Evolução da técnica de PCR: sua contribuição no diagnóstico da infecção por HPV / Evolution of techinique PCR: its contribution to infection diagnosis by HPV

Introdução: a reação em cadeia da polimerase (PCR) é a técnica de biologia molecular mais utilizada na detecção viral, principalmente em situações onde a quantidade de DNA disponível é pequena. O papilomavírus humano (HPV) representa um dos mais graves problemas de saúde pública e está associado ao câncer do colo do útero, especialmente em países em desenvolvimento, como o Brasil, que desde 2009 já apresentava 40 mil novos casos por ano. Objetivo: descrever a evolução da PCR e sua contribuição no diagnóstico do HPV. Metodologia: realizou-se uma revisão de literatura a partir de publicações disponíveis em base de dados eletrônicos, como Science Direct, SciELO, Pubmed, Instituto Nacional do Câncer e Ministério da Saúde do Brasil, nos últimos cinco anos. Resultados: dentre as técnicas citadas nesta revisão de literatura, todas têm alta relevância na detecção de genotipagem do HPV, embora a escolha quanto ao melhor desempenho fique a critério do pesquisador. A técnica de Nested PCR demonstra ser a mais vantajosa na detecção do vírus, pelo fato de ter uma maior sensibilidade, em comparação com as demais. Conclusão: a técnica PCR possui alta sensibilidade (90-100%) e apresenta 92,8 a 100% de especificidade, sendo padrão ouro para a detecção de DNA do HPV, em amostras citológicas do câncer de colo do útero. Assim, os dados obtidos permitem constatar que a técnica PCR, utilizada para o rastreamento do HPV, é considerada padrão ouro, tendo maior sensibilidade, especificidade e velocidade de análise, devendo ser o método de escolha para o diagnóstico eficiente do HPV.

Introduction: polymerase chain reaction (PCR) is the most widely used molecular biology technique for viral detection, especially in situations where the amount of available DNA is small. Human papillomavirus (HPV) represents one of the most serious public health problems and is associated with cervical cancer, especially in developing countries such as Brazil that has had 40,000 (forty thousand) new cases a year, since 2009. Objective: to describe the evolution of PCR and its contribution to HPV diagnosis. Methodology: a literature review was conducted from publications available in electronic databases, such as Science Direct, SciELO, Pubmed, National Cancer Institute and Ministry of Health of Brazil, in the last five years. Results: among the techniques cited in this literature review, all have high relevance in the detection of HPV genotyping, although the choice for the best performance is at the discretion of the researcher. The Nested PCR technique proves to be the most advantageous in detecting the virus because it has a higher sensitivity compared to the others. Conclusion: the PCR technique has high sensitivity (90-100%) and presents 92.8 to 100% specificity, being the gold standard for the HPV DNA detection in cytology samples of uterus cervix cancer. Thus, the data obtained show that the PCR technique used for HPV screening is considered the gold standard, having greater sensitivity, specificity and speed of analysis, and should be the method of choice for the efficient diagnosis of HPV.

Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report.

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.

Association of type 1 diabetes mellitus and autoimmune disorders in Brazilian children and adolescents.

CONTEXT: Type 1 diabetes mellitus (T1DM) is caused by an immune-mediated destruction of pancreatic beta cells. Other autoimmune diseases can be observed in association with T1DM. The screening for celiac disease (CD) and Hashimoto's thyroiditis is necessary due to the increased prevalence of these pathologies in T1DM patients. AIMS: This study aimed to investigate the prevalence of autoimmune markers for pancreatitis, thyroiditis, and CD in racially admixtured children and adolescents with T1DM. SETTINGS AND DESIGN: Cross-sectional clinic-based study. METHODS: Seventy-one patients with T1DM (average: 11.6 ± 5.1 years). In all patients, the following antibodies were surveyed: Anti-glutamic acid decarboxylase (anti-GAD), immunoglobulin A (IgA) anti-transglutaminase (anti-tTG), Antithyroglobulin (AAT), anti-thyroid peroxidase (anti-TPO), and IgA. STATISTICAL ANALYSIS USED: The quantitative variables were expressed as a mean and standard deviation and the qualitative variables in contingency tables. Student's t-test and χ(2) tests were used to assess the differences between the groups. The level of significance was established as P < 0.05. RESULTS: The prevalence of anti-GAD antibodies was 5.9%; anti-tTG IgA, 7.4%; anti-TPO, 11.8%; and AAT, 11.8%. CONCLUSIONS: Children and adolescents with T1DM have increased the prevalence of antithyroid and CD-related antibodies. The positivity for anti-GAD and antithyroid antibodies was less frequent than in other studies. The prevalence of anti-tTG antibodies was similar to the literature.

