Effects of unilateral electrical stimulation of various thalamic nuclei on the release of dopamine from dendrites and nerve terminals of neurons of the two nigrostriatal dopaminergic pathways

The role of several motor and intralaminar thalamic nuclei in the regulation of dopamine release from terminals and dendrites of the nigrostriatal dopaminergic neurons was investigated in halothane-anaesthetized cats. For this purpose, the effects of the unilateral electrical stimulation of various thalamic nuclei on the release of newly synthesized [3H]dopamine were simultaneously determined in both substantiae nigrae and caudate nuclei using the push-pull cannula method. The electrical stimulation of the motor nuclei was the only one to induce asymmetric changes in the four structures since [3H]dopamine release was enhanced in the ipsilateral caudate nucleus and reduced in the contralateral structure while opposite responses were observed in the corresponding substantiae nigrae. A reduction of [3H]dopamine release occurred in the four structures or only in the contralateral substantia nigra and caudate nucleus following the stimulation of the parafascicularis nucleus and the adjacent posterior part of the nucleus centrum medianum or of the nucleus centralis lateralis and the adjacent paralaminar part of the nucleus medialis dorsalis, respectively. The stimulation of the anterior part of the nucleus centrum medianum, which in contrast to other thalamic nuclei examined, receives few nigral inputs, selectively enhanced [3H]dopamine release in the contralateral substantia nigra. No significant changes in [3H]dopamine release were seen either in the substantiae nigrae or in the caudate nuclei following the stimulation of midline thalamic nuclei. These results indicate that the motor and intralaminar thalamic nuclei exert multiple and selective influences on the release of dopamine from terminals and/or dendrites of the dopaminergic neurons. They also further support a role of thalamic nuclei in the transfer of information from one substantia nigra to the contralateral dopaminergic neurons. The possible involvement of connections between paired thalamic nuclei was underlined by the observations of evoked potentials in contralateral homologous nuclei following unilateral stimulation of motor, or some intralaminar, nuclei. The present report provides new insights on the mechanisms contributing to the reciprocal and/or bilateral regulations of nigrostriatal dopaminergic pathways.     

施万细胞对大鼠脊髓半横切后背核神经元存活及其表达NOS的影响

目的：探讨移植的施万细胞对大鼠脊髓半横切后背核神经元存活及其表达NOS的影响。方法：50只成年SD大鼠被分为实验组和对照组。在胸11脊髓段半横切后立即在损伤处移植入施万细胞。结果：脊髓半横切后，15d和25d对照组L1脊髓段损伤侧背核神经元的存活数均比未损伤侧的明显减少。存活的神经元胞体出现明显皱缩，有些神经元呈现NADPH－d阳性。15d和25d施万细胞组L1脊髓段损伤侧背核神经元的存活数则比同期对照组的明显增加，表达NOS的存活神经元数也随之增多。但存活的神经元胞体仍然是皱缩的。结论：移植的SCs可促进受损伤的背核神经元存活及其表达NOS，但不能阻止其胞体出现皱缩。     

Colocalization of a carnosine-splitting enzyme,tissue carnosinase (CN2)/cytosolic non-specific dipeptidase 2 (CNDP2), with histidine decarboxylase in the tuberomammillary nucleus of the hypothalamus

Carnosine is a naturally occurring dipeptide (β-alanyl-l-histidine) present in mammalian tissues such as the brain and skeletal muscles. Carnosine is not only a radical scavenger but also a possible neurotransmitter-like molecule that regulates neuronal functions such as hypothalamic control of the autonomic nervous system. CN2 (CNDP2) is a cytosolic enzyme that can hydrolyze carnosine to yield l-histidine and β-alanine. In order to understand the functions of carnosine and CN2 in the brain, we have investigated the immunohistochemical localization of CN2 in the hypothalamus. CN2-immunoreactivity was highly concentrated in neuronal cells in the dorsal part of the tuberomammillary nucleus of the posterior hypothalamus. Since the tuberomammillary nucleus is the exclusive origin of histaminergic neurons, we further investigated whether CN2 is present in the histaminergic neurons. We found that CN2-immunoreactivity was colocalized with that of histidine decarboxylase, which is the key enzyme for histamine biosynthesis specifically expressed in the histaminergic neurons of the tuberomammillary nucleus. These results suggest that CN2 is highly expressed in the histaminergic neurons in the tuberomammillary nucleus, implying that it may supply histidine to histaminergic neurons for histamine synthesis.     

