Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

BRI2 ectodomain affects Aß42 fibrillation and tau truncation in human neuroblastoma cells.

Alzheimer's disease (AD) is pathologically characterized by the presence of misfolded proteins such as amyloid beta (Aß) in senile plaques, and hyperphosphorylated tau and truncated tau in neurofibrillary tangles (NFT). The BRI2 protein inhibits Aß aggregation via its BRICHOS domain and regulates critical proteins involved in initiating the amyloid cascade, which has been hypothesized to be central in AD pathogenesis. We recently detected the deposition of BRI2 ectodomain associated with Aß plaques and concomitant changes in its processing enzymes in early stages of AD. Here, we aimed to investigate the effects of recombinant BRI2 ectodomain (rBRI276-266) on Aß aggregation and on important molecular pathways involved in early stages of AD, including the unfolded protein response (UPR), phosphorylation and truncation of tau, as well as apoptosis. We found that rBRI276-266 delays Aß fibril formation, although less efficiently than the BRI2 BRICHOS domain (BRI2 residues 113-231). In human neuroblastoma SH-SY5Y cells, rBRI276-266 slightly decreased cell viability and increased up to two-fold the Bax/Bcl-2 ratio and the subsequent activity of caspases 3 and 9, indicating activation of apoptosis. rBRI276-266 upregulated the chaperone BiP but did not modify the mRNA expression of other UPR markers (CHOP and Xbp-1). Strikingly, rBRI276-266 induced the activation of GSK3ß but not the phosphorylation of tau. However, exposure to rBRI276-266 significantly induced the truncation of tau, indicating that BRI2 ectodomain can contribute to NFT formation. Since BRI2 can also regulate the metabolism of Aß, the current data suggests that BRI2 ectodomain is a potential nexus between Aß, tau pathology and neurodegeneration.

Transmission of shiga toxin-producing Escherichia coli O104:H4 at a family party possibly due to contamination by a food handler, Germany 2011.

We investigated a cluster of shiga toxin-producing Escherichia coli (STEC) O104:H4 infections after a family party during a large STEC O104:H4 outbreak in Germany. To identify the vehicle we conducted a retrospective cohort study. Stool samples of party guests, and food and environmental samples from the catering company were tested for STEC. We defined cases as party guests with gastrointestinal symptoms and laboratory-confirmed STEC infection. We found 23 cases among 71 guests. By multivariable analysis consumption of salmon [odds ratio (OR) 15, 95% confidence interval (CI) 2.3-97], herb cream (OR 6.5, 95% CI 1.3-33) and bean salad (OR 6.1, 95% CI 1.4-26) were associated with STEC infection. STEC O104:H4 was detected in samples of bell pepper and salmon. The food handler developed STEC infection. Our results point towards transmission via several food items contaminated by a food handler. We recommend regular education of food handlers emphasizing their role in transmitting infectious diseases.

[Serious clinical manifestations of vitamin deficiency after a "sleeve" gastrectomy: role of psychogenic anorexia]. / Anorexie psychogène et carences vitaminiques sévères dans les suites d'une gastrectomie longitudinale.

INTRODUCTION: Morbid obesity is an emerging condition in the general population. Bariatric surgery, which has demonstrated its effectiveness for weight loss, mortality and morbidity related to obesity, is required in some patients. However, it may be associated with various adverse effects, including vitamin deficiencies. CASE REPORT: We report a 33-year old man who presented central and peripheral neurological deficits and cardiac manifestations related to multiple vitamin deficiencies, following "sleeve" gastrectomy. The vitamin deficiencies were related to insufficient ingesta secondary to psychogenic anorexia. The patient improved with vitamins, antidepressant drugs and atypical neuroleptics. CONCLUSION: Post-operative complications of "sleeve" gastrectomy include vitamin deficiencies that can develop in the context of psychogenic anorexia and ingesta reduction, in the absence of any digestive malabsorption.

Depression in patients referred for psychiatric consultation. A need for a new diagnosis.

The authors analyzed 329 referrals for psychiatric consultation from medical and surgical wards. They found depression to be the most prevalent diagnosis (34%), with Major Depression being the most common DSM-III subtype (49%). Depression was predominant in the elderly (p less than 0.05), in women (p less than 0.05), and in patients with a high degree of psychosocial stressors (p less than 0.01). There were significant differences among the DSM-III subtypes of depression in some of these correlates. The authors emphasize the importance of DSM-III in differentiating among the subtypes of depression in referred patients but they suggest the need for a new diagnosis for depression in the physically ill.

Development and exploratory trials of a cognitive preference inventory for medical students.

