精神分裂症免疫指标与精神症状的关系

为探讨精神分裂症精神病理与免疫指标的相关性、评估抗精神病药对免疫指标的影响及其与疗效的关系，用固定剂量氟哌啶醇治疗５０例慢性精神分裂症患者１２周，在治疗前后测查Ｔ细胞亚群和白细胞介素２（ＩＬ－２）分泌细胞，并采用简明精神病评定量表（ＢＰＲＳ）、阳性症状评定量表（ＳＡＰＳ）和阴性症状评定量表（ＳＡＮＳ）进行评定。结果显示，治疗前ＣＤ３阳性细胞（ＣＤ＋３）、ＣＤ４阳性细胞（ＣＤ＋４）、ＣＤ４／ＣＤ８阳性细胞比值（ＣＤ４／ＣＤ８）和ＩＬ－２分泌细胞均明显低于正常人，治疗后ＣＤ＋４呈显著性增高；治疗前ＣＤ４／ＣＤ８与ＳＡＰＳ总分呈显著负相关，ＢＰＲＳ、ＳＡＰＳ和ＳＡＮＳ减分率与治疗前ＣＤ＋３细胞数均呈显著正相关，ＳＡＮＳ减分率与治疗前ＣＤ＋４细胞数亦呈正相关。研究表明，抗精神病药在改善患者精神症状的同时，也使其免疫功能得到改善；临床症状改善程度与治疗前的免疫功能状态相关。     

精神分裂症白细胞介素2和CD4 细胞的相关研究

目的　探讨精神分裂症患者 Ｃ Ｄ４ ＋ 细胞与白细胞介素２（ Ｉ Ｌ２） 之间的关系。方法　对３０ 例精神分裂症和２５例正常对照分别采用碱性磷酸酶抗碱性磷酸酶桥联酶标法、放射免疫法进行外周血 Ｃ Ｄ４ ＋ 细胞、 Ｉ Ｌ２ 分泌细胞数和 Ｉ Ｌ２ 含量检测。结果　精神分裂症组外周血 Ｃ Ｄ４ ＋ 细胞、 Ｉ Ｌ２ 分泌细胞和 Ｉ Ｌ２ 含量均显著低于正常组（ Ｐ＜ ００５） ；正常组血 Ｃ Ｄ４ ＋细胞数与外周 Ｉ Ｌ２ 含量显著正相关（ Ｐ＜ ００５） ，病人组无相关。结论　精神分裂症可能存在免疫激活，与其自身免疫假说相符；同时，分泌 Ｉ Ｌ２ 的 Ｔ 细胞也可能存在自身缺陷。     

Alzheimer病的T淋巴细胞功能活性检测

目的　探讨外周Ｔ淋巴细胞功能活性与Ａｌｚｈｅｉｍ ｅｒ病（ＡＤ）病情的关系。方法　流式细胞仪测定Ｔ细胞亚群;ＭＴＴ法检测ＣｏｎＡ刺激ＡＤ外周淋巴细胞的增殖功能;ＥＬＩＳＡ法检测细胞因子及其受体表达。结果　（１）ＣＤ４＋ 、ＣＤ８＋ Ｔ细胞比例和ＣＤ４＋ ／ＣＤ８＋ 比值各组间无统计学差异。（２）淋巴细胞增值在轻、重ＡＤ组略下降,但刺激指数（ＳＩ）都大于２,与对照无明显差异。（３）ＩＬ－２的分泌在重度ＡＤ组和ｓＩＬ－２Ｒ表达在轻、重度ＡＤ组明显升高（Ｐ＜ ０．０５）,ＩＬ－２Ｒ的表达各组间差异无显著性。结论　Ｔ淋巴细胞亚群变化与ＡＤ病情的联系不明显,细胞因子分泌功能与ＡＤ进展有关。     

