肥胖相关性肾病诊疗研究进展

肥胖相关性肾病已呈流行发展趋势,已成为终末期肾病的主要原因之一。目前认为其发病机制主要与肥胖所致肾小球血流动力学改变和脂质异位沉积等相关,但其机制仍未完全阐明。减轻体重是治疗肥胖相关性肾病的重要方法,但常因环境、个人执行情况的影响而收效甚微,且有部分患者体重控制后肾病仍持续进展。综合应用有效的肥胖相关性肾病治疗方法,对控制其进展十分重要。该文综述肥胖相关性肾病的致病机制和诊疗进展,探讨中药在肥胖相关性肾病治疗中的价值,旨在为临床提供参考,提高肥胖相关性肾病一体化管理水平。     

Efficacy of intranasal administration of neostigmine in myasthenic patients

Summary The efficacy of intranasally administered neostigmine was tested in 22 patients with generalized myasthenia gravis (MG). Topical therapy to the highly vascularized oropharynx proved to be quickly effective in 5–15 min both clinically and electrophysiologically. Twenty-eight MG patients were then recruited from different centres and their morning doses of oral pyridostigmine were substituted with intranasal neostigmine over a period of 2 or 3 weeks. Intranasal neostigmine proved to be equally efficacious in this regimen. No side-effect was noted even in 4 patients treated in this way for 1 year. Intranasal administration of anti-acetylcholinesterase may be very beneficial: (1) for patients with irregular absorption of oral doses; (2) early in the morning and every time a fast and temporary effect is needed; (3) in bulbar impairment and emergencies, in which a handy atomizer may be life-saving.Presented in part at the XIV World Congress of Neurology, New Delhi, 22–27 October 1989     

Uptake inhibitors do not change the effect of imidazoline α2-adrenoceptor agonists on transmitter release evoked by single pulse stimulation in mouse vas deferens

Summary The present study was undertaken to compare the presynaptic interaction of neuronal noradrenaline uptake inhibitors with imidazoline and phenylethylamine ₂adrenoceptor agonists under two different conditions: at low and high noradrenaline concentrations in the biophase.Isolated mouse vasa deferentia were stimulated with trains of 7 pulses given at 0.2 Hz and the inhibition by the ₂-adrenoceptor agonists clonidine, -methylnoradrenaline, and UK-14,304 of twitch responses was measured in the absence and in the presence of either cocaine (12 mol/l) or desipramine (40 nmol/l). The effects were determined for the first (equivalent to single pulse stimulation) and the last stimulus of each train. Both uptake inhibitors antagonized the presynaptic inhibitory effects of imidazolines (clonidine and UK-14,304) on the last twitch; the effects on the first twitch remained unchanged. In contrast, the uptake inhibitors potentiated the inhibitory effect of the phenylethylamine (-methylnoradrenaline) on both the first and the last twitches.These results support the view that the concentration of noradrenaline in the biophase plays a decisive role in the inhibition by a₂-adrenoceptor agonists of the electrically evoked release of noradrenaline. Agonists that are not substrates of neuronal uptake (i.e., clonidine, UK-14,304) become less effective when noradrenaline is present in the biophase while substrates of neuronal uptake (i. e., -methylnoradrenaline) do not. The results argue against the hypothesis that uptake inhibitors interact directly with presynaptic ₂-adrenoceptors or act at some link between uptake and receptor sites. Send offprint requests to S. Guimarães at the above address     

Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics

The effects of hemicholinium-3 (HC-3) on spatial discriminaton learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical float (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 g/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 g/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46–460 g/kg/SC) and tetrahydroaminoacridine (THA) (2.2–10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046–1 mg/kg/SC), aceclidine (1–10 mg/kg/SC), oxotremorine (30–100 g/kg/SC) and RS-86 (0.46, 1.0 g/kg/SC) were also effective. Pilocarpine (0.22–2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6–10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The ₂ agonist, clonidine (46, 100 g/kg SC) and the antagonist idazoxan (32, 100 g/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 g/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT_1A agonist 8-OH-DPAT (30, 100 g/kg) or by the benzodiazapine antagonist ZK 93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.     

Characterization of htAKR, a novel gene product in the aldo-keto reductase family specifically expressed in human testis

In human testis, expression of a novel member of the aldo-keto reductase family was identified. Based on its testis-specific expression, we termed this protein human testis aldo-keto reductase (htAKR). In addition to four major isoforms, the existence of multiple alternatively spliced products of htAKR was detected using RT-PCR followed by nested PCR. htAKR was a homologue of mouse liver keto-reductase, AKR1E1, with close similarity in their genomic organizations. htAKR4, the longest isoform, was expressed as a non-fused native form. It exhibited a limited activity toward 9,10-phenanthrenequinone, while no activity toward the steroids or prostaglandins was demonstrated. Using the laser capture microdissection technique and RT-PCR, expression of htAKR was detected in testicular germ cells as well as in interstitial cells. The levels of htAKR mRNA in the tissues obtained from seminoma were much lower than those in normal testes. A significant decline in the htAKR expression was observed when NEC8, a cell line originated from a human testicular germ cell tumour, was exposed to phorbol 12-myristate 13-acetate or 5alpha-dihydrotestosterone. These results indicate that the expression of htAKR, down-regulated in the testicular tumour, is possibly controlled by mitogenic and hormonal signals.     

