Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.     

Kinetic analysis of wild-type and YMDD mutant hepatitis B virus polymerases and effects of deoxyribonucleotide concentrations on polymerase activity

Mutations in the YMDD motif of the hepatitis B virus (HBV) DNA polymerase result in reduced susceptibility of HBV to inhibition by lamivudine, at a cost in replication fitness. The mechanisms underlying the effects of YMDD mutations on replication fitness were investigated using both a cell-based viral replication system and an in vitro enzyme assay to examine wild-type (wt) and YMDD-mutant polymerases. We calculated the affinities of wt and YMDD-mutant polymerases for each natural deoxyribonucleoside triphosphate (dNTP) and determined the intracellular concentrations of each dNTP in HepG2 cells under conditions that support HBV replication. In addition, inhibition constants for lamivudine triphosphate were determined for wt and YMDD-mutant polymerases. Relative to wt HBV polymerase, each of the YMDD-mutant polymerases showed increased apparent K(m) values for the natural dNTP substrates, indicating decreased affinities for these substrates, as well as increased K(i) values for lamivudine triphosphate, indicating decreased affinity for the drug. The effect of the differences in apparent K(m) values between YMDD-mutant polymerase and wt HBV polymerase could be masked by high levels of dNTP substrates (>20 microM). However, assays using dNTP concentrations equivalent to those measured in HepG2 cells under physiological conditions showed decreased enzymatic activity of YMDD-mutant polymerases relative to wt polymerase. Therefore, the decrease in replication fitness of YMDD-mutant HBV strains results from the lower affinities (increased K(m) values) of the YMDD-mutant polymerases for the natural dNTP substrates and physiological intracellular concentrations of dNTPs that are limiting for the replication of YMDD-mutant HBV strains.     

自体干细胞移植治疗老年心肌梗死后心力衰竭

目的：实验以移植后3个月、6个月时间超声心动图客观指标评估了自体干细胞冠状动脉内移植治疗老龄心肌梗死后心力衰竭的效果和安全性。方法：选择2004—06／2006—06江苏省苏北人民医院心内科自愿接受干细胞移植的7例心肌梗死后心力衰竭患者，平均年龄69岁，心功能Ⅲ-Ⅳ级，左室射血分数〈50％。药物治疗基础上加用自体干细胞冠状动脉内移植治疗的方法，其中2例骨髓干细胞在体外扩增后获得，5例经粒细胞集落刺激因子皮下注射动员自体骨髓干细胞后分离外周血获得干细胞悬液。将采集的干细胞悬液经0ver-the-wire球囊导管中心腔注入梗死相关动脉。观察自体干细胞动员，培养，采集和回输过程中的不良反应。在移植前、移植后3月、6月应用超声心动图评价左室形态和心功能变化，室壁运动积分指数及6min步行距离。结果：7例患者均进入结果分析。移植3个月后，心功能得到改善，超声心动图检查左室收缩期内径及射血分数变化不大，6min步行距离有所提高，但差异无显著性（P〉0．05）。移植6个月后，患者心功能明显改善，超声心动图检查左室收缩期内径及射血分数和室壁运动积分均有明显提高（P〈0．05），6min步行距离也有明显提高（P〈0．05）。整个过程中未出现严重并发症。结论：自体干细胞冠状动脉内移植治疗老龄心肌梗死后心力衰竭，6个月时超声心动图客观指标评估能够改善患者心功能，且安全。     

ANTIDEPRESSANT THERAPY AND BEHAVIOURAL COMPETENCE

SUMMARY Major depression can impair an individual's motivation to perform routine daily activities and cause a deterioration in cognitive and psychomotor function. Some antidepressants add to pathological dysfunction through unwanted side-effects. Although most patients eventually recover as a simultaneous consequence of tolerance and therapeutic response, some may not. Where side-effects continue to retard normal recovery they can be called behaviourally toxic, which can be classified as disruptive, inhibitory or provocative. Disruptive behavioural toxic effects are measured using either psychometric tests or simulations of real-life activities (for example, a driving test). There are no widely-accepted tests for inhibitory or provocative behavioural toxicity, and assessments of antidepressants are made on the basis of case studies. This review summarises the results of psychometric and real-life simulation tests and compares the effects of antidepressants on behaviour competence. The purpose is to identify those drugs that seem to be the most and least likely to produce behavioural toxicity.     

