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AM drafted the manuscript, performed statistical analyses and carried out the bibliography research. MS participated by coordinating and orienting the designated study. BA carried out HLA phenotyping and participated in the study design. KM recruited the eligible subjects. All authors read and approved the final version of the manuscript.
|
15331022_p18
|
15331022
|
Author's contributions
| 0.808463 |
biomedical
|
Other
|
[
0.500679612159729,
0.0060258288867771626,
0.4932945668697357
] |
[
0.01837385818362236,
0.9771192669868469,
0.0031684653367847204,
0.0013384234625846148
] |
en
| 0.999997 |
Cerebrovascular stroke is a highly prevalent condition and the major cause of language impairment in adults. Immediately following a stroke about 38% of the affected population experience aphasia . Spontaneous recovery is reported within the first six months after the event, while only minimal spontaneous improvements of language functions are expected after more than one year post-stroke . Additional rehabilitation efforts have produced beneficial effects, as reported for speech and language therapy on the basis of different performance indices . In accordance with recent progress in neurorehabilitation, which takes into account evidence of the brain's capacity for reorganization , intensive language training (several hours per week) seems to be the premise for substantial improvement of language functions in the chronic stage .
|
15331014_p0
|
15331014
|
Background
| 4.040742 |
biomedical
|
Review
|
[
0.9967478513717651,
0.0016243295976892114,
0.0016278065741062164
] |
[
0.06873004883527756,
0.0035133836790919304,
0.9272826910018921,
0.0004739152791444212
] |
en
| 0.999996 |
To date, the evaluation of impairment and recovery of function, including training-induced improvement in aphasia, has been based mainly on performance in neuropsychological tests. This is now being increasingly complemented by measures of brain function. Different mechanisms and time courses of recovery of language function after brain damage have been discussed. Hemodynamic imaging suggests the involvement of two mechanisms: (1) regression of diaschisis (reduced metabolism and function in areas connected with the damaged brain tissue, which have been cut off from essential input) and (2) functional reorganization of the neuronal networks involved in language processing. Regression of diachisis in perilesional and more distant regions have been shown to contribute to recovery of function particularly in early phases of the recovery process . In contrast, "re"-recruitment (that is, reorganization) of perilesional areas of the left hemisphere or reactiviation of left hemisphere network components predict long-term recovery of language function. Moreover, recruitment of homotopic right-hemispheric areas may contribute to language recovery when the left-hemisphere language network components are permanently impaired . However, it has been debated whether the recruitment of right hemispheric networks constitutes an additional potential for language processing or whether it is just a by-product of increased general activation. Others suggest this recruitment may even impair the recovery of left hemispheric areas, leading to a persistence of deficits .
|
15331014_p1
|
15331014
|
Background
| 4.583695 |
biomedical
|
Review
|
[
0.9966925382614136,
0.0014869722072035074,
0.0018204268999397755
] |
[
0.30878588557243347,
0.0021486287005245686,
0.6882808804512024,
0.0007845215150155127
] |
en
| 0.999998 |
Brain structures in the vicinity of structural lesions produce a larger amount of slow wave activity. This might be due to a loss of afferent input (e.g. from the lesion) or to a primary metabolic change within these perilesional areas .
|
15331014_p2
|
15331014
|
Background
| 3.188047 |
biomedical
|
Other
|
[
0.9975033402442932,
0.0004816352447960526,
0.0020150975324213505
] |
[
0.2081906944513321,
0.7874954342842102,
0.0032911202870309353,
0.0010228038299828768
] |
en
| 0.999997 |
These abnormal slow waves can be detected in the electroencephalogram (EEG) and, due to their focal generators, they can be localized using magnetic source imaging, a magnetencephalogram (MEG) based technique. In Abnormal Slow Wave Activity Mapping (ASWAM) , generators of abnormal slow waves are localized and mapped on to brain structures in order to identify areas that are active but incapable of normal function. A number of studies have demonstrated that focal slow waves indicate abnormality resulting from neurological damage such as contusions, tumors, or cerebrovascular stroke. In particular, abnormal slow wave activity in the delta-frequency range (1–4 Hz) has been found in areas adjacent to the structural lesion . Since focal slow wave activity varies with changes in metabolism and blood flow due to the insult , it has been described as characteristic of a 'dysfunctional state' of the neuronal tissue or a dysfunctional border zone with little ongoing information processing. In patients with brain tumors, this relationship between slow wave activity and metabolic changes was further elucidated by combining MEG and proton MR spectroscopic imaging . A mild reduction of N-acetyl aspartate (NAA) and slight accumulation of lactate (Lac) was found in association with sources of focal slow wave activity in the border zones of the tumors, suggesting a border zone between seriously damaged and normal tissue with potential for re-recruitment in the course of the disease.
|
15331014_p3
|
15331014
|
Background
| 4.514009 |
biomedical
|
Study
|
[
0.9994089603424072,
0.00037006899947300553,
0.00022102822549641132
] |
[
0.993996262550354,
0.0004433078574948013,
0.005364422220736742,
0.00019600376253947616
] |
en
| 0.999996 |
The mapping of abnormal slow wave activity can be used not only to identify dysfunctional neuronal networks, but also to track changes in the course of recovery or treatment. For instance, de Jongh et al. reported increased focal delta activity in the MEG before and a reduction after resection of brain tumors. The utility of 'abnormal slow wave mapping' (ASWAM) in diagnostics, recovery, or treatment evaluation may be validated by covariation with neuropsychological measures. Lewine et al. found a correlation between symptom resolution and MEG-slow wave reduction in patients with minor traumatic brain injury (TBI) and Hensel et al. reported a decrease of EEG-delta amplitude and dipole strength parallel to spontaneous recovery of language functions across the first year post stroke in aphasia patients.
|
15331014_p4
|
15331014
|
Background
| 4.092156 |
biomedical
|
Study
|
[
0.9991059899330139,
0.0003391031641513109,
0.0005548754706978798
] |
[
0.7065184116363525,
0.0018358007073402405,
0.2912680506706238,
0.0003777648671530187
] |
en
| 0.999995 |
The present study employed ASWAM before and after intensive language training in aphasic patients. If ASWAM qualifies for the evaluation of treatment or training-supported rehabilitation in chronic aphasics, changes in the intensity and distribution of focally generated abnormal slow wave activity should vary with improvement of language function after a specific intervention. Aphasics were recruited from an ongoing project evaluating the effectiveness of an intensive language training program. This program combines the learning principles of shaping and the efficacy of concentrated training while considering the principles of cortical reorganization . In order to minimize any influence of spontaneous recovery on changes in the brain-function measure, only chronic aphasics were selected to participate either in 30 hours of Constrained-Induced Aphasia Therapy (CIAT) or in 30 hours of massed model-based (MB) aphasia therapy . All training sessions were scheduled within a two-week period.
|
15331014_p5
|
15331014
|
Background
| 4.1094 |
biomedical
|
Study
|
[
0.9988694787025452,
0.0008036898798309267,
0.0003268959990236908
] |
[
0.9992679953575134,
0.000278427847661078,
0.00035504510742612183,
0.00009849716298049316
] |
en
| 0.999999 |
It was hypothesized that (a) aphasics would display an increased density of slow wave generators in the damaged (left) hemisphere before training, (b) this density would be reduced in the perilesional zone following language training and (c) there would be an improvement of language functions as evaluated by a standardized language test (Aachen Aphasia Test Battery, AAT) .
|
15331014_p6
|
15331014
|
Background
| 4.036849 |
biomedical
|
Study
|
[
0.9990605711936951,
0.0006709607550874352,
0.000268415518803522
] |
[
0.9974517226219177,
0.0019413774134591222,
0.00046372052747756243,
0.00014313939027488232
] |
en
| 0.999998 |
The average test performance of the entire patient group increased after language training, as indicated by the AAT profile (t(27) = 9.85, p < 0.0001, paired t-test, two tailed). Similar improvements were found for the Token Test (t(27) = 6.10, p < 0.0001). The average improvement of the profile score was 2.9 ± 1.3 points and 6.1 ± 5.3 points on the Token Test (T-scores). Twenty-five of the 28 patients improved on at least one subtest (N = 19) or subscale (N = 6) of the AAT.
|
15331014_p7
|
15331014
|
Language functions
| 4.094582 |
biomedical
|
Study
|
[
0.9984878301620483,
0.0006578101892955601,
0.0008544091251678765
] |
[
0.9994590878486633,
0.0001801328471628949,
0.0002975978422909975,
0.00006315856444416568
] |
en
| 0.999997 |
In 26 subjects the maximum activity of delta dipoles was found in the left hemisphere and in the vicinity of the structurally obvious lesion . In one patient, the maximum delta activity was located in the right hemisphere anterior to the homologue of the lesion, a finding consistent across measurements. (The patient had a very mild amnesic aphasia, displayed the highest AAT profile score of the entire group [63.15] and showed the least amount of delta activity.) In another subject, the maximum delta activity was located at the posterior border of a large left fronto-temporal lesion due to an ischemic infarct of the middle cerebral artery in the first measurement. After training, the maximum delta activity was found in the right-hemispheric area anterior to the homologue of the lesion. Notably, both measurements showed that this patient had clusters of delta activity next to the lesion and its right hemispheric homologue. Left hemispheric Delta Dipole Density (DDD) decreased after training and increased in the right hemisphere, which might explain the shift of peak activity to the right.
|
15331014_p8
|
15331014
|
Maximum delta activity
| 4.191769 |
biomedical
|
Study
|
[
0.9989643096923828,
0.0008181025041267276,
0.00021757587091997266
] |
[
0.9990805387496948,
0.00037857273127883673,
0.0003282554098404944,
0.00021264582755975425
] |
en
| 0.999998 |
The location of this delta focus remained stable across the two measurements . The coordinates of maximum delta dipole density were exactly the same in eleven patients, while maximum delta activity shifted by one voxel in one of the three cardinal planes in eight patients, and by more than one voxel in nine patients. (As emphasized above, one patient displayed a reversal in hemispheric lateralization after training).
|
15331014_p9
|
15331014
|
Maximum delta activity
| 3.989926 |
biomedical
|
Study
|
[
0.9986866116523743,
0.000998165225610137,
0.00031519413460046053
] |
[
0.9987152814865112,
0.0008555402746424079,
0.0002519784029573202,
0.00017726021178532392
] |
en
| 0.999998 |
Thresholds were significantly higher in the left hemisphere (F(1,54) = 49.03, p < 0.0001). Clusters of voxels with delta activity > 2 SD above the average DDD in a group of 25 healthy controls were found in 26 of the 28 patients in the left hemisphere before training. Such clusters were found in the right hemisphere in only 7 patients. In two patients only, delta activity in the right hemisphere exceeded left hemisphere activity. Average delta activity was significantly more pronounced in the left hemisphere before and after training (for the pre-measurement the main effect HEMISPHERE was F(1,54) = 55.35, p < 0.0001; for the post-measurement, F(1,54) = 46.55, p <0 .0001: Figure 2 ).
|
15331014_p10
|
15331014
|
Hemisphere-specific average delta activity
| 4.131879 |
biomedical
|
Study
|
[
0.9993100166320801,
0.0004371721879579127,
0.0002527452597860247
] |
[
0.9994756579399109,
0.00019264551519881934,
0.00025391645613126457,
0.00007782780448906124
] |
en
| 0.999996 |
Twelve patients showed an increase in left hemisphere delta activity after training, while a decrease occurred in sixteen patients . This diverging pattern became evident in the non-significant interaction TIME*HEMISPHERE (F(1,54) < 1). An increase in delta activity of the left hemisphere tended to covary with a longer amount of time since the lesion (F(1,26) = 3.69, p = 0.06).
|
15331014_p11
|
15331014
|
Hemisphere-specific average delta activity
| 4.116731 |
biomedical
|
Study
|
[
0.9991568326950073,
0.0004850999976042658,
0.00035803994978778064
] |
[
0.9995436072349548,
0.00017512279737275094,
0.0002172316744690761,
0.00006403798761311918
] |
en
| 0.999996 |
"Magnitude of change" in the left hemisphere was more pronounced in those patients who displayed significant improvement in at least one subtest of the AAT (N = 19) compared to patients with minor improvements (in at least one subscale) or no improvements (N = 9; F(1,26) = 4.95, p < 0.05). Magnitude of change of left-hemispheric delta activity varied significantly with improvements in language functions , while there was no correlation between right hemisphere magnitude of change and language measures (AAT profile: r = .-0.07; Token Test: r = 0.01).
