MicroRNA: An Emerging Predictive,Diagnostic, Prognostic and Therapeutic Strategy in Ischaemic Stroke

Cellular and Molecular Neurobiology - Stroke continues to be the third-leading cause of death and disability worldwide. The limited availability of diagnostic tools approved therapeutics and...     

Adaptive Vaccination Strategies to Mitigate Pandemic Influenza: Mexico as a Case Study

Background

We explore vaccination strategies against pandemic influenza in Mexico using an age-structured transmission model calibrated against local epidemiological data from the Spring 2009 A(H1N1) pandemic.

Methods and Findings

In the context of limited vaccine supplies, we evaluate age-targeted allocation strategies that either prioritize youngest children and persons over 65 years of age, as for seasonal influenza, or adaptively prioritize age groups based on the age patterns of hospitalization and death monitored in real-time during the early stages of the pandemic. Overall the adaptive vaccination strategy outperformed the seasonal influenza vaccination allocation strategy for a wide range of disease and vaccine coverage parameters.

Conclusions

This modeling approach could inform policies for Mexico and other countries with similar demographic features and vaccine resources issues, with regard to the mitigation of the S-OIV pandemic. We also discuss logistical issues associated with the implementation of adaptive vaccination strategies in the context of past and future influenza pandemics.     

Targeting the Hedgehog Pathway to Mitigate Treatment Resistance

‘Hedgehog’ (HH) molecules are secretory signaling proteins that were first discovered in Drosophila. Three HH homologues have been identified in humans including Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH). During embryonic development, the Hedgehog (HH) signaling pathway is critical, and it regulates both proliferation and differentiation of various types of stem cells.1This article provides a brief overview of HH signaling, summarizes the correlation between HH signaling and treatment resistance of cancer cells, and discusses the recent advances in targeting this signaling cascade to overcome treatment resistance with supporting experimental results.     

Hierarchy of Dysfunction Related to Dressing Performance in Stroke Patients: A Path Analysis Study

Previous reports indicated that various dysfunctions caused by stroke affect the level of independence in dressing. These dysfunctions can be hierarchical, and these effects on dressing performance can be complicated in stroke patients. However, there are no published reports focusing on the hierarchical structure of the relationships between the activities of daily living and balance function, motor and sensory functions of the affected lower limb, strength of the abdominal muscles and knee extension on the unaffected side, and visuospatial deficits. The purpose of this study was to elucidate the hierarchical and causal relationships between dressing performance and these dysfunctions in stroke patients. This retrospective study included 104 first-time stroke patients. The causal relationship between the dressing performance and age, time post stroke, balance function, motor and sensory functions of the affected lower limb, strength of the abdominal muscles and knee extension on the unaffected side, and visuospatial deficits were examined using path analysis. A hypothetical path model was created based on previous studies, and the goodness of fit between the data and model were verified. A modified path model was created that achieved an almost perfect fit to the data. Balance function and abdominal muscle strength have direct effects on dressing performance, with standardized direct effect estimates of 0.78 and 0.15, respectively. Age, motor and sensory functions of the affected lower limb, and strength of abdominal muscle and knee extension on the unaffected side have indirect effects on dressing by influencing balance function. Our results suggest that dressing performance depends strongly on balance function, and it is mainly influenced by the motor function of the affected lower limb.     

Exploiting Social Networks to Mitigate the Obesity Epidemic

Despite significant efforts, obesity continues to be a major public health problem, and there are surprisingly few effective strategies for its prevention and treatment. We now realize that healthy diet and activity patterns are difficult to maintain in the current physical environment. Recently, it was suggested that the social environment also contributes to obesity. Therefore, using network‐based interaction models, we simulate how obesity spreads along social networks and predict the effectiveness of large‐scale weight management interventions. For a wide variety of conditions and networks, we show that individuals with similar BMIs will cluster together into groups, and if left unchecked, current social forces will drive these groups toward increasing obesity. Our simulations show that many traditional weight management interventions fail because they target overweight and obese individuals without consideration of their surrounding cluster and wider social network. The popular strategy for dieting with friends is shown to be an ineffective long‐term weight loss strategy, whereas dieting with friends of friends can be somewhat more effective by forcing a shift in cluster boundaries. Fortunately, our simulations also show that interventions targeting well‐connected and/or normal weight individuals at the edges of a cluster may quickly halt the spread of obesity. Furthermore, by changing social forces and altering the behavior of a small but random assortment of both obese and normal weight individuals, highly effective network‐driven strategies can reverse current trends and return large segments of the population to a healthier weight.     