脑出血大鼠脑组织膜型基质金属蛋白酶、基质金属蛋白酶2和基质金属蛋白酶9表达及益气活血中药的干预效应

目的:观察益气活血中药对脑出血大鼠脑组织中膜型基质金属蛋白酶、基质金属蛋白酶2和基质金属蛋白酶9表达量的影响,从脑出血损伤区微血管系统重建的角度,探讨益气活血中药治疗脑出血的作用机制。方法:实验于2006-03/10在中南大学湘雅医院中西医结合研究所实验室完成。实验材料:补阳还五汤全方(黄芪,当归,赤芍,红花,川芎,地龙,桃仁按20∶3∶3∶3∶2∶3∶3的比例);补阳还五汤益气成分(黄芪按上述比例);补阳还五汤活血成分(当归,赤芍,地龙,川芎,桃仁,红花按3∶3∶3∶2∶3∶3的比例)。用蒸馏水两次水煎,分别浓缩为1.54,0.81和0.73g/mL。实验分组:155只SD大鼠随机分为正常对照组、假手术组、模型组、益气活血组、益气组、活血组。正常对照组5只大鼠,其余每组30只,再随机分为术后灌胃2,4,7,14,21,28d6个观察时间点,各个时间点5只大鼠。实验干预:造模:采用立体定位技术将胶原酶Ⅶ注入大鼠大脑右苍白球制成脑出血大鼠模型。假手术组大鼠仅注入2μL生理盐水,其余手术过程相同。给药:正常对照组:普通饲养,自由饮水;假手术组和模型组术后予蒸馏水灌胃2次/d,2mL/次;益气活血组、益气组、活血组分别给予补阳还五汤全方、补阳还五汤益气成分、补阳还五汤活血成分30.80,16.20,14.60g/(kg·d)(按体表面积计算为临床70kg成人剂量的3倍)灌胃,2次/d,2mL/次。各组大鼠分别于灌胃2,4,7,14,21,28d麻醉下取脑,制备切片;正常组动物于28d处死。实验评估:免疫组织化学染色方法检测各组灌胃不同时间脑组织基质金属蛋白酶2、基质金属蛋白酶9和膜型基质金属蛋白酶的阳性微血管数。结果:155只大鼠均进入结果分析。①正常组、假手术组皮质偶见膜型基质金属蛋白酶、基质金属蛋白酶2和基质金属蛋白酶9表达。②模型组膜型基质金属蛋白酶、基质金属蛋白酶2呈双峰表达,4d为最高峰,至14～21d再有小高峰出现。③益气活血组给药4d时,膜型基质金属蛋白酶、基质金属蛋白酶2为表达低谷,低于模型组(P<0.01)、益气组和活血组(P<0.05);在中后期,益气活血组膜型基质金属蛋白酶表达高峰为7～14d,较模型组提前出现,21d后与模型组比,各治疗组膜型基质金属蛋白酶已表达极少(P<0.01);益气活血组基质金属蛋白酶2在7d后一直呈高水平维持,高于其他各组(P<0.05),28d后开始逐渐下降。④模型组基质金属蛋白酶9在造模后4d达最高峰(P<0.01),两周后几乎无表达。益气活血组基质金属蛋白酶9高峰推迟至7d出现(P<0.05),之后逐渐下降。结论:益气活血中药可通过调节脑出血后膜型基质金属蛋白酶、基质金属蛋白酶2和基质金属蛋白酶9表达,改善出血后脑组织的微环境,有利于微血管系统重建,促进组织修复。     

Push enteroscopy in the investigation of small-intestinal disease

We report our experience with small-bowel push enteroscopy in 50 patients. The indications for push enteroscopy were: anaemia/occult gastrointestinal bleeding (22 patients); overt gastrointestinal bleeding (17 patients); abnormal small-bowel radiology (8 patients) and miscellaneous (3 patients). In those with undiagnosed gastrointestinal bleeding/anaemia, abnormalities were detected in 24/39 patients (62%): small bowel arteriovenous malformations (AVMs) were detected in 19 (49%), and five (13%) had lesions in the upper gastrointestinal tract. Seventeen patients had heater-probe ablation therapy of vascular lesions: nine patients had small-intestinal lesions, four patients gastric lesions, and four patients combined gastric and small- intestinal lesions. In those with abnormal small-bowel radiology, abnormalities were detected in 6/8 patients. We conclude that (i) push enteroscopy can establish a diagnosis in a high proportion of patients with gastrointestinal bleeding; (ii) heater-probe ablation therapy of vascular lesions can be performed routinely at the time of enteroscopy; (iii) a significant proportion of patients (9/50) referred for enteroscopy with undiagnosed gastrointestinal bleeding have lesions in the stomach/proximal duodenum missed at diagnostic endoscopy. Push enteroscopy is a valuable diagnostic and therapeutic endoscopic procedure.      

