Evolución clínica de pacientes con esclerosis múltiple remitente- recurrente tratados con interferón beta-1a / Clinical evolution of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1a

RESUMEN Introducción: El inicio de la terapia con interferón ha sido y es el primer paso en el tratamiento de muchos pacientes con esclerosis múltiple, con el propósito de retrasar la progresión de la enfermedad. Objetivo: Identificar los marcadores clínicos de respuesta al tratamiento con interferón beta-1a de pacientes con esclerosis múltiple remitente-recurrente. Métodos: Se realizó un estudio observacional, descriptivo, longitudinal, prospectivo, de una serie de casos de pacientes con diagnóstico de esclerosis múltiple remitente-recurrente, que recibían tratamiento con interferón beta-1a, en el periodo comprendido entre enero del 2014 a diciembre del 2020. Se incluyeron los 39 pacientes. Resultados: La media de edad fue de 34,54 años. La media del nivel de discapacidad en la línea base, 12, 24 y a los 36 meses fue de 1,76; 1,91; 2,1 y 2,37 respectivamente. La media de los brotes en la línea base, 12, 24 y a los 36 meses fue de 1,13; 0,26; 0,38 y 0,13 respectivamente. Se muestra la cifra de progresiones inferior en un 51 % a los 36 meses. La razón de ventajas (odds ratio) para la no presencia de brotes se muestra entre 2 y 4 veces en estos pacientes. Conclusiones: Se identifican marcadores clínicos de respuesta al tratamiento con interferón beta-1a que ayudan a valorar la respuesta al tratamiento, lo cual repercute de forma positiva en la evolución de la enfermedad.

ABSTRACT Introduction: The initiation of interferon therapy has been and is the first step in the treatment of many patients with multiple sclerosis, with the aim of delaying the progression of the disease. Objective: To identify the clinical markers of response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis. Methods: An observational, descriptive, longitudinal, prospective study was carried out of a series of cases of patients diagnosed with relapsing-remitting multiple sclerosis, who received treatment with interferon beta-1a, in the period between January 2014 and December 2020. All 39 patients were included. Results: The mean age was 34.54 years. The mean disability level at baseline, 12, 24, and 36 months was 1.76; 1.91; 2.1 and 2.37 respectively. The mean number of flares at baseline, 12, 24, and 36 months was 1.13; 0.26; 0.38 and 0.13 respectively. The number of progressions lower by 51% at 36 months is shown. The odds ratio for the absence of relapses is between 2 and 4 times in these patients. Conclusions: Clinical markers of response to treatment with Interferon beta-1a are identified that help assess the response to treatment, which has a positive impact on the evolution of the disease.

Intravenous tocilizumab in the management of rheumatoid arthritis: Clinical practice findings from a 6-month international, multicentre, observational study in Central America and the Caribbean / El tocilizumab intravenoso en el tratamiento de la artritis reumatoide: resultados de la práctica clínica de un estudio internacional, multicéntrico y observacional de 6 meses de duración en América Central y el Caribe

ABSTRACT Tocilizumab (TCZ), an 1interieukin-6 receptor-α Inhibitor, is Indicated in patients with moderate to severe rheumatoid arthritis with inadequate response to disease modifying drugs. ACT UP is a multinational project co11ecting information from severa1 post-marketing TCZ studies. Aim: To determine the proportion of patients in the routine clinical care setting receiving intravenous TCZ after 6 months treatment. Identification of TCZ treatment patterns, efficacy, and safety were also recorded. Method: This prospective non-interventional 6-month study, collected real-world information from 169 Central American and Caribbean patients. No interventional procedures or additional visits outside routine clinical care practice were performed. Statistical analysis was essentially descriptive. Results: Adherence rate was 74.0%, with 97% of patients receiving TCZ as first biological therapy line and there were no deviations from the local label. Almost 85% of patients started with combination therapy, and the majority remained under this scheme throughout the study. A significant decrease in disease activity assessments and acute phase reactants values were detected during TCZ treatment. The percentage of patients that achieved improvement according to the different levels of the American College of Rheumatology (ACR) increased during the study, and relevant enhancements in quality of life were also accomplished. Adverse events (AEs) occurred in 35 patients, with metabolic and nutritional disorders being the most common. Serious AEs were reported in 3% of patients, and special interest AEs occurred in 6 patients. Conclusion: Treatment adherence was mainly determined by follow-up and compliance with the administration schedule. Efficacy analysis showed better results than those reported in international literature. The incidence of AEs was also lower than in previously published data.