重症肌无力患者细胞免疫及免疫调节 与临床疗效关系的分析

目的探讨周围血中ＮＫ细胞、Ｔ细胞亚群、细胞膜白细胞介素－２受体（ｍＩＬ－２Ｒ）阳性细胞与重症肌无力（ＭＧ）发病及临床疗效的关系。方法用流式细胞仪计数３９例ＭＧ患者ＣＤ３、ＣＤ４、ＣＤ８、ＣＤ２５和ＣＤ５６抗体阳性细胞的百分率,应用许氏临床评分法对病情的严重程度和转归进行评定。结果ＭＧ患者的ｍＩＬ－２Ｒ（ＣＤ２５）阳性细胞无明显改变。ＣＤ３阳性细胞在肾上腺皮素激素治疗前、后无明显改变。ＮＫ细胞（ＣＤ５６）和ＣＤ４阳性细胞在治疗前均明显高于正常（Ｐ＜００１）,治疗２个月后均明显下降（Ｐ＜０．０１,０．０５）。ＣＤ８阳性细胞治疗前后明显降低和增高（Ｐ＜００５）。结论ｍＩＬ－２Ｒ阳性细胞百分率不能直接反映ＭＧ的免疫功能紊乱,并对ＮＫ细胞和Ｔ细胞亚群的变化无直接调节作用。ＮＫ细胞增高,可能为其功能下降的代偿性变化。ＣＤ４增高,ＣＤ８下降提示免疫功能紊乱,符合自身免疫性疾病的特点。     

精神分裂症免疫功能紊乱机理的研究

为探讨精神分裂症免疫功能紊乱的机理，检测了２８例精神分裂症患者外周血Ｔ细胞亚群、Ｂ细胞百分率及外周血单个核细胞白细胞介素（ＩＬ－２）、白细胞介素－４（ＩＬ－４）的诱生能力。发现患者组外周血全体Ｔ细胞（ＣＤ＋３）及辅助Ｔ细胞（ＣＤ＋４）均值明显低于对照组，ＩＬ－２诱生能力低下而ＩＬ－４诱生能力、血清总ＩｇＥ含量明显增高，与正常对照组相比有显著性差异。提示精神分裂症患者免疫功能紊乱主要表现为ＴＨ１细胞减少，ＴＨ２细胞相对或绝对增多。     

AChRAb阳性和阴性重症肌无力患者IL—4和IFN—γ…

将行胸腺切除术的重症肌无力（ＭＧ）患者分成乙酰胆碱受体抗体（ＡＣｈＲＡｂ）阳性和阴性２组，采用免疫酶点法检测其外周血、骨髓和胸腺白细胞介素４－（ＩＬ－４）分泌细胞和干扰素－γ（ＩＦＮ－γ）分泌细胞的数量，结果表明ＡＣｈＲＡｂ阳性组其外周血和骨髓中ＩＬ－４和ＩＦＮ－γ分泌细胞数量均显著高于ＡＣｈＲＡｂ阴性组（Ｐ〈０．０５），而胸腺细胞两组间差异无显著性意义（Ｐ〉０．０５）。提示ＩＬ－４和ＩＦＮ－γ在     

脑胶质瘤患者外周血T淋巴细胞亚群及β2—微球蛋白的初步研究

本文对胶质瘤病人及对照组分别检测了周围血中Ｔ淋巴细胞亚群及β２－微球蛋白（β２－ｍＧ）含量及脑脊液中β２－ｍＧ含量，结果表明，脑胶质瘤病人ＣＤ４＋（辅助／诱导性Ｔ淋巴细胞）降低，ＣＤ８＋（细胞毒／抑制性Ｔ淋巴细胞）增高，ＣＤ４＋／ＣＤ８＋降低，与对照组有显著差异（Ｐ＜０．０５），脑胶质瘤病人血及脑脊液中β２－ｍＧ含量增高与对照组比较有显著差异（Ｐ＜０．０５）。脑胶质瘤病人β２－ｍＧ增高与ＣＤ４＋／ＣＤ８＋比值之间呈负相关性。本组实验证明，脑胶质瘤患者存在细胞免疫功能低下，且β２－ｍＧ含量与细胞免疫功能呈负相关。β２－ｍＧ可反映细胞免疫功能状态。     

首发精神分裂症患者的细胞免疫改变

目的研究未经治疗的首发精神分裂症患者细胞免疫功能状态。方法３０例符合入组标准的首发精神分裂症患者和１１名正常人，用流式细胞仪测定外周血ＣＤ＋３、ＣＤ＋４和ＣＤ＋８Ｔ淋巴细胞，ＭＴＴ法检测患者血浆ＩＬ－２活性和酶标法检测血浆ｓＩＬ－２Ｒ水平。比较细胞免疫功能。结果发现精神分裂症患者血浆ＩＬ－２水平显著高于正常志愿者，ＣＤ＋３、ＣＤ＋４Ｔ淋巴细胞数量降低，ｓＩＬ－２Ｒ水平和ＣＤ＋８Ｔ淋巴细胞没有明显变化。结论精神分裂症患者细胞免疫功能异常活化，活化的细胞免疫功能可能与精神分裂症的发生有关，作用机制有待进一步研究。     

