Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke

Stroke,including cerebral ischemia,intracerebral hemorrhage,and subarachnoid hemorrhage,is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding of the risk factors and the pathophysiology of stroke,as well as the development of therapeutic strategies for its treatment. Further development and investigation of experimental models,however,are needed to elucidate the pathogenesis of stroke and to enhance and expand novel therapeutic targets. In this article,we provide an overview of the characteristics of commonly-used animal models of stroke and focus on the infl ammatory responses to cerebral stroke,which may provide insights into a framework for developing effective therapies for stroke in humans.     

Experimental models of neuromyelitis optica: current status,challenges and future directions

Neuromyelitis optica(NMO) is a recurrent infl ammatory disease that predominantly attacks the optic nerves and spinal cord. NMO-IgG,the specific autoantibody present in the vast majority of NMO patients,targets the astrocytic water channel protein aquaporin 4(AQP4),and differentiates NMO from multiple sclerosis. The growing clinical and research interest in NMO makes it urgent to produce an animal model of NMO. The pathogenic effect of anti-AQP4 antibodies derived from the serum of patients paves the way to generating an experimental model based on the anti-AQP4-mediated astrocyte damage. In this review,we discuss the contribution of experimental models to the understanding of the pathogenesis of the disease and drug development. Key questions raised by the existing models are also discussed.     

Incidence,early case fatality and determinants of stroke in Iran: Golestan Cohort Study

Objectives: While few studies investigated the incidence of stroke in Iran, no Iranian cohort has estimated the standardized-incidence rate and early fatality of first-ever-stroke subtypes along with associated factors. Methods: Golestan Cohort Study is a prospective study launched in northeastern Iran in 2004, including 50,045 individuals aged 40-75 at baseline. Age-standardized incidence rate of first-ever-stroke was calculated per 100,000 person-years, according to World Standard Population. The 28-day case fatality was calculated by dividing the number of fatal first-ever-stroke during the first 28 days by total events. Cox proportional hazard models were conducted to assess incidence and fatality risk factors. We used Population Attributable Fractions to estimate the incidence and early fatality proportions reduced by ideal risk factor control. Results: 1,135 first-ever-strokes were observed during 8.6 (median) years follow-up. First-ever-stroke standardized incidence rate was estimated 185.2 (95% CI: 173.2-197.2) per 100,000 person-years. The 28-day case fatality was 44.1% (95% CI: 40.4-48.2). Hypertension and pre-stroke physical activity were the strongest risk factors associated with first-ever-stroke incidence (Hazard ratio: 2.83; 2.47-3.23) and 28-day case fatality (Hazard ratio: 0.59; 0.44-0.78), respectively. Remarkably, opium consumption was strongly associated with hemorrhagic stroke incidence (Hazard ratio: 1.52; 1.04-2.23) and ischemic stroke fatality (Hazard ratio: 1.44; 1.01-2.09). Overall, modifiable risk factors contributed to 83% and 61% of first-ever-stroke incidence and early fatality, respectively. Conclusion: Efficient risk factor control can considerably reduce stroke occurrence and fatality in our study. Establishing awareness campaigns and 24-hour stroke units seem necessary for improving the stroke management in this area.     

Post-stroke cognitive impairment and the risk of stroke recurrence and death in patients with insulin resistance

ObjectivePost-stroke cognitive impairment (PSCI) is associated with etiology, severity, and functional outcome of stroke. The risks of recurrent stroke and death in patients with PSCI and insulin resistance (IR) is unknown. The goal of this study was to determine whether global and domain-specific cognitive impairment after stroke in patients with IR was associated with recurrent stroke and death.Materials and MethodsWe studied patients with recent stroke or transient ischemic attack (TIA) and IR with a baseline Modified Mini-Mental State Examination (3MS) cognitive exam at median of 79 days after stroke. We considered a baseline score of ≤ 88 on the 3MS to indicate global cognitive impairment, and domain-specific summary scores in the lowest quartile to indicate language, attention, orientation, memory and visuospatial impairments. The primary endpoint was fatal or non-fatal recurrent stroke, and the secondary endpoints were all-cause mortality, and fatal or non-fatal myocardial infarction (MI).ResultsAmong studied n = 3,338 patients 13.6% had global cognitive impairment. During the median 4.96 years of follow-up, 7.4% patients experienced recurrent stroke, 3.5% MI, and 7.3% died. In the fully adjusted model, impairment in language (HR 1.35; 95% CI 1.01—1.81) and orientation (HR 1.41; 95% CI: 1.06—1.87) were associated with a higher risk of recurrent stroke, while attention impairment was associated with all-cause mortality (HR 1.34; 95% CI: 1.01—1.78).Discussion/ConclusionIn patients with recent stroke/TIA and IR, post-stroke language and orientation impairments independently predicted recurrent stroke, while attention deficit was associated with increased risk of all-cause mortality.     

Nerve cell function and synaptic mechanisms

Nerve cells (neurones) are ‘excitable’ cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone ‘integrates’ this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory).     

