Molecular genetics of rare hereditary diseases via genome-wide and integrated approaches

ABSTRACTThe Online Mendelian Inheritance in Man database (OMIM) reports about 3000 Mendelian diseases of known causal gene and about 2000 that remain to be mapped. These cases are often difficult to solve because of the rareness of the disease, the structure of the family (too big or too small) or the heterogeneity of the phenotype. The goal of this thesis is to explore the current genetic tools, before the advent of ultra high throughput sequencing, and integrate them in the attempt to map the genes behind the four studied cases. In this framework we have studied a small family with a recessive disease, a modifier gene for the penetrance of a dominant mutation, a large extended family with a cardiac phenotype and clinical and/or allelic heterogeneity and we have molecularly analyzed a balanced chromosomal translocation.RESUMELa base de données des maladies à transmission mendélienne, Online Mendelian Inheritance in Man (OMIM), contient environ 3000 affections à caractère mendélien pour lesquelles le gène responsable est connu et environ 2000 qui restent à élucider.Les cas restant à résoudre sont souvent difficiles soit par le caractère intrinsèquement rare de ces maladies soit à cause de difficultés structurelles (famille trop petite ou trop étendue) ou hétérogénéité du phénotype ou génétique. Cette thèse s'inscrit avant l'arrivée des nouveaux outils de séquençage à haut débit. Son but est d'explorer les outils génétiques actuels, et de les intégrer pour trouver les gènes impliqués dans quatre cas représentant chacun une situation génétique différente : nous avons étudié une famille de quatre individus avec une transmission récessive, recherché un gène modificateur de la pénétrance de mutations dominantes, étudié une famille étendue présentant un phénotype cardiaque cliniquement et/ou allèliquement hétérogène et nous avons fait l'analyse moléculaire d'une translocation chromosomique balancée.

Evaluación y Promoción de Competencias Parentales en el Sistema Sanitario Público Andaluz. Proceso Asistencial Integrado Embarazo, Parto y Puerperio.

Con la colaboración del Departamento de Psicología Evolutiva y de la Educación de la Universidad de Sevilla

Comodidad materna y reducción del dolor en mujeres con posición fetal occipitoposterior durante el parto con el uso de las posturas de decúbito lateral y manos-rodillas: Ensayo clínico aleatorizado

Objective: To assess the maternal comfort and reduction of pain associated with contractions during labor with “hands-knees” (HK) maternal posture compared with “lateral maternal postures toward the fetal back” in pregnant women with occipitoposterior (OP) fetal position. Methods: In the multicenter trial by randomization, 70 women with OP fetal position during labor took the lateral posture and 65 women the HK posture for at least 30 minutes. We analyzed maternal comfort, perceived pain, influence of epidural analgesia and use of fit-ball on posture HK. Results: Back pain and abdominal pain reduction was higher with HK posture. With lateral posture 78.6% of women expressed comfort versus 73.8% of women with HK posture. Regarding the lateral posture, the comfort with HK posture reduces in multiparous women, with an odds ratio (OR) of 0.29, for a confidence interval (CI) 95% 0.12 to 0.76, and epidural analgesia (OR= 0.39; CI 95%: 0.15-1.03), comfort with K posture is higher with reduction of pain (OR= 4.13, 95% CI: 1.34- 12.72) and abdominal pain compared with back pain (OR= 4.05, 95% CI: 1.36-11.85). Conclusions: Women consider comfortable lateral and HK maternal postures during labor. The lateral posture is most comfortable for multiparous and epidural analgesia. The reduction of pain during labor is higher with HK posture, recommending this posture in primiparous women without epidural analgesia.

Stability of cascade networks via fluid models

Vegeu el resum a l'inici del document de l'arxiu adjunt

Embarazo, parto y puerperio : proceso asistencial integrado. 3ª ed

Publicado en la página web de la Consejería de Igualdad, Salud y Políticas Sociales: www.juntadeandalucia.es/salud (Consejería de Igualdad, Salud y Políticas Sociales / Profesionales / Nuestro Compromiso por la Calidad / Procesos Asistenciales Integrados). Revisión externa: Servicio Andaluz de Salud (SAS); Plan Andaluz de Diabetes; Sociedades Científicas: ASANEC, ASENHOA, SAGO, SAMFYC, SEMG-Andalucía, SEMERGEM-Andalucía

CD36 deficiency leads to choroidal involution via COX2 down-regulation in rodents.