A medical cognitive preference inventory was developed and tested with two samples, one in Israel and the other in the United States. Acceptable levels of internal consistency of the whole test and of its three subtests were demonstrated. Direct and indirect evidence for the validity of the test was provided. The potential uses of the test for student selection and evaluation as well as for programme evaluation were discussed. Two forms, E and F, each consisting of eighteen items, are recommended for use with medical students. A combination of these two forms is designed as form G. Administration of one form to half of a sample and the other form to the other half, followed by pooling the individual scores, thereby obtaining results comparable to those of form G, is recommended when time to administer the inventory is limited.

A new approach to teaching normal human growth and development. The role of clinical simulations as a teaching and evaluation device for preclinical medical students.

A new approach to teaching Normal Growth and Development to preclinical medical students is described. By using specially constructed multidisciplinary clinical simulations as training and evaluation devices, students were gradually and simultaneously exposed to: (1) subject matter; (2) the concept of multidisciplinary health care delivery; and (3) the objectives, strategies, and techniques of problem solving and diagnostic reasoning that characterize experienced physicians. The course, designed by a child psychiatrist and medical educators, was taught by a multidisciplinary teaching team drawn from faculty and health care representatives. Student evaluations of the course were favorable.

Interrelations between age and plasma renin, aldosterone and cortisol, urinary catecholamines, and the body sodium/volume state in normal man.

Interrelations between age and plasma renin, aldosterone and cortisol levels, urinary catecholamiens, plasma and blood volumes, exchangeable body sodium and blood pressure wwere studied in 28 young (19 to 29 years), 16 middle-aged (32 to 58 years) and 15 elderly (60 to 74 years) healthy subjects. Supine and upright plasma renin and supine aldosterone levels decreased while urinary noradrenaline excretion rate increased progressively with aging (r= greater than 0.34; p less than 0.05), with significant differences in mean values between young and elderly subjects (p less than 0.02). There was also an age-related decrease in upright plasma aldosterone concentration, although this was no statistically significant. Furthermore, mean plasma cortisol concentrations increased in response to upright posture in elderly ( + 50%; p less than 0.02), but not in young ( --10%) or middle-aged ( --8%) subjects. Blood pressure correlated with age ( r =0.35; p less than 0.05) or noradrenaline excretion rate ( r= 0.34) in the entire study population and with blood volume in the elderly ( r = 0.68), but not in the young or middle-aged study. Groups. There were no significant age-related differences in the body sodium/volume state, basal plasma cortisol levels or urinary adrenaline excretion rate, and plasma renin or aldosterone levels did not correlate with these parameters or with blood pressure. It is concluded that the influence of age on plasma renin or aldosterone levels, plasma cortisol responsiveness to upright posture, and urinary noradrenaline excretion should be taken into consideration, whenever these factors have to be interpreted in patients with arterial hypertension or other clinical disorders. Further more, these data are conssitent with the possiblity that in normal man increases in supine blood pressure with aging may be related at least partly to concomitant changes in free peripheral noradrenaline.

An approach to teaching the introduction to clinical medicine.

An approach to teaching the introduction of clinical medicine to medical students is described. It is based on (A) gradual exposure to patients and step-by-step introduction to the objectives and techniques of history taking, with emphasis on training for symptom identification; (B) early exposure to the problem-oriented approach; (C) early diagnostic hypothesis generation; and (D) self-directed learning. The objectives of the proposed approach are to teach students to communicate with patients, to teach the skills of history taking and physical examination, and to introduce the problem-solving strategies that characterize the diagnostic reasoning of experienced physicians.

Comparative study of Hebrew University-Hadassah Medical School participation in education council ofr foreign medical graduates (ECFMG) examination.

The achievements of the 874 (55%) medical graduates of Hebrew University-Hadassah School who took the ECFMG examination from 1962, when it was introduced in Israel, to 1972, were compared with those of candidates from other schools during the same period. The achievement level of candidates was high: usually above the 90th percentile rank position; 80 to 85% of its candidates passed the examination (compared to about 40% from all other schools); and the frequency distribution of ECFMG examination scores of HUHMS candidates in 1965 revelas a similarity to the achievements in American medical schools. The difference between the percentage of candidates passing the ECFMG examination from year to year supports the contention that the level of difficulty of the examinations varies. Candidates taking the examination after several years of clinical experience do not perform better. Since only 19% of all HUHMS graduates have gone abroad for postgraduate training, and only 11% have remained abroad for 4 or more consecutive years, participation in ECFMG has not been reflected in an increase in 'brain drain'.