Peptide-based immunotherapy of experimental autoimmune encephalomyelitis without anaphylaxis

Administration of peptide antigens in tolerogenic form holds promise as a specific treatment for autoimmune and allergic disorders. However, experiments in rodent autoimmune models have highlighted the risk of anaphylaxis in response to systemic peptide application once the aberrant immune response is underway. Thus, mice with clinical signs of experimental autoimmune encephalomyelitis (EAE) or diabetes have been reported to suffer fatal anaphylaxis upon administration of native autoantigenic peptides. Clearly, this might represent a significant barrier to the use of synthetic peptides in the treatment of ongoing human autoimmune conditions. Here we describe the development of an altered peptide ligand (APL) engineered to prevent anaphylaxis (no antibody binding) whilst retaining the ability to silence pathogenic myelin-reactive T lymphocytes. Administration of the APL to mice with an ongoing anti-myelin immune response did not cause anaphylaxis, but led to complete protection from the subsequent induction of EAE and, when given during ongoing EAE, led to a rapid remission of clinical signs. The approach of removing antibody recognition whilst maintaining the desired functional effect (in this case T cell tolerance) may be of value in other situations in which there is a risk of triggering anaphylaxis with peptide-based drugs.     

IVIG enters the central nervous system during treatment of experimental autoimmune encephalomyelitis and is localised to inflammatory lesions

Intravenous immunoglobulin (IVIG) treatment reduces the relapse rate in relapsing–remitting multiple sclerosis (MS) and may interfere with MS pathology through its various anti-inflammatory and immunomodulatory properties. It is presently unknown whether IVIG enters the central nervous system (CNS) in sufficient amounts to influence the local immune response within the brain and spinal cord, or if the treatment effects are entirely due to peripheral actions of IVIG. The purpose of the present study was to evaluate if IVIG radiolabeled with ^99mTc enters the CNS during treatment of experimental autoimmune encephalomyelitis (EAE) in the susceptible rat strain Dark Agouti. After in vivo administration of ^99mTc-IVIG we observed significantly increased accumulation in the brain and spinal cord from rats with EAE. Accumulation of ^99mTc-IVIG was not detectable in CNS tissue from control animals. In peripheral tissue samples minor increases in ^99mTc-IVIG organ binding were observed in the liver and kidney during EAE. Localisation of ^99mTc-IVIG in the brain tissue was visualised by autoradiography and revealed significant accumulation of IVIG only in areas also affected by perivascular inflammation and leakage of serum proteins. In conclusion, the results indicate that significant extravasation of IVIG to the CNS only occurs when blood–brain barrier function is compromised during EAE.     

“Life behind the mask”: Sexual life of Iranian women with multiple sclerosis

Background

Multiple sclerosis (MS) is a debilitating and life-long disease that affects the sexual life of people. However, in Iran little attention has been paid to the sexual life of women with MS.

老年呼吸机相关肺炎患者死亡的危险因素

目的分析老年呼吸机相关肺炎(VAP)患者死亡的危险因素。方法调查2011年4月—2017年2月某院年龄≥60岁且发生VAP的患者,收集患者的临床资料,包括基本情况、感染情况、预后等,并对其死亡的危险因素进行分析。结果共有老年VAP患者682例,198例患者死亡,病死率为29.03%。APACHEⅡ评分15分(OR=2.482,95%CI=1.473~4.183)、机械通气时间15 d(OR=2.526,95%CI=1.661~3.840)、多重耐药菌感染(OR=3.379,95%CI=2.008~5.686)、真菌感染(OR=3.414,95%CI=1.830~6.370)、使用糖皮质激素(OR=2.075,95%CI=1.265~3.403)、血清清蛋白浓度35 g/L(OR=2.129,95%CI=1.386~3.268)、器官损伤数目≥3个(OR=3.438,95%CI=2.165~5.459)、血糖≥10 mmol/L(OR=1.744,95%CI=1.106~2.751)等8个因素均为老年VAP患者死亡的独立危险因素。结论老年VAP患者死亡与多种因素有关,临床应采取以干预主要危险因素为主的综合防控措施,降低其病死率。     

Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches

This work investigated the impact of formulation including in vitro release profile, repeated dosing, and nail poration on the ex vivo nail delivery performance of antifungal formulations. Chitosan coated and uncoated tioconazole-loaded nanocapsules and a nano-based film-forming vehicle were assessed via in vitro release and in vitro permeation tests using an artificial membrane and human nail clippings, respectively. The later involved single and daily dosing experiments with intact and porated nails. Additional experiments with Nile Red-loaded formulations evaluated the depth of penetration of the fluorescent marker into the nail by laser scanning confocal microscopy. The nanocapsule formulations prolonged release of tioconazole for longer than the control solutions and this ability was related to an enhanced nail penetration of the drug. Further, the new film-forming formulation delivered its drug payload more efficiently than a marketed product. Daily dosing of the formulations doubled the amount of drug recovered from the nails. Porating the nails enhanced tioconazole delivery in single dose experiments only. The depth of penetration of Nile Red into the nails clippings ranged between 90–160?μm. This research suggests that ensuring prolonged release of a drug is fundamental to develop efficacious topical nail formulations.     

