ABSTRACT
Down syndrome is a well-studied aneuploidy condition in humans, which is associated with various disease phenotypes including cardiovascular, neurological, haematological and immunological disease processes. This review paper aims to discuss the research conducted on gene expression studies during fetal development. A descriptive review was conducted, encompassing all papers published on the PubMed database between September 1960 and September 2022. We found that in amniotic fluid, certain genes such as COL6A1 and DSCR1 were found to be affected, resulting in phenotypical craniofacial changes. Additionally, other genes such as GSTT1, CLIC6, ITGB2, C21orf67, C21orf86 and RUNX1 were also identified to be affected in the amniotic fluid. In the placenta, dysregulation of genes like MEST, SNF1LK and LOX was observed, which in turn affected nervous system development. In the brain, dysregulation of genes DYRK1A, DNMT3L, DNMT3B, TBX1, olig2 and AQP4 has been shown to contribute to intellectual disability. In the cardiac tissues, dysregulated expression of genes GART, ETS2 and ERG was found to cause abnormalities. Furthermore, dysregulation of XIST, RUNX1, SON, ERG and STAT1 was observed, contributing to myeloproliferative disorders. Understanding the differential expression of genes provides insights into the genetic consequences of DS. A better understanding of these processes could potentially pave the way for the development of genetic and pharmacological therapies.
Subject(s)
Down Syndrome , Intellectual Disability , Pregnancy , Female , Humans , Down Syndrome/metabolism , Core Binding Factor Alpha 2 Subunit/genetics , Phenotype , Gene ExpressionABSTRACT
Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke.
Subject(s)
Ischemic Stroke , Transcutaneous Electric Nerve Stimulation , Vagus Nerve Stimulation , Animals , Humans , Vagus Nerve/physiologyABSTRACT
PURPOSE OF REVIEW: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic approach for neurological and psychiatric disorders. In recent years, there has been increasing interest in VNS for treating ischemic stroke. This review discusses the evidence supporting VNS as a treatment option for ischemic stroke and elucidates its underlying mechanisms. RECENT FINDINGS: Preclinical studies investigating VNS in stroke models have shown reduced infarct volumes and improved neurological deficits. Additionally, VNS has been found to reduce reperfusion injury. VNS may promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulating the release of neurotransmitters. Additionally, VNS may stimulate neuroplasticity, thereby facilitating post-stroke recovery. The Food and Drug Administration has approved invasive VNS (iVNS) combined with rehabilitation for ischemic stroke patients with moderate to severe upper limb deficits. However, iVNS is not feasible in acute stroke due to its time-sensitive nature. Non-invasive VNS (nVNS) may be an alternative approach for treating ischemic stroke. While the evidence from preclinical studies and clinical trials of nVNS is promising, the mechanisms through which VNS exerts its beneficial effects on ischemic stroke are still being elucidated. Therefore, further research is needed to better understand the efficacy and underlying mechanisms of nVNS in ischemic stroke. Moreover, large-scale randomized clinical trials are necessary to determine the optimal nVNS protocols, assess its long-term effects on stroke recovery and outcomes, and identify the potential benefits of combining nVNS with other rehabilitation strategies.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke Rehabilitation , Stroke , Vagus Nerve Stimulation , Humans , Brain Ischemia/therapy , Vagus Nerve Stimulation/methods , Stroke/therapy , Upper ExtremityABSTRACT
BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.
