Interplay of Oxidative Stress and Nitric Oxide Synthase Gene Expression on Cardiovascular Responses in Preeclampsia / Interação do estresse oxidativo e da expressão dos genes das óxido nítrico sintases nas respostas cardiovasculares na pré-eclâmpsia

Abstract Objective To assess the influence of oxidative stress on the gene expression of nitric oxide synthases (NOS 3 and NOS 2) and, hence, the cardiovascular responses in preeclampsia. Methods This was a case control study in which patients with preeclampsia (PE group) and normal pregnancy controls (NP group) were included according to the guidelines of the American College of Obstetricians and Gynecologists (ACOG). The serum levels of malondialdehyde (MDA), total antioxidant capacity, and nitric oxide (NO) were estimated, and the heart rate andmean arterial pressure were recorded. The gene profiling of NOS3 and NOS2 was performed through real-time polymerase chain reaction (RT-PCR). The statistical analysis was performed using the Student t-test, and values of p<0.05 were considered statistically significant. Results The serum levels of malondialdehyde were increased (p<0.0001), and the total antioxidant capacity was reduced in the PE group (p=0.034), indicating oxidative stress. In the PE group, themean arterial pressure was significantly higher (p<0.0001), but the serum levels of NO did not show a statistically significant reduction (p=0.20). The gene expression profiling of NOS3 and NOS2 revealed a down regulation in the PE group by 8.49 and 51.05 times respectively. Conclusion Oxidative stress may lead to endothelial dysfunction, which could result in increased mean arterial pressure. Nitric oxide may play a role in this mechanism, but interactions with other vasoactive /biological substances cannot be overlooked, as the gene expression of NOS3 and NOS2 has been reduced.

Resumo Objetivo Avaliar a influência do estresse oxidativo na expressão genética das óxido nítrico sintases (nitric oxide synthases, NOS, em inglês; NOS 3 e NOS 2) e, consequentemente, nas respostas cardiovasculares na pré-eclâmpsia. Métodos Este foi um estudo caso-controle no qual pacientes com pré-eclâmpsia (grupo PE) e controles comgravidez normal (grupo GN) foramincluídos de acordo com as diretrizes do American College of Obstetricians and Gynecologists (ACOG). Foram estimados os níveis séricos de malondialdeído (MDA) da capacidade antioxidante total, e de óxido nítrico (nitric oxide, NO, em inglês). A frequência cardíaca e a pressão arterial média foram registradas. O perfil genético da NOS3 e da NOS2 foi feito por reação em cadeia de polimerase em tempo real (real-time polymerase chain reaction, RT-PCR, em inglês). A análise estatística foi feita utilizando-se o teste t de Student, e valores de p<0,05 foram considerados estatisticamente significativos. Resultados Os níveis séricos de malondialdeído sérico estavam aumentados (p<0,0001), e a capacidade antioxidante total, reduzida no grupo PE (p=0,034), o que indicava estresse oxidativo. No grupo PE, a pressão arterial média era significativamente maior (p<0,0001), mas os níveis séricos de NO não demostraram redução estatisticamente significativa (p=0,20). O perfil de expressão genética da NOS3 e da NOS2 revelou uma regulação negativa no grupo PE de 8,49 e 51,05 vezes, respectivamente. Conclusão O estresse oxidativo pode levar à disfunção endotelial, o que pode resultar em aumento da pressão arterialmédia. O NO pode desempenhar umpapel neste mecanismo, mas as interações com outras substâncias vasoativas/biológicas não podem ser negligenciadas, uma vez que a expressão genética da NOS3 e da NOS2 foi reduzida.

El paciente hemofílico: consideraciones clínicas y moleculares de importancia para el odontólogo / Hemophilic patients: clinical and molecular considerations of interest to dentists