|
15331014_p12
|
15331014
|
Changes in DDD relative to improvement of langauge functions
| 4.128144 |
biomedical
|
Study
|
[
0.9991752505302429,
0.0005698720342479646,
0.0002548698685131967
] |
[
0.9993736147880554,
0.00019953692390117794,
0.00034990994026884437,
0.00007692606595810503
] |
en
| 0.999997 |
The present results provide further evidence that Abnormal Slow Wave Activity Mapping (ASWAM) discloses generators of abnormal slow waves. The mapping of abnormal slow wave activity on to brain structures allows for the identification of areas that are active, but not capable of normal function. This is, to the best of our knowledge, the first report of a re-test after controlled neuropsychological/-linguistic intervention within the same subjects. The comparison between the two measurements indicates a high reliability of peak locations in left hemispheric perilesional areas, even though successful training modified this activity in magnitude and spatial distribution. In almost all patients, the region surrounding the structural lesion continuously and reliably produced abnormal slow waves, whereas only very few patients presented slow wave activity distant from the structurally confirmed lesion. The amount of perilesional slow wave activity was markedly altered in patients who had improved after training, and the magnitude of this change was related to the changes in language functions.
|
15331014_p13
|
15331014
|
Discussion
| 4.172863 |
biomedical
|
Study
|
[
0.9993828535079956,
0.0004219006223138422,
0.00019530497957020998
] |
[
0.9993482232093811,
0.00022093999723438174,
0.0003246570413466543,
0.000106206709460821
] |
en
| 0.999998 |
Substantial functional improvements were achieved even in chronic aphasic states by shaping procedures, constraint of non-verbal communication and massed practice. This replicates and extends the findings of Pulvermüller et al. . The present results further suggest that similar improvements can be achieved irrespective of the particular training procedures (a comparable improvement occurred in the model-based group). Both strategies might produce their effects – at least in part – by reorganizing brain regions next to a lesion. Following Liepert et al. , who demonstrated with transcranial magnetic stimulation that constraint-induced (CI) movement training of the arm expanded the area of the brain involved in generating activity in the muscles of the hand, we might assume a similar mechanism for the presently observed language improvements after intensive speech and language training in aphasics, namely an increased number of increasingly functional areas.
|
15331014_p14
|
15331014
|
Discussion
| 4.130409 |
biomedical
|
Study
|
[
0.9995074272155762,
0.0003105702344328165,
0.0001819150784285739
] |
[
0.9981786012649536,
0.0002169536310248077,
0.0015043425373733044,
0.00010020814079325646
] |
en
| 0.999998 |
In contrast, some patients, though displaying language improvement after training, exhibited an increase of delta activity in the vicinity of the lesion. One explanation for this might be that the functional capabilities of the affected brain area remain disturbed, with no further potential to be restored or re-integrated in the language 'network', and this might inhibit or impair functionally intact regions. Further segregation of these continuously dysfunctional areas from the remaining network might then lead to improved language functions and consequently to increased delta activity. This hypothesis is supported by the correlation between language improvements and either decrease or increase of delta activity in perilesional areas. Moreover, the increase of delta activity was related to longer duration of disease. In most of the patients, re-integration of 'spared' brain areas into the language network should be completed in time (in patients exhibiting an increase of slow wave activity, the time-since-lesion averaged 55.4 ± 39.3 months, compared to 35 ± 13.9 months in patients exhibiting a decrease). Therefore, "dysfunctional" delta activity might be related, at least in a subgroup of chronic patients, to functionally more favorable outcomes. The increase of delta activity might be explained by reduced reciprocal exchange of information within functionally intact and permanently impaired network components.
|
15331014_p15
|
15331014
|
Discussion
| 4.321043 |
biomedical
|
Study
|
[
0.9990697503089905,
0.0007244545849971473,
0.00020577495160978287
] |
[
0.9985641837120056,
0.00040113466093316674,
0.0008502503042109311,
0.00018446167814545333
] |
en
| 0.999996 |
Compared to the more conventional procedures for aphasia treatment in the chronic stage, the present training involved an intense use of language capabilities and a restraining of alternative, non-verbal methods of communication. In our opinion, any training that encourages speech production several hours a day over several days has the potential to be efficacious. Massed practice is likely to produce activity-dependent cortical reorganization, found to result from CI-movement therapy . It is also presumed to be the basis for a long-term increase in the amount of use of the more-affected extremity and of improved language functions following short-term intensive training.
|
15331014_p16
|
15331014
|
Conclusions
| 3.966541 |
biomedical
|
Study
|
[
0.9976092576980591,
0.001167598064057529,
0.0012231575092300773
] |
[
0.8464160561561584,
0.1260165423154831,
0.02594788558781147,
0.0016194730997085571
] |
en
| 0.999996 |
Twenty-eight patients suffering from chronic aphasia participated in the training (14 females, mean age 55 years, range 35–80 years; see Table 1 for clinical data). All patients were right-handed before brain injury, as assessed with the Edinburgh inventory . In 20 patients, aphasia resulted from left-hemispheric ischemic stroke; in 8 patients it resulted from a hemorrhage affecting left-hemispheric areas. All patients were in a chronic state as defined by a time-since-lesion > 12 months. The average duration of the time-since-lesion was 43.78 months (range 12–156 months). Structural whole-head MRI was available in 26 patients and the scans were performed within the two week training period. For the other 2 patients, a left hemisphere lesion was verified by inspection of earlier MRI examination.
|
15331014_p17
|
15331014
|
Subjects
| 4.003186 |
biomedical
|
Study
|
[
0.9835519194602966,
0.016043750569224358,
0.0004044289526063949
] |
[
0.9944003224372864,
0.002433717017993331,
0.0007470487616956234,
0.002418871270492673
] |
en
| 0.999996 |
Prior to training, aphasia was diagnosed according to guidelines of the Aachen Aphasia Test , and aphasic syndromes were classified as Wernicke (N = 4), Broca (N = 13), amnesic (N = 2) and global aphasia (N = 3). Six patients could not be classified according to the 4 syndromes given on the basis of the AAT. Aphasia was evaluated as mild (N = 11), moderate (N = 16), or severe (N = 1). Patients were recruited from the local rehabilitation centre (Kliniken Schmieder Allensbach & Konstanz) or from self-help groups, or were referred by neurologists and speech therapists.
|
15331014_p18
|
15331014
|
Subjects
| 3.758562 |
biomedical
|
Study
|
[
0.9941619038581848,
0.005197691731154919,
0.0006404833984561265
] |
[
0.9948170781135559,
0.0037424247711896896,
0.0007236581295728683,
0.0007167927105911076
] |
en
| 0.999998 |
Since this report focuses on changes in slow wave activity, principles of speech and language training and results will only be summarized (a detailed description will be provided elsewhere). Training took place 3 hours/day for 10 consecutive days and included (for 18 patients) language exercises with increasing levels of difficulty or (for 10 patients) model-based intervention (training based on the patients' functional deficit, with the main aim of gradually improving spoken word production).
|
15331014_p19
|
15331014
|
Design and procedure
| 3.241202 |
biomedical
|
Study
|
[
0.9903422594070435,
0.007586810737848282,
0.002070987829938531
] |
[
0.9576587677001953,
0.037346191704273224,
0.0033175782300531864,
0.0016775509575381875
] |
en
| 0.999997 |
The patients received only language therapy during the two-week training period to ensure that changes in slow wave activity were not induced by improvement of potential comorbid neurological impairment (e.g. hemiplegia). Language function was evaluated by two sensitive measures of change of aphasia severity: the profile score and the Token Test of the Aachen Aphasia Test . Tests were administered by trained psychologists or speech therapists one day before the onset of training and one day after the completion of training. Language function improved significantly after training in both groups (see results) regardless of the type of training (TREATMENT*TIME interaction for AAT profile: F(1,26) = .72, p > 0.3; for Token Test: F(1,26) = 3.59, p= 0.07), therefore data from the two groups were pooled for ASWAM. Training groups did not differ significantly with respect to age or time-since-lesion.
|
15331014_p20
|
15331014
|
Design and procedure
| 4.120184 |
biomedical
|
Study
|
[
0.997930645942688,
0.0016078450717031956,
0.00046148174442350864
] |
[
0.9992202520370483,
0.0003095293650403619,
0.00034777948167175055,
0.00012239851639606059
] |
en
| 0.999998 |
Using a 148-channel whole-head neuromagnetometer , MEG-measurements were collected twice: once on the day before training and once on the day after training. MEG was measured in a 5-minute resting period, during which subjects were asked to relax while staying awake, and to not engage in any specific mental activity. MEG recordings were obtained in a supine position. Subjects were asked to fixate a colored mark on the ceiling of the magnetically shielded room throughout the recording in order to avoid eye- and head-movement. A video camera installed inside the magnetically shielded room allowed for a monitoring of the subject's behavior and compliance throughout the experiment. Written informed consent was obtained from subjects prior to each MEG-session and the study was approved by the ethics committee of the University of Konstanz.
|
15331014_p21
|
15331014
|
Data acquisition and analysis
| 4.067832 |
biomedical
|
Study
|
[
0.9994181394577026,
0.00029502520919777453,
0.00028686458244919777
] |
[
0.9993873834609985,
0.00034934477298520505,
0.00019732973305508494,
0.00006595833110623062
] |
en
| 0.999999 |
The fiducial points, coils, and head shape were digitized with a Polhemus 3Space ® Fasttrack prior to each measurement. The subject's head position relative to the pickup coils of the sensor was estimated before and after each measurement. MEG was recorded with a sampling rate of 678.17 Hz, using a 0.1–200 Hz band-pass filter. For artifact control, eye movements (EOG) were recorded from four electrodes attached to the left and right outer canthus and above and below the right eye. The electrocardiogram (ECG) was monitored via electrodes attached to the right collarbone and the lowest left rib using a Synamps amplifier (NEUROSCAN ® ).
|
15331014_p22
|
15331014
|
Data acquisition and analysis
| 4.129406 |
biomedical
|
Study
|
[
0.999420166015625,
0.0002959777775686234,
0.00028392032254487276
] |
[
0.9992027878761292,
0.0005014667985960841,
0.00023117894306778908,
0.00006457517156377435
] |
en
| 0.999998 |
Data were reduced by a factor of 16 and digitally filtered for the delta (1.5–4.0 Hz) frequency band using a digital band pass filter (Butterworth filter of the order 6). Artifact-free time segments were determined by visual inspection. Single equivalent current dipoles were fitted for each time point in the selected artifact free segments (distance of time points 24 ms.). Five non-overlapping channel groups over left, right, center, anterior, posterior regions were chosen for dipole modeling. A homogeneous sphere, which gives the best least-squares fit to the digitized patient's headshape below the selected sensors, served as a model for the volume conductor.
|
15331014_p23
|
15331014
|
Data reduction and analysis
| 4.121588 |
biomedical
|
Study
|
[
0.9993199110031128,
0.0003886826743837446,
0.0002913567877840251
] |
[
0.999302864074707,
0.0004240073903929442,
0.00020542214042507112,
0.00006774439680157229
] |
en
| 0.999996 |
Dipole fit solutions at time points satisfying the following requirements were accepted: (1) a dipole moment (q) of 10 nAm < q < 100 nAm; (2) a goodness of fit (GOF) greater than 0.90. These restrictions should ensure that neither artifacts nor small amplitude biological noise would affect the results, and that only dipolar fields that were generated by focal sources were analyzed. Each data-set was divided into 1000 voxels, each of 20 mm 3 , using the AFNI-to3d-software (AFNI-Analysis of functional neuroimages ). For each patient, the percentage of dipoles in the delta frequency band per second in each voxel was z-transformed and statistically compared to the dipole density distribution of a group of 25 healthy controls, which were considered a 'norm' group .
|
15331014_p24
|
15331014
|
Data reduction and analysis
| 4.102011 |
biomedical
|
Study
|
[
0.9994907379150391,
0.0002772404986899346,
0.00023203199089039117
] |
[
0.9994381070137024,
0.0002734643639996648,
0.0002291695273015648,
0.00005925321238464676
] |
en
| 0.999997 |
Whole brain magnetic resonance images (TR = 19, TE = 5,6, Flip angle = 30°, FOV = 256 mm, 1 mm isotropic resolution) were acquired within the 2-week training period across a 256 mm slab from each subject using a Philips Gyroscan 1.5 Tesla scanner (Philips Medical Systems, Gyroscan ACS-T). MRIs were aligned to the coordinates of the MEG according to anatomical landmarks, coil positions and head shape information using the AFNI software.