Subject(s)
Implantable Neurostimulators/adverse effects , Ischemic Stroke/complications , Stroke Rehabilitation/methods , Upper Extremity/physiopathology , Vagus Nerve Stimulation/instrumentation , Aged , Case-Control Studies , Combined Modality Therapy/methods , Exercise Therapy/methods , Female , Humans , Ischemic Stroke/rehabilitation , Male , Middle Aged , Outcome Assessment, Health Care , Paresis/etiology , Recovery of Function/physiology , Treatment Outcome , Vocal Cord Paralysis/epidemiologyABSTRACT
OBJECTIVE: Extracellular vesicles (EVs) derived from neural progenitor cells enhance poststroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced poststroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of neural progenitor cells, we examined if neural progenitor cell-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process. Approach and Results: Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain ECs (ECs) and astrocytes exposed to oxygen glucose deprivation, we examined the effects of EVs or vehicle on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ABCB1 (ATP-binding cassette transporter B1) levels when exposed to oxygen glucose deprivation, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB (nuclear factor-κB) pathway. Using a BBB co-culture model of ECs and astrocytes exposed to oxygen glucose deprivation, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway, and downstream matrix metalloproteinase 9 (MMP-9) activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a poststroke modulation of immune responses. CONCLUSIONS: Our findings suggest that EVs enhance poststroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway. Graphic Abstract: A graphic abstract is available for this article.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Blood-Brain Barrier/physiology , NF-kappa B/metabolism , Stroke/metabolism , Animals , Cell Survival , Cells, Cultured , Coculture Techniques , Disease Models, Animal , Endothelial Cells/metabolism , Extracellular Vesicles/metabolism , Glucose/metabolism , Hypoxia/metabolism , Hypoxia/pathology , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/pathology , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Neural Stem Cells/metabolism , Oxygen/metabolism , Stroke/pathology , Transcription Factor RelA/metabolism , Zonula Occludens-1 Protein/metabolismABSTRACT
OBJECTIVE: A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit. DATA SOURCES: Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). Abstracts from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors. STUDY SELECTION AND DATA EXTRACTION: English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors. DATA SYNTHESIS: An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed. CONCLUSIONS: Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.
Subject(s)
Ischemic Stroke , Stroke , Aspirin , Cilostazol/therapeutic use , Clopidogrel , Drug Therapy, Combination , Humans , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Stroke/chemically induced , Stroke/drug therapy , Stroke/prevention & controlABSTRACT
Exercise interventions have been shown to help physical fitness, walking, and balance after stroke, but data are lacking on whether such interventions lead to improvements in health-related quality of life (HRQoL). In this systematic review and meta-analysis, 30 randomized controlled trials (n=1836 patients) were found from PubMed, OVID MEDLINE, Web of Science, CINAHL, SCOPUS, The Cochrane Library, and TRIP databases when searched from 1966 to February 2020 that examine the effects of exercise interventions on HRQoL after stroke or transient ischemic attack. Exercise interventions resulted in small to moderate beneficial effects on HRQoL at intervention end (standardized mean difference, -0.23 [95% CI, -0.40 to -0.07]) that appeared to diminish at longer-term follow-up (standardized mean difference, -0.11 [95% CI, -0.26 to 0.04]). Exercise was associated with moderate improvements in physical health (standardized mean difference, -0.33 [95% CI, -0.61 to -0.04]) and mental health (standardized mean difference, -0.29 [95% CI, -0.49 to -0.09]) domains of HRQoL while effects on social or cognitive composites showed little difference. Interventions that were initiated within 6 months, lasted at least 12 weeks in duration, involved at least 150 minutes per week, and included resistance training appeared most effective. Exercise can lead to moderate beneficial effects on HRQoL and should be considered an integral part of stroke rehabilitation.
Subject(s)
Exercise/physiology , Ischemic Attack, Transient/therapy , Quality of Life , Stroke Rehabilitation/methods , Stroke/therapy , Exercise/psychology , Exercise Therapy/methods , Exercise Therapy/psychology , Humans , Ischemic Attack, Transient/psychology , Physical Fitness/physiology , Quality of Life/psychology , Randomized Controlled Trials as Topic/methods , Stroke/psychology , Stroke Rehabilitation/psychology , Treatment OutcomeABSTRACT
Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.
