Kidney regeneration: common themes from the embryo to the adult

The vertebrate kidney has an inherent ability to regenerate following acute damage. Successful regeneration of the injured kidney requires the rapid replacement of damaged tubular epithelial cells and reconstitution of normal tubular function. Identifying the cells that participate in the regeneration process as well as the molecular mechanisms involved may reveal therapeutic targets for the treatment of kidney disease. Renal regeneration is associated with the expression of genetic pathways that are necessary for kidney organogenesis, suggesting that the regenerating tubular epithelium may be “reprogrammed” to a less-differentiated, progenitor state. This review will highlight data from various vertebrate models supporting the hypothesis that nephrogenic genes are reactivated as part of the process of kidney regeneration following acute kidney injury (AKI). Emphasis will be placed on the reactivation of developmental pathways and how our understanding of the resulting regeneration process may be enhanced by lessons learned in the embryonic kidney.Fil: Cirio, Maria Cecilia. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Groh, Eric D.. University of Pittsburgh; Estados UnidosFil: de Caestecker, Mark P.. Vanderbilt University; Estados UnidosFil: Davidson, Alan J.. The University of Auckland; Nueva ZelandaFil: Hukriede, Neil A.. University of Pittsburgh; Estados Unido

The waiting time paradox: population based retrospective study of treatment delay and survival of women with endometrial cancer in Scotland

No abstract available

BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series)

Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH

Partner Choices in Long Established Migrant Communities in Belgium

This paper aims to shed light on the partner choices of Moroccan, Turkish, Congolese, and Algerian migrants in Belgium. Three partner choices are distinguished: marrying a partner from the country of origin (partner migration), marrying a local co-ethnic partner, and establishing a mixed marriage. We focused on the role of migration history and transnational links, culture (religion, language), skin colour and structural characteristics of the district migrants live in (mainly community size) to gain further insight into the partner choices of migrants in Belgium. Our data comprise an extraction of the Belgian national register (2001-2008) and focus on first marriages among first, 1.5, and second generation migrants of Moroccan, Turkish, Algerian, and Congolese origin (N=52,142). We apply a multinomial logistic multilevel design to simultaneously incorporate individual and contextual effects at the district level. The main conclusion from this paper is that the partner selection pattern in early 21st century Belgian society still bears the traces of the starting conditions that migrant groups experienced when they first entered the country. While this continuity is important to understand the situation citizens with a migrant origin have to deal with today, it does not make change impossible. In fact, for the Turkish and Moroccan group, research recently showed a quite strong decline in transnational marriages and a modest increase in mixed marriages. These are indications that after 50 years of migration a transition towards full inclusion in Belgian society is not beyond reach. The conditions analysed in this paper, namely the strength of transnational networks, the cultural boundaries and the ethnic community size, may help to understand why this inclusion takes such a long period of time

The cessation in pregnancy incentives trial (CPIT): study protocol for a randomized controlled trial

Background: Seventy percent of women in Scotland have at least one baby, making pregnancy an opportunity to help most young women quit smoking before their own health is irreparably compromised. By quitting during pregnancy their infants will be protected from miscarriage and still birth as well as low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. In the UK, the NICE guidelines: 'How to stop smoking in pregnancy and following childbirth' (June 2010) highlighted that little evidence exists in the literature to confirm the efficacy of financial incentives to help pregnant smokers to quit. Its first research recommendation was to determine: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? <p/>Design and Methods: This study is a phase II exploratory individually randomised controlled trial comparing standard care for pregnant smokers with standard care plus the additional offer of financial voucher incentives to engage with specialist cessation services and/or to quit smoking during pregnancy. Participants (n=600) will be pregnant smokers identified at maternity booking who when contacted by specialist cessation services agree to having their details passed to the NHS Smokefree Pregnancy Study Helpline to discuss the trial. The NHS Smokefree Pregnancy Study Helpline will be responsible for telephone consent and follow-up in late pregnancy. The primary outcome will be self reported smoking in late pregnancy verified by cotinine measurement. An economic evaluation will refine cost data collection and assess potential cost-effectiveness while qualitative research interviews with clients and health professionals will assess the level of acceptance of this form of incentive payment. Research questions What is the likely therapeutic efficacy? Are incentives potentially cost-effective? Is individual randomisation an efficient trial design without introducing outcome bias? Can incentives be introduced in a way that is feasible and acceptable? <p/>Discussion: This phase II trial will establish a workable design to reduce the risks associated with a future definitive phase III multicentre randomised controlled trial and establish a framework to assess the costs and benefits of financial incentives to help pregnant smokers to quit

Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension

More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations

Identity dynamics as a barrier to organizational change

This article seeks to explore the construction of group and professional identities in situations of organizational change. It considers empirical material drawn from a health demonstration project funded by the Scottish Executive Health Department, and uses insights from this project to discuss issues that arise from identity construction(s) and organizational change. In the course of the project studied here, a new organizational form was developed which involved a network arrangement with a voluntary sector organization and the employment of “lay-workers” in what had traditionally been a professional setting. Our analysis of the way actors made sense of their identities reveals that characterizations of both self and other became barriers to the change process. These identity dynamics were significant in determining the way people interpreted and responded to change within this project and which may relate to other change-oriented situations

Acceptability to patients of screening disposable transnasal endoscopy: qualitative interview analysis

OBJECTIVES: Screening in selected high risk populations for Barrett's oesophagus (BO) and oesophageal varices (OVs) has been proposed, but there are obstacles with conventional oesophagogastroduodenoscopy (C-OGD), including patient acceptability. Portable and disposable office-based transnasal endoscopy (TNE) is a feasible and accurate alternative to C-OGD that may have use in primary and secondary care. This article outlines a qualitative analysis of patient experiences of TNE and C-OGD in order to gain an insight into an acceptable delivery of an endoscopic screening service. DESIGN: Purposeful sampling identified 23 participants who then underwent semi-structured interviews to determine their experiences of both procedures. Thematic analysis was conducted to derive meaning from their lived experiences. SETTING: A secondary care endoscopy unit, clinic room and interview room. PARTICIPANTS: Patients referred for BO or OV surveillance and for endoscopy to investigate dyspepsia underwent unsedated TNE using the EG Scan II device followed by C-OGD with or without sedation (patient choice), as part of a clinical trial. RESULTS: The themes that arose from our analysis were: inclusivity in one's own healthcare, comfort level and convenience, validity of the procedure and application to a screening population and a sense of altruism and reciprocity. Positive aspects of TNE included participant empowerment, reduced discomfort and avoidance of conscious sedation. Participants felt that if TNE screening was of proven efficacy it would be welcomed, though views on use in a community setting were mixed. CONCLUSIONS: Most patients preferred TNE to unsedated C-OGD and the reasons they gave featured strongly in the emerging themes. Preferences between TNE and sedated C-OGD were more subtle, with equivalent comfort scores but merits and drawbacks of both being discussed. This information identifies opportunities and challenges in establishing an endoscopic screening service. Trial registration number ISRCTNregistry identifier: 70595405; Pre-results