Evolution of ischemic damage and behavioural deficit over 6 months after MCAo in the rat: Selecting the optimal outcomes and statistical power for multi-centre preclinical trials

Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue

Pengaruh Latihan Kegel Terhadap Frekuensi Inkontinensia Urine Pada Lansia Di Unit Rehabilitasi Sosial Margo Mukti Rembang

The purpose of this study was to determine the influence of the Kegel exercise on frequency of urinary incontinence in the elderly. This study used a quasi -experimental with one group pre and post test study design, conducted on 27 respondents selected by purposive sampling technique. Respondents were divided into three groups which were the first group with frequency of exercise 2 times, the second group with 3 times and the third group 4 times a day for six weeks. Data on the frequency of urinary incontinence were collected in pre and post intervention Kegel exercise. Data were analyzed using t-test (paired t-test).The results of the study revealed that group I , II & III in sequence value of t-count 21.92, t=11,418 and t=15.307 with P values p=0, 00. Further comparisons between the three groups showed group III showed the mean frequency of urinary incontinence at least. It can be concluded that Kegel exercises affect the decrease in the frequency of urinary incontinence in the elderly, and it is suggested that Kegel exercises should be done regularly

Fish oil diet associated with acute reperfusion related hemorrhage, and with reduced stroke-related sickness behaviors and motor impairment

Ischemic stroke is associated with motor impairment and increased incidence of affective disorders such as anxiety/clinical depression. In non-stroke populations, successful management of such disorders and symptoms has been reported following diet supplementation with long chain omega-3-polyunsaturated-fatty-acids (PUFAs). However, the potential protective effects of PUFA supplementation on affective behaviors after experimentally induced stroke and sham surgery have not been examined previously. This study investigated the behavioral effects of PUFA supplementation over a 6-week period following either middle cerebral artery occlusion or sham surgery in the hooded-Wistar rat. The PUFA diet supplied during the acclimation period prior to surgery was found to be associated with an increased risk of acute hemorrhage following the reperfusion component of the surgery. In surviving animals, PUFA supplementation did not influence infarct size as determined 6 weeks after surgery, but did decrease omega-6-fatty-acid levels, moderate sickness behaviors, acute motor impairment, and longer-term locomotor hyperactivity and depression/anxiety-like behavior

Can Animal Models of Disease Reliably Inform Human Studies?

H. Bart van der Worp and colleagues discuss the controversies and possibilities of translating the results of animal experiments into human clinical trials

Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia

No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research

Development of damage after ischemic stroke

© 2014 Dr. Sarah Susan Jane RewellStroke is an important disease which urgently needs new treatments. However, despite the promise of animal experimentation, new therapies have not been forthcoming. One plausible reason for this translational impasse is the way we use the available animal models of stroke. In this thesis, I explore shortcomings in the employment of the most commonly used animal model of stroke, thread occlusion of the rat middle cerebral artery. A retrospective analysis of in house infarct volume data after thread occlusion MCAo within and between strains of rat found success of stroke induction and the resulting infarct volume to be highly strain dependent. The widely used Sprague Dawley strain had the most variable data, suggesting that they are an unsuitable strain in which to model stroke. In the Spontaneously Hypertensive Rat (SHR), infarcts involving both the cortex and striatum could be consistently induced. This was chosen as the most appropriate strain of rat in which to model stroke. In the SHR, the dimensions of the occluding thread, together with the duration of MCA occlusion, were modified to produce a moderately sized infarct that has potential to demonstrate protection or exacerbation of damage. Protection of ischemic damage was demonstrated using hypothermia treatment (33°C for 130 minutes initiated at the onset of MCAo). Differences in the protective effect of hypothermia across three different experiments were thought to be in part due to differences in the rate of hypothermia induction and the size of the infarct in normothermic animals. To more closely align our animal model to the clinical situation, behavioural and histological outcomes were assessed for up to 6 months after stroke. Animals could be successfully maintained for up to 6 months with moderately sized infarcts. Mortality when it occurred (21% overall) was attributable to unintentional subarachnoid haemorrhage or potential infection, with little subsequent mortality observed beyond 21 days. Rats exhibited stroke related impairments that were strong during the early period after stroke, but with improvement over time. Differences between stroke and sham animals were evident for the entire observation period for the adhesive removal test of sensory neglect. Sample size calculations based on the time to remove the contralateral tape at different timepoints after stroke revealed that large numbers of animals would be required if the adhesive removal test were to be used as the primary outcome measure for future studies. Success of stroke induction was high, with all animals showing histological evidence of ischemic damage. The type and size of damage was examined and mapped according to time, following a similar pattern to that described in the literature. Damage progressed from a necrotic infarct to fluid filled cavity over 6 months. As the cellular and connective tissue makeup of the damaged area changes with progression of the infarct, this study highlights how expression of damage becomes an important factor in allowing fair comparison across groups collected at different timepoints. Oedema and later atrophy have significant impacts on the volume of damaged tissue. When these were taken into account by expressing damage as proportional tissue loss, all groups had a similar proportion of tissue damaged by the stroke, with the difference being only the composition of that damage. Sample size calculations revealed that the most practical time after stroke to detect a 30% difference in tissue loss (n=10 per experimental group) was at 28 days post stroke. The approaches taken in this thesis to enhance reproducibility and examine stroke in animal models at times and with outcome measures that are clinically relevant may help overcome the translational roadblock in stroke research, and ultimately to new treatments for ischemic stroke

Rewell - Raw data - PLOS One

This Excel file tabulates the raw infarct and behavioural data described in our manuscript

Randomisation, blinded outcome assessment, and sample size calculation in systematic reviews of animal studies.

a<p>Summarises the data of six systematic reviews of treatment strategies for acute ischemic stroke. There is an overlap of 18 publications between references <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-Sena1" target="_blank">[16]</a> and <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000245#pmed.1000245-VanderWorp2" target="_blank">[19]</a>.</p><p>ALS, amyotrophic lateral sclerosis; N/A, data not available; RDS, respiratory distress syndrome.</p