RESUMEN Introducción: La hemofilia es una enfermedad genética poco frecuente en la consulta odontológica. En algunas situaciones se presenta como una urgencia odonto-estomatológica, en la que el profesional debe relacionar las manifestaciones clínicas generales de la enfermedad, con una correcta semiología, paraclínicos y análisis genético-molecular, para diagnosticar y aplicar pertinentes terapéuticas dirigidas a resolver el motivo de consulta del paciente así como el manejo y control de sus complicaciones. Objetivo: Describir los principales aspectos fisiopatológicos generales y de importancia odontológica de la hemofilia, así como las herramientas diagnósticas desde el punto de vista clínico, paraclínico y genético-molecular. Métodos: Búsqueda bibliográfica en las bases de datos Pubmed, Proquest, Scielo y Elsevier, en idioma inglés y español, en las que se seleccionaron artículos publicados en un periodo de 13 años para un total de 50 (2005-2018), empleando los descriptores "hemophilia A, hemophilia B, diagnostic criteria, genetic, molecular, oral health, clinical diagnosis". Análisis e integración de la información: Los estudios han demostrado que la hemofilia, una condición genética y sistémica, tiene repercusiones bucales en el contexto de sus manifestaciones y complicaciones, lo que la hace importante para el odontólogo, debido a que debe ser diagnosticada desde el punto de vista genético-molecular y manejada interdisciplinariamente. Conclusiones: La implicación del diagnóstico genético-molecular por parte del genetista soporta la integración del hematólogo y el odontólogo para el manejo y control de la interconsulta cuando se trata de pautar procedimientos en pacientes con hemofilia(AU)

ABSTRACT Introduction: Hemophilia is a genetic disease scarcely found in dental practice. On occasion it presents as a dental emergency in face of which the professional should relate the general clinical manifestations of the disease to an appropriate semiological, paraclinical and genetic-molecular analysis to diagnose the condition and apply relevant therapies aimed at solving the patient's main concern as well as managing and controlling its complications. Objective: Describe the main general pathophysiological features and aspects of dental interest of hemophilia, as well as the diagnostic tools related to the condition from a clinical, paraclinical and genetic-molecular perspective. Methods: A bibliographic search was conducted in the databases Pubmed, Proquest, Scielo and Elsevier of papers published in English and Spanish in a period of 13 years (2005-2018), using the search terms "hemophilia A", "hemophilia B", "diagnostic criteria", "genetic", "molecular", "oral health", "clinical diagnosis". A total 50 papers were selected. Data analysis and integration: Studies have shown that hemophilia, a genetic systemic condition, may have oral manifestations and complications. This makes it important to dentists, since the disease should be diagnosed from a genetic-molecular point of view and managed in an interdisciplinary manner. Conclusions: Genetic-molecular diagnosis by geneticists implies involvement of hematologists and dentists in the management and control of the condition via interconsultation, when it comes to deciding on procedures for hemophilic patients(AU)

[Diagnosis and follow-up of patients with congenital hypothyroidism detected by neonatal screening]. / Diagnóstico y seguimiento de los pacientes con hipotiroidismo congénito diagnosticados por cribado neonatal.

The screening program of congenital hypothyroidism (CH) is probably one of the best achievements in paediatrics. Thyroid hormones are essential for brain development and brain maturation that continue through the neonatal period. Hypothyroidism that begins in the first months of life causes irreversible damage to the central nervous system, and is one of the most frequent and preventable causes of mental retardation. As children with congenital hypothyroidism are born with a normal appearance, analytical studies are required to immediately start the appropriate therapy. This article analyses the aims, diagnostic procedures, tests required, aetiology, and differential diagnosis in this disorder. Especially relevant is to perform frequent monitoring to ensure dose adjustments of L-Thyroxine therapy, avoiding infra- or supra-dosing that negatively affects neurosensory functions. Re-evaluation of the aetiology permanent vs transient hypothyroidism is always recommended after 3years of chronological age. The relevance of this screening program should be widely discussed in paediatrics. The main objective is to avoid cerebral damage in these patients, and has been highly successful and economically beneficial. Other aspects are required to optimise patient outcomes, to perform all the controls according to the recommendations and to include, in the near future, the diagnosis of central hypothyroidism. Implementation of this program is necessary to progress in accordance with current scientific knowledge.

Assessment of the impact of glioma diagnostic reclassification following the new 2016 WHO classification on a series of cases. / Evaluación del impacto del cambio diagnóstico de los gliomas aplicando la nueva clasificación de la OMS de 2016 sobre una serie de casos.