孤独症患者T淋巴细胞功能及其亚群的研究

为研究孤独症患者免疫学方面的异常，探索孤独症的病理学机制，对２７例孤独症、１６例精神发育迟滞（ＭＲ）和１８名正常儿童进行了Ｔ淋巴细胞增殖反应及其亚群的测定，应用ｔ检验进行统计学处理。结果显示：孤独症组的ＣＤ４阳性细胞百分数明显低于其它两组（ｔ值分别为２．６４，２．２１；Ｐ平均值＜０．０５），孤独症ＣＤ３阳性细胞也较ＭＲ组显著为低（ｔ＝２．４７４，Ｐ＜０．０２）。在淋巴细胞增殖反应方面，孤独症组也较对照组明显降低（ｔ＝２．１７５，Ｐ＜０．０５）。提示ＣＤ４阳性细胞数下降与孤独症的发病有关，并讨论了孤独症与Ｔ淋巴细胞功能间的联系     

精神分裂症病人的外周血免疫学参数

为探讨不同亚型精神分型精神分裂症患者的免疫功能状态，对４１例病人Ｔ细胞亚群、ＮＫ细胞ＣＤ５６的的表达、白细胞介素４（ＩＬ－４）及可溶性白细胞介素２受体进行检测，并以１５例健康人为对照。结果显示，Ⅰ型患者ＣＤ３＋、ＣＤ４＋细胞数、ＣＤ４／ＣＤ８比值显著低于对照组，ＣＤ５６＋细胞数、ｓＩＬ－２Ｒ显著高于对照组；Ⅱ型患者ＣＤ８＋细胞数明显升高，ＣＤ４／ＣＤ８比值下降，而ＣＤ５６＋、ＣＤ３＋、ＣＤ４＋ＩＬ     

Modulation of astrocytic activation by arundic acid (ONO-2506) mitigates detrimental effects of the apolipoprotein E4 isoform after permanent focal ischemia in apolipoprotein E knock-in mice.

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we have shown that delayed infarct expansion and reactive astrocytosis after permanent middle cerebral artery occlusion (pMCAO) were markedly exacerbated in 4/4-KI mice as compared with 2/2- or 3/3-KI mice. Here, we probed the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using arundic acid (ONO-2506, Ono Pharmaceutical Co. Ltd), which is known to oppose astrocytic activation through its inhibitory action on S100B synthesis. In all of the KI mice, administration of arundic acid (10 mg/kg day, intraperitoneal, started immediately after pMCAO) induced significant amelioration of brain damage at 5 days after pMCAO in terms of infarct volumes (results expressed as the mean infarct volume (mm(3)) +/-1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 16 +/- 2, 15 +/- 2, or 22 +/- 2; in the arundic acid groups: 11 +/- 2 (P < 0.001), 11 +/- 2 (P < 0.001), or 12 +/- 2 (P < 0.001), as compared with the vehicle groups), neurologic deficits, and S100/glial fibrillary acidic protein burden in the peri-infarct area. The beneficial effects of arundic acid were most pronounced in 4/4-KI mice, wherein delayed infarct expansion together with deterioration of neurologic deficits was almost completely mitigated. The above results support the notion that the apoE4 isoform exacerbates brain damage during the subacute phase of pMCAO through augmentation of astrocytic activation. Thus, pharmacological modulation of astrocytic activation may confer a novel therapeutic strategy for ischemic brain damage, particularly in APOE epsilon4 carriers.     

Augmented delayed infarct expansion and reactive astrocytosis after permanent focal ischemia in apolipoprotein E4 knock-in mice.

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we aimed to examine whether an apoE isoform-specific exacerbation of delayed infarct expansion occurs after permanent middle cerebral artery occlusion (pMCAO). Compared with 2/2- or 3/3-KI mice, 4/4-KI mice exhibited significantly larger infarct volumes and worse neurologic deficits after pMCAO, with no significant differences between the latter two groups. Infarct volume in 4/4-KI mice was significantly increased from 1 to 5 days after pMCAO, whereas that in 2/2- or 3/3-KI mice was not significantly altered. DNA fragmentation in the peri-infarct area as detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatenick end-labeling was increased to a similar degree in all of the KI mice by 5 days after pMCAO, with no significant differences among the mouse groups. At every time-point examined, human apoE was most markedly expressed in the peri-infarct area, with similar immunoreactivity among the three lines of KI mice. The glial fibrillary acidic protein immunoreactive burden in the peri-infarct area was progressively increased through 7 days in 4/4-KI mice, but not in 2/2- or 3/3-KI mice. Taken together, these data show that the apoE4 isoform acts to aggravate delayed infarct expansion and peri-infarct reactive astrocytosis during the subacute phase of pMCAO in genetically engineered apoE-KI mice.     

