentiates tumor cell motility, protease secretion and invasion, and also modulates cell cycle checkpoint function, DNA repair, apoptotic responses and multidrug resistance . The findings of "conversion to positive" in cells of recurrent cervical tumors showed by us and other authors strongly suggest that expression of HER2 may have a role in tumor resistance and progression as shown in experimental models, and therefore its targeting in recurrent cervical cancer could have therapeutic value.
|
15341668_p16
|
15341668
|
Discussion
| 4.265182 |
biomedical
|
Study
|
[
0.9995226860046387,
0.0002526606840547174,
0.00022467820963356644
] |
[
0.9589352011680603,
0.0008947111200541258,
0.039966896176338196,
0.00020319309260230511
] |
en
| 0.999995 |
It is remarkable the finding that none of the four recurrent cases, including the two that converted to IHC positive analyzed by FISH showed HER2 gene amplification. This result is unlikely to be a false negative as the green signal was perfectly observed in most of the cells. Previous studies in cervical cancer have shown that the frequency of gene amplification as determined by FISH is low irrespective of tumor histology. Mark et al., reported only 2 out of 23 cases amplified using the Her-2/neu FISH probe (Vysis, Inc., Downers Grove, IL) both of which were adenocarcinomas . In a more recent study looking at DNA copy number of cervical adenocarcinomas, it was found that despite more than 50% of patients had chromosome 17q copy number gains, only 9% (2 out of 22) of these tumors showed an HER-2/neu protein over-expression at the level of 2+ with the Hercep test. These findings suggest that amplification of HER-2/ neu is rare in cervical adenocarcinomas and that low level chromosome 17q copy number gains are not associated with HER-2/ neu overexpression . Such overexpression without gene amplification could result from transcriptional deregulation leading to increased receptor expression and is not a rare phenomenon in breast carcinoma .
|
15341668_p17
|
15341668
|
Discussion
| 4.293399 |
biomedical
|
Study
|
[
0.9994816184043884,
0.0003281454846728593,
0.000190329083125107
] |
[
0.9989776611328125,
0.000246971205342561,
0.0006723994738422334,
0.00010298434790456668
] |
en
| 0.999997 |
In conclusion, our study suggest that the clinical usefulness of anti-HER2 antibodies in the primary treatment of cervical cancer patients may be limited due to the low frequency of HER overexpression, nevertheless, it is desirable to further test a larger number of recurrent cervical cancer patients by IHC and FISH analyses regardless of the histological type, as a start point for clinical trials design using trastuzumab.
|
15341668_p18
|
15341668
|
Conclusions
| 4.070821 |
biomedical
|
Study
|
[
0.9992628693580627,
0.0005774655728600919,
0.00015967640501912683
] |
[
0.9985951781272888,
0.0007495380123145878,
0.0005391546874307096,
0.00011613284004852176
] |
en
| 0.999997 |
None declared.
|
15341668_p19
|
15341668
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649328336119652,
0.97890704870224,
0.0020668187644332647,
0.0013767849886789918
] |
it
| 0.999994 |
A C-B, AG-F, carried out the tissue culture work and immunohistochemical analysis; VP-S and T V-C interpreted the histological data; MC critically analyzed and participated in manuscript; CP, contribute with the clinical data; SV performed the FISH analysis; and AD-G conceived the study and wrote the manuscript. All authors read and approved the final manuscript.
|
15341668_p20
|
15341668
|
Authors'contributions
| 0.717835 |
other
|
Other
|
[
0.4666948914527893,
0.0072067538276314735,
0.526098370552063
] |
[
0.010475006885826588,
0.9860202670097351,
0.0022387460339814425,
0.0012659367639571428
] |
en
| 0.999996 |
The pre-publication history for this paper can be accessed here:
|
15341668_p21
|
15341668
|
Pre-publication history
| 1.031347 |
other
|
Other
|
[
0.013091341592371464,
0.0014214670518413186,
0.9854872226715088
] |
[
0.0015875872923061252,
0.997281551361084,
0.0006836647517047822,
0.0004471398133318871
] |
en
| 0.999998 |
Although dental problems are widespread in number and impose a large burden on society in terms of lost production, pain and suffering, and health expenditure there is a tendency to underestimate their importance due to the generally non-fatal nature of most oral diseases and complacency arising from acknowledged improvements in oral health, such as trends toward lower caries levels among children and decreased edentulism in adults. Australians spend $2.6 billion on dental services, some 5.4% of recurrent health expenditure for 1998–99 . While dental diseases are not usually life-threatening, the importance of delivering services needs to be considered in view of the repetitive and ubiquitous nature of dental problems which combine to create a large burden. For example, dental problems were ranked as the fourth most frequent illness condition, behind headache, hypertension and colds in a two week survey period , dental caries (decay) has been ranked as the highest diet-related disease in Australia in terms of both total costs and health care costs , and periodontal (gum) disease has been reported to be the fifth most prevalent health condition in Australia .
|
15345059_p0
|
15345059
|
Background
| 3.94308 |
biomedical
|
Review
|
[
0.9938634634017944,
0.0013129528379067779,
0.004823637194931507
] |
[
0.13411486148834229,
0.022213518619537354,
0.8431885242462158,
0.00048303251969628036
] |
en
| 0.999998 |
The disability-adjusted life year or DALY provides a summary measure of population health that combines information on the impact of premature death and of disability and other non-fatal health outcomes. The Australian Burden of Disease and Injury Study used the DALY approach to assess the magnitude and impact of health problems in Australia . This burden of disease methodology is designed to inform health policy in relation to the prevention and treatment of health problems. This provides a different picture to traditional approaches that take into account deaths, but not disability. However, the authors acknowledge that further work is required to refine and develop the data and methods.
|
15345059_p1
|
15345059
|
Background
| 3.65081 |
biomedical
|
Study
|
[
0.9973511695861816,
0.00030837871599942446,
0.0023403712548315525
] |
[
0.8145264387130737,
0.08830395340919495,
0.09676958620548248,
0.00040007062489166856
] |
en
| 0.999998 |
Estimates of DALYs are limited by inadequate information on the distribution of severity of disease and the course of a disease. Due to limitations in the data many of the disease models are necessarily simple and approximate, with their precision reflecting the source and nature of the data underlying the model. Also, the lack of Australian disease weights may mean that they are not completely representative of Australian societal preferences . Hence the estimates of YLD (Years Lost due to Disability) and DALYs (Disability-Adjusted Life Years) should be regarded as provisional and developmental.
|
15345059_p2
|
15345059
|
Background
| 3.674846 |
biomedical
|
Study
|
[
0.9983183145523071,
0.0002575623511802405,
0.0014242329634726048
] |
[
0.7527919411659241,
0.09741204977035522,
0.14932221174240112,
0.00047387988888658583
] |
en
| 0.999997 |
The DALY estimates for oral health in the Australian Burden of Disease and Injury Study seemed inconsistently low with other reports of the high prevalence and incidence of oral health conditions such as dental caries and periodontal disease . There are a number of specific problems associated with estimating oral health DALYs. There is a lack of recent national data on oral health. Just one national oral health survey (NOHSA) has been performed in Australia, which was conducted in 1987–88 and hence is now out of date. Data from other sources indicates that oral health status in Australia is changing, which makes it difficult to estimate disease models for caries and periodontal disease based on data from NOHSA. Sequelae need to be included in disease models, for example disease models should account for sequelae of caries such as pulpal/periapical infection. Oral health estimates need to include a fuller range of oral conditions such as cuspal fractures. Edentulism estimates were based on self-reported data, and may be under-estimates if edentulous persons are less likely to participate in population surveys of oral health. The disease models were based on assumptions regarding severity and duration of symptoms that may require quantitative confirmation and revision.
