转化生长因子β细胞内信号转导负调控蛋白Smad6，7在肾间质纤维化大鼠肾脏表达与益气活血法的影响

目的:观察肾间质纤维化大鼠肾组织中转化生长因子β细胞内信号转导负调控蛋白Smad6,7表达变化与益气活血法中药制剂的影响。方法:实验于2006-12/2007-06在首都医科大学解剖与组织胚胎学系实验室完成。①实验动物:Wistar雄性大鼠30只,采用随机数字法随机分为模型组、中药大剂量组、中药中剂量组、中药小剂量组、西药蒙诺组、假手术组,每组5只。益气活血法中药提取液(生黄芪15g,当归10g,赤白芍10g,丹参30g,黄芩10g,车前草15g,牛膝15g等)经水提醇沉得4.4kg/L生药提取液。实验过程中对动物处置符合动物伦理学要求。②实验方法:其中前5组行单侧输尿管梗阻致肾小管间质纤维化模型手术。假手术组打开大鼠腹腔后分离左侧输尿管,并不结扎即关闭腹腔。中药大剂量组、中药中剂量组、中药小剂量组、西药蒙诺组,于手术前2d给予灌胃给药0.072mL/(kg·d),0.036mL/(kg·d),0.018mL/(kg·d),10mg/(kg·d),1次/d,连续2周。模型组及假手术组用相同体积的生理盐水灌胃。③实验评估:6组大鼠于术后14d麻醉后处死,观察梗阻肾组织病理改变,用免疫组化方法检测肾组织Smad6,7蛋白表达,通过医学病理图像分析系统对Smad6,7蛋白的积分光密度进行统计学分析。结果:30只大鼠全部进入结果分析。苏木精-伊红染色显示模型组肾小管上皮细胞萎缩,大部分肾小管管腔扩张,间质纤维组织增生,大量炎性细胞浸润,肾小球数目明显减少。中药大剂量组、中剂量组、西药蒙诺组较模型组肾间质炎性细胞浸润、纤维组织增生、肾小管扩张情况明显减轻。Smad6,7蛋白主要在肾皮质肾小管上皮细胞内表达,在模型组它们的表达较假手术组明显减弱且分布面积减少,两组间积分光密度差异具有统计学意义(P<0.05);中药中剂量组、大剂量组、西药蒙诺组Smad6,7蛋白的表达较模型组明显增强、面积增加,积分光密度差异具有统计学意义(P<0.05)。结论:益气活血法可以通过诱导肾组织Smad6,7蛋白表达而抑制肾间质纤维化。     

Percutaneous umbilical blood sampling and umbilical vein transfusions. Rapid serologic differentiation of fetal blood from maternal blood

Percutaneous umbilical blood samples (PUBS), obtained under ultrasound guidance, are used for prenatal diagnosis and management of hemolytic disease of the newborn (HDN) and other fetal disorders. Rapid testing at the time of sampling is vital to distinguish fetal from maternal blood. Blood typing was performed by slide technique in the treatment room during 38 procedures on 25 patients. Anti-I was used to test 50 presumed PUBS; venous I-positive maternal blood was tested in parallel. Because anti-I cannot detect fetal blood after umbilical vein transfusion (UVT) of I-positive donor blood, ABO and Rh blood typing reagents were used to test 29 samples when maternal and fetal or donor blood groups differed. Monoclonal reagents were used for optimal detection of weak AB antigens in fetal blood. Avid, chemically modified anti-D was used for Rh typing. Blood typing showed 27 (34%) of 79 samples to be maternal blood. Fetal blood was obtained in 8 of 10 cases investigated for fetal disorder and in 16 cases of potential HDN (anti-D, 5; -CD, 5; -cE, 2; -K, 2; -c; -E). The absence of HDN (antigen-negative fetus) was determined in 4 cases. UVT afforded live birth of 9 of 10 infants with HDN and was not indicated in two cases.     