BACKGROUND AND OBJECTIVES: The aim of this project is to assess diagnostic reclassification based on molecular data over morphology in a series of glial tumours since the introduction of the 2016 WHO classification of brain tumours. MATERIALS AND METHODS: Retrospective review of glial tumours (oligodendrogliomas and astrocytomas) treated in our centre between January 2012 and June 2016 in which a review of diagnosis was performed when molecular studies were added. Statistical analysis included evaluation of variables of epidemiology, morphology and molecular data (mainly IDH mutation and 1p19q codeletion), diagnostic changes after new classification was considered, and clinical impact in cases of diagnostic reclassification. RESULTS: From a total of 147 glial tumours reviewed in our centre, molecular diagnosis was obtained in 74 cases (50.3%). Initial diagnosis changed in 23 cases (31%), and 20 (87%) of them had a prior histological diagnosis of oligodendroglioma (69.6% grade ii and 17.4% grade iii). Only 3 of these 23 cases diagnosis changed from astrocytoma to oligodendroglioma. Among reclassified tumours, there was a common molecular pattern, as findings showed mutant IDH in 16 cases (69.6%) and no codeletion in 20 cases (87%). According to the cell of origin, of the whole group of 27 oligodendrogliomas in our series (reclassified and non-reclassifed), 20 cases (74%) became astrocytomas, despite typical oligodendroglial morphology, due to absence of 1p19q codeletion. There was a trend for diagnosis reclassification in younger patients (<40 years), P=.065, mainly in those with a prior diagnosis of oligodendroglioma, with no statistical differences based on gender or clinical data. Besides, reclassification was more common among tumours with mutant IDH (69.6%), P=.003, than those with wild type IDH. In terms of survival, despite receiving different treatments, no significant changes were detected between reclassified and non-reclassified tumours after a mean follow-up of 16 months, partly related to lower grade of these lesions. CONCLUSIONS: Within the spectrum of the glial tumours treated in our institution, this new classification including molecular genetics over morphological data has provided marked diagnostic changes. These changes appear mainly in tumours previously diagnosed as oligodendrogliomas and in younger patients, with molecular patterns of mutant IDH and 1p19q codeletion. Although diagnosis reclassification may affect clinic, prognosis or therapeutic management of these tumours, deeper and prospective studies on these specific aspects are needed.

La historia de la genética, se considera que comienza con el trabajo del monje Agustino Gregor Mendel; su investigación sobre hibridación en guisantes, publicada en 1866, describe lo que más tarde se conocería como las leyes de Mendel. [Editorial] / The history of genetics is considered to begin with the work of the Augustinian monk Gregor Mendel; his research on hybridization in peas, published in 1866, describes what would later be known as the laws of Mendel. [Editorial]

La historia de la genética, se considera que comienza con el trabajo del monje Agustino Gregor Mendel; su investigación sobre hibridación en guisantes, publicada en 1866, describe lo que más tarde se conocería como las leyes de Mendel. En 1900 marcó el redescubrimiento de Mendel por parte de Hugo de Vries, Carl Correns y Erich Von Tschermak. En 1915 los principios básicos de la genética mendeliana habían sido aplicados a una amplia variedad de organismos, donde destaca notablemente el caso de la mosca de la fruta Drosophila melanogaster. Bajo el liderazgo de Thomas Hunt Morgan y sus compañeros drosofilistas (especialistas en genética), desarrollaron la teoría mendeliana-cromosómica de la herencia, la cual fue mpliamente aceptada para el año de 1925

The apoptotic, angiogenic and cell proliferation genes CD63, S100A6 e GNB2L1 are altered in patients with endometriosis / Os genes apoptóticos, angiogênicos e de proliferação celular CD63, S100A6 e GNB2L1 estão alterados em pacientes com endometriose

Abstract Objective The aim of the present study was to analyze the expression of the CD63, S100A6, and GNB2L1genes, which participate in mechanisms related to the complex pathophysiology of endometriosis. Methods A case-control study was conducted with 40 women who were diagnosed with endometriosis, and 15 fertile and healthy women. Paired samples of eutopic endometrium and endometriotic lesions (peritoneal and ovarian endometriotic implants) were obtained from the women with endometriosis in the proliferative (n = 20) or secretory phases (n = 20) of the menstrual cycle. As controls, paired endometrial biopsy samples were collected from the healthy women in the proliferative (n = 15) and secretory (n = 15) phases of the samemenstrual cycle.We analyzed the expression levels of the CD63, S100A6, and GNB2L1 genes by real-time polymerase chain reaction. Results An increase in CD63, S100A6, and GNB2L1 gene transcript levels was observed in the ectopic implants compared with the eutopic endometrium of the women with and without endometriosis, regardless of the phase of the menstrual cycle. Conclusion These findings suggest that the CD63, S100A6, and GNB2L1 genesmay be involved in the pathogenesis of endometriosis, since they participate in mechanisms such as inhibition of apoptosis, angiogenesis and cell proliferation, which lead to the loss of cell homeostasis in the ectopic endometrium, thus contributing to the implantation and survival of the tissue in the extrauterine environment.

Resumo Objetivo O objetivo do presente estudo foi analisar a expressão dos genes CD63, S100A6 e GNB2L1, que participam em mecanismos relacionados à complexa fisiopatologia da endometriose. Métodos Um estudo caso-controle foi realizado com 40 mulheres diagnosticadas com endometriose e 15 mulheres férteis e saudáveis. Amostras pareadas de endométrio eutópico e de lesões endometrióticas (implantes endometrióticos peritoneais e ovarianos) foram obtidas de mulheres com endometriose nas fases proliferativa (n = 20) ou secretora (n = 20) do ciclo menstrual. Como controle, amostras pareadas de biópsia endometrial foram coletadas de mulheres saudáveis nas fases proliferativa (n = 15) e secretora (n = 15) nomesmo ciclomenstrual. Foram analisados os níveis de expressão dos genes CD63, S100A6 e GNB2L1 por reação em cadeia da polimerase em tempo real. Resultados Foi observado um aumento nos níveis de transcritos dos genes CD63, S100A6 e GNB2L1 em implantes ectópicos quando comparado ao endométrio eutópico de mulheres com e sem endometriose, independente da fase do ciclo menstrual. Conclusão Estes achados sugerem que os genes CD63, S100A6 e GNB2L1 podem estar envolvidos na patogênese da endometriose, pois participam de mecanismos como inibição de apoptose, angiogênese e proliferação celular, os quais levam à perda da homeostase celular no endométrio ectópico e, portanto, contribuem para o implante e a sobrevivência do tecido no ambiente extrauterino.

[New mutation in a young woman diagnosed with Niemann-Pick disease type C]. / Nueva mutación descrita en una mujer joven con esplenomegalia, diagnosticada de enfermedad de Niemann-Pick tipo C.

BACKGROUND AND OBJETIVE: To describe a new molecular variant of Niemann-Pick disease type C (NPC) in a 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes. MATERIAL AND METHODS: NPC1 is the main gene with described mutation in NPC disease. Here we report a case with a new mutation, p.N916S, not described before in a patient diagnosed with NPC. RESULTS: p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master, PolyPhen2 and SIFT. CONCLUSIONS: p.N916S is a new mutation detected as a cause of NPC disease in a patient without severe neurological symptoms.

Análisis molecular de familias uruguayas con Enfermedad de Huntington / Molecular analysis of the Uruguayan families with Huntington’s Disease

Introducción: La Enfermedad de Huntington (EH) es un trastorno neurodegenerativo; autosómico dominante, con expresividad variable y penetrancia completa. La prevalencia estimada es entre 1-4 cada 100.000 habitantes. Es causada por expansión de tripletes CAG en el exón 1 del gen IT-15 que conduce a la síntesis de una proteína con una región de poliglutaminas expandidas que forman agregados en el núcleo celular induciendo a la apoptosis. Los alelos normales presentan un número menor a 26 tripletes CAG, y aquellos con más de 40 conducirán siempre a la enfermedad. Alelos de entre 26 a 36 repetidos se consideran normales “mutables” y de 36 a 39 repetidos generan un riesgo aumentado de desarrollar la enfermedad. Objetivo: Poner a punto el diagnóstico molecular en una población uruguaya, mediante la determinación del tamaño exacto de la mutación en personas afectadas o con sospecha clínica de EH, mediante el uso de técnicas de biología molecular. Métodos: Pacientes de la Policlínica de Enfermedad de Parkinson y Movimientos Anormales del Hospital de Clínicas. La determinación del número de repetidos se realizó mediante técnicas de amplificación del ADN por PCR y posterior análisis en geles de poliacrilamida y secuenciación. Resultados: Realizamos el diagnóstico molecular de 16 pacientes, 15 con un diagnóstico clínico previo, y uno asintomático. Se descartó el diagnóstico de EH en otros dos individuos analizados. Conclusiones: Hemos logrado la puesta a punto del estudio molecular para la enfermedad de EH por primera vez en nuestro país. Esta prueba es de gran utilidad como diagnóstico confirmatorio, etiológico o diferencial de EH.