|
15345059_p3
|
15345059
|
Background
| 4.116036 |
biomedical
|
Study
|
[
0.9992420673370361,
0.0003297541115898639,
0.0004282235458958894
] |
[
0.9976091384887695,
0.00045122214942239225,
0.0018721581436693668,
0.0000675580813549459
] |
en
| 0.999997 |
The broad aims of the project were to evaluate methods used to measure the burden of disease associated with oral conditions in Australia. The specific aims were to obtain measures of burden of disease related to specific oral conditions, measure these in terms of the nature, severity and duration of symptoms, and calculate disability weights from these measures.
|
15345059_p4
|
15345059
|
Background
| 2.780001 |
biomedical
|
Study
|
[
0.99432373046875,
0.001093097496777773,
0.004583206959068775
] |
[
0.9825166463851929,
0.016578402370214462,
0.0007273160736076534,
0.00017764051153790206
] |
en
| 0.999997 |
The study was conducted using a 2-stage sampling design whereby dentists were randomly sampled from the South Australian Dental Register, randomised into one of seven equal-sized study groups and sent a mailed self-complete dentist questionnaire along with up to five self-complete patient questionnaires depending on the study group. Dentists were provided with a practitioner logbook in which to record for the first 1 to 5 adult patients (depending on study group assignment of dentist) of a random clinical day the treatment they performed and diagnosis of the oral disease or condition treated. At the conclusion of treatment the practitioner passed on a survey kit to their sampled patient(s) containing a patient questionnaire, cover letter and explanation sheet. Sampled patients completing the patient questionnaire recording basic socio-demographic characteristics and data concerning the nature, severity and duration of their symptoms. The patient questionnaires were identified using the practitioner identification number allowing linkage between the practitioner logbook data and patient questionnaire data, but maintaining the anonymity of each patient to the investigators.
|
15345059_p5
|
15345059
|
Design
| 4.060437 |
biomedical
|
Study
|
[
0.9969979524612427,
0.002279524225741625,
0.0007225428707897663
] |
[
0.9991626739501953,
0.0005209955852478743,
0.00020017975475639105,
0.00011615939001785591
] |
en
| 0.999998 |
The emphasis of the project was to obtain precise estimates of the component measures of the burden of oral disease. These are typically expressed as percentages, such as the percentage of persons or percentage of time experiencing symptoms of a given degree of severity. Taking a parameter size of 10% as a reference estimate for any given measure, in order to achieve a level of precision of 20% or less relative standard error, a minimum target sample of 225 patients was required. This would provide an acceptable minimum level of precision for estimates as low as 10% in size, and better precision for any estimates larger than 10% in size.
|
15345059_p6
|
15345059
|
Sampling and data collection
| 3.854319 |
biomedical
|
Study
|
[
0.998842179775238,
0.0006104369531385601,
0.0005473341443575919
] |
[
0.9943699240684509,
0.005272558890283108,
0.0002473163476679474,
0.0001102553796954453
] |
en
| 0.999997 |
Data were collected during 2001–2 with a primary approach letter sent initially to each dentist, followed a week later by the survey materials, with a reminder card two weeks later, and up to four follow-up mailings of survey materials to dentists who had not yet responded in order to ensure higher response rates .
|
15345059_p7
|
15345059
|
Sampling and data collection
| 1.84163 |
biomedical
|
Study
|
[
0.9317842721939087,
0.0043554226867854595,
0.06386023759841919
] |
[
0.9448237419128418,
0.05390537902712822,
0.0005878352094441652,
0.0006830494967289269
] |
en
| 0.999996 |
Dentists recorded the details of the dental conditions that patients had, and patients recorded their experience of those dental conditions. Diagnosis of dental conditions was collected from dentists using an open-ended question in the dentist questionnaire and coded using the coding scheme adopted in the Longitudinal Study of Dentists' Practice Activity . Data on dental conditions in both the practitioner logbook and patient questionnaire were collected for the main dental condition that was currently being treated, another dental condition being treated besides the main condition, and for dental conditions that were not currently treated. In the patient questionnaire, patients were asked if the dental conditions had caused problems in each of six health state dimensions, the severity of the problem (prevalence and percent of time that problems were experienced in relation to each health state dimension) and duration of problems in each dimension. The six health state dimensions were: mobility (e.g, walking about), self-care (e.g, washing, dressing), usual activities (e.g., work, study, housework, family or leisure), pain/discomfort, anxiety/depression and cognition (e.g, memory, concentration, coherence, IQ). They were measured using the European Quality of Life indicator or EuroQol (EQ-5D+) instrument . The EuroQol measures each of these six dimensions according to a 3-level response grading from 1 = no problems, 2 = some / moderate problems and 3 = extreme problems.
|
15345059_p8
|
15345059
|
Data items
| 4.069228 |
biomedical
|
Study
|
[
0.9938410520553589,
0.005446069408208132,
0.0007128723082132638
] |
[
0.9984707236289978,
0.0007423022761940956,
0.0005939873517490923,
0.0001929719146573916
] |
en
| 0.999997 |
Following descriptive analysis of response rates and characteristics of respondents, the distribution of dental conditions was examined for the 11 most common dental conditions. These dental conditions were then examined in terms of the nature, severity and duration of each condition. Disability weights were then calculated for each dental condition by using a health state valuation algorithm based on UK population data . A patient could have more than one dental condition and hence have more than one disability weight. This initial disability weight was then adjusted by multiplying the coefficients from the health state valuation by the percentage of time affected by the problem. A final adjustment to the disability weights was performed by subtracting the intercept term from the health state valuation equation from the disability weight that had been adjusted by the percentage of time affected by the problem (see appendix 1: additional file 1 for details), as there was some conjecture as to how such an intercept term should be interpreted . For each type of disability weight (i.e., unadjusted and adjusted) a dental condition-specific weight was calculated as the average of the weights for each patient that had reported having that specific dental condition. Results are reported adjusted for the survey design effect of clustering of patient observations within the primary sampling unit of dentists . Disability weights were also calculated using the multiplicative EQ-5D+ regression model from the Australian Burden of Disease and Injury Study as a form of cross-validation of the approach (see appendix 2: additional file 1 for details).
|
15345059_p9
|
15345059
|
Data analysis
| 4.096123 |
biomedical
|
Study
|
[
0.9990466237068176,
0.0006671521114185452,
0.0002861812827177346
] |
[
0.9993112087249756,
0.00023670717200729996,
0.000375281524611637,
0.00007683994772378355
] |
en
| 0.999999 |
A total of 378 dentists responded to the survey (response rate = 60%). Response rates between study groups ranged from 49% to 70% and tended to be higher in study groups that required dentists to sample less patients, but the effect was not monotonic (Table 1 ). Data were available for 375 patients from the patient questionnaire, comprising a response rate of 72% of patients sampled, with response rates between study groups ranging from 69% to 92%.
