Polimorfismos de número variable de repeticiones en tándem del intrón 2 de 5-htt y MUC 7 en pacientes venezolanos con asma o EPOC / 5-HTT intron 2 and MUC7 variable number of tandem repeats polymorphisms in a Venezuelan population with asthma or COPD

El asma y la enfermedad pulmonar obstructiva crónica (EPOC) son enfermedades inflamatorias crónicas. En ambas patologías existe broncoconstricción, producción de mediadores inflamatorios, hipersecreción de moco y migración de células inflamatorias. La serotonina tiene propiedades inmunomoduladoras que facilitan la broncoconstricción y su transportador (5-HTT) es el principal determinante de su concentración plasmática. Las mucinas (MUC) son glicoproteínas involucradas en la inmunidad innata local. El objetivo del presente trabajo fue estudiar la asociación entre polimorfismos de número variable de repeticiones en tándem (VNTR) del intrón 2 de 5-HTT (STin2) y MUC7 en pacientes venezolanos con asma o EPOC. El grupo de estudio consistió en 301 individuos (102 asmáticos, 99 EPOC, y 100 controles). No se observaron diferencias en las frecuencias de polimorfismos de MUC7 entre los grupos. Sin embargo, se encontró asociación entre alelos y genotipos de STin2 con presencia de asma o EPOC (p <0,001). El alelo STin2.9 tuvo un odds ratio (OR) de 0,15 (p=0,16) en los pacientes con asma, mientras que en los pacientes con EPOC los genotipos STin2.10/10 y 10/12 presentaron un OR de 0,33 (p=0,002) y 3,64 (p=0,002), respectivamente. Con relación a los haplotipos, el STin2/MUC7 10/10-6/6 se relacionó con riesgo en asma (OR=1,6, p=0,02) y protección en EPOC (OR=0,3, p=0,006) y el 10/12-6/6 (OR=3,7, p=0,002) fue un factor de riesgo para EPOC. En conclusión, en la población venezolana los polimorfismos de STin2 son importantes para definir factor de riesgo de enfermedad y, en consecuencia, el transportador de serotonina es relevante en ambas patologías.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are chronic inflammatory diseases. Both entities are characterized by bronchoconstriction, production of inflammatory mediators, mucus hypersecretion and inflammatory cell migration. Serotonin has immunomodulatory properties facilitating bronchoconstriction and its plasma concentration is transporter dependent (5-HTT). Mucins are glycoproteins involved in local innate immunity. The aim of this study was to assess the association between the variable number of tandem repeat polymorphisms (VNTR) of intron 2 of the serotonin ransporter (5-HTT) (STin2) and MUC7 in Venezuelan asthmatic or COPD patients. The group consisted of 301 individuals (102 asthmatics, 99 with COPD and 100 controls). There were no differences in the frequencies of MUC7 polymorphisms among the groups. However, there is a significant association between some alleles and genotypes with the presence of asthma or COPD (p <0.001). The STin2.9 allele had an odds ratio (OR) of 0.15 (p=0.16) in patients with asthma, while in patients with COPD, the STin2.10/10 and 10/12 genotypes had 0.33 (p=0,002) and 3.64 (p=0,002) OR, respectively. Regarding haplotypes, the STin2/ MUC7 10/10-6/6 is related to asthma risk (OR = 1.6, p=0.02) and COPD protection (OR=0.3, p=0.006) and 10/12-6/6 (OR=3.7, p=0.002), is a risk factor for COPD. In conclusion, in the Venezuelan population STin2 polymorphisms are important to define disease risk factor and consequently, the serotonin transporter is relevant to both pathologies.

