Toll样受体4的基因多态性与脓毒症

脓毒症是指机体感染微生物后发生的全身炎性反应综合征.在该疾病发生发展中是基因多态性影响着机体对该综合征的遗传易感性.其中Toll样受体4(toll-like receptor4,TLR4)作为识别病原微生物的主要受体之一,在自身免疫中起着重要的作用.已有研究表明TLR4的基因多态性与脓毒症的遗传易感性密切相关,其中TLR4基因的Asp299Gly和Thr399Ile位点的突变与脓毒症的发生发展及预后有关.现就TLR4的功能、信号转导通路及其基因多态性与脓毒症易感性的相关关系作一综述.     

内毒素受体基因多态性与脓毒症

脓毒症是临床危重患者的主要死亡原因之一,已成为现代危重病医学亟待解决的重大难题.以往脓毒症的不良预后一直归结为诊断错误或不及时,以及抗炎治疗不充分,现在人们认识到脓毒症临床表型及治疗反应不同与其遗传基因背景的差异可能有内在联系.免疫相关基因多态性(polymorphism)在一定程度上决定了机体免疫应答状态的差异,基因多态性与脓毒症关系的研究日益成为人们关注的焦点[1].这样我们不难理解,为什么在遭受相似程度打击后,有些人群易于发生脓毒症和多器官功能障碍综合征,有的人却病情较轻而易于恢复?同是脓毒症患者,治疗措施相同,结果却截然不同?目前随着人类基因组计划的完成,全面深入地了解个体和群体间基因组的变异或多态性已成为可能.     

椎间盘退变易感基因研究进展

目前研究认为,椎间盘退行性变(IDD)是环境因素和遗传因素共同作用的结果.遗传因素涉及体内广泛存在的IDD易感基因,大致包括椎间盘结构相关基因、骨质疏松相关基因、代谢相关基因、细胞因子相关基因、疼痛信号通路相关基因等.基因突变及多态性与IDD具有相关性,某些基因存有一定的种族差异.近年研究表明,目的基因转染退变椎间盘纤维环及髓核等可延缓,甚至逆转IDD发生.进一步揭示IDD遗传学机制,有助于通过转基因方法治疗IDD.     

脓毒症相关因子基因多态性的研究进展

基因多态性在脓毒症、MODS等炎症反应紊乱相关疾病的病理生理变化中起着重要的作用,基因多态性是决定人体对应激打击和感染的易感性与耐受性、临床表现多样性及药物治疗反应性差异的重要内在因素。近年来的研究发现炎症反应中的一些关键分子的基因多态性在很大程度上确定着患者的命运,现就此方面作一综述     

股骨头坏死与基因遗传多态性

股骨头坏死(ONFH)系遗传易感因素和危险因素共同作用的多因素疾病,研究证实多种与凝血纤溶状态、脂质代谢、血管再生及激素代谢等相关的基因遗传多态性均与之发生存在显著相关性。ONFH基因遗传多态性相关研究,为ONFH易感人群筛查、早期诊断和早期干预提供了重要理论依据。更大规模、更加深入的研究以及实验技术的完善,将成为今后研究的方向。     

单核苷酸多态性与原发性肝癌的研究进展

原发性肝癌的发生是一个多因素的复杂的生物学过程,在其发生发展机制的研究中,对宿主遗传易感性的研究越来越受到重视.作为第三代分子遗传标记的单核苷酸多态性,是目前原发性肝癌研究中的一个热点.本文对原发性肝癌易感相关基因的单核苷酸多态性与原发性肝癌的易感相关关系的研究进展进行综述.     

脓毒症相关因子基因多态性的研究进展

基因多态性在脓毒症、MODS等炎症反应紊乱相关疾病的病理生理变化中起着重要的作用，基因多态性是决定人体对应激打击和感染的易感性与耐受性、临床表现多样性及药物治疗反应性差异的重要内在因素。近年来的研究发现炎症反应中的一些关键分子的基因多态性在很大程度上确定着患者的命运，现就此方面作一综述。     

细胞色素酶CYP3A4基因多态性研究进展

背景 药物代谢酶的基因多态性是导致药物在体内处置和反应存在明显个体差异的重要因素之一,而细胞色素酶P450家族的CYP3A4 (cytochrome P450 3A4)酶是药物及外源性物质的主要代谢酶.CYP3A4基因多态性是导致这些药物代谢个体差异的主要原因.目的 就CYP3A4基因多态性对药物代谢的影响作一综述.内容 CYP3A4主要分布于肝脏和小肠内,其基因结构、酶活性的个体差异以及遗传多态性的种族差异,是导致药物作用和副作用个体差异的主要原因,甚至与许多疾病包括肿瘤等的发病有关.趋向 对CYP3A4基因多态性的研究将有助于提高药物疗效,避免副作用发生,预防和治疗某些疾病尤其是肿瘤等疾病.     