|
15345059_p10
|
15345059
|
Response
| 2.511572 |
biomedical
|
Study
|
[
0.9803438186645508,
0.0043570538982748985,
0.015299178659915924
] |
[
0.9968608617782593,
0.0027940382715314627,
0.00019794753461610526,
0.0001471874420531094
] |
en
| 0.999998 |
The characteristics of patients are presented in Table 2 where data from private general practice and Australian population estimates are presented for comparison. The majority of patients were female (59.5%), born in Australia (75.5%), had dental insurance (64.8%) and had visited a dentist in the last 12 months (65.3%). The main reason for dental visiting was for other dental problems not involving relief of pain (46.7%), followed by check-ups (35.2%) and emergency visits involving relief of pain (18.1%).
|
15345059_p11
|
15345059
|
Characteristics of patients
| 2.337743 |
biomedical
|
Study
|
[
0.9261140823364258,
0.06907273083925247,
0.0048132059164345264
] |
[
0.9819484353065491,
0.01431188639253378,
0.0009627589024603367,
0.0027768574655056
] |
en
| 0.999996 |
The distribution of dental conditions is presented in Fig 1 for the 11 most common conditions. Recall/maintenance (26.7%) and caries (23.7%) were the most common conditions followed by tooth fracture (18.4%), failed restorations (14.9%), pulpal infection and denture problems (both 12.3%), and periodontal disease (11.2%). Further analysis assumes zero disability weights for the conditions of recall/maintenance care and oral hygiene conditions due to the lack of symptoms associated with them, and therefore excludes each of these conditions from further consideration.
|
15345059_p12
|
15345059
|
Dental condition
| 3.563847 |
biomedical
|
Study
|
[
0.9983185529708862,
0.001177611411549151,
0.0005038745584897697
] |
[
0.998140811920166,
0.0014070250326767564,
0.00028877449221909046,
0.00016334690735675395
] |
en
| 0.999998 |
Dental conditions are presented in Table 3 by health state dimensions and duration. A high percentage of patients reported problems (defined as level 2 = some/moderate or level 3 = extreme) with the dimension of pain or discomfort for problems such as pulpal infection (63%), dentinal sensitivity (55%), tooth wear (40%), caries and denture problems (both 38%) and tooth fracture and periodontal disease (both 35%). A high percentage of patients also reported problems with the dimension of anxiety or depression for problems such as periodontal disease (32%), tooth wear (30%) and dentinal sensitivity (27%). The percentage of time affected by dental conditions was generally high for most dimensions for dental conditions such as caries, tooth fracture, and denture problems, and for the dimensions of pain or discomfort and anxiety or depression for dental problems such as failed restoration, periodontal disease and pulpal infection. Aesthetics had the longest duration among dental conditions, however aesthetic problems comprised relatively low percentages of total conditions . Among the more common conditions caries and denture problems had long durations (ranging between 66 and 81 weeks).
|
15345059_p13
|
15345059
|
Dental conditions by health state dimensions and duration
| 4.149803 |
biomedical
|
Study
|
[
0.9978281855583191,
0.0018099246080964804,
0.00036189291859045625
] |
[
0.9986400008201599,
0.00039827771252021194,
0.0008275278378278017,
0.00013426241639535874
] |
en
| 0.999996 |
Unadjusted disability weights derived from the additive model (DW a ) were highest for pulpal infection, dentinal sensitivity and caries, followed by denture problems, periodontal disease, tooth wear and tooth fractures (Table 4 ). When adjusted by the percentage of time that dental conditions were experienced all disability weights (DW b ) were reduced. Pulpal infection remained the highest adjusted disability weight, followed by caries and dentinal sensitivity, followed by denture problems, periodontal disease and failed restorations. Subtracting the intercept from the unadjusted disability weight reduced all weights (DW c ) by a constant amount.
|
15345059_p14
|
15345059
|
Dental conditions by disability weights
| 4.071021 |
biomedical
|
Study
|
[
0.9989725351333618,
0.0006212674197740853,
0.00040621048538014293
] |
[
0.9991471767425537,
0.0003664175164885819,
0.0004121147794649005,
0.0000742510164855048
] |
en
| 0.999999 |
The disability weights derived from the multiplicative model are presented in Table 5 . The unadjusted disability weights derived from the multiplicative model (DW d ) followed a similar rank order as for the unadjusted disability weights derived from the additive model (DW a ), being highest for pulpal infection with caries ranked second-highest, but with some re-ordering of the next highest conditions (i.e., denture problems were ranked second rather than fourth, while dentinal sensitivity was ranked fourth rather than second, then followed in the same order by periodontal disease and tooth wear). When adjusted by the percent of time that dental conditions were experienced all disability weights derived from the multiplicative model (DW e ) were reduced, with pulpal infection ranked highest, followed by caries, dentinal sensitivity, denture problems, tooth wear and periodontal disease.
|
15345059_p15
|
15345059
|
Dental conditions by disability weights
| 4.096553 |
biomedical
|
Study
|
[
0.9989539384841919,
0.00044907399569638073,
0.0005969652556814253
] |
[
0.9993483424186707,
0.00030847889138385653,
0.0002953852526843548,
0.00004783461190527305
] |
en
| 0.999998 |
The final adjusted disability weights derived from the additive (DW c ) and multiplicative (DW e ) models were similar in rank ordering, with pulpal infection, caries, dentinal sensitivity and denture problems ranked highest. While the adjusted disability weights derived from both models were also similar in magnitude those derived from the additive model were lower for all oral conditions except aesthetics, which was identical for both models. In the remainder of the paper the final adjusted disability weights derived from the additive model (DW c ) will be presented, as this provided the most conservative estimate.
|
15345059_p16
|
15345059
|
Dental conditions by disability weights
| 3.801553 |
biomedical
|
Study
|
[
0.9986153841018677,
0.0004369491070974618,
0.0009477552957832813
] |
[
0.9988683462142944,
0.0006278598448261619,
0.00044501619413495064,
0.00005887362567591481
] |
en
| 0.999994 |
The disability weights for oral conditions are presented in Table 6 along with the weights for oral conditions from the Australian Burden of Disease and Injury Study . Comparing edentulism with denture problems shows a higher disability weight in the Burden of Oral Disease Study estimate. For periodontal disease the disability weight estimate from the Burden of Oral Disease Study was higher. For caries, the disability weight was higher for the Burden of Oral Disease Study estimate than either of the two estimates for caries from the Australian Burden of Disease and Injury Study.
|
15345059_p17
|
15345059
|
Comparison of disability weights
| 3.148271 |
biomedical
|
Study
|
[
0.9962363839149475,
0.0007188857416622341,
0.003044770797714591
] |
[
0.9969160556793213,
0.0025226690340787172,
0.0004596613289322704,
0.00010164455306949094
] |
en
| 0.999997 |
The disparity in disability weights for oral health conditions between the Australian Burden of Disease and Injury Study and the Burden of Oral Disease Study is examined further in Table 7 , which compares the assumptions for oral health disability weights by source. Comparing edentulism estimates with those for denture problems shows a slightly higher estimate for percentage of time affected and a more marked difference in percentage of cases affected in the Burden of Oral Disease Study estimates. For periodontal disease the estimates from the Burden of Oral Disease Study are higher for both percentage of time and percentage of cases. For caries, estimates of percentage of time and duration for moderate pain and moderate anxiety were both higher for the Burden of Oral Disease Study, as was the estimate for extreme pain.