Effects of Pamidronate on Dental Enamel Formation Assessed by Light Microscopy, Energy-Dispersive X-Ray Analysis, Scanning Electron Microscopy, and Microhardness Testing.

The aim of the present work was to investigate birefringence and morphology of the secretory-stage enamel organic extracellular matrix (EOECM), and structural and mechanical properties of mature enamel of upper incisors from adult rats that had been treated with pamidronate disodium (0.5 mg/kg/week for 56 days), using transmitted polarizing and bright-field light microscopies (TPLM and BFLM), energy-dispersive X-ray (EDX) analysis, scanning electron microscopy (SEM) and microhardness testing. BFLM showed no morphological changes of the EOECM in pamidronate and control groups, but TPLM revealed a statistically significant reduction in optical retardation values of birefringence brightness of pamidronate-treated rats when compared with control animals (p0.05). The present study indicates that pamidronate can affect birefringence of the secretory-stage EOECM, which does not seem to be associated with significant changes in morphological and/or mechanical properties of mature enamel.

Interstitial 14q24.3 to q31.3 deletion in a 6-year-old boy with a non-specific dysmorphic phenotype.

BACKGROUND: Few patients with interstitial deletions in the distal long arm of chromosome 14 have been reported, and these patients showed rather indistinct features, including growth and mental retardation and phenotypic alterations. RESULTS: We describe a de novo 14q interstitial deletion in a 6-year-old boy with dysmorphic facial traits such as hypertelorism, short and narrow palpebral fissures, broad nose with anteverted nostrils, long philtrum, thin upper lip with cupid's bow, prominent and everted lower lip, mildly low-set ears, as well as moderate developmental delay and mild mental retardation. Array-CGH mapped the deletion to the region 14q24.3 to 14q31.3, including 13.11 Mb, proximal to the imprinted genomic region of 14q32. CONCLUSION: This mild phenotypic presentation suggests that the deleted segment does not contain essential genes for early organ development. Twenty-two genes with known functions, including Neurexin III (NRXN3, OMIM 600567), map to the region deleted in the propositus.

Proteus syndrome: Clinical diagnosis of a series of cases.

OBJECTIVES: This paper describes the clinical diagnosis of Proteus syndrome (PS) in children referred for evaluation of asymmetric disproportionate overgrowth. MATERIALS AND METHODS: Retrospective, descriptive, cross-sectional study conducted from January 1998 to December 2010. RESULTS: During the study period, 2011 new patients were evaluated. Thirteen (0.65%) patients presented features suggestive of PS. These patients were formally evaluated based on the revised diagnostic criteria proposed by Biesecker. The mean age was 6.92 ± 5.1 years. Ten patients (76.9%) were females. All subjects had asymmetric disproportionate overgrowth. Other dysmorphic features were as follows: macrodactily (84.6%); linear epidermal nevus (41.6%); hemangioma (30.7%); and lipoma (23%). Six patients fulfilled the diagnostic criteria for PS. CONCLUSIONS: The diagnostic rate of only 46.1% of patients with PS confirms the diagnostic difficulties and the need for continuous monitoring and periodic review of these patients since the clinical manifestations of this syndrome become more evident with aging. Molecular tests may help the differential diagnosis of Proteus syndrome when they became commercially available.

Effect of soy protein supplementation in patients with chronic hepatitis C: a randomized clinical trial.

