Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract

Background: Mutations in hepatocyte nuclear factor 1B (HNF1B) have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis. Methods: This study reports the results of HNF1B screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting HNF1B mutations. Results: This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an HNF1B mutation but without diabetes or prediabetes (14.4 versus 3.3years, P<0.05). Furthermore, patients with HNF1B mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P<0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well. Conclusions: Renal anomalies found in patients with HNF1B mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify HNF1B mutations

Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract

CAKUT; HNF1B; MODYCAKUT; HNF1B; MODYCAKUT; HNF1B; MODYBACKGROUND: Mutations in hepatocyte nuclear factor 1B (HNF1B) have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis. METHODS: This study reports the results of HNF1B screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting HNF1B mutations. RESULTS: This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an HNF1B mutation but without diabetes or prediabetes (14.4 versus 3.3 years, P < 0.05). Furthermore, patients with HNF1B mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P < 0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well. CONCLUSIONS: Renal anomalies found in patients with HNF1B mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify HNF1B mutations

Morbidity and mortality in patients over 60 years with hip fracture in the San Vicente Foundation University Hospital of Medellin

ABSTRACT: Clinical, radiological, and functional outcomes as well as postoperative complications among adults aged 60 years or more with hip fractures have been extensively described in the medical literature; nonetheless, information is rather limited concerning this lesion in Antioquia, Colombia. Between March 2009 and June 2010, 106 elderly patients (mean age 79 years, 83 of them women) were surgically treated for hip fracture at a third-level hospital in Medellín, Colombia. Ninety two patients (86.6%) had two or more chronic diseases associated with the hip fracture. Early postoperative complications occurred in 40 patients (37.7%), most of them unrelated to the surgical intervention. Out of the 79 patients followed at six months, only 25 (31.6%) had recovered a gait pattern similar to the previous one. These results were similar to those published by other authors; they show that much of the morbidity and mortality of these patients is associated with their underlying medical conditions. The importance of this work lies in determining the characteristics of our elderly population with hip fractures as a basis to design management protocols in Colombian institutions that allow an improvement in the functional results of these patients.RESUMEN: En la literatura se han revisado ampliamente los resultados clínicos, radiológicos y funcionales y las complicaciones postoperatorias de los pacientes mayores de 60 años con fracturas de cadera; sin embargo, la información disponible acerca de este problema en el departamento de Antioquia es escasa. Entre marzo de 2009 y junio de 2010 se intervino quirúrgicamente a 106 pacientes ancianos (edad promedio; 79 años; 83 de ellos mujeres) con fracturas de cadera, en el Hospital Universitario San Vicente Fundación, de Medellín. Se halló que 92 (86,8%) de dichos pacientes presentaban dos o más enfermedades crónicas asociadas a la fractura. Se presentaron complicaciones postoperatorias tempranas en 40 pacientes (37,8%), la mayoría de ellas no relacionadas con la intervención. De los 79 pacientes seguidos a los seis meses, solamente 25 (31,6%) habían recuperado un patrón de marcha igual al previo. Los resultados se asemejan a los publicados por otros autores y evidencian que gran parte de la morbilidad y la mortalidad de estos pacientes está relacionada con las condiciones médicas subyacentes y con el estado general previo. La importancia de este trabajo radica en la determinación de las características de nuestra población anciana con fracturas de cadera como base para diseñar protocolos de manejo en instituciones colombianas que mejoren los resultados funcionales en este grupo de pacientes

Propulsión eléctrica a partir de celdas de hidrógeno: impacto en mitigación de huella de carbono

El aumento de la temperatura global, como consecuencia de las emisiones de gases de efecto invernadero, sigue siendo una de las principales preocupaciones que ha provocado un profundo interés en la implementación del hidrógeno como fuente de generación de energía eléctrica, por lo que en el mercado se han desarrollado y están disponibles tecnologías de celdas de combustible de hidrógeno para mitigar las emisiones de CO2 generadas por el uso de combustibles fósiles. En este artículo, se describe la metodología empleada para el diseño de un sistema de propulsión eléctrica con suministro de energía a partir de una celda de combustible de hidrógeno en un Buque de Apoyo Logístico y de Cabotaje Liviano - BALC-L. El diseño actual del buque cuenta con una propulsión convencional con dos motores diésel de 224 bkW cada uno y dos generadores diésel de 99 ekW cada uno, como base para la propuesta de un análisis de un sistema de propulsión eléctrica energizado a través de un sistema de celdas de combustible de hidrógeno. Como resultado, se propone un cambio en el perfil operativo del buque y una reducción de las emisiones de CO2 a lo largo de su ciclo de vida útil. La investigación descrita en este documento es un punto de partida para la implementación de estas tecnologías en la industria marítima y fluvial en Colombia

Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Background: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubulopathy characterized by excessive urinary wasting of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure in childhood or adolescence. FHHNC is caused by mutations in CLDN16 and CLDN19, which encode the tight-junction proteins claudin-16 and claudin-19, respectively. Most of these mutations are missense mutations and large deletions are rare. Methods: We examined the clinical and biochemical features of a Spanish boy with early onset of FHHNC symptoms. Exons and flanking intronic segments of CLDN16 and CLDN19 were analyzed by direct sequencing. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) to investigate large CLDN16 deletions. Results: Genetic analysis revealed two novel compound heterozygous mutations of CLDN16, comprising a missense mutation, c.277G>A; p.(Ala93Thr), in one allele, and a gross deletion that lacked exons 4 and 5,c.(840+25_?)del, in the other allele. The patient inherited these variants from his mother and father, respectively. Conclusions: Using direct sequencing and our QMPSF assay, we identified the genetic cause of FHHNC in our patient. This QMPSF assay should facilitate the genetic diagnosis of FHHNC. Our study provided additional data on the genotypic spectrum of the CLDN16 gene.This work was supported by Grant PI17/00153 co-financed by the Instituto de Salud Carlos III (Spain) and the European Regional Development Fund "Another way to build Europe". Editoria

Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome

Excreció; Genètica humana; MutacióExcreción; Genética humana; MutaciónExcretion; Human genetics; MutationIntroduction Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. Methods Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. Results Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype. Conclusion A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohortThis study was supported by two grants (PI09/90888 and PI11/01412) from the FIS of the Instituto de Salud Carlos III, Madrid, Spain, the Department of Health of the Basque Government (2014111064), and the Department of Education of the Basque Government (IT795-13)

Genetics of Type III Bartter Syndrome in Spain, Proposed Diagnostic Algorithm

9 p.The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.This study was supported by two grants (PI09/90888 and PI11/01412) from the FIS of the Instituto de Salud Carlos III, Madrid, Spain, and the Eitb Maratoia-Bioef (BIO08/ER/020) the Basque Foundation for Health Innovation and Research (BIOEF, from the Basque Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Efectos de la fatiga sobre la actividad muscular durante sucesivos test de sentadilla (30 seg).

Resumen:  Introducción: La fatiga se define como la incapacidad del Sistema neuromuscular para mantener un nivel determinado de potencia. La monitorización de la pérdida de Altura de salto ha sido utilizada como un indicador de fatiga muscular. La Electromiografía (EMG) es también una herramienta adecuada para determinar la fatiga ya que tiene una alta correlación con las unidades motoras activas (reclutamiento de fibras musculares). El objetivo del presente estudio es evaluar los efectos de la fatiga sobre la actividad muscular en las extremidades inferiores durante sucesivos test de media sentadilla (30 segundos). Métodos: 5 sujetos sanos entrenados participaron en el estudio. Realizaron 2 sesiones de test, un test de potencia máxima de media sentadilla y 4 series de un test de capacidad anaeróbica de media sentadilla (30 seg.). Resultados: Se observaron diferencias significativas (P=0.002) en la comparativa de los efectos inter-sujetos (Vasto lateral vs. Recto femoral). Observamos también diferencias significativas en la comparación por pares (P<0.001). Conclusiones: Observamos cómo la fatiga modifica la activación neuromuscular del vasto lateral y el recto femoral durante la ejecución de 4 test consecutivos de media sentadilla (30 seg.).Peer Reviewe

Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features and Somatostatin Analogs Resistance

Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs

Uso del tape dinámico en el posicionamiento y fuerza muscular del hombro

Objective: To determine the acute effects of dynamic tape on scapular positioning and isometric muscle strength of the shoulder in swimmers with rounded shoulders. Methods: Randomized controlled trial on 40 active swimmers, 20 assigned to an experimental group with application of dynamic tape with tension and 20 to the control group with application without tension. Scapular positioning and isometric muscle strength measurements of the shoulder were made before (ST), immediately after (TA) and on the third day (T3D) after tape application. Results: There were no statistically significant differences in most of variables of study, only for lateral scapular slide test 30º and isometric muscle strength of rhomboids on dominant upper limb (p &lt;0.05), no statistically significant difference between the experimental and control group were detected (p &lt;0.05). Conclusion: The application of dynamic tape does not produce statistically significant changes in scapular positioning and isometric muscle strength of the shoulder in swimmers.Objetivo: Determinar los efectos agudos del tape dinámico en la estática escapular y fuerza muscular isométrica del hombro en nadadores con hombros redondeados. Materiales y métodos: Ensayo aleatorio controlado en 40 nadadores activos, 20 asignados a un grupo experimental con aplicación de tape dinámico con tensión y 20 a grupo control con aplicación de tape sin tensión. Se realizaron mediciones de estática escapular y fuerza muscular isométrica del hombro antes (ST), inmediatamente después (TA) y al tercer día (T3D) después de la aplicación. Resultados: No se presentaron diferencias estadísticamente significativas en la mayoría de las variables de estudio, con excepción del deslizamiento lateral escapular 30º y fuerza muscular isométrica de romboides del miembro superior dominante (p &lt; 0,05). No se presentaron diferencias estadísticamente significativas entre el grupo&nbsp; experimental y control (p &lt; 0,05). Conclusión: La aplicación de tape dinámico no produce cambios estadísticamente significativos en el posicionamiento escapular y en la fuerza muscular isométrica del hombro en nadadores