Direct Detection of Radical Production in the Ischaemic and Reperfused Myocardium: Current Status

Electron spin resonance (em.) spectroscopy, which is a specific method for directly detecting free radicals in biological systems, has now been used in a number of studies to examine free radical generation in both ischaemic and reperfused myocardial tissue. This review critically assesses the information which has been obtained to date with particular reference to the elucidation of the nature and source of the radicals observed in these studies.     

老年男性脑卒中患者排尿功能障碍的尿动力学评估

目的:存在阻塞性尿路疾患的老年男性在发生脑血管意外后,是否可通过早期症状或排尿症状类型(梗阻性还是刺激性)来预判排尿功能障碍的病因。方法:选择57例脑卒中后主诉排尿障碍的老年男性患者,所有患者均有继发于良性前列腺增生(BPH)的膀胱出口梗阻(BOO)症状。采集病史并行体检,57位患者均实行尿动力学检查,检查结果行A-G图分析并分类为:有梗阻,无梗阻及可疑梗阻。结果:患者平均年龄70岁(54-87),按排尿障碍的主诉类型分组(纯刺激症状42%,纯梗阻症状34%,两者混合24%),其中51例(89%)在脑卒中发生后即出现排尿症状,47(82%)例患者出现逼尿肌反射亢进(DH),在三组患者中无显著统计学差异。压力流率分析显示,36(63%)位患者有出口梗阻,无梗阻14(24%)例,可疑梗阻7(13%)例。在3组患者中亦无显著统计学差异。结论:所有老年男性患者呈现的症状不能预测膀胱出口梗阻或逼尿肌反射亢进的尿动力学结果。中风发生后排尿功能障碍症状的发生率明显升高,表明由脑血管意外引起的排尿功能障碍合并前期具有膀胱出口梗阻疾病时,可能会使后者的症状恶化,反之亦然。     

Recent Developments to Mitigate Selenium Deficiency in Agricultural Eco-Systems

Under changing climate, trace elements like selenium (Se) have emerged as vital constituent of agro-ecosystems enabling crop plants to off-set the adverse effects of suboptimal growth conditions. The available form of selenium is important for boosting its bioavailability to crop plants having varied agro-botanical traits and root architectural systems. As compared to selenite, the selenate has a weaker soil bonding, higher absorption in the soil solution which results in a comparatively absorption by plant roots. Various factors including dry climate, high pH, optimal ambient air temperature, less accumulation of water, and low concentration of organic matter in the soil tend to boost the selenate ratio in the soil. The use of selenium pelleted seeds has emerged as an interesting and viable alternative to alleviate selenium deficiency in agricultural eco-systems. Similarly, the co-inoculation of a mixture of Selenobacteria and Arbuscular mycorrhizal fungi represents an evolving promising strategy for the bio-fortification of wheat plants to produce selenium-rich flour to supplement human dietary needs. Furthermore, in-depth research is required to assure the effectiveness of biological fertilization procedures in field conditions as well as to explore and increase our understanding pertaining to the underlying main mechanisms and channels of selenium absorption in plants. The focus of this review is to synthesize the recent developments on Se dynamics in soil-plant systems and emerging promising strategies to optimize its levels for crop plants. Recent developments regarding the use of micro-organisms as a biotechnological mean to enhance plant nutrition and crop quality have been objectively elaborated. The study becomes even more pertinent for arid and semi-arid agro-ecosystems owing to the potential role of selenium in providing stress tolerance to crop plants. Moreover, this review synthesizes and summarizes the recent developments on climate change and bioavailability, and the protective role of selenium in crop plants.

     

Bowel Dysfunction in Spinal Cord Injury: Current Perspectives

Permanent disruptions of gastrointestinal function are very common sequel of spinal cord injury (SCI). When motor and sensory nervous integrity are severely affected, neurogenic gastrointestinal dysfunction is an inevitable consequence. Autonomic nervous system miss function has significantly diminished or lost sensory sensations followed with incomplete evacuation of stool from the rectal vault, immobility, and reduced anal sphincter tone all of those predisposing to increased risk of fecal incontinence (FI). The FI is, beside paralysis of extremities, one of the symptoms most profoundly affecting quality of life (QOL) in patients with SCI. We are reviewing current perspectives in management of SCI, discussing some pathophysiology mechanisms which could be addressed and pointing toward actual practical concepts in use for evaluation and improvements necessary to sustain SCI patients QOL.     