|
15331014_p25
|
15331014
|
Data reduction and analysis
| 4.078506 |
biomedical
|
Study
|
[
0.9995787739753723,
0.00026025346596725285,
0.00016103322559501976
] |
[
0.9986658096313477,
0.0009375330992043018,
0.0002913830103352666,
0.00010524961544433609
] |
en
| 0.999997 |
A spatial clustering algorithm (FWHM, Filter Width Half Maximum, 60 mm) was applied to smooth the data. Maximum activity, i.e. the voxel with the highest percentage of delta dipoles, was determined using the AFNI subroutine 3dExtrema. The localization of this maximum was determined on the x- (medial-lateral), y- (anterior-posterior) and z- (inferior-superior) plane for the two measurements (pre- & post-training).
|
15331014_p26
|
15331014
|
Maximum delta activity
| 4.053496 |
biomedical
|
Study
|
[
0.9993539452552795,
0.00019717490067705512,
0.0004489368584472686
] |
[
0.9986360669136047,
0.0011084247380495071,
0.00019161499221809208,
0.00006380697595886886
] |
en
| 0.999995 |
The localization of areas with high dipole densities (adjacent clusters of voxels) within each hemisphere was analyzed by applying a narrow filter of FWHM 20 mm to the original data. A narrow filter was used to minimize the influence of more distant voxels with low dipole density on the areas of higher density. First, the voxel with maximum activity was determined for each hemisphere in each patient. By setting thresholds according to the following criteria, voxels with high dipole density were extracted and averaged for each hemisphere:
|
15331014_p27
|
15331014
|
Hemisphere-specific areas of high delta dipole density
| 4.081327 |
biomedical
|
Study
|
[
0.9994331002235413,
0.0003789422626141459,
0.00018787647422868758
] |
[
0.9992651343345642,
0.0003403972659725696,
0.00031073580612428486,
0.00008363978122361004
] |
en
| 0.999998 |
a. Only voxels with z-values within one standard deviation below the maximum of each patient were considered for averaging within each hemisphere.
|
15331014_p28
|
15331014
|
Hemisphere-specific areas of high delta dipole density
| 2.877151 |
biomedical
|
Study
|
[
0.9971923232078552,
0.0009672185988165438,
0.0018405328737571836
] |
[
0.9322506785392761,
0.06471610814332962,
0.001854230766184628,
0.001178936567157507
] |
en
| 0.999999 |
b. If the z-value was smaller than 2 standard deviations, voxels were not considered.
|
15331014_p29
|
15331014
|
Hemisphere-specific areas of high delta dipole density
| 2.431074 |
biomedical
|
Study
|
[
0.9837517738342285,
0.0011528737377375364,
0.01509526651352644
] |
[
0.658592164516449,
0.3377038538455963,
0.0023667453788220882,
0.0013371920213103294
] |
en
| 0.999996 |
c. If the peak density was below 2 SD, an iterative process was initiated. Thresholds were lowered until at least one voxel became apparent where the dipole densities were different before and after training.
|
15331014_p30
|
15331014
|
Hemisphere-specific areas of high delta dipole density
| 2.995999 |
biomedical
|
Study
|
[
0.9909845590591431,
0.001027498859912157,
0.007987864315509796
] |
[
0.7314339280128479,
0.26677078008651733,
0.0009703633841127157,
0.0008249161764979362
] |
en
| 0.999996 |
A measure of the "Magnitude of change" was determined to evaluate changes in dipole density relative to changes in language functions pre- and post-treatment. The averaged (absolute) intensity of delta dipoles in voxels above threshold (in each hemisphere and each patient) was scaled by dividing the magnitude of change in each hemisphere (|T 2 -T 1 |) by the mean of both hemispheres before and after training ((T 1left +T 1right +T 2left +T 2right )/4). This number was then log transformed (to ensure a Gaussian distribution with respect to statistical tests) and submitted to statistical analyses. Two patients were excluded from this final analysis (12: predominantly right hemispheric delta, and 20: shift in lateralization).
|
15331014_p31
|
15331014
|
DDD changes relative to improvement of language functions
| 4.116742 |
biomedical
|
Study
|
[
0.9991853833198547,
0.0005931887426413596,
0.0002214805135736242
] |
[
0.9992921352386475,
0.0003844688180834055,
0.00022534023446496576,
0.00009804613364394754
] |
en
| 0.999998 |
Changes in AAT test scores across the two assessments were verified by two-tailed t-tests. Stability of the location of the maximum delta activity was verified by correlation coefficients (Spearman's Rho) for the posterior-anterior, medial-lateral, and inferior-superior axes. Differences in thresholds and average DDD between hemispheres (for both measurements) were verified by means of analysis of variance (ANOVA), as were differences between patients that exhibited an increase or decrease of DDD concerning time-since-onset. Changes in language functions (Token Test, profile score AAT) relative to changes in DDD-magnitude were evaluated by Pearson correlation.
|
15331014_p32
|
15331014
|
Statistics
| 4.073526 |
biomedical
|
Study
|
[
0.9992579817771912,
0.0004776430723723024,
0.0002643126354087144
] |
[
0.9992885589599609,
0.00022293537040241063,
0.00041452472214587033,
0.00007390727114398032
] |
en
| 0.999995 |
MM, TE and BR participated in the design of the study. MM was responsible for conducting the study, performed data analysis and drafted the manuscript. TE and BR participated in the discussion and general conclusions. CW provided knowledge of data analysis and wrote most of the scripts used for data analysis. DD and GB conducted therapy, assisted in collecting the data, and provided experience of therapeutic issues.
|
15331014_p33
|
15331014
|
Authors' contributions
| 0.936253 |
other
|
Other
|
[
0.07593320310115814,
0.0017537536332383752,
0.9223130941390991
] |
[
0.009612512774765491,
0.989128053188324,
0.0007331898668780923,
0.0005262811318971217
] |
en
| 0.999997 |
The Campanulaceae sensu stricto are a nearly cosmopolitan angiosperm family consisting of latex-bearing, primarily perennial herbs or occasional subshrubs that typically have alternate leaves, sympetalous corollas, inferior ovaries, and capsular fruits. Allied to the Campanulaceae are the Lobeliaceae, Cyphiaceae, Cyphocarpaceae, Nemacladaceae, Pentaphragmataceae, and Sphenocleaceae; at times, all of these taxa have been included in the Campanulaceae at varying taxonomic rank by different authors (Table 1 ). Taxonomic treatments lack consensus (Table 1 ) and phylogenetic work has only recently been attempted. Campanulaceae in the strict sense are recognized as 600 to 950 species distributed among 35 to 55 genera. Generic circumscription and intrafamilial classification vary widely according to author. Within the family as few as two and as many as 18 tribes have been recognized (Table 1 ). Fedorov's more recent work recognized eight tribes (Table 1 ), but only included taxa present in the former Soviet Union. Although Kolakovsky's treatment of Old World Campanulaceae is the most recently published attempt to produce a more complete intrafamilial classification of the Campanulaceae (Table 1 ), the scope of the work is limited compared to that of either A. de Candolle or Fedorov . In all treatments, the Campanuleae and Wahlenbergieae (at whatever rank) are typically the largest, most inclusive taxa, with segregate tribes consisting of only one to a few genera.
|
15324459_p0
|
15324459
|
Background
| 4.165051 |
biomedical
|
Study
|
[
0.8384276032447815,
0.0009698467329144478,
0.16060267388820648
] |
[
0.9109818935394287,
0.0045535932295024395,
0.08423537760972977,
0.00022917591559235007
] |
en
| 0.999997 |
The most comprehensive treatment of the Campanulaceae remains the monograph of A. de Candolle , who recognized two groups corresponding to the Wahlenbergieae and Campanuleae (Table 1 ). Simple basal leaves and simple, alternate or occasional whorled, cauline leaves that are often different in shape than the basal leaves, characterize the Campanuleae in de Candolle's sense. Flowers are solitary or borne in cymes or racemes, and have five corolla lobes that are mostly fused proximally. The inferior ovary usually has 3–5 carpels and develops into a capsule that mostly dehisces by lateral pores (rarely a berry). The Wahlenbergieae are mostly perennials characterized by simple, alternate, cauline leaves. Flowers are solitary or borne in cymes or heads, and petals may be free, proximally fused, or distally fused. The ovary is inferior, semi-inferior, or superior, and consists of two, three, or five carpels. The fruit is generally a capsule dehiscing by apical pores or valves (rarely a berry). Both groups have five stamens with filaments that are often proximally dilated and anthers with introrse dehiscence; nectaries are generally present, and many ovules are attached to axile placentae. The entire family is characterized by secondary pollen presentation in which protandry is combined with a close association of anthers around the style and introrse pollen discharge onto the style for presentation to pollinators. This syndrome is similar to that found in Lobeliaceae and Asteraceae, but invaginating stylar hairs are unique to the Campanulaceae.
|
15324459_p1
|
15324459
|
Background
| 4.250912 |
biomedical
|
Study
|
[
0.9468279480934143,
0.0009423880255781114,
0.05222967267036438
] |
[
0.7709786295890808,
0.007913008332252502,
0.220686137676239,
0.00042229017708450556
] |
en
| 0.999997 |
Capsule characters vary considerably and provide the basis for most intrafamilial classification schemes. Campanuleae typically include taxa with capsules dehiscing by lateral pores, whereas Wahlenbergieae usually include taxa with capsules dehiscing by apical valves. Ovary characters, such as carpel number and position, have also been important in traditional classifications. For example, the monotypic tribe Platycodoneae or subtribe Platycodinae (Table 1 ) is sometimes segregated. It is defined by carpels that are equal in number to and alternate with the calyx lobes, whereas in Campanuleae and Wahlenbergieae the carpels are often fewer than the calyx lobes, or if the same in number then opposite them . Little correlation appears to exist among diagnostic features; therefore there is considerable taxonomic disagreement among classifications. In certain instances it is difficult to discern the rationale behind tribal placement of individual genera.
|
15324459_p2
|
15324459
|
Background
| 3.951532 |
biomedical
|
Study
|
[
0.7971965670585632,
0.000666316132992506,
0.20213709771633148
] |
[
0.9681813716888428,
0.01662539690732956,
0.014981727115809917,
0.0002115698589477688
] |
en
| 0.999998 |
The high level of disagreement among both inter- and intrafamilial classifications of the Campanulaceae indicates that phylogenetic assessment of the family is needed. Cosner, in her thesis , included an early version of a portion of the work described here, and Eddie, in his thesis developed phylogenetic hypotheses based on ITS sequence data and morphology. An expanded version of the ITS work has been published but leaves some major lineages unsampled and the relationships among some major groups are unresolved or poorly supported. Further phylogenetic work is clearly warranted. The chloroplast genome has proven to be a useful tool for phylogenetic reconstruction. Chloroplast DNA (cpDNA) of land plants is highly conserved in nucleotide sequence as well as gene content and order; its relatively slow rate of evolution makes it an excellent molecule for phylogenetic and evolutionary studies . Chloroplast genomes of photosynthetic angiosperms average about 160 kilobase pairs (kb) in size; the circular chromosome is divided by two copies of a large (in angiosperms usually about 25 kb) inverted repeat (IR) into large and small single copy regions (LSC and SSC, respectively) . Restriction site mapping, gene sequencing, and analysis of gene order rearrangements have been used to study cpDNA variation for phylogenetic investigations . Here we use the distribution of gene order changes in the chloroplast genomes of the Campanulaceae to estimate phylogenetic relationships in the family.
|
15324459_p3
|
15324459
|
Background
| 4.313365 |
biomedical
|
Study
|
[
0.9985484480857849,
0.0003613051667343825,
0.0010902249487116933
] |
[
0.9989010095596313,
0.00023723907361272722,
0.0007983841351233423,
0.00006327107985271141
] |
en
| 0.999996 |
Generally, major gene order changes are rare. Therefore, when they occur, such mutations are extremely useful as phylogenetic markers because they are readily polarized and typically lack homoplasy . Four categories of cpDNA gene order rearrangements have been proposed: 1) inversions, 2) insertions or deletions, 3) IR expansion or contraction or loss, and 4) transpositions; all of which may have occurred during chloroplast genome evolution in the Campanulaceae . When rearrangements have been discovered elsewhere, they are generally few and easily characterized. The distributions of such characters make effective markers of monophyletic groups. For example, both the loss of one copy of the IR and inversions are extremely useful characters in legume phylogeny , defining large clades within the family. Other examples of phylogenetically informative inversions are found within Asteraceae , Ranunculaceae , ferns , and vascular plants . Many other examples could be cited.