Introduction: Huntington disease (HD) is a neurodegenerative disorder with an autosomal dominant inheritance mode, complete penetrance and variable clinical expressivity. The estimated prevalence is 1 to 4 per 100.000 individuals. It is caused by a CAG triplet expansion in exon 1 of the IT-15 gene which codes for a protein with an enlarged polyglutamine region. This leads to the formation of protein aggregates in the cell nucleus and induces apoptosis. Normal alleles show less than 26 CAG repeats, and those over 40 always lead to the disease. Alleles with 26 to 36 repeats are considered normal “mutable” alleles and those between 36 to 39, are considered in a gray zone with increased risk of developing the disease. Aims: To develop a diagnosis of HD in a uruguayan population and determine the exact size of the mutation in clinically affected subjects using molecular biology techniques. Methods: Patients were derived from Neurology Clinic of the “Hospital de Clínicas”. The determination of the CAG repeat number was done using polymerase chain reaction (PCR) technique, subsequent analysis on polyacrilamide gels and sequencing. Results: We performed the molecular diagnosis in 18 patients with clinical suspicion of HD. Fifteen of them had a previous clinical diagnosis and one had no symptoms. Besides, in two additional individuals this test allowed us to discard HD. Conclusions: A molecular diagnostic for HD disease was developed for the first time in our country. This test is of great clinical utility as a confirmatory, etiological, or differential diagnosis.

La genética del trastorno antisocial de la personalidad: Una revisión de la bibliografía / Genetics of antisocial personality disorder: review of the literature

The antisocial personality disorder (ASPD) is characterized by an incapacity for an individual to adapt himself or herself to the social norms. These social norms are extremely important because they govern many aspects of behavior during adolescence and adulthood. Patients with ASPD typically have irritability problems and aggressive feelings toward other people. These aggressive feelings toward other people are expressed in a context of threat and intimidation. The ASPD is less common in clinical settings comparing the total population, in which the prevalence is 1.1. The familial aggregation for ASPD has been registered, in which the 40-50% of the variance can be explained to genetic influences. Most of the studies of ASPD in molecular genetics have been applying the hypothesis of association of candidate genes, focusing on genes associated with neurotransmission pathways. This has been greatly relevant to the monoamine oxidase gene (MAO). Genes that promote specific behavior between individuals must have been selected through the process of natural selection. Aggressive behaviors and other types of behavior that have an evolutionary origin are similar in the fact that they have to be codified in the genes and will later be transmitted to their descendants.

El trastorno antisocial de la personalidad (TAP) consiste en una incapacidad para adaptarse a las normas sociales que habitualmente rigen numerosos aspectos de la conducta de las personas en la adolescencia y la edad adulta. Los pacientes con TAP característicamente tienen problemas de irritabilidad y sentimientos agresivos hacia los demás, los cuales se expresan en el contexto de la amenaza o la intimidación. El TAP es menos común en la clínica comparándolo con la población general en la que se reporta una prevalencia media del 1.1. Se ha registrado una agregación familiar para el TAP en la que el 40-50% de la varianza puede ser explicada por influencias genéticas. La mayoría de los estudios de genética molecular en el TAP se han realizado utilizando la hipótesis basada en los estudios de asociación con genes candidatos, enfocándose en los genes relacionados a vías de neurotransmisión, siendo uno de los más relevantes, hasta el momento, el gen para la monoamino oxidasa (MAOA). Aquellos genes que promueven que cierta conducta exista entre los individuos debieron haberse elegido a través del proceso de la selección natural. De manera similar a otros comportamientos que tienen orígenes evolutivos, los comportamientos agresivos también deben ser codificados en los genes, que a la postre serán transmitidos a la descendencia.

Molecular Markers in Thyroid Cancer / Marcadores moleculares en el cáncer de tiroides

Advances in thyroid molecular biology studies are providing not only insight into thyroid development of diseases but may offer diagnostic and therapeutic potential in thyroid cancer. Objective: To describe the molecular aspects of thyroid cancer reported in international scientific literature, as well as their indications and epidemiological impact, through a descriptive bibliographical review. Method: Articles were searched in the EMBASE, and PubMed/Medline databases. Inclusion criteria were: publication between 1985 and 2012; keywords "molecular" AND "markers" AND "thyroid" AND "cancer". With these documents in hands, an analytical reading was done and the papers organized by themes. Results: Out of the 609 documents found, 85 were selected to present information on several molecular, epidemiological, and practices-related aspects of thyroid cancer. Articles were assessed and classified according to predetermined categories, especially number and types of markers analyzed. Among the most relevant information, we can mention the indications for use of molecular markers in thyroid cancer, which are found in more than 70 % of papillary and follicular thyroid carcinomas. The use of these markers will probably improve the diagnosis of malignancy in thyroid nodules and it may also allow individualization of surgical therapy and postoperative management. Conclusion: This study shows the importance of knowledge of molecular aspects of thyroid cancer, which allows identification of the correlation between specific mutations and phenotypic characteristics of thyroid cancer, which is essential for its prognosis.

