Expression of Vitamin D Receptor and Vitamin D Receptor Gene Polymorphisms (BsmI, FokI, and TaqI) in Patients with Pterygium / Expressão do gene do receptor da vitamina D e de seus polimorfismos (BsmI, FokI e TaqI) em pacientes com pterígio

ABSTRACT Purpose: This study aimed to determine the role of vitamin D receptor in the pathogenesis of pterygium. The vitamin D receptor eexpression levels in pterygium tissue, blood vitamin D levels, and frequency of selected vitamin D receptor gene polymorphisms (BsmI, FokI, and TaqI) were compared between patients with pterygium and healthy participants. Methods: The study included patients with pterygiumeee (n=50) and healthy volunteers (n=50). The serum vitamin D levels were measured for both groups. Immunohistochemical staining for vitamin D receptor ewas performed on sections obtained from the pterygium and adjacent healthy conjunctival tissues of the same individuals. The genomic existence of vitamin D receptor epolymorphisms (BsmI, FokI, and TaqI) were analyzed in DNA obtained from venous blood of participants using polymerase chain reaction and restriction fragment length polymorphism methods. Results: There was no difference found between the serum vitamin D levels of patients with pterygium and healthy controls. However, tissue expression of vitamin D receptor was higher in the pterygium endothelial cells of micro-vessels (p=0.002), subepithelial stromal (p=0.04), and intravascular inflammatory cells (p=0.0001), in comparison with the adjacent healthy conjunctival tissue. Moreover, while the BBtt haplotype was 2-fold higher, the bbTt haplotype was 2.5-fold lower, and the BbTT haplotype was 2.25-fold lower in the control group than in the pterygium group (p<0.001). Conclusions: Vitamin D serum levels did not differ between the healthy and pterygium groups. Vitamin D receptor expression was increased in the pterygium tissue versus the adjacent healthy tissue. However, vitamin D receptor polymorphism analysis in patients with pterygium did not reveal any significant difference in BsmI, FokI, or TaqI polymorphisms in comparison with the healthy volunteers.(AU)

RESUMO Objetivo: Determinar o papel do receptor da vitamina D na patogênese do pterígio. Os níveis de expressão do receptor da vitamina D no tecido do pterígio, os níveis sanguíneos de vitamina D e a frequência de alguns polimorfismos do gene do receptor da vitamina D (BsmI, FokI e TaqI) foram comparados entre pacientes com pterígio e participantes saudáveis. Métodos: Foram incluídos pacientes com pterígio (n=50) e voluntários saudáveis (n=50). Os níveis séricos de vitamina D foram medidos em ambos os grupos. Foi feita uma coloração imuno-histoquímica para o receptor da vitamina D em cortes obtidos do pterígio e dos tecidos conjuntivais saudáveis adjacentes dos mesmos indivíduos. A existência de polimorfismos do receptor da vitamina D (BsmI, FokI e TaqI) no genoma foi analisada em DNA obtido do sangue venoso dos participantes, usando métodos de Polymerase chain reaction (PCR) e RFLP. Resultados: Não foi observada nenhuma diferença entre os níveis séricos de vitamina D dos pacientes com pterígio e os dos controles saudáveis. Entretanto, a expressão tissular do receptor da vitamina D foi maior nas células endoteliais dos microvasos do pterígio (p=0,002), nas células estromais sub-epiteliais (p=0,04) e nas células inflamatórias intravasculares (p=0,0001), quando comparada à expressão no tecido conjuntival saudável adjacente. Além disso, embora o haplótipo BBtt tenha sido duas vezes mais frequente, o haplótipo bbTt foi 2,5 vezes menos frequente e o haplótipo BbTT foi 2,25 vezes menos frequente no grupo de controle do que no grupo com pterígio (p<0,001). Conclusões: Os níveis séricos de vitamina D não apresentaram diferenças entre o grupo de pessoas saudáveis e o com pterígio. A expressão do receptor da vitamina D mostrou-se maior no grupo com pterígio do que no tecido saudável adjacente. Entretanto, a análise dos polimorfismos do receptor da vitamina D nos pacientes com pterígio não revelou qualquer diferença significativa nos polimorfismos BsmI, FokI ou TaqI em comparação com os voluntários saudáveis.(AU)

Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review protocol

Gastrointestinal bleedings (GIB) are one of the most frequent adverse drug reactions. Among the GIB upper gastrointestinal bleeding (UGIB) stands out due to their high mortality. The different idiosyncratic responses related to UGIB ​​in medication users may be due to the presence of genetic variants in the genes that encode enzymes that are targets of pharmacokinetic and pharmacodynamic activity of the metabolism of the drugs, such as cyclooxygenase 1, endothelial nitric oxide synthase, cytochrome P450, among others. Although a review has focused on assessment whether the presence of CYP2C9*2 and CYP2C9*3 could increase UGIB diagnosis, the search is outdated, and more evidence can be identified regarding both CYP polymorphisms and other genes potentially involved with UGIB. The objective of the systematic review is to explore case-control or case-case studies to assess the epidemiological association between genetic polymorphisms and UGIB. This review will consider genetic polymorphisms of case-control and case-case studies and their association with the UGIB, in the presence or absence of drugs exposure. Electronic searches will be performed in PubMed, Scopus and the Cochrane Library with no time limit. Two researchers will select registries and extract data on study and population characteristics, exposure, covariates, and outcomes. Critical appraisal will consider Joanna Briggs tool for case-control studies. Studies will, where possible, be pooled with statistical meta-analysis. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation, where appropriate.(AU)

ERG11 gene polymorphisms and susceptibility to fluconazole in candida isolates from diabetic and kidney transplant patients

Abstract INTRODUCTION: Candidiasis is the most frequent opportunistic mycosis in humans and can cause mortality, particularly in immunodeficient patients. One major concern is the increasing number of infections caused by drug-resistant Candidas trains, as these cannot be efficiently treated with standard therapeutics. The most common mechanism of fluconazole resistance in Candida is mutation of ERG11, a gene involved in the biosynthesis of ergosterol, a compound essential for cell integrity and membrane function. METHODS: Based on this knowledge, we investigated polymorphisms in the ERG11 gene of 3 Candida species isolated from immunocompromised and immunocompetent patients. In addition, we correlated the genetic data with the fluconazole susceptibility profile of the Candida isolates. RESULTS: A total of 80 Candida albicans, 8 Candida tropicalis and 6 Candida glabrata isolates were obtained from the saliva of diabetic, kidney transplant and immunocompetent patients. Isolates were considered susceptible to fluconazole if the minimum inhibitory concentration was lower than 8 μg/mL. The amino acid mutations F105L, D116E, K119N, S137L, and K128T were observed in C. albicans isolates, and T224C and G263A were found in C. tropicalis isolates. CONCLUSIONS: Despite the high number of polymorphisms observed, the mutations occurred in regions that are not predicted to interfere with ergosterol synthesis, and therefore are not related to fluconazole resistance.

Miopatía por estatinas y vitamina D / Statin-Related Myopathy and Vitamin D

Las estatinas son fármacos habitualmente seguros y bien tolerados, muy eficaces para la prevención de trastornos cardiovasculares. La presencia de mialgias, poco frecuente, pero con incidencia dispar en diversos reportes, es una de las causas de abandono de su uso. También las distintas denominaciones (mialgia, miopatía, rabdomiólisis) y la subjetividad de cada paciente para referirlas han creado confusión en el tema. Se ha comenzado a reportar asociación entre niveles de vitamina D sérica disminuida y mayor riesgo de miopatía, por un lado, y trabajos donde pacientes que las abandonaban a causa de mialgias, con deficiencia de vitamina D, pueden tolerarlas una vez que se suplementa la vitamina hasta valores deseables. La presencia de polimorfismos en genes de enzimas que metabolizan o transportan a las estatinas es otro factor claramente relacionado con miopatía. Es posible que el déficit de vitamina D deba ser considerado un factor de riesgo para desarrollar miopatía por estatinas, como lo serían también la administración simultánea de fármacos que se metabolizan por la misma vía de citocromo P450, o la presencia de los polimorfismos mencionados. En conclusión, el hallazgo de tener deficiencia de vitamina D se asocia a miopatía por estatinas, o que es un factor de riego para desarrollarla, abre nuevas perspectivas para un gran número de pacientes que abandonan este tratamiento debido a esta patología. (AU)

