494 research outputs found

    A genetic-epidemiologic study of Alzheimer’s disease

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    Alzheimer's disease (AD) is the most frequent cause of dementia and thus is a major public-health problem. Age and genetic predisposition to the disease are the most important risk factors. In 2001 more than 24 million people in the western world had dementia. This number is expected to double every 20 years up to 81 million in 2040 because of the anticipated increase in life expectancy. Genetically, AD is a heterogeneous disorder with both familial and sporadic forms. Chapter 1 is a general introduction on epidemiological and genetic factors of AD and also describes the different studies performed in this thesis. In chapter 2 the linkage studies are presented. Chapter 2.1 describes a whole genome screen on 112 AD patients and their first-degree relatives from the Genetics Research in Isolated Populations (GRIP) study. Of the 112 patients, 103 could be connected into an extremely large and complex pedigree. This pedigree cannot be analyzed with available linkage software. In this study, we developed an algorithm for splitting complex pedigrees to allow us to conduct linkage analysis. Then we determined genome wide significance thresholds for linkage analysis using the sub pedigrees obtained by our pedigree cutting algorithm and finally, we performed linkage analys

    ¿Cuánta carga asistencial suponen las dermatosispediátricas en la actividad ambulatoria en ladermatología espa˜nola? Resultados del muestreoaleatorio nacional DIADERM

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    Un total de 20.097 diagnósticos fueron efectuados en pacientes menores de18 a˜nos, lo que supone un 12% del total de los codificados en DIADERM. Las infecciones víri-cas, el acné y la dermatitis atópica fueron los diagnósticos más comunes (43,9% de todos losdiagnósticos). No se observaron diferencias estadísticamente significativas en la proporción dediagnósticos atendidos en las consultas monográficas frente a las generales, así como en losregistrados en el ámbito público frente al privado. Tampoco las hubo en los diagnósticos enfunción de la época de la encuesta (enero y mayo).Conclusiones: La atención a pacientes pediátricos por parte de dermatólogos en Espa˜na suponeuna proporción significativa de la actividad habitual. Estos datos nos permiten descubrir áreasde mejora en la comunicación y la formación de los pediatras de atención primaria, comola necesidad del refuerzo de actividades formativas dirigidas al mejor tratamiento de acné ylesiones pigmentadas (y manejo básico de la dermatoscopia) en este ámbito asistencial.SurveyAbstractBackground: Visits for skin conditions are very common in pediatric primary care, and many ofthe patients seen in outpatient dermatology clinics are children or adolescents. Little, however,has been published about the true prevalence of these visits or about their characteristics.Material and methods: Observational cross-sectional study of diagnoses made in outpatientdermatology clinics during 2 data-collection periods in the anonymous DIADERM National Ran-dom Survey of dermatologists across Spain. All entries with an International Classification ofDiseases, Tenth Revision code related to dermatology in the 2 periods (84 diagnoses) were collec-ted for patients younger than 18 years and classified into 14 categories to facilitate analysisand comparison.Results: In total, the search found 20 097 diagnoses made in patients younger than 18 years (12%of all coded diagnoses in the DIADERM database). Viral infections, acne, and atopic dermatitiswere the most common, accounting for 43.9% of all diagnoses. No significant differences wereobserved in the proportions of diagnoses in the respective caseloads of specialist vs. generaldermatology clinics or public vs. private clinics. Seasonal differences in diagnoses (January vs.May) were also nonsignificant.Conclusions: Pediatric care accounts for a significant proportion of the dermatologist’s caseloadin Spain. Our findings are useful for identifying opportunities for improving communication andtraining in pediatric primary care and for designing training focused on the optimal treatmentof acne and pigmented lesions (with instruction on basic dermoscopy use) in these settings.El estudio DIADERM fue promovido por la Fundación Piel Sanade la AEDV, que recibió ayuda económica de Novarti

    Lactococcus garvieae, an unusual pathogen in infective endocarditis: case report and review of the literature

