一个中枢炎性免疫诱发长时程抑郁样行为的新模型

脂多糖(lipopolysaccharide, LPS)免疫激活模型是研究抑郁症细胞因子假说的重要动物模型, 目前国际上常用外周单次LPS注射诱发抑郁样行为, 但该模型中抑郁样行为持续仅有数小时。为建立诱发较长时程抑郁样行为的免疫激活动物模型, 本研究尝试侧脑室注射LPS激活大鼠中枢免疫炎性反应, 考察单次以及重复中枢LPS注射诱发抑郁样行为的效果, 以及中枢炎性免疫诱发行为改变的时程。结果显示：单次中枢LPS注射后24 h只能诱发旷场自发活动和探索行为下降等部分抑郁样行为, 未能诱导糖水偏好下降和悬尾不动时间增加; 3次重复注射则在末次LPS注射后24 h表现出显著的糖水偏好下降, 自发活动和探索行为减少, 悬尾不动时间增加等行为。且自发活动、探索行为减少和悬尾不动时间增加能够延续至末次LPS注射后72 h。这些结果表明脑室重复LPS注射可诱发较长时程的抑郁样行为, 这种新的中枢炎性免疫激活诱发的抑郁症模型, 为研究抑郁症炎性免疫机制提供了更为有效的动物模型, 有助于深入探讨行为和免疫功能间的复杂关系。     

增龄性记忆改变规律及影响因素的研究

本研究用多维记忆量表对280名50～91岁的老年人做了测查,同时收集了一般资料,以探讨增龄性记忆改变的规律和年龄、教育和职业等因素对增龄性记忆改变的影响。结果表明：随年龄增长,各记忆组合分和分测验成绩均呈下降趋势,外显记忆成绩在70岁后呈快速下降,内隐记忆和日常生活记忆在75岁后才有明显下降;记忆总分、外显记忆和日常生活记忆均受年龄和教育的影响,内隐记忆不受教育的影响。结果提示老年人记忆随年龄增长呈渐渐下降,不同记忆功能开始下降的年龄和下降速率不同,教育对增龄性记忆改变有保护作用。     

整体运动知觉老化伴随颞中回静息态功能改变

以个体整体运动一致性阈值为指标, 探讨老年人整体运动敏感性(GMS)下降和静息态下兴趣脑区功能活动的关系。发现与阈值负相关且老年人低于青年人的指标主要有：MT/V5区的ReHo和ALFF值, 各网络拓扑属性; 与阈值正相关且老年人显著高于青年人的有：MT/V5区与前运动皮层之间的、各兴趣脑区之间的功能连接。结果用“去分化”等观点进行了解释, 提示老年人GMS的下降可能不仅与安静状态下MT/V5区的功能改变有关, 还可能与全脑更广泛区域的功能改变有关。     

情绪加工老化效应的神经机制

行为学研究发现,老年人对消极情绪的辨别、注意和记忆都有所下降,而对积极情绪并未表现出类似的现象。情绪加工老化效应的神经影像学研究发现,老年人在情绪加工过程中边缘系统（尤其杏仁核）的激活强度低于年轻人,但额叶皮层区域的激活却有所增强。研究者对该结果提出了两种假说,一种是功能代偿假说,另一种是策略改变假说。功能代偿假说认为老年人额叶皮层区域的激活增强是为了弥补边缘系统功能的下降,反映了大脑功能的代偿;策略改变假说认为老年人主动使用了不同于年轻人的策略,情绪加工方式的不同导致了两组人群大脑活动的差异。未来这方面研究可以从研究层面、研究方法、研究问题等方面逐步完善     

Ⅱ型糖尿病人认知功能特点

综述了近10国内外关于Ⅱ型糖尿病人认知功能特点的研究。结果表明：（1）流行病学筛查因天花板效应难以发现认知损伤。（2）采用对年老化较敏感的行为学指标证实,60~70岁的糖尿病人认知能力显著低于对照组;但60岁以下或70以上病人则少有类似表现。认知阈限理论可解释这一年龄相关现象。（3）Ⅱ型糖尿病人认知功能损伤主要表现为语词记忆损伤、学习能力下降、脑电（P300）潜伏期延长等。（4）认知损伤程度与血糖和胰岛素水平相关,也受高血压等共病因素的影响。控制糖代谢可改善认知功能。糖尿病人的认知损伤与年龄相关,但其机制不同于正常年老化过程中的认知衰退     

