Clinical manifestations of intermediate allele carriers in Huntington disease

OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. METHODS: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington\u27s Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. RESULTS: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p = 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p = 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p = 0.002). CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. CLINICALTRIALSGOV IDENTIFIER: NCT01590589

Bordetella hinzii Endocarditis, A Clinical Case Not Previously Described

Objective: To review infections by Bordetella hinzii. Materials and methods: A 79-year-old male patient, with a chronic aortic valve biological prosthesis, presented to hospital because of fever. First examinations were normal. However, 72 hours later B. hinzii was isolated in blood cultures, and so meropenem was prescribed. Nevertheless, fever and B. hinzii bacteraemia were still present 7 days later. Results: The transoesophageal echocardiogram revealed an enlarged image suggesting a periprosthetic abscess, confirmed with a PET-CT scan. The patient was sent for cardiac surgery, and biopsy samples confirmed the presence of B. hinzii. Conclusion: There are very few cases of B. hinzii infection in humans. Ours is the first described case of B. hinzii endocarditis

Recomendaciones sobre la valoración integral y multidimensional del anciano hospitalizado. Posicionamiento de la Sociedad Española de Medicina Interna

Este documento de posicionamiento describe los aspectos más relevantes e imprescindibles sobre la valoración integral y multidimensional del anciano hospitalizado. El cambio del patrón demográfico y del perfil epidemiológico de las enfermedades requiere una adaptación de los Servicios de Medicina Interna, que tengan en cuenta las vulnerabilidades de las personas ancianas en este contexto. Una valoración integral y multidimensional y la elaboración multidisciplinar de un plan de atención durante el ingreso pueden tener un impacto para evitar mortalidad, discapacidad e institucionalización al alta. Es necesario que todos los internistas adquiramos competencias para mejorar la experiencia de la hospitalización en la persona mayor y obtengamos mejores resultados en salud en nuestros pacientes. Este documento lo ha desarrollado el Grupo Focal de Envejecimiento y el Grupo de Trabajo de Pluripatología y Edad Avanzada, y está avalado por la Sociedad Española de Medicina Interna. This position paper describes the most relevant and essential aspects of a comprehensive, multidimensional assessment of hospitalized elderly people. The change in demographic patterns and the epidemiological profiles of diseases makes it necessary for internal medicine departments to adapt in order to take into account the vulnerabilities of the elderly in this context. A comprehensive, multidimensional assessment and the multidisciplinary development of a care plan during hospitalization can have an impact in terms of preventing mortality, disability, and institutionalization at discharge. It is necessary for all internists to acquire skills to improve the hospitalization experience in the elderly and obtain better health outcomes in our patients. This document has been developed by the Focus Group on Aging and the Polypathological and Advanced Age Working Group and endorsed by the Spanish Society of Internal Medicine

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Prognostic significance of Ultrasound Assessment of the Inferior Vena Cava in Acute Heart Failure Patients

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 19/04/2017La insuficiencia cardiaca (IC) es una enfermedad muy prevalente, responsable de un elevado número de ingresos hospitalarios y una elevada mortalidad. Es importante conocer que pacientes tienen peor pronóstico a corto plazo, para plantear una optimización del tratamiento y una adecuada planificación de los cuidados. La congestión sistémica y la hipertensión pulmonar son predictores de mal pronóstico en la insuficiencia cardiaca aguda (ICA). La determinación del diámetro de la vena cava inferior (VCI) y su grado de colapsabilidad, permite estimar la presión venosa central y la presión de la aurícula derecha. Por este motivo el diámetro de la VCI y su colapsabilidad podrían ser predictores de reingreso y mortalidad en los pacientes con ICA. Métodos. Se realizó un estudio observacional prospectivo desde enero de 2011 hasta enero de 2012, en el que se incluyeron 95 pacientes consecutivos, que ingresaron con el diagnóstico de ICA en el servicio de Medicina Interna del Hospital Universitario Infanta Cristina (Parla, Madrid. Fueron excluidos los enfermos que precisaban ingreso en UCI, que estaban en programa de hemodiálisis o que al ingreso estaban en fase agónica. Para el diagnóstico de IC se utilizaron los criterios diagnósticos de IC de la Sociedad Europea de Cardiología del año 2008...Heart failure is a major source of hospitalizations and high mortality rate. It is important to know what patients have the worst short-term outcome in order to optimize treatment and an adequate planning of medical care. Systemic congestion and pulmonary hypertension are poor outcomes in acute heart failure (AHF). The inferior vena cava (IVC) diameter and collapsibility is an accurate predictor of central venous pressure and right atrial pressure. Therefore, the IVC diameter and its collapsibility could be predictors of hospital readmission and mortality in AHF patients. Methods. A prospective observational study, of 95 consecutive patients admitted to the Service of Internal Medicine of the “Hospital Universitario Infanta Cristina (Parla, Madrid)” with AHF between January 2011 and January 2012, was performed. Patients were excluded if: they were admitted to an intensive care unit, required renal replacement therapy or were in agony. Diagnosis of AHF was performed according the guidelines of the 2008 European Society of Cardiology...Depto. de MedicinaFac. de MedicinaTRUEunpu

Valoración de la fragilidad en la persona con Diabetes Mellitus Tipo 2: análisis de expertos.

Introducción: Las personas con diabetes mellitus tipo 2 (DM2) tienen una prevalencia de fragilidad que se estima entre 3 y 5 veces mayor que aquellos que no la padecen, sin embargo, no existe un consenso claro sobre el diagnóstico y manejo clínico durante el itinerario de la persona frágil con DM2. Objetivos: El objetivo principal de este estudio es identificar las limitaciones y necesidades actuales en el uso del concepto de fragilidad en personas con DM2 (PCDM2), así como definir y evaluar, según su importancia y novedad, las dimensiones que podrían incluirse en su valoración clínica de rutina. Métodos: Se llevó a cabo un proceso basado en la técnica de grupo nominal con la participación de un equipo multidisciplinario de 8 profesionales de la salud que trabajan en diferentes hospitales de Espana. Resultados: Se identificaron y clasificaron según su importancia un total de 8 limitaciones en la evaluación de la fragilidad en PCDM2, así como 10 necesidades no satisfechas relacionadas con el diagnóstico y seguimiento de la enfermedad. Además, se identificaron 7 dimensiones que consideramos que deben incluirse en la definición de la persona frágil con DM2, ordenadas por importancia y novedad