Polimorfismos de nucleótidos simples V4 y T1 del gen ADAM33 en pacientes venezolanos con asma o enfermedad pulmonar obstructiva crónica / Single nucleotide polymorphisms V4 and T1 of the ADAM33 gene in Venezuelan patients with asthma or chronic obstructive pulmonary disease

ADAM33 es una metaloproteinasa de la matriz extracelular involucrada en la remodelación tisular y, por ello, en el asma y la enfermedad pulmonar obstructiva crónica (EPOC). Se han reportado varios polimorfismos del gen de ADAM33 asociados a la actividad enzimática. Los polimorfismos más estudiados son el V4, citosina por una guanina en la región 3’ UTR, y el T1, adenina por una guanina en el exón 19 del gen. El objetivo del presente trabajo fue determinar la posible asociación de los polimorfismos de nucleótido simple de ADAM33, V4 y T1, con la presencia de asma o EPOC en pacientes venezolanos. Los polimorfismos V4 y T1 fueron analizados en 303 individuos (103 asmáticos, 100 EPOC, y 100 controles) mediante PCR-RFLP (reacción en cadena de la polimerasa y análisis de polimorfismos por longitud de fragmentos de restricción enzimática). La frecuencia genotípica del polimorfismo V4 fue significativamente mayor (p<0,05) en ambos grupos de pacientes, asmáticos y EPOC, con respecto al control. No se encontraron diferencias significativas (P=0,4) en el polimorfismo T1. Sin embargo, se evidenció una diferencia significativa (p<0,05) cuando los haplotipos y diplotipos de ADAM33 V4/T1 se compararon entre los tres grupos. Se concluye que el polimorfismo ADAM33 V4 está asociado con la presencia de asma o EPOC en pacientes venezolanos.

ADAM33 is a metalloproteinase important in the extracellular matrix for tissue remodeling, and, consequently, in asthma and chronic obstructive pulmonary disease (COPD). Several polymorphisms of the ADAM33 gene have been associated with enzyme activity. One of the most studied polymorphisms is V4, cytosine for guanine in the 3’UTR region, and T1, adenine for guanine in the exon 19 of the gen. The aim of this study was to ascertain the possible association among single polymorphisms of ADAM33, V4 and T1, in Venezuelan patients with asthma or COPD. The polymorphisms V4 and T1 were analyzed in 303 individuals (103 asthmatic, 100 COPD and 100 controls) by PCR-RFLP (polymerase chain reaction and restriction fragment length polymorphisms). There was a significant difference (P<0.05) in the frequency of ADAM33 V4 polymorphism in both, asthmatic and COPD patients groups, as compared to controls. No significant differences (P=0.4) were found for T1 polymorphism. However, there were significant differences (P<0.05) when haplotypes and diplotypes of ADAM33 V4/T1 were compared in all three groups. It can be concluded that the polymorphism V4 of ADAM33 is associated with asthma or COPD in Venezuelan patients.

Niveles séricos de metaloproteinasa 9 (mmp-9) y del inhibidor tisular de mmp tipo 1 (timp-1) en pacientes venezolanos con asma o con enfermedad pulmonar obstructiva crónica (epoc) / Serum metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP-1 (TIMP-1) in venezuelan patients with asthma or chronic obstructive pulmonary disease (copd)

Los niveles séricos de la metaloproteinasa (MMP) 9, enzima involucrada en inflamación, y su contraparte, el inhibidor tisular de la metaloproteinasas tipo 1 (TIMP-1), se encuentran significativamente (P < 0,01) incrementados en pacientes con asma o con enfermedad pulmonar obstructiva crónica (EPOC) en comparación con los grupos control del mismo rango etario. El incremento de ambos parámetros se hace más significativo en los pacientes severos de ambos grupos (P < 0,0001) y particularmente en los pacientes con EPOC severo en comparación con los asmáticos severos (P < 0,01). El incremento en los niveles séricos de MMP-9 en relación con severidad es mayor que lo observado para TIMP-1 en ambas patologías. Se concluye que los niveles séricos de MMP-9 y TIMP-1 pueden ser un marcador importante para determinar severidad en estas enfermedades

Serum levels of metalloproteinase (MMP) 9, an enzyme involved in inflammation, and its counterpart, the tissue inhibitor of metalloproteinases type 1 (TIMP-1) are significantly (P < 0.01) increased in patients with asthma or with chronic obstructive pulmonary disease (COPD) as compared with controls of the same age. The increase in both parameters is more significant (P < 0.0001) in severe patients of both groups, and particularly in patients with severe COPD as compared to severe asthmatics (P < 0.01). The increase in serum MMP-9 levels in relation with severity is higher than the observed values for TIMP-1 in both diseases. It is concluded that serum levels of MMP-9 and TIMP-1 may be important markers to establish severity in these diseases