Statins are usually safe and well tolerated drugs, very effective for preventing cardiovascular complications. The rare presence of myalgia, with different incidence as reported by several studies, is one of the causes of lack of drug compliance. Also the different symptoms referred (myalgia, myopathy, rhabdomyolysis) and the lack of objetivity of each patient when referring to the symptoms, have created confusion in this matter. Associations between decreased vitamin D levels and increased risk of myopathy has been reported. Indeed, studies describing patients with vitamin D deficiency who are not compliant due to myalgia show that they become tolerant to the drugs once the vitamin is supplemented to desirable values. The presence of gene polymorphisms for enzymes that metabolize or transport statins is another factor clearly related to myopathy. Therefore, we should consider vitamin D deficiency and other conditions such as the simultaneous administration of drugs that are metabolized by the same cytochrome P450 pathway, or the presence of mentioned polymorphisms as a risk factor for developing myopathy due to statins. In conclusion, the finding that vitamin D deficiency is associated with statin myopathy, or is a risk factor its develpoment, opens new perspectives for a large number of patients who leave this treatment due to this condition. (AU)

Status de selênio de uma população residente em área de risco de contaminação por mercúrio: influência de polimorfismos e ação sobre o estresse oxidativo / Selenium status of a population living in a mercury contamination risk area: influence of polymorphisms and action on oxidative stress

Estudos apontam que a região Amazônica apresenta concentrações significativas de selênio nos solos e que, por isso, a população não estaria susceptível à deficiência desse mineral. Em contrapartida, a região também apresenta dados de concentrações elevadas de mercúrio nos solos e rios, entretanto, a população não apresenta sinais clínicos evidentes de contaminação. Acredita-se que o selênio, um mineral antioxidante, possa ser um possível colaborador para a aparente tolerância ao mercúrio, pois uma das ações desse mineral é a de destoxificar o organismo contra metais tóxicos. Dependendo das concentrações no organismo, o mercúrio pode potencializar a geração das espécies reativas de oxigênio e, dessa forma, as defesas antioxidantes intrínsecas das células podem ser prejudicadas, resultando na condição conhecida por estresse oxidativo. A contaminação por mercúrio pode, ainda, comprometer a saúde tanto das mulheres quanto das crianças, pois esse metal, na forma de metilmercúrio, pode atravessar a barreira placentária e se concentrar, principalmente, no cérebro do feto. Aliado a isso, a presença de polimorfismos em certos genes podem alterar a expressão de enzimas antioxidantes como a glutationa peroxidase 1, que é dependente de selênio, assim como da glutationa S-transferase, que atua na destoxificação do mercúrio no organismo. Vários estudos apresentam dados de concentrações de mercúrio em ribeirinhos da Amazônia, no entanto, resultados referentes às concentrações de selênio, ao estresse oxidativo e a polimorfismos genéticos na população da área urbana são raros. Diante disso, este estudo objetivou avaliar o estado nutricional relativo ao selênio, concentrações de mercúrio e a possível relação desses parâmetros com o estresse oxidativo e os polimorfimos Pro198Leu (rs 1050450) no gene da glutationa peroxidase 1 e GSTM1 no gene da glutationa S-transferase em mulheres em idade fértil residentes em área de risco de exposição ao mercúrio, da cidade de Porto Velho (RO). As voluntárias foram avaliadas por meio de medidas antropométricas (peso, estatura e circunferência da cintura) e aplicou-se o registro alimentar para avaliação do consumo alimentar. Realizou-se uma coleta de sangue para análise de selênio, atividade da enzima glutationa peroxidase, marcadores de estresse oxidativo e polimorfismos genéticos. O selênio foi determinado por espectrometria de absorção atômica com geração de hidretos acoplados à cela de quartzo (HGQTAAS). Para análise de mercúrio, foi coletada uma amostra do cabelo das voluntárias, sendo sua concentração determinada pelo método de espectrometria de absorção atômica com geração de vapor frio (CV AAS). Para avaliar o estresse oxidativo foram determinadas: a concentração plasmática de Malondialdeído (MDA) e a Capacidade de Absorção de Radicais de Oxigênio (ORAC). Participaram do estudo 200 mulheres com idade entre 19 e 50 anos. A ingestão alimentar média de selênio foi de 49,3 ± 19,2 µg/dia e a prevalência de ingestão inadequada foi de 40,9%. As concentrações médias do mineral no plasma e nos eritrócitos foram, respectivamente, 49,8 + 18,6 µg/L e 75,4 + 29,9 µg/L. A atividade média da glutationa peroxidase foi de 45,1+ 19,4 U/g Hb. A concentração média de mercúrio nos cabelos foi de 625 + 766 ng g-1. Ao avaliar a presença do SNP Pro198Leu, observou-se que 56,7% das participantes apresentaram genótipo selvagem, 36,8% heterozigotos e 6,8% homoizgotos para leucina. Quanto ao polimorfismo de deleção GSTM1, 42,5% das voluntárias apresentaram o genótipo nulo ou deletado, ou seja, relacionado a ausência de expressão da glutationa S-transferase. Esses resultados permitem concluir que a maioria das participantes apresentou estado nutricional deficiente em relação ao selênio. Apesar disso, tanto a atividade enzimática da glutationa peroxidase, como os biomarcadores do estresse oxidativo não sofreram interferência desta deficiência. O polimorfismo Pro198Leu, também não interferiu no status de selênio e no estresse oxidativo. Quanto à avaliação do polimorfismo GSTM1, o genótipo nulo ou deletado também não mostrou associação com as concentrações de mercúrio e o estresse oxidativo