Fractionation of Spatial Memory in GRM2/3 (mGlu2/mGlu3) Double Knockout Mice Reveals a Role for Group II Metabotropic Glutamate Receptors at the Interface Between Arousal and Cognition

Group II metabotropic glutamate receptors (mGluR2 and mGluR3, encoded by GRM2 and GRM3) are implicated in hippocampal function and cognition, and in the pathophysiology and treatment of schizophrenia and other psychiatric disorders. However, pharmacological and behavioral studies with group II mGluR agonists and antagonists have produced complex results. Here, we studied hippocampus-dependent memory in GRM2/3 double knockout (GRM2/3^−/−) mice in an iterative sequence of experiments. We found that they were impaired on appetitively motivated spatial reference and working memory tasks, and on a spatial novelty preference task that relies on animals'' exploratory drive, but were unimpaired on aversively motivated spatial memory paradigms. GRM2/3^−/− mice also performed normally on an appetitively motivated, non-spatial, visual discrimination task. These results likely reflect an interaction between GRM2/3 genotype and the arousal-inducing properties of the experimental paradigm. The deficit seen on appetitive and exploratory spatial memory tasks may be absent in aversive tasks because the latter induce higher levels of arousal, which rescue spatial learning. Consistent with an altered arousal–cognition relationship in GRM2/3^−/− mice, injection stress worsened appetitively motivated, spatial working memory in wild-types, but enhanced performance in GRM2/3^−/− mice. GRM2/3^−/− mice were also hypoactive in response to amphetamine. This fractionation of hippocampus-dependent memory depending on the appetitive-aversive context is to our knowledge unique, and suggests a role for group II mGluRs at the interface of arousal and cognition. These arousal-dependent effects may explain apparently conflicting data from previous studies, and have translational relevance for the involvement of these receptors in schizophrenia and other disorders.     

Effects of L-histidine depletion and L-tyrosine/L-phenylalanine depletion on sensory and motor processes in healthy volunteers

Background and purpose:

Animal studies show that histamine plays a role in cognitive functioning and that histamine H₃-receptor antagonists, which increase histaminergic function through presynaptic receptors, improve cognitive performance in models of clinical cognitive deficits. In order to test such new drugs in humans, a model for cognitive impairments induced by low histaminergic functions would be useful. Studies with histamine H₁-receptor antagonists have shown limitations as a model. Here we evaluated whether depletion of L-histidine, the precursor of histamine, was effective in altering measures associated with histamine in humans and the behavioural and electrophysiological (event-related-potentials) effects.

Experimental approach:

Seventeen healthy volunteers completed a three-way, double-blind, crossover study with L-histidine depletion, L-tyrosine/L-phenylalanine depletion (active control) and placebo as treatments. Interactions with task manipulations in a choice reaction time task were studied. Task demands were increased using visual stimulus degradation and increased response complexity. In addition, subjective and objective measures of sedation and critical tracking task performance were assessed.

Key results:

Measures of sedation and critical tracking task performance were not affected by treatment. L-histidine depletion was effective and enlarged the effect of response complexity as measured with the response-locked lateralized readiness potential onset latency.

Conclusions and implications:

L-histidine depletion affected response- but not stimulus-related processes, in contrast to the effects of H₁-receptor antagonists which were previously found to affect primarily stimulus-related processes. L-histidine depletion is promising as a model for histamine-based cognitive impairment. However, these effects need to be confirmed by further studies.     

Comparison of inhibitors of superoxide generation in vascular smooth muscle cells

Background and purpose:

We compared the dose-dependent reductions in cellular superoxide anion (O₂⁻) by catalytic agents: superoxide dismutase (SOD), polyethylene glycol (PEG)-SOD and the nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (tempol) with uncharacterized antioxidants: 5,10,15,20-tetrakis (4-sulphonatophenyl) porphyrinate iron (III)(Fe-TTPS), (-)-cis-3,3′,4′,5,7-pentahydroxyflavane (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol (-epicatechin), 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) and N-acetyl-L-cysteine (NAC) with the spin trap nitroblue tetrazolium (NBT) and with the vitamins or their analogues: ascorbate, α-tocopherol and 6-hydroxy-2,5,7,8-tetramethylkroman-2-carboxy acid (trolox).

Experimental approach:

O₂⁻ was generated in primary cultures of angiotensin II-stimulated preglomerular vascular smooth muscle cells from spontaneously hypertensive rats and detected by lucigenin-enhanced chemiluminescence.