Current Strategies in Ulcer Management with Special Reference to the Use of Antibiotics

Antibiotics, commonly amoxycillin, tetracycline, metronidazole and clarithromycin, are presently used in combination with anti-ulcer agents such as omeprazole, colloidal bismuth subcitrate, and sucralfate to treat Helicobacter pylori infection in patients with peptic ulcer, and compelling evidence has accumulated that eradication of the organism prevents duodenal ulcer relapse. The latest combination (MACH I) involved omeprazole, amoxycillin or metronidazole, and clarithromycin and claimed 90-96 percent success in H. pylori eradication. While the eradication rates of the bacteria are usually between 60-80 percent, the healing rates of duodenal ulcer using these regimens have been remarkably high, often over 90 percent, even with regimens that do not contain proton-pump inhibitors. Antibiotics alone, such as furazolidone and metronidazole, have been reported to heal peptic ulcer with various successes. In a recent double-blind placebo-controlled study, we showed that antibiotics alone, in the form of metronidazole, amoxycillin and clarithromycin, effectively healed 92.5 percent of patients with duodenal ulcer, and that the healing was largely accountable by clearance of H. pylori. Thus, the present day evidence indicates that both healing and prevention of relapse of peptic ulcer can be achieved by treatment of H. pylori. Metronidazole resistance is emerging rapidly, especially in Asia, and is likely to affect eradication success. At this point in time, the best regimen for peptic ulcer associated with H. pylori includes the use of a proton-pump inhibitor plus two antibiotics for one to two weeks.     

No Relation between Body Temperature and Arterial Recanalization at Three Days in Patients with Acute Ischaemic Stroke

Background

Recanalization of an occluded intracranial artery is influenced by temperature-dependent enzymes, including alteplase. We assessed the relation between body temperature on admission and recanalization.

Methods

We included 278 patients with acute ischaemic stroke within nine hours after symptom onset, who had an intracranial arterial occlusion on admission CT angiography, in 13 participating centres. We calculated the relation per every 0.1°Celsius increase in admission body temperature and recanalization at three days.

Results

Recanalization occurred in 80% of occluded arteries. There was no relation between body temperature and recanalization at three days after adjustments for age, NIHSS score on admission and treatment with alteplase (adjusted odds ratio per 0.1°Celsius, 0.99; 95% confidence interval, 0.94–1.05; p = 0.70). Results for patients treated or not treated with alteplase were essentially the same.

Conclusions

Our findings suggest that in patients with acute ischaemic stroke there is no relation between body temperature on admission and recanalization of an occluded intracranial artery three days later, irrespective of treatment with alteplase.     

MMP-9 Inhibition: a Therapeutic Strategy in Ischemic Stroke

Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood–brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia.     

Current Management Strategies in Acid-Related Disorders

Acid-related disorders include not only reflux esophagitis and peptic ulcer, but also a subset of patients with endoscopy-negative dyspepsia. The management strategy differs between these diseases and therefore a precise diagnosis is important. The unaided clinical diagnosis is of limited value in patients with pain or discomfort in the upper abdomen, and endoscopy is therefore an important and cost-effective diagnostic tool.Duodenal ulcer is caused by an interplay between gastric acid and Helicobacter pylori. The treatment is aimed at rapid symptom relief and healing and at the same time eradication of H. pylori. At present the best choice is the combination of a proton pump inhibitor and two effective antimicrobial drugs, e.g., clarithromycin and metronidazole. The proton pump inhibitor has dual effect in this combination it provides optimal symptom relief and healing, and it increases the anti-H. pylori-effect of the antimicrobial drugs. The risk of reinfection varies geographically; in Europe it is around 1 percent per year, and cure of the infection provides long-term, maybe life-long, cure of the ulcer disease. Some gastric ulcers are not H. pylori-related and the treatment strategy therefore includes a diagnostic test for this infection. If positive, treatment is similar to that in duodenal ulcer, while H. pylori-negative gastric ulcer patients are treated with antisecretory drugs alone.Reflux esophagitis correlates with the degree of acid exposure to the esophagus, and intensive acid inhibition is the most effective non-surgical therapy. In most cases the disease is chronic and needs continuous long-term therapy to prevent relapse. A staged reduction in dosage of the acid inhibitory drug may be attempted when the esophagitis is healed and the patient has become symptom free, but full dose therapy is often needed.Patients with endoscopy-negative dyspepsia are a heterogenous group and a more precise identification of the cause of the symptoms is a prerequisite for rational treatment. Empiric treatment can be tried in patients without alarm symptoms like bleeding or a palpable abdominal mass, and often an acid inhibitory drug is used. A more precise identification of those patients who have acid-related symptoms is possible using placebo controlled single-subject trials with an effective acid inhibitory drug, but in daily routine these drugs are simply given for a short period of time, and in case symptomatic relief is observed, the symptoms may be regarded as being acid-related and treated accordingly.     

