The seasonal cycle of energetics from the GLAS/UMD climate GCM

The annual cycle of atmospheric energetics from a 2-year integration of the GLAS/UMD Climate GCM is computed and compared to results from the European Centre analyses of the GWE year, and to previously published results on a global basis. All calculations are done in the mixed space-time domain. The main conclusions are: (1) the seasonal cycle of today's eddy kinetic energy (in both hemispheres), and of the transient eddy available potential energy and the potential-to-kinetic energy conversions (mean and eddy) in the Northern Hemisphere are well simulated by the GCM; (2) the GCM's tendency to have anomalously large mean u-winds at upper levels in high latitudes leads to excessive wintertime values of mean kinetic and available potential energies, and causes distortions in the GCM latitude-height distribution of kinetic energy and of many of the conversions; (3) the eddy conversion of available potential-to-kinetic energy obtained from the ageostrophic wind in these analyses; and (4) the conversions in the Southern Hemisphere are not well simulated by the GCM, although the observations are somewhat questionable

HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism

The mechanism by which HIV-1 induces CD4+ T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4+ T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism

Dose-Reduced Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation for Human Immunodeficiency Virus–Associated Lymphoma: AIDS Malignancy Consortium Study 020

AbstractIntensive chemotherapy for human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) has resulted in durable remissions in a substantial proportion of patients. High-dose chemotherapy and autologous stem cell transplantation (AuSCT), moreover, has resulted in sustained complete remissions in selected patients with recurrent chemosensitive disease. Based on a favorable experience with dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT for older patients with non-HIV–associated aggressive lymphomas, an AIDS Malignancy Consortium multicenter trial was undertaken using the same dose-reduced busulfan and cyclophosphamide preparative regimen with AuSCT for recurrent HIV-associated NHL and HL. Of the 27 patients in the study, 20 received an AuSCT. The median time to achievement of an absolute neutrophil count (ANC) of ≥ 0.5×109/L was 11 days (range, 9-16 days). The median time to achievement of an unsupported platelet count of ≥ 20×109/L was 13 days (range, 6-57 days). One patient died on day +33 posttransplantation from hepatic veno-occlusive disease (VOD) and multiorgan failure. No other fatal regimen-related toxicity occurred. Ten of 19 patients (53%) were in complete remission at the time of their day +100 post-AuSCT evaluation. Of the 20 patients, 10 were alive and event-free at a median of 23 weeks post-AuSCT. Median overall survival (OS) was not reached by 13 of the 20 patients alive at the time of last follow-up. This multi-institutional trial demonstrates that a regimen of dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT is well tolerated and is associated with favorable disease-free survival (DFS) and OS probabilities for selected patients with HIV-associated NHL and HL

CD28 and the Tyrosine Kinase Lck Stimulate Mitogen-Activated Protein Kinase Activity in T Cells via Inhibition of the Small G Protein Rap1

Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation

A third of systematic reviews changed or did not specify the primary outcome : A PROSPERO register study

OBJECTIVES: To examine outcome reporting bias of systematic reviews registered in PROSPERO. STUDY DESIGN AND SETTING: Retrospective cohort study. The primary outcomes from systematic review publications were compared with those reported in the corresponding PROSPERO records; discrepancies in the primary outcomes were assessed as upgrades, additions, omissions or downgrades. Relative risks (RR) and 95% confidence intervals (CI) were calculated to determine the likelihood of having a change in primary outcome when the meta-analysis result was favourable and statistically significant. RESULTS: 96 systematic reviews were published. A discrepancy in the primary outcome occurred in 32% of the included reviews and 39% of the reviews did not explicitly specify a primary outcome(s); 6% of the primary outcomes were omitted. There was no significant increased risk of adding/upgrading (RR 2.14, 95% CI 0.53 to 8.63) or decreased risk of downgrading (RR 0.76, 0.27-2.17) an outcome when the meta-analysis result was favourable and statistically significant. As well, there was no significant increased risk of adding/upgrading (RR 0.89, 0.31-2.53) or decreased risk of downgrading (RR 0.56, 0.29-1.08) an outcome when the conclusion was positive. CONCLUSIONS: We recommend review authors carefully consider primary outcome selection and journals are encouraged to focus acceptance on registered systematic reviews

SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor–induced apoptosis at the plasma membrane

Fas (CD95, APO-1, TNFRSF6) is a TNF receptor superfamily member that directly triggers apoptosis and contributes to the maintenance of lymphocyte homeostasis and prevention of autoimmunity. Although FADD and caspase-8 have been identified as key intracellular mediators of Fas signaling, it is not clear how recruitment of these proteins to the Fas death domain leads to activation of caspase-8 in the receptor signaling complex. We have used high-resolution confocal microscopy and live cell imaging to study the sequelae of early events in Fas signaling. These studies have revealed a new stage of Fas signaling in which receptor ligation leads to the formation of surface receptor oligomers that we term signaling protein oligomerization transduction structures (SPOTS). Formation of SPOTS depends on the presence of an intact Fas death domain and FADD but is independent of caspase activity. Analysis of cells expressing Fas mutations from patients with the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted by distinct mechanisms in ALPS

Core competencies in the science and practice of knowledge translation: description of a Canadian strategic training initiative

<p>Abstract</p> <p>Background</p> <p>Globally, healthcare systems are attempting to optimize quality of care. This challenge has resulted in the development of implementation science or knowledge translation (KT) and the resulting need to build capacity in both the science and practice of KT.</p> <p>Findings</p> <p>We are attempting to meet these challenges through the creation of a national training initiative in KT. We have identified core competencies in this field and have developed a series of educational courses and materials for three training streams. We report the outline for this approach and the progress to date.</p> <p>Conclusions</p> <p>We have prepared a strategy to develop, implement, and evaluate a national training initiative to build capacity in the science and practice of KT. Ultimately through this initiative, we hope to meet the capacity demand for KT researchers and practitioners in Canada that will lead to improved care and a strengthened healthcare system.</p