Key results:

SOD, PEG-SOD, NAC and tempol produced a similar maximum inhibition of O₂⁻ of 80–90%. -Epicatechin, NBT, ebselen and Fe-TTPS were significantly (P < 0.0125) less effective (50–70%), whereas trolox, α-tocopherol and ascorbate had little action even over 24 h of incubation (<31%). Effectiveness in disrupted and intact cells was similar for the permeable agents, PEG-SOD and tempol, but was enhanced for SOD. Generation of O₂⁻ was increased by NAC and NBT at low concentrations but reduced at high concentrations.

Conclusions and implications:

Maximum effectiveness against cellular production of O₂⁻ requires cell membrane permeability and catalytic action as exemplified by PEG-SOD or tempol. NAC and NBT have biphasic effects on O₂⁻ production. Vitamins C and E or analogues have low efficacy.     

Rates and risk factors for homelessness after successful housing in a sample of formerly homeless veterans

OBJECTIVE: Research suggests that subsidized housing combined with mental health services may be an effective intervention for successfully placing individuals who have a mental illness and a history of homelessness into community housing. However, there is limited longitudinal information available about the risk of loss of housing after a successful exit from homelessness. METHODS: The study presented here examined the risk and predictors of returning to homelessness after successful housing in a sample of 392 formerly homeless veterans involved in an experimental trial of case management plus rent subsidy vouchers, case management only, or standard care. RESULTS: Over the course of a five-year period, 44% of all participants experienced a period of homelessness for at least one day after successful placement into housing. Cox regression analysis found that participants in the case management plus voucher condition had significantly longer periods of continuous housing, compared with participants in the other two groups. Other predictors of decreased housing tenure were drug use and a diagnosis of posttraumatic stress disorder. CONCLUSIONS: Subsidized housing vouchers, combined with intensive case management, are advantageous both for facilitating the initial transition from homelessness to being housed and for reducing the risk of discontinuous housing, even among individuals with more severe substance abuse problems.     

Reducing Diagnostic Errors in Musculoskeletal Trauma by Reviewing Non-Admission Orthopaedic Referrals in the Next-Day Trauma Meeting

INTRODUCTION

Diagnostic errors in orthopaedics are usually caused by missing a fracture or misreading radiographs. The aim of this study was to document the pick-up rate of the wrong diagnoses by reviewing X-rays and casualty notes in the next-day trauma meeting.

PATIENTS AND METHODS

The casualty notes and radiographs of 503 patients were prospectively reviewed in the daily trauma meeting between August 2002 and December 2002 in a district general hospital. The relevant data were collected and analysed by a single assessor.

RESULTS

The false positive rate for making an orthopaedic diagnosis was 12.6% (i.e.) diagnosing a fracture, when none existed). The false negative (missing) rate was 4%, while 2.4% incidental findings were missed, or at least not documented, after reading the X-rays. There were 7.8% wrong diagnoses made. The majority of the patients were seen by the senior house officers.

CONCLUSIONS

The medicolegal significance of false negative diagnosis is obviously greater. In a busy emergency department, where a large number of patients are seen, there is a greater risk. This study shows the importance in a small-to-medium sized accident and emergency unit as well, where there is no senior cover available out-of-hours for final radiological interpretation. A morning trauma meeting which covers reviewing admitted patients as well as non-admission orthopaedic referrals has an effective risk management solution to early detection of missed and wrong diagnoses.     

性腺切除及急性饥饿对大鼠垂体-甲状腺功能的影响

本实验采用性腺摘除或经假摘除手术的两性SD大鼠,其中部分动物分别予以睾酮(T)或雌二醇(E_2),观察它们在急性饥饿或非饥饿状态下血清T_4、TSH与T浓度变化。结果提示急性饥饿可使雄鼠甲状腺合成或分泌T_4和性腺分泌睾酮减少,从而不完全地抑制了雄激素所介导的对垂体TSH分泌的兴奋作用。外源性T替代虽然可以使去势雄鼠血清T浓度恢复正常,但却无兴奋TSH分泌的作用;饥饿组去势雄鼠接受外源性T后血清TSH更为减少。提示外源性T可抑制此组雄鼠垂体TSH合成及(或)释放。