|
15324459_p4
|
15324459
|
Background
| 4.214884 |
biomedical
|
Study
|
[
0.9987208247184753,
0.0002329443523194641,
0.001046121004037559
] |
[
0.962681770324707,
0.0019501110073179007,
0.03519277274608612,
0.0001753194519551471
] |
en
| 0.999997 |
The earlier work of Cosner and Knox characterized some chloroplast genomes of the Campanulales and identified a number of rearrangements relative to the consensus gene order of angiosperms found in tobacco. Members of the Lobeliaceae exhibit multiple rearrangements but are less rearranged than the Campanulaceae. Three rearrangements may be shared between the two families – a loss of the accD gene, the expansion of the inverted repeat into the small single copy region, and, perhaps, an inversion of the region corresponding to tobacco probes 40–44. Then, within the Campanulaceae, more than 40 inversions, more than eight putative transpositions, two additional gene losses, additional IR expansion or contraction events and 18 large insertions greater than 5 kb in size may have contributed to observed differences among the chloroplast genomes sampled . Due to this unprecedented number of gene order mutations, it is not possible to unambiguously determine the evolutionary order of most events or in some cases to even define the events themselves. This complex situation poses special problems for using these rearrangements to estimate phylogenetic relationships. In this paper we develop alternative character codings for the data and compare the results of parsimony analyses of the different data sets. In addition, we compare the ability of the gene order data to support robust phylogenetic hypotheses to that of sequence data from rbcL and ITS. Finally, the phylogenetic implications of the cpDNA rearrangement data for the Campanulaceae are discussed.
|
15324459_p5
|
15324459
|
Background
| 4.266884 |
biomedical
|
Study
|
[
0.9985004663467407,
0.00042247181409038603,
0.0010771510424092412
] |
[
0.9992238283157349,
0.00015190754493232816,
0.0005604068865068257,
0.00006378227408276871
] |
en
| 0.999997 |
Our data indicate that the eighteen mapped Campanulaceae chloroplast genomes (Table 2 ) are drastically rearranged relative to those of other land plants . The tobacco cpDNA gene order represents the consensus gene order for angiosperms . Therefore rearrangements in Campanulaceae chloroplast genomes were identified relative to tobacco. Because characterizing specific mutational events was not always possible three different coding methods (Matrix 1, 2 and 3) were developed. Matrix 1 coded all gene order changes as endpoints (derived adjacencies, relative to tobacco, were identified and scored for presence/absence). Matrix 2 and 3 involved recoding some endpoint characters to recognize 31 specific mutations. Matrix 2 and 3 were analyzed with and without weighting. See Methods for additional details on character encoding and analyses.
|
15324459_p6
|
15324459
|
Results
| 4.101982 |
biomedical
|
Study
|
[
0.9978813529014587,
0.0003690370940603316,
0.0017496126238256693
] |
[
0.9995865225791931,
0.0002078631368931383,
0.0001611075858818367,
0.000044495940528577194
] |
en
| 0.999996 |
Seventy-nine variable characters were included in the endpoints only matrix (Matrix 1). Forty-two of the derived character states were unique to a single taxon and 37 were phylogenetically-informative. Six trees of 97 steps were obtained with consistency indices of 0.81 with autapomorphies included and 0.67 with autapomorphies excluded (CI = 0.81/0.67). Ten nodes were common to the six shortest trees . Eight of those ten nodes have bootstrap values (BS) greater than 50, but BS exceeded 90 for only three nodes.
|
15324459_p7
|
15324459
|
Results
| 4.143398 |
biomedical
|
Study
|
[
0.9987438321113586,
0.00034188985591754317,
0.0009142953203991055
] |
[
0.9995679259300232,
0.00024727603886276484,
0.00013804905756842345,
0.00004671660281019285
] |
en
| 0.999998 |
To construct Matrix 2 and Matrix 3, we interpreted endpoints as events where possible. Under our interpretation, several types of rearrangements contributed to cpDNA evolution in the family, including multiple inversions (scored primarily as endpoints), five IR expansion or contraction events, eight transpositions, two deletions, and 14 large insertions greater than 5 kb in size (Table 3 ). Although transposition probably does occur, at least occasionally, in the chloroplast genome , it is not a common mechanism of rearrangement. Still, in some instances transposition could explain rearranged gene orders with fewer steps than multiple inversions and so we hypothesized transposition events in some cases. Matrix 2 and 3 each were composed of 84 variable characters of which thirty-one and thirty-four, respectively, were parsimony informative.
|
15324459_p8
|
15324459
|
Results
| 4.136829 |
biomedical
|
Study
|
[
0.9983301758766174,
0.0003395437088329345,
0.001330312225036323
] |
[
0.9995866417884827,
0.0001917827466968447,
0.00017440482042729855,
0.00004713951057055965
] |
en
| 0.999995 |
The unweighted analysis of Matrix 2 produced 241 equally parsimonious trees of 93 steps (CI = 0.90/0.79). The strict consensus of the 241 trees includes six resolved nodes all six of which were supported by BS values of at least 50 and five nodes were supported at 90% or above. The weighted analysis of Matrix 2 resulted in 12 equally parsimonious trees of 125 steps (CI = 0.93/0.82). The strict consensus of the twelve trees retains ten resolved nodes. Seven of the ten nodes have BS values over 50 and for five nodes BS ≥ 90. Both analyses of Matrix 3 generated the same two equally parsimonious trees . The lengths of the two trees were 87 steps (CI = 0.97/0.92) or 118 steps (CI = 0.97/0.93) depending on whether unweighted or weighted analyses were conducted. Only three endpoint characters are homoplasious in the Matrix 3 analyses . The strict consensus of these two trees retains nine resolved nodes, all nine of which are supported with BS ≥ 50. Six (or five in the weighted analysis) nodes received strong support (BS ≥ 90).
|
15324459_p9
|
15324459
|
Results
| 4.217057 |
biomedical
|
Study
|
[
0.9989339709281921,
0.00030450383201241493,
0.0007615485810674727
] |
[
0.9994530081748962,
0.00023600498388987035,
0.00026229320792481303,
0.00004880574488197453
] |
en
| 0.999999 |
All results indicate that Codonopsis , Platycodon , and Cyananthus are basal within the family. Analyses on Matrix 2 and 3 support a Codonopsis + Cyananthus sister group relationship and a monophyletic basal clade whereas the Matrix 1 analysis supports a Codonopsis + Platycodon sister group and a paraphyletic basal grade. Neither outcome is very well supported; the alternative scenarios each require only a single additional step in the other data set. Within the fifteen derived taxa some of the relationships are not resolved or resolved but weakly supported. However, some groupings are well supported in all analyses. The South African taxa, Merciera , Prismatocarpus and Roella , form a clade (BS = bootstrap value = 98 - 100). Wahlenbergia is the sister to these three taxa in all analyses with varying levels of support (BS = 82, 60, 69, 99, 99, in the five analyses based on gene order changes). Other groupings include a Symphyandra + Edraianthus clade (BS = 86-91) and Legousia + Asyneuma + Petromarula + Triodanis (BS = 94-100).
|
15324459_p10
|
15324459
|
Results
| 4.195681 |
biomedical
|
Study
|
[
0.995790421962738,
0.0003668889694381505,
0.0038426558021456003
] |
[
0.9994353652000427,
0.0002437794755678624,
0.0002745511883404106,
0.000046384448069147766
] |
en
| 0.999996 |
The five analyses had somewhat different characteristics (Table 4 ). For example, Matrix 1 and Matrix 3 analyses generated fewer equally-parsimonious trees than Matrix 2. The Matrix 1 analyses resolved the most nodes. Matrix 3 analyses exhibited the lowest amounts of homoplasy and supported the highest number of nodes BS ≥ 90. Comparing all results, no nodes with high bootstrap values (BS ≥ 90) were conflicted by other nodes of equally high value. However, there were three instances of incongruence involving nodes of lesser support – Matrix 1 and 3 analyses supported Campanula + Adenophora , whereas Matrix 2 supported Adenophora + Jasione ; Matrix 1 supported Codonopsis + Platycodon (BS = 50), whereas Matrix 2 and 3 supported Codonopsis + Cyananthus (BS = 94-99); and Matrix 1 supported (weakly, BS = 57) the placement of Cyananthus at the base of the derived clade, whereas Matrix 2 and 3 analyses supported the monophyly of the basal group (BS = 56-68). One clade, Legousia + Asyneuma (BS = 87), was recovered only by the Matrix 1 analysis within a clade not further resolved by the other gene order analyses.
|
15324459_p11
|
15324459
|
Results
| 4.188502 |
biomedical
|
Study
|
[
0.9983749389648438,
0.00034268005401827395,
0.0012824247824028134
] |
[
0.999526858329773,
0.00017114545335061848,
0.00025944822118617594,
0.000042587453208398074
] |
en
| 0.999998 |
We included sequence data here mainly to allow for a comparison with gene order data in terms of phylogenetic utility. The rbcL data from the same eighteen taxa (Table 5 ) provided 116 parsimony-informative characters that, when analyzed, yielded nine shortest equally-parsimonious trees of 338 steps (C = 0.77/0.66). The strict consensus of the nine trees retained fourteen nodes , thirteen of which had BS ≥ 50 and four of which were supported BS ≥ 90. The ITS data of Eddie et al from taxa equivalent to fifteen of the eighteen mapped taxa (Table 5 ) provided 196 parsimony-informative characters from which a single most parsimonious tree of 716 steps was generated (CI = 0.69/0.60). The tree contains thirteen resolved nodes of which ten had BS ≥ 50 and four had BS ≥ 90. The two sequence data sets had lower CI values than any of the gene order analyses and a higher percentage of homoplastic characters (Table 4 ). The ITS data had especially high levels of homoplasy; the ITS data had a higher percentage of characters that change three or more times in excess than the Matrix 3 analyses had for total homoplastic characters (Table 4 ). In the Matrix 3 analysis only three characters (endpoints) are required to change more than once over the most parsimonious tree; each has one excess change. With the inclusion of the sequence-based analyses, there were additional instances of incongruence between weakly supported nodes: 1) The placement of Musschia and Jasione varies between the rbcL and ITS results (the placement of these taxa is largely unresolved by the gene order data); 2) In both sequence-based trees, Campanula and Adenophora are separate lineages (rather than sister taxa) basal to the Legousia - Asyneuma - Triodanis - Petromarula clade, whereas in the gene order analyses they are allied to Symphyandra - Edraianthus , and Trachelium ; 3) Matrix 1 supports a Legousia - Asyneuma clade, whereas a Legousia - Triodanis clade occurs in the sequence-based trees; and 4) Matrix 1 and ITS support a Codonopsis - Platycodon grouping within the basal clade, whereas rbcL and Matrix 2 and 3 analyses support Codonopsis - Cyananathus. Among these instances of disagreement between weakly supported nodes, there is no general pattern of disagreement between the sequence data and the gene order analyses. And among strongly supported nodes, again, there is complete agreement, among all analyses-sequence and gene order.
|
15324459_p12
|
15324459
|
Results
| 4.374927 |
biomedical
|
Study
|
[
0.9990683197975159,
0.00041032518493011594,
0.0005214672419242561
] |
[
0.9991716146469116,
0.0002202215400757268,
0.0005266456864774227,
0.00008158593846019357
] |
en
| 0.999996 |
The relatively large number of gene order mutations that have occurred in the Campanulaceae chloroplast genomes causes difficulties when interpreting their phylogenetic significance. The phylogenetic analysis of such a complex set of cpDNA rearrangements within a group of plants is without precedent. The first problem was simply defining individual mutational events. Although the ideal way to analyze rearrangement data is to determine presence or absence of specific events, in the Campanulaceae, this was not possible in many cases given our present knowledge. Where multiple overlapping rearrangements have occurred between genomes, the two specific endpoints that define a particular inversion may not be determinable. Because of the inherent complexity of the data, we felt a new method of character analysis of the rearrangement data was warranted. Our approach involved coding endpoints, along with more easily defined rearrangements, as characters for different cladistic analyses. Endpoints were defined as two non-contiguous tobacco regions that are now adjacent in the genomes of one or more species.