机械力学对体外骨髓间充质干细胞的影响

目的:分析力学刺激体外骨髓间充质干细胞所产生增殖分化等生物学效应的影响及其力化学信号转导途径。资料来源:因特网上检索PubMed数据库中2000-01/2006-06期间有关力学刺激对骨髓干细胞作用效应进展的英文文章,检索词“stem cel1,marrow mesenchymal stem cells,mechanical stimulation,stress”,同时检索CNKI中国知网医学文献数据库2000-01/2006-06期间的相关文章,检索词为“干细胞、骨髓间充质干细胞、机械刺激、应力”。资料选择:对资料进行筛选,选取相关文章查找全文。纳入标准:①骨髓间充质干细胞相关生物学特性。②体外细胞加载的应力分类及相应力学装置的特点。③应力对细胞影响的研究。④能获取文章的全文。排除标准:①较陈旧的文献。②重复研究。资料提炼:共收集关于86篇体外骨髓干细胞及力学干预的相关文献。其中30篇符合纳入标准。资料综合:①骨髓干细胞具有高度增殖及多向分化能力,可通过体外培养、干预作为细胞组织工程的理想种子细胞。②力学刺激是体外调节细胞生物学效应的重要途径,其中力学分类有:流体切应力、静止压应力、张应力、离心力以及单个细胞的吸吮力等,介绍各种力以及相应的力学装置的特点。③骨髓干细胞加载各种应力干预后产生的生物学效应,以及细胞应力学刺激的机制、信号转导途径。结论:力学刺激可影响骨髓间充质干细胞生物学特性,在适当的力学刺激条件下,促进细胞的增殖与分化,为骨组织工程提供新的技术手段,同时也为临床应用牵拉成骨的骨再生过程提供理论依据。     

脊髓损伤后真皮多能干细胞移植时机的选择

目的:观察脊髓损伤后不同时间移植真皮多能干细胞对大鼠运动功能修复的影响。方法:实验于2006-06/2007-03在第三军医大学生理学教研室完成。①实验材料:实验动物2～4月龄SPF级SD大鼠,体质量(210±40)g,雌雄不限,由第三军医大学实验动物中心提供。真皮多能干细胞为第三军医大学防原医学系从SD大鼠真皮中提取和分离。②实验方法:将42只SD大鼠在L4水平制成脊髓全横断损伤模型。将动物随机分为对照组(n=6)、真皮多能干细胞移植组(n=36)。真皮多能干细胞移植组又分为6个时间点:损伤后1,4,7,10,14,21d移植组,每组6只。各移植组于伤处移植大鼠真皮多能干细胞,而对照组于损伤后7d注射等量磷酸盐缓冲液。③实验评估:分别于移植后1d、1周、4周、8周、12周对各组大鼠进行动物行为学和脊髓诱发电位检测。结果:42只实验大鼠均进入结果分析,无脱落。①动物行为学评分:4周以后各组动物行为学评分比较差异有显著性意义(P<0.05),移植组明显高于对照组(P<0.05),各移植组间比较,以损伤后7,10d移植组动物行为学评分改善最显著。②各组大鼠脊髓诱发电位检查:体感诱发电位和运动诱发电位潜伏期和波幅值于移植后8,12周后明显高于对照组(P<0.05),各移植组间比较,以损伤后7,10d移植组体感诱发电位和运动诱发电位潜伏期和波幅值改善最显著。结论:脊髓损伤后7～14d进行真皮多能干细胞移植可明显改善大鼠后肢的运动功能。     

上海市0～6岁小儿佝偻病的现状调查

目的:了解上海市小儿佝偻病的现状及影响因素。方法:2005年春季以整群和分层随机抽样法抽取上海市部分城区0～6岁小儿821名,采取问卷调查方法了解小儿的生活环境、饮食习惯、户外活动、营养状况、既往疾病史及母亲的妊娠情况等。佝偻病的诊断以1996年国家卫生部颁布的"婴幼儿佝偻病防治方案"为诊断标准。结果:取得完整有效资料769名,其中男童396名,女童373名;集居儿童456名,散居儿童313名。①小儿佝偻病患病率为17.3%(133/769),其中男童患病率为17.4%、女童为17.2%。②佝偻病与喂养方式(母乳喂养的患病率为13.0%、混合喂养的患病率为17.5%、人工喂养的患病率为25.2%)、鱼肝油添加(按时添加维生素D的患病率为13.5%、偶加或未加维生素D的患病率为32.5%)、居住环境(居住在市区的患病率为23.6%、居住在郊区的患病率为10.6%;集居儿童患病率为13.8%、散居儿童患病率为22.4%)、户外活动时间(经常户外活动的患病率为12.9%、偶尔户外活动的患病率为31.8%)、反复呼吸道感染(小儿有反复呼吸道感染的患病率为26.9%、无反复呼吸道感染的患病率为12.9%)、母孕期缺钙(母孕期有缺钙的患病率为33.2%、无缺钙的患病率为12.0%)等因素有关(P<0.01)。结论:上海市小儿佝偻病患病率有上升趋势。影响因素与城市环境污染、母乳喂养减少、年轻父母科学育儿知识缺乏等有关。     

Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency

We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up.