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Malassezia are common yeasts in human skin microbiome. Under certain conditions these yeasts may cause disease from skin disorders to systemic infections. In the absence of clinical breakpoints, epidemiological cutoff values (ECVs) are useful to differentiate isolates with acquired or mutational resistance. The aim of this work was to propose tentative ECVs of Malassezia furfur, M. sympodialis, M. globosa for fluconazole (FCZ), itraconazole (ITZ), voriconazole (VCZ), ketoconazole (KTZ) and amphotericin B (AMB). A total of 160 isolates (80 M. furfur, 50 M. sympodialis, and 30 M. globosa) were tested. Minimal inhibitory concentrations (MICs) were determined by modified broth microdilution method (CLSI). ECVs were estimated by ECOFFinder software and twofold dilutions beyond the mode. ITZ, KTZ, and VCZ showed the lowest MICs. The highest MIC and widest ranges were for FCZ and AMB. For ITZ, KTZ, and VCZ both ECVs were similar. For FCZ, AMB especially M. furfur, modal ECVs were lower than values obtained by statistical method. When MIC distribution is the only data available, ECV could provide information to help guide therapy decisions. In that drug/species combination in which different peaks in the MIC distribution were observed, difference between both ECV was greater. This is the first study that provides ECV data of 160 Malassezia yeasts. Although ECVs cannot be used as predictors of clinical response, identification of non wild-type isolates suggests that it may be less likely to respond to a given antifungal agent. LAY SUMMARY: Malassezia species causes skin disorders to systemic infections. Epidemiological cutoff value (ECV) allows for differentiation of wild-type and non wild-type isolates. Based on MIC data of 160 isolates we propose tentative ECVs for three Malassezia species. ECVs are useful in surveillance and guide therapy decisions.

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RESUMEN: El Premio Nobel 2019 en Fisiología-Medicina se confirió a los Profesores Gregg Semenza, William Kaelin y Sir Peter Ratcliffe por sus investigaciones en la maquinaria molecular que regula la expresión de genes sensibles a los cambios en los niveles de oxígeno. La síntesis de eritropoyetina inducida por la disminución de los niveles sanguíneos de oxígeno condujo al estudio del gen de la eritropoyetina y descubrimiento de los elementos de respuesta a hipoxia (HRE) en la región promotora y posteriormente al factor transcripcional inducible por hipoxia tipo 1 (HIF-1). Este factor consta de dos subunidades: HIF-1α, sensible al oxígeno, y HIF-1β, expresada constitutivamente. HIF1 activa la transcripción de genes que codifican enzimas, transportadores y proteínas mitocondriales que disminuyen la utilización de oxígeno al cambiar el metabolismo oxidativo al metabolismo glicolítico y además aquellos involucrados en la angiogénesis y diferenciación celular. Las investigaciones paralelas en la enfermedad von Hippel-Lindau (VHL), un desorden autosómico dominante, permitieron descubrir el mecanismo de degradación de HIF1 en condiciones de normoxia y como se estabiliza bajo hipoxia. El impacto de HIF en clínica radica en el establecimiento de nuevas dianas terapéuticas para combatir la anemia y diversas enfermedades cardiovasculares. HIF promueve la angiogénesis a través de la expresión del factor de crecimiento vascular endotelial (VEGF), agente cardioprotector con potencial para tratar la isquemia/reperfusión, hipertrofia patológica e insuficiencia cardíaca.

ABSTRACT: The Nobel Prize in Physiology-Medicine was awarded to Drs. Gregg Semenza, William Kaelin and Sir Peter Ratcliffe for their research in the molecular machinery that regulates the expression of genes sensitive to the change in oxygen levels. The synthesis of erythropoietin induced by the decrease levels of oxygen in the blood led to investigate the promoter of the erythropoietin gene where the so-called hypoxia response elements (HRE) were described. Semenza et al. described a protein that binds to HREs and called it hypoxia-inducible transcriptional factor (HIF) that regulates gene expression among those involved in angiogenesis, cell differentiation and glycolytic enzymes. HIF presents two oxygen-sensitive subunits HIF-1α and HIF-1β constitutively expressed. In parallel, Kaelin et al. investigated von Hippel-Lindau disease (VHL), an autosomal dominant disorder, discovering a mutation of this protein generated a behavior similar to hypoxia. The impact of HIF-1α lies in the search for new strategies such as hydrolase inhibitors to combat prevalent diseases, including anemia and cardiovascular diseases These compounds promote the expression of vascular endothelial growth factor (VEGF), a cardioprotective agent with potential use in pre- and post-conditioning therapy, cardiac hypertrophy and heart failure.