|
15345059_p18
|
15345059
|
Comparison of disability weights
| 4.079521 |
biomedical
|
Study
|
[
0.9985975623130798,
0.00040152447763830423,
0.0010009414982050657
] |
[
0.9991801381111145,
0.0002867859147954732,
0.0004909579292871058,
0.00004210692350170575
] |
en
| 0.999997 |
For comparison purposes the disability weights for oral conditions are presented in Table 8 along with a range of weights for other health conditions from the Australian Burden of Disease and Injury Study classified into disability classes . Some oral conditions such as dental aesthetics have very low weights, (e.g., 0.002). Conditions such as tooth wear and tooth fracture had weights comparable with moderate anaemia. Denture problems, failed restorations and periodontal disease were lower but comparable with the weight for mild asthma. Dentinal sensitivity and caries were comparable with the weight for an episode of influenza. Pulpal infection, which had the highest weight of all oral conditions, had a weight comparable with acute sinusitis and lower than other conditions such as severe anaemia and gastroenteritis.
|
15345059_p19
|
15345059
|
Comparison of disability weights
| 3.762493 |
biomedical
|
Study
|
[
0.9972102046012878,
0.0007909233099780977,
0.00199893512763083
] |
[
0.9978433847427368,
0.0013817865401506424,
0.0006925532943569124,
0.00008229056402342394
] |
en
| 0.999997 |
Response rates to the survey were adequate for both the dentist and patient questionnaires . Comparison of respondents against estimates for private general practice and the Australian population indicated a slightly higher percentage of female patients compared to the population consistent with higher reported visiting rates by females , but both place of birth and time since last visit was similar. While dental insurance was higher, the percentage of check-up visits was lower among patients indicating a higher percentage of dental problems for patients compared to the population. The method of sampling patients showed that response rates tended to be higher among dentists who had to sample fewer patients consistent with a lower response burden, but selection of an optimal collection methodology requires consideration of efficiency of collection as well as response rates.
|
15345059_p20
|
15345059
|
Response
| 2.992918 |
biomedical
|
Study
|
[
0.9870209097862244,
0.006344600114971399,
0.006634518504142761
] |
[
0.995324969291687,
0.004066027235239744,
0.00039091528742574155,
0.00021805903816130012
] |
en
| 0.999996 |
The burden of disease approach is grounded on the use of the DALY to quantify the burden of disease that treats 'like as like' within an information set of health conditions of individuals . While use of DALYs has been criticised on the basis of its assumptions and value judgements , Murray & Acharya argue that the widespread use of DALYs makes them a convenient tool for comparative burden of disease and cost-effectiveness analyses.
|
15345059_p21
|
15345059
|
Burden of disease approach
| 3.713861 |
biomedical
|
Review
|
[
0.993299126625061,
0.0008259729947894812,
0.0058747814036905766
] |
[
0.06326280534267426,
0.18479947745800018,
0.7511967420578003,
0.0007410348043777049
] |
en
| 0.999998 |
The EuroQol was developed as a standardised non-disease-specific instrument for describing and valuing health-related quality of life and hence represents the best method to quantify DALYs. The EuroQol is intended to complement other forms of quality of life measures and it was purposefully developed to generate a generic index of health. Any classified health state can be valued using preferences elicited from a general population , and values can be modelled from such data sets . The EuroQol is widely used internationally and reported to have adequate construct and convergent validity, but is highly skewed and has relatively poor sensitivity especially in relation to disease-based outcomes research .
|
15345059_p22
|
15345059
|
Burden of disease approach
| 4.014866 |
biomedical
|
Review
|
[
0.9942852854728699,
0.0019926975946873426,
0.003722036024555564
] |
[
0.07657379657030106,
0.3509500026702881,
0.5713346004486084,
0.0011416272027418017
] |
en
| 0.999996 |
The six dimensions of the EuroQol were used as a standardized description of health status in the development of disability weights for the Dutch Disability Weights Study . The Australian Burden of Disease and Injury Study adopted the Dutch weights where possible. While both DALYs and the EuroQol instrument have their critics, if these approaches continue to influence policy decisions as to the scope and importance of oral disease then there will be an increasing need to assess the validity of the estimates and to address any shortcomings that are identified.
|
15345059_p23
|
15345059
|
Burden of disease approach
| 2.736561 |
biomedical
|
Study
|
[
0.986506462097168,
0.0007717208936810493,
0.012721803970634937
] |
[
0.7918201684951782,
0.1785605549812317,
0.028968682512640953,
0.0006505832425318658
] |
en
| 0.999997 |
Differences in disability weights between the Australian Burden of Disease and Injury Study and this paper probably reflect a lack of quantitative data in the Dutch study related to the nature of symptoms experienced by persons with dental conditions. The data from this paper shows that many common dental conditions are associated with symptoms that on average were more severe and of longer duration than previously assumed by Stouthard et al. .
|
15345059_p24
|
15345059
|
Assumptions of disability weights
| 2.473592 |
biomedical
|
Study
|
[
0.9926844835281372,
0.000929880072362721,
0.006385595537722111
] |
[
0.9927374720573425,
0.006204940378665924,
0.0008810823201201856,
0.00017652350652497262
] |
en
| 0.999996 |
The calculation of disability weights in this paper was based on the use of EuroQol health state descriptions as in the Dutch study, but instead of using a panel approach to elicit valuations we adopted a model-based approach to estimate health state valuations for each individual response and then derive a disability weight as the average of those individual estimates. Such a model-based approach was also used as a source of validation in the original Dutch study but was not developed in detail due to the lack of an adequate statistical model at the time of development . Two strategies are recognised as ways of arriving at a link between epidemiological data and disability weights . The first one is derivation of disease-specific disability weights using health state descriptions with a disease label. The second approach, adopted in this study, is derivation of disability weights using generic descriptions of health states associated with specific diseases. In this study disability associated with oral disease was described using a generic measure (the EuroQol) valued by applying an existing formula . The advantage of this approach is the transparency of the valuation task and the use of the formula provides the facility to cover generic health states without additional valuation studies .
|
15345059_p25
|
15345059
|
Assumptions of disability weights
| 4.118671 |
biomedical
|
Study
|
[
0.9992955923080444,
0.0003566186351235956,
0.0003477272402960807
] |
[
0.9991422891616821,
0.00024680374190211296,
0.0005559960845857859,
0.00005493916978593916
] |
en
| 0.999997 |
Disability weights reflect health state valuations whereby weights are assigned to health states that are worse than ideal health. A range of methods can be used to elicit health state valuations including visual analogue scale, time trade-off and person trade-off. The visual analogue scale method uses a scale anchored by the best imaginable health state at 100 and death at 0, with respondents asked to indicate the exact point on the scale they would place a particular health state relative to the best imaginable health, death and all other health states. Time trade-off methods ask respondents to imagine choosing between the two options of remaining in a particular health state for 10 remaining years of life or be restored to perfect health but live for a shorter time. Person trade-off methods ask respondents to choose between two different programmes, one that would prevent the deaths of 100 perfectly healthy individuals and one that would prevent the onset of a particular health problem in a certain number of healthy people. While there is little agreement as to which method is most appropriate , it has been shown that visual analogue scale methods tend to give lower values for particular health states, than time trade-off methods, which give lower health state values than person trade-off methods. The additive model weights in this study were derived from a U.K. study based on valuations produced from visual analogue scale and time trade-off methods whereas the multiplicative model weights were derived from a Dutch study based on visual analogue scale and person trade-off methods . It could be argued that since the Australian Burden of Disease and Injury Study used disability weights based on person trade-off methods and this study used disability weights based on time trade-off methods that any differences between the disability weights from this study with the Australian Burden of Disease and Injury Study could reflect differences in methodology. Also, the Australian Burden of Disease and Injury Study used a multiplicative model fitted to the Dutch weights for 153 disease sequelae or stages as multiplicative multi-attribute functions were preferred for providing better fit to observed preference data than additive models . However, the final adjusted disability weights derived from the additive model produced results that were consistent with, but slightly lower than, the multiplicative model. Therefore methodological issues stemming from valuation and modelling strategies do not seem to explain the differences that were observed.