P-选择素基因多态性与急性胰腺炎相关性分析

目的 ：探讨P-选择素（P-s electin）基因启动子区C-2123G多态性与急性胰腺炎（acute pan-creatitis,AP）发展及预后的相关性。方法：应用聚合酶链反应-限制性片段长度多态性（PCR-RELP）的分析方法,检测102例健康志愿者和119例AP患者P-selectin基因启动子区C-2123G的基因多态性,计算其基因型频率及等位基因频率。结果：健康对照组与AP组C-2123G等位基因频率（C32.35%,G 67.65%）及基因型分布（C纯合子占19.33%,CG占26.05%,G纯合子占54.62%）一致。轻症急性胰腺炎（MAP）组和重症急性胰腺炎（SAP）组等位基因频率及基因型分布差别无统计学意义。发生重症脓毒症患者G等位基因频率（83.33%）高于非脓毒症组（56.76%,P〈0.05）,GG纯合子患者发生重症脓毒症比例高于非脓毒症组（P〈0.05）。结论：P-selectin C-2123G基因多态性在AP发生重症脓毒症中具有重要的作用,是AP病情进展的危险因素。     

单核苷酸多态性与骨髓炎易感性关系的研究进展

骨髓炎目前仍是困扰骨科医师的一大难题。大量研究表明,遗传因素可能在骨髓炎的发病中起重要作用。单核苷酸多态性(SNPs)作为第3代遗传标记,在骨髓炎遗传易感性方面的研究越来越受关注。对骨髓炎易感性基因的单核苷酸多态性进行深入研究,有助于探索骨髓炎预防、诊断和治疗的新策略。本文就目前基因SNPs与骨髓炎易感性的研究进展作一...     

Effectiveness of treatments for severe sepsis: data from the bundle implementation programs

In severe sepsis, several studies, a recent meta--analysis and studies evaluating multifaceted strategies for quality improvement, have shown that bundled care can improve survival. Here, the effectiveness of treatments for severe sepsis included in the bundles was analyzed. Despite the observational design of the studies, possible biases are minimized using propensity scores and other adjustments. The results of are very consistent: early sepsis recognition with the administration of broad-spectrum antibiotics in all patients and specific treatments for patients in shock, such as activated protein C, or those on mechanical ventilation play a role in improving sepsis outcome. Hospitals should recognize this new evidence and design strategies to guarantee bundled care for severe sepsis.     

Genetic variation and risk of sepsis

Sepsis is the leading cause of death in non-coronary intensive care unit patients. Sepsis is caused by the immune response to infection and is manifest by pain, fever and edema as the result of the activation of coagulation and inflammatory responses. In severe cases, sepsis leads to organ dysfunction and failure. Sepsis affects more than 750,000 people each year in the US alone, with a mortality rate of over 35 percent making it one of the leading causes of death in developed countries. In addition many patients that die of other diseases have their hospital courses complicated by sepsis. Most patients with infection do not develop severe sepsis and septic shock and yet those that do have a significantly increased risk of death. Genetic and environmental variables may influence why one patient with infection gets sicker than the next. For example, people may be programmed to respond to infection in different ways; some with aggressive immune responses that may be able to wipe out infection before it manifests itself in physical symptoms, while others may have less aggressive immune systems that allow them to get sick more often. The discovery of various common genetic polymorphisms in genes that control the inflammatory response (e.g. tumor necrosis factor) has lent credence to this hypothesis. Yet discovery of the actual relationship between risks of infection / severe sepsis and individual genotypes will require larger, more rigorously designed studies.     

Antiinflammatorische Therapie in der Sepsis

A systemic inflammation with the release of multiple cytokines plays an important role in the pathophysiology of sepsis. During the last years, several anti-inflammatory substances have been investigated with respect to their effects on mortality in patients with sepsis. However, only the antibody fragment of the TNFα binding antibody afelimomab and the recombinant human activated protein C (drotrecogin α [acivated]) were capable of improving the outcome in controlled studies with large sample sizes. The possible administration of these substances should be restricted to patients who meet the inclusion criteria of these studies. In particular, the tight time window, which usually ends 24 h after the onset of sepsis, should be taken into consideration before starting an anti-inflammatory medication. In addition to the anti-inflammatory treatment, the control of the infectious focus and an aggressive hemodynamic stabilization must not be neglected. Ibuprofen, interleukin-1 receptor antagonists and soluble TNFα-receptors as well as high dosages of corticosteroids and antithrombin III do not have a place in the anti-inflammatory treatment of sepsis.     

