scholarly journals Risk of bias reporting in the recent animal focal cerebral ischaemia literature

2017 ◽  
Vol 131 (20) ◽  
pp. 2525-2532 ◽  
Author(s):  
Zsanett Bahor ◽  
Jing Liao ◽  
Malcolm R. Macleod ◽  
Alexandra Bannach-Brown ◽  
Sarah K. McCann ◽  
...  
Keyword(s):  
Sample Size ◽  
Animal Experiments ◽  
Sample Size Calculation ◽  
Artery Occlusion ◽  
Experimental Models ◽  
Risk Of Bias ◽  
Experimental Stroke ◽  
Lacunar Stroke ◽  
Automated Tools

Background: Findings from in vivo research may be less reliable where studies do not report measures to reduce risks of bias. The experimental stroke community has been at the forefront of implementing changes to improve reporting, but it is not known whether these efforts are associated with continuous improvements. Our aims here were firstly to validate an automated tool to assess risks of bias in published works, and secondly to assess the reporting of measures taken to reduce the risk of bias within recent literature for two experimental models of stroke. Methods: We developed and used text analytic approaches to automatically ascertain reporting of measures to reduce risk of bias from full-text articles describing animal experiments inducing middle cerebral artery occlusion (MCAO) or modelling lacunar stroke. Results: Compared with previous assessments, there were improvements in the reporting of measures taken to reduce risks of bias in the MCAO literature but not in the lacunar stroke literature. Accuracy of automated annotation of risk of bias in the MCAO literature was 86% (randomization), 94% (blinding) and 100% (sample size calculation); and in the lacunar stroke literature accuracy was 67% (randomization), 91% (blinding) and 96% (sample size calculation). Discussion: There remains substantial opportunity for improvement in the reporting of animal research modelling stroke, particularly in the lacunar stroke literature. Further, automated tools perform sufficiently well to identify whether studies report blinded assessment of outcome, but improvements are required in the tools to ascertain whether randomization and a sample size calculation were reported.

scholarly journals Contraceptive drugs mitigate experimental stroke-induced brain injury

2018 ◽  
Vol 115 (3) ◽  
pp. 637-646 ◽  
Author(s):  
Mohamad El Amki ◽  
Nadine Binder ◽  
Riccardo Steffen ◽  
Hannah Schneider ◽  
Andreas R Luft ◽  
...  
Keyword(s):  
Brain Injury ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Experimental Models ◽  
Experimental Stroke ◽  
Protective Effects ◽  
New Generation ◽  
Cerebral Artery Occlusion

AbstractAimsEffective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells.Methods and resultsMCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.ConclusionFor the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.

scholarly journals Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

2019 ◽  
Author(s):  
Zahraa S. Al-Ahmady ◽  
Dhifaf Jasim ◽  
Sabahuddin Syed Ahmad ◽  
Raymond Wong ◽  
Michael Haley ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Experimental Stroke ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Ischaemic Brain

AbstractThe development of new therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair.These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify for the first time two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of new stroke treatments.

scholarly journals The AAA + ATPase Thorase is neuroprotective against ischemic injury

2018 ◽  
Vol 39 (9) ◽  
pp. 1836-1848 ◽  
Author(s):  
Jianmin Zhang ◽  
Jia Yang ◽  
Huaishan Wang ◽  
Omar Sherbini ◽  
Matthew J Keuss ◽  
...  
Keyword(s):  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Glutamate Excitotoxicity ◽  
Experimental Stroke ◽  
Dependent Manner ◽  
Aaa Atpase ◽  
Neurologic Disorders ◽  
Cerebral Artery Occlusion

Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo. Thorase provides neuroprotection in an ATP-dependent manner against oxygen–glucose deprivation (OGD) neurotoxicity or glutamate N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in vitro. Knock-down of Thorase prevents the establishment of preconditioning induced neuroprotection against OGD or NMDA neurotoxicity. Transgenic overexpression of Thorase provides neuroprotection in vivo against middle cerebral artery occlusion (MCAO)-induced stroke in mice, while genetic deletion of Thorase results in increased injury in vivo following stroke. These results define Thorase as a neuroprotective protein and understanding Thorase signaling could offer a new therapeutic strategy for the treatment of neurologic disorders.

scholarly journals Findings of a retrospective, controlled cohort study of the impact of a change in Nature journals' editorial policy for life sciences research on the completeness of reporting study design and execution

2017 ◽  
Author(s):  
Malcolm Robert Macleod ◽  
Keyword(s):  
Cohort Study ◽  
Sample Size ◽  
Standard Procedure ◽  
Life Sciences ◽  
Sample Size Calculation ◽  
Editorial Policy ◽  
Sensitive Information ◽  
The Impact

