Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Deficiencies in the transfer and availability of clinical trials evidence: A review of existing systems and standards

Background: Decisions concerning drug safety and efficacy are generally based on pivotal evidence provided by clinical trials. Unfortunately, finding the relevant clinical trials is difficult and their results are only available in text-based reports. Systematic reviews aim to provide a comprehensive overview of the evidence in a specific area, but may not provide the data required for decision making. Methods: We review and analyze the existing information systems and standards for aggregate level clinical trials information from the perspective of systematic review and evidence-based decision making. Results: The technology currently used has major shortcomings, which cause deficiencies in the transfer, traceability and availability of clinical trials information. Specifically, data available to decision makers is insufficiently structured, and consequently the decisions cannot be properly traced back to the underlying evidence. Regulatory submission, trial publication, trial registration, and systematic review produce unstructured datasets that are insufficient for supporting evidence-based decision making. Conclusions: The current situation is a hindrance to policy decision makers as it prevents fully transparent decision making and the development of more advanced decision support systems. Addressing the identified deficiencies would enable more efficient, informed, and transparent evidence-based medical decision making

The Female Athlete's Heart: Facts and Fallacies.

Purpose of the review For many years, competitive sport has been dominated by men. Recent times have witnessed a significant increase in women participating in elite sports. As most studies investigated male athletes, with few reports on female counterparts, it is crucial to have a better understanding on physiological cardiac adaptation to exercise in female athletes, to distinguish normal phenotypes from potentially fatal cardiac diseases. This review reports on cardiac adaptation to exercise in females. Recent findings Recent studies show that electrical, structural, and functional cardiac changes due to physiological adaptation to exercise differ in male and female athletes. Women tend to exhibit eccentric hypertrophy, and while concentric hypertrophy or concentric remodeling may be a normal finding in male athletes, it should be evaluated carefully in female athletes as it may be a sign of pathology. Although few studies on veteran female athletes are available, women seem to be affected by atrial fibrillation, coronary atherosclerosis, and myocardial fibrosis less than male counterparts. Summary Males and females exhibit many biological, anatomical, and hormonal differences, and cardiac adaptation to exercise is no exception. The increasing participation of women in sports should stimulate the scientific community to develop large, longitudinal studies aimed at a better understanding of cardiac adaptation to exercise in female athletes

The future distribution of wetland birds breeding in Europe validated against observed changes in distribution

Wetland bird species have been declining in population size worldwide as climate warming and land-use change affect their suitable habitats. We used species distribution models (SDMs) to predict changes in range dynamics for 64 non-passerine wetland birds breeding in Europe, including range size, position of centroid, and margins. We fitted the SDMs with data collected for the first European Breeding Bird Atlas and climate and land-use data to predict distributional changes over a century (the 1970s-2070s). The predicted annual changes were then compared to observed annual changes in range size and range centroid over a time period of 30 years using data from the second European Breeding Bird Atlas. Our models successfully predicted ca. 75% of the 64 bird species to contract their breeding range in the future, while the remaining species (mostly southerly breeding species) were predicted to expand their breeding ranges northward. The northern margins of southerly species and southern margins of northerly species, both, predicted to shift northward. Predicted changes in range size and shifts in range centroids were broadly positively associated with the observed changes, although some species deviated markedly from the predictions. The predicted average shift in core distributions was ca. 5 km yr(-1) towards the north (5% northeast, 45% north, and 40% northwest), compared to a slower observed average shift of ca. 3.9 km yr(-1). Predicted changes in range centroids were generally larger than observed changes, which suggests that bird distribution changes may lag behind environmental changes leading to 'climate debt'. We suggest that predictions of SDMs should be viewed as qualitative rather than quantitative outcomes, indicating that care should be taken concerning single species. Still, our results highlight the urgent need for management actions such as wetland creation and restoration to improve wetland birds' resilience to the expected environmental changes in the future

Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice

Background Complement activation plays an important role in the pathogenesis of renal ischemia-reperfusion (IR) injury (IRI), but whether this involves damage to the vasculoprotective endothelial glycocalyx is not clear. We investigated the impact of complement activation on glycocalyx integrity and renal dysfunction in a mouse model of renal IRI. Methods Right nephrectomized male C57BL/6 mice were subjected to 22 minutes left renal ischemia and sacrificed 24 hours after reperfusion to analyze renal function, complement activation, glycocalyx damage, endothelial cell activation, inflammation, and infiltration of neutrophils and macrophages. Results Ischemia-reperfusion induced severe renal injury, manifested by significantly increased serum creatinine and urea, complement activation and deposition, loss of glycocalyx, endothelial activation, inflammation, and innate cell infiltration. Treatment with the anti-C5 antibody BB5.1 protected against IRI as indicated by significantly lower serum creatinine (P = 0.04) and urea (P = 0.003), tissue C3b/c and C9 deposition (both P = 0.004), plasma C3b (P = 0.001) and C5a (P = 0.006), endothelial vascular cell adhesion molecule-1 expression (P = 0.003), glycocalyx shedding (tissue heparan sulfate [P = 0.001], plasma syndecan-1 [P = 0.007], and hyaluronan [P = 0.02]), inflammation (high mobility group box-1 [P = 0.0003]), and tissue neutrophil (P = 0.0009) and macrophage (P = 0.004) infiltration. Conclusions Together, our data confirm that the terminal pathway of complement activation plays a key role in renal IRI and demonstrate that the mechanism of injury involves shedding of the glycocalyx