Differential immune responses to HIV-1 envelope protein induced by liposomal adjuvant formulations containing monophosphoryl lipid A with or without QS21

Liposomes have shown promise as constituents of adjuvant formulations in vaccines to parasitic and viral diseases. A particular type of liposomal construct, referred to as Army Liposome Formulation (ALF), containing neutral and anionic saturated phospholipids, cholesterol, and monophosphoryl lipid A (MPLA), has been used as an adjuvant for many years. Here we investigated the effects of physical and chemical changes of ALF liposomes on adjuvanted immune responses to CN54 gp140, a recombinant HIV-1 envelope protein. While holding the total amounts of liposomal MPLA and the gp140 antigen constant, different liposome sizes and liposomal MPLA:phospholipid molar ratios, and the effect of adding QS21 to the liposomes were compared for inducing immune responses to the gp140. For liposomes lacking QS21, higher titers of IgG binding antibodies to gp140 were induced by small unilamellar vesicle (SUV) rather than by large multilamellar vesicle (MLV) liposomes, and the highest titers were obtained with SUV having the MPLA:phospholipid ratio of 1:5.6. ALF plus QS21 (ALFQ) liposomes induced the same maximal binding antibody titers regardless of the MPLA:phospholipid ratio. ALF MLV liposomes induced mainly IgG1 and very low IgG2a antibodies, while ALF SUV liposomes induced IgG1 ≥ IgG2a > IgG2b antibodies. Liposomes containing QS21 induced IgG1 > IgG2a > IgG2b > IgG3 antibodies. ELISPOT analysis of splenocytes from immunized mice revealed that ALF liposomes induced low levels of IFN-γ, but ALFQ induced high levels. ALF and ALFQ liposomes each induced approximately equivalent high levels of IL-4. Based on antibody subtypes and cytokine secretion, we conclude that ALF liposomes predominantly stimulate Th2, while ALFQ strongly induces both Th1 and Th2 immunity. When CN54 gp140 was adjuvanted with either ALF or ALFQ liposomes, antibodies were induced that neutralized two HIV-1 tier 1 clade C strain pseudoviruses.     

先天性马蹄内翻足基因学研究进展CSCD

先天性马蹄内翻足(congenital talipes equinovarus,CTEV)是儿童最常见的骨骼肌肉出生缺陷畸形之一,临床特征包括跟骨内翻、前足内收、高弓足和后足跖屈畸形。目前CTEV的发病机制仍不清楚,不同的学说包括:神经细胞损伤、肌肉异常、血管缺陷、子宫内限制、遗传因素、特发性先天性畸形、基因-环境的相互作用、骨骼发育不良、细胞外基质异常、分子转运和代谢异常等。遗传因素对于CTEV的致病起着重要作用,但尚未发现主要的致病基因。普遍认为CTEV是环境因素和遗传因素共同作用的结果。现对CTEV致病基因的研究进展做一综述。     

Clinical importance of "breakthrough" bacteremia

Fifty-one episodes of bacteremia and a single episode of fungemia occurred during treatment with seemingly adequate doses of appropriate antibiotics. Clinical findings in these "breakthrough" bacteremias and fungemia were compared with those in 448 non-breakthrough episodes. Breakthrough was more likely to be caused by facultative or aerobic gram-negative rods (e.g., Enterobacteriaceae and Pseudomonas species) than by anaerobes. Of the underlying conditions examined, immunosuppressive doses of glucocorticosteroids, diabetes mellitus, and moderate renal failure were significantly more frequent in patients with breakthrough. A significant association was also observed between an intra-abdominal primary focus of infection (abscesses, biliary tract or bowel infections) and the occurrence of breakthrough. Mortality in breakthrough bacteremia was 61 percent compared with 40 percent in non-breakthrough episodes. The phenomenon of breakthrough bacteremia shows the potential limitations of antibiotic therapy alone.     