Apolipoprotein E Genotype and Alzheimer's Disease in an Elderly Norwegian Cohort

Apolipoprotein E (Apo E) genotyping was performed on an autopsy cohort of neuropathologically verified non-demented controls and subjects with Alzheimer's disease (AD) resident in nursing homes in the Oslo area. AD was associated with a significantly increased frequency of the Apo E ϵ4 allele; the frequency of the ϵ2 and ϵ3 alleles was lower in AD but not significantly so. Age at death in the control group and the AD group did not differ significantly; neither did age at death nor age at onset of dementia in AD vary according to Apo E genotype, though tendencies towards an earlier age at death was seen in individuals with ϵ4/4 and earlier age at onset dementia in the presence of an ϵ4 allele and a later age of onset the presence of an ϵ3 allele were seen. Possession of an ϵ2 allele had no effect on age at onset of dementia or age at death. Among the possible genotypes there was a trend towards a progression of earliest onset ϵ4/4, ϵ2/4, ϵ3/4, ϵ3/3, ϵ2/3 latest onset of dementia and longest duration ϵ2/4, ϵ4/4, ϵ3/4, ϵ3/3, ϵ2/3 to shortest duration of dementia.     

Semaphorin 4C and 4G are ligands of Plexin-B2 required in cerebellar development

Semaphorins and Plexins are cognate ligand-receptor families that regulate important steps during nervous system development. The Plexin-B2 receptor is critically involved in neural tube closure and cerebellar granule cell development, however, its specific ligands have only been suggested by in vitro studies. Here, we show by in vivo and in vitro analyses that the two Semaphorin-4 family members Sema4C and Sema4G are likely to be in vivo ligands of Plexin-B2. The Sema4C and Sema4G genes are expressed in the developing cerebellar cortex, and Sema4C and Sema4G proteins specifically bind to Plexin-B2 expressing cerebellar granule cells. To further elucidate their in vivo function, we have generated and analyzed Sema4C and Sema4G knockout mouse mutants. Like Plexin-B2-/- mutants, Sema4C-/- mutants reveal exencephaly and subsequent neonatal lethality with partial penetrance. Sema4C-/- mutants that bypass exencephaly are viable and fertile, but display distinctive defects of the cerebellar granule cell layer, including gaps in rostral lobules, fusions of caudal lobules, and ectopic granule cells in the molecular layer. In addition to neuronal defects, we observed in Sema4C-/- mutants also ventral skin pigmentation defects that are similar to those found in Plexin-B2-/- mutants. The Sema4G gene deletion causes no overt phenotype by itself, but combined deletion of Sema4C and Sema4G revealed an enhanced cerebellar phenotype. However, Sema4C/Sema4G double mutants showed overall less severe cerebellar phenotypes than Plexin-B2-/- mutants, indicating that further ligands of Plexin-B2 exist. In explant cultures of the developing cerebellar cortex, Sema4C promoted migration of cerebellar granule cell precursors in a Plexin-B2-dependent manner, supporting the model that a reduced migration rate of granule cell precursors is the basis for the cerebellar defects of Sema4C-/- and Sema4C/Sema4G mutants.     

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post- and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2- and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2- and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.     

A monoclonal antibody (LK-4) which differentiates PLA1 from PLA2 platelet extracts but not intact platelets.

A unique murine monoclonal antibody (LK-4) is described which differentiates PLA1/PLA1 platelet extracts from PLA2/PLA2 and PLA1/PLA2 platelet extracts on solid phase ELISA and immunoblot at the 100kD GPIIIa location, but not on intact platelets. LK-4 reacts equally with intact PLA1/PLA2 and PLA2/PLA2 platelets. Adsorbtion of LK-4 with PLA1/PLA1 platelets results in loss of reactivity for intact platelets as well as platelet extracts on ELISA or immunoblot. LK-4 inhibits platelet aggregation induced by ADP, epinephrine, collagen and thrombin, suggesting reactivity at or near the fibrinogen binding site on GPIIIa. It is suggested the LK-4 reacts with a conformation-induced common epitope for PLA1 and PLA2 on GPIIIa, with loss of this conformation for PLA2 GPIIIa following solubilization with Triton X-100.     