AIM: To evaluate the effects of soy supplementation on insulin resistance, fatty liver and alanine aminotransferase (ALT) levels in non-diabetic patients with chronic hepatitis C (CHC). METHODS: In a prospective, randomized and single-blinded clinical trial, we compared patients with CHC who had casein as a supplement (n = 80) (control group), with patients who consumed a soy supplement diet (n = 80) [intervention group (IG)]. Both groups received 32 g/d of protein for 12 wk. RESULTS: Patients' baseline features showed that 48.1% were overweight, 43.7% had abdominal fat accumulation, 34.7% had hepatic steatosis and 36.3% had an homeostasis model assessment index of insulin resistance (HOMA-IR) ≥ 3.0. Descriptive analysis showed that protein supplementation diet reduced hepatic steatosis in both groups; however, significant reductions in ALT levels occurred in the soy group. Multiple regression modeling indicated that in the presence of severe fibrosis (F3/F4), γ glutamyl transferase elevation and high density lipoprotein (HDL) reduction, the intervention group had 75% less chance of developing hepatic steatosis (OR= 0.25; 95% CI: 0.06-0.82) and 55% less chance of presenting with an ALT level ≥ 1.5 × the upper limit of normal (ULN) (OR = 0.45, 95% CI: 0.22-0.89). Soy treatment did not have any effect on insulin resistance (OR = 1.92; 95% CI: 0.80-4.83), which might be attributed to the fact that the HOMA-IR values at baseline in most of our patients were in the normal range. Advanced hepatic fibrosis, an ALT level > 1.5 × ULN and visceral fat were predictors of an HOMA-IR ≥ 3. The IG group had a reduced risk of an ALT level > 1.5 × ULN. An HOMA-IR ≥ 3.0 and HDL < 35 mg/dL were also risk factors for increased ALT. CONCLUSION: Soy supplementation decreased ALT levels and thus may improve liver inflammation in hepatitis C virus (HCV) patients; it also reduced hepatic steatosis in a subgroup of patients but did not change insulin resistance. It should be considered in the nutritional care of HCV patients.

HLA class II polymorphism in patients with type 1 diabetes mellitus from a Brazilian racially admixtured population.

BACKGROUND: Several studies have demonstrated a fundamental role for the histocompatibility antigens (ie, human leukocyte antigens or HLA) in the susceptibility of, or protection to, type 1 diabetes mellitus (T1DM). However, this has not been adequately studied in racially admixtured populations. OBJECTIVES: To assess the frequency of HLA class II (DQA1, DQB1 and DRB1) associated to susceptibility or protection toT1DM in a Brazilian racially admixtured with diabetes. METHODS: Cross-sectional study. The HLA genotyping was performed by a polymerase chain reaction hybridization assay. The racial groups were categorized by self-report and phenotype. The results are expressed as means and standard deviations of the mean, proportions and frequencies. The chi2 and Fisher exact tests were used for the inferential statistics. RESULTS: The study population comprised 55 children and adolescents with T1DM. The phenotypic racial group classification demonstrated that, 60% were Mulattoes, 25.5% Whites, 12.7% Blacks and 1.8% from Indian ancestry. The T1DM's susceptibility was associated with an increased frequency of the HLA of risk (-DRB1*0401, -DRB1*0402, DQA1*03, -DQA1*05, -DQB1*02 e -DQB1*0302); and a small frequency of protective alleles (-DRB1*0404, -DRB1*0407, -DQA1*0201, -DQB1*0602, -DQB*0603 e -DQB1*0604) in all subjects. We found a greater frequency of the HLA-DRB1*0302 among Whites when compared to Blacks. CONCLUSIONS: This study demonstrates that the frequency and distribution of the susceptibility and protective HLA alleles were similar to studies performed in the Brazilian Southeast and in North Americans and European Caucasians, suggesting that the genetic basis of T1DM has a common origin being little modified by racial characteristics.

O papel do complexo principal de histocompatibilidade na fisiologia da gravidez e na patogênese de complicações obstétricas / Major histocompatibility complex: its role in the physiology of pregnancy and in the pathogenic mechanisms of obstetric complications

Este trabalho tem por objetivo discutir a estrutura e função dos Antígenos Leucocitários Humanos (HLA), seus métodos de detecção, nomenclatura e os mecanismos imunopatológicos que o associam com a fisiologia da gestação e morbidades obstétricas. Sabe-se que o equilíbrio imunológico entre mãe e concepto é imprescindível na manutenção da gravidez. Moléculas do HLA - notadamente o HLA-G expresso na interface materno-fetal - exercem função importante na tolerância imunológica materna, evitando rejeição fetal e algumas complicações obstétricas. Além disso, o HLA permeia diversas etapas do desenvolvimento conceptual como clivagem, formação do trofoblasto e implantação. Para revisão, foram pesquisados os bancos de dados MEDLINE e LILACS, utilizando os descritores: "HLA antigens"; "pregnancy"; "embryonic development"; "pregnancy complication"; "abortion, habitual"; "pre-eclampsia". O conhecimento sobre a influência do HLA na gravidez é necessário para melhor manejo da gestação e patologias obstétricas auto-imunes, favorecendo intervenções precoces e terapêutica específica, reduzindo a morbimortalidade materna e perinatal.