红细胞参数和血浆蛋白对脑梗死早期进展及预后的影响

目的探讨脑梗死患者红细胞分布宽度及血浆白蛋白水平对脑梗死进展、预后及再发的影响。方法分析105例脑梗死患者临床资料,将病情在早期呈逐渐进展或阶梯式加重的患者归为进展型卒中组,其余归为完全型卒中组;根据脑梗死发生3个月、18个月后m RS评分情况分为短期和远期预后良好组及预后不良组;以18个月内是否再发脑梗死分再发组和未再发组。比较不同分组情况下患者的红细胞参数和血浆蛋白水平。结果进展型卒中组较完全型卒中组平均红细胞体积(f L:85.92±4.50 vs 83.79±4.64,t=2.164,P<0.05)、红细胞分布宽度(f L:13.50±2.45 vs 11.90±2.90,t=2.694,P<0.01)和球蛋白(g/L:27.46±4.33 vs 24.79±4.03,t=3.029,P<0.01)高,白蛋白低(g/L:39.00±3.86 vs 42.89±4.45,t=4.242,P<0.01),差异均有统计学意义;高红细胞分布宽度、低白蛋白水平是进展型卒中的危险因素;短期预后不良组红细胞分布宽度高于预后良好组(f L:13.90±2.45 vs 12.00±2.12,t=2.905,P<0.01);红细胞分布宽度与脑梗死3个月、18个月后m RS评分正相关(P<0.01)。结论高红细胞分布宽度和低白蛋白的脑梗死患者进展型卒中发生率增加,红细胞分布宽度对预测脑梗死预后具有一定的参考价值。     

Cognitive interventions for mild cognitive impairment and dementia: An overview of systematic reviews

PurposeConducting an overview of systematic reviews (SRs)/Meta analyses (MAs) to assess the effectiveness of cognitive interventions on participants with mild cognitive impairment (MCI) or dementia and evaluate the methodological quality of SRs/MAs.MethodsPubMed, EMBASE, Cochrane library, Web of science, China National Knowledge Infrastructure (CNKI) and Chinese Biomedical Databases (CBM) were systematically searched from inception to January 1, 2019 to identify SRs/MAs. Three reviewers independently screened the articles, extracted data and assessed the quality of the included studies according to the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), the Grading of Recommendations Assessment Development and Evaluation (GRADE) was used to evaluate the quality of evidence.ResultsA total of 22 reviews were included. New meta-analyses (36 RCTs) showed that cognitive interventions were more effective than routine therapies for the alleviation of MCI and dementia symptoms (SMD: 0.62; 95%CI: 0.47, 0.78; I² = 53.9%). The results of AMSTAR-2 showed that the methodological quality of most included studies was critically low, and two reviews were low quality. The lowest score was item 10, none of reviews reported on the sources of funding for the included studies. Followed by the “provide a list of excluded studies and justify the exclusions” item with only one (4.5%) reviews conforming to this item. Results of GRADE manifested that moderate quality evidence was provided in 11 reviews (39.3%), 12 (42.9%) were low quality and 5 (17.8%) were very low.ConclusionThe present SRs/MAs indicated that persons with MCI or dementia could benefit from cognitive interventions. Future trial designs should focus on measuring changes in individual specific cognitive functions. More high-quality evidence is needed to further determine the effectiveness of cognitive interventions.     

Contact heat-evoked potentials as a useful means in patients with Guillain–Barré syndrome

Few objective methods have been utilized to identify the small myelinated fiber impairment causing neuropathic pain in Guillain–Barré syndrome (GBS). In this study, contact heat-evoked potentials (CHEPs) were applied to study the nociceptive pathway in GBS. Sixty GBS patients and fifty healthy controls were enrolled. The 60 GBS patients were divided into two subgroups presenting with or without subjective lower limb paresthesia (21/39). CHEPs were recorded at Cz and Pz with a peak thermal stimuli of 47 °C applied to the skin of the leg above the internal malleolus (AIM) and of the waist at the anterior superior iliac spine (ASIS) level. The N2 latency and N2–P2 amplitude of CHEPs were compared. When the skin of the leg AIM was stimulated, the N2 latency was significantly postponed (425.23 ± 28.66 vs. 402.30 ± 19.48 ms, P < 0.05) and the N2–P2 amplitude significantly decreased in GBS patients as compared to controls (32.71 ± 7.49 vs. 42.77 ± 8.71 μV, P < 0.05). Slower nerve conduction velocity was observed in GBS patients (11.84 ± 1.45 vs. 13.28 ± 0.66 ms, P < 0.05). However, no differences in N2 latency or N2–P2 amplitude were detected between the two subgroups of GBS patients with or without subjective lower limb paresthesia (P all >0.05). Moreover, there were no differences in N2 latency and N2–P2 amplitude among different groups when the waist was stimulated at the ASIS level. Our study suggested that CHEPs could be utilized as an objective and non-invasive tool to detect small myelinated fiber damage in GBS patients, especially for those without subjective paresthesia.