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Both normal and tumorous stem cells can arrest cell division, avoid apoptosis, and then regenerate lost daughter cells following acute genotoxic insult. This protective, reversible proliferative arrest, known as “quiescence,” is still poorly understood. Here, we show that mTOR-regulated mitophagy is required for radiation insult-induced quiescence in Drosophila germline stem cells (GSCs). In GSCs, depletion of mito-fission (Drp1) or mitophagy (Pink1 and Parkin) eliminates entry into quiescence, while depletion of mitochondrial biogenesis (PGC1α) or fusion (Mfn2) eliminates exit from quiescence. We also find that mitophagy-dependent quiescence is under epigenetic control; knockdown of Jarid2 (PRC2) or Pc or Sce (PRC1) stabilizes the mitochondria and locks GSCs out of quiescence, while knockdown of PRC2-specific demethylase, Utx, prevents re-accumulation of the mitochondria and locks GSCs in quiescence. These data suggest that mitochondrial number coordinates reversible quiescence. We further identify that the mechanism of quiescence in both GSCs and human induced pluripotent stem cells (iPSCs) relies on mitophagy to deplete the mitochondrial pool of CycE and limit cell cycle progression. This alternative method of G1/S regulation may present new opportunities for therapeutic purposes.

Contains fulltext : 153534.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Adults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the "DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study," a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries. METHODS AND ANALYSIS: DIET-HD will recruit approximately 10,000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA(2)LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation. ETHICS AND DISSEMINATION: The study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease.

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects. (C) 2014 Elsevier Inc. All rights reserved.

10.3390/ijms151222173 Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRa, SREBP1c, ACC1, FAS), FA uptake and transport (PPAR?, CD36, FABP4), FA oxidation (PPARa), and inflammation (IL6, TNFa, CRP, PPARd) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFa mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRa, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis.

Background. Recent reports suggest a role for the endocannabinoid system in the pathology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the relationship between liver expression of cannabinoid (CB) receptor subtypes, CB1 and CB2, in morbidly obese (MO) women with different histological stages of NAFLD. Methods. We analysed hepatic CB1 and CB2 mRNA expression, and the expression of genes involved in lipid metabolism in 72 MO women, subclassified by liver histology into MO with normal liver (NL, n=16), simple steatosis (SS, n=28), and nonalcoholic steatohepatitis (NASH, n=28) by enzyme-linked immunosorbent assay and RT-PCR. Results. We found that CB1 mRNA expression was significantly higher in NASH compared with SS and correlated negatively with PPARa. Regarding CB2, CB2 mRNA expression correlated positively with ACC1, PPAR?, IL6, TNFa, resistin, and adiponectin. Conclusions. The increased expression of CB1 in NASH and the negative correlation with PPARa suggest a deleterious role of CB1 in NAFLD. Regarding CB2, its positive correlation with the anti-inflammatory molecule adiponectin and, paradoxically, with inflammatory genes suggests that this receptor has a dual role. Taken together, our results suggest that endocannabinoid receptors might be involved in the pathogenesis of NAFLD, a finding which justifies further study.

10.1016/j.ciresp.2012.05.019

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.

10.1111/j.1365-2265.2011.04327.x.

1. There is great interest among policy makers in the potential of carbon‐based payments for ecosystem services (PES) to reduce carbon emissions from deforestation and protect forests in tropical countries. We discuss the contributions that ecologists can make to the interdisciplinary research required to inform the design of these initiatives. 2. First, we highlight the need to quantify the full range of processes that determine temporal variation in carbon stocks at a landscape‐scale due to cycles of forest disturbance and recovery. Second, we discuss the importance of understanding how the impact of climate change on the carbon stocks of intact forests may affect the emissions reductions achieved by any given project: we show that this may reduce the effectiveness of one carbon‐based PES project in southern Peru by 15%. We also discuss the need to assess project impacts on deforestation in the surrounding region and explore how different project designs influence the balance between the conservation of carbon and biodiversity. 3. The need to demonstrate emissions reductions or carbon storage to investors in carbon‐based payment schemes provides an imperative for monitoring their effectiveness. Monitoring will be a significant cost in any PES project and, together with project set‐up, on average accounts for more than 40% of project expenditure across six emerging Peruvian PES schemes. Ecologists will therefore have an important role in designing cost‐effective monitoring strategies. The impetus for monitoring also provides opportunities to carry out research addressing many of the uncertainties highlighted above. 4. Synthesis and applications. By working closely with a range of carbon‐based PES projects, ecologists can answer important fundamental questions related to the provision of ecosystem services and help improve the design of these schemes. The large number of projects currently being implemented provides an unprecedented opportunity to develop a proper evidence base for measuring and improving the practices that most successfully conserve tropical forest ecosystems.

Las denuncias contra los médicos son cada vez más frecuentes. Un hecho que hasta hace poco era relativamente anecdótico, se ha convertido en una situación jurídica habitual en la actualidad. El propósito de este estudio es recopilar los datos que desde nuestro punto de vista son más relevantes, de los existentes en los archivos del IML de Málaga, correspondientes a las denuncias por malpraxis en esta provincia. El objetivo es realizar una aproximación global, dada la nueva estructura del trabajo medico legal, a determinados aspectos periciales y aportar nuevos criterios a la hora de realizar dichas periciales. Al mismo tiempo se analiza la práctica de la medicina en esta provincia y su relación con los pacientes. Suits against doctors are now more frequent than ever. A situation that was almost anecdotic some years ago have become very common nowadays. The aim of this study is to compile main data which, from our point of view, are more relevant of the obtained from the files of the Institute of Legal Medicine of Malaga (Spain) related to the medical malpractice suits in this province. The objective is to carry out an approach, taken into account the new structure of the medico-legal work, to some expert witness report and to propose new criteria to perform those evaluations. At the same time, the practice of medicine in this province and its relation with the patients are analyzed.