|
15345059_p26
|
15345059
|
Assumptions of disability weights
| 4.122602 |
biomedical
|
Study
|
[
0.999056875705719,
0.00036543942405842245,
0.0005776833277195692
] |
[
0.9930863380432129,
0.00047025660751387477,
0.006357764359563589,
0.00008566254109609872
] |
en
| 0.999997 |
One consideration arising from the disability weights derived in the present study was the reliance on the use of data from patients seeking care. The experience of dental problems from the perspective of a patient may be different than that from the population as a whole. If the symptoms experienced by patients were more severe compared to the general population then some further adjustment may be required to reduce the disability weights appropriately. However, it would not be right to assume that most patients attending for dental care would be symptomatic as patient-based data have shown that the majority of patients reported no problems on the six EuroQol dimensions (ranging from 69.7% for pain/discomfort to 98.6% for self-care), with 39.6% of patients reporting symptoms on one or more of the six dimensions . Conversely, patients who are unable or unwilling to seek care can be expected to have a longer duration, and perhaps severity of dental symptoms and associated health problems than subjects in this study. There is some evidence of a symptom iceberg with respect to oral and facial pain, with Canadian population data showing that less than one in two who experience such pain consult a dentist or physician . Since there are plausible arguments as to why patient-based estimates might reflect either more severe or less severe conditions the question of possible bias in a patient population remains open and perhaps could be settled by further research. An important design feature of this study was the use of dentists to diagnose the oral health conditions that were subsequently reported on by the patients. Further refinement of these disability weights could be achieved through the use of an oral health survey based on a population sample that also uses a linked questionnaire to survey the experience of oral health problems. It may also be the case that further refinements to the algorithm for estimating disability weights that incorporates the cognitive dimension may also increase the size of weights although oral health conditions related to this dimension were not as prevalent as other dimensions that were included such as pain/discomfort and anxiety/depression. The weights derived from the multiplicative model included the cognitive dimension and this may help explain why they were observed to be slightly larger than the weights derived from the additive model. Detailed prospective data would be required to evaluate whether persons report the experience of their symptoms accurately or are more influenced by the end-stage of their disease experience than by the average experience over the period of their symptoms. Generic measures such as SF-36 have been found to be less sensitive to changes in oral health and to exhibit limited construct validity in comparison to specific measures of oral health . Despite being a generic measure the EuroQol has shown discriminant validity in relation to a range of dental patient, visit and oral health measures . However, in general there can be problems assigning disability weights to diseases with high prevalence and low severity, relating to the lack of differentiation at this low end of the scale .
|
15345059_p27
|
15345059
|
Assumptions of disability weights
| 4.208452 |
biomedical
|
Study
|
[
0.9988742470741272,
0.0006847457843832672,
0.0004409730318002403
] |
[
0.9987949132919312,
0.00024065871548373252,
0.0008825802360661328,
0.00008175460970960557
] |
en
| 0.999998 |
The findings from this study indicate that oral health conditions may account for a considerably higher level of DALYs than previously thought, due to the lack of quantitative data on the nature of dental conditions. While Australia has not had another national oral health survey since the initial survey of 1987–88, there have been other studies that suggest that dental problems are common , and account for large amounts of health care costs . Further work could be done to incorporate the revised disability weights for oral health into new estimates of the burden of disease in order to estimate the impact that such revisions to the disability weights have on the number of DALYs, and how this affects the ranking of oral health problems in relation to other health conditions.
|
15345059_p28
|
15345059
|
Implications of oral health disability weights
| 3.973084 |
biomedical
|
Study
|
[
0.9988589286804199,
0.0003613532171584666,
0.0007796433055773377
] |
[
0.9992863535881042,
0.00034797447733581066,
0.0003208633279427886,
0.00004473685839911923
] |
en
| 0.999997 |
Compared to the Australian Burden of Disease and Injury Study the adjusted disability weights for oral health conditions in this study were higher for comparable oral conditions of caries (0.044 versus 0.005 for caries involving a filling and 0.014 for caries involving an extraction), periodontal disease (0.023 versus 0.007) and denture problems (0.026 versus 0.004 for edentulism). In addition there were a range of common oral health problems such as pulpal infection, failed restorations and tooth fracture that were not included in the Australian Burden of Disease and Injury Study which had relatively high disability weights. The inclusion of a fuller range of oral health conditions along with revised disability weights would result in oral health accounting for a much larger amount of disability than originally estimated.
|
15345059_p29
|
15345059
|
Conclusions
| 4.082177 |
biomedical
|
Study
|
[
0.999173104763031,
0.0003413570811972022,
0.0004855145525652915
] |
[
0.9991558790206909,
0.00028943034703843296,
0.0005056634545326233,
0.00004910337884211913
] |
en
| 0.999997 |
None declared.
|
15345059_p30
|
15345059
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649328336119652,
0.97890704870224,
0.0020668187644332647,
0.0013767849886789918
] |
it
| 0.999998 |
DSB and AJS were chief investigators on the grants obtained to fund the study. DSB performed data collection, analysis and drafting of the manuscript. AJS participated in the design and coordination of the study, and completion of the manuscript. All authors read and approved the manuscript.
|
15345059_p31
|
15345059
|
Authors' contributions
| 0.949792 |
other
|
Other
|
[
0.01522832177579403,
0.0012600586051121354,
0.9835116863250732
] |
[
0.0019350869115442038,
0.9971339702606201,
0.0005354844615794718,
0.0003954527492169291
] |
en
| 0.999998 |
Insulin-like growth factors (IGF-I and II) have a broad range of biological activities that include the stimulation of mitogenesis and differentiation, and insulin-like effects on glucose uptake and lipogenesis . These activities are modulated by a family of six binding proteins, termed the IGF-binding proteins (IGFBPs 1–6) that bind IGF-I and IGF-II with high affinity (for review see ). IGFBP-1 binds and inhibits the activity of IGF-I and IGF-II in plasma, by regulating their bioavailability . Administration of excess IGFBP-1, or overexpression of IGFBP-1 in transgenic mice, leads to glucose intolerance and hyperinsulinaemia . Meanwhile, IGFBP-1 expression can be dynamically regulated by nutritional status, increasing during fasting, malnutrition and diabetes but decreasing upon re-feeding or insulin treatment . Hepatic IGFBP-1 gene transcription is rapidly and completely inhibited by insulin , however, the signalling pathway(s) that mediates this effect is less well defined. Insulin induces multiple intracellular signalling pathways in liver. Stimulation of the small G-protein Ras leads to activation of a protein kinase cascade consisting of Raf-1, MAP kinase kinase-1, p42/p44 MAP kinases and p90Rsk, while the activation of phosphoinositide (PI) 3-kinase promotes the generation of 3-phosphoinositides that induce the activity of protein kinases such as 3-phosphoinositide dependent kinase (PDK1) and protein kinase B (PKB) . PKB subsequently phosphorylates glycogen synthase kinase -3 (GSK-3) at an N-terminal serine residue (Ser-21 on GSK-3α and Ser-9 on GSK-3β) rendering it inactive . This PKB-mediated inhibition of GSK-3 contributes to insulin activation of glycogen and protein synthesis .
