复合杂合parkin基因突变家族的不同表型

背景：Parkin基因（PRKN）突变可导致常染色体隐性遗传性早发帕金森病（EOPD）。目的：探讨EOPD白人家族PRKN突变的表现和基因型-表型关系。设计：对EOPD家族的3代20例成员进行基因分析，该家族有4例患者。应用直接基因组DNA测序、半定量聚合酶链反应、实时定量聚合酶链反应以及逆转录酶聚合酶链反应分析以确定PRKN突变。结果：4例早发患者（年龄30—38岁）被确定有PRKN复合杂合突变（T240M和EX5_6缺失），虽然PRKN的杂合T240M和纯合EX5_6缺失突变已有描述，但是据悉，本文为上述复合杂合突变的首次报道。患者的表型为典型常染色体隐性遗传性EOPD的表现，其特征是对左旋多巴治疗有效、相对缓慢的进展和运动障碍。所有杂合突变的基因携带者（T240M或EX5_6缺失）和1例56岁的复合杂合突变女性携带者（T240M和EX5_6缺失）无任何神经系统症状。结论：研究发现，PRKN基因复合杂合突变（T240M和EX5_6缺失）导致一个大的白人家族中4例成员发生常染色体隐性遗传性EOPD。另外1例成员具有相同的突变，比4例患者的平均发病年龄大10岁，并且无本病的临床表现。不完全的外显率对遗传咨询具有暗示作用，并且提示复杂的基因一环境交互作用在PRKN相关EOPD的发病机制中发挥作用。     

Hippocampal damage and cytoskeletal disruption resulting from impaired energy metabolism

To determine if impaired energy metabolism might contribute to some aspects of Alzheimer disease (AD), including the vulnerability of the CA1 region of the hippocampal formation and the altered cytoskeleton evident in neurofibrillary tangles, we examined the effects of metabolic poisons on neuronal damage and cytoskeletal disruption in the hippocampal formation. Intrahippocampal injection of 3-nitropropionic acid (3-NP) and malonic acid resulted in neuronal death, particularly in CA1. Cytoskeletal disruption included loss of dendritic MAP2, but sparing of axonal τ. MK-801 (a noncompetitive NMDA receptor antagonist) did not atenuate the lesions produced by intrahippocampal injection of malonate. MK-801, however, was effective against intrastriatal malonate. Acute systemic 3-NP resulted in neuronal damage and cytoskeletal disruption in the CA1 region of the hippocampal formation, including an extensive loss of MAP2 immuno-reactivity, but sparing of τ. The neuronal loss in CA1 was delayed as compared to striatum. Chronic intraventricular infusion of 3-NP produced a different pattern of neuronal damage. Loss of τ-1 immuno-reactivity was observed in CA3 and CA1 s. oriens, whereas MAP2 immunostaining was preserved. These results demonstrate that chronic and acute administration of metabolic inhibitors produce distinct patterns of neuronal damage and cytoskeletal disruption. The results further suggest a differential involvement of the NMDA receptor in malonate-induced neuronal damage in striatum as compared to the hippocampus. The pattern of neuronal damage and cytoskeletal disruption observed following acute metabolic impairment resembled some aspects of neurofibrillary pathology in AD, but did not result in τ hyperphosphorylation.     

Bayesian inference of hemodynamic changes in functional arterial spin labeling data.

The study of brain function using MRI relies on acquisition techniques that are sensitive to different aspects of the hemodynamic response contiguous to areas of neuronal activity. For this purpose different contrasts such as arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional MRI techniques have been developed to investigate cerebral blood flow (CBF) and blood oxygenation, respectively. Analysis of such data typically proceeds by separate, linear modeling of the appropriate CBF or BOLD time courses. In this work an approach is developed that provides simultaneous inference on hemodynamic changes via a nonlinear physiological model of ASL data acquired at multiple echo times. Importantly, this includes a significant contribution by changes in the static magnetization, M, to the ASL signal. Inference is carried out in a Bayesian framework. This is able to extract, from dual-echo ASL data, probabilistic estimates of percentage changes of CBF, R(2) (*), and the static magnetization, M. This approach provides increased sensitivity in inferring CBF changes and reduced contamination in inferring BOLD changes when compared with general linear model approaches on single-echo ASL data. We also consider how the static magnetization, M, might be related to changes in CBV by assuming the same mechanism for water exchange as in vascular space occupancy.     

Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma.

PURPOSE: Few published studies have addressed individual patient risk after R0 resection for gastric cancer. We developed and internally validated a nomogram that combines these factors to predict the probability of 5-year gastric cancer-specific survival on the basis of 1,039 patients treated at a single institution. METHODS: Nomogram predictor variables included age, sex, primary site (distal one-third, middle one-third, gastroesophageal junction, and proximal one-third), Lauren histotype (diffuse, intestinal, mixed), number of positive lymph nodes resected, number of negative lymph nodes resected, and depth of invasion. Death as a result of gastric cancer was the predicted end point. The concordance index was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. RESULTS: Gastric cancer-specific survival at 5 years was 50%. A nomogram was constructed on the basis of a Cox regression model. The bootstrap-corrected concordance index was 0.80. When compared with the predictive ability of American Joint Committee on Cancer stage, the nomogram discrimination was superior (P <.001). Nomogram calibration appeared to be excellent. CONCLUSION: A nomogram was developed to predict 5-year disease-specific survival after R0 resection for gastric cancer. This tool should be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.     

Zinc sulfate addition to glass-ionomer-based cements: influence on physical and antibacterial properties, zinc and fluoride release.

OBJECTIVES: The aim of this study is to evaluate the effect of ZnSO(4) addition to a conventional glass ionomer and a resin-modified glass ionomer on solubility, flexural strength, zinc and fluoride (F) release, and Streptococcus mutans growth inhibition. METHODS: 5 or 10% ZnSO(4) was added to Vitremer and Ketac-Fil powders. Solubility test was performed based on ISO 7489. Flexural strength was determined by 3-point bending test based on ISO 4049. Zn release/uptake was determined by atomic emission spectrometry; F release/uptake was measured using a F-specific electrode. Both release measurements were performed for 15 d before and 15 d after recharging. Antibacterial test was conducted according to agar plate methods against S. mutans, by measuring the inhibition halos in 1-h and 15-d specimens. Data were analyzed by ANOVA. RESULTS: Solubility increased with higher ZnSO(4) content, but remained below the ISO 7489 limit. Flexural strength was not affected by ZnSO(4) addition, and Vitremer performed better than Ketac-Fil. The control materials released no zinc. Vitremer with 10% ZnSO(4) released the highest amount of zinc. Fluoride release was similar for Ketac-Fil and Vitremer. In both cases, the highest amounts were released in the first 24 h. The growth inhibition halo of S. mutans was similar for both materials with highest content of ZnSO(4) and occurred only with 1-h specimens. SIGNIFICANCE: Zinc addition decreased microorganisms growth and improved fluoride release, without significantly affecting the materials' flexural strength and solubility.     

Neuropsychological changes following electrical injury.

The clinical presentation of electrical injury commonly involves physical, cognitive, and emotional complaints. Neuropsychological studies, including case reports, have indicated that electrical injury (EI) survivors may experience a broad range of impaired neuropsychological functions, although this has not been clarified through controlled investigation. In this study, we describe the neuropsychological test findings in a series of 29 EI patients carefully screened and matched to a group of 29 demographically similar healthy electricians. Participants were matched by their estimated premorbid intellectual ability. Multivariate analysis of variance was used to assess group differences in the following neuropsychological domains: attention and mental speed, working memory, verbal memory, visual memory, and motor skills. EI patients performed significantly worse on composite measures of attention/mental speed and motor skills, which could not be explained by demographic differences, injury parameters, litigation status, or mood disturbance. Results suggest that cognitive changes do occur in patients suffering from electrical injury.