Subject(s)
Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Disinfectants/toxicity , Thiazoles/toxicity , Acetylcysteine/pharmacology , Animals , Antioxidants/pharmacology , Blood-Brain Barrier/pathology , Brain/drug effects , Brain/metabolism , Brain/pathology , Cell Death/drug effects , Cell Line , Disinfectants/antagonists & inhibitors , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Energy Metabolism/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Proteolysis/drug effects , Reactive Oxygen Species/metabolism , Sulfhydryl Compounds/metabolism , Thiazoles/antagonists & inhibitors , Tight Junction Proteins/metabolismABSTRACT
Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.
Subject(s)
Brain Ischemia/drug therapy , Carnosine/pharmacology , Infarction, Middle Cerebral Artery/complications , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 9/chemistry , Matrix Metalloproteinase Inhibitors/pharmacology , Reperfusion Injury/drug therapy , Animals , Brain Ischemia/enzymology , Brain Ischemia/etiology , Brain Ischemia/pathology , Female , Rats , Rats, Sprague-Dawley , Reperfusion Injury/enzymology , Reperfusion Injury/etiology , Reperfusion Injury/pathologyABSTRACT
BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.
Subject(s)
Brain Ischemia/therapy , Neural Stem Cells/transplantation , Recovery of Function/physiology , Stem Cell Transplantation/methods , Stroke/therapy , Adult , Aged , Brain Ischemia/physiopathology , Female , Humans , Male , Middle Aged , Prospective Studies , Stroke/physiopathology , Stroke Rehabilitation , Treatment Outcome , Upper Extremity/physiopathologyABSTRACT
l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. We hypothesized that d-carnosine, which is not a substrate for carnosinases, may have a better pharmacological profile and may be more efficacious at lower doses than l-carnosine. To test our hypothesis, we explored the comparative pharmacokinetics and neuroprotective properties of d- and L-carnosine in acute ischaemic stroke in mice. We initially investigated the pharmacokinetics of d- and L-carnosine in serum and brain after intravenous (IV) injection in mice. We then investigated the comparative efficacy of d- and l-carnosine in a mouse model of transient focal cerebral ischemia followed by in vitro testing against excitotoxicity and free radical generation using primary neuronal cultures. The pharmacokinetics of d- and l-carnosine were similar in serum and brain after IV injection in mice. Both d- and l-carnosine exhibited similar efficacy against mouse focal cerebral ischemia. In vitro studies in neurons showed protection against excitotoxicity and the accumulation of free radicals. d- and l-carnosine exhibit similar pharmacokinetics and have similar efficacy against experimental stroke in mice. Since humans have far higher levels of carnosinases, d-carnosine may have more favorable pharmacokinetics in future human studies.
Subject(s)
Carnosine/administration & dosage , Ischemic Stroke/drug therapy , Neurons/cytology , Neuroprotective Agents/administration & dosage , Animals , Brain Chemistry , Carnosine/chemistry , Carnosine/pharmacokinetics , Cells, Cultured , Disease Models, Animal , Humans , Injections, Intravenous , Ischemic Stroke/blood , Male , Mice , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Primary Cell CultureABSTRACT
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system. Animal models of MS have been critical for elucidating MS pathological mechanisms and how they may be targeted for therapeutic intervention. Here we review the most commonly used animal models of MS. Although these animal models cannot fully replicate the MS disease course, a number of models have been developed to recapitulate certain stages. Experimental autoimmune encephalomyelitis (EAE) has been used to explore neuroinflammatory mechanisms and toxin-induced demyelinating models to further our understanding of oligodendrocyte biology, demyelination and remyelination. Zebrafish models of MS are emerging as a useful research tool to validate potential therapeutic candidates due to their rapid development and amenability to genetic manipulation.