Los avances en biología molecular de la tiroides no solo proporcionan una visión sobre el desarrollo de la enfermedad de la tiroides, sino que además pueden ofrecer posibilidades diagnósticas y terapéuticas para el cáncer de tiroides. Objetivo: Describir los aspectos moleculares del cáncer de tiroides presentados en la literatura científica internacional, así como sus indicaciones y el impacto epidemiológico, a través de una revisión bibliográfica descriptiva. Método: Se buscaron artículos en las bases de datos EMBASE y PubMed / Medline. Los criterios de inclusión fueron: publicación entre 1985 y 2012; palabras clave "molecular" + "marcadores" + "tiroides" + "cáncer". Con estos documentos en mano, se realizó una lectura analítica y se organizaron los trabajos por temas. Resultados: De los 609 artículos encontrados, 85 fueron seleccionados para presentar información sobre los aspectos moleculares, epidemiológicos y de prácticas de cáncer de tiroides. Los artículos fueron evaluados y clasificados de acuerdo con categorías predefinidas, especialmente el número y los tipos de marcadores analizados. Entre la información más relevante, cabe mencionar las indicaciones de uso de los marcadores moleculares en el cáncer de tiroides, que se encuentran en más del 70 % de los carcinomas papilar y folicular de la tiroides. El empleo de estos marcadores probablemente mejore el diagnóstico de malignidad en los nódulos tiroideos, y quizás permita individualizar el tratamiento quirúrgico y el seguimiento posoperatorio. Conclusión: Este estudio muestra la importancia del conocimiento de aspectos moleculares del cáncer de tiroides, que permite la identificación de la correlación entre las mutaciones específicas y las características fenotípicas del cáncer de tiroides, esencial para su pronóstico.

Molecular Markers in Thyroid Cancer / Marcadores moleculares en el cáncer de tiroides

Advances in thyroid molecular biology studies are providing not only insight into thyroid development of diseases but may offer diagnostic and therapeutic potential in thyroid cancer. Objective: To describe the molecular aspects of thyroid cancer reported in international scientific literature, as well as their indications and epidemiological impact, through a descriptive bibliographical review. Method: Articles were searched in the EMBASE, and PubMed/Medline databases. Inclusion criteria were: publication between 1985 and 2012; keywords "molecular" AND "markers" AND "thyroid" AND "cancer". With these documents in hands, an analytical reading was done and the papers organized by themes. Results: Out of the 609 documents found, 85 were selected to present information on several molecular, epidemiological, and practices-related aspects of thyroid cancer. Articles were assessed and classified according to predetermined categories, especially number and types of markers analyzed. Among the most relevant information, we can mention the indications for use of molecular markers in thyroid cancer, which are found in more than 70 % of papillary and follicular thyroid carcinomas. The use of these markers will probably improve the diagnosis of malignancy in thyroid nodules and it may also allow individualization of surgical therapy and postoperative management. Conclusion: This study shows the importance of knowledge of molecular aspects of thyroid cancer, which allows identification of the correlation between specific mutations and phenotypic characteristics of thyroid cancer, which is essential for its prognosis.(AU)

Los avances en biología molecular de la tiroides no solo proporcionan una visión sobre el desarrollo de la enfermedad de la tiroides, sino que además pueden ofrecer posibilidades diagnósticas y terapéuticas para el cáncer de tiroides. Objetivo: Describir los aspectos moleculares del cáncer de tiroides presentados en la literatura científica internacional, así como sus indicaciones y el impacto epidemiológico, a través de una revisión bibliográfica descriptiva. Método: Se buscaron artículos en las bases de datos EMBASE y PubMed / Medline. Los criterios de inclusión fueron: publicación entre 1985 y 2012; palabras clave "molecular" + "marcadores" + "tiroides" + "cáncer". Con estos documentos en mano, se realizó una lectura analítica y se organizaron los trabajos por temas. Resultados: De los 609 artículos encontrados, 85 fueron seleccionados para presentar información sobre los aspectos moleculares, epidemiológicos y de prácticas de cáncer de tiroides. Los artículos fueron evaluados y clasificados de acuerdo con categorías predefinidas, especialmente el número y los tipos de marcadores analizados. Entre la información más relevante, cabe mencionar las indicaciones de uso de los marcadores moleculares en el cáncer de tiroides, que se encuentran en más del 70 % de los carcinomas papilar y folicular de la tiroides. El empleo de estos marcadores probablemente mejore el diagnóstico de malignidad en los nódulos tiroideos, y quizás permita individualizar el tratamiento quirúrgico y el seguimiento posoperatorio. Conclusión: Este estudio muestra la importancia del conocimiento de aspectos moleculares del cáncer de tiroides, que permite la identificación de la correlación entre las mutaciones específicas y las características fenotípicas del cáncer de tiroides, esencial para su pronóstico.(AU)