RESUMEN El tocilizumab (TCZ) está indicado en la artritis reumatoide moderada a severa, principalmente en respuestas inadecuadas a fármacos convencionales. ACT UP es un proyecto multinacional que recopila información relacionada con varios estudios de poscomercialización. Objetivo: Determinar la proporción de pacientes en la atención clínica de rutina que continúan en tratamiento con TCZ intravenoso después de 6 meses. Se llevó a cabo la identificación de patrones de administración, eficacia y seguridad. Método: Este estudio observacional prospectivo recopiló información de la vida real de 169 pacientes de América Central y el Caribe. No se hicieron intervenciones ni visitas adicionales fuera de la práctica clínica habitual. El análisis estadístico fue esencialmente descriptivo. Resultados: La tasa de adherencia al tratamiento fue del 74,0%, el 97% de los pacientes reci bieron TCZ como primera línea biológica y no existieron desviaciones en las indicaciones de administración según el inserto local. Aproximadamente el 85% de los pacientes inició TCZ como terapia combinada, y la mayoría permaneció bajo este esquema. Se evidenció una dis minución en la actividad de la enfermedad y un aumento en el porcentaje de pacientes que lograron respuesta según los diferentes grados del Colegio Americano de Reumatología. En 35 pacientes se presentaron eventos adversos (EA), siendo los relacionados con metabolismo y nutrición los más comunes. Se informaron EA graves en el 3% de los pacientes y de interés especial en 6 casos. Conclusión: El seguimiento de los pacientes y el cumplimiento del programa fueron los prin cipales determinantes en la adherencia. El análisis de eficacia mostró mejores resultados que los reportados previamente y la incidencia de EA fue menor que en otros estudios.

O efeito do calor e do frio na mortalidade não-acidental da população residente nas regiões metropolitanas brasileiras ao longo do período de 2000-2014: estudo de série temporal / Heat and cold effect on non-accidental mortality of the population living in brazilian metropolitan regions over the period 2000-2014: time series study

O aumento do risco relativo de mortalidade por diversas causas é associado a temperatura ambiente extremas. Fatores a nível individual e comunitários podem influenciar esta associação podendo aumentar ou diminuir seus efeitos. Estes podem ser variáveis ao longo do tempo, o que poderia fazer esta associação oscilar ao longo dos anos. Esta tese investigou os efeitos a curto prazo da temperatura ambiente na mortalidade da população geral e idosos do Brasil, bem como a modificação desta associação ao longo do tempo. O primeiro manuscrito verificou quais modificadores de efeito modulam a associação temperatura-mortalidade a curto prazo. O segundo manuscrito verificou se houve mudança na associação temperatura-mortalidade ao longo de três períodos sequenciais. Foi analisado mortalidade não-acidental da população geral e idosa, e para estes foi subdividido em causas circulatórias, respiratórias e outras causas. Ambos os estudos utilizaram um modelo aditivo generalizado combinado com distributed lag non-linear models e período de defasagem de 21 dias para estimar a associação temperatura-mortalidade para cada região metropolitana, grupo e período. Os estudos incluíram um teste de heterogeneidade entre os locais e estimativas combinadas para Brasil e regiões geográficas via metanálise. Modelos de metarregressão incluindo fatores a nível do local foram utilizados para análise de possíveis modificadores da associação. Os resultados do primeiro manuscrito evidenciam um efeito do frio e do calor na mortalidade não-acidental da população geral e idosa, bem como para mortalidade cardiovascular, respiratória e outras causas dos idosos do Brasil, principalmente nas regiões metropolitanas e geográficas do Sudeste e Sul do Brasil, sendo geralmente as baixas temperaturas as promotoras de maiores riscos relativos de óbitos. Os fatores geográficos foram os responsáveis por explicar a maior parte da heterogeneidade entre os locais, com destaque para amplitude da temperatura média. Os resultados do segundo manuscrito exibem estimativas pontuais de risco relativo de mortalidade associado ao frio e ao calor diferentes a cada quinquênio, sendo esta flutuação de padrões distintos conforme tipo de causa e região brasileira. A heterogeneidade da associação temperatura-mortalidade entre os locais cresceu ao longo dos períodos para todos os grupos. Nos grupos mortalidade não-acidental e circulatório, nos três períodos, a amplitude da temperatura é a variável que melhor explica esta heterogeneidade. No grupo respiratório a amplitude diária da temperatura foi forte explicador nos dois primeiros períodos. Os resultados desta tese sugerem efeito da temperatura ambiente sobre a mortalidade no Brasil, com maior foco nas regiões Sul e Sudeste. Assim, planejamento de ações com foco de adaptação as temperaturas extremas tanto altas quanto baixas são necessárias e de imediato foco nas regiões Sul e Sudeste.