Subject(s)
Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , AnimalsABSTRACT
OBJECTIVE: An association between cerebral venous sinus thrombosis (CVST) and high altitude has been previously proposed, but limited published data exist to support this association. We investigated 28 cases of CVST occurring at high altitude and sought to describe patient demographics, altitude and acclimatization, hematological laboratory findings, neuroimaging, treatment, and prognosis in these cases. METHODS: Twenty-eight cases of symptomatic CVST occurring at high altitude were identified between the months of August 2017 and December 2018, in collaboration with Military Hospital, Rawalpindi and Combined Military Hospital, Skardu (Pakistan). Follow-up visits were performed at 1 and 6 months. RESULTS: Twenty-seven (96%) of the patients were males, and the mean age was 33 years. In total, 32.1% were smokers. The mean NIHSS score on presentation was 5.5. 85.7% of the cases occurred at altitude higher than 8,000 feet. On average 107.8 days were spent at a high altitude prior to CVST. Totally, 71.4% had acclimatized for >2 weeks. The mean hemoglobin (Hb) value was 16.7 g/dL and 50% had d-dimer levels higher than 1,000 ng/mL. On MRI, 25% showed signs of hemorrhage and 14.3% showed infarcts. Treatments provided include low-molecular-weight heparin and Rivaroxaban and were associated with good outcomes. CONCLUSION: CVST is not uncommon at high altitude (>8,000 feet). It is predominantly a male disease. Most patients have high Hb and high D-dimer levels. The overall outcome was good.
Subject(s)
Altitude , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Factor Xa Inhibitors/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Rivaroxaban/therapeutic use , Sinus Thrombosis, Intracranial/drug therapy , Venous Thrombosis/drug therapy , Acclimatization , Adult , Anticoagulants/adverse effects , Biomarkers/blood , Factor Xa Inhibitors/adverse effects , Female , Fibrin Fibrinogen Degradation Products/metabolism , Hemoglobins/metabolism , Heparin, Low-Molecular-Weight/adverse effects , Hospitals, Military , Humans , Male , Middle Aged , Military Personnel , Pakistan , Retrospective Studies , Risk Factors , Rivaroxaban/adverse effects , Sinus Thrombosis, Intracranial/blood , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/etiology , Time Factors , Treatment Outcome , Venous Thrombosis/blood , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/etiology , Young AdultABSTRACT
OBJECTIVE: Secondary vascular risk reduction is critical to preventing recurrent stroke. We aimed to evaluate the effect of exercise interventions on vascular risk factors and recurrent ischaemic events after stroke or transient ischaemic attack (TIA). DESIGN: Intervention systematic review and meta-analysis. DATA SOURCES: OVID MEDLINE, PubMed, The Cochrane Library, Web of Science, The National Institute for Health and Care Excellence, TRIP Database, CINAHL, PsycINFO, SCOPUS, UK Clinical Trials Gateway and the China National Knowledge Infrastructure were searched from 1966 to October 2017. ELIGIBILITY CRITERIA: Randomised controlled trials evaluating aerobic or resistance exercise interventions on vascular risk factors and recurrent ischaemic events among patients with stroke or TIA, compared with control. RESULTS: Twenty studies (n=1031) were included. Exercise interventions resulted in significant reductions in systolic blood pressure (SBP) -4.30 mm Hg (95% CI -6.77 to -1.83) and diastolic blood pressure -2.58 mm Hg (95% CI -4.7 to -0.46) compared with control. Reduction in SBP was most pronounced among studies initiating exercise within 6 months of stroke or TIA (-8.46 mm Hg, 95% CI -12.18 to -4.75 vs -2.33 mm Hg, 95% CI -3.94 to -0.72), and in those incorporating an educational component (-7.81 mm Hg, 95% CI -14.34 to -1.28 vs -2.78 mm Hg, 95% CI -4.33 to -1.23). Exercise was also associated with reductions in total cholesterol (-0.27 mmol/L, 95% CI -0.54 to 0.00), but not fasting glucose or body mass index. One trial reported reductions in secondary vascular events with exercise, but was insufficiently powered. SUMMARY: Exercise interventions can result in clinically meaningful blood pressure reductions, particularly if initiated early and alongside education.