|
15350195_p0
|
15350195
|
Background
| 4.804204 |
biomedical
|
Review
|
[
0.9941986799240112,
0.0034195110201835632,
0.002381906844675541
] |
[
0.15921254456043243,
0.0037996009923517704,
0.8347862362861633,
0.002201575320214033
] |
en
| 0.999998 |
Studies using inhibitors of PI 3-kinase have demonstrated a requirement for this enzyme in insulin regulation of IGFBP-1 . Indeed, overexpression of an active mutant of PKB mimics the effects of insulin on the IGFBP-1 promoter . This effect, at least in part, is mediated through the inhibition of a Thymine-rich Insulin Response Element (TIRE) that lies between residues -120 and -96 relative to the transcription start site of the human gene promoter. Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-Phosphatase (G6Pase), rate-controlling enzymes of hepatic gluconeogenesis, possess a related regulatory element within their gene promoters . Interestingly, members of the FOX(O) family of transcription factors (FKHR/FKHR-L1/AFX) have been linked to the regulation of the TIRE's found in these promoters . The expression of all of these genes, as well as the regulation of FOX(O), is inhibited by insulin through a PI 3-kinase-dependent mechanism , suggesting that a common signalling pathway is utilised by insulin to regulate these related TIREs. However, insulin regulation of IGFBP-1 but not G6Pase or PEPCK gene expression is sensitive to an inhibitor of the mammalian Target of Rapamycin (mTOR) . In addition, agents that strongly induce the MAPK pathway (e.g. phorbol esters) , as well as the protein phosphatase inhibitor okadaic acid , reduce the sensitivity of the IGFBP-1, but not the G6Pase and PEPCK promoters to insulin. Therefore, aspects of the signalling networks used by insulin to repress each of these TIRE containing promoters appear distinct. Recently, we observed that GSK-3 activity was required for both PEPCK and G6Pase promoter activity . Selective inhibitors of GSK-3 reduce PEPCK and G6Pase gene transcription without requiring the activation of PKB. Indeed, the inhibition of GSK-3 may explain some of the effects of PKB overexpression on PEPCK and G6Pase gene expression. However, it was not clear why inhibition of GSK-3 should repress these promoters, whether inhibition of GSK-3 was actually required for insulin regulation of the genes, and whether the effect of GSK-3 inhibition was mediated through the TIRE.
|
15350195_p1
|
15350195
|
Background
| 4.743473 |
biomedical
|
Study
|
[
0.9987637996673584,
0.0007953605381771922,
0.00044083368266001344
] |
[
0.9962899684906006,
0.0007651422056369483,
0.0025502368807792664,
0.00039463446591980755
] |
en
| 0.999997 |
In the present study, we have examined the role of GSK-3 in the regulation of a third TIRE-containing gene promoter, namely IGFBP-1. We demonstrate that four different classes of inhibitors of GSK-3 can mimic the action of insulin and reduce IGFBP-1 gene expression. Furthermore, we find that inhibition of GSK-3 reduces the activity of a heterologous promoter containing the IGFBP-1 TIRE, and propose that this mechanism underlies the repression of all three promoters by inhibitors of GSK-3. Finally, we demonstrate for the first time a requirement for inhibition of GSK-3 in the insulin regulation of the TIRE, and hence IGFBP-1 expression.
|
15350195_p2
|
15350195
|
Background
| 4.189948 |
biomedical
|
Study
|
[
0.9995211362838745,
0.00027181589393876493,
0.00020702795882243663
] |
[
0.9993744492530823,
0.00022325408644974232,
0.0003338381357025355,
0.00006846174073871225
] |
en
| 0.999997 |
Treatment of H4IIE cells with insulin completely inhibits both basal and glucocorticoid-induced IGFBP-1 gene expression. Lithium chloride, an inhibitor of GSK-3 in vivo , reduces both basal and glucocorticoid-induced IGFBP-1 gene expression . The effect of 20 mM lithium is not as complete as observed with insulin, resulting in only a 60–70% reduction of IGFBP-1 gene expression. However, treatment of H4IIE cells with the same concentration of potassium chloride has no effect on IGFBP-1 expression. The cyclophilin mRNA levels remain unchanged throughout these experiments. This highlights a role of a target of lithium ions in the specific regulation of IGFBP-1 gene expression.
|
15350195_p3
|
15350195
|
Lithium ions reduce IGFBP-1 gene expression in H4IIE cells
| 4.185631 |
biomedical
|
Study
|
[
0.9995648264884949,
0.00020633410895243287,
0.00022875638387631625
] |
[
0.9992539286613464,
0.0003165308735333383,
0.00037166496622376144,
0.000057842302339849994
] |
en
| 0.999998 |
SB 214763 and SB 415286 are cell-permeable maleimide compounds that selectively inhibit GSK-3 . Treatment of H4IIE cells with either compound reduces IGFBP-1 gene expression . Expression is more sensitive to SB 214763 than SB 415286 (consistent with its lower IC-50 towards GSK-3 in vitro ). Importantly, cyclophilin mRNA levels remain unchanged in the presence of these compounds. Furthermore, under these conditions the regulatory phosphorylations of PKB and FOXO-1 are unaffected by SB214763, SB415286 or lithium . In addition, SB214763 or SB415286 do not affect the phosphorylation of Ser-9 (GSK-3β) or Ser-21 (GSK-3α). Similarly, MAPK and S6K activity are not significantly affected by these compounds, as judged by the phosphorylation status of these insulin-regulated signalling molecules . Hence, the effects seen with these compounds on IGFBP-1 are likely to be due to the inhibition of GSK-3 rather than as a consequence of down/up-regulation of PKB, FOXO-1, MAPK or the mTOR pathway, which are known to effect IGFBP-1 gene expression.
|
15350195_p4
|
15350195
|
More selective inhibitors of GSK-3 also reduce IGFBP-1 gene expression
| 4.392503 |
biomedical
|
Study
|
[
0.9993695616722107,
0.0003967070661019534,
0.00023377398611046374
] |
[
0.998794436454773,
0.00041832178249023855,
0.0006817528628744185,
0.00010540973744355142
] |
en
| 0.999996 |
Paullones are a family of benzazepinones that are potent (IC50; 20–200 nM), ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) and the closely related neuronal CDK5/p25 . Subsequently, they have been shown to be very potent inhibitors of GSK-3β . Two members of this family, kenpaullone and alsterpaullone, reduce IGFBP-1 gene expression in a dose dependent manner . Alsterpaullone is much more potent than kenpaullone, reducing IGFBP-1 mRNA levels by 90% at 5 μM compared to a 50% reduction seen with 10 μM kenpaullone . Once more, this is consistent with the lower IC50 of alsterpaullone toward GSK-3 in vitro . Alsterpaullone (like the maleimides) does not affect the phosphorylation of PKB, FOXO-1, MAPK, S6K or S6 . Similarly, phosphorylation at residues Ser-9 (GSK-3β) and Ser-21 (GSK-3α) of GSK-3 is unaffected by alsterpaullone treatment . Phosphorylation of Thr-308 (PKB) correlates with the activation of PKB while phosphorylation of Ser-9 (GSK-3β), Ser-21 (GSK-3α) and Thr-32 (FKHRL1) is indicative of inhibition of these PKB substrates.