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The vascular endothelial growth factor (VEGF) is an essential factor to pathologic angiogenesis. Disruption of VEGF/VEGF receptor interaction in cancer patients inhibits the development of new and pre-existing tumor blood vessels. Consequently, VEGF becomes an important therapeutic target for handling solid tumors. In this work, human VEGF was produced in the culture supernatant of SiHa cells transduced with a replication-defective adenoviral vector (pAdhVEGF121) encoding this molecule. The 35 kDa VEGF121 homodimer was obtained from clarified culture media as a glycosylated protein. VEGF121 expression levels were strictly dependent on the adenoviral viral load used. VEGF121 was produced with purity over 98% after a single step chromatography by immobilized metal affinity chromatography. Additionally, VEGF121 binds Bevacizumab antibody with a KD of 7 nM. Biological characterization by mitogenic assay in HUVEC and ECV-304 cells showed that VEGF121 stimulates cell proliferation in a dose-dependent manner in both cells. Finally, the neovascularization activity of VEGF121 was demonstrated by vascular permeability assays in matrigel plug-bearing mice, showing significantly increased vasculature leakage after treatment with VEGF121. Consequently, transduction of SiHa cells with adenovirus is a suitable alternative for manufacture heterologous proteins of therapeutic interest.

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La Hiperhomociteinemia (HHcy) se considera como un factor de riesgo idenpendiente para el desarrollo de aterosclerosis y de enfermedad arterial coronaria (EAC). Los polimorfismos en encimas involucradas en la regulación del metabolismo de la Hcy como la metiltetrahidrofolato reductasa (MTHFR), metionina sintasa (MTR), y la metionina sintasa reductasa (MTRR) pueden contribuir a la variación de los niveles de homocisteína en plasma (Hcy). En este estudio investigamos la asociación de los polimorfismos genéticos de las enzimas involucradas en la remetilación de la homocisteínia: metionina sintasa (MTR), metil N-tetrahidrofolato reductasa (MTHFR) y metionina sintasa reductasa (MTRR), con los niveles de Hcy en pacientes con EAC y sujetos sanos. Población 136 individuos de los cuales 90 presentaron diagnóstico de enfermedad cardiovascular (IAM y ACV) y 46 eran aparentemente sanos (controles). La concentración de Hcy fue significativamente más alta en pacientes con ECV que en los sujetos control (P<0,001). HHcy (>15 µmol/L) confirió un RR de IAM de 2.52 (95% IC: 1.4-4.4, P<0,001) y de ACV de 1.88 (95% IC: 1.0-3-5, P<0,05). Los niveles de vitamina B12 y folato se encontraba en el rango de los valores de referencia en el 86% de los individuos. La frecuencia del alelo T para C677T de MTHFR, del alelo G para A66G de MTRR y del alelo G para A2756G de MTR fueron 0.31, 0.30, 0.22 respectivamente para los sujetos casos. Los polimorfismos C677T, A66G y A276G de los genes MTHFR, MTRR y MTR no tuvieron diferencia estadísticamente significativa entre el grupo de casos con respecto al grupo control. Los polimorfismos estudiados no se relacionaron estadísticamente con la HHcy en los individuos en estudio. Sugerimos que HHcy confiere riesgo para ECV. En nuestro estudio encontramos evidencia de que la regulación de Hcy es poligénica.

The Hiperhomocysteinemia (HHcy) is considered an independent risk factor for developing atherosclerosis and cardiovascular arterial disease (CAD). The polymorphisms of the enzymes involved in the regulation of homocysteine (Hcy) metabolism as the methyltetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) may contribute to the elevation of Hcy in plasma. The main aim of the this study was to investigate the association of genetic polymorphisms of the enzymes involved in remethylation of homocysteine: methionine synthase (MTR), N-methyl tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), with levels of Hcy in patients with CHF and healthy subjects. Population: 136 subjects of whom 90 had a diagnosis of cardiovascular disease (heart failure and stroke) and 46 were apparently healthy (controls). The concentration of Hcy was significantly higher in patients with cardiovascular disease than compare with the control group (P<0.001). HHcy (>15 mmol/L) conferred a relative risk (RR) of heart failure of 2.52 (95% CI: 1.4-4.4, P <0.001) and stroke, RR of 1.88 (95% CI: 1.0-3.5, P <0.05). The levels of vitamin B12 and folate was in the range of reference values in 86% of subjects. The frequency of the T allele of MTHFR C677T was 0,31, for the G allele of MTRR A66G was 0,30 and for the G allelwe for MTR A2756G was 0.22 for the subjects with heart failure and stroke referred as case. C677T polymorphism, A66G and A2756G of the genes MTHFR, MTRR and MTR had no associated statistically with HHcy in the subjects of the study. We suggest that HHcy confers risk for CVD. In our study we found evidence that the regulation of Hcy is polygenic.