The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 1: central nervous system, lung, and heart

Although several clinical studies show a gender dimorphism of immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis, there are conflicting reports on the role of gender in outcomes. In contrast, results obtained from experimental studies clearly support the suggestion that gender plays a significant role in post-injury pathogenesis. Studies performed in a rodent model of trauma-hemorrhage have confirmed that alterations in immune and organ functions after trauma-hemorrhage are more markedly depressed in adult males and in ovariectomized and aged females; however, both are maintained in castrated males and in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than in age-matched males or ovariectomized females. In this respect, organ functions and immune responses are depressed in males with sepsis or trauma, whereas they are unchanged or are enhanced in females. This article reviews studies delineating the mechanism by which estrogen regulates cerebral nervous, lung, and heart systems in an experimental model of sepsis, trauma, or reperfusion injury.     

Clinical trials in sepsis: an update

In this article, we place clinical sepsis trials from the past year in the context of similar sepsis trials run over the past three decades. These recent clinical sepsis trials include studies of agents administered to limit the effects of specific host proinflammatory mediators (tumor necrosis factor, platelet-activating factor and prostaglandins), studies of use of corticosteroids at low doses late in sepsis, and studies of administration of high doses of a nonspecific nitric oxide synthase inhibitor to decrease nitric oxide production in septic shock. The three trials of agents designed to limit host proinflammatory mediators showed minimal beneficial effects, results that are similar to those of the approximately 20 previous trials of similar agents. Low-dose corticosteroid therapy reversed shock and showed nonsignificant trends towards improvements in survival rates. In contrast, high doses of corticosteroids given early in sepsis have shown harmful effects in clinical sepsis trials. Finally, inhibition of nitric oxide production was lethal, indicating that high doses of nonspecific inhibitors of nitric oxide production are contraindicated in septic shock.     

The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 2: liver, intestine, spleen, and kidney

Several clinical studies show a gender dimorphism of immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis. However, there are conflicting reports on the role of gender in outcomes. Animal studies of shock, trauma, and sepsis have confirmed that alterations in immune and organ functions are more markedly depressed in adult males and in ovariectomized and aged females. In this review, we discuss the effect of estrogen on liver, intestinal, splenic, and renal functions in an experimental model of sepsis, trauma, and reperfusion injury. To establish the role of gender in the outcome of these patients, more studies in clinical and experimental settings are required to determine whether gender-specific responses are global across the injuries or are observed in specific injury situations. Studies are also needed to delineate underlying mechanisms responsible for differences between males and females. The findings gained from the experimental studies will help in designing innovative therapeutic approaches for the treatment of sepsis, trauma, and reperfusion injury patients.     

Management of sepsis

Severe sepsis remains a common cause of death in surgical patients. Eradication of the septic source and supportive care has long been the mainstay of treatment. In recent years, however, early goal-directed therapy, tighter glucose control, administration of drotrecogin alfa (activated), and steroid replacement have produced improved morbidity and mortality. In the future, a better understanding of the pathophysiology of sepsis and clinical studies may further improve outcomes from severe sepsis.     

睡眠障碍对机体免疫功能及脓毒症发生发展的影响

背景 神经免疫内分泌系统在脓毒症发生发展的过程中发挥着关键的作用,而睡眠障碍显著影响机体神经免疫系统的功能.不同类型睡眠障碍导致的机体免疫功能紊乱在脓毒症研究中受到越来越多的关注. 目的 系统阐述不同类型睡眠障碍对机体免疫功能的调控及对脓毒症发生发展的影响,为进一步完善脓毒症的神经-免疫-内分泌治疗提供防治新策略. 内容 综述睡眠障碍的类型和其对免疫功能及脓毒症发生发展的基础与临床研究进展. 趋向 睡眠障碍是目前普遍存在且严重影响人类健康的社会问题,由此引起的神经免疫内分泌功能障碍导致脓毒症患者预后不佳,神经-免疫-内分泌调节将开启脓毒症治疗的新靶向.     

Markers of hyperinflammation

The inflammatory events responsible for clinical derangements such as severe infection, sepsis, or septic shock are thought to be similar. Defining different mediators of inflammatory response, and describing failures of multiple immunomodulator studies to reduce morbidity and mortality of clinical sepsis, the author reconsiders the pathogenesis of sepsis. Septic patients may undergo various stages of disease. In each stage a pro- or a anti-inflammatory process may be predominant. Moreover different subgroups of infection, e.g. fungal sepsis, have different characteristics compared to bacterial infection. Future experiments and clinical trial may help defining circumstances under which inhibiting or augmenting endogenous mediators may be a helpful adjunctive therapy for sepsis.