Acetylcholinesterase activity in senile plaques of aged macaques

A modified acetylcholinesterase (AChE)-histochemical technique, which demonstrates axonal morphology to a high degree, was used to examine the neocortices of aged monkeys. This approach disclosed slender linear axonal profiles in young animals. In older monkeys, there was a variety of abnormalities of AChE-containing fibers, including multifocal distentions of individual fibers and aggregations of neuritesized, AChE-rich swellings. Combined with thioflavin-T staining to visualize amyloid, this histochemical technique showed that some of these AChE-containing fibers were present in proximity to deposits of amyloid. This association suggests that abnormal AChE-rich axons participate in the formation of some senile plaques in the neocortices of aged nonhuman primates. While it is probable that many of these AChE-rich fibers are axons of cholinergic neurons residing in the basal forebrain, it is also likely that some of these fibers are derived from noncholinergic neuronal populations known to synthesize AChE. Immunocytochemical strategies can be used to assess the involvement of other systems, including cholinergic, noradrenergic, dopaminergic, somatostatinergic, and serotonergic neurons in the formation of senile plaques in the brains of aged nonhuman primates.     

Immunohistological study of senile brains by using a monoclonal antibody recognizing β amyloid precursor protein: significance of granular deposits in relation with senile plaques

Summary Immunochemical analyses revealed that a monclonal antibody Am-3 recognized amyloid precursor protein (APP) in senile plaques extracted from Alzheimer's brain, but did not recognize amyloid protein. Immunohistochemically, however, the staining pattern of Am-3 in frozen section of Alzheimer's brain was almost the same with that of rabbit polyclonal antibody to amyloid peptide which could recognize both amyloid protein and APP. In other words, APP was present in senile plaques of various types, cerebrovascular amyloid and granular deposits. The granular deposits were 5–10 m in size and laminarily distributed in the 1st, 3rd and 4th layers of cerebral cortex. They were especially abundant in 1st and 4th layers where senile plaques were usually fewer in number. Although the distribution in the cerebral cortex was different between the senile plaques and the granular deposits, the number of the granular deposits was well correlated with that of senile plaques. The granular deposits were negative in Congo-red birefringence, but contained amyloid protein as well as APP fragment judging from positive staining by both Am-3 and polyclonal antibody to synthetic amyloid peptide. Thus, they could be regarded as pre-amyloid.     

老年皮肤性病患者诊疗过程中的伦理探讨

探讨了目前临床上诊疗老年皮肤性病患者时存在的伦理道德问题,主要有（1）询问病史时道德责任感不强,问诊不讲究技巧;（2）检查时不细致,伤害患者的人格;（3）临床检验态度不严谨,操作不规范;（4）治疗方案不规范,未考虑老年人的特点,提出了解方案,包括(1)询问病只时要有高度的道德责任感,结合老年人的特点问疹;（2）体格检查时全面系统、认真负责,尊重和关心老年患者;（3）临床检验要态度严谨、操作规范,方便老年患者;（4）治疗时尽可能考虑老年人的特点,合理治疗;（5）尊重和爱护生命,重视老年皮肤病患者的生活质量。     

舌下含服卡托普利与硝苯地平治疗老年急重症高血压的比较

目的 :为了探讨一种不仅能有效降压 ,使用方便而且副作用少的一种降压药物。方法 :选择老年重症高血压患者6 0例 ,随机分成舌下含服卡托普利组和硝苯地平组 ,随时相观察血压、脉搏、心电图、临床症状改善情况及药物的副作用等。结果 :两组间降压总疗效无显著性差异 (P>0 .0 5 ) ,但血压下降高峰值比较 ,差异非常显著 (P<0 .0 1) ;卡托普利组用药 5 m in心率即开始减慢 ,30 min心率减慢达高峰 ,而硝苯地平组用药 5 min心率即开始增快 ,30 min心率增快达高峰 ,两组分别与用药前比较差异非常显著 (P<0 .0 1)。卡托普利组除感味苦外无其他不良反应 ,而硝苯地平组出现不同程度的颜面潮红、心悸、心绞痛以及心电图出现心肌缺血改变等副作用。结论 :舌下含服卡托普利治疗老年重症高血压 ,降压效果好 ,持续时间长 ,副作用少 ,优于硝苯地平     

Amyloid-P-component-like immunoreactivity in β/A4-immunoreactive deposits in Alzheimer-type dementia brains

An immunohistochemical study using the mirror-image technique was performed in order to establish whether amyloid P component is involved in the mechanism of deposition of amyloid fibrils in senile plaques (SPs) in Alzheimer-type dementia (ATD). Ninety percent of /A4 protein-immunoreactive SPs were also stained by the anti-amyloid P component immunchistochemistry, and this applied to all of the diffuse, primitive and classical types of /A4 deposits. These findings may suggest an involvement of amyloid P component in the formation of amyloid fibrils in senile plaques in ATD brains.     

Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin?