早期口腔癌扩大切除颈部淋巴结处理的回顾性研究

目的探讨早期口腔癌扩大切除颈部淋巴结观察的临床疗效。方法收集45例早期口腔癌患者,男性20例,女性25例,其中舌癌18例,下颌牙龈癌8例,上颌牙龈癌7例,口底癌6例,颊癌3例,软腭癌3例。对本组患者均采用原发灶外1cm扩大切除术,不同期行颈淋巴结清扫术,术后对患者进行严密随访,最长5年,最短1年。结果 3例患者1年后失访。在随访期内有1例舌癌患者扩大切除原发灶后2个月复发,41例患者随访期内原发灶控制良好。有6例舌癌患者,术后3个月内出现颈部以及颌下出现肿大的淋巴结,并且伴有疼痛,1例下颌牙龈癌的患者术后6个月出现颌下淋巴结肿大,均行治疗性颈清术,病理证实均为颈部转移淋巴结,其余35例患者在随访期内颈部淋巴结未见明显异常。结论早期口腔癌患者可以单纯行原发灶扩大切除术,术后进行密切随访,如有颈部肿大淋巴结,应给予积极的手术治疗。     

33例先天性食管狭窄的诊治分析

目的总结先天性食管狭窄的诊治经验,探讨先天性食管狭窄的早期诊治方法,降低误诊率。方法回顾性分析1990—2012年我们收治的33例先天性食管狭窄患儿临床资料,对其临床表现、诊断、治疗方法及病理结果进行分析。结果 33例患儿中,男性16例,女性17例,仅17例(51%)首次就诊得以确诊,首次就诊误诊率达49%,平均首次发病年龄为8.6个月,确诊平均年龄为33.8个月。以进食后呕吐、生长发育迟缓、吞咽固体食物困难、贫血为主要表现。患儿术前均行钡餐检查。26例(79%)予手术治疗,疗效好,术后并发症少,随访1个月至10年,远期预后良好。术后病理活检21例,诊断为气管软骨食管异位症13例,纤维肌层肥厚8例。结论对于进食后反复呕吐及吞咽困难的患儿均应想到先天性食管狭窄的可能。食管钡餐检查是最简单有效的诊断方法。食管扩张术治疗先天性食道狭窄存在争议,手术是治疗先天性食管狭窄可靠、有效、安全的方法 。     

Detection of metabolites of the new synthetic cannabinoid CUMYL‐4CN‐BINACA in authentic urine samples and human liver microsomes using high‐resolution mass spectrometry

CUMYL‐4CN‐BINACA(1‐(4‐cyanobutyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H–indazole‐3‐carboxamide) is a recently introduced indazole‐3‐carboxamide‐type synthetic cannabinoid (SC) that was detected in herbal incense seized by of the Council of Forensic Medicine, Istanbul Narcotics Department, in May 2016 in Turkey. Recently introduced SCs are not detected in routine toxicological analysis; therefore, analytical methods to measure these compounds are in demand. The present study aims to identify urinary marker metabolites of CUMYL‐4CN‐BINACA by investigating its metabolism in human liver microsomes and to confirm the results in authentic urine samples (n = 80). In this study, 5 μM CUMYL‐4CN‐BINACA was incubated with human liver microsomes (HLMs) for up to 3 hours, and metabolites were identified using liquid chromatography–high‐resolution mass spectrometry (LC–HRMS). Less than 21% of the CUMYL‐4CN‐BINACA parent compound remained after 3 hours of incubation. We identified 18 metabolites that were formed via monohydroxylation, dealkylation, oxidative decyanation to aldehyde, alcohol, and carboxylic acid formation, glucuronidation or reaction combinations. CUMYL‐4CN‐BINACA N‐butanoic acid (M16) was found to be major metabolite in HLMs. In urine samples CUMYL‐4CN‐BINACA was not detected; CUMYL‐4CN‐BINACA N‐butanoic acid (M16) was major metabolite after β‐glucuronidase hydrolysis. Based on these findings, we recommend using M16 (CUMYL‐4CN‐BINACA N‐butanoic acid), M8 and M11 (hydroxylcumyl CUMYL‐4CN‐BINACA) as urinary marker metabolites to confirm CUMYL‐4CN‐BINACA intake.