全身炎症反应综合征发病机制理性辨析

全身炎症反应综合征是多器官功能障碍综合征的重要病理生理发展过程。全身炎症反应综合征的发生和病理机制尚不十分清楚。目前有三种学说:细胞因子风暴说、正反馈说、促炎/抗炎因子平衡说。本文选择以"平衡论"思想为指导、以"系统论、信息论、控制论"观点假定系统免疫功能保持衡定、以免疫系统功能自身调节代偿为内在动力,对全身炎症反应综合征免疫学发病机制进行哲学探讨,提出了以适应性免疫功能被最大激活为前提,固有免疫功能"代偿/失代偿"的理论观点。     

失眠障碍的治疗

失眠障碍是目前最常见的睡眠-觉醒障碍之一,其本质特征是入睡困难,早醒以及对睡眠质量的不满意等,并且影响记忆力、情绪等日间功能,此外患有失眠的高龄人群会有认知功能下降的风险。随着对失眠的认识的加深,针对失眠的治疗也越发重要。失眠的治疗主要包括生活习惯的改变、睡眠卫生的教育、心理和药物治疗等,本文着重介绍药物治疗及认知行为治疗。     

氧化型低密度脂蛋白：致动脉粥样硬化和抗动脉粥样硬化的双重作用

研究证明,氧化型低密度脂蛋白（oxLDL）,而不是低密度脂蛋白,是致动脉粥样硬化的独立危险因素。oxLDL主要通过巨噬细胞上的清道夫受体摄入oxLDL,引起血管壁泡沫细胞的堆积和脂纹的形成;oxLDL还改变了内皮细胞、平滑肌细胞、血小板的多种功能,使之释放多种致炎细胞因子,促进了炎症细胞的趋化和聚集。但最近有报道认为,口服免疫耐量的oxLDL可弱化早期和晚期动脉粥样硬化。因此,oxLDL不仅能导致动脉粥样硬化,在某些情况下,还具有抗动脉粥样硬化的作用。本文从辩证法的角度出发,系统的阐述oxLDL的这一双重作用。     

氧化型低密度脂蛋白:致动脉粥样硬化和抗动脉粥样硬化的双重作用

研究证明,氧化型低密度脂蛋白(oxLDL),而不是低密度脂蛋白,是致动脉粥样硬化的独立危险因素.oxLDL主要通过巨噬细胞上的清道夫受体摄入oxLDL,引起血管壁泡沫细胞的堆积和脂纹的形成;oxLDL还改变了内皮细胞、平滑肌细胞、血小板的多种功能,使之释放多种致炎细胞因子,促进了炎症细胞的趋化和聚集.但最近有报道认为,口服免疫耐量的oxLDL可弱化早期和晚期动脉粥样硬化.因此,oxLDL不仅能导致动脉粥样硬化,在某些情况下,还具有抗动脉粥样硬化的作用.本文从辩证法的角度出发,系统的阐述oxLDL的这一双重作用.     

关于炎症概念的发展与更新

近年来随着分子生物学技术的进展,发现在炎症过程中众多细胞因子的参与和作用,可发展为全身炎性反应综合征。目前对其诊断标准已有一致的看法。细胞因正面和负面作用,一旦失控,则出现“瀑布效应”,最终导致多器官功能不全。对全身炎性反应综合征的深入认识有助于改善临床的防治、但尚有不少问题有待进一步研究。     

通过打破抗原特异性T细胞免疫耐受控制慢性HBV感染

乙型肝炎病毒(HBV)感染诱导机体抗病毒免疫应答,若不能对病毒有效清除,体内抗原特异的CTL降低,出现抗原特异性T细胞免疫耐受,造成慢性肝脏炎症。分析HBV感染时抗原特异性T细胞免疫耐受机制,并通过打破免疫耐受预防HBV感染。     

Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells

Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress-induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (αβ) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature αβ T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not αβ T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation.     