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Un aumento de las enfermedades cardiovasculares (ECV) mundialmente, la existencia de un porcentaje más alto que el promedio nacional de éstas para la región de Maule (Chile), y una atención incrementada en el análisis de factores psicológicos, motivan el análisis del Patrón de Comportamiento Tipo A (PCTA) y la ira respecto de las ECV. Se trabajó con 1007 participantes de 18 a 74 años (ciudadanos de Talca, Chile), mayoritariamente mujeres, quienes respondieron un cuestionario (información socio demográfica, hábitos alimentarios y de estilo de vida), la Escala Retiro de Patrón de Conducta tipo A (ERCTAa), y el Inventario de Ira de Novaco. Se les midió peso, masa corporal, presión arterial y sangre, como factores de riesgo cardiovascular. Los participantes son altamente sedentarios (79.9%), tabáquicos (53.6%), hipercolesterolémicos (44.5%), con sobrepeso (40.7%) y obesidad (32.6%), un cuarto de los cuales presenta hiperglicemia e hipertensión y con PCTA equirepartido según sexo. Es la ausencia de PCTA (ó presencia de PCTB) la que aparece asociada a factores tradicionales de riesgo cardiovascular (FRCV). La ira alta se presenta más en mujeres que en hombres (2.1% vs. 0.3%; c²(3) = 27.99, p<.0001), disminuyendo para ambos sexos con la edad, pero los infartos acaecen igualmente según sexo.

A worldwide raise in the number of cardiovascular disease (CVD) and the existence of a higher percentage in Maule (Chile) than the national media, and increased attention in the analysis of psychological factors motivate to analyze the Type A Behavior Pattern (TABP) and anger in relation to CVD. The sample was 1007 adults between 18 and 74 years old (citizens of Talca, Chile), mostly women. They provided information about their demographic details, eating habits and lifestyle, answered the Novaco's Anger Inventory and the Retiro Scale of Type A Behavior (RSTAB), and also were taken measurements like weight, body mass index and blood pressure and blood tests related to risk factors to traditional cardiovascular diseases. The results show Overall, that the participants appear highly sedentary (79.9%) with relatively high levels of tabaquism (53.6%), and hypercholesterolemia (44.5%), overweight (40.7%) and obesity (32.6%). A quarter of the sample also presents hyperglycemic indexes, hypertension and TABP unequally distributed by sex. The absence of PCTA (or PCTB presence) appeared mostly associated with traditional cardiovascular risk factors (CRF). Regarding anger, women present more high than men (2.1% against 0.3%; c²(3) = 27.99, p<.0001), decreasing for both sexes with age, while also befall stroke by sex.

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El pseudoxantoma elástico (PXE) es un trastorno hereditario poco común del tejido conectivo, que se caracteriza por lesiones cutáneas, oculares y cardiológicas originadas por fragmentación y calcificación de las fibras elásticas. La mayoría de casos se hereda con un patrón autosómico recesivo, y, en menos proporción, autosómico dominante. El propósito del presente reporte es dar a conocer un caso de pseudoxantoma elástico con complicaciones tardías y asociaciones infrecuentes, como son una ECV (enfermedad cerebro vascular) recidivante, abortos recurrentes, la presencia de un bocio multinodular unilateral derecho, fibromatosis uterina gigante no sintomática, hipertensión arterial, y un antecedente no bien clarificado con respecto a la presencia de diabetes mellitus.

Pseudoxanthoma elasticum (PXE) is connective tissue's rare inherited disorder, characterized by skin, eye and cardiac lesions, originated by fragmentation and calcification of elastic fibers. Most cases are inherited with an autosomal recessive pattern, and in a little proportion, with an autosomal dominant pattern. This paper has the purpose of reporting a case of pseudoxanthoma elasticum with late complications and unusual associations, such as recidivated stroke, recurrent aborts, right multinodular unilateral goiter, giant uterine fibromatosis, arterial hypertension, and an unclear antecedent of diabetes mellitus.

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Tipo de estudio: prospectivo, observacional, analítico, con un universo de 32 pacientes quienes presentaron por primera ocasión crisis convulsiva después de los 15 años e ingresados al hospital Abel Gilbert Pontón de la ciudad de Guayaquil entre septiembre 2001 y agosto 2002.Objetivos: Establecer:a) El factor de riesgo más importante.b) El grupo etario más susceptible.c) El tipo de crisis más frecuente.d) La importancia de la TC.Resultados: Se demostró lesión en 26 pacientes (81%), en 6 (19%) no se halló la causa. La etiología más frecuente fue la ECV con 16 pacientes (50%); 5 con neuroinfección (15%).La TC encontró lesiones hipodensas en 14 pacientes, 2 hiperdensas; 3 con signos de atrofia. En 10 reporta normal. Conclusiones: La ECV es la principal causa. La TC cerebral .demostró ser útil al evidenciar lesiones. Las crisis generalizadas son las más frecuentes (84%).

Type of study: Prospectivo, observacional, analitic study; with a universe of 32 patients who presented by first time convulsive crisis after 15 years and entered the Guayaquil Hospital between September 2001 and August 2002. Objectives: Are to establish: a) The factor of more important risk. b) The more susceptible etario group. c) The type of more frequent crisis. d) The importance of the TC. Results: Injury in 26 patients (81%) in 6(19 %) was demonstrated was not the cause. The etiología but frequents was him ECV with 16 patients (50%); 5 patients with neuroinfección (15%) the TC found injuries hypodense in 14 patients, 2 hyperdense ones; 3 with atrophy signs. In 10 it reports normal. Conclusions: ECV is the main cause TC is important for demonstrating injuries The generalized crises are most frequent (84%).

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