甲叉四氢叶酸还原酶C677T与精神分裂症的连锁不平衡研究

目的 通过对甲叉四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR)C677T错义突变与精神分裂症的连锁不平衡研究，探讨该突变与精神分裂症的关系。方法 对115个精神分裂症同胞及核心家系中，用XDT和MAPMAKER／SIBS软件系统进行MTHFRC677T与精神分裂症的连锁不平衡分析。按照不同的诊断范围将家系分类，分别在全体家系及发病年龄小于25岁的家系中进行连锁不平衡分析。结果 在4种不同的诊断分类下，对全体家系进行连锁不平衡分析未发现阳性结果。对发病年龄小于25岁的患者家系进行分析时发现，在4种不同的诊断灵感上均具有显著性意义，P值分别小于0．05及0．01。结论 MTHFR C677T错义突变可能为影响精神分裂症易感性的基因之一，尤其是在发病年龄较早的患病群体中。     

血管生成及其抑制剂在前列腺癌中的研究进展

Angiogenesis plays a key role in progression of prostate cancer. Antigiogenesis becomes a new treament target for prastate cancer. In this review, we focus on the current knowledge of angiogenesis and tumor angiogenesis inhibitor in prastate cancer.     

Dynamics of HIV replication in lymphocytes and the efficacy of protease inhibitors

Using a system that allows transfection of resting peripheral blood lymphocytes (PBLs) two questions were addressed: the kinetics of HIV replication from the state of proviral latency, and the impact of different parameters on the efficacy of protease inhibitors to control HIV replication. PBLs were transfected with an infectious full length HIV-DNA harboring a luciferase reporter gene and activated thereafter. Ritonavir was added at different times at doses ranging from to 0.06 to 1 microM. Viral expression was assessed by quantifying luciferase activity in cell extracts and levels of p24 HIV antigen in culture supernatants. After transfection and cell activation, intracellular expression of HIV proteins, as assessed by luciferase detection, occurred within 2 hr. HIV-gag p24 antigen was detected in culture supernatants between 6 and 8 hr post-activation. Ritonavir was effective in blocking viral replication when given within 4 hr following HIV reactivation, but a delay in ritonavir administration or breaches in ritonavir levels after 6 hr from transfection resulted in viral escape. HIV reactivation from proviral latency in PBLs is an extremely rapid process, faster than estimated from previous models. These data stress the need for maintaining effective antiretroviral concentrations to block completely viral replication.     

Identification of a Thymidylate Synthase Gene within the Genome of Chilo Iridescent Virus

The thymidylate synthase (TS, EC 2.1.1.45) is essential for the de novo synthesis of dTMP in pro- and eucaryotic organisms. Consequently it plays a major role in the replication of the DNA genome of a cell or a DNA virus. The gene encoding the TS of Chilo iridescent virus (CIV) was identified by nucleotide sequence analysis of the viral genome and was mapped within the EcoRI CIV DNA fragments G and R. Computer assisted analysis of the DNA nucleotide sequence between the genome coordinates 0.482 and 0.489 revealed an open reading frame (ORF) of 885 nucleotides. This ORF was found to encode a polypeptide of 295 amino acid residues (33.9 kDa) that showed significant homologies to known TS of different species including mammals, plants, fungi, protozoa, bacteria, and DNA viruses. The highest amino acid homologies were found between the CIV-TS and the TS of herpesvirus ateles (54.0%), Saccharomyces cerevisiae (51.8%), herpesvirus saimiri (51.0%), rhesus monkey rhadinovirus (50.7%), mouse (50.5%), rat (50.2%), varicella-zoster virus (50.2%), equine herpesvirus 2 (50.0%), and the human TS (48.4%). The CIV-TS contains six amino acid domains that are highly conserved in the TS of other species. Within these domains the major amino acid residues are present for which a functional role has been reported. The CIV-TS was found to be more closely related to the TS of eucaryotes than to the TS of procaryotes indicating the phylogenetic origin of the CIV-TS gene. The identification of a TS gene in the genome of CIV is the first report of a viral TS that is not encoded by a herpesvirus or a bacteriophage.     

Eradication of Helicobacter pylori heals atrophic corpus gastritis caused by long-term treatment with omeprazole

 Long-term treatment with proton pump inhibitors in patients with Helicobacter pylori gastritis can lead to atrophic changes in the corpus mucosa. What is still unclear, however, is whether this atrophy can regress in response to Helicobacter pylori eradication. We report on a male patient with Helicobacter pylori gastritis receiving long-term treatment (4 years) with omeprazole for gastro-oesophageal reflux disease, who developed autoaggressive gastritis with progressive atrophy, hypochlorhydria, hypergastrinaemia and nodular ECL-cell hyperplasia. To determine whether these changes might be induced to regress, Helicobacter pylori eradication therapy was administered. Ten months after Helicobacter pylori eradication autoaggressive lymphocytic infiltrates were no longer detectable, and the glands in the corpus mucosa had normalised despite continued treatment with omeprazole – a finding that was confirmed at two further follow-up surveys performed at 6-month intervals. This case report shows that atrophy of the corpus mucosa developing under long-term treatment with a proton pump inhibitor can be cured by eradicating Helicobacter pylori. Received: 21 April 1998 / Accepted: 10 August 1998