The increase in the relative risk of mortality from various causes is associated with extreme ambient temperatures. Factors at the individual and community level can influence this association and may increase or decrease its effects. These can be variable over time, which could cause this association to fluctuate over the years. This thesis investigated the short-term effects of ambient temperature on mortality in the general population and the elderly in Brazil, as well as the modification of this association over time. The first manuscript verified which effect modifiers modulate the short-term association of temperature and mortality. The second manuscript verified whether there was a change in the association between temperature and mortality over three sequential periods. Non-accidental mortality of the general and elderly population was analyzed, and for these it was subdivided into circulatory, respiratory and other causes. Both studies used a generalized additive model combined with distributed lag non-linear models and a lag of 21 days, to estimate the temperature-mortality association for each metropolitan region, group and period. The studies included a test of heterogeneity between locations and combined estimates for Brazil and geographic regions via meta-analysis. Meta-regression models including factors at the local level were used to analyze possible modifiers of the association. The results of the first manuscript show an effect of cold and heat on non-accidental mortality in the general and elderly population, as well as for cardiovascular, respiratory and other causes of the elderly in Brazil, especially in the metropolitan and geographic regions of the Southeast and South of Brazil. Brazil, with low temperatures being generally the promoters of higher relative risks of death. The geographical factors were responsible for explaining most of the heterogeneity between the locations, with emphasis on the amplitude of the average temperature. The results of the second manuscript show specific estimates of the relative risk of mortality associated with cold and heat differently every five years, with this fluctuation of different patterns according to the type of cause and the Brazilian region. The heterogeneity of the temperature-mortality association between sites increased over the periods for all groups. In the non-accidental and circulatory mortality groups, in the three periods, the temperature amplitude is the variable that best explains this heterogeneity. In the respiratory group, the daily temperature range was a strong factor in the first two periods. The results of this thesis suggest the effect of ambient temperature on mortality in Brazil, with a greater focus on the South and Southeast regions. Thus, action planning with a focus on adaptation to extreme temperatures, both high and low, is necessary and immediately focus on the South and Southeast regions.

Métodos para la medición de la adherencia a medicamentos modificadores de la enfermedad orales en artritis reumatoide y factores asociados con baja adherencia farmacológica / Methods for measuring adherence to oral disease-modifying drugs in rheumatoid arthritis and factors associated with low adherence to pharmacological treatment