|
15324459_p13
|
15324459
|
Phylogenetic analysis of cpDNA rearrangements
| 4.147369 |
biomedical
|
Study
|
[
0.9984492063522339,
0.0002941789571195841,
0.0012565284268930554
] |
[
0.9993476271629333,
0.0003554332070052624,
0.00024718971690163016,
0.00004979101868229918
] |
en
| 0.999997 |
Using endpoints as characters is advantageous. It allows for the incorporation into the analysis of data that could not be used if only unambiguously interpreted events were included. However, using endpoints as characters has several drawbacks, including the inadvertent weighting of certain events over others. Inversions necessarily produce two endpoints, and transpositions three, whereas gene losses and IR boundary changes produce a single endpoint. Therefore inversions would be included twice and transpositions three times if scored as "independent" endpoints rather than events. Plus, if both endpoints of an inversion are still intact in a genome, the inversion is scored twice, if only a single endpoint remains the inversion is counted only once, and if both endpoints have been lost (through further mutation) the inversion will not be included at all. This may represent a problem in the Campanulaceae analyses because there appears to be a mixture of event types and at least some endpoint reuse .
|
15324459_p14
|
15324459
|
Phylogenetic analysis of cpDNA rearrangements
| 4.097157 |
biomedical
|
Study
|
[
0.9984508752822876,
0.00015693700697738677,
0.0013921455247327685
] |
[
0.9848464727401733,
0.013297406025230885,
0.0017427102429792285,
0.00011344542144797742
] |
en
| 0.999997 |
Our inclusion of transposition as a possible mechanism for gene order mutation in the Campanulaceae chloroplast genomes is problematic. Definitive evidence supporting the occurrence of transposition in the plastid genome is lacking. Transposition has been invoked to explain chloroplast DNA rearrangements, for example in "subclover" and wheat . In these cases, transposition has been supported using parsimony arguments (one transposition explaining a change with fewer steps than three inversions) or using the existence of inverted- and direct-repeat sequence motifs near the boundaries of rearrangements . In Campanulaceae, some lines of evidence in addition to parsimony suggest the possibility of transposition as a mechanism. First, the abundance of rearrangement events within the family suggests some mechanism that facilitates gene order mutation; transposition is one such process. Second, the segment of the genome defined by tobacco probes 53–56 is now located, in most of the derived taxa, within the inverted repeat. The region from which it has been removed appears otherwise undisturbed. In Asyneuma , the 53–56 region has been secondarily removed from the IR and returned to near its original location leaving behind small portions of 53 and 56 in the IR, detectable using southern hybridization. In Wahlenbergia , Merciera , Prismatocarpus and Roella , the 53, 54 portion of the 53–56 block has moved from the IR back to the LSC. One explanation for the high level of rearrangement apparently associated with this segment is that the region contains a transposable element. Third, a possible duplicative transposition is suggested in Trachelium and five other taxa . In addition to a full-length (presumably functional) copy of the 23S rRNA gene, a partial copy is located within ycf1 . Transposition is one manner in which segments of DNA can be both copied and moved within a genome. None of our data are definitive. The observed rearrangements could have taken place as the result of multiple inversions. Therefore, it is important to note that if transposition is not active in the Campanulaceae genome, our phylogenetic results will not be greatly affected. Events coded in Matrix 2 and 3 as single transpositions would be underweighted inversions if incorrectly interpreted. The fact that the analysis of Matrix 1 yields results compatible with those of the matrices that include transpositions suggests that, if our interpretation is erroneous, it does not affect the phylogenetic conclusions.
|
15324459_p15
|
15324459
|
Phylogenetic analysis of cpDNA rearrangements
| 4.445128 |
biomedical
|
Study
|
[
0.9986053109169006,
0.0005223653861321509,
0.0008723277715034783
] |
[
0.9990516304969788,
0.0003156285674776882,
0.000538378139026463,
0.00009429737110622227
] |
en
| 0.999996 |
Our three methods of character scoring did yield largely compatible results in our analyses. Relationships that were strongly supported in one analysis were found in all analyses. Events make more desirable characters but they will only improve analyses if the postulated events are the correct ones. Comparing analyses that include event interpretations with endpoint only analyses is one way to determine the phylogenetic effects of the hypotheses of events used. Endpoint only analyses also allow studies that minimize a priori assumptions about the evolutionary events. It is possible that more complex evolutionary scenarios occurred, in which some inversions evolved in parallel, or in which similar gene orders resulted from a different set of inversions. The parsimony analyses may underestimate the number of inversions shared between primitive and advanced genera, because evidence of shared inversions may have been lost. Although we have attempted to produce the simplest evolutionary schemes, it is very possible that longer, more complicated scenarios actually occurred, especially given that the Campanulaceae seem predisposed to cpDNA rearrangements. However, given the congruence of the results among our various analyses, we feel our phylogeny is a reasonable estimate of relationships within the family. Elsewhere, we have analyzed a reduced subset of characters and taxa for the Campanulaceae cpDNA data set using endpoint scoring and constructing trees using breakpoint distances among other methods (e.g., ). Other computational biologists have also used this reduced data matrix to test different methods of phylogeny reconstruction based on gene order data (e.g., ). These various studies produced trees that are largely congruent with those generated in this paper suggesting that the Campanulaceae cpDNA gene order data are providing a consistent estimate of phylogenetic relationships given any logical method of scoring and analysis. Although the rearrangements in Campanulaceae are complex, the phylogenetic utility of the gene order data is evident. In most previous examples of phylogenetic use of rearrangements the small number of events allowed for the circumscription of only very broad groups . Because there are so many rearrangements in the Campanulaceae, smaller groups can be identified. This has resulted in the most highly resolved phylogeny as yet developed based entirely on cpDNA rearrangements.
|
15324459_p16
|
15324459
|
Phylogenetic analysis of cpDNA rearrangements
| 4.282155 |
biomedical
|
Study
|
[
0.9989425539970398,
0.0003758512029889971,
0.0006816558889113367
] |
[
0.9991532564163208,
0.00021422479767352343,
0.0005659983144141734,
0.0000665274856146425
] |
en
| 0.999997 |
Not only do these data support a well-resolved phylogeny but they provide robust support of several nodes. Matrix 3 supports as many nodes at BS ≥ 90 as ITS and more than rbcL . In matrix 3, only three endpoint characters (8.8% of parsimony-informative characters) are homoplastic, each changing one extra time over the tree. In contrast, within ITS, 18 characters (9.2% of parsimony-informative characters) change three or more extra times over the tree, and 71.9% of characters are homoplastic. Presumably because of this high level of homoplasy, only two nodes are retained in the consensus of all ITS trees from the shortest to 1% longer, whereas seven nodes are retained in matrix 3 trees "to 1% longer" – the highest number of any of the analyses. Matrix 3, the matrix in which characters are most interpreted as mutational events, is especially strong in its performance, exceeding both sequence data sets in average bootstrap value per resolved node and CI (in addition to those characteristics just discussed). This suggests that the closer we can get to scoring the actual mutations the stronger gene order data will perform. Although the endpoint only matrix provides useful insights on relationships, we would argue that the extent to which these gene order characters cannot recover the phylogeny is directly related to our ability to define individual mutational events.
|
15324459_p17
|
15324459
|
Phylogenetic analysis of cpDNA rearrangements
| 4.227539 |
biomedical
|
Study
|
[
0.9991399049758911,
0.00027231380227021873,
0.0005878238007426262
] |
[
0.9993211030960083,
0.00026220077415928245,
0.0003635766333900392,
0.000053143030527280644
] |
en
| 0.999998 |
Most traditional classifications of the Campanulaceae are based mainly on capsule dehiscence and ovary position and arrangement. As Kovanda and Thulin recognized, classification of the Campanulaceae based on capsule characters alone brings together otherwise radically different taxa. Neither the Campanuleae nor Wahlenbergieae (at whatever taxonomic rank) are monophyletic based on cpDNA rearrangements . Likewise, no traditional classification (Table 1 ) suggests that Codonopsis , Platycodon , and Cyananthus are basal in the family as supported by both gene order and sequence data. Takhtajan's system is something of an exception among traditional classifications; however, he suggested only Cyananthus (in its own tribe Cyanantheae) as the most primitive member of the family, placing Platycodon and Codonopsis in other tribes (Table 1 ).
|
15324459_p18
|
15324459
|
Phylogenetic implications of the rearrangement data
| 4.096661 |
biomedical
|
Study
|
[
0.9387366771697998,
0.0004724517639260739,
0.06079090014100075
] |
[
0.9878901839256287,
0.0026228183414787054,
0.009387967176735401,
0.00009910710650729015
] |
en
| 0.999998 |
In contrast, studies of pollen ultrastructure have indicated that Platycodon , Codonopsis , and Cyananthus are basal members of Campanulaceae . These taxa have colpate to colporate apertures, whereas the remaining family members (as surveyed here) have porate grains . The evolutionary scheme based on pollen morphology presented by Dunbar suggests that Cyananthus (colpate) and Codonopsis (colpate) are more closely related to each other than either is to Platycodon (colporate), which is also supported by the gene order tree . Thulin believed that pollen morphology should constitute a key part of any modern reassessment of relationships in the Campanulaceae. He suggested that all taxa with elongated apertures should be removed from Campanuleae and Wahlenbergieae, and those with porate grains removed from Schönland's Platycodinae. Following the removal of colpate and colporate taxa, Campanuleae sensu Schönland are comprised of Northern Hemisphere genera, whereas Wahlenbergieae contain Southern Hemisphere taxa, with the exceptions of Edraianthus and Jasione (although Jasione occurs in North Africa as well as Europe). The gene order data indicate that the affinities of Jasione and Edraianthus lie with Northern Hemisphere species rather than with Wahlenbergieae. The gene order data also are compatible with other available nucleotide data in addition to those reported here [, L. Raubeson, A. Oestriech and R. Jansen, unpublished data], a morphology-based cladistic study and are also largely congruent with a serological study of the Campanulaceae . Although the gene order and serological studies differed somewhat in the taxa sampled, both included a group containing Trachelium and Campanula . They also agreed in the grouping of Asyneuma and Petromarula . The only discrepancy was in the placement of Legousia ; the serological study placed this genus basal to all others surveyed .
|
15324459_p19
|
15324459
|
Phylogenetic implications of the rearrangement data
| 4.423852 |
biomedical
|
Study
|
[
0.9957510232925415,
0.0005202190368436277,
0.0037286377046257257
] |
[
0.9960266351699829,
0.00046054174890741706,
0.0034141801297664642,
0.00009866038453765213
] |
en
| 0.999998 |
The groups delimited by cpDNA rearrangements also exhibit geographical integrity. Wahlenbergia is primarily a Southern Hemisphere Old World genus ; W. gloriosa , mapped for this study, is Australian . Roella , Merciera , and Prismatocarpus are all endemic to South Africa . The nine genera in the Trachelium and Legousia clades are primarily European to Eurasian, although Triodanis is endemic to North America and Campanula has a few North American representatives . Musschia is endemic to the island of Madeira .
|
15324459_p20
|
15324459
|
Phylogenetic implications of the rearrangement data
| 2.421053 |
biomedical
|
Study
|
[
0.6800283789634705,
0.0008907925221137702,
0.31908074021339417
] |
[
0.8089369535446167,
0.1886383295059204,
0.0017693465342745185,
0.0006554204155690968
] |
en
| 0.999997 |
There has been considerable debate regarding the relationships among the four centers of taxonomic diversity of the Campanulaceae: Asia, Europe (especially the Mediterranean), South Africa, and western North America. Bentham hypothesized a northern origin for Campanulaceae but he did not specify a particular region. Takhtajan suggested a basal position of the Asian genus Cyananthus . Studies of pollen ultrastructure indicated that the Asian genera Codonopsis , Cyananthus , and Platycodon are basal members of the Campanulaceae . Recent studies of the Campanulales indicate that the order consists of several families, including the Campanulaceae, Cyphiaceae, Cyphocarpaceae, Lobeliaceae, Nemacladaceae, and Stylidaceae. Several of these families are restricted to the Southern Hemisphere (all but Nemacladaceae from North America and Campanulaceae which is cosmopolitan), implying that the Southern Hemisphere may be the ancestral area for the Campanulaceae . Phylogenies based on rbcL sequence data position the Campanulaceae sister to the North American family Nemacladaceae . Our cpDNA phylogeny based on genome rearrangements provides strong support for the basal position of the three examined Asian platycodonoid genera, suggesting that the early radiation of the family may have occurred in Asia rather than Africa. The genera from the Southern Hemisphere ( Merciera , Prismatocarpus , Roella , and Wahlenbergia ) are in a much more derived position in the cpDNA tree.