BACKGROUND: In the Western world, a major cause of blindness is age-related macular degeneration (AMD). Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the "wet" form of AMD. In contrast, very little is known about the mechanisms of the predominant, "dry" form of AMD, which is characterized by retinal atrophy and choroidal involution. The aim of this study is to elucidate the possible implication of the scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features of the dry form of AMD. METHODS AND FINDINGS: We here show that deficiency of CD36, which participates in outer segment (OS) phagocytosis by the retinal pigment epithelium (RPE) in vitro, leads to significant progressive age-related photoreceptor degeneration evaluated histologically at different ages in two rodent models of CD36 invalidation in vivo (Spontaneous hypertensive rats (SHR) and CD36-/- mice). Furthermore, these animals developed significant age related choroidal involution reflected in a 100%-300% increase in the avascular area of the choriocapillaries measured on vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats fail to induce COX2 and subsequent vascular endothelial growth factor (VEGF) expression upon OS or antibody stimulation in vitro. CD36-/- mice express reduced levels of COX2 and VEGF in vivo, and COX2-/- mice develop progressive choroidal degeneration similar to what is seen in CD36 deficiency. CONCLUSIONS: CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These results show a novel molecular mechanism of choroidal degeneration, a key feature of dry AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed, with important implications for the development of new therapies.

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation.

Host-cell factor 1 (HCF-1) is an unusual transcriptional regulator that undergoes a process of proteolytic maturation to generate N- (HCF-1(N)) and C- (HCF-1(C)) terminal subunits noncovalently associated via self-association sequence elements. Here, we present the crystal structure of the self-association sequence 1 (SAS1) including the adjacent C-terminal HCF-1 nuclear localization signal (NLS). SAS1 elements from each of the HCF-1(N) and HCF-1(C) subunits form an interdigitated fibronectin type 3 (Fn3) tandem repeat structure. We show that the C-terminal NLS recruited by the interdigitated SAS1 structure is required for effective formation of a transcriptional regulatory complex: the herpes simplex virus VP16-induced complex. Thus, HCF-1(N)-HCF-1(C) association via an integrated Fn3 structure permits an NLS to facilitate formation of a transcriptional regulatory complex.

Controlador de protocol Zigbee amb Servei de monitarització de dades (Dashboar) via web

Aquest projecte es desenvolupa a l'empresa DsetSolutions S.L “spin-off” de la Universitat de Gironanascuda l’any 2004 a iniciativa del grup de visió per Computador i Robòtica (VICOROB) de laUniversitat de Girona.Els objectius d'aquest projecte consisteixen en el disseny i desenvolupament d'un sistema demonitorització i anàlisi de dades de consum d'una instal•lació de monitorització (consum energètic,temperatura , etc.). Aquesta informació està recopilada i mesurada per dispositius que disposin delprotocol de comunicacions de baix consum i sense fils Zigbee, entre d'altres.Aquest projecte s'implementarà sobre el dispositiu tipus “gateway”, en concret el “ConnectPortX2Smart Energy” de l'empresa Digi.Com a punt i final, les dades s'envien a una passarel•la intermediària, que mitjançant “web service”viatgen a un servidor de DsetSolutions S.L, on es tracten i es mostren mitjançant un aplicatiu webd'una manera agradable al client. En aquest aplicatiu web hi ha una sèrie de gadgets que és on esdesenvolupa la segona part del projecte, una nova opció de visualització d'aquests.Un dels punts principals de la creació del projecte per part de l'empresa DsetSolutions S.L és lamillora econòmica d'una solució pròpia de l'empresa ja existent

Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine.

BACKGROUND: A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons, which are essential for the coordination of neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. However, it is unknown whether the deleterious effect of oxidative stress is particularly prevalent during specific developmental time windows. METHODS: We used mice with impaired synthesis of glutathione (Gclm knockout [KO] mice) to investigate the effect of redox dysregulation and additional insults applied at various periods of postnatal development on maturation and long-term integrity of parvalbumin interneurons in the anterior cingulate cortex. RESULTS: A redox dysregulation, as in Gclm KO mice, renders parvalbumin interneurons but not calbindin or calretinin interneurons vulnerable and prone to exhibit oxidative stress. A glutathione deficit delays maturation of parvalbumin interneurons, including their perineuronal net. Moreover, an additional oxidative challenge in preweaning or pubertal but not in young adult Gclm KO mice reduces the number of parvalbumin-immunoreactive interneurons. This effect persists into adulthood and can be prevented with the antioxidant N-acetylcysteine. CONCLUSIONS: In Gclm KO mice, early-life insults inducing oxidative stress are detrimental to immature parvalbumin interneurons and have long-term consequences. In analogy, individuals carrying genetic risks to redox dysregulation would be potentially vulnerable to early-life environmental insults, during the maturation of parvalbumin interneurons. Our data support the need to develop novel therapeutic approaches based on antioxidant and redox regulator compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects.