全身炎症反应综合征治疗新策略——胆碱能抗炎通路

全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)是各种原因刺激机体产生失控的全身性炎症反应的统称,严重者可致多器官功能障碍综合征。迷走神经及其递质乙酰胆碱所构成的胆碱能抗炎通路可以有效抑制局部和全身炎症反应。本文将从胆碱能抗炎通路的作用特点分析激活胆碱能抗炎通路对全身炎症反应综合征的潜在治疗前景。     

Anomalous brain dominance and the immune system: Do left-handers have specific immunological patterns?

Geschwind and Behan (1982) and Geschwind and Galaburda (1985a, 1985b, 1985c) suggested a correlation between brain laterality and immune disorders. To test whether this hypothesis holds true not only for the frequency of immune diseases and circulating autoantibodies, but extends also to cellular immunity, we examined the association between handedness and markers of cellular immunity. Twenty-seven left-handed and 37 right-handed subjects were serologically screened for cellular parameters and 22 left-handed subjects were typed for human leukocyte antigen (HLA). When compared to the right-handers, the left-handed group showed a significant decrease in the inflammatory cell types CD3(+) T cells (total T cells), CD4(+) T cells (T-helper cells), and HLA-Dr (MHC-II, antigen-presenting cells) as well as in the CD19(+) cells (B cells) and CD16/CD57(+) cells (natural killer cells). We assume a relationship exists between cerebral hemispheric specialisation and the immune system not only for humoral but also for cellular immunity, and we discuss the role of the major histocompatibility complex in neurological and immunological development.     

Effects of repetitive stress during the acute phase of Trypanosoma cruzi infection on chronic Chagas' disease in rats

The effect of repetitive stress during acute infection with Trypanosoma cruzi (T. cruzi) on the chronic phase of ensuing Chagas' disease was the focus of this investigation. The aim of this study was to evaluate in Wistar rats the influence of repetitive stress during the acute phase of infection (7 days) with the Y strain of T. cruzi on the chronic phase of the infection (at 180 days). Exposure to ether vapor for 1 min twice a day was used as a stressor. Repetitive stress enhanced the number of circulating parasites and cardiac tissue disorganization, from a moderate to a severe diffuse mononuclear inflammatory process and the presence of amastigote burden in the cardiac fibers. Immunological parameters revealed that repetitive stress triggered a reduced concanavalin A induced splenocyte proliferation in vitro with major effects on the late chronic phase. Serum interleukin-12 concentration decreased in both stressed and infected rats in the early phase of infection although it was higher on 180 days post-infection. These results suggest that repetitive stress can markedly impair the host's immune system and enhance the pathological process during the chronic phase of Chagas' disease.     

Cytokine production by spleen cells after social defeat in mice: activation of T cells and reduced inhibition by glucocorticoids

Social disruption (SDR) is an effective model of social stress associated with an enhanced inflammatory reactivity of the immune system. The aim of the present study was to further describe SDR effects on cytokine production by spleen cells, testing selectively monocyte and T cell functions as a result of this stressor. For this purpose, splenocytes from control mice (C) and mice socially stressed for 7 days (SDR) were cultured in the presence of lipopolysaccharide (LPS) or concanavalin A (Con A). Splenocyte proliferation, cytokine production and sensitivity of spleen cells to corticosterone were assessed in vitro. The humoral response to keyhole limpet hemocyanin (KLH) immunization was assessed. SDR induced splenomegaly and enhanced splenocyte basal proliferation. The pro-inflammatory influence of SDR was confirmed by an increased release of interleukin-6 (IL-6) by LPS-stimulated cultures and by a reduced sensitivity of spleen cells to the anti-inflammatory effect of corticosterone. The mechanism increasing cytokine production in response to LPS was cytokine specific, since among inflammatory cytokines, IL-6 but not interferon-gamma (IFN-gamma) was enhanced by stress. In stressed mice, the increase in IL-6 and IFN-gamma and the decrease in IL-10 release in Con A-stimulated cultures indicate that SDR did not modify the Th1/Th2 cytokine balance but globally activated T cells. Plasma anti-KLH antibody levels were similar in both groups. Wounded and non-wounded mice presented similar responses to stress. This study shows that social disruption stress enhances the reactivity of cells from both the acquired and innate immune systems.     

The central nucleus of the amygdala; a conduit for modulation of HPA axis responses to an immune challenge?

