Association between β2-adrenoceptor (ADRB2) haplotypes and insulin resistance in PCOS

OBJECTIVE: The aim of this study was to explore β2-adrenoceptor (ADRB2) haplotype associations with phenotypes and quantitative traits related to insulin resistance (IR) and the metabolic syndrome (MS) in a polycystic ovary syndrome (PCOS) population. A secondary purpose was to assess the association between ADRB2 haplotype and PCOS. DESIGN: Genetic polymorphism analysis. Cross-sectional case-control association study. SETTING: Medical University Hospital and research laboratory. PATIENTS: One hundred and sixty-five unrelated women with PCOS and 116 unrelated women without PCOS (control sample). MEASUREMENTS: Clinical and biochemical measurements, and ADRB2 genotyping in PCOS patients and control subjects. METHODS: ADRB2 haplotypes (comprising rs1042711, rs1801704, rs1042713 and rs1042714 in that order), genotyping and statistical analysis to evaluate associations with continuous variables and traits related to IR and MS in a PCOS population. Associations between ADRB2 haplotypes and PCOS were also assessed. RESULTS: We observed an age-adjusted association between ADRB2 haplotype CCGG and lower insulin (P = 0·018) and HOMA (P = 0·008) in the PCOS sample. Interestingly, the expected differences in surrogate measures of IR between cases and controls were not significant in CCGG/CCGG carriers. In the case-control study, genotype CCGG/CCGG was associated with a 14% decrease in PCOS risk (P = 0·043), taking into account confounding variables. CONCLUSIONS: Haplotype I (CCGG) has a protective role for IR and MS in PCOS.Fil: Tellechea, Mariana Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Muzzio, Damián Oscar. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Iglesias Molli, Andrea Elena. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Belli, Susana H.. Hospital Carlos Durand; ArgentinaFil: Graffigna, Mabel N.. Hospital Carlos Durand; ArgentinaFil: Levalle, Oscar A.. Hospital Carlos Durand; ArgentinaFil: Frechtel, Gustavo Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cerrone, Gloria Edith. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentin

Structure-Based Analysis of Five Novel Disease-Causing Mutations in 21-Hydroxylase-Deficient Patients

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90–95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients

Caracterización molecular del módulo rccx en pacientes con deficiencia de 21-hidroxilasa de la población argentina

Fil: Fernández, CS. Instituto de Biología y Medicina Experimental; Argentina.Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Oneto, A. Hospital Durand. División Endocrinología; Argentina.Fil: Stivel, M. Hospital Durand. División Endocrinología; Argentina.Fil: Belli, Susana. Hospital Italiano. Servicio de Pediatría; Argentina.Fil: Paqualini, T. Hospital Italiano. Servicio de Pediatría; Argentina.Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina

Caracterización molecular del módulo rccx en pacientes con deficiencia de 21-hidroxilasa de la población argentina

Fil: Fernández, CS. Instituto de Biología y Medicina Experimental; Argentina.Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Oneto, A. Hospital Durand. División Endocrinología; Argentina.Fil: Stivel, M. Hospital Durand. División Endocrinología; Argentina.Fil: Belli, Susana. Hospital Italiano. Servicio de Pediatría; Argentina.Fil: Paqualini, T. Hospital Italiano. Servicio de Pediatría; Argentina.Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina

La proteína transportadora del factor de crecimiento insulínico Tipo 1: ¿un nuevo marcador para la enfermedad hepática grasa no alcohólica?

Objetivo: evaluar la presencia de enfermedad hepáticagrasa no alcohólica en pacientes con factores de riesgo para esta patología (obesidad, síndrome metabólico y diabetes tipo 2) y determinar el papel de la insulina, índice HOMA, IGFBP-1, SHBG y PAI-1, como marcadores bioquímicos. Métodos: se evaluaron 91 pacientes con factores de riesgo para desarrollar enfermedad hepática grasa no alcohólica. Se determinaron en plasma transaminasas, insulina, SHBG, IGFBP-1 y PAI-1. El diagnóstico de enfermedad hepática se efectuó por ecografía y a 31 individuos, los cuales tenían esteatosis por ecografía y alanina aminotransferasa elevada, y a quienes se les practicó biopsia hepática. Resultados: la enfermedad hepática estuvo presente en 65 de los 91 pacientes (71,4%). La biopsia hepática efectuada en 31 pacientes diagnosticó la esteatohepatitis no alcohólica en todos y 25 pacientes tuvieron diferentes grados de fibrosis. Aquellos individuos con hígado graso tenían mayor circunferencia de cintura, niveles séricos de triglicéridos, insulina e índice HOMA y niveles más bajos de IGFBP-1, comparada con aquellos sin esteatosis. El grado de esteatosis hepática por ecografía correlacionó positivamente con la circunferencia de cintura, triglicéridos, insulina e índice HOMA (p<0,003; p<0,003; p<0,002 y p<0,001, respectivamente) y negativamente con HDL-colesterol e IGFBP-1 (p<0,025 y p<0,018, respectivamente). Conclusiones: se encontró una alta prevalencia de la EHGNA en pacientes con factores de riesgo metabólico, la mayoría con sobrepeso u obesidad. La SHBG y el PAI-1, aunque están íntimamente relacionados con la insulinorresistencia, no mostraron ser un marcador bioquímico de EHGNA. Si bien la disminución del nivel de IGFBP- 1 correlacionó con EHGNA, su determinación no sólo es menos accesible que la insulina, los triglicéridos, el índice HOMA y la circunferencia de cintura, sino además, la IGFBP-1 no es mejor marcador que los anteriormente nombrados

Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients

Fil: Minutolo, Carolina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Nadra, Alejandro D. Universidad de Buenos Aires. Departamento de Fisiología Biología Molecular y Celular; Argentina.Fil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Casali, Bárbara. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Belli, Susana. Hospital Durand. División Endocrinología; Argentina.Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90–95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients

Screening for primary aldosteronism in an argentinian population: a multicenter prospective study

Objectives Primary aldosteronism (PA) is characterized by the autonomous overproduction of aldosterone. Its prevalence has increased since the use of the aldosterone (ALD)/plasma renin activity (PRA) ratio (ARR). The objective of this study is to determine ARR and ARC (ALD/plasma renin concentration ratio) cut-off values (COV) and their diagnostic concordance (DC%) in the screening for PA in an Argentinian population.Design multicenter prospective study.Subjects and methods We studied 353 subjects (104 controls and 249 hypertensive patients). Serum aldosterone, PRA and ARR were determined. In 220 randomly selected subjects, 160 hypertensive patients and 60 controls, plasma renin concentration (PRC) was simultaneously measured and ARC was determined.Results According to the 95th percentile of controls, we determined a COV of 36 for ARR and 2.39 for ARC, with ALD &#8805; 15 ng/dL. In 31/249 hypertensive patients, ARR was &#8805; 36. PA diagnosis was established in 8/31 patients (23/31 patients did not complete confirmatory tests). DC% between ARR and ARC was calculated. A significant correlation between ARR and ARC (r = 0.742; p < 0.0001) was found only with PRA > 0.3 ng/mL/h and PRC > 5 pg/mL. DC% for ARR and ARC above or below 36 and 2.39 was 79.1%, respectively.Conclusion This first Argentinian multicenter study determined a COV of 36 for ARR and 2.39 for ARC. Applying an ARR &#8805; 36 in the hypertensive group, we confirmed PA in a higher percentage of patients than the previously reported one in our population. As for ARC, further studies are needed for its clinical application, since DC% is acceptable only for medium range renin values

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially