N-Alkoxycarbonyl-glutamic and aspartic acids

N-Alkoxycarbonylaminodicarboxylic acids were reacted in dichloromethane with N-ethyl-N′-(dimethylaminopropyl)carbodiimide hydrochloride, and with methyl chloroformate in the presence of N-methylmorpholine. Removal of secondary products by washing the mixtures with aqueous solutions gave good yields of the pure crystalline internal anhydrides. Anhydrides of N-benzyloxycarbonyl- (Z) and N-9-fluorenylmethoxycarbonyl-(Fmoc) L-glutamic and L-aspartic acids and of N-tert.-butoxycarbonyl-L-aspartic acid were prepared in this way. The compounds were shown to be amenable to normal phase high-performance liquid chromatography (NP-HPLC) on a CN-column using tert.-butanol-hexane as solvent. The products of the reactions of Z- and Fmoc-glutamic acid with hot acetic anhydride were examined by nuclear magnetic resonance and NP-HPLC before and after methanolysis in an attempt to establish if any of the corresponding pyroglutamates were formed. The reaction of Fmoc-chloride with Fmoc-glutamate was examined for the same reason. It is concluded that the side product generated during the reaction of Fmoc-chloride with glutamic acid which is used for analysis of the latter is the N-protected internal anhydride and not the pyroglutamate as reported in the literature.     

Differential modification of muscarinic cholinergic receptors in the hippocampus of patients with Alzheimer''s disease: an autoradiographic study

We have used quantitative light microscopic autoradiographic techniques to analyze changes in muscarinic cholinergic receptors in the hippocampus in Alzheimer type dementia (ATD). The density and distribution of muscarinic cholinergic receptors has been correlated with the density of neurons, neuritic plaques and neurofibrillary tangles in the CA1 subfield of the hippocampus of control and ATD patients. The number of pyramidal cells per mm² in the CA1 sector was significantly decreased in ATD cases as compared to controls, although there were large variations among cases. The most marked reductions in cell counts were observed in patients with a history of profound dementia. The densities of muscarinic receptors, as well as the proportions of M₁ and M₂ subtypes, in the CA1 sector and dentate gyrus were not significantly different between ATD and old non-demented patients. Neuritic plaques, even in high numbers, did not affect the density of muscarinic receptors; moreover, the densities of receptors over the neuritic plaques did not differ from the surrounding neuropil. However, in some ATD cases there was a marked decrease in the concentration of these receptors in the CA1 sector and subiculum, with no change in the proportions of muscarinic receptor subtypes. These patients exhibited frequent extracellular remnants of neurofibrillary tangles (ghost tangles), but scarce neuritic plaques, and were those showing severe losses of pyramidal cells. There was a significant positive correlation between the total concentration of muscarinic receptors in the CA1 and the density of pyramidal cells, suggesting that decreases in receptor concentration result from a severe neuronal loss. We observed that the ratio of muscarinic receptors per pyramidal cell was significantly increased in ATD patients. This might indicate a possible upregulatory mechanism for muscarinic receptors in the population of remaining neurons in ATD. However, decreases of receptor numbers following severe neuronal fall out suggest that compensatory mechanisms are no longer possible in such cases. The question is raised whether these differences between cases reflect different diseases or different stages of the same disease.     

Activation of the langendorff perfused rat heart depolarized by increased external potassium concentration

Myocardial activation under depolarized conditions was studied in spontaneously beating Langendorff perfused hearts from albino rats. Depolarization was obtained by increasing external potassium concentration in steps (5.4, 7.4, 10, 10.5, 11 and 11.5 mM) in the perfusing solution with or without adrenaline (Adr). Left ventricle isovolumic systolic pressure and coronary flow did not change as external potassium increased, albeit being larger with Adr in the perfusing solution. Atrial and ventricular rates decreased, the latter showing a larger decline. The same behaviour was displayed by perfused hearts, with higher rates being developed by the group with Adr. PR interval and QRS complex duration increased as a function of external potassium. PR intervals were the same in both groups but QRS duration was larger in the Adr group, indicating that AV conduction was not changed in presence of Adr but intraventricular conduction was delayed in that situation. It was also observed that in the great majority of perfused hearts, differing from isolated preparations, ventricular mechanical activity ceased at around 11.5 mM external potassium.     

Basic principles of immunology (immune response) for hemapheresis practitioners

Advances in medical knowledge and technology have identified the essential elements involved in the human immune system, their relationships and interactions, and offer more advanced concepts in the design, function, and maintenance of immune response. Immune response begins with the earliest progenitor cell and transfers its legacy of protection through white blood cells and the complement system. A basic understanding of immunology is essential to the hemapheresis practitioner as new treatment regimens requiring hemapheresis interventions develop. © 1992 Wiley-Liss, Inc.     