RESUMEN Objetivos: Revisar definiciones, factores asociados a adherencia, métodos para medición y determinación de adherencia a medicamentos modificadores de la enfermedad orales en artritis reumatoide. Métodos: Se realizó una búsqueda de la literatura en las bases de datos de Pubmed hasta diciembre de 2017 mediante términos MeSH (((«Arthritis, Rheumatoid¼ [Mesh] AND «Medication Adherence¼ [Mesh]) OR «Patient Compliance¼ [Mesh]) AND «Antirheumatic Agents¼ [Mesh]) de artículos que estuvieran en idioma espafñol o inglés e incluyeran solo población adulta. Resultados: De un total de 387 artículos encontrados, 43 se incluyeron para la revisión general, con información sobre definiciones de adherencia, cumplimiento, concordancia y persistencia, componentes, clasificación y dimensiones, factores de riesgo relacionados con la no adherencia al tratamiento, descripción de los métodos de medición. Solo 9 artículos midieron adherencia e incluyeron información sobre factores relacionados con adherencia a medicamentos orales en artritis reumatoide. Conclusiones: La adherencia al tratamiento farmacológico en artritis reumatoide es subóptima y se relaciona con menor efectividad en el control de la actividad inflamatoria. Los principales factores relacionados con baja adherencia incluyen problemas de acceso y disponibilidad del medicamento, mayor actividad y duración de la enfermedad, polifarmacia, uso de medicamentos por periodos prolongados, bajo estrato socioeconómico, etnia, reacciones adversas por medicamentos, percepción de inefectividad de la medicación y enfermedades concomitantes. Es necesario incorporar de forma sistemática la medición de adherencia farmacológica dentro de la práctica clínica rutinaria y la identificación de los factores de riesgo más frecuentes asociados a una baja adherencia con el fin de diseñar estrategias encaminadas a mejorar la adherencia de los pacientes y lograr mejores desenlaces clínicos.

ABSTRACT Objectives: To review the definitions, associated factors, as well as the methods for the measurement and determination of adherence to oral disease modifying drugs in rheumatoid arthritis. Methods: A search of the literature was carried out in the PUBMED databases up to December 2017 using MeSH terms: ((("Arthritis, Rheumatoid" [Mesh] AND "Medication Adherence" [Mesh]) OR "Patient Compliance" [Mesh]) AND "Antirheumatic Agents" [Mesh]). Only articles that included an adult population and were in Spanish or English were reviewed. Results: From the 387 articles found, 43 were included for general review (definitions of adherence, compliance, concordance and persistence, components, classification and dimensions of adherence, risk factors related to non-adherence, description of direct and indirect methods for measuring adherence). Only 9 articles measured adherence and included information about risk factors related to non-adherence to oral treatment in rheumatoid arthritis. Conclusions: The adherence to pharmacological treatment in rheumatoid arthritis is sub-optimal and is associated with less effectiveness in the control of inflammatory activity. The main factors related to low adherence include problems of drug access and availability, increased activity and duration of the disease, polypharmacy, use of medications for prolonged periods, socioeconomic stratum, ethnicity, adverse drug reactions, perception of ineffectiveness of the medication, and concomitant diseases. It is necessary to incorporate the systematic measurement of pharmacological adherence within clinical practice. It is also important to identify the most frequent risk factors associated with low adherence, in order to design strategies aimed at improving patient adherence and achieve better clinical outcomes.

Beta talasemia intermedia: características clínicas y estudio molecular. Serie de casos clínicos / Beta thalassemia intermedia: clinical characteristics and molecular analysis. Case series

La beta talasemia intermedia es una hemoglobinopatía de amplio espectro clínico, que surge de la presencia de una o dos mutaciones en el gen HBB, asociada a modificadores genéticos secundarios y/o terciarios. Analizamos las características clínicas y de laboratorio de 29 pacientes con beta talasemia intermedia, evaluados en un período de 23 años. La edad mediana fue de 10,8 años (rango: 0,34-60,4). El 100% de los pacientes mostró anemia microcítica hipocrómica, y solo el 17,2% presentó esplenomegalia y requerimiento transfusional esporádico. El análisis molecular de los pacientes detectó 3 con los dos genes HBB afectados; 2 con un gen HBB afectado y genes alfa cuadriplicados/triplicados; 23 con un gen HBB afectado y genes alfα triplicados; y 1 con dos genes HBB afectados y polimorfismos de genes gama. La correcta identificación de estos pacientes aseguró un adecuado consejo genético y la implementación de controles clínicos regulares.