Subject(s)
Blood Pressure/physiology , Exercise Therapy/methods , Ischemic Attack, Transient/prevention & control , Ischemic Attack, Transient/physiopathology , Secondary Prevention , Stroke/prevention & control , Stroke/physiopathology , Blood Glucose/metabolism , Body Mass Index , Cholesterol/blood , Exercise , Humans , Ischemic Attack, Transient/blood , Risk Factors , Stroke/bloodABSTRACT
BACKGROUND: Sensory impairment is associated with reduced functional recovery in stroke survivors. Invasive vagus nerve stimulation (VNS) paired with rehabilitative interventions improves motor recovery in chronic stroke. Noninvasive approaches, for example, transcutaneous auricular VNS (taVNS) are safe, well-tolerated and may also improve motor function in those with residual weakness. We report the impact of taVNS paired with a motor intervention, repetitive task practice, on sensory recovery in a cohort of patients with chronic stroke. METHODS: Twelve participants who were more than 3 months postischemic stroke with residual upper limb weakness received 18â¯×â¯1 hour sessions over 6 weeks with an average of at least 300 repetitions of functional arm movements per session concurrently with taVNS at maximum tolerated intensity. Light touch and proprioception were scored as part of the Upper Limb Fugl-Meyer (UFM) assessment at baseline and postintervention (score range for sensation 0-12). RESULTS: Eleven participants (92%) had sensory impairment at baseline of whom 7 (64%) regained some sensation (proprioception nâ¯=â¯6 participants, light touch nâ¯=â¯2, both modalities n =â¯1) postintervention. The maximal increase in UFM sensation score (3 points) was seen in the patient with the greatest improvement in motor function. CONCLUSIONS: taVNS paired with motor rehabilitation may improve sensory recovery in chronic stroke patients. The relative contribution of motor and sensory rehabilitation to overall functional recovery in chronic stroke needs further characterization in a larger, phase 2 study.
Subject(s)
Exercise Therapy , Motor Activity , Sensation , Stroke Rehabilitation/methods , Stroke/therapy , Transcutaneous Electric Nerve Stimulation , Upper Extremity/innervation , Vagus Nerve Stimulation , Aged , Chronic Disease , Ear , Feasibility Studies , Female , Humans , Male , Middle Aged , Neuronal Plasticity , Proprioception , Recovery of Function , Stroke/diagnosis , Stroke/physiopathology , Time Factors , Touch , Touch Perception , Treatment OutcomeABSTRACT
Endothelial cells (ECs) maintain the structure and function of blood vessels and are readily exposed to exogenous and endogenous toxic substances in the circulatory system. Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the blood and differentiate to EC, which are known to participate in angiogenesis and regeneration of injured vessels. Dysfunction in EPC contributes to cardiovascular complications in patients with diabetes, but the precise molecular mechanisms underlying diabetic EPC abnormalities are not completely understood. The aim of this study was to investigate the mechanisms underlying diabetic EPC dysfunction using methylglyoxal (MG), an endogenous toxic diabetic metabolite. Data demonstrated that MG decreased cell viability and protein expression of vascular endothelial growth factor receptor (VEGFR)-2 associated with functional impairment of tube formation in EPC. The generation of advanced glycation end (AGE) products was increased in EPC following exposure to MG. Blockage of receptor for AGE (RAGE) by FPS-ZM1, a specific antagonist for RAGE, significantly reversed the decrease of VEGFR-2 protein expression and angiogenic dysfunction in MG-incubated EPC. Taken together, data demonstrated that MG induced angiogenic impairment in EPC via alterations in the AGE/RAGE-VEGFR-2 pathway which may be utilized in the development of potential therapeutic and preventive targets for diabetic vascular complications.