Depression in Alzheimer's disease might be associated with apolipoprotein E epsilon 4 allele frequency in women but not in men

The association between depression and apolipoprotein E (apoE) was investigated in 137 out-patients with Alzheimer's disease. An ICD-10 diagnosis of depression was found in 21.1% of all patients. There was a good correlation between clinicians' diagnoses and blinded rating by the Montgomery-Asberg Depression Rating Scale (r = 0.70). In male patients, apoE 3/3 was detected in 34.1%, 3/4 in 38.6%, 4/4 in 13.6%, 2/4 in 6.8% and 2/3 in 6.8% of cases. In female patients, apoE 3/3 was detected in 35.5%, 3/4 in 45.2%, 4/4 in 12.8%, 2/4 in 3.2% and 2/3 in 3.2% of cases. When analyzing the variance of gene dosage effect, the frequency of the apoE epsilon 4 allele was significantly increased in depressed women but not in men. This effect remained stable in stepwise regression analysis when depression as the dependent variable was tested against the independent variables age, age of onset, duration of disease, cognitive status and years of school education.     

Development of cortical connections as measured by EEG coherence and phase delays

The purpose of this study was to explore human development of EEG coherence and phase differences over the period from infancy to 16 years of age. The electroencephalogram (EEG) was recorded from 19 scalp locations from 458 subjects ranging in age from 2 months to 16.67 years. EEG coherence and EEG phase differences were computed for the left and right hemispheres in the posterior-to-anterior direction (O1/2-P3/4, O1/2-C3/4, O1/2-F3/4, and O1/2-Fp1/2) and the anterior-to- posterior direction (Fp1/2-F3/4, Fp1/2-C3/4, Fp1/2-P3/4, and Fp1/2-O1/2) in the beta frequency band (13-25 Hz). Sliding averages of EEG coherence and phase were computed using 1 year averages and 9 month overlapping that produced 64 means from 0.44 years of age to 16.22 years of age. Rhythmic oscillations in coherence and phase were noted in all electrode combinations. Different developmental trajectories were present for coherence and phase differences and for anterior-to-posterior and posterior-to-anterior directions and inter-electrode distance. Large changes in EEG coherence and phase were present from approximately 6 months to 4 years of age followed by a significant linear trend to higher coherence in short distance inter-electrode distances and longer phase delays in long inter-electrode distances. The results are consistent with a genetic model of rhythmic long term connection formation that occurs in cycles along a curvilinear trajectory toward adulthood. Competition for dendritic space, development of complexity, and nonlinear dynamic oscillations are discussed.     

Effects of short-term exposure to catecholestrogens on catecholamine turnover in the preoptic-hypothalamic brain of ovariectomized rats

The effects of a series of catecholestrogens (2-hydroxyestrogens and 4-hydroxyestrogens) were compared to those of a primary estrogen, ethynylestradiol (EE₂), on the catecholaminergic system in the preoptic-hypothalamic rat brain. Adult ovariectomized rats received single injections (100 μg s.c.) of EE₂, 2-hydroxyestradiol (2-OHE₂), 2-hydroxyethynylestradiol (2-OHEE₂), 4-hydroxyestradiol (4-OHE₂) or 4-hydroxyethynylestradiol (4-OHEE₂). Eight hours after estrogen administration the animals were killed, and the concentrations of dopamine (DA), noradrenaline (NA) and adrenaline (A) were determined radioenzymatically in the preoptic area (POA) and the mediobasal hypothalamus (MBH).

EE₂ and all the catecholestrogens tested uniformly suppressed(P < 0.01) serum LH levels. This correlated well with the decreased turnover rate of A in the POA. In both the POA and the MBH of EE₂-treated animals the turnover rate of NA was markedly decreased whereas the concentrations of catecholamines remained unaffected. The catecholethynylestrogens, potent inhibitors of catechol O-methyltransferase, caused two-fold increases of NA concentrations in the POA (2-OHEE₂ and 4-OHEE₂) and MBH (2-OHEE₂) without affecting the turnover rate. Thus, although EE₂ and all the catecholestrogens tested uniformly suppressed LH release they induced highly different effects on the noradrenergic system in the preoptic-hypothalamic brain.     

载脂蛋白E基因多态性和脑梗死关系的研究

目的探讨载脂蛋白E基因(ApoE)多态性与脑梗死的关系.方法采用病例-对照研究,对379例脑梗死患者和351例对照组进行研究.采用聚合酶链式反应-限制性片段长度多态性方法测定ApoE基因多态性.结果脑梗死组ApoE基因型频率E3/3、E3/4、E3/2、E2/4和E4/4型分别为72.3%、14.5%、11.6%、0.8%、0.8%.在脑梗死组中未发现E2/2.E2/2在脑梗死组和对照组之间有显著性差异(P＜0.05.)结论ApoE2/2对脑梗死可能具有保护作用.