Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities

Social cognition has become a high priority area for the study of schizophrenia. However, despite developments in this area, progress remains limited by inconsistent terminology and differences in the way social cognition is measured. To address these obstacles, a consensus-building meeting on social cognition in schizophrenia was held at the National Institute of Mental Health in March 2006. Agreement was reached on several points, including definitions of terms, the significance of social cognition for schizophrenia research, and suggestions for future research directions. The importance of translational interdisciplinary research teams was emphasized. The current article presents a summary of these discussions.     

Functional analysis of CD8+ T cell responses to the onconeural self protein cdr2 in patients with paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration (PCD) is linked to an immune response against cerebellar degeneration related antigen 2 (cdr2) co-expressed in tumor and Purkinje neurons. Here, comprehensive immune-assessment assays were used to analyze CD8(+) T cells from 7 PCD patients, but no evidence was found of CD8(+) T cells specific for either of two previously described cdr2 epitopes (cdr2-1 and cdr2-2). In contrast, viral-specific CD8(+) T cells from healthy volunteers and PCD patients were measurable. These findings are inconsistent with an obligate role for cdr2-1- or cdr2-2-specific CD8(+) T cells in the pathogenesis of PCD.     

Immunological Aspects of Polymer Microsphere Vaccine Delivery Systems

In vitro studies using dendritic cells have identified that microencapsulated antigens are taken up and processed differently as compared with soluble proteins, and these findings have been reviewed. Similarly, in vivo, it is evident that microencapsulated materials have different properties in terms of uptake and trafficking. Intranasal (IN) instillation of encapsulated protective antigen resulted in a significant increase in the percentage of activated CD4₊ and B-cells in the spleens of immunised mice, whereas IN instillation of soluble antigen failed to do so. This corroborates earlier findings concerning the uptake and trafficking of microparticles following bronchopulmonary administration. These data support the tenet that microencapsulation serves to modify the uptake, trafficking and processing of antigens.     

Genetic testing for alpha1-antitrypsin deficiency.

PURPOSE: The Alpha Coded Testing Study investigated the risks, benefits, and psychological impact of home genetic testing for alpha1-antitrypsin deficiency. METHODS: In the study, 996 adult individuals requested and returned a home-administered, confidential, fingerstick blood test. RESULTS: Individuals highly rated the benefits of establishing a diagnosis (82%), helping family members (86%), and anticipating peace of mind (79%). 78% of 239 current smokers reported a high likelihood of smoking cessation if diagnosed with AATD. After testing, more than 60% indicated that they would share the results with family and physicians but < 30% would share results with insurance companies. CONCLUSIONS: Confidential home testing for genetic disorders requires a comprehensive program of participant support.     

Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease.

Psoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin.     

Lower tidal volume at initiation of mechanical ventilation may reduce progression to acute respiratory distress syndrome: a systematic review

Introduction

The most appropriate tidal volume in patients without acute respiratory distress syndrome (ARDS) is controversial and has not been rigorously examined. Our objective was to determine whether a mechanical ventilation strategy using lower tidal volume is associated with a decreased incidence of progression to ARDS when compared with a higher tidal volume strategy.

Methods

A systematic search of MEDLINE, EMBASE, CINAHL, the Cochrane Library, conference proceedings, and clinical trial registration was performed with a comprehensive strategy. Studies providing information on mechanically ventilated patients without ARDS at the time of initiation of mechanical ventilation, and in which tidal volume was independently studied as a predictor variable for outcome, were included. The primary outcome was progression to ARDS.

Results

The search yielded 1,704 studies, of which 13 were included in the final analysis. One randomized controlled trial was found; the remaining 12 studies were observational. The patient cohorts were significantly heterogeneous in composition and baseline risk for developing ARDS; therefore, a meta-analysis of the data was not performed. The majority of the studies (n = 8) showed a decrease in progression to ARDS with a lower tidal volume strategy. ARDS developed early in the course of illness (5 hours to 3.7 days). The development of ARDS was associated with increased mortality, lengths of stay, mechanical ventilation duration, and nonpulmonary organ failure.

Conclusions

In mechanically ventilated patients without ARDS at the time of endotracheal intubation, the majority of data favors lower tidal volume to reduce progression to ARDS. However, due to significant heterogeneity in the data, no definitive recommendations can be made. Further randomized controlled trials examining the role of lower tidal volumes in patients without ARDS, controlling for ARDS risk, are needed.2013 Fuller et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.     

Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states

ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. In mammals ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is therefore a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role. The crystal structure of apo-ABCB10 shows a classic exporter fold ABC transporter structure, in an open-inwards conformation, ready to bind the substrate or nucleotide from the inner mitochondrial matrix or membrane. Unexpectedly, however, ABCB10 adopts an open-inwards conformation when complexed with nonhydrolysable ATP analogs, in contrast to other transporter structures which adopt an open-outwards conformation in complex with ATP. The three complexes of ABCB10/ATP analogs reported here showed varying degrees of opening of the transport substrate binding site, indicating that in this conformation there is some flexibility between the two halves of the protein. These structures suggest that the observed plasticity, together with a portal between two helices in the transmembrane region of ABCB10, assist transport substrate entry into the substrate binding cavity. These structures indicate that ABC transporters may exist in an open-inwards conformation when nucleotide is bound. We discuss ways in which this observation can be aligned with the current views on mechanisms of ABC transporters.