Utilização de marcadores moleculares no estudo populacional de Leishmania infantum chagasi no Brasil / Utilization of molecular markers in the study population of Leishmania infantum chagasi in Brazil

A leishmaniose é uma doença parasitária causada por protozoários do gênero Leishmania, e transmitida através da picada de fêmeas de mosquitos da família Plebotomidae. As formas clínicas da leishmaniose são particularmente variadas tendo como forma mais grave a leishmaniose visceral (LV) ou calazar. No Brasil a LV é causada pelo protozoário L.infantum chagasi e transmitida pelo flebotomíneo Lutzomyia longipalpis, os principais reservatórios que participam do ciclo zoonótico são canídeos selvagens e cães domésticos. O fato de as leishmanioses, de uma maneira geral, apresentarem um amplo espectro no que diz respeito à sintomatologia da doença, aliado a grande diversidade das espécies de hospedeiros infectados, sugere a presença de variantes genéticas do parasita. No caso da leishmaniose visceral, por exemplo, variantes genotípicas de L.infantum chagasi interagindo com diferentes espécies de hospedeiros podem ter papel fundamental na dinâmica de transmissão e virulência de possíveis epidemias. O presente estudo teve como meta identificar possíveis variantes genotípicas de L. infantum chagasi presentes na área endêmica de Teresina no Estado do Piauí, e comparar com os genótipos encontrados em Campo Grande no Estado de Mato Grosso do Sul e Bauru no Estado de São Paulo, visto que a história natural da doença nessas regiões é muito mais recente do que no Estado do Piauí...

Leishmaniasis is a parasitary disease caused by Leishmania protozoans and transmitted by female Phebotomidae sandflies. Clinical manifestations are particularly diverse, being visceral leishmaniasis (VL) the most severe form. In Brazil VL is caused by Leishmania infantum chagasi and transmitted by Lutzomyia longipalpis sandfly; the main zoonotic reservoirs are dogs and wild canids. Due to a broad range of disease manifestations and great variety of host species infected, Leishmania parasites are thought to possess great genotypic variability. This is of major significance in epidemiological features and in disease transmission. The aim of this study is to identify different genotypic strains of L. infantum chagasi in endemic areas of Teresina, Piauí State; Campo Grande, Mato Grosso do Sul State and Bauru, São Paulo State, and after that, select an appropriate molecular marker in order to study population genetics of L. infantum chagasi in Brazil. Microsatellites markers, sequencing of DNA coding and non-coding regions and PCR-RFLP of kinetoplast DNA (kDNA) were used in order to compare genetic profiles in parasites from different geographical origins...

Atrofia muscular espinal en el niño / Spinal muscular atrophy present in children

Las atrofias musculares espinales en la infancia (AME) son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001. Se recopilaron los datos de 35 pacientes, 4 de ellos, fetos con confirmación prenatal de AME. Se precisaron las principales características clínicas, electromiográficas, de la biopsia muscular y de los estudios genéticos moleculares realizados en cada caso. RESULTADOS. La AME de tipo II resultó la forma clínica mas frecuente (58 por ciento), seguida por la AME de tipo I (42 por ciento). Las principales manifestaciones clínicas resultaron la debilidad muscular generalizada con predominio proximal en extremidades, asociada a hipotonía y arreflexia osteotendinosa. La deleción de los exones 7 y 8 del gen SMN1 se detectó en 20 de 23 casos estudiados (87 por ciento).

Spinal muscular atrophies (SMA) in childhood are autosomal recessive genetic disorders, characterized by spinal and bulbar motoneurons degenerations. Aim of present paper was to describe the main clinical features in a series of children presenting SMA. METHODS: A retrospective study of patients with SMA seen in the Neurology and Neurosurgery Institute of Cuba from January, 2997 and December, 2001 was made. Data from 35 patients were available; four of them were fetus with prenatal confirmation of SMA. Main clinical, electromyography, muscular biopsy, and of molecular genetic studies performed in each case were determined. RESULTS: Type II SMA was the more frequent clinical presentation (58 percent), followed by type I SMA (42, percent). Main clinical manifestations were a systemic muscular weakness with predominance of the proximal type in limbs, associated to hypoxia and osteotendinous areflexia. Seven and eight exons deletion SMN1 gen was detected in 20 from 23 study cases (87 percent).