The aim of this paper is to review Human Histocompatibility Antigens (HLA) structure and function, its detection methods, nomenclature and pathogenic mechanisms associated with pregnancy physiology and obstetrics diseases. Immunological equilibrium between mother and conceptus is indispensable for the maintenance of pregnancy. Molecules from the HLA - mainly HLA-G expressed in the mother-fetus interface - fulfill an important function in maternal immune tolerance, contributing to avoid fetal rejection and obstetrical complications. In addition, HLA influences different stages of fetal development, such as embryonic cleavage, trophoblast, formation and implantation. For this review, were surveyed in the MEDLINE and LILACS databases, using the following keywords: "HLA antigens", "pregnancy", "embryonic development", "pregnancy complication", "abortion, habitual", "pre-eclampsia". Knowledge of the HLA role in pregnancy is necessary to improve pregnancy management and autoimmune obstetrical illnesses, by allowing early interventions and specific therapeutics to reduce maternal and perinatal morbidity and mortality.

Síndromes genéticas: uma causa de diabetes mellitus na infância e adolescência / Genetic syndromes: a cause of diabetes mellitus in infancy and adolescence

Muitas síndromes genéticas se associam ao desenvolvimento de diabetes mellitus, como resultado de resistência insulínica, insulinopenia e deficiências vitamínicas. Em algumas delas o diabetes está sempre presente, como nas síndromes de Wolfram, Wolcott-Rallison, Rogers, Donohue e Rabson-Mendehall. Em outras o diabetes, embora nem sempre esteja presente, está freqüentemente associado, como nas síndromes de Prader-Willi, Bardet-Biedl, Alstrõm, Turner, Down e Klinefelter. Apesar das manifestações clínicas serem bastante variadas, recomenda-se a investigação de síndromes genéticas em todo paciente com diabetes que apresente surdez neurossensorial, atrofia óptica, anemia megaloblástica, diabetes insipidus, história familiar materna de diabetes, alterações urinárias e respiratórias, distúrbios neurológicos, miopatias e dismorfias ao exame clínico. Também devem ser investigados os portadores de síndromes genéticas comumente associadas ao diabetes. A disponibilidade de testes genéticos, o diagnóstico pré-natal e a identificação precoce das complicações tratáveis associadas a estas síndromes justificam a revisão desse tema.

Frequency of celiac disease and its serological markers in patients with autoimmune hepatitis

Transglutaminase (anti-tTG) and anti-endomysial (AEA) antibodies were reported to occur in patients with autoimmune hepatitis (AIH) as well as in subjects with advanced cirrhosis, but the prevalence of celiac disease (CD) in patients with AIH is either negligible or unknown. The frequency of IgA anti-tTG and IgA AEA was determined in 64 patients (54 females, mean age 19[5-67] years ) with AIH diagnosed according to international criteria. Patients with positive or intermediate results for those antibodies were submitted to duodenal biopsy and HLA-DQ2 or DQ8 typing. Anti-tTG and AEA were detected in 6 (9 por cento) and one patient (1.6 por cento) with AIH, respectively. Positive and borderline results for IgA anti-tTG were detected, respectively, in two (3 por cento) and four (6 por cento) patients. Only one patient with HLA-DQ2 and IgA anti-tTG and IgA AEA had CD on duodenal biopsy. Two patients with either positive or borderline results for IgA anti-tTG antibody and HLA-DQ2 had normal histology on duodenal biopsy. IgA anti-tTG antibody and/or AEA were observed in 9% of AIH patients, but CD was confirmed in only one of them. The occurrence of IgA anti-tTG antibody in the other patients could be ascribed to the presence of chronic liver disease or to latent or potential CD.

