Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors

N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ(1-42) (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor.     

Evaluation of the three-dimensional soft tissue changes after anterior segmental maxillary osteotomy

The aim of this study was to assess the three-dimensional soft tissue changes following anterior segmental maxillary osteotomy, in terms of magnitude and direction in correlation to hard tissue changes, using cone beam computed tomography (CBCT). The study included 6 patients (age range 17-35 years) suffering from dental maxillary protrusion that required surgical correction by anterior segmental maxillary osteotomy. For each patient, preoperative and postoperative CBCT, photographs, and orthodontic casts were taken before and 6 months after operation to analyse soft tissue changes, in terms of magnitude and direction in correlation to hard tissue changes, using linear and angular measurements. Hard and soft tissue changes were only observed in the maxillary region, upper lip area and nasal tip. Soft tissue mean change included 53% backward displacement of the labrale superius in relation to bone displacement and 18.7% mean increase in the naso-labial angle. The highest correlation coefficient was obtained between the hard and soft tissue changes in the upper lip region. Anterior segmental maxillary osteotomy might be recommended as the treatment modality of choice in patients with maxillary or dento-alveolar protrusion, the technique is simple, safe, and postoperative complications are minimal.     

Partial compliance with antipsychotics and its impact on patient outcomes

Partial compliance with antipsychotic medications is a common and complex phenomenon that is underestimated by physicians. The consequences of partial compliance include an increased risk of relapse, rehospitalization and suicide attempts. Stigma, negative attitudes towards medications, cognitive impairment and diminished insight negatively impact treatment adherence. Oral atypical antipsychotics may improve both insight and cognitive function, but compliance with these agents is not assured. Depot conventional antipsychotics ensure medication delivery but are associated with side-effects such as EPS and dysphoria that decrease compliance. Long-acting atypicals provide significant symptom improvement, foster adherence and may help achieve improvement in insight and cognition. Addressing issues of partial and non-compliance is a significant consideration in relapse prevention strategies for patients with schizophrenia, given the devastating consequences associated with psychotic relapses.     

Pregnancy among residents enrolled in general surgery: a nationwide survey of attitudes and experiences

Background

Medical student interest in general surgery has declined, and the lack of adequate accommodation for pregnancy and parenting during residency training may be a deterrent. We explored resident and program director experiences with these issues in general surgery programs across Canada.

Methods

Using a web-based tool, residents and program directors from 16 Canadian general surgery programs were surveyed regarding their attitudes toward and experiences with pregnancy during residency.

Results

One hundred seventy-six of 600 residents and 8 of 16 program directors completed the survey (30% and 50% response rate, respectively). Multiple issues pertaining to pregnancy during surgical residency were reported including the lack of adequate policies for maternity/parenting, the major obstacles to breast-feeding, and the increased workload for fellow resident colleagues. All program directors reported the lack of a program-specific maternity/parenting policy.

Conclusions

General surgery programs lack program-specific maternity/parenting policies. Several issues have been highlighted in this study emphasizing the importance of creating and implementing such a policy.     

Corticosteroid Therapy, Vitamin D Status, and Inflammatory Cytokine Profile in the HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Background.?Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients. Methods.?Plasma from 39 TB-IRIS and 42 non-IRIS patients was collected during a prospective study of HIV-associated tuberculosis patients starting ART. In total, 26% of patients received corticosteroid (CTC) therapy pre-ART for severe tuberculosis. Concentrations of total 25-hydroxyvitamin D (25(OH)D) and 14 cytokines/chemokines were determined at ART initiation and 2 weeks later. Results.?Patients prescribed concurrent CTC had lower interferon γ (IFN-γ), IP-10, tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, IL-10, IL-12p40, and IL-18 pre-ART (P?≤?.02). TB-IRIS presented at 12 days (median) of ART, irrespective of CTC use. In patients who developed TB-IRIS (not on CTC) IL-6, IL-8, IL-12p40, IL-18, IP-10, and TNF increased during 2 weeks (P?≤?.04) of ART. Vitamin D deficiency (total 25(OH)D <75?nmol/L) was highly prevalent (89%) at baseline. Although vitamin D deficiency at either baseline or 2 weeks was not associated with TB-IRIS, in those not on CTC the median 25(OH)D decreased during 2 weeks (P?=?.004) of ART. Severe vitamin D deficiency (total 25(OH)D <25?nmol/L) was associated with higher baseline TNF, IL-6, and IL-8 irrespective of IRIS status. Conclusions.?CTC modifies the inflammatory profile of those who develop TB-IRIS. The association between severe vitamin D deficiency and elevated proinflammatory cytokines support a study of vitamin D supplementation in HIV-TB co-infected patients starting ART.     

Bilateral stress fractures of femoral neck in non-athletes: a report of four cases

Femoral neck stress fractures (FNSFs) are rare,constituting only 5％ of all stress fractures in young adults.These fractures are usually seen in athletes,military recruits and patients with underlying m...