Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.

Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc

Decorin transfection induces proteomic and phenotypic modulation in breast cancer cells 8701-BC

Decorin is a prototype member of the small leucine-rich proteoglycan family widely distributed in the extracellular matrices of many connective tissues, where it has been shown to play multiple important roles in the matrix assembly process, as well as in some cellular activities. A major interest for decorin function concerns its role in tumorigenesis, as growth-inhibitor of different neoplastic cells, and potential antimetastatic agent. The aim of our research was to investigate wide-ranged effects of transgenic decorin on breast cancer cells. To this purpose we utilized the well-characterized 8701-BC cell line, isolated from a ductal infiltrating carcinoma of the breast, and two derived decorin-transfected clones, respectively, synthesizing full decorin proteoglycan or its protein core. The responses to the ectopic decorin production were examined by studying morphological changes, cell proliferation rates, and proteome modulation. The results revealed new important antioncogenic potentialities, likely exerted by decorin through a variety of distinct biochemical pathways. Major effects included the downregulation of several potential breast cancer biomarkers, the reduction of membrane ruffling, and the increase of cell-cell adhesiveness. These results disclose original aspects related to the reversion of malignant traits of a prototype of breast cancer cells induced by decorin. They also raise additional interest for the postulated clinical application of decori

A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype

Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias including, in order of decreasing severity, achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia. The gene encodes a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate, which is needed for proteoglycan sulfation. To provide new insights in the pathogenetic mechanisms leading to skeletal and connective tissue dysplasia and to obtain an in vivo model for therapeutic approaches to DTD, we generated a Dtdst knock-in mouse with a partial loss of function of the sulfate transporter. In addition, the intronic neomycine cassette in the mutant allele contributed to the hypomorphic phenotype by inducing abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth. The similarity with human DTD makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorder

El laberinto político judicial de la corrupción Una mirada sobre las causas de corrupción de los juzgados de Comodoro Py

En las últimas décadas la opinión pública argentina ha demostrado una preocupación central por la corrupción política. La percepción ciudadana sobre el involucramiento de funcionarios públicos en casos de corrupción y la baja capacidad del Estado para lidiar con este problema han sido inquietudes sumamente frecuentes en múltiples encuestas de opinión. Aun así, el accionar de los jueces sobre las causas de corrupción ha sido insuficientemente investigado por la Ciencia Política. En esta investigación se analiza el manejo de las causas de corrupción de funcionarios públicos en la Justicia Nacional en lo Criminal y Correccional Federal y el impacto de la influencia política en el comportamiento de los magistrados. Se identifica mediante un análisis estadístico cuáles son posibles factores que explican la extensa y variable duración, así como las resoluciones que los expedientes de esta jurisdicción obtienen. A través de un análisis empírico de 150 causas de corrupción que van desde 1992 hasta 2019, donde 113 funcionarios que ocuparon más de 70 cargos diferentes se encuentran o encontraron comprometidos, se concluye que el tiempo en que el proceso penal se desarrolla, así como las sentencias con las que finalizan estas causas, pueden variar según la capacidad de influencia de los funcionarios sobre los jueces. Se presenta evidencia empírica que demuestra que las causas de corrupción de los imputados que estuvieron en funciones al momento de cierre del expediente, así como los funcionarios que han ocupado un cargo de rango alto en la Administración pública, no sólo han durado menos tiempo que las de los ex funcionarios y de los cargos de menor jerarquía, sino que también han obtenido sentencias más favorables

Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management.

Purpose Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar. Methods Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias. Results Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty. Conclusion Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2018.30

Impacto de la forma de administración de insulina en la calidad de vida de niños y adolescentes con Diabetes tipo 1: revisión sistemática