Beta thalassemiaintermediaisaquantitative haemoglobinopathy covering a broad clinical spectrum, that results from the presence of one or two HBB gene mutations associated with secondary and/or tertiary genetic modifiers. We analyze the clinical and laboratory features of 29 patients with beta thalassemia intermedia, assessed over a period of 23 years. Median age was 10.8 years (range: 0.34-60.4). Hypochromic microcytic anemia was seen in 100% of the patients, while only 17.2% had splenomegaly and occasional transfusion requirement. The molecular analysis of patients detected: 3 with two HBB affected genes; 2 with one HBB affected gene and alpha quadruplicate/triplicate genes; 23 with one HBBaffected gene and alpha triplicate genes and 1 with two HBB affected genes and polymorphisms of gamma genes. The adequate identification of these patients enables us to give appropriate genetic counseling and implementation of regular clinical follow up

Floating microspheres: a review

Gastric emptying is a complex process, one that is highly variable and that makes in vivo performance of drug delivery systems uncertain. A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. The main limitations are attributed to the inter- and intra-subject variability of gastro-intestinal (GI) transit time and to the non-uniformity of drug absorption throughout the alimentary canal. Floating or hydrodynamically controlled drug delivery systems are useful in such applications. Various gastroretentive dosage forms are available, including tablets, capsules, pills, laminated films, floating microspheres, granules and powders. Floating microspheres have been gaining attention due to the uniform distribution of these multiple-unit dosage forms in the stomach, which results in more reproducible drug absorption and reduced risk of local irritation. Such systems have more advantages over the single-unit dosage forms. The present review briefly addresses the physiology of the gastric emptying process with respect to floating drug delivery systems. The purpose of this review is to bring together the recent literature with respect to the method of preparation, and various parameters affecting the performance and characterization of floating microspheres.

O esvaziamento gástrico é um processo complexo, com elevada variabilidade e responsável pela incerteza do desempenho dos medicamentos in vivo. Dessa forma, os sistemas de liberação modificada de fármacos, com tempo de residência prolongado no estômago, em especial, considerando aqueles fármacos com janela de absorção na porção superior do intestino delgado, apresentam fundamental importância. As principais limitações relativas à absorção do fármaco são, no geral, atribuídas à variabilidade inter e intra-paciente do tempo de trânsito gastro-intestinal (GI) e da não-uniformidade da absorção do fármaco na extensão do canal alimentar. Assim, justifica-se a utilização dos sistemas flutuantes ou hidrodinâmicos de liberação de fármacos. Vários medicamentos gastrorretentivos estão disponibilizados no mercado e incluem comprimidos, cápsulas, pílulas, filmes laminados, microesferas flutuantes, grânulos e pós. As microesferas flutuantes apresentam maior destaque em função da distribuição granulométrica uniforme dessas formulações de dose múltipla. Como resultado, a absorção do fármaco apresenta maior reprodutibilidade e os riscos associados à irritação local são reduzidos. Tais sistemas apresentam maior vantagem quando comparado às formulações de dose única. A presente revisão tem como objetivo apresentar as publicações recentes referentes aos métodos de preparação, os vários parâmetros que afetam o desempenho e a caracterização das microesferas flutuantes. Além disso, o presente trabalho aborda a fisiologia do processo de esvaziamento gástrico no que se refere aos sistemas flutuantes de liberação de fármacos.

Medicação anti-inflamatória alternativa aos glicocorticóides para o tratamento da asma: papel dos modificadores de leucotrienos, estabilizadores de mastócitos e outras perspectivas / Anti-inflammatory medication beyond glucocorticoids for asthma therapy: role of leukotriene

A inalação de agentes anti-inflamatórios esteroidais, administrados isoladamente ou combinados a agonistas β2-adrenérgicos de longa duração, é a melhor opção disponível para o controle farmacológico da asma, embora efeitos adversose resistência aos glicocorticóides limitem seu benefício. Inibidores da síntese de leucotrienos, antagonistas do receptor CysLT1 e estabilizadores de mastócitos têm sido empregados, como monoterapias alternativas, no tratamento da asma branda e moderada, porém sem a mesma eficácia dos anti-inflamatórios esteroidais. Há evidências de que a combinação do antagonista CysLT1 e glicocorticóide inalado seja eficaz no tratamento de asmáticos graves, com diminuição da dosagem do agente esteroidal. Inibidores da enzima fosfodiesterase 4, bem como lidocaína e análogos não anestésicos da lidocaína, têm igualmente atraído atenção como opções terapêuticas no controle da asma. Esta revisão analisa avanços recentes no campo das alternativas ao uso dos glicocorticóides para regulação anti-inflamatória da asma