|
15324459_p21
|
15324459
|
Phylogenetic implications of the rearrangement data
| 4.348211 |
biomedical
|
Study
|
[
0.9958218336105347,
0.0004097531200386584,
0.003768411697819829
] |
[
0.9982200264930725,
0.00030936344410292804,
0.0014032196486368775,
0.00006741140532540157
] |
en
| 0.999996 |
In addition, the gene order data suggest affinities of several controversial genera . Schönland united Musschia and Platycodon as Platycodinae, clearly incompatible with both our results and pollen evidence. Musschia is placed in the derived clade (A), although its exact placement varies among all the analyses, including rbcL and ITS. De Candolle was unsure of Merciera 's taxonomic position because its four basal ovules and single-seeded (by abortion) unilocular capsule are unique in the Campanulaceae . This genus was later recognized as a separate tribe, Merciereae , but is allied with other southern African genera in the cpDNA analysis . Takhtajan placed Merciera with Wahlenbergia , Roella and Prismatocarpus in his Wahlenbergieae but also included other genera forming a polyphyletic group according to our results.
|
15324459_p22
|
15324459
|
Phylogenetic implications of the rearrangement data
| 4.150846 |
biomedical
|
Study
|
[
0.9857586622238159,
0.00038722637691535056,
0.013854109682142735
] |
[
0.9983956217765808,
0.0006904990877956152,
0.0008496253285557032,
0.00006421840225812048
] |
en
| 0.999998 |
Adenophora and Symphyandra have been segregated from Campanula based on the presence of a conspicuous tubular nectariferous disc and connate anthers, respectively. Adenophora and Campanula are sister taxa in the gene order analyses (except those based on Matrix 2) and Adenophora' s chloroplast genome is derived relative to Campanula' s . Further sampling within Adenophora and the large genus Campanula will be necessary to determine if this is a general result. Symphyandra is more closely related to Edraianthus than Campanula but all are within the A3 Clade . Edraianthus has traditionally been considered close to Wahlenbergia but this is not supported by any of the results reported here or by morphological studies of Hilliard and Burtt .
|
15324459_p23
|
15324459
|
Phylogenetic implications of the rearrangement data
| 3.854542 |
biomedical
|
Study
|
[
0.9136847257614136,
0.0005593971582129598,
0.08575589209794998
] |
[
0.9961899518966675,
0.0031505078077316284,
0.0005556279793381691,
0.00010390188253950328
] |
en
| 0.999996 |
Much controversy surrounds the taxonomy of the genera Triodanis and Legousia . In some treatments, both genera were included under the illegitimate name Specularia (e.g. ). McVaugh and Fernald disagreed regarding the circumscription of the genera; Fernald felt that Triodanis as a genus is very weak and should be merged with Legousia . McVaugh argued that the two genera should either remain separate or both be subsumed into Campanula . In his system, both species studied here ( T. perfoliata and L. falcata ) belong to Triodanis . As expected, Triodanis and Legousia belong to the same cpDNA clade (A2), united by an unusual mutation that transferred a large segment of the large single copy (LSC) region to the SSC region . However, Legousia has a putative transposition not found in Triodanis , whereas Triodanis has a unique large insertion .
|
15324459_p24
|
15324459
|
Phylogenetic implications of the rearrangement data
| 4.097889 |
biomedical
|
Study
|
[
0.9435268044471741,
0.00042205999488942325,
0.05605117231607437
] |
[
0.993309497833252,
0.00484282523393631,
0.0017348837573081255,
0.00011281741171842441
] |
en
| 0.999998 |
Despite the difficulties in interpreting such a complex set of rearrangements, the systematic utility of chloroplast DNA in the Campanulaceae is evident. Our results support the division of the family into two groups previously unrecognized in any taxonomic treatment. In addition, numerous groupings within the larger, derived clade are strongly supported. The data indicate that traditional classifications based on fruit and ovary characters are unnatural, and suggest affinities of several difficult genera. Additional sampling within large genera, such as Campanula and Wahlenbergia , will be necessary to fully elucidate relationships among chloroplast genomes. It is likely that intrafamilial relationships can be further resolved by including other genera in rearrangement analyses. Although homoplasy is not absent in our data, it is low and considerably lower than some sequence data such as ITS. Although any reasonable scoring method for the gene order data generates results that are largely compatible among the different analyses, the more that the gene order data can be interpreted as actual mutational events (and the presence or absence of those events used as characters) the stronger will be the results. Even in cases such as this, with high levels of gene order complexity, cpDNA gene order mutations make excellent phylogenetic markers.
|
15324459_p25
|
15324459
|
Conclusions
| 4.277834 |
biomedical
|
Study
|
[
0.9981499910354614,
0.0004946779808960855,
0.001355373882688582
] |
[
0.9991357922554016,
0.00019210251048207283,
0.0006077038124203682,
0.00006441824370995164
] |
en
| 0.999997 |
Total DNA was isolated from one species in each of 18 genera in the Campanulaceae (Table 2 ) according to the CTAB method of Doyle and Doyle . DNAs were digested with the restriction endonucleases Bam HI, Bgl II, Eco RI, Eco RV, Hind III, and Sst I, and double digests were carried out using Hind III and the remaining five enzymes. Hybridization probes consisted of 106 small tobacco cpDNA probes (average size 1.2 kb) provided by J. Palmer . Twenty-one cloned Hind III cpDNA fragments from Trachelium caeruleum of the Campanulaceae were also used as hybridization probes . Complete single and double digest restriction site maps were constructed for 16 of the 18 taxa, and nearly complete maps were constructed for the remaining two taxa, Jasione and Roella . It was not possible to map the small single copy (SSC) region of Roella because hybridization signals became increasingly weak in later rounds of hybridization. In Jasione , rearrangements involving the IR/SSC junction and SSC region prohibited the complete resolution of the map. The restriction site maps were then interpreted as linear "number" maps representing the hybridization patterns of 106 consecutively numbered tobacco cpDNA probes for the 18 taxa .
|
15324459_p26
|
15324459
|
Methods
| 4.195805 |
biomedical
|
Study
|
[
0.9989141225814819,
0.0003307256265543401,
0.0007551633752882481
] |
[
0.9994432330131531,
0.00021630340779665858,
0.00029207300394773483,
0.000048452024202561006
] |
en
| 0.999995 |
Rearrangements were recognized as any change in the order of gene segments relative to the order observed in tobacco. The recognition of such disruptions is straightforward; the interpretation of the disruptions as actual mutational events can be quite complicated. As a hypothetical example, the ancestral order in a region may be 1-2-3-4-5-6; while the order 1-2-5-3-4-6 may be observed in a rearranged genome. In the rearranged genome 2-5, 5-3, and 4-6 are adjacencies that are derived relative to the ancestral order. But what set of events is responsible for the change? A simple transposition of 5 to the position between 2 and 3 can account for the difference in a single event. Alternatively, two inversions with one shared endpoint may be responsible or two inversions with unique endpoints followed by a transposition can explain the differences. Additional explanations would also be compatible with these data. On what basis do we choose among multiple scenarios? As an actual example, the chloroplast genome of Platycodon could have evolved from a tobacco-like ancestor by two different models each involving seven inversions ; not one inversion is common to the two scenarios. Thus in our initial approach to data analysis (generating Matrix 1) we did not define events, but utilized endpoints only. In the hypothetical example 2-5, 5-3, and 4-6 are "endpoints" -derived adjacencies absent in the ancestral gene order. Taxa with genomes that exhibit the derived adjacencies are coded as 1 for those characters and those with the ancestral condition as 0.
|
15324459_p27
|
15324459
|
Methods
| 4.208179 |
biomedical
|
Study
|
[
0.9987055063247681,
0.00018851045751944184,
0.0011059611570090055
] |
[
0.9965724945068359,
0.002359948819503188,
0.0009770491160452366,
0.00009058669093064964
] |
en
| 0.999995 |
We constructed two additional matrices that did include events since some endpoints (or combination of endpoints) seemed readily interpretable. For example, if a region of the genome was simply reversed in order (i.e., 1-4-3-2-5 relative to 1-2-3-4-5) we assumed that an inversion had taken place to result in the different arrangements of gene segments. Likewise if genomes differed in content of the IR, we assumed that single duplication or loss events were responsible. Making such inferences, we constructed Matrix 2 that is composed of 31 events and 53 endpoints. We then went further and constructed hypotheses of rearrangement events to account for the differences among the genomes of the three major clades delimited among the fifteen derived taxa . If these scenarios indicated that an inversion likely was shared between two or more genera, the taxa were coded as having an endpoint even if the endpoint has been lost due to disruption by subsequent events. We were conservative in our application of this approach and only six endpoint scorings were modified in Matrix 3 compared to Matrix 2. To summarize, we produced three data matrices that represented increasing levels of interpretation of endpoints as actual events.
|
15324459_p28
|
15324459
|
Methods
| 4.123024 |
biomedical
|
Study
|
[
0.9991902709007263,
0.00025646170252002776,
0.0005533152725547552
] |
[
0.9994495511054993,
0.00019825916388072073,
0.0003063870535697788,
0.000045794713514624164
] |
en
| 0.999997 |
Cladistic analyses were performed on each of the three data sets using equal weighting of all included characters. The second and third matrices were also analyzed giving weights of two to all non-endpoint characters. This weighting represents an attempt to compensate for the unintentional weight given to inversions in which both endpoints are present. This, of course, results in down-weighting inversions in which only one endpoint remains and fails to include inversions whose endpoints are both absent.
|
15324459_p29
|
15324459
|
Methods
| 3.750946 |
biomedical
|
Study
|
[
0.9934757351875305,
0.00031455137650482357,
0.006209705490618944
] |
[
0.9979973435401917,
0.0016537162009626627,
0.00027933658566325903,
0.00006954291893634945
] |
en
| 0.999998 |
Finally, to allow for a direct comparison of performance between gene order data and sequence data over the same taxa, we conducted maximum parsimony analyses of ITS and rbcL data. The ITS sequences were generated and aligned by Eddie et al . We determined taxa equal or equivalent to our taxa and performed analyses on just those taxa from the Eddie matrix (Table 5 ); only fifteen of our eighteen taxa were represented. We generated rbcL data to add to the two taxa already available so that we had rbcL sequence data from all of the eighteen mapped taxa. Exactly the same DNAs were used.
|
15324459_p30
|
15324459
|
Methods
| 4.071984 |
biomedical
|
Study
|
[
0.9988534450531006,
0.0002745653910096735,
0.0008719968027435243
] |
[
0.9996337890625,
0.0001944803516380489,
0.00013374687114264816,
0.00003805175219895318
] |
en
| 0.999996 |
In generating the rbcL sequences, we PCR-amplified about 1370 bp of the gene in 50 μl reactions containing: 1 μl unquantified total genomic DNA, 0.2 mM each dNTP, 2.5 mM MgCl2, 50 mM KCl, 10 mM Tris-HCl (pH 9.0), 0.4 μM each primer, and 1 unit Taq polymerase. Cycling conditions were as follows: 1 95°C denaturation step for 3 minutes 30 seconds, 30 cycles of 1 minute at 95°C, 1 minute at 55°C, and 1 minute 30 seconds at 72°C, and finally a 7 minute 72°C step. The PCR primers plus two internal primers were used for sequencing; the forward amplification primer and two internal primers were designed by G. Zurawski (his Z-1, Z-427 and Z-895). The Zurawski primer commonly used as the reverse amplification primer did not work in many Campanulaceae; we designed an alternative: 5'-GTATCCATTGCGCAAACTC-3'. For sequencing, two successful PCR reactions were combined and then cleaned (and concentrated) using the Qiagen QIAquick PCR Purification Kit . Depending on the concentration of the recovered product, 0.5–2 μl of this template was cycle sequenced and resolved on an ABI Prism 377 Automatic DNA Sequencer. Electropherograms were inspected, and then sequences were edited and assembled using Sequencher, vers 3.1 (Gene Codes Corp.) The sequences have been deposited in GenBank (accession numbers in Table 5 ). Alignment was performed by Sequencher and adjusted manually. Alignment of the rbcL sequences was very straightforward.
|
15324459_p31
|
15324459
|
Methods
| 4.20561 |
biomedical
|
Study
|
[
0.9992738366127014,
0.0003999924228992313,
0.0003261241945438087
] |
[
0.9991227984428406,
0.0006010211654938757,
0.00018701847875490785,
0.00008922012057155371
] |
en
| 0.999999 |
For all parsimony analyses, searches were conducted using the branch and bound algorithm in PAUP* 4.0b10 (PPC) . Tobacco was used as the outgroup for the gene order data since it has the ancestral chloroplast genome gene order for the angiosperms and Lobelia was used as the outgroup for the sequence data. See the additional file - data file 1 – for the Nexus file used in the PAUP analyses. This file includes the three gene order matrices and the rbcL alignment. The ITS alignment of Eddie et al is available online . The strength of the support, in each data set, for monophyletic groups was evaluated by calculating bootstrap values using 10,000 heuristic (TBR, multrees option) replicates. In addition, for each matrix, analyses were performed to generate all trees from the shortest to one percent longer. We used a percentage rather than an equal number of steps in an attempt to make an equivalent comparison among the different sized data sets. A consensus of these trees was determined and the number of nodes retained "to 1% longer" was calculated.