|
15350195_p5
|
15350195
|
Paullones are potent inhibitors of GSK-3 that reduce IGFBP-1 gene expression
| 4.439614 |
biomedical
|
Study
|
[
0.9995806813240051,
0.00022299180272966623,
0.00019636700744740665
] |
[
0.9983793497085571,
0.0004318713035900146,
0.0010859863832592964,
0.0001026922618621029
] |
en
| 0.999998 |
Although alsterpaullone, kenpaullone, SB214763, and SB415286 are potent inhibitors of GSK-3, they also exhibit activity against CDKs. However, the aminopyrimidine CHIR99021 shows 350-fold selectivity toward GSK-3 compared to CDKs (Jenny Bain and Sir Philip Cohen, University of Dundee, personal communication), and exhibits a Ki of < 10 nM in vitro . It is the most selective inhibitor of this enzyme reported to date . Treatment of H4IIE cells with CHIR99201 dramatically reduced basal and glucocorticoid-induced IGFBP-1 gene transcription, at concentrations between 1 and 10 μM
|
15350195_p6
|
15350195
|
CHIR99021, the most specific GSK-3 inhibitor reported to date, also represses IGFBP-1 gene expression
| 4.193715 |
biomedical
|
Study
|
[
0.9996490478515625,
0.00016178451187442988,
0.00018913949315901846
] |
[
0.9979346990585327,
0.0011370531283318996,
0.0008361501968465745,
0.00009212800796376541
] |
en
| 0.999998 |
H4IIE cells were transiently transfected with a luciferase-reporter construct containing TCF/LEF binding sites, whose activity is regulated by the GSK-3 substrate, β-catenin. Inhibition of GSK-3 results in the accumulation of β-catenin in the cytoplasm where it can form complexes with TCF/LEF. The complex translocates to the nucleus and activates transcription of target genes. Treatment of transfected H4IIE cells with CHIR99021 results in a dose-dependent increase in luciferase activity, regulated by the β-catenin/TCF complex . The β-catenin mediated transcription is induced two-fold by 2 μM CHIR99021, reaching six to seven-fold at 10 μM. Therefore the concentration required to induce β-catenin activity is equivalent to that required for reduction of endogenous IGFBP-1 mRNA .
|
15350195_p7
|
15350195
|
CHIR99021 reciprocally regulates β-catenin activity and IGFBP-1 gene transcription
| 4.244058 |
biomedical
|
Study
|
[
0.9994981288909912,
0.0002842822577804327,
0.00021760433446615934
] |
[
0.9990935325622559,
0.0005091822822578251,
0.00031491179834119976,
0.0000823370210127905
] |
en
| 0.999998 |
Meanwhile, insulin treatment of H4IIE cells previously transfected with a luciferase reporter construct under the control of a thymidine kinase promoter containing the IGFBP-1 TIRE (BP-1WT), reduces luciferase expression by 60% . This effect is abolished by a two base pair mutation of the TIRE (BP-1DM5) . Interestingly, 2 μM CHIR99021 reduces BP-1 WT activity by around 50% , while 10 μM inhibits luciferase expression by 70%, with no effect on BP-1 DM5 activity. This demonstrates that CHIR99021 reduces TIRE activity, at a concentration that also induces β-catenin-mediated gene transcription (2–10 μM). This strongly argues that the effects of CHIR99021 on TIRE activity are mediated through inhibition of GSK-3.
|
15350195_p8
|
15350195
|
CHIR99021 reciprocally regulates β-catenin activity and IGFBP-1 gene transcription
| 4.22726 |
biomedical
|
Study
|
[
0.9995135068893433,
0.0002635321579873562,
0.0002229327947134152
] |
[
0.9992842078208923,
0.00033016325323842466,
0.00031434980337508023,
0.00007134372572181746
] |
en
| 0.999997 |
In order to assess the requirement for inhibition of GSK-3 in insulin regulation of the IGFBP-1 TIRE we over expressed wild-type GSK-3 (GSK-3β-WT), insulin-insensitive GSK-3 (GSK-3β-S9A) or control protein (β-galactosidase) in H4IIE cells using adenoviral vectors. Infected cells were subsequently transfected with BP-1-WT and treated with or without insulin . The inhibitory effect of insulin on the BP-1 TIRE was significantly reduced when GSK-3 was over expressed , demonstrating that inhibition of GSK-3 is required for full repression of this element by insulin. Both wild-type (p < 0.001) and S9A-GSK-3 (p < 0.001) over expression (around 3 to 5-fold increase in expression) reduced insulin regulation of this element. Meanwhile, adenoviral expression of GSK-3β-S9A also reduced the ability of insulin to repress IGFBP-1 mRNA in the H4IIE cells .
|
15350195_p9
|
15350195
|
Enhanced expression of GSK-3 reduces insulin regulation of the IGFBP-1 TIRE
| 4.19201 |
biomedical
|
Study
|
[
0.9995282888412476,
0.00026273104595020413,
0.00020899932133033872
] |
[
0.9993661046028137,
0.00023061443062033504,
0.00033623678609728813,
0.00006707698048558086
] |
en
| 0.999997 |
BP-1 TIRE activity can be regulated by co-expression of FOXO-1 . Therefore, we examined the effect of CHIR99021 on the ability of FOXO-1 to regulate TIRE activity. When FOXO-1 is co-expressed with BP-1 WT in H4IIE cells, the expression of luciferase is induced around 3-fold . Insulin inhibits this FOXO-1-induced luciferase activity, while sensitivity to 2 μM CHIR99021 is completely lost in the presence of co-expressed FOXO-1 . The concentration of FOXO-1 used is less than maximal for induction of the BP-1 WT. This data suggests that FOXO-1 overexpression desensitises the TIRE to CHIR99021 and therefore that GSK-3 does not significantly regulate FOXO-1 activity.
|
15350195_p10
|
15350195
|
CHIR99021 does not regulate FOXO-1 transactivation potential
| 4.137499 |
biomedical
|
Study
|
[
0.9994958639144897,
0.00021620321786031127,
0.0002878247178159654
] |
[
0.9994366765022278,
0.00034782543662004173,
0.00016098239575512707,
0.00005454725032905117
] |
en
| 0.999997 |
This study demonstrates that six agents, of four different chemical classes, which share an ability to inhibit GSK-3 mimic the effect of insulin on IGFBP-1 gene expression. This is reminiscent of the effect of lithium ions, SB216763 and SB415286 on two other insulin repressed gene promoters, PEPCK and G6Pase . Indeed, a heterologous promoter containing the IGFBP-1 TIRE (a related sequence is common to all three of these insulin-regulated gene promoters), is also inhibited by CHIR99021 . Similar promoter sequences are important for the insulin regulation of the tyrosine aminotransferase , aspartate aminotransferase , IRS-2 , and HMG CoA Synthase gene promoters. Our data would predict that all of these genes, and any other promoters containing a TIRE, are likely to be repressed by treatment of cells with inhibitors of GSK-3. This provides an apparent paradox since we and others have found that insulin does not regulate every TIRE-containing gene promoter by an identical mechanism. For example, insulin regulation of the IGFBP-1 (but not the PEPCK or G6Pase) gene promoter requires mTOR activity . Meanwhile, FOXO-1 is a TIRE-binding protein that has been proposed to regulate these three genes. However, cells that stably overexpress FOXO-1 show increased G6Pase but not PEPCK expression , and genetic manipulation of FOXO-1 has differential effects on these three gene promoters . These data demonstrate that distinct signalling mechanisms control the regulation of these three TIRE-containing genes. Therefore, each TIRE structure may require GSK-3 activity for function but distinct signalling networks link each gene promoter with the insulin receptor. The common requirement for GSK-3 activity suggests that a GSK-3 substrate is key for the initiation of gene transcription for each TIRE-containing promoter.