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    Lactococcus garvieae is an unusual cause of infective endocarditis (IE). No current diagnostic and therapeutic guidelines are available to treat IE caused by these organisms. Based on a case report, we provide a review of the literature of IE caused by L. garvieae and highlight diagnostic and treatment challenges of these infections and implications for management. A 50-year-old Asian male with mitral prosthetic valve presented to the hospital with intracranial haemorrhage, which was successfully treated. Three weeks later, he complained of generalized malaise. Further work up revealed blood cultures positive for Gram-positive cocci identified as L. garvieae by MALDI-TOF. An echocardiogram confirmed the diagnosis of IE. Susceptibility testing showed resistance only to clindamycin. Vancomycin plus gentamicin were started as empirical therapy and, subsequently, the combination of ceftriaxone plus gentamicin was used after susceptibility studies were available. After two weeks of combination therapy, ceftriaxone was continued as monotherapy for six additional weeks with good outcome. Twenty-five cases of IE by Lactococcus garvieae have been reported in the literature. Compared to other Gram-positive cocci, L. garvieae affects more frequently patients with prosthetic valves. IE presents in a subacute manner and the case fatality rate can be as high as 16%, comparable to that of streptococcal IE (15.7%). Reliable methods for identification of L. garvieae include MALDI-TOF, 16S RNA PCR, API 32 strep kit and BD Automated Phoenix System. Recommended antimicrobials for L. garvieae IE are ampicillin, amoxicillin, ceftriaxone or vancomycin in monotherapy or in combination with gentamicin

    Defining the multiplicity and type of infection for the production of Zaire Ebola virus-like particles in the insect cell baculovirus expression system

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    Ebola virus hemorrhagic fever affects thousands of people worldwide with high mortality rates. The Ebola virus has a short incubation time between 2-21 days and death usually occurs within 4-10 days1. Ebola virus disease is characterized by a sudden onset of fever, weakness, headache, diarrhea and vomiting, internal and external bleeding2. In the Filovirus family, Zaire Ebola virus (ZEBOV) is the most aggressive and virulent species, its fatality rates have been reported to be up to 90%3. Even when important advances in vaccine development have occurred, the need of safe and effective vaccines persists4. An alternative is the production of virus-like particles, which are formed by the recombinant virus structural proteins that self-assemble into highly immunogenic structures5. The ZEBOV contains three main structural proteins: the glycoprotein (GP), the viral matrix protein 40 (VP40) and the nucleoprotein (NP). GP induces humoral and cellular responses by itself but when VP40 is co-expressed, the immune response increases in a mouse model6. NP determines the structure of the resulting VLP. To our knowledge, there is no information about the production conditions that result in coexpression and assembly of ZEBOV recombinant proteins. In this work, a multifactorial experimental design was used to evaluate 32 different conditions for the production of the ZEBOV structural proteins utilizing the insect cell-baculovirus expression system technology (BEST). Multiplicity (MOI = 0.1 or 5 ufp/cell) and consecutive times of infection (0 or 6 hours after the first infection) were the principal factors, and the production of each recombinant protein and assembly of VLP were the evaluated responses. We observed that multiplicity of infection had an impact over expression of the recombinant proteins, higher multiplicities increased yield and VLP assembly. In contrast, later times of infection reduced the production of each protein. The initial presence of VP40 resulted in a higher concentration of NP. The conditions where the simultaneous expression of the three structural proteins and where VLP were detected were identified. The highest MOIs for bacVP40 and bacGP were needed. bacNP should be added during the initial infection with an MOI of 0.1, or at 6 hpi at MOI of 5. The obtained ZEBOV-VLPs were similar to native virus. The obtained VLP are a candidate vaccine under evaluation. Research performed thanks to the financial support of PAPIIT-UNAM IT200418 and CONACyT 247101. References: 1. Shuaib F, Gunala R, Musa EO, Mahoney FJ, et al., 2014. Ebola virus disease outbreak-Nigeria, July–September 2014. Morb. Mortal. Wkly. Rep. 63 (39),867–872. 2. Qiu X, Audet J, Wong G. Fernando L, et al., 2013. Sustained protection virus infection following treatment of infected nonhuman primates with ZMAb. Sci. Rep. 3, 3. Richardson JS, Wong G, Pillet S, Schindle S, et al., 2011. Evaluation of different strategies for post-exposure treatment of Ebola virus infection in rodents. J.Bioterror. Biodef. S1, 007 4. Ige, Ohimain E, 2016. Recent advances in the development of vaccines for Ebola virus disease. Virus Research 211: 174-185. 5. Palomares LA, Ramírez OT, 2009. Challenges for the production of virus-like particles in insect cells: The case of rotavirus-like particles. Biochem. Eng. J. 45: 158-167. 6. Wahl-Jensen, V. et al (2005). Role of Ebola virus secreted glycoproteins and virus-like particles in activation of human macrophages. Journal of Virology, 79(4), 2413-241

    The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

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    Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport

    Two new pulsating low-mass pre-white dwarfs or SX Phoenicis stars?