Introducción: La Diabetes Mellitus es una de las enfermedades más prevalentes mundialmente. Concretamente el manejo de la Diabetes tipo I (DM1) en niños y adolescentes ha supuesto un reto para el desarrollo de nuevas tecnologías que permitan manejar la enfermedad y, por ende, mejorar la calidad de vida de los pacientes. Desde los principios del tratamiento con inyecciones de insulina hasta los sistemas de infusión continua de insulina más novedosos se ha evolucionado de forma notable, con la meta de mejorar la calidad de vida y los parámetros de control glucémico en dichos pacientes. Objetivos: El objetivo principal de esta revisión es determinar el impacto de los nuevos sistemas de infusión de insulina en la calidad de vida de niños y adolescentes con diabetes tipo 1. Metodología: Se realizó una búsqueda bibliográfica sobre la influencia de los nuevos sistemas de infusión continua de insulina en la calidad de vida en niños y adolescentes con DM1 en las bases de datos: MEDLINE (a través de PubMed), SCOPUS, CINAHL, SciELO (Web of Science) y COCHRANE desde enero del 2024 hasta marzo del 2024. Resultados: 18 artículos fueron seleccionados del total de la búsqueda. Se clasificaron según el tipo de estudio encontrado, autor, año, muestra y conclusiones. Además, se expusieron los datos obtenidos según el impacto de los sistemas de Infusión Continua de insulina en los parámetros glucémicos y en la calidad de vida de los pacientes pediátricos en cada estudio. Discusión: Los resultados se clasificaron según los objetivos de los estudios y las conclusiones obtenidas en cuanto al control glucémico, HbA1 y el TIR en niños con DM1 en tratamiento con dispositivos de infusión continua de insulina y por otro lado, en cuanto al impacto directo en la calidad de vida en dichos pacientes pediátricos. Conclusión: La revisión concluyó con la efectividad de los SICI, así como de la MCG y otras tecnologías en la mejora de la calidad de vida en la mayoría de los niños ya adolescentes con DM1, así como el impacto beneficioso en el control de los diferentes parámetros glucémicos

¿Utopía o realidad? Explorando la inserción de beneficiarios de programas de empleo en el mercado laboral

La disminución de la pobreza representa una deuda irresuelta de larga data para la Argentina actual. Durante las últimas dos décadas, una de las principales acciones estatales para combatir este problema ha consistido en robustecer el sistema de protección social mediante, por ejemplo, programas de empleo que buscan aliviar la pobreza y apoyar a personas desocupadas en su inserción en el mercado de trabajo. El objetivo de esta investigación es analizar la inserción de beneficiarios de planes de empleo en el mercado laboral, evaluando el efecto de algunas características personales de los participantes sobre la probabilidad de realizar una transición desde los programas hacia el empleo. Los resultados indican que factores tales como el ser hombre, no tener hijos a cargo, tener más años de educación formal, y vivir en el Gran Buenos Aires incrementan significativamente las chances que tienen los beneficiarios de salir del programa y conseguir un empleo

Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although antiresorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials show improved vertebral parameters but equivocal effects on long‐bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl‐Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl‐Ab therapy was investigated in mice heterozygous for a typical OI‐causing Gly→Cys substitution in col1a1 . Two weeks of Scl‐Ab successfully stimulated osteoblast bone formation in a knock‐in model for moderately severe OI (Brtl/+) and in WT mice, leading to improved bone mass and reduced long‐bone fragility. Image‐guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl‐Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short‐term Scl‐Ab was successfully anabolic in osteoblasts harboring a typical OI‐causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI. © 2013 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95242/1/1717_ftp.pd

Bone robusticity in two distinct skeletal dysplasias diverges from established patterns

Achondroplasia (ACH) is a heritable disorder of endochondral bone formation characterized by disproportionate short stature. Osteogenesis imperfecta (OI) is a heritable bone and connective tissue disorder characterized by bone fragility. To investigate bone morphology of these groups, we retrospectively reviewed 169 de‐identified bone age films from 20 individuals with ACH, 39 individuals with OI and 37 age‐ and sex‐matched controls (matched to historical measurements from the Bolton–Brush Collection). We calculated robustness (Tt.Ar/Le) and relative cortical area (Ct.Ar/Tt.Ar) from measurements of the second metacarpal, which reflect overall bone health. Relative cortical area (RCA) is a significant predictor of fracture risk and correlates with robustness at other sites. Individuals with OI had RCH values above and robustness values below that of the control population. Bisphosphonate treatment did not significantly impact either robustness or RCA. In contrast to that reported in the unaffected population, there was no sexual dimorphism found in OI robustness or relative cortical area. We suggest that the underlying collagen abnormalities in OI override sex‐specific effects. Individuals with ACH had robustness values above and RCA values below that of the control population. Sexual dimorphism was found in ACH robustness and RCH values. Clinical significance: Identifies morphologic trends in two distinct skeletal dysplasia populations (OI and ACH) to better understand development of bone robusticity and slenderness in humans. Understanding these patterns of bone morphology is important to predict how individuals will respond to treatment and to increase treatment effect. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2392–2396, 2017.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139130/1/jor23543_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139130/2/jor23543.pd

XX males SRY negative: a confirmed cause of infertility

BACKGROUND: SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility. METHODS AND RESULTS: We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative. CONCLUSIONS: Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background