Subject(s)
Angiogenesis Inhibitors/metabolism , Endothelial Progenitor Cells/drug effects , Glycation End Products, Advanced/pharmacology , Hazardous Substances/toxicity , Pyruvaldehyde/toxicity , Receptor for Advanced Glycation End Products/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Animals , Bone Marrow/physiology , Endothelial Progenitor Cells/physiology , Male , Mice , Mice, Inbred C57BLABSTRACT
BACKGROUND: Invasive vagus nerve stimulation (VNS) has the potential to enhance the effects of physiotherapy for upper limb motor recovery after stroke. Noninvasive, transcutaneous auricular branch VNS (taVNS) may have similar benefits, but this has not been evaluated in stroke recovery. We sought to determine the feasibility of taVNS delivered alongside upper limb repetitive task-specific practice after stroke and its effects on a range of outcome measures evaluating limb function. MATERIALS AND METHODS: Thirteen participants at more than 3 months postischemic stroke with residual upper limb dysfunction were recruited from the community of Sheffield, United Kingdom (October-December 2016). Participants underwent 18 × 1-hour sessions over 6 weeks in which they made 30-50 repetitions of 8-10 arm movements concurrently with taVNS (NEMOS; Cerbomed, Erlangen, Germany, 25 Hz, .1-millisecond pulse width) at maximum tolerated intensity (mA). An electrocardiogram and rehabilitation outcome scores were obtained at each visit. Qualitative interviews determined the acceptability of taVNS to participants. RESULTS: Median time after stroke was 1.16 years, and baseline median/interquartile range upper limb Fugl-Meyer (UFM) score was 63 (54.5-99.5). Participants attended 92% of the planned treatment sessions. Three participants reported side effects, mainly fatigue, but all performed mean of more than 300 arm repetitions per session with no serious adverse events. There was a significant change in the UFM score with a mean increase per participant of 17.1 points (standard deviation 7.8). CONCLUSION: taVNS is feasible and well-tolerated alongside upper limb repetitive movements in poststroke rehabilitation. The motor improvements observed justify a phase 2 trial in patients with residual arm weakness.
Subject(s)
Stroke Rehabilitation , Upper Extremity , Vagus Nerve Stimulation , Aged , Combined Modality Therapy , Ear , Feasibility Studies , Female , Humans , Interviews as Topic , Male , Middle Aged , Paresis/etiology , Paresis/physiopathology , Paresis/therapy , Patient Satisfaction , Pilot Projects , Qualitative Research , Recovery of Function , Stroke/complications , Stroke/physiopathology , Stroke/therapy , Stroke Rehabilitation/adverse effects , Treatment Outcome , Upper Extremity/physiopathology , Vagus Nerve Stimulation/adverse effects , Vagus Nerve Stimulation/methodsABSTRACT
Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.
Subject(s)
Biomedical Research/methods , Clinical Trials as Topic/methods , Drug Evaluation, Preclinical/methods , Research Design , AnimalsABSTRACT
BACKGROUND AND PURPOSE: Atrial fibrillation (AF) confers a high risk of recurrent stroke, although detection methods and definitions of paroxysmal AF during screening vary. We therefore undertook a systematic review and meta-analysis to determine the frequency of newly detected AF using noninvasive or invasive cardiac monitoring after ischemic stroke or transient ischemic attack. METHODS: Prospective observational studies or randomized controlled trials of patients with ischemic stroke, transient ischemic attack, or both, who underwent any cardiac monitoring for a minimum of 12 hours, were included after electronic searches of multiple databases. The primary outcome was detection of any new AF during the monitoring period. We prespecified subgroup analysis of selected (prescreened or cryptogenic) versus unselected patients and according to duration of monitoring. RESULTS: A total of 32 studies were analyzed. The overall detection rate of any AF was 11.5% (95% confidence interval, 8.9%-14.3%), although the timing, duration, method of monitoring, and reporting of diagnostic criteria used for paroxysmal AF varied. Detection rates were higher in selected (13.4%; 95% confidence interval, 9.0%-18.4%) than in unselected patients (6.2%; 95% confidence interval, 4.4%-8.3%). There was substantial heterogeneity even within specified subgroups. CONCLUSIONS: Detection of AF was highly variable, and the review was limited by small sample sizes and marked heterogeneity. Further studies are required to inform patient selection, optimal timing, methods, and duration of monitoring for detection of AF/paroxysmal AF.