|
15324459_p32
|
15324459
|
Methods
| 4.130792 |
biomedical
|
Study
|
[
0.9987730383872986,
0.0003126866358797997,
0.0009142502094618976
] |
[
0.9994407296180725,
0.0002467979211360216,
0.00026353157591074705,
0.000048921501729637384
] |
en
| 0.999998 |
MEC performed the DNA isolations and Southern hybridizations, mapped the genomes, performed character codings and analyses for Matrix 2 and Matrix 3, and wrote up her work as a chapter of her Ph.D. thesis. LAR confirmed genome maps and character codings, updated MEC's analyses, added MATRIX 1 and its analysis, generated the rbcL sequence data, analysed ITS and rbcL data, and modified the thesis chapter for publication. RKJ assisted in all aspects of the work.
|
15324459_p33
|
15324459
|
Authors' contribution
| 0.978784 |
other
|
Other
|
[
0.2589820921421051,
0.00413477374240756,
0.7368831038475037
] |
[
0.007683880161494017,
0.9902958273887634,
0.0010868567042052746,
0.0009334735223092139
] |
en
| 0.999997 |
A work-related musculoskeletal disorder (WRMD) is defined as a musculoskeletal injury that results from a work-related event. This may result in lost work time, work restriction, or transfer to another job . These types of injuries are common among physiotherapists . This group has a moderately high prevalence of occupational low-back pain . Physical therapists routinely perform manual therapy, such as soft-tissue mobilization, which means that the upper limb is also exposed to risk factors associated with musculoskeletal and neurovascular disorders . In addition, these professionals routinely perform activities that involve transferring a patient (from exercise mat to chair, to parallel bar etc), assisting with activities on the exercise mat, and lifting and using cumbersome equipment . These work tasks put therapists at risk for both acute and cumulative musculoskeletal pain.
|
15315712_p0
|
15315712
|
Background
| 3.960885 |
biomedical
|
Other
|
[
0.9929637908935547,
0.00564690213650465,
0.001389268902130425
] |
[
0.059047263115644455,
0.9074926376342773,
0.03181967884302139,
0.001640350790694356
] |
en
| 0.999997 |
Understanding the issues related to musculoskeletal disorders in physical therapists requires some awareness of the context in which these professionals work. In Turkey, physiotherapists cannot treat patients directly. According to law, direct accesses to physiotherapists are not possible . Further, physiotherapists are not allowed to plan patients' physiotherapy programs; this is done by a physiatrist. Currently, efforts are underway to enact legal amendments that will permit a doctor to direct a patient to a physiotherapist, with the physiotherapist creating the physiotherapy program him- or herself.
|
15315712_p1
|
15315712
|
Background
| 1.825928 |
biomedical
|
Other
|
[
0.783520519733429,
0.01893601566553116,
0.19754347205162048
] |
[
0.003280953736975789,
0.9957367181777954,
0.0004863613867200911,
0.0004959637299180031
] |
en
| 0.999998 |
The purpose of this study was to investigate the prevalence and features of WRMDs in a group of Turkish physiotherapists working in various capacities in a large Turkish city, and to compare the findings to reports from other countries.
|
15315712_p2
|
15315712
|
Background
| 2.646984 |
biomedical
|
Study
|
[
0.9918317198753357,
0.0014011638704687357,
0.006767127197235823
] |
[
0.9986931681632996,
0.0010233114007860422,
0.0001538376382086426,
0.00012972713739145547
] |
en
| 0.999998 |
The study was approved by the Ethics Committee of Dokuz Eylül University. The research population was selected physiotherapists who were employed in a broad spectrum of practice settings in İzmir, Turkey. All data were collected by a mailed questionnaire (Appendix 1 [see Additional file 1 ]) that consisted of 17 close-ended questions. Questionnaires were distributed to all physiotherapists (205 total, 157 females and 48 males) who were registered members of the Izmir Branch of the Turkish Physiotherapy Association. Each member was asked to complete the self-administered questionnaire if they had more than 2 years of experience in practice. One hundred and twenty questionnaires were returned and analyzed (total response rate 59%, for women 59%, for men 58%).
|
15315712_p3
|
15315712
|
Methods
| 2.418926 |
biomedical
|
Study
|
[
0.9912049174308777,
0.001663542934693396,
0.00713151041418314
] |
[
0.9979875087738037,
0.001704688649624586,
0.0001602299598744139,
0.00014759512851014733
] |
en
| 0.999998 |
The questionnaire was based on another published survey and simply adapted and translated for the Turkish context. The questionnaire was composed of two parts, personal and occupational. The personal portion asked about general characteristics, including sex, age, weight, and height. The occupational portion inquired about years of experience, work setting, and number of hours of contact with patients per week. This section also asked whether the subject had experienced any WRMDs. If the answer was yes, the person was asked to state the type of injury, the body part affected, specific activities caused on occupational injury, the work setting in which the injury occurred, whether the injury was reported or a physician was consulted, and what sort of treatment was applied. They were also asked whether they lost work time as a result of the injury, what activities caused symptoms to recur, and whether the injury had caused the respondent to alter his or her work habits, reduce hours with patients, or change employment settings.
|
15315712_p4
|
15315712
|
Methods
| 3.014537 |
biomedical
|
Study
|
[
0.9932119846343994,
0.0016888161189854145,
0.005099148489534855
] |
[
0.9915688633918762,
0.007933915592730045,
0.00029378454200923443,
0.00020346386008895934
] |
en
| 0.999995 |
Data were analyzed using SPSS 10.0 for Windows. Results for the general information items were expressed as mean ± standard deviation, and results for items in the occupational portion were expressed as percentages. χ 2 were used to analyze influence personal characteristics (sex, age, number of years in physiotherapy practice, number of hours per week in direct patient care) to WRMDs.
|
15315712_p5
|
15315712
|
Methods
| 2.330471 |
biomedical
|
Study
|
[
0.9974059462547302,
0.0008321070345118642,
0.0017619469435885549
] |
[
0.9869822859764099,
0.012243983335793018,
0.000403151148930192,
0.00037064196658320725
] |
en
| 0.999997 |
The 120 respondents included 92 females and 28 males of mean age 30.4 ± 6.9 years (range, 22–55 years). Total response rate was 59%, for women 59%, for men 58%. General information about the group is given in Table 1 . The questionnaire answers indicated that the respondents spent an average of 38.8 ± 9.2 hours per week in direct patient care, and had 8.0 ± 6.0 years of work experience on average. Eighty-six of the physiotherapists worked in general hospitals, 24 worked at hydrotherapy centers, and 10 worked at pediatric rehabilitation centers.
|
15315712_p6
|
15315712
|
Results
| 2.504191 |
biomedical
|
Study
|
[
0.9844785928726196,
0.011124363169074059,
0.0043970444239676
] |
[
0.9920280575752258,
0.006985022220760584,
0.0003315279318485409,
0.0006554919527843595
] |
en
| 0.999997 |
Frequency of WRMDs was not correlated with sex (χ 2 =.234, P=.629), age (χ 2 =.383, P=.536), number of years in physiotherapy practice (χ 2 =.067, P=.795), or number of hours per week in direct patient care (χ 2 =.151, P=.698) (Table 2 ).
|
15315712_p7
|
15315712
|
Results
| 3.811565 |
biomedical
|
Study
|
[
0.998350977897644,
0.001046836143359542,
0.0006021796143613756
] |
[
0.9993389248847961,
0.00039175504934974015,
0.00018954066035803407,
0.0000798173641669564
] |
en
| 0.999997 |
One hundred and two respondents (85%) reported that they had experienced work-related musculoskeletal pain or discomfort at some time in their occupational lives. Seventy-eight (65%) reported that they had sustained more than one WRMD.
|
15315712_p8
|
15315712
|
Results
| 1.958367 |
biomedical
|
Study
|
[
0.9870595932006836,
0.00485246954485774,
0.008087961003184319
] |
[
0.9515739679336548,
0.0468030609190464,
0.0006550611578859389,
0.000967848056461662
] |
en
| 0.999997 |
The lower back was the body part with the highest frequency of occupational injury (26%), and wrist-hand (18%), shoulder (14%), and neck (12%) were other sites frequently affected (Table 3 ). The main types of injury reported were tendinitis (21%), vertebral disk problems (16%), muscle strain (16%), ligament sprain (16%), degeneration (15%), synovitis (6%), tear (2%), dislocation (1%), fracture (1%) and other (6%). The factors that most frequently led to WRMD were transferring patients (15%), performing repetitive tasks (14%), and lifting (14%) (Table 4 ).
|
15315712_p9
|
15315712
|
Results
| 4.037126 |
biomedical
|
Study
|
[
0.9989045858383179,
0.0007824054919183254,
0.00031303876312449574
] |
[
0.9992045760154724,
0.00033469044137746096,
0.0003638047492131591,
0.00009702000534161925
] |
en
| 0.999998 |
The respondents who had experienced a WRMD indicated that lifting (18%), maintaining a position for prolonged period of time (17%), performing repetitive tasks (16%), and transferring patients (16%) were the activities that most often exacerbated their symptoms during clinical practice (Table 5 ). Improvements in body mechanics (21%), avoiding lifting (16%), and changing working positions frequently (14%) were the top three changes that the injured respondents said they made in their working habits (Table 6 ).
|
15315712_p10
|
15315712
|
Results
| 3.602885 |
biomedical
|
Study
|
[
0.9968392848968506,
0.0020106674637645483,
0.0011500760447233915
] |
[
0.9986209869384766,
0.001014684559777379,
0.00023766251979395747,
0.0001267499610548839
] |
en
| 0.999994 |
Sixty-nine percent of the respondents with WRMDs had visited a physician for the problem, and 46% of whom stated that they had officially reported the injury to their employer. The respondents who had suffered WRMDs reported they used their own occupational knowledge, rest, medications, and exercise to treat the problem (Table 7 ). Sixty-seven percent of the respondents who had had WRMDs indicated that they had not permanently reduced their patient-contact time as a result of their injury, and 82% said they did not limit their areas of practice after sustaining the injury. Most of the physiotherapists (63%) who had had WRMDs indicated that they would not consider a job change because of their injury or due to the risk of sustaining another injury.
|
15315712_p11
|
15315712
|
Results
| 2.972143 |
biomedical
|
Study
|
[
0.986746609210968,
0.006048072129487991,
0.007205369882285595
] |
[
0.9955353736877441,
0.003930200356990099,
0.0002778249036055058,
0.00025662375264801085
] |
en
| 0.999998 |
Musculoskeletal system problems connected to occupational conditions are common among health care workers. The costs of these are substantial, both in terms of money and in terms of work time lost . Research has shown that musculoskeletal problems are particularly common in health care workers who are in direct contact with patients . Physiotherapists have a high prevalence of WRMDs .
|
15315712_p12
|
15315712
|
Discussion
| 2.047446 |
biomedical
|
Other
|
[
0.9897679686546326,
0.002063099294900894,
0.008168953470885754
] |
[
0.0852208361029625,
0.9028998017311096,
0.010514357127249241,
0.0013649921165779233
] |
en
| 0.999996 |
The results from studies on WRMDs in physiotherapists have generally been similar, though some have differed according to country. Such variations are linked to level of development, the status of the profession of physiotherapy in a given country, psychosocial, and epidemiological factors . In Turkey the law bars physiotherapists from providing primary care; each patient must be referred. Considering the differences in physiotherapy practice among countries and regions, we felt it would be valuable to investigate the prevalence and features of WRMDs in a group of Turkish physiotherapists working in various capacities, and to compare to findings in other countries.