Transtornos mentais na gravidez, parto e puerpério, na região de Ribeirão Preto-SP-Brasil

O presente trabalho tem como objetivo levantar o número de pacientes atendidas no Setor de Urgências Psiquiátricas (SUP) e Clínica Obstétrica do Hospital das Clínicas (COHC) da FMRP-USP, com o diagnóstico 648.4 (Transtornos Mentais na Gravidez, Parto e Puerpério), conforme CID-9, no período de 1988 a 1993. Solicitou-se um registro ao hospital, contendo informações sobre os atendimentos destes serviços. A população constitui-se de mulheres entre 15 e 29 anos cujos transtornos apresentados incluíram distúrbios psicóticos, quadros depressivos com ou sem tentativas de suicídio e transtornos mentais não especificados. Alguns desses distúrbios apresentaram-se em comorbidade com outros diagnósticos. Os resultados evidenciaram a necessidade do enfermeiro estar atento às manifestações sugestivas dos mesmos, bem como ajudar na busca de meios que facilitem a identificação de mulheres com alto risco.

Missed opportunities among HIV-positive women to control viral replication during pregnancy and to have a vaginal delivery.

INTRODUCTION: Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe. METHODS: In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre- or postpublication of national guidelines recommending vaginal delivery. RESULTS: Overall, 2663 women with 3013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2354) before to 7% (42/599) after the change in guidelines (P < 0.001). CONCLUSION: There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.

Administração de medicamentos injetáveis por via intramuscular: conhecimento dos ocupacionais de farmácias

Complicações advindas da aplicação incorreta das injeções intramusculares podem acarretar sérios prejuízos orgânicos, favorecer o aparecimento de infecções e aumentar a permanência do paciente na instituição ou prejudicar as funções no trabalho. Estudo anterior detectou vários casos de pacientes com complicações locais após aplicação intramuscular de diclofenaco sódico em farmácias e concluiu que a falta de conhecimento da técnica de administração desse medicamento pode ter sido uma das causas das complicações. Diante disso o estudo atual teve o objetivo de identificar e avaliar o nível de conhecimentos de ocupacionais que administram medicamentos injetáveis intramusculares à população, em farmácias de Ribeirão Preto - SP. O estudo se constituiu num levantamento, a partir de um questionário contendo 20 questões abertas e fechadas, aplicado a uma população constituída por ocupacionais atuando em farmácias, selecionadas através do método da amostragem simples casual estratificada -partilha proporcional, resultando num total de 41 sujeitos. Concluímos que a população vem recebendo medicamento s injetáveis de ocupacionais com déficit de informações a respeito da técnica de aplicação de injetáveis. Os sujeitos referiram não receber treinamento adequado para exercer esse procedimento, terminando por aprendê-lo com outro funcionário ou observando alguém que o realize. Disto resulta lacunas de conhecimento em uma amostra de ocupacionais que podem, realmente, levar ao aparecimento de complicações pós injeções intramusculares na população que utiliza os serviços desses estabelecimentos.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1β (IL-1β), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1β, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1β was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Vivenciando o parto humanizado: um estudo fenomenológico sob a ótica de adolescentes

Este estudo teve por objetivo compreender o que significa para as adolescentes passarem pelo parto dito humanizado. Paraisso, utilizei a fenomenologia como trajetória de pesquisa, para chegar a essência do fenômeno. Participaram do estudooito adolescentes que foram atendidas no Hospital Sofia Feldman, instituição filantrópica, sem fins lucrativos - BeloHorizonte/MG. Para a coleta de dados utilizei observação de campo e entrevista aberta. O estudo possibilitou apreender trêscategorias de análise: Pré-parto/Parto: o corpo sendo controlado; Pré-parto/Parto: misto de dor e de prazer; PartoHumanizado: a assistência esperada e desejada.