Diabetic nephropathy, autophagy and proximal tubule protein endocytic transport: A potentially harmful relationship

Diabetic nephropathy (DN) is the most frequent cause of chronic renal failure. Until now, the pathophysiological mechanisms that determine its development and progression have not yet been elucidated. In the present study, we evaluate the role of autophagy at early stages of DN, induced in type 2 diabetes mellitus (T2DM) mouse, and its association with proximal tubule membrane endocytic receptors, megalin and cubilin. In T2DM animals we observed a tubule-interstitial injury with significantly increased levels of urinary GGT and ALP, but an absence of tubulointerstitial fibrosis. Kidney proximal tubule cells of T2DM animals showed autophagic vesicles larger than those observed in the control group, and an increase in the number of these vesicles marked with LBPA by immunofluorescence. Furthermore, a significant decrease in the ratio of LC3II/LC3I isoforms and in p62 protein expression in DN affected animals is shown. Finally, we observed a marked increase in urinary albumin and vitamin D binding-protein levels in T2DM animals as well as a significant decrease in expression of megalin in the renal cortex. These results indicate an alteration of the tubular endocytic transporters in DN, which could be related to autophagic dysfunction, which would in turn result in impaired organelle recycling, thus contributing to the progression of this disease.Fil: Giraud Billoud, Maximiliano German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Agüero, Rocio. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo; Chil

Factores de riesgo para mortalidad por cirrosis hepática en el Hospital Regional Docente Clínico Quirúrgico Daniel Alcides Carrión 2018-2021

La investigación tuvo como objetivo, “determinar la relación existente entre los factores de riesgo y la mortalidad por cirrosis hepática en el Hospital Regional Docente Clínico Quirúrgico Daniel Alcides Carrión 2018 – 2021. Se tomó en cuenta el nivel correlacional, además, la investigación es de tipo aplicada, con un diseño no experimental de cohorte. La población estuvo formada por 565 historias clínicas de pacientes con cirrosis hepática, se tuvo una muestra de 230 pacientes, el muestreo fue probabilístico aleatorio simple, y se usó una ficha de acopio de datos. Los resultados señalan que los pacientes con cirrosis hepática atendidos durante el periodo 2018 – 2021, se encuentran entre 46 y 75 años, y la mayoría de ellos eran del sexo masculino. El 84,4 % de los pacientes tuvieron un peso entre lo normal y sobrepeso. Asimismo, solo el 15,2 % de los pacientes con cirrosis hepática evidenciaron tener diabetes mellitus tipo I o II, el 89,1 % no tenían hipertensión arterial. El 81,3 % obtuvieron un resultado anormal en su hemograma. Se observó una relación significativa entre los factores de riesgo y mortalidad por cirrosis hepática (sig.< 0,05). Los de sexo masculino, tienen antecedentes patológicos como: diabetes mellitus, insuficiencia renal, tuberculosis y alcoholismo, como etiología de la cirrosis hepática

Metabolomic-Based Noninvasive Serum Test to Diagnose Nonalcoholic Steatohepatitis: Results From Discovery and Validation Cohorts

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 +/- 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 +/- 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 +/- 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy.Supported by the National Institutes of Health Blueprint for Neuroscience Research (R01AT001576 to S.C.L., J.M.M.), Agencia Estatal de Investigacion of the Ministerio de Economia, Industria y Competitividad (SAF2014-52097R to J.M.M.), CIBER Hepatic and Digestive Diseases and Instituto de Salud Carlos III (PIE14/0003 to J.M.M.), Etorgai 2015-Gobierno Vasco (ER-2015/00015 to R.M., I.M.A., C.A., A.C.), Plan de Promocion de la Innovacion 2015-Diputacion Foral de Bizkaia (6/12/IN/2015/00131 to A.C., C.A.), National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK81410 to A.J.S.), and Czech Ministry of Health (RVO VFN64165 to L.V.)

Feminismos sob ataque: reação ou negligência?