Studies have shown that the Amazon region has significant concentrations of selenium in soils and therefore, the population is not susceptible to deficiency of this mineral. However, the region also presents data from high levels of mercury in soils and rivers, however, the population has no obvious clinical signs of contamination. It is believed that selenium, an antioxidant mineral may be a possible contributor to the apparent tolerance because of its actions in the detoxification of the body from toxic metals. Depending on the concentrations in the body, mercury can increase the generation of reactive oxygen species and thus the intrinsic antioxidant defenses of cells can be damaged, resulting in the condition known as oxidative stress. The mercury contamination may also compromise the health of both women and children, since this metal in the form of methylmercury can cross the placental barrier and concentrate mainly in the fetal brain. In addition, the presence of genetic polymorphisms can alter the expression of antioxidant enzymes such as glutathione peroxidase 1, which is selenium dependent, as well as glutathione S-transferase, which can be responsible for the mercury detoxification in the body. Several studies have shown mercury levels of riverine people from Amazon, however, results regarding selenium concentrations, oxidative stress and polymorphisms in the urban population are area. Thus, this study aimed to evaluate selenium status, mercury levels and the possible relationship of these with oxidative stress and genetic polymorphisms Pro198Leu (rs 1050450) in glutathione peroxidase 1 gene and GSTM1 in the glutathione S-transferase gene in women living in mercury exposure risk area, from the city of Porto Velho (RO). The of the volunteers was assessed using anthropometric measurements (weight, height and waist circumference) and evaluation of food consumption, by the food record. Blood samples were collected for selenium analysis, glutathione peroxidase enzyme's activity, oxidative stress and genetic polymorphisms. Selenium was determined by hydride generation quartz tube atomic absorption spectroscopy (HGQT AAS). For mercury analysis, a hair sample of volunteers was collected, and its concentration was determined by atomic absorption spectrometry method with cold vapor (CV AAS). To evaluate oxidative stress plasma concentrations of malondialdehyde (MDA) and Oxygen Radical Absorbance Capacity (ORAC) were determined We enrolled 200 volunteers aged between 19 and 50. The average of selenium intake was 49,3 ± 19,2 µg/day and the prevalence of inadequate intake was 40,9%. Mean selenium concentration on plasma and erythrocytes were respectively 49,8 + 18,6 µg/L and 75,4 + 29,9 µg/L. Glutathione peroxidase showed mean activity of 45,1 + 19,4 U/g Hb and mercury levels of 625 + 766 ng g-1. Evaluating the presence of the SNP Pro198Leu, it was observed that 56,7% of the were participants had wild type genotype, 36,8% heterozygous and 6,8% were homozygous for leucine. For the GSTM1 null deletion polymorphism, 42,5% of the volunteers had a null genotype, ie, do not express the enzyme glutathione S-transferase. These results indicate that the majority of participants had selenium deficiency in plasma and erythrocytes. Nevertheless, most of them had adequate activity of glutathione peroxidase. There was no association between selenium concentrations and the biomarkers used to assess oxidative stress. The Pro198Leu polymorphism did not interfere in selenium concentrations, as well as in the oxidative stress. The evaluation of GSTM1 polymorphism had no association with mercury levels and oxidative stress

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association / Polimorfismos NR3C1 em brasileiros de ascendência caucasiana, africana e asiática: sensibilidade aos glicocorticoides e associação de genótipos

Objective : The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population. Materials and methods : We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K d ), and DEX-50% inhibition (IC 50 ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced. Results : Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K d , IC 50 , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG- (0.7 ± 0.2 mg) compared to GC- (0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg). Conclusion : The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism ...