Caracterización de la resistencia a aminoglicósidos mediada por enzimas modificadoras y metilasas de ARN16S en aenterobacterias / Characterization of resistance to aminoglycoside mediated by modifying enzymes and methylases ARN16S in aenterobacterias

Los aminoglicósidos son antimicrobianos ampliamente usados en la práctica clínica. El objetivo del estudio fue evaluar fenotípica y genotípicamente la resistencia a aminoglicósidos en enterobacterias aisladas de centros de salud del área metropokitana de caracas. Se estudiaron 76 cepas de enterobacterias (14 Escherichia coli, 34 klebsiella pneumoniae, 6 Serratia marcescens, 1 citrobacer freundii, 3 Enterobacter aerogenes y 18 Entorabacter cloacae) aisladas de muestras clínicas de pacientes de 11 centros hospitalarios de Caracas entre noviembre 2009 y marzo 2010, incluyéndose solo cepas con resistencia a aminoglicósidos. La identificación bioquímica fue realizada por métodos convencionales y mediante el sistema automatizado VITEK-2. Se determinó su suseptibilidad antibiótica por la técnica de difusión con discos de gentamicina, amikacina, netilmecina y tobramicina según lo establecido por CLSI 2010. Los genes de resistencia se investigaron por PCR empleando iniciadores para los genes codificantes de las enzimas AAC(3')la, AAC(3') lla AAC(6')lb, ANT(2')la, AAC(6')lbcr, APH(3') Vla y las metilasa armA, rmtA, rmtB, rmtC, rmtD y npmA. Fenotípicamente se detectó que 90,8 % de las cepas fueron resistentes a amikacina y 57,9 % presentaron resistencia cruzada a amikacina, gentamicina, tobramicina y netilmicina. De las enzimas modificadoras investigadas la más prevalente fue APH(3')Vla (56,6%) y de las metilasas la RmtD (25 %). Estos resultados sugieren que la APH(3')Vla pudiera ser la responsable de generar altos niveles de resistencia a amikacina en estas cepas, mientras que la RmtD podría ser la causante de la resistencia cruzada a amikacina, gentamicina, tobramicina y netilmicina.

Aminoglycosides are antimicrobials widely used in clinical practice. The objective of this study was to assess from a phenotypic and genotypic point of view aminoglycoside resistance in enterobacteria isolated from health centers in the metropitan area of Caracas. Seventy six enterobacteriaceae isolates (14 Escherichia coli 34 Klebsiella pneumoniae, 6 serratia marcescens, 1 Citrobacter freundii, 3 Enterobacter aerogenes and 18 Enterobacter cloacae) from clinical samples of patientes from 11 hospitals in Caracas between November 2009 and march 2010 were analyzed, including anly strains with resistance to aminoglycosides. Biochemical identification was carried out by conventional methods and automated VITEK-2. Antibiotic susceptibility was determined by disk diffusion using gentamicin, amikacin, netilmicin and tobramycin discs, according with CLSI 2010. Resistnce genes were investigated by PCR using primers for the genes coding for AAC (3') la, AAC (3') AAC(6')Ib lla, ANT(2') la, AAC(6')Ibcr, Vla APH (3') enzymes and armA, rmtA, rmtB, rmtC, rmtD and npmA metilases. Phenotypically 90.8 % of isolates were resistant to amikacin, and 57.9 % presented cross-resistance to amikacin, gentamicin, tobramycin and netilmicin. The most prevalent modifying ensymes was APH(3')Vla (53.6 %9 and the most prevalent metilase was RmtD (25 %). These results suggest that the APH(3') Vla migth be responsible for generatin high levels of resistance to amikacin inthese isolates, while RmtD was the cause of cross resistance to amikacin, gene, gentamicin, tobramycin and netilmicin.