|
15315712_p13
|
15315712
|
Discussion
| 2.313093 |
biomedical
|
Study
|
[
0.9931017160415649,
0.002018010476604104,
0.00488028721883893
] |
[
0.9622959494590759,
0.035785552114248276,
0.0012648362899199128,
0.0006536937435157597
] |
en
| 0.999996 |
In this study, we collected demographic and WRMD data from 120 physiotherapists in Izmir, Turkey, and analyzed rates of injury, risk factors, injury types and sites, and post-injury management. We asked to complete the self-administered questionnaire if they had more than 2 years of experience in practice. Thus, response rate of questionnaire was low (58.5 %) in our study. The survey answers revealed that 85% of the respondents had experienced WRMDs. Cromie reported that younger physiotherapists have a higher prevalence of musculoskeletal problems related to occupational conditions. Rugelj investigated low-back pain in physiotherapists, and found an incidence of 66% in subjects between the ages of 20 and 40 years . In line with this, a study of Australian physiotherapy students by Nyland revealed that the 20- to 21-year age group had the highest frequency of low-back pain. The average age of the physiotherapists in our study was 30.4 years. This mean age corresponds with other findings in the literature, and confirms that physiotherapists tend to experience WRMDs at young age. Such injuries in younger physiotherapists may be associated with lack of professional experience, and the lower knowledge and skill levels people tend to have in the early years of this career.
|
15315712_p14
|
15315712
|
Discussion
| 4.119981 |
biomedical
|
Study
|
[
0.9988186955451965,
0.0007255622767843306,
0.00045571065857075155
] |
[
0.9993958473205566,
0.00015866763715166599,
0.00036374948103912175,
0.00008169800275936723
] |
en
| 0.999997 |
Concerning sites of musculoskeletal injury during professional activities, the highest incidence is in the low-back region. Biomechanical studies have shown that physical loading factors, such as body flexion, rotation and weight loading, play a role in this . In a study that covered 25% of all physiotherapists working in Australia (824 total studied), Cromie found that the rate of work-related low-back pain was 48%. Other authors have revealed various rates of this problem in physiotherapists: Bork 45%, Holder 62%, Molumphy 29%, Scholey and Hair 38%, Mierzejewski 49.2%, Rugelj 73.7%, and Nyland 69%. Our survey of Turkish physiotherapists revealed a 25.5% incidence of low-back pain. Interestingly, this figure is lower than most other rates reported in the literature. In our study, when we categorized physiotherapists according to practice setting, low-back pain was the most common WRMD in all subgroups.
|
15315712_p15
|
15315712
|
Discussion
| 4.0847 |
biomedical
|
Study
|
[
0.9992302656173706,
0.00037924348725937307,
0.000390502653317526
] |
[
0.9991357922554016,
0.00016833189874887466,
0.0006364911678247154,
0.000059379006415838376
] |
en
| 0.999996 |
Studies of WRMDs in health care of professionals have identified the lower back as the most commonly involved area of the body, followed by neck and upper extremities . Investigations of physiotherapists have revealed similar results. Bork and Holder and et al. listed the regions most commonly involved musculoskeletal injuries as the lower back, hand-wrist, and neck, respectively among physiotherapists. On analyzing the different body parts injured in our subjects, we found the highest frequency of injuries in the lower back, followed by the hand-wrist (18.2%), shoulder (14.4%) and neck (11.8%).
|
15315712_p16
|
15315712
|
Discussion
| 3.952182 |
biomedical
|
Study
|
[
0.9994762539863586,
0.00018869298219215125,
0.0003350382321514189
] |
[
0.998353123664856,
0.00033439090475440025,
0.0012586187804117799,
0.000053928029956296086
] |
en
| 0.999997 |
According to the literature the work-related activities that most commonly lead to injury in health professionals are lifting heavy equipment and patients, transferring patient, maintaining the same posture for a long period, manual therapy practices, responding to patients' sudden movements, and repeated movements . Bork identified the main causes of WRMDs in physiotherapists as staying in the same position for along time and continuing to work when tired; Molumphy emphasized lifting and leaning downwards with sudden maximal effort; and West highlighted maintaining the same posture for along time, manual therapy, repeated movements, and increased work load. In our survey, the main causes of WRMDs were patient transfer, repeated movements, lifting heavy equipment, patients and working when too physically tired.
|
15315712_p17
|
15315712
|
Discussion
| 3.743471 |
biomedical
|
Study
|
[
0.996086835861206,
0.00033235616865567863,
0.003580828895792365
] |
[
0.9610990285873413,
0.010138719342648983,
0.02857663296163082,
0.00018562699551694095
] |
en
| 0.999996 |
Holder et al. identified three activities that aggravate the symptoms of former WRMDs in physiotherapists and assistant physiotherapists as staying in the same position for a long period, lifting and patient transfer. In our study, the respondents to our questionnaire noted lifting, staying in the same position for a long time, patient transfers, and repeated movements.
|
15315712_p18
|
15315712
|
Discussion
| 2.347767 |
biomedical
|
Study
|
[
0.9937812685966492,
0.0022500865161418915,
0.003968690987676382
] |
[
0.9874944090843201,
0.011302745901048183,
0.0006454623653553426,
0.0005574436509050429
] |
en
| 0.999998 |
In Turkey, most physiotherapists work in general hospitals. In these facilities, the daily treated patient number is too high, and this number far exceeds the number of physiotherapists on staff. In addition, the majority of patients in these hospitals are seriously ill .
|
15315712_p19
|
15315712
|
Discussion
| 1.500179 |
biomedical
|
Other
|
[
0.6989845037460327,
0.013912297785282135,
0.28710323572158813
] |
[
0.009743448346853256,
0.9889040589332581,
0.0006181304343044758,
0.0007344534969888628
] |
en
| 0.999997 |
People who suffer injuries on the job may be treated with medication, rest and exercise. Physiotherapists have fundamental knowledge about ergonomics and biomechanics, and using this knowledge may vary depending on professional knowledge and skills. In Turkey, physiotherapists are trained in ergonomic working principles at the undergraduate level. However, in many working environments the equipment used (treatment table, chair, etc .) is not ergonomic, and consequently the physiotherapist cannot follow ergonomic principles while doing his or her job.
|
15315712_p20
|
15315712
|
Discussion
| 2.031803 |
biomedical
|
Other
|
[
0.9515453577041626,
0.007778591476380825,
0.040676116943359375
] |
[
0.006127260625362396,
0.9927417039871216,
0.0005377951310947537,
0.0005932034109719098
] |
en
| 0.999997 |
A study conducted by Cromie in 2002 examined whether physiotherapists use their own knowledge to prevent WRMDs. The author found that this was true for most of the physiotherapists investigated. In our survey, of the physiotherapists who had suffered WRMDs, 27.6% said they used their professional knowledge and 26% said they used rest to manage the injury.
|
15315712_p21
|
15315712
|
Discussion
| 2.438708 |
biomedical
|
Study
|
[
0.9922162294387817,
0.0012773418566212058,
0.006506405305117369
] |
[
0.9927460551261902,
0.006262528710067272,
0.0007230261107906699,
0.0002682569611351937
] |
en
| 0.999998 |
Previous research has shown that physiotherapists who have suffered a WRMD tend to change their professional attitudes to avoid additional injuries. Holder et al. found that 79% of physiotherapists and 81% of assistant physiotherapists who had suffered injuries on the job changed their professional attitudes to avoid other WRMDs. It has been reported that the most common strategies used by physiotherapists to avoid WRMDs are correction of body mechanics, and frequent postural changes. The respondents to our questionnaire said that, after suffering a WRMD, they paid more attention to correcting body mechanics, avoided lifting heavy equipment or patients, changed position frequently, and got other personnel to help them with tasks that involved lifting.
|
15315712_p22
|
15315712
|
Discussion
| 3.263803 |
biomedical
|
Study
|
[
0.9858875870704651,
0.000814857252407819,
0.01329764537513256
] |
[
0.9919079542160034,
0.006238793954253197,
0.0017152235377579927,
0.00013806136848870665
] |
en
| 0.999998 |
Mierzejewski reported that 13.7% of physiotherapists in Edmonton, gave up their career after suffering work-related low-back pain, and that 35.3% continued to work after this problem. Cromie found that 17.7% of physiotherapists changed their field of practice in connection with WRMDs. Of the respondents in our Turkish survey who had suffered WRMDs, 67% did not change their field of practice after the injury, 82% did not restrict their time with patients, and 64% said they would not consider changing their field or department of practice due to their WRMD. This means that 33% did change field of practice after a WRMD, which is 1.9 times the rate of those who changed field in Cromie's study. As noted above, most physiotherapists in Turkey work in general hospitals, and it is not usually possible for such physiotherapists to change their field of work.
|
15315712_p23
|
15315712
|
Discussion
| 2.849271 |
biomedical
|
Study
|
[
0.9785594344139099,
0.0017506630392745137,
0.019689975306391716
] |
[
0.976374089717865,
0.021642766892910004,
0.001646260148845613,
0.00033685786183923483
] |
en
| 0.999995 |
Some professions have very high WRMD prevalence, and this has led to more intensive research in recent years. These types of injury have major consequences for society, workers, employers, and the insurance sector due to loss of labor force, long-term disability and delay in returning to work, decreased productivity, and psychological effects on employees. Therefore, minimizing and preventing WRMDs has significant potential social and economic benefits. It is important to invest in studies aimed at reducing these types of injuries in physiotherapists.
|
15315712_p24
|
15315712
|
Discussion
| 2.037781 |
biomedical
|
Other
|
[
0.8726094961166382,
0.002470889361575246,
0.1249196007847786
] |
[
0.01768011413514614,
0.9750667810440063,
0.00680553400889039,
0.0004474664165172726
] |
en
| 0.999998 |
Our study has three main limitations. A physiotherapist's working time in a day is not long, but he or she treats a very large number of patients during this time. Our survey would have been more informative if we collected data for the number of daily treated patients. We also did not inquire about the physiotherapists' activity levels. This would have been valuable information, as sports and recreational activity may affect WRMD frequency. Another limitation of our study was comparing various areas of practice and techniques used by physiotherapists and investigating their relationship to WRMDs.
|
15315712_p25
|
15315712
|
Discussion
| 2.168682 |
biomedical
|
Study
|
[
0.9929989576339722,
0.0025518012698739767,
0.004449268337339163
] |
[
0.9947768449783325,
0.004453849978744984,
0.00035751989344134927,
0.0004117843636777252
] |
en
| 0.999997 |
Our survey reveals that the WRMDs in physiotherapists in Turkey are similar to rates reported in other countries. Physiotherapists in our country suffer similar work-related injuries as their counterparts elsewhere, despite different legal working conditions and cultural differences. This study provides data related to WRMDs in physiotherapists in Turkey. Further studies can be very useful if it research prevalence of WRMDs in physiotherapists who have employed different working conditions.
|
15315712_p26
|
15315712
|
Conclusions
| 2.094105 |
biomedical
|
Study
|
[
0.9657813906669617,
0.001495239557698369,
0.032723404467105865
] |
[
0.9772018194198608,
0.02198871411383152,
0.0004744304751511663,
0.00033501777215860784
] |
en
| 0.999996 |
None declared.
|
15315712_p27
|
15315712
|
Competing interests
| 0.828596 |
other
|
Other
|
[
0.19056588411331177,
0.00526782963424921,
0.804166316986084
] |
[
0.017649328336119652,
0.97890704870224,
0.0020668187644332647,
0.0013767849886789918
] |
it
| 0.999995 |
YS participated in the design, managed the data collection and performed statistical analysis.
|
15315712_p28
|
15315712
|
Authors' Contributions
| 0.859983 |
other
|
Other
|
[
0.3291272222995758,
0.0032070819288492203,
0.6676657199859619
] |
[
0.012772941030561924,
0.9854471683502197,
0.001131797325797379,
0.0006480955053120852
] |
en
| 0.999997 |
AO participated in designed the study protocol, managed the coordination.
|
15315712_p29
|
15315712
|
Authors' Contributions
| 0.838221 |
other
|
Other
|
[
0.1474955528974533,
0.003774798009544611,
0.84872967004776
] |
[
0.00968135241419077,
0.9879043698310852,
0.001561671611852944,
0.0008526319288648665
] |
en
| 0.999996 |
All authors read and approved the final manuscript.
|
15315712_p30
|
15315712
|
Authors' Contributions
| 0.878058 |
other
|
Other
|
[
0.05443527549505234,
0.0028271139599382877,
0.9427376985549927
] |
[
0.002803728450089693,
0.9938488602638245,
0.002403399208560586,
0.0009439756977371871
] |
en
| 0.999997 |
Subsets and Splits
SQL Console for rntc/test-pp-aa
The query retrieves a sample of documents that are clinical cases with an educational score above 3, providing limited analytical value.
Clinical Cases Sample
Returns a sample of 100 clinical case documents, providing a basic overview of the document type's content.