|
15350195_p11
|
15350195
|
GSK-3 activity is required for IGFBP-1 promoter activity through direct regulation of the TIRE
| 4.539369 |
biomedical
|
Study
|
[
0.9990925788879395,
0.0006248122663237154,
0.0002826285199262202
] |
[
0.998275876045227,
0.00046348245814442635,
0.001058348105289042,
0.0002023233682848513
] |
en
| 0.999998 |
Insulin induces PKB activity, promoting phosphorylation of Ser-21 of GSK-3α and Ser-9 of GSK-3β, thereby reducing total GSK-3 activity by between 20 and 80%, dependent on cell type. Therefore, expression of a mutant GSK-3β with Ser-9 replaced by alanine renders cellular GSK-3 activity insensitive to insulin . Indeed, expression of this mutant significantly reduces the ability of insulin to repress BP-1 WT , or the endogenous gene promoter , demonstrating that insulin requires to inhibit GSK-3 for full repression of this gene promoter element. Similarly, four to five fold over expression of wild-type GSK-3β antagonises insulin repression of the BP-1 WT . Although insulin will promote phosphorylation and inhibition (50–60% in H4IIE cells) of this recombinant GSK-3 in cells, the overall activity remains higher than un-stimulated control cells. This suggests that insulin must reduce GSK-3 activity below a threshold in order to fully repress BP-1 WT. This is the first demonstration of an absolute requirement for GSK-3 inhibition in insulin regulation of gene transcription.
|
15350195_p12
|
15350195
|
Inhibition of GSK-3 is required for full inhibition of the IGFBP-1 TIRE by insulin
| 4.618289 |
biomedical
|
Study
|
[
0.9991785883903503,
0.0005801261868327856,
0.00024136726278811693
] |
[
0.997412383556366,
0.0009212265140376985,
0.0013956347247585654,
0.0002707828825805336
] |
en
| 0.999997 |
The GSK-3 inhibitors regulate IGFBP-1 gene expression in the absence of regulation of PKB, MAP kinase, FOXO-1 or mTOR , known regulators of the IGFBP-1 promoter. This suggests a more direct regulation of this element, possibly of a TIRE-interacting protein itself. There are numerous transcription factors that have been proposed to be substrates for GSK-3 in vitro and in some cases in vivo (for review see ). These include β-catenin, c-jun, CREB, glucocorticoid receptor (GR) and c-myc. The phosphorylation of β-catenin , c-jun , GR and c-myc by GSK-3 promotes their destruction or reduces their activity, while the phosphorylation of CREB (at Ser-129) is thought to increase CREB activity , although this has been subsequently questioned . Since inhibition of GSK-3 reduces TIRE activity, one presumes that GSK-3 mediated phosphorylation of a TIRE-binding protein would result in its activation (although possibly a permissive effect allowing activation by an additional mechanism), nuclear localisation or stabilisation. This would seem to rule out β-catenin, c-jun, GR and c-myc in the GSK-3-mediated regulation of the TIRE. Meanwhile CREB does not bind directly to a TIRE in vitro . The only known GSK-3 substrates that have been demonstrated to bind to or regulate the TIRE are members of the CAAT-enhancer binding protein (C/EBP) family of transcription factors. GSK-3 phosphorylates C/EBPα at Thr-222/Thr-226 while C/EBPβ can regulate TIRE activity and is itself regulated by insulin . The reported regulation of C/EBPβ by insulin is PI 3-kinase and PKB-dependent but is mediated through phosphorylation of the co-regulator protein p300/CBP . We are currently examining whether the GSK-3 inhibitors regulate C/EBP and p300 phosphorylation and/or activity. Meanwhile, Granner and colleagues have found that insulin treatment of H4IIE cells increases the cellular levels of LIP (an inhibitory form of C/EBPβ that lacks the p300/CBP binding and activation domain) . LIP subsequently replaces LAP (the activating form of C/EBPβ) on the endogenous PEPCK promoter. This prevents the recruitment of RNA polymerase II and p300/CBP, eventually leading to the repression of PEPCK gene expression. However, the LIP/LAP interacting elements within the PEPCK promoter are distinct from the TIRE . Finally, our data suggests that the effect of GSK-3 inhibitors is independent of regulation of FOXO-1 , the best characterised TIRE-binding protein. Therefore, much more work will be required to identify the GSK-3 substrate that regulates this DNA element.
|
15350195_p13
|
15350195
|
What is the molecular link between GSK-3 and the TIRE?
| 4.71952 |
biomedical
|
Study
|
[
0.9989281296730042,
0.0006422291044145823,
0.0004296384868212044
] |
[
0.9969735145568848,
0.0006974638090468943,
0.0020743142813444138,
0.0002547658223193139
] |
en
| 0.999998 |
Agents that mimic the physiological processes that are regulated by insulin have the potential to be of therapeutic value for the treatment of insulin resistant states such as diabetes. Lithium chloride, SB216763, SB415286 and CHIR99021 inhibit GSK-3 and therefore mimic many of the actions of insulin. For instance, lithium chloride stimulates glucose transport and glycogen synthesis in adipocyte and muscle cell lines , while SB216763 and SB415286 stimulate glycogen synthesis in hepatocytes . Meanwhile, CHIR99021 potentiates insulin activation of glucose transport and utilisation in vitro and in vivo , and related compounds reduce muscle insulin resistance in animal models of diabetes. We have found that GSK-3 inhibitors also mimic the ability of insulin to repress key metabolic genes such as PEPCK, G6Pase and IGFBP-1 . Studies in animal models of diabetes suggest that these agents alleviate hyperglycaemia through both activation of glycogen synthesis and inhibition of hepatic glucose production . However, a vast number of biological processes are known to be regulated by GSK-3, thereby questioning their long term use as regulators of glucose homeostasis. Importantly, GSK-3 associates with and regulates proteins linked to the development of colonic cancer (APC, axin and β-catenin). Meanwhile, ablation of one of the two genes for GSK-3 (GSK-3β) in mice proved to be fatal due to increased hepatic sensitivity to TNFα-induced apoptosis . Despite all of the potential problems that may be associated with GSK-3 inhibitors, deleterious effects of such compounds in animals remain to be formally reported. Currently, GSK-3 inhibitors are being investigated for the treatment of numerous psychiatric disorders , neurodegeneration and even hair loss .
|
15350195_p14
|
15350195
|
GSK-3 inhibitors as therapeutics
| 4.582786 |
biomedical
|
Review
|
[
0.9979957342147827,
0.0012020189315080643,
0.0008022236870601773
] |
[
0.31583696603775024,
0.0019406731007620692,
0.6811513900756836,
0.0010710583301261067
] |
en
| 0.999999 |
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