Acompanhamento ambulatorial de crianças e adolescentes com diabetes melito tipo 1 na cidade de Salvador / Outpatient follow-up for children and adolescents with diabetes mellitus type 1 in the city of Salvador

Conhecer o perfil do acompanhamento ambulatorial de indivíduos com enfermidades crônicas como o diabetes melito tipo 1 (DM1) é importante para avaliar a qualidade do atendimento, identificar falhas e propor ações que visem a melhorar os serviços médicos prestados a essa população. Para isso, realizou-se estudo de corte transversal, aplicando um questionário a uma amostra de 71 crianças e adolescentes com DM1, acompanhadas em 3 ambulatórios de Endocrinologia Pediátrica na cidade de Salvador (BA), entre agosto a outubro de 2004. Os resultados demonstram dificuldades quanto ao satisfatório acompanhamento ambulatorial devido ao elevado custo financeiro do tratamento, escassez de equipes multidisciplinares, pouco conhecimento sobre aspectos importantes no cuidado da doença e inexistência de um laboratório central onde todos os exames possam ser realizados gratuitamente. Ao retratar as dificuldades encontradas no acompanhamento ambulatorial de crianças e adolescentes com DM1, este trabalho contribui para o planejamento de ações e desenvolvimento de estratégias com o objetivo de reduzir a morbi-mortalidade associada ao diabetes. Além disso, é essencial que as comunidades médica e leiga exijam políticas públicas de apoio e gratuidade para tratamento desta doença.

It is important to know the outpatient follow-up profile of individuals with chronic illnesses such as diabetes mellitus type I (DM1), to evaluate the quality of care, identify mistakes, and propose measures to improve the medical services offered to this population. To achieve these objectives, a cross-sectional study was performed using a survey with a sample of 71 children and teenagers with DM1, treated in three Pediatric Endocrinology clinics in Salvador, BA, from August to October 2004. The results demonstrate difficulties in achieving an optimal level of outpatient health care due to the high costs of treatment, shortage of multidisciplinary teams, poor knowledge regarding important aspects of treating the disease, and absence of a central laboratory where all the necessary exams could be performed free. The recognition of these factors will help to develop plans and strategies to reduce the morbidity and mortality rates of this disease. In addition, it is essential that the medical and social communities demand public policies to support and offer medical follow-ups at no costs to these patients.

[Environmental exposure to endocrine disruptors with estrogenic activity and the association with pubertal disorders in children]. / Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças.

Endocrine disruptors are exogenous substances with adverse health effects in intact organisms or their progeny, secondary to changes in endocrine function. Recent years have witnessed constant reports of environmental factors with hormone-like effects causing pubertal or reproductive abnormalities in animals. The few cases proven to be associated with pubertal disorders in humans have been related to accidental exposure. Nevertheless, pediatricians and parents recommend suspending all possible estrogen-contaminated food, especially meat (poultry, beef) and soy products, when the child presents with a pubertal disorder. These recommendations, if not scientifically sound, may have deleterious consequences by eliminating sources of dietary protein and possibly delaying the investigation of other potential and treatable causes. On the other hand, not investigating potential side effects of these products could have similar harmful effects. The current article describes the main endocrine disruptors associated with pubertal disorders in humans and concludes that except for accidental exposure to high doses, more research is needed on the effects of chronic and low-dose exposures in altering human pubertal development.

Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças / Environmental exposure to endocrine disruptors with estrogenic activity and the association with pubertal disorders in children

A substância exógena que causa efeitos adversos na saúde de um organismo ou sua descendência, como resultado de distúrbios na função hormonal, é denominada interferente endócrino. Nos últimos anos, produtos ambientais com atividades hormonais têm sido documentados como causadores de anormalidades puberais ou reprodutivas em animais. Os poucos casos comprovados em humanos foram aqueles relacionados a exposições acidentais. Apesar disso, pediatras e pais recomendam a suspensão de todos os alimentos potencialmente contaminados, em especial carne (aves, gado) e derivados da soja quando a criança apresenta alguma alteração puberal. Estas recomendações, se não embasadas cientificamente, podem ter conseqüências deletérias, não apenas pela eliminação de fontes protéicas da dieta, como também por retardar a investigação de causas tratáveis. Por outro lado, a não investigação dos efeitos adversos destes produtos é da mesma forma danosa. Esta revisão descreve os principais interferentes endócrinos responsáveis por alterações puberais em humanos e conclui que, excetuando exposições acidentais a altas quantidades destes produtos, mais estudos são necessários para responsabilizar a ação crônica e em baixas doses destas substâncias na alteração do tempo de desenvolvimento puberal em nossa espécie.