Estudio piloto de marcadores inflamatorios en el sindrome de apnea obstructiva del sueño / Pilot study of inflammatory markers in the syndrome of obstructive sleep apnea

El síndrome de Apnea Obstructiva del Sueño (SAOS), consiste en la aparición repetida de episodios de obstrucción faríngea durante el sueño como consecuencia de un colapso de la vía respiratoria. La respuesta fisiológica a la hipoxia intermitente crónica es la generación de una respuesta inflamatoria local y sistémica. Se han evidenciado cambios importantes a nivel cardiovascular en pacientes con SAOS; sin embargo, se desconocen cuáles marcadores séricos y genéticos pudieran ser de utilidad. En el presente estudio, se presentan 15 marcadores séricos y 3 genéticos (IL-6, IL-1β y TNF-α) en un grupo de cinco pacientes para determinar cuáles pueden ser los marcadores de interés en la aparición y en el desarrollo de esta patología respiratoria. Se proponen como marcadores los niveles séricos: proteína C reactiva, TNFα, IL-6, el receptor soluble de TNF I, sCD62, sCD154, nitrotirosina y anti-oxLDL. Los niveles de IL-1 β, el receptor de TNF soluble II, sCD25, sCD54, nitritos y nitratos no parecieran ser buenos marcadores en SAOS. Los estudios genéticos no fueron concluyentes.

Obstructive sleep apnea syndrome (OSAS) is a repeated sequences of pharynx obstruction during sleep as a consequence of airway collapse. The physiological response to the desaturation is the generation of a local and systemic inflammatory immune response. Important changes at cardiovascular levels in patients with OSAS have been observed; however, it is not know which serum or genetic parameters could be useful. In the present study, we present 15 serum and 3 genetic (IL-6, IL-1β y TNF-α) markers in a group of five patients in order to determine which marker could be useful to study the genesis and progression of this respiratory pathology. The proposed serum markers are C reactive proteín, TNFα, IL-6, soluble de TNF receptor I, sCD62, sCD154, nitrotirosine and anti-oxLDL. The levels of IL-1 β, soluble TNF receptor II, sCD25, sCD54, nitrite y nitrate do not seem to be good markers for OSAS. The genetic studies were not conclusive.

Avaliação antropométrica e bioquímica em pacientes com esquizofrenia usuários de clozapina / Anthropometric and biochemical assessment of schizophrenic patients taking clozapine

OBJETIVO: Avaliar a proporção de sobrepeso/obesidade e alterações em parâmetros bioquímicos sangüíneos em pacientes com esquizofrenia do sexo masculino, usuários de medicação antipsicótica (clozapina). MÉTODOS: Estudo transversal com 40 pacientes do sexo masculino, diagnosticados com esquizofrenia, em uso de clozapina, atendidos no Hospital de Clínicas de Porto Alegre. Foram verificadas as relações entre o índice de massa corporal, a circunferência abdominal, o percentual de gordura corporal, o perfil lipídico e o exame de glicose de jejum e a dosagem da medicação, o acompanhamento dietoterápico e a monoterapia de clozapina. RESULTADOS: Os pacientes apresentaram freqüências de 71,8 por cento de sobrepeso/obesidade, 76,9 por cento de circunferência abdominal aumentada e 94,1 por cento de percentual de gordura elevada. Foram encontrados 56,8 por cento de pacientes com lipoproteína de baixa densidade-colesterol acima do normal e 64,1 por cento com triglicerídeos elevados. Quanto maior a dosagem de clozapina utilizada maiores foram os níveis de lipoproteína de baixa densidade-colesterol (p=0,01). CONCLUSÃO: Pacientes tratados com clozapina apresentam aumento de peso e significante anormalidade lipídica, necessitando de monitoramento freqüente dos níveis plasmáticos e intervenção nutricional precoce, visando à otimização do tratamento.