Genes modificadrres en enfermedades poliglutamínicas / Modifying genes in poliglutaminic diseases

Las enfermedades poliglutamínicas constituyen un grupo creciente de enfermedades neurodegenerativas humanas, causadas por la expansión de secuencias repetitivas de CAG que son traducidas para dar lugar a proteínas con dominios poliglutamínicos expandidos. La edad de inicio es un marcador fenotípico para estas enfermedades, y muestra una gran variación en las familias afectadas. El número de repeticiones de CAG contenido en los genes causales, explica entre el 47 y 80% de la variabilidad observada en la edad de inicio. Para explicar la varianza restante ha sido propuesta la hipótesis de la existencia de genes modificadores. Aquí realizamos una revisión actualizada acerca de esta temática, abordando las estrategias más usadas para su identificación, los principales hallazgos obtenidos y sus implicaciones. La identificación de estos genes contribuye al esclarecimiento de los mecanismo patológicos involucrados en estas enfermedades, y puede conducir a la proposición y diseño de estrategias terapéuticas potenciales.

Poliglutaminic diseases are an increasing group of human neurodegenerative diseases caused by the expansion of repetitive sequences of CAG which give way to expanded poliglutaminic domains proteins. Ages of onset are a phenotypic marker for these diseases and show a great variation in the affected families. The number of CAG content repetitions in the causal genes, explains a 47 to 80 % of the variability of the age of onset. To explain the remaining variability, the hypothesis of modifying genes has been proposed. We have performed an updated revision of the the subject approaching the more utilized techniques to its identification, the principal findings and its implications. The identification of these genes contribute to clarify the involved pathological mechanisms in these diseases and might conduct to the proposition of potential therapeutic strategies.

Determinación y estandarización de plomo en sangre en operarios de estaciones de servicio del Estado Mérida / Blood lead determination and standardization in petrol station workers in the State of Merida

En este trabajo se ha determinado el contenido de plomo (Pb) en sangre en operarios de estaciones de servicio de la ciudad de Mérida (Venezuela) y en un grupo de personas no expuestas ocupacionalmente. Las muestras de sangre provenientes de sujetos de ambos sexos n=21 (controles) y n=65 (personal expuesto) fueron procesadas por absorción atómica con atomización electrotérmica (ETAAS). Las concentraciones obtenidas de 15,27±9,62 y 83,74±28,95 µg/L para los grupos denominados como control y expuesto respectivamente, muestran diferencias altamente significativas que evidencian una exposición directa al Pb, por cuanto los valores del grupo expuesto ocupacional son más de 5 veces superiores a los del grupo control. Los resultados obtenidos también muestran que valores iguales o superiores a 54,79 µg/L son indicadores de exposición directa al Pb, permitiendo establecer valores de tolerancia entre los intervalos de 24,89 y 112,69 µg/L. Estos valores de referencia se encuentran por debajo de lo descripto por Burguera y cols. (1997), lo cual podría atribuirse al reemplazo gradual de la gasolina con plomo, en los últimos años, que ha llevado a una disminución de un 27% en los niveles de plomo en sangre, en comparación con un estudio similar realizado en esta misma ciudad en el año 1997.

In this work the lead (Pb) content in blood was determined in petrol station workers in the city of Merida-Venezuela and in a group of people not occupationally exposed. The blood samples coming from subjects of both sexes n=21 controls and n=65 exposed workers were processed by atomic absorption with electrothermal atomization (ETAAS). The 15.27±9.62 and 83.74±28.95 µg/L concentrations obtained for the group referred to as control and exposed respectively show highly significant differences that evidence a direct exposure to Pb, since the values of the occupationally exposed group are more than 5 times higher than those of the control group. The results obtained also show that values equal to or higher than 54.79 µg/L are indicative of direct exposure to Pb, making it possible to establish tolerance values between the 24.89 and 112.69 µg/L intervals. These reference values are below what was reported by Burguera et al (1997) which could be attributed to the gradual substitution of gasoline for lead that has originated a 27% decrease in lead levels in blood, if compared with a similar study carried out in the same city in 1997.