Endocrine disruptors are exogenous substances with adverse health effects in intact organisms or their progeny, secondary to changes in endocrine function. Recent years have witnessed constant reports of environmental factors with hormone-like effects causing pubertal or reproductive abnormalities in animals. The few cases proven to be associated with pubertal disorders in humans have been related to accidental exposure. Nevertheless, pediatricians and parents recommend suspending all possible estrogen-contaminated food, especially meat (poultry, beef) and soy products, when the child presents with a pubertal disorder. These recommendations, if not scientifically sound, may have deleterious consequences by eliminating sources of dietary protein and possibly delaying the investigation of other potential and treatable causes. On the other hand, not investigating potential side effects of these products could have similar harmful effects. The current article describes the main endocrine disruptors associated with pubertal disorders in humans and concludes that except for accidental exposure to high doses, more research is needed on the effects of chronic and low-dose exposures in altering human pubertal development.

A clinical study of 77 patients with mucopolysaccharidosis type II.

AIM: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II). METHODS: Details of the patients and their disease manifestations were obtained from a review of medical records, interviews with the patients and/or their families, and physical examination of the patients. RESULTS: Mean birth weight was 3360 g, median age at onset of symptoms was 18 months and median age at diagnosis was 6 years. For the whole sample (median age, 8.2 years; range, 2.8-53.0 years), neurological degeneration, typical pebbly skin lesions, seizures and extensive dermal melanocytosis were found in 23.3, 13.0, 13.0 and 1.3% of the cases, respectively. The most frequently reported echocardiogram abnormality was mitral valve regurgitation. Refraction errors were the most common ophthalmological manifestation. The following characteristics were found to be associated with the severe form of MPS II: earlier age at biochemical diagnosis, higher levels of urinary glycosaminoglycans, language development delay, behavioural disturbances, poor school performance and mental retardation. CONCLUSION: Our results suggest that there is a considerable delay between the onset of signs and symptoms and the diagnosis of MPS II in Brazil (and probably in South America as well), and that many complications of this disease are underdiagnosed and undertreated. Therefore, the implementation of programmes aiming to increase the awareness of the disease, the availability of biochemical diagnostic tests and the provision of better support to affected patients is urgently needed.

[Distribution and frequency of HLA alleles and haplotypes in Brazilians with type 1 diabetes mellitus]. / Distribuição e freqüência de alelos e haplotipos HLA em brasileiros com diabetes melito tipo 1.

The genetic predisposition to type 1 diabetes (DM1) is associated with genes of the human leukocyte antigen (HLA) system, specially the HLA-DR and -DQ. In Caucasians, the HLA-DR3 and -DR4 antigens are associated with susceptibility and the -DR2, with protection. In Brazil, a country with a large miscegenation of European Caucasians, Native Amerindians and African Blacks, the genetic basis of DM1 has not been adequately studied. The aim of this paper is to present a critical review of articles indexed in the MEDLINE and LILACS-BIREME data basis about the association of HLA with DM1 in Brazilians. Eight papers, all of them from the Southeast region, were found. Immunogenetic susceptibility to DM1 in Brazilians was associated with HLA-DRB1*03, -DRB*04, -DQB1*0201, -DQB1*0302 alleles, and protection against DM1 was associated with HLA-DQB1*0602, -DQB1*0301 alleles and -DR2 and -DR7 antigens. Since the Brazilian population is not racially homogeneous, it is not possible to extrapolate studies from a single region to the remainder of the country. It is necessary to study populations from different regions to identify new associations or to strengthen associations with the ones already identified. This knowledge will contribute to future prophylactic or therapeutic interventions in the group of Brazilians at risk of developing DM1.

Immunogenetics and infectious diseases: special reference to the mayor histocompatibility complex.

Many studies have tried to identify genetic markers for infectious diseases, some of them have focused on human leukocyte antigens (HLA). The products of HLA genes interact with surface-specific receptors of T lymphocytes, resulting in activation of the host's immune response. Association of bacterial, viral, parasitic and fungal infections with the host's HLA has been widely investigated. The type and strength of this association differs among distinct populations, as well as among racial and/or ethnic groups. The new molecular methods for the identification of the HLA alleles, and the resulting new nomenclature, have contributed to a better understanding of this system. Unfortunately, this information has not been adequately transmitted to clinicians, which hampers the understanding of the association between the HLA system and diseases. We revised relevant studies on the association of HLA genes with infectious diseases, demonstrating their importance in the pathogenic mechanisms, through increased susceptibility or protection against infections and their complications.