OBJECTIVE: The objective was to access the overweight/obesity rates and variations of biochemical blood parameters in male schizophrenic outpatients taking antipsychotic medication (clozapine), treated at the Schizophrenia and Dementia First Aid Station of the Clinics Hospital in Porto Alegre. METHODS: This is a cross-sectional study with 40 male outpatients diagnosed with schizophrenia and taking clozapine, from the Clinics Hospital in Porto Alegre. Associations between body mass index, waist circumference, body fat percentage, lipid levels and fasting glucose and medication dosage, diet therapy and clozapine monotherapy were verified. RESULTS: There was a rate of 71.8 percent of overweight/obesity, 76.9 percent of increased waist circumference and 94.1 percent of high body fat percentage. More than half of the patients (56.8 percent) had low density lipoprotein cholesterol levels above normal and 64.1 percent had high triglycerides. LDL-cholesterol levels increased with increasing clozapine dose (p=0.01). CONCLUSION: Patients on clozapine presented excess weight and significant lipid abnormality, needing frequent monitoring of the biochemical blood parameters and early nutritional intervention to optimize treatment.

HLA y enfermedad pulmonar obstructiva crónica (EPOC) / HLA and chronic obstructive pulmonary disease (COPD)

La enfermedad pulmonar obstructiva crónica se caracteriza por una obstrucción al flujo aéreo a consecuencia de un proceso inflamatorio crónico que depende de muchos factores, entre ellos, el control a nivel genético. La presencia de polimorfismos en el sistema de antígenos leucocitarios humanos ha sido asociado con varias enfermedades. Pocos estudios se han enfocado hacia el posible rol de las variaciones en el locus antígenos leucocitarios humanos humano y el desarrollo de la enfermedad pulmonar obstructiva crónica. Se realizó la tipificación de antígenos leucocitarios humanos clase I y II en 50 pacientes de raza mestiza, con diagnóstico de enfermedad pulmonar obstructiva crónica, utilizando la técnica de PCR-SSP, comparando los pacientes estudiados con 108 controles. No se encontró diferencia estadísticamente significativa entre pacientes con enfermedad pulmonar obstructiva crónica y controles, con respecto a la frecuencia de los alelos antígenos leucocitarios humanos clase I y II. No se encontró asociación de alelos del sistema antígenos leucocitarios humanos con presencia de enfermedad pulmonar obstructiva crónica

Obstructive pulmonary disease is characterized by the progressive obstruction of air flow and it is partially reversible due to the destruction of the pulmonary parenchyma and inflammation of the air ways. The development of this inflammatory pathology depends on several factors including the major histocompatibility complex. Few studies have dealt with the possible role of major histocompatibility complex variations and obstructive pulmonary disease development and chronicity. Major histocompatibility complex class I and II genetic analysis was performed in 50 hybrid patients, with technique of amplification of specific primers (PCR-SSP) (Genovision®). As a comparison 108 controls were used. No significant differences were encountered in frequencies of class I and II patients with obstructive pulmonary disease and controls. No association was found in major histocompatibility complex polymorphism and obstructive pulmonary disease. Further studies should assess other genes for ascertain susceptibility to develop the disease

Polimorfismos de receptores semejantes a Toll 2 y 4 en pacientes con asma bronquial y enfermedad pulmonar obstructiva crónica (EPOC) / Polymorphisms of Toll-like receptors 2 and 4 in patients with bronchial asthma and chronic obstructive pulmonary disease (COPD)

Los receptores semejantes a Toll forman parte del sistema inmune. Algunas mutaciones en estos receptores se han relacionado con el desarrollo de enfermedades como el asma bronquial y la enfermedad pulmonar obstructiva crónica. Se realizó un estudio de casos-controles, en el que se incluyeron 100 pacientes con asma bronquial, 100 pacientes con enfermedad pulmonar obstructiva crónica y 100 controles. A través de la técnica de reacción en cadena de la polimerasa, se investigó la presencia de polimorfismos en TLR2 (Arg677Trp y Arg753Gln) y TLR4 (Asp299Gly y Thr399Ile) y su asociación con asma y enfermedad pulmonar obstructiva crónica. Se demostró la presencia de polimorfismos en TLR4 con una frecuencia del 9 por ciento en cada grupo de estudio. No se observó relación alguna entre la presencia de polimorfismos en TLR4 y los índices de gravedad para asma bronquial o enfermedad pulmonar obstructiva crónica. La gravedad de los pacientes con asma y enfermedad pulmonar obstructiva crónica no está relacionada con los polimorfismos en TLR 4