Objetivo : Este estudo avalia polimorfismos (SNPs) do NR3C1 na população brasileira, que possui origem étnica heterogênea. Materiais e métodos : SNPs do NR3C1 foram avaliados em brasileiros de ancestralidade caucasiana, africana ou japonesa (n = 380). Em um subgrupo (n = 40), os genótipos foram comparados à sensibilidade aos glicocorticoides (GC), previamente avaliada por cortisol plasmático (PF) e salivar (SF) após supressão com dexametasona (DEX), ensaio de afinidade do receptor ao GC (K d ) e inibição por DEX de 50% da proliferação de mononucleares estimulada por concanavalina-A (IC 50 ). Discriminação alélica de p.N363S (rs6195), p.ER22/23EK (rs6189-6190) e BclI (rs41423247) foi realizada por PCR em tempo real. Éxons 3 a 9 e transições éxon/íntron foram amplificados e sequenciados. Resultados : Frequências genotípicas (%) foram: rs6195 (n = 380; AA:96,6/AG:3,14/GG:0,26), rs6189-6190 (n = 264; GG:99,6/GA:0,4), rs41423247 (n = 264; CC:57,9/CG:34,1/GG:8,0), rs6188 (n = 155; GG:69,6/GT:25,7/TT:4,7), rs258751 (n = 150; CC:88,0/CT:10,7/TT:1,3), rs6196 (n = 176; TT:77,2/TC:20,4/CC:2,4), rs67300719 (n = 137; CC:99,3/CT:0,7), e rs72542757 (n = 137; CC:99,3/CG:0,7). Enquanto rs67300719 e rs72542757 foram exclusivos dos nipodescendentes, p.N363S e p.ER22/23EK estavam ausentes nesses indivíduos. p.ER22/23EK foi exclusivo dos descendentes de caucasianos. Equilíbrio de Hardy-Weinberg foi observado, exceto nos nipodescendentes para rs6188 e rs258751 e nos afrodescendentes para p.N363S. K d , IC 50 , PF ou SF basal ou após DEX foram semelhantes entre os genótipos. Entretanto, a dose média de DEX que suprimiu PF ou SF diferiu entre os genótipos BclI (P = 0,03), sendo maior nos carreadores GG (0,7 ± 0,2 mg) comparada aos GC (0,47 ± 0,2 mg) e CC (0,47 ± 0,1 mg). Conclusão : As ...

Tabagismo e variação ponderal: a fisiopatologia e genética podem explicar esta associação?: [revisão] / Smoking and changes in body weight: can physiopathology and genetics explain this association?: [review]

O tabagismo é a principal causa de morte prevenível na maioria dos países, inclusive no Brasil. Parar de fumar é uma estratégia importante para reduzir a morbidade e mortalidade associada às doenças tabaco-relacionadas. Sabe-se da relação inversa entre uso de nicotina e peso corporal, onde o índice de massa corporal tende a ser menor em fumantes quando comparados aos não fumantes. Além disso, abstinência tabágica resulta em aumento de peso, sendo que ex-fumantes geralmente aumentam de 5 a 6 kg, mas cerca de 10 por cento adquirem mais de 10 kg. O tratamento farmacológico para a cessação do tabagismo pode atenuar este ganho de peso. O aumento de peso na cessação do tabagismo como contributório à epidemia de obesidade é pouco estudado. Nos EUA, calcula-se que a fração do problema atribuível à cessação do tabagismo seja de 6 por cento para homens e 3,2 por cento para mulheres. Os mecanismos não são claros, mas há evidências mostrando que a dopamina e serotonina diminuem a ingestão alimentar. A administração de nicotina por qualquer via eleva agudamente os níveis destes neurotransmissores no cérebro, causando menor necessidade de ingestão energética e diminuindo o apetite. Além disso, a nicotina tem efeito direto no metabolismo do tecido adiposo, influenciando a taxa de ganho ponderal após a cessação do tabagismo. A leptina, grelina e neuropeptídio Y são peptídeos que podem contribuir para esta relação inversa entre nicotina e índice de massa corporal, em um papel ainda não determinado como conseqüente ou causador das variações ponderais.