Deficits in early stages of information processing, specifically the inability to disattend irrelevant stimuli and to selectively allocate processing resources (i.e., hyperattention), have been associated with the development of psychotic symptoms. Opposite deficits, i.e., the failure to attend and select stimuli, and to divide attention (i.e., hypoattention), represent a major variable in the development of dementia. The hypothesis that hyperattention and hypoattention are mediated via cortical cholinergic hyperactivity and hypoactivity, respectively, is discussed. Several lines of evidence support the role of cholinergic hyperactivity in the development of psychotic symptoms, including the therapeutic effects of anticholinergic drugs in schizophrenic patients, the psychotic effects of chronic exposure to irreversible cholinesterase inhibitors, and the worsening of psychotic symptoms as a result of the treatment with cholinomimetic compounds. The potent impairments of attentional abilities as a result of the administration of muscarinic antagonists in intact subjects, and the attentional effects of cholinomimetic compounds in demented patients are two examples of the evidence that supports the role of cholinergic hypofunction in the cognitive impairments of dementia. A neuronal model of dopamine-GABAergic modulation of cortical acetylcholine is proposed on the basis of evidence indicating that nucleus accumbens dopamine, via a GABAergic pathway to the substantia innominata of the basal forebrain, modulates cortical acetylcholine release. The available evidence confirms several predictions derived from this model, including the dopaminergic regulation of cortical acetylcholine (ACh) release, the bidirectional modulation of this release by benzodiazepine receptor (BZR) agonists and inverse agonists, and the antipsychotic effects of BZR agonists. Bidirectional deviations in the activity of cortical cholinergic inputs are hypothesized to represent a major neuronal substrate of the attentional dysfunctions associated with, or even underlying, the development of psychotic symptoms and dementia. The walk of a stranger on the street could be a sign to me which I must interpret. Every face in the windows of a passing streetcar would be engraved on my mind, all of them concentrating on me and trying to pass me some sort of message. McDonald N (1960) Living with schizophrenia. Can Med Assoc J 82:218–227 Today my mother did not recognize me. Dette U (1991) Ein langer Abschied. Der Verlauf einer Alzheimer-Krankheit. (A long farewell. A case of Alzheimer's disease). Fischer Taschenbuch, Frankfurt [in German]     

Monitoring pathological assembly of tau and β-amyloid proteins in Alzheimer's disease

This double-labelling confocal microscopy study of the neuropathology of Alzheimer's disease (AD) reports the use of a fluorescent dye, thiazin red, which has staining properties similar to thioflavin-S. Thiazin red fluorescence can be visualised selectively in the red channel, and we have used this property to compare it with the labelling seen using monoclonal antibody (mAb) 423, which detects tau protein C-terminally truncated at Glu-391, and mAb 4G8, which detects -amyloid protein. Thiazin red is shown to recognized the typical histopathological deposits associated with both proteins. However, not all deposits containing these proteins are stained. Specifically, diffuse -amyloid plaques and severely degraded extracellular tangles are unlabelled. Likewise a characteristic mAb 423-reactive granular plaque-like structure, typically present in cases with abundant extracellular tangels, is unlabelled by thiazin red. Such plaques can be shown to be continuous with the basal dendrites of degraded tanglebearing pyramidal cells. These findings suggest that paired helical filaments (PHFs) continue to undergo degradation in the extracellular space, which is associated with loss of thiazin red binding sites, but preservation of mAb 423 immunoreactivity. This epitope appears to be characteristic of a stable core element of the PHF which is highly resistant to proteolysis. Compounds such as thiazin red with high affinity for -pleated protein structures can be used to monitor the state of pathological assembly of amyloidogenic protein species found in AD.Supported in part by CONACyT grant #1624-N9208 (to R.M.), the Medical Research Council (U.K.), Zeneca Pharmaceuticals and the Alzheimer Disease Research Fund and the Leopold Muller Estate     

Senile plaques in an aged two-humped (Bactrian) camel (Camelus bactrianus)

Senile plaques with -protein as a major constituent are a conspicuous feature in the brains of aged humans, monkeys, dogs, and bears. We found cerebral senile plaques of the diffuse and primitive type, but not the classical type, in an aged female camel of more than 20 years old. The senile plaques and a few cortical capillaries were immunoreactive with anti--protein serum. Congophilic amyloid deposition was detected in a small number of the capillaries, but not in the senile plaques. We believe this to be the first detailed report of senile plaques in a herbivore, and these findings suggest the ossibility of senile plaque formation in a wide variety of mammlian species.     

神经生长因子对老年退变性膝骨关节炎疼痛模型的影响

目的:探讨体外模型评价神经生长因子(nerve growth factor,NGF)抗体在膝骨关节炎(knee osteoarthritis,KOA)疼痛模型中的作用。方法:选取30只8周龄雄性SPF大鼠,分为空白组10只;其余20只行右膝关节单碘乙酸 (monoiodoacetate,MIA) 注射,制备骨性关节炎疼痛模型。造模成功后,再根据干预方法不同分为对照组(生理盐水腹腔注射)、治疗组(抗NGF 腹腔注射),每组10只。所有动物右膝关节进行荧光金 (fluorogold,FG) 逆行神经示踪剂注射。分别在治疗前,治疗后1、2周使用猫道步态分析系统评估步态。治疗后3周,从L₃-L₅水平切除右背根神经节(dorsal root ganglia,DRG),进行降钙素基因相关肽 (calcitonin gene-related peptide,CGRP) 免疫染色,并计算DRG数量。结果:在使用猫道系统的步态分析中,与空白组相比,对照组、治疗组占空比、摆动速度和触地面积比率明显降低(P<0.05);与对照组相比,治疗组占空比、摆动速度明显改善(P<0.05),触地面积比率与空白组比较,差异无统计学意义(P>0.05)。对照组中FG标记的DRG神经元数量高于治疗组和空白组(P<0.05);对照组CGRP表达上调,与治疗组比较,差异有统计学意义(P<0.05)。结论:腹腔注射抗 NGF抗体抑制了步态损伤和 DRG 神经元中CGRP 的上调。这些发现提示抗神经生长因子治疗可能对治疗膝关节疼痛有价值。NGF可能是治疗KOA疼痛的重要靶点。     

Inflammatory mechanisms in Alzheimer's disease

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as 1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.