Influência dos antígenos de histocompatibilidade humanos na susceptibilidade e expressão clínica de doenças psiquiátricas / Influence of human histocompatibility antigens on susceptibility to and clinical expression of psychiatric diseases

A compreensão da base molecular das doenças é cada vez mais importante para seu diagnóstico, prevenção e tratamento. Localizado no braço curto do cromossomo 6, o sistema de histocompatibilidade humano - human leukocyte antigen (HLA) - participa da patogênese de algumas enfermidades psiquiátricas. O surgimento de métodos moleculares para tipificação dos alelos HLA e as recentes atualizações de sua nomenclatura têm contribuído para um melhor entendimento desse sistema. Infelizmente, essas informações não têm sido adequadamente veiculadas na literatura clínica. São objetivos desse trabalho: revisar a estrutura e função dos antígenos HLA, métodos de tipificação e nomenclatura atual e descrever seus mecanismos de associação com esquizofrenia, transtorno bipolar do humor e autismo. Foram pesquisados, através das bases de dados MEDLINE e LILACS, artigos publicados no período de 1995 a 2005, a fim de refletir o conhecimento mais recente sobre o assunto. Conclui-se que os antígenos de histocompatibilidade humanos influenciam o risco, quadro clínico e resposta terapêutica de algumas doenças psiquiátricas, mesmo não sendo eles os únicos atuantes no processo patológico. Embora o HLA tenha sido associado com esquizofrenia (HLA-DRB1*0101), autismo (HLA-DR4) e transtorno bipolar do humor (HLA de classe I), essas associações variam entre diferentes etnias e formas clínicas das doenças. A melhor definição de marcadores genéticos associados a distúrbios psiquiátricos é importante para elucidar possíveis mecanismos envolvidos na sua patogenia, estimar o risco individual de desenvolver essas doenças e contribuir para futuras intervenções profiláticas ou terapêuticas.

Understanding the molecular basis of diseases is increasingly more important for their diagnosis, prevention, and treatment. Located in the short arm of chromosome 6, the human histocompatibility system - human leukocyte antigens (HLA) - participates in the pathogenesis of some psychiatric disorders. Development of new molecular methods to typify HLA alleles and recent nomenclature updates have been contributing to a better understanding of this system. Unfortunately, this information has not been adequately disclosed in the medical literature. This article aims to review HLA structure, antigen function, detection methods, and current nomenclature, as well as to describe its association with schizophrenia, bipolar disorder, and autism. Articles published between 1995 and 2005 (to reflect the most recent knowledge of the subject) were searched in the MEDLINE and LILACS databases. It is concluded that HLA antigens influence risk, clinical status, and therapeutic response of some mental disorders, even if they do not act alone on these pathologic processes. Although HLA has been associated with schizophrenia (HLA-DRB1*0101), autism (HLA-DR4), and bipolar disorder (HLA class I), these associations vary across different ethnicities and clinical manifestations. The best definition of genetic markers associated with mental disorders is important to understand possible pathogenic mechanisms, predict individual risk of developing these diseases, and contribute to future prophylactic or therapeutic interventions.

[Human histocompatibility system association with gastrointestinal diseases]. / Associação do sistema de histocompatibilidade humano com doenças gastrintestinais.

Genetic, immunological and environmental factors are involved in the pathogenesis of the gastrointestinal diseases. Situated on the short arm of the chromosome 6, the HLA system is very polymorphic and has the capacity to confer susceptibility or resistance to different diseases. The relationship HLA vs. disease differs with the disease and, sometimes, with the ethnic-racial group studied. Histocompatibility molecules could determine the age of onset, the treatment response and the clinical course for some diseases. The recent discovery of new methods to typify HLA alleles and the changes in its nomenclature has contributed to a better understanding of this system. Nevertheless, has not thoroughly widespread. The aim of this review is to discuss the HLA structure and function, methods of detection, nomenclature and its association with celiac disease, Crohn's disease, autoimmune hepatitis, autoimmune pancreatitis and oral recurrent ulcers.