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    Context. The discovery of pulsations in low-mass stars opens an opportunity to probe their interiors and determine their evolution by employing the tools of asteroseismology. Aims. We aim to analyse high-speed photometry of SDSS J145847.02+070754.46 and SDSS J173001.94+070600.25 and discover brightness variabilities. In order to locate these stars in the Teff - log g diagram, we fit optical spectra (SDSS) with synthetic non-magnetic spectra derived from model atmospheres. Methods. To carry out this study, we used the photometric data we obtained for these stars with the 2.15 m telescope at CASLEO, Argentina. We analysed their light curves and applied the discrete Fourier transform (FT) to determine the pulsation frequencies. Finally, we compare both stars in the Teff - log g diagram, with two known pre-white dwarfs and seven pulsating pre-ELM white dwarf stars, δ Scuti, and SX Phe stars Results. We report the discovery of pulsations in SDSS J145847.02+070754.46 and SDSS J173001.94+070600.25. We determine their effective temperature and surface gravity to be Teff = 7972 ± 200 K, log g = 4.25 ± 0.5 and Teff = 7925 ± 200 K, log g = 4.25 ± 0.5, respectively. With these parameters, these new pulsating low-mass stars can be identified with either ELM white dwarfs (with ∼0.17 MO) or more massive SX Phe stars. We identified pulsation periods of 3278.7 and 1633.9 s for SDSS J145847.02+070754.46 and a pulsation period of 3367.1 s for SDSS J173001.94+070600.25. These two new objects, together with those of Maxted et al. (2013, 2014), indicate the possible existence of a new instability domain towards the late stages of evolution of low-mass white dwarf stars, although their identification with SX Phe stars cannot be discarded.Facultad de Ciencias Astronómicas y GeofísicasInstituto Argentino de Radioastronomí

    Mitogenome and Nuclear-encoded Fungicide-target Genes of Thecaphora frezii - Causal Agent of Peanut Smut

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    Background: Thecaphora frezii Carranza and Lindquist causes smut disease in peanut (Arachis hypogaea L.) resulting in up to 35% yield losses. Fungicides have shown ineffective in controlling the disease; whereas research on the molecular basis of that fungicide resistance has been hindered because of the lack of genetic information about T. frezii. The goal of this work was to provide molecular information about fungicide-target loci in T. frezii, including its mitochondrial genome (mitogenome) and critical nuclear-encoded genes. Results: Here we report the complete annotated mitogenome of T. frezii, a 123,773 bp molecule containing the standard 14 genes that form part of mitochondrial complexes I, III, IV and V, 22 transfer RNAs, small and large subunits of ribosomal RNA, DNA polymerase, ribonuclease P, GII-reverse transcriptase/maturase, nine hypothetical open-reading frames and homing endonucleases (LAGLIDADG, GIY-YIG, HEG). In addition, we report the full-length cDNA sequence of T. frezii cytochrome b (cob) and cytochrome oxidase 1 (cox1) genes; as well as partial sequences of T. frezii succinate dehydrogenase (sdhb), ergosterol biosynthesis (Erg4), cytochrome P450 (cyp51), and beta tubulin (β-tubulin) genes, which are respective targets of strobilurins, quinone oxidation inhibitors, triazoles and beta-tubulin inhibitor fungicides commonly used in the peanut crop. Translation of cob and sdhb genes in this particular T. frezii isolate suggests potential resistance to strobilurin and carboxamide fungicides. Conclusion: The mitogenome and nuclear-encoded gene sequences presented here provide the molecular tools to research T. frezii fungicide-target loci
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