In the current Argentinean situation and after the desolate electoral results - whose devastating effects are being the daily bread in terms of multiplied and brutal violence - there are social discourses that circulate and function with force, both binding and (dis)articulating, questioning feminisms and dissidence in what they have been provoking, in what they apparently did not take into account, in what is pending and open and unresolved, or even in what they are hindering. In this context, there are positions which, contrary to understanding the attacks on feminisms as a backlash - that is, as an adverse reaction on the part of the conservative sectors that historically oppose them, a counterattack on their transformative achievements - tend to challenge feminist and sex-dissident agendas as radical, decontextualised and/or ‘piantavotos’. Other readings point to problems in priorities: the centrality of abortion legalisation is recognised, in some cases also of gender-inclusive language, but it is also pointed out that, in this context, there are other social and economic priorities; in colloquial terms, the priority is to ‘stand the pot, not to talk with \u27they’. In this context, where the banners of equality and social justice are openly questioned, what struggles and principles do you think we should prioritise in order to strengthen collective action and create a feminist present? What kind of freedom are we building? And, specifically, would you say that in this context it is necessary to de-centre the prominence that the discussion on inclusive language has acquired or, in reality, privileging such a demand represents today an unavoidable expression of resistance?En la coyuntura argentina actual y tras el desolador resultado electoral –cuyos efectos devastadores están siendo el pan de cada día en términos de violencias multiplicadas y brutales–, hay discursos sociales que circulan y funcionan con fuerza, tanto aglutinante como (des)articuladora, interpelando a los feminismos y a las disidencias en lo que vienen provocando, en lo que aparentemente no tuvieron en cuenta, en aquello que quedó entre los pendientes y abiertos sin resolver, o incluso, en lo que están obstaculizando. Existen, en ese marco, posiciones que, contrarias a entender los ataques a los feminismos como un backlash -esto es, como un reacción adversa por parte de los sectores conservadores que históricamente se le oponen, un contragolpe a sus logros de transformación- tienden a impugnar las agendas feministas y sexodisidentes por radicales, decontextualizadas y/o “piantavotos”. Otras lecturas señalan problemas en las prioridades: se reconoce la centralidad de la legalización del aborto, en algunos casos también del lenguaje inclusivo, pero también se señala que, en este contexto, hay otras prioridades sociales y económicas; en términos coloquiales, lo prioritario es “parar la olla, no hablar con la e”. En este contexto, donde se cuestionan abiertamente las banderas de igualdad y justicia social, ¿qué luchas y principios pensás que debemos priorizar para fortalecer la acción colectiva y crear un presente feminista?, ¿Qué tipo de libertad estamos construyendo? Y, en concreto, ¿dirías que en este contexto es necesario descentrar el protagonismo que ha adquirido la discusión sobre lenguaje inclusivo o, en realidad, privilegiar una demanda como ésa representa hoy una expresión ineludible de resistencia?Na atual conjuntura argentina e após os desoladores resultados eleitorais - cujos efeitos devastadores estão sendo o pão de cada dia em termos de violência multiplicada e brutal -, há discursos sociais que circulam e funcionam com força, tanto vinculando quanto (des)articulando, questionando os feminismos e as dissidências naquilo que vêm provocando, naquilo que aparentemente não levaram em conta, naquilo que está pendente e aberto e não resolvido, ou mesmo naquilo que estão impedindo. Nesse contexto, há posições que, ao contrário de entender os ataques aos feminismos como um backlash - ou seja, como uma reação adversa por parte dos setores conservadores que historicamente se opõem a eles, um contra-ataque às suas conquistas transformadoras -, tendem a contestar as pautas feministas e sexo-dissidentes como radicais, descontextualizadas e/ou “piantavotos”. Outras leituras apontam para problemas de prioridades: reconhece-se a centralidade da legalização do aborto e, em alguns casos, também da linguagem inclusiva, mas também se aponta que, nesse contexto, há outras prioridades sociais e econômicas; em termos coloquiais, a prioridade é “parar a panela, não falar com o e”. Nesse contexto, em que as bandeiras da igualdade e da justiça social são abertamente questionadas, quais lutas e princípios você acha que devemos priorizar para fortalecer a ação coletiva e criar um presente feminista? Que tipo de liberdade estamos construindo? E, especificamente, você diria que, nesse contexto, é necessário desentranhar o destaque que a discussão sobre a linguagem inclusiva adquiriu ou, na realidade, privilegiar essa demanda representa hoje uma expressão inevitável de resistência