Tobacco use is the leading preventable cause of death in most countries, including Brazil. Smoking cessation is an important strategy for reducing the morbidity and mortality associated with tobacco-related diseases. An inverse relationship between nicotine use and body weight has been reported, in which body weight tends to be lower among smokers than among nonsmokers. Smoking abstinence results in an increase in body weight for both males and females. On average, sustained quitters gain from 5 to 6 kg, although approximately 10 percent gain more than 10 kg. Pharmacological treatment for smoking cessation attenuates weight gain. The importance of smoking cessation as a contributing cause of the current obesity epidemic has been little studied. In the USA, the rate of obesity attributable to smoking cessation has been estimated at approximately 6.0 and 3.2 percent for males and females, respectively. Although the mechanisms are unclear, there is evidence that dopamine and serotonin are appetite suppressants. The administration of nicotine, regardless of the delivery system, acutely raises the levels of these neurotransmitters in the brain, reducing the need for energy intake and consequently suppressing appetite. In addition, nicotine has a direct effect on adipose tissue metabolism, influencing the rate of weight gain following smoking cessation. Leptin, ghrelin and neuropeptide Y are substances that might constitute factors involved in the inverse relationship between nicotine and body mass index, although their roles as determinants or consequences of this relationship have yet to be determined.

Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells

The BubR1 mitotic-checkpoint protein monitors proper attachment of microtubules to kinetochores, and links regulation of chromosome-spindle attachment to mitotic-checkpoint signaling. Thus, disruption of BubR1 activity results in a loss of checkpoint control, chromosomal instability caused by a premature anaphase, and/or the early onset of tumorigenesis. The mechanisms by which deregulation and/or abnormalities of BubR1 expression operate, however, remain to be elucidated. In this study, we demonstrate that levels of BubR1 expression are significantly increased by demethylation. Bisulfite sequencing analysis revealed that the methylation status of two CpG sites in the essential BubR1 promoter appear to be associated with BubR1 expression levels. Associations of MBD2 and HDAC1 with the BubR1 promoter were significantly relieved by addition of 5-aza-2'-deoxycytidine, an irreversible DNA methyltransferase inhibitor. However, genomic DNA isolated from 31 patients with colorectal carcinomas exhibited a +84A/G polymorphic change in approximately 60% of patients, but this polymorphism had no effect on promoter activity. Our findings indicate that differential regulation of BubR1 expression is associated with changes in BubR1 promoter hypermethylation patterns, but not with promoter polymorphisms, thus providing a novel insight into the molecular regulation of BubR1 expression in human cancer cells.

Chromosomal comparisons among and within populations of Simulium (Chirostilbia) pertinax (Diptera, Simuliidae)

Chromosomal studies were carried on six larval populations of Simulium (Chirostilbia) pertinax from different locations in Brazil. Larvae were collected in the states of Paraná, Rio Grande do Sul, Rio de Janeiro and São Paulo. Polytene chromosome map comparisons within and among populations showed no differences in banding pattern, except for some limited polymorphism (secondary NOR and four band polymorphisms). There were no chromosomal variations associated with the resistance or susceptibility of the larvae to temephos. The chromosomal homosequentiality found among the six populations suggests that S. pertinax may be a monomorphic species

La biotransformación de la esparteína en amerindios cunas de Panamá / Biotransformation of sparteine in Amerindians cunas of Panamá

Reportamos, por vez primera, un estudio de oxidación metabólica en un grupo amerindio: los cunas de Panamá. Estudios genéticos indican un escaso mestizaje de menos del 1% de mezcla racial y establecen la identidad genética del grupo cuna con respecto a otros grupos amerindios que se remonta, a lo menos, a 5,000 años. Ciento nueve voluntarios recibieron 50 mg de esparteína y recogieron sus orinas por 12 horas, para determinar la cantidad que contenían de esparteína y de sus dos productos de oxidación. El porcentaje del medicamento intacto recuperado de la orina, así como de sus metabolitos, fue menor que el encontrado en otros grupos étnicos y está normalmente distribuido. La razón metabólica, que es un índice de eficiencia de la actividad de la isozima involucrada en la biotransformación de la esparteína, indica que no existen metabolizadores deficientes en este grupo y que la frecuencia de los metabolizadores extensos muestra una distribución unimodal. Por esas razones concluimos diciendo que en el grupo cuna, a diferencia de los grupos caucasoides, no existe polimorfismo en la oxidación de la esparteína. Además la ausencia de metabolizadores deficientes entre los cunas indica que este grupo, en comparación con los caucasoides, se encuentra en menor riesgo de desarollar reacciones tóxicas al usar medicamentos que siguen la ruta de la esparteína