RESPONSIVENESS AND SENSITIVITY TO CHOLINERGIC AGONISTS AND ANTAGONISTS IN BOVINE ISOLATED BRONCHIAL MUSCLE

1. Airways derived from different levels of the lung exhibit a difference in the reactivity and sensitivity to agonists. We have evaluated the effect of acetylcholine and cholinergic selective (pirenzepine, gallamine and 4-dipherylacetoxymethyl piperidine [4-DAMP]) and non-selective (atropine) antagonists on bovine proximal and distal smooth muscle preparations. 2. The distal preparations are more sensitive to acetylcholine than proximal bronchi. The relaxant effect of three selective antagonists on the distal and proximal tissues was the same when the results for each drug were compared. 3. Atropine and 4-DAMP were more potent than pirenzepine and gallamine in relaxing both proximal and distal bovine smooth muscle preparations. 4. These data suggest that the muscarinic sites on the smooth muscle of bovine airways are of the M3 subtype.     

Neuronal adrenergic and muscular cholinergic contractile hypersensitivity in canine jejunum after extrinsic denervation

Extrinsic denervation may be responsible for motor dysfunction after small bowel transplantation. The aim of this study was to examine the role of extrinsic innervation of canine jejunum on contractile activity. An in vitro dose response of cholinergic and adrenergic agonists was evaluated in canine jejunal strips of circular muscle at 0, 2, and 8 weeks in a control group and after jejunoileal extrinsic denervation (EX DEN). Neurons in circular muscle were quantitated by means of immunohistochemical techniques. Adrenergic and cholinergic responses did not differ at any time in the control group. However, at 2 and 8 weeks, extrinsic denervation caused an increased sensitivity to the procontractile effects of the cholinergic agonist bethanechol at the level of the smooth muscle cells, and increased sensitivity to the inhibitory effects of the adrenergic agent norepinephrine mediated at the level of the enteric nervous system. Immunohistochemical analysis showed a reduction in all neurons and a complete lack of adrenergic fibers in the EX DEN group after 2 and 8 weeks. Extrinsic denervation induces enteric neuronal cholinergic and adrenergic smooth muscle hypersensitivity in canine jejunal circular muscle. Presented in part at the annual meeting of the American Gastroenterological Association, Orlando, Florida, May 18, 1999 (poster presentation), and published as an abstract in Gastroenterology 116:A1075, 1999. Supported by United States Public Health Service grant DK39337 from the National Institutes of Health (M.G.S.); the Swiss National Science Foundation; the Swiss Society of Gastroenterology and Hepatology; the Swiss Foundation for Medical and Biological Science; the Novartis Foundation; Astra Zeneca Pharmaceuticals, Switzerland; and the Department of Visceral and Transplantation Surgery, University of Bern, Switzerland.     

血小板活化与冠心病关系的研究进展

病理性血小板活化与血栓性疾病密切相关,在心血管疾病中,这一病理生理过程不仅与冠心病的发生、发展有着非常重要的联系,而且对于该病的治疗策略的优化和近、远期预后等方面都有直接的影响。     

Cholinergic therapy in dementia

After reviewing the evidence for cholinergic pathology in Alzheimer's disease and related disorders, this paper reviews strategies for treating dementia using cholinomimetic drugs. Special attention is paid to cholinesterase inhibitors, particularly tacrine, the drug recently approved by the FDA. New studies suggesting that muscarinic and nicotinic cholinergic receptor active drugs may be more effective will be reviewed. Brief mention will be made of strategies to slow the progression of Alzheimer's disease.     

老年大鼠脑M_1亚型受体的变化及黄芪的调节作用

目的：观察老年大鼠不同脑区胆碱能Ｍ１亚型受体的变化和黄芪对其的调节作用。方法：采用放射自显影技术显示大鼠脑Ｍ１受体，并用图像分析仪进行灰度分析，以反映Ｍ１受体在不同脑区的相对定量分布。结果：所得脑切片自显影灰度层次清晰，主要分布在大脑皮质、海马、纹状体部位，非特异结合灰度很低，老年大鼠皮质、海马、纹状体的灰度显著低于青年鼠，分别降低１５７８％，８６９％，１２３６％（Ｐ＜００５），老年服黄芪组三个部位的灰度均明显高于老年对照组，分别升高１６６３％，９８１％，１０３２％，（Ｐ＜００５）。结论：黄芪对老年大鼠降低的脑胆碱能Ｍ１亚型受体具有上调作用。     

大鼠食管颈段神经形态的组化研究

本文采用多种组化方法结合神经银染技术,对大鼠的食管颈段神经形态观察发现:延髓内双侧疑核的咀侧端及迷走神经背核闩平而附近,分别见散在的多极和梭形标记细胞;颈前、中节、颈胸节和胸交感节(T_2-T_4),结状节,脊神经节(C_2-C_8)内均见标记细胞。 食管壁内的神经束及分支,由粗、细两类神经纤维组成。其中AchE阳性的胆碱能纤维占优势,分别见于外膜丛、肌内丛、粘膜下丛,腺体血管周围和粘膜肌内,粗纤维末梢伸向上皮基部和上皮之间,肌内的神经末梢呈结状膨大。外膜和肌肉见有神经节和散在的神经细胞。而食管壁内肾上腺素能纤维稀少,仅见于神经束和分支内及血管壁周围。