Individuals with psychosis present a reduced lung diffusion capacity and early spirometry alterations: results from a cross-sectional study

Objective: Individuals with psychosis present a greater prevalence of chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). These chronic respiratory diseases are preceded by early lung function alterations; such as preserved ratio impaired spirometry (PRISm) or normal spirometry but low diffusion capacity of the lung for carbon monoxide (DLCO). However, there is no previous evidence on these lung function alterations in psychosis. The aim of this study is to evaluate the risk of having spirometry and DLCO alterations in subjects with psychosis compared with a control group. Methods: Cross-sectional study on a cohort of 170 individuals including 96 subjects with psychosis and 74 sex-age-and smoking habit matched healthy controls. All subjects were under 60 years-old, and without COPD or asthma. Respiratory function was evaluated through spirometry. Clinical characteristics and DLCO values were recorded. Results: Patients with psychosis showed lower spirometry results, both in terms of absolute and percentage of Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1). Absolute and percentage levels of diffusion were also lower in patients with psychosis. The percentage of individuals with DLCO<80% was higher among patients with psychosis (75% vs. 40%, p < 0.001). And the prevalence of PRISm was higher among patients with psychosis (10.4% vs. 1.4%, p < 0.001). Multivariate logistic regression analysis indicated that psychosis was an independent predictor of DLCO<80% (OR 5.67, CI95% 1.86?17.27). Conclusion: Patients with psychosis and females had early alterations in lung function. These results suggest that early screening for lung disease should be encouraged in psychosis.Funding: This work was supported by the Instituto de Investigación Sanitaria Valdecilla [grant numbers PRIMVAL17/06, INT/A20/04, and INT/A21/10]; and the Instituto de Salud Carlos III [grant number INT22/00029]. These sponsors did not have any involvement in any of the following: the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the article for publication. Acknowledgements: We are highly indebted to the participants and their families for their cooperation in this study. We also wish to thank all members of the PAFIP team for their clinical work

Quality of Chronic Anticoagulation Control in Patients with Intracranial Haemorrhage due to Vitamin K Antagonists

Introduction. Patients treated with vitamin K antagonists (VKA) are at increased risk of intracranial haemorrhage (ICH). The purpose of our study was to determine the quality of previous anticoagulation control in patients with VKA-associated ICH. Materials and Methods. We prospectively assessed every consecutive patient admitted to our stroke unit with VKA-associated ICH between 2013 and 2016. Demographic, clinical, and radiological variables, as well as consecutive international normalized ratios (INR) during 7 previous months, were extracted. Time in therapeutic range (TTR), time over range (TOR), time below range (TBR), and percentage of INR within range (PINRR) were calculated. Results and Discussion. The study population comprised 53 patients. Mean age was 79 years; 42% were women. Forty-eight patients had atrial fibrillation (AF) and 5 mechanical prosthetic valves. Therapeutic or infratherapeutic INR on arrival was detected in 64.4% of patients (95% CI 2.7 to 3.2). TTR was 67.8% (95% CI: 60.2 to 75.6 %) and PINRR was 75% (95% CI: 49.9-100). TOR was 17.2% (95% CI: 10.4 to 23.9% ) and TBR was 17% (95% CI: 10.6 to 23.9%). Conclusion. VKA-associated ICH happens usually in the context of good chronic anticoagulation control. Newer risk assessment methods are required

Externado de Pediatría - ME82 201402

El inicio del ciclo académico 12 marca un cambio importante en el proceso de formación del estudiante de la carrera al tratarse de un ciclo eminentemente práctico. Durante el externado, el alumno rotará por las principales áreas clínico quirúrgicas que le permitirán ir consolidando las competencias del perfil del egresado propuestas por la Escuela de Medicina. Cada alumno rotará 3 semanas por un servicio de Pediatría y 1 semana en Neonatología de los diferentes hospitales concertados

Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n 5 43), PSC (n 5 30), or HCC (n 5 29) patients and healthy individuals (control, n 5 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I-II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I-II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Conclusion: Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools

Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis and prognostication of cholangiocarcinoma

Background & Aims Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. Results High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients’ survival, respectively. Conclusions Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. Impact and implications The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.publishedVersio