AbstractObjectiveTo determine whether a change in editorial policy, including the implementation of a checklist, has been associated with improved reporting of measures which might reduce the risk of bias.MethodsThe study protocol has been published at DOI: 10.1007/s11192-016-1964-8.DesignObservational cohort study.PopulationArticles describing research in the life sciences published in Nature journals, submitted after May 1st 2013.InterventionMandatory completion of a checklist at the point of manuscript revision.Comparators(1) Articles describing research in the life sciences published in Nature journals, submitted before May 2013; (2) Similar articles in other journals matched for date and topic.Primary OutcomeChange in proportion of Nature publications describing in vivo research published before and after May 2013 reporting the Landis 4 items (randomisation, blinding, sample size calculation, exclusions).We included 448 NPG papers (223 published before May 2013, 225 after) identified by an individual hired by NPG for this specific task, working to a standard procedure; and an independent investigator used Pubmed Related Citations to identify 448 non-NPG papers with a similar topic and date of publication in other journals; and then redacted all publications for time sensitive information and journal name. Redacted manuscripts were assessed by 2 trained reviewers against a 74 item checklist, with discrepancies resolved by a third.Results394 NPG and 353 matching non-NPG publications described in vivo research. The number of NPG publications meeting all relevant Landis 4 criteria increased from 0/203 prior to May 2013 to 31/181 (16.4%) after (2-sample test for equality of proportions without continuity correction, X2 = 36.2, df = 1, p = 1.8 x 10-9). There was no change in the proportion of non‐ NPG publications meeting all relevant Landis 4 criteria (1/164 before, 1/189 after). There were more substantial improvements in the individual prevalences of reporting of randomisation, blinding, exclusions and sample size calculations for in vivo experiments, and less substantial improvements for in vitro experiments.ConclusionsThere was a substantial improvement in the reporting of risks of bias in in vivo research in NPG journals following a change in editorial policy, to a level that to our knowledge has not been previously observed. However, there remain opportunities for further improvement.

scholarly journals Improved reperfusion following alternative surgical approach for experimental stroke in mice

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 188
Author(s):  
Melissa Trotman-Lucas ◽  
Raymond Wong ◽  
Stuart M. Allan ◽  
Claire L. Gibson
Keyword(s):  
Ischemic Stroke ◽  
Surgical Approach ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Experimental Stroke ◽  
Contrast Imaging ◽  
Ipsilateral Hemisphere ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery.  In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion.  We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability.  Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion.  All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.

scholarly journals What exactly is ‘N’ in cell culture and animal experiments?

2017 ◽  
Author(s):  
Stanley E. Lazic ◽  
Charlie J. Clarke-Williams ◽  
Marcus R. Munafò
Keyword(s):  
Sample Size ◽  
Ex Vivo ◽  
Animal Experiments ◽  
Statistical Inferences ◽  
Independent Replication ◽  
Biological Entities ◽  
Positive Results ◽  
Apparent Evidence

AbstractBiologists establish the existence of experimental effects by applying treatments or interventions to biological entities or units, such as people, animals, slice preparations, or cells. When done appropriately, independent replication of the entity-intervention pair contributes to the sample size (N) and forms the basis of statistical inference. However, sometimes the appropriate entity-intervention pair may not be obvious, and the wrong choice can make an experiment worthless. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents but effects examined in the offspring, as regulatory authorities have provided clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17% to 29%) replicated the correct entity-intervention pair and thus made valid statistical inferences. Approximately half of the studies (46%, 95% CI = 38% to 53%) had pseudoreplication while 32% (95% CI = 26% to 39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, leading to more false positive results and inflating the apparent evidence supporting a scientific claim. It is hard for science to advance when so many experiments are poorly designed and analysed. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide guidelines for designing and analysing in vitro, ex vivo, and in vivo experiments.

scholarly journals Did a change in Nature journals’ editorial policy for life sciences research improve reporting?

