Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies

Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation

During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity. Here, we address whether transient inhibition of apoptosis can serve as a safe but efficient alternative to improve the outcome of stem cell transplantation. We show that transient apoptosis inhibition by short-term overexpression of prosurvival BCL-XL, known to block BIM and BMF, is not only sufficient to increase the viability of hematopoietic stem and progenitor cells during engraftment but also improves transplantation outcome without signs of adverse pathologies. Hence, this strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability

Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries

Background: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decisionmaking. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peerreviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. Copyright:Methods and Findings: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2594.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2598.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6- 2.5). The probability of publication within two years after study completion ranged from 7% to 30%.Conclusions: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased

The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

<p>Abstract</p> <p>Background</p> <p>Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature.</p> <p>Methods</p> <p>Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss.</p> <p>Results</p> <p>Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain.</p> <p>Conclusions</p> <p>BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.</p

Does the development of new medicinal products in the European Union address global and regional health concerns?

<p>Abstract</p> <p>Background</p> <p>Since 1995, approval for many new medicinal products has been obtained through a centralized procedure in the European Union. In recent years, the use of summary measures of population health has become widespread. We investigated whether efforts to develop innovative medicines are focusing on the most relevant conditions from a global public health perspective.</p> <p>Methods</p> <p>We reviewed the information on new medicinal products approved by centralized procedure from 1995 to 2009, information that is available to the public in the European Commission Register of medicinal products and the European Public Assessment Reports from the European Medicines Agency. Morbidity and mortality data were included for each disease group, according to the Global Burden of Disease project. We evaluated the association between authorized medicinal products and burden of disease measures based on disability-adjusted life years (DALYs) in the European Union and worldwide.</p> <p>Results</p> <p>We considered 520 marketing authorizations for medicinal products and 338 active ingredients. New authorizations were seen to increase over the period analyzed. There was a positive, high correlation between DALYs and new medicinal product development (ρ = 0.619, p = 0.005) in the European Union, and a moderate correlation for middle-low-income countries (ρ = 0.497, p = 0.030) and worldwide (ρ = 0.490, p = 0.033). The most neglected conditions at the European level (based on their attributable health losses) were neuropsychiatric diseases, cardiovascular diseases, respiratory diseases, sense organ conditions, and digestive diseases, while globally, they were perinatal conditions, respiratory infections, sense organ conditions, respiratory diseases, and digestive diseases.</p> <p>Conclusions</p> <p>We find that the development of new medicinal products is higher for some diseases than others. Pharmaceutical industry leaders and policymakers are invited to consider the implications of this imbalance by establishing work plans that allow for the setting of future priorities from a public health perspective.</p

A customized distraction device for alveolar ridge augmentation and alignment of ankylosed teeth.

The purpose of this study was to develop an extraosseous, tooth-supported miniature intraoral device that could produce prosthetically driven bone distraction of small atrophic alveolar ridge segments. Extraosseous distraction requires that the distraction device be anchored to a dental implant previously placed into the ridge according to its anatomic axis. A distractor can also correct the position of implants placed in young patients before skeletal growth is completed. Similarly, it allows the alignment of ankylosed teeth not treatable by orthodontics. The device is made of (1) an engine consisting of an orthodontic micrometric screw; (2) a joint between the implant and the engine, ie, the ball attachment/o-ring system; and (3) an anchorage system to the oral cavity provided by an orthodontic appliance and a mini-implant for possible additional support. Surgery involves an osteotomy of the atrophic alveolar ridge segment, incorporating the implant, from the basal bone; afterward the device can be applied and distraction of the segment can be carried out. Distraction was successfully performed in 3 clinical cases: 2 bone-implant segments and 1 bone-ankylosed tooth segment. All cases were clinically uneventful. This mini-device for osteogenic distraction of small atrophic ridge segments can provide for accurate and precise ridge augmentation, as is required for ideal prosthetic rehabilitation