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

Autoimmune diseases reflect a breakdown in self-tolerance that results from defects in thymic deletion of potentially autoreactive T cells (central tolerance) and in T-cell intrinsic and extrinsic mechanisms that normally control potentially autoreactive T cells in the periphery (peripheral tolerance). The mechanisms leading to autoimmune diseases are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in pathogenic inflammatory responses in peripheral tissues driven by self-antigen-specific T cells. In this article, we describe the different checkpoints of tolerance that are defective in autoimmune diseases as well as specific events in the autoimmune response which represent therapeutic opportunities to restore long-term tolerance in autoimmune diseases. We present evidence for the role of different pathways in animal models and the therapeutic strategies targeting these pathways in clinical trials in autoimmune diseases.Autoimmune diseases are debilitating conditions that affect a large and growing portion of the population (∼3%–5% in the United States) (Jacobson et al. 1997). Autoimmune diseases take a devastating toll on affected families and have a considerable economic impact. Thus, improving the understanding of autoimmune diseases and developing novel therapies have been significant goals in public health. The development of autoimmune diseases reflects a loss of tolerance of the immune system for self-antigens. With the exception of a few rare monogenic diseases such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, the development of autoimmunity is a complex and multifactorial process. This process usually involves genetic predispositions and poorly defined environmental factors that result in slight alterations in many different checkpoints, which in turn tilts the balance toward autoreactivity and away from immunoregulation. Although clearly there are key roles for B cells, antigen-presenting cells (APCs), and the innate immune response in the development and progression of autoimmune diseases, this article will focus on autoreactive T cells and potential targets of tolerogenic treatments (Fig. 1). In addition, we will discuss selected strategies currently available or being developed in the clinic as well as future opportunities to prevent and treat these diseases. Finally, current clinical strategies available as the standard of care for autoimmune diseases rely on immunosuppressive and anti-inflammatory treatments that curtail the pathological events, alleviate symptoms, and provide short-term relief in some patients. Thus, we will focus for the most part on immunotherapies aimed at reestablishing long-term tolerance.Open in a separate windowFigure 1.Development of the pathogenic autoimmune response and targets for immunotherapy. Autoreactive T cells that escape thymic negative selection are usually controlled by intrinsic (inhibitory receptors) and extrinsic (regulatory cell populations) mechanisms of tolerance in the periphery. In individuals genetically prone to autoimmunity, one or several of these checkpoints are defective, resulting in expansion of autoreactive T cells that cannot be controlled by Tregs (red, autoreactive effector T cells; green, Tregs; gray, polyclonal conventional T cells). Autoreactive T cells migrate to their targeted tissue where cytotoxic mechanisms and uncontrolled inflammation mediated by soluble mediators released by T cells and innate cells result in tissue damage. Various immunotherapeutic strategies target different steps in this process. (A) The ultimate goal of immunotherapy is to alter the balance of pathogenic versus regulatory T cells to restore tolerance, as detailed in Figure 2. (B) Anti-CD3 mAbs, antigen-specific therapies, and costimulation blockade alter the interactions between autoreactive T cells and antigen-presenting cells (APCs) and/or the signaling pathways resulting from productive T-cell receptor (TCR) ligation after presentation of cognate self-peptide/MHC (major histocompatibility complexes) in the presence of costimulatory signals, leading to deletion, anergy, immune deviation, or induction of Tregs. (C) Many strategies aim at boosting Tregs, either by concomitantly deleting Teff and promoting Tregs, and thus resetting the immune system to various degrees, such as antithymocyte globulin (ATG), rapamycin plus IL-2, and autologous hematopoietic stem cell transplantation (HSCT), or directly providing Tregs through cellular therapy. (D,E) Some therapies target populations of APCs, such as depletion of B cells by rituximab or the promotion of self-antigen presentation specifically by tolerogenic dendritic cells (DCs). (F) The migration of autoreactive T cells to their target tissue is being altered by inhibitors of leukocyte trafficking such as natalizumab and fingolimod. These drugs may further promote tolerance by keeping autoreactive T cells in the lymph nodes (LN) during immunosuppression, a prerequisite for efficient immunomodulation in some cases. (G) Anti-inflammatory therapies such as tumor necrosis factor (TNF) antagonists reduce tissue damage but also create an immunological environment more favorable to the induction of Tregs and restoration of tolerance.