老年心血管病患者潜在性不适当用药及影响因素分析

目的:评价某院老年心血管病患者药物潜在不适当应用情况,并对其影响因素进行分析。方法:抽取某院2015年10月到2016年8月的老年心血管病例,以2014年版STOPP/START标准为依据,对年龄在65岁及以上的出院患者潜在不适当用药(PIM)进行评价,并采用多因素Logistic回归分析确定其影响因素。结果:通过病例筛选纳入514份病例,患者平均年龄(77.44±8.48)岁,平均罹患疾病数(5.93±2.34)种,联合用药总数(16.84±8.89)种;其中涉及2014年版STOPP标准不适当用药190例次,START标准处方遗漏419例次。单因素卡方分析提示,年龄(P=0.022)、罹患疾病数(P=0.041)、联合用药数(P=0.000)、心血管疾病史(P=0.001)及是否接受抗栓治疗(P=0.000)与PIM的发生具有相关性,且差异具有显著性(P<0.05);多因素Logistic回归分析提示稳定型心绞痛(OR=2.543,P=0.025),心房颤动(OR=2.304,P=0.024),冠状动脉粥样硬化(OR=2.659,P=0.005),联合用药数(≥10)(OR=1.040,P=0.026)及接受抗栓治疗(OR=3.037,P=0.007)的患者均会增加潜在不适当用药的风险,采用拟合的Logistic回归预测模型对入选病例预测总的预测正确率为74.5%。结论:老年心血管疾病患者发生潜在不适当用药是稳定型心绞痛、心房颤动、冠状动脉粥样硬化,联合用药数(≥10)及接受抗栓治疗多因素相互影响的结果。基于相关危险因素的PIM预防有助于减少不良事件的发生,促进临床合理用药。     

Survey on changes in subjective symptoms,onset/trigger factors,allergic diseases,and chemical exposures in the past decade of Japanese patients with multiple chemical sensitivity

Background

Recently, with rapid changes in the Japanese lifestyle, the clinical condition of patients with multiple chemical sensitivity (MCS) may also have undergone change. Thus, we conducted a new survey for subjective symptoms, ongoing chemical exposures, the prevalence of allergic diseases, and presumed onset/trigger factors in patients with MCS and compared results with those of an old survey from ten years ago.

Nutrition et sclérose en plaques : le point de la littérature

Introduction and objectives

Nutritional data on multiple sclerosis are discordant and have a low accuracy. The objective of this article was to focus on the nutritional factors involved in multiple sclerosis, from the prevention of disease to the specific management of patients.

膝骨性关节炎患者平衡功能障碍及其影响因素分析

目的 探讨膝骨性关节炎（KOA）患者平衡功能及其相关影响因素。方法 选取2014年12月至2017年9月合肥市第二人民医院骨科收治的单膝受累30例KOA患者为观察对象,采用平衡测试仪对患者进行平衡功能检测,比较健、患侧测试完成耗时及平均轨迹误差,收集患者体质量指数、K-L分级、疼痛指数、美国膝关节协会评分（KSS）等指标,利用多元回归分析上述指标对患者平衡功能的影响。结果 患者健、患侧平衡指标比较,患侧平均轨迹误差值（46.63±25.30）%大于健侧值（40.77±23.85）%,差异有统计学意义（t=-2.299,P<0.05）;多元回归分析示：KSS临床评分对睁眼时前-后平均运动速度（t=-2.593,P<0.05）及重心摆动轨迹长度（t=-2.178,P<0.05）的影响具有统计学意义,对两者变异的解释比例分别为19%、15%,而疼痛指数对闭眼轨迹长度/睁眼轨迹长度比（Romberg值长度比）的影响具有统计学意义（t=-2.641,P<0.05）,解释比例为20%。结论 KOA患者存在平衡功能障碍;膝关节疼痛指数及KSS临床评分对于评估KOA患者平衡功能障碍具有重要意义。     

Bayesian design for two-arm randomized Phase II clinical trials with endpoints from the exponential family using multiple constraints

Frequentist design for two-arm randomized Phase II clinical trials with outcomes from the exponential dispersion family was proposed previously, where the total sample sizes are minimized under multiple constraints on the standard errors of the estimated group means and their difference. This design was generalized from an approach specific for dichotomous outcomes. The two previous approaches measure the central tendency of each group and treatment effect based on mean and difference in means. Other measures such as median or hazard ratio are more appropriate under certain situations. In addition, the frequentist approaches assume that unknown parameters are fixed values. This does not reflect the reality that uncertainty always exists for unknowns. Compared to the frequentist methods, the Bayesian approach offers a flexible way to measure central tendency and treatment effect, and incorporate uncertainty in parameters of interest into considerations. In this article, we generalize a Bayesian design for Phase II clinical trials with endpoints in the exponential family from the two previously developed frequentist approaches. The proposed design minimizes the total sample sizes under pre-specified constraints on the expected length of posterior credible intervals for measures of treatment effect and central tendency in each group. The design is applicable for trials with fixed or optimal randomization allocation ratio and can be applied under adaptive procedure. Examples of method implementations are provided for different types of endpoints from the exponential family in both fixed and adaptive settings.