Toll like receptors are important in the inflammatory immune response. Several mutations of these receptors have been related to the development and chronicity of different inflammatory diseases as bronchial asthma and obstructive pulmonary disease. A case control study was performed, 100 patients with bronchial asthma, 100 obstructive pulmonary disease and 100 controls. Restriction based polymorphism PCR analysis was performed for TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes and its association with asthma and obstructive pulmonary disease was assessed. The frequency of TLR4 polymorphism was 9 percent in each group studied (asthma, obstructive pulmonary disease and controls). No association was found among TLR4 polymorphism and stage of disease for asthma or obstructive pulmonary disease. TLR4 polymorphism are not associated with the presence or severity of asthma or obstructive pulmonary disease in the Venezuelan population

Sobrepeso e obesidade em pacientes esquizofrênicos em uso de clozapina comparado com o uso de outros antipsicóticos / Overweight and obesity in schizophrenic patients taking clozapine compared to the use of other antipsychotics

INTRODUÇÃO: O uso de antipsicóticos tem sido fundamental no tratamento de portadores de esquizofrenia. Entretanto, tanto a clozapina quanto a maior parte dos antipsicóticos atípicos podem induzir um maior ganho de peso corporal e alterações metabólicas. OBJETIVO: Comparar a freqüência de sobrepeso e obesidade em pacientes esquizofrênicos expostos à clozapina com a dos expostos a demais antipsicóticos. MÉTODO: Foram estudados 121 pacientes esquizofrênicos, com idade de 18 anos ou mais, de ambos os sexos, atendidos no Ambulatório de Esquizofrenia e Demências do Hospital de Clínicas de Porto Alegre, encaminhados de forma consecutiva. Foram avaliadas medidas antropométricas de 53 pacientes em uso de clozapina e de 68 usando outros antipsicóticos, e todos preencheram os critérios diagnósticos de esquizofrenia do DSM-IV e CID-10. RESULTADOS: Não houve diferença significativa na freqüência do IMC entre os esquizofrênicos em uso de clozapina, quando comparado com o dos que usam os demais antipsicóticos. As análises mostraram uma elevada prevalência de pacientes (72,7 por cento) com excesso de peso (sobrepeso + obesidade). DISCUSSÃO: Devido à maior freqüência de excesso de peso na população esquizofrênica, pode-se evidenciar na amostra um indicativo de maior risco para transtornos vasculares e metabólicos. A ausência de diferença significativa em relação ao uso de clozapina, comparada com os demais antipsicóticos, demonstra a necessidade da montagem de estudos prospectivos determinando a magnitude de ganho de peso e o aumento de risco relativo à exposição específica de cada antipsicótico.

BACKGROUND: The use of antipsychotics has been crucial in the treatment of schizophrenic patients. However, clozapine, as well as most atypical antipsychotics, may lead to higher weight gain and metabolic changes. OBJECTIVE: To compare the frequency of overweight and obesity between schizophrenic patients exposed to clozapine to the prevalence of patients exposed to other antipsychotics. METHOD: This study assessed 121 schizophrenic outpatients aged 18 years or older, both genders, consecutively referred to an outpatient clinic for schizophrenia and dementia at Hospital de Clínicas de Porto Alegre, a public hospital in Porto Alegre, Brazil. Anthropometric measures of 53 patients taking clozapine and of 68 taking other antipsychotics were assessed. All patients met DSM-IV and ICD-10 diagnostic criteria for schizophrenia. RESULTS: There was no significant difference in body mass index between schizophrenic patients taking clozapine and patients taking other antipsychotics. Analyses showed high frequency of overweight and obesity (72.7 percent). DISCUSSION: Due to higher frequency of overweight in the schizophrenic population, it was possible to confirm a higher risk of vascular and metabolic disorders in the sample. Absence of a significant difference with regard to the use of clozapine, compared to other antipsychotics, provides evidence for the need of prospective studies in order to determine the magnitude of weight gain and risk increase related to specific exposure to each antipsychotic drug.