2019 ◽  
Vol 3 (1) ◽  
pp. e000035 ◽  
Author(s):  
Keyword(s):  
Sample Size ◽  
Primary Outcome ◽  
Standard Procedure ◽  
Life Sciences ◽  
Sample Size Calculation ◽  
Editorial Policy ◽  
Sensitive Information ◽  
In Vivo Experiments

ObjectiveTo determine whether a change in editorial policy, including the implementation of a checklist, has been associated with improved reporting of measures which might reduce the risk of bias.MethodsThe study protocol has been published at doi: 10.1007/s11192-016-1964-8.DesignObservational cohort study.PopulationArticles describing research in the life sciences published in Nature journals, submitted after 1 May 2013.InterventionMandatory completion of a checklist during manuscript revision.Comparators(1) Articles describing research in the life sciences published in Nature journals, submitted before May 2013; and (2) similar articles in other journals matched for date and topic.Primary outcomeThe primary outcome is change in the proportion of Nature articles describing in vivo research published before and after May 2013 reporting the ‘Landis 4’ items (randomisation, blinding, sample size calculation and exclusions). We included 448 Nature Publishing Group (NPG) articles (223 published before May 2013, and 225 after) identified by an individual hired by NPG for this specific task, working to a standard procedure; and an independent investigator used PubMed ‘Related Citations’ to identify 448 non-NPG articles with a similar topic and date of publication from other journals; and then redacted all articles for time-sensitive information and journal name. Redacted articles were assessed by two trained reviewers against a 74-item checklist, with discrepancies resolved by a third.Results394 NPG and 353 matching non-NPG articles described in vivo research. The number of NPG articles meeting all relevant Landis 4 criteria increased from 0/203 prior to May 2013 to 31/181 (16.4%) after (two-sample test for equality of proportions without continuity correction, Χ²=36.2, df=1, p=1.8×10−9). There was no change in the proportion of non-NPG articles meeting all relevant Landis 4 criteria (1/164 before, 1/189 after). There were more substantial improvements in the individual prevalences of reporting of randomisation, blinding, exclusions and sample size calculations for in vivo experiments, and less substantial improvements for in vitro experiments.ConclusionThere was an improvement in the reporting of risks of bias in in vivo research in NPG journals following a change in editorial policy, to a level that to our knowledge has not been previously observed. However, there remain opportunities for further improvement.

The Quality of Reporting Raises Questions on the Experimental Validity of Animal Studies Conducted in India and Sri Lanka: Preliminary Analysis of a Systematic Survey

2020 ◽  
Vol 48 (2) ◽  
pp. 85-91
Author(s):  
Vijay Pal Singh ◽  
Ayushi Jain ◽  
Shubhra Gupta ◽  
Manudharshy Vijayakumar ◽  
Kunal Pratap ◽  
...  
Keyword(s):  
Sri Lanka ◽  
Animal Studies ◽  
Peer Review Process ◽  
Animal Experiments ◽  
Sample Size Calculation ◽  
Quality Of Reporting ◽  
Systematic Survey ◽  
In Vivo Experiments

The quality of animal experiments in terms of appropriate reporting is a concern, particularly with regard to their validity and the recording of the measures taken to reduce various types of bias. A systematic survey of 1371 and 236 publications from India and Sri Lanka, respectively, which were published between 1905 and 2017 and indexed in NCBI-PubMed, Cinhal, MEDLINE and Scopus, was carried out. The level of detail in the descriptions of animals used and the measures taken to reduce bias were analysed in each article. Selected parameters from the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, such as age, weight, sex, sample size calculation, blinding and randomisation were considered. The findings revealed poor reporting standards in animal experiments carried out in India and Sri Lanka, confirming the limited impact of the ARRIVE guidelines. These findings emphasise the urgent need for improvements in the peer review process, both prior to a study being set up and in the post-study reporting phase, and for more stringent adherence to the ARRIVE guidelines in the reporting of animal experiments.

scholarly journals Microcirculatory Changes in Experimental Models of Stroke and CNS-Injury Induced Immunodepression

2019 ◽  
Vol 20 (20) ◽  
pp. 5184 ◽  
Author(s):  
Sarah Lunardi Baccetto ◽  
Christian Lehmann
Keyword(s):  
Immune Response ◽  
Cause Of Death ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Artery Occlusion ◽  
Experimental Models ◽  
Experimental Stroke ◽  
Cns Injury ◽  
Peripheral Immune Response ◽  
The Impact

Stroke is the second-leading cause of death globally and the leading cause of disability in adults. Medical complications after stroke, especially infections such as pneumonia, are the leading cause of death in stroke survivors. Systemic immunodepression is considered to contribute to increased susceptibility to infections after stroke. Different experimental models have contributed significantly to the current knowledge of stroke pathophysiology and its consequences. Each model causes different changes in the cerebral microcirculation and local inflammatory responses after ischemia. The vast majority of studies which focused on the peripheral immune response to stroke employed the middle cerebral artery occlusion method. We review various experimental stroke models with regard to microcirculatory changes and discuss the impact on local and peripheral immune response for studies of CNS-injury (central nervous system injury) induced immunodepression.

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