Physical stressors such as infection, inflammation and tissue injury elicit activation of the hypothalamic-pituitary-adrenal (HPA) axis. This response has significant implications for both immune and central nervous system function. Investigations in rats into the neural substrates responsible for HPA axis activation to an immune challenge have predominantly utilized an experimental paradigm involving the acute administration of the pro-inflammatory cytokine interleukin- 1β (IL-1β). It is well recognized that medial parvocellular corticotrophin-releasing factor cells of the paraventricular nucleus (mPVN CRF) are critical in generating HPA axis responses to an immune challenge but little is known about how peripheral immune signals can activate and/or modulate the mPVN CRF cells. Studies that have examined the afferent control of the mPVN CRF cell response to systemic IL-1β have centred largely on the inputs from brainstem catecholamine cells. However, other regulatory neuronal populations also merit attention and one such region is a component of the limbic system, the central nucleus of the amygdala (CeA). A large number of CeA cells are recruited following systemic IL-lβ administration and there is a significant body of work indicating that the CeA can influence HPA axis function. However, the contribution of the CeA to HPA axis responses to an immune challenge is only just beginning to be addressed. This review examines three aspects of HPA axis control by systemic IL-1β: (i) whether the CeA has a role in generating HPA axis responses to systemic IL-1β, (ii) the identity of the neural connections between the CeA and mPVN CRF cells that might be important to HPA axis responses and(iii) the mechanisms by which systemic IL-Iβ triggers the recruitment of CeA cells.     

Chronic restraint stress impairs T-cell immunity and promotes tumor progression in mice

Long-term exposure to stressful situations can affect the immune system. The T-cell response is an important component of anti-tumoral immunity. Hence, impairment of the immune function induced by a chronic stressor has been postulated to alter the immunosurveillance of tumors, thus leading to a worse neoplastic prognosis. Here, we show that chronic restraint stress affects T-cell mediated immunity in mice. This was evidenced by a decrease of mitogen-induced T-cell proliferation, a reduction in CD4(+)T lymphocyte number and a decrease of tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) production in stressed mice. Additionally, mice subjected to chronic restraint stress displayed an enhancement of tumor growth in a syngeneic lymphoma model, i.e. an increase of tumor proliferation and a reduction of animal survival. Finally, stressed mice had a reduced specific cytotoxic response against these tumor cells. These results suggest that chronic exposure to stress promotes cancer establishment and subsequent progression, probably by depressing T-cell mediated immunity. The T-cell immunity impairment as well as the tumor progression enhancement emphasize the importance of the therapeutic management of stress to improve the prognosis of cancer patients.     

慢性应激对大鼠行为和免疫细胞热休克蛋白70表达的影响

目的：研究慢性不确定应激对大鼠急性整体热水浴后外周血和脾脏免疫细胞热休克蛋白70（Heat shock protein 70, HSP70）表达的影响。方法：随机将大鼠分成慢性应激组和控制组（每组14只）。通过4周的慢性不确定性应激诱发实验组大鼠明显的抑郁行为,此期间控制组大鼠正常饲养。随后给予大鼠42度整体热水浴刺激,维持直肠温度41度25min。热刺激后6h,采用流式细胞仪测定大鼠外周血和脾脏免疫细胞HSP70 水平。结果：与控制组大鼠相比,慢性应激大鼠在急性热刺激后HSP70合成明显减少。控制组大鼠的所有被检测的免疫细胞热应激后HSP70合成均明显增加。相反,慢性应激大鼠仅在外周血的单核细胞和粒细胞检测到HSP70合成增加,同时升高的水平明显低于控制组大鼠。结论：慢性应激降低大鼠免疫细胞HSP70的热诱导反应,提示HSP70保护性作用减弱可能参与了慢性应激损害免疫细胞功能的生物学过程     

针对T细胞介导的胰岛自身免疫的治疗策略

1A型糖尿病是由T细胞所介导的器官特异性自身免疫性疾病。人们利用转基因技术、自身抗原疫苗接种、单克隆抗体治疗等新兴技术通过诱导自身免疫耐受,改变免疫调节因子,调节细胞凋亡等途径阻止了自身免疫反应对胰岛的攻击。这些针对其发病机制所提出的新型治疗策略让人们看到了治疗自身免疫型糖尿病的希望。