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ObjectiveIncreasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism.DesignWe created a mouse model ofPnlipp.T221M and characterised the structural and biochemical changes in the pancreas aged 1–12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR.ResultsWe demonstrated the hallmarks of human CP inPnlipp.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. ThePnlipp.T221M pancreas had increased ER stress evidenced by dilated ER, increasedHspa5(BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation ofDdit3(CHOP), nuclear factor-κB and cell death.ConclusionExpression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.

BACKGROUND: We evaluated the epidemiology of fluid balance (FB) over the first postnatal week and its impact on outcomes in a multi-center cohort of premature neonates from the AWAKEN study. METHODS: Retrospective analysis of infants

The structure and spectroscopic properties of the amide bond are a topic of fundamental interest in chemistry and biology. Herein, we report 17O NMR and 15N NMR spectroscopic data for four series of sterically-hindered acyclic amides. Despite the utility of 17O NMR and 15N NMR spectroscopy, these methods are severely underutilized in the experimental determination of electronic properties of the amide bond. The data demonstrate that a combined use of 17O NMR and 15N NMR serves as a powerful tool in assessing electronic effects of the amide bond substitution as a measure of electrophilicity of the amide bond. Notably, we demonstrate that steric destabilization of the amide bond results in electronically-activated amides that are comparable in terms of electrophilicity to acyl fluorides and carboxylic acid anhydrides.

Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop

Omics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called "Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment" (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function.

Multidisciplinary evaluation (MDE) of hepatocellular cancer (HCC) is the current standard, often provided through a tumor board (TB) forum; this standard is limited by oncology workforce shortages and lack of a TB at every institution. Virtual TBs (VTBs) may help overcome these limitations. Our study aim was to assess the impact of a regional VTB on the MDE process for patients with HCC.A retrospective cohort study was conducted, including patients with HCC referred to a tertiary cancer center from regional facilities (2009 to 2013). Baseline characteristics and outcomes were compared based on the referral mechanism: VTB versus subspecialty consultation (non-VTB). The primary outcome was comprehensive MDE (all required specialists present and key topics discussed). Secondary outcomes included timeliness of MDE and travel burden to complete MDE. Univariable and multivariable logistic regressions were performed to examine the association of a VTB with comprehensive MDE.A total of 116 patients were included in the study; 48 (41.4%) were evaluated through the VTB. A higher proportion of VTB patients received comprehensive MDE (91.7% v 64.7%; P = .001); the VTB was independently associated with higher odds of accomplishing comprehensive MDE (odds ratio, 6.0; 95% CI, 1.2 to 29.9; P = .02). VTB patients completed MDE significantly faster (median, 23 v 39 days; P.001), with lower travel burden (median, 0 v 683 miles traveled; P.001).This VTB program positively affected the process of care for patients with HCC by improving the quality and timeliness of the MDE process, while avoiding the burden arising from travel needs. Future studies should focus on implementation of VTB programs on a wider scale.

ResumenObjetivosExplorar las intenciones y motivaciones de la migración profesional y los países de preferencia para la misma en un grupo de estudiantes avanzados de la carrera de Medicina.DiseñoEstudio de corte transversal y descriptivo.EmplazamientoOnce universidades de España.ParticipantesSetecientos cuarenta estudiantes de los últimos dos cursos de la carrera de Medicina.Mediciones principalesSe utilizó un cuestionario autoadministrado sobre los planes de emigrar, los países de destino y las razones motivadoras de esta decisión.ResultadosDe las 740 respuestas válidas, 711 (96%) correspondían a estudiantes españoles. La opción de emigrar fue elegida por 375 (51%) de los estudiantes. Los países de destino por orden de elección fueron Reino Unido, Estados Unidos, Canadá y Portugal. Para 276 estudiantes, una razón muy importante fue trabajar en un mejor sistema de salud, para 160 continuar con su educación médica, para 269 trabajar en un mejor ambiente que le permita progresar y para 243 la razón más importante fue ganar un mejor salario.ConclusionesNuestro estudio identifica factores emocionales que predisponen a la migración de los futuros médicos. El uso de intervenciones apropiadas podría modificar estas actitudes. Este estudio podría ser el punto de partida para explorar y analizar más en detalle las condiciones en que se forman y perciben al Sistema Nacional de Salud los futuros médicos de cara a su retención en España.AbstractObjectivesTo explore intentions, motivations and country preferences related with professional emigration in a sample of advanced medical students.DesignCross sectional and descriptive study.Setting11 Universities in Spain.ParticipantsA total of 740 students in their two final courses.Primary measurementsThe survey used a self administered questionnaire asking about plans to emigrate, preferred destination countries and reasons for wishing to work abroad.ResultsA total of 740 valid questionnaires were collected, 711 (96%) from Spanish students and 26 (4%) from foreigner students. A preference to move abroad was indicated by 375 (51%) students, the most popular destinations being United Kingdom, USA, Canada and Portugal. The answers were classified using categories from “very important” to “not important”. As a “very important” reason, “To work in a better health care system” was chosen by 276 students, “To continue with my medical education and training” by 160, “To work in an environment that allows me to progress” by 269, and “To earn a better salary” by 243 students.ConclusionsThe study illustrates various motivational factors which of why medical students wish to move abroad in search of better professional conditions. The use of appropriate interventions could modify these attitudes. This study could be a starting point for exploring and analyzing the conditions of undergraduate medical students in Spain as a key to address the problem of medical emigration.