Atrofia muscular espinal en el niño / Spinal muscular atrophy present in children

Las atrofias musculares espinales en la infancia (AME) son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001. Se recopilaron los datos de 35 pacientes, 4 de ellos, fetos con confirmación prenatal de AME. Se precisaron las principales características clínicas, electromiográficas, de la biopsia muscular y de los estudios genéticos moleculares realizados en cada caso. RESULTADOS. La AME de tipo II resultó la forma clínica mas frecuente (58 por ciento), seguida por la AME de tipo I (42 por ciento). Las principales manifestaciones clínicas resultaron la debilidad muscular generalizada con predominio proximal en extremidades, asociada a hipotonía y arreflexia osteotendinosa. La deleción de los exones 7 y 8 del gen SMN1 se detectó en 20 de 23 casos estudiados (87 por ciento)(AU)

Spinal muscular atrophies (SMA) in childhood are autosomal recessive genetic disorders, characterized by spinal and bulbar motoneurons degenerations. Aim of present paper was to describe the main clinical features in a series of children presenting SMA. METHODS: A retrospective study of patients with SMA seen in the Neurology and Neurosurgery Institute of Cuba from January, 2997 and December, 2001 was made. Data from 35 patients were available; four of them were fetus with prenatal confirmation of SMA. Main clinical, electromyography, muscular biopsy, and of molecular genetic studies performed in each case were determined. RESULTS: Type II SMA was the more frequent clinical presentation (58 percent), followed by type I SMA (42, percent). Main clinical manifestations were a systemic muscular weakness with predominance of the proximal type in limbs, associated to hypoxia and osteotendinous areflexia. Seven and eight exons deletion SMN1 gen was detected in 20 from 23 study cases (87 percent)(AU)

Contribution of conservation genetics in assessing neotropical freshwater fish biodiversity / Contribuição da Genética da Conservação para o conhecimento da biodiversidade dos peixes de água doce neotropicais

Human activities have a considerable impact on hydrographic systems and fish fauna. The present review on conservation genetics of neotropical freshwater fish reveals that DNA analyses have been promoting increased knowledge on the genetic structure of fish species and their response to environmental changes. This knowledge is fundamental to the management of wild fish populations and the establishment of Evolutionary Significant Units capable of conserving genetic integrity. While population structuring can occur even in long-distance migratory fish, isolated populations can show reduced genetic variation and be at greater risk of extinction. Phylogeography and phylogeny have been powerful tools in understanding the evolution of fish populations, species and communities in distinct neotropic environments. Captive fish can be used to introduce new individuals and genes into the wild and their benefits and disadvantages can be monitored through genetic analysis. Understanding how fish biodiversity in neotropical freshwaters is generated and maintained is highly important, as these habitats are transformed by human development and fish communities are increasingly exploited as food sources to sustain a growing human population.

Atividades humanas têm um grande impacto sobre os sistemas hidrográficos e a fauna de peixes. A presente revisão em genética da conservação dos peixes de água doce neotropicais revela que as análises de DNA têm promovido um crescimento no conhecimento da estrutura genética das espécies e suas respostas às alterações ambientais. Este conhecimento é fundamental para o manejo das populações de peixes nativos e para o estabelecimento de Unidades Evolutivas Significantes capazes de conservar a integridade genética dessas populações. Enquanto o fenômeno de estruturação de populações pode ocorrer mesmo em peixes migradores de longas distâncias, populações isoladas podem mostrar reduzida variação genética e apresentar grande risco de extinção. Em adição, a filogeografia e a filogenia têm dado importantes contribuições para o entendimento da evolução das populações, espécies e comunidades de peixes em distintos ambientes neotropicais. Populações de cativeiro podem ser utilizadas como fonte de introdução de novos indivíduos e genes no ambiente natural e seus benefícios e desvantagens podem ser monitorados por meio de análises genéticas. É altamente importante, portanto, entender como é gerada e mantida a biodiversidade de peixes de água doce neotropicais, uma vez que os habitats são transformados pelo desenvolvimento humano e as comunidades de peixes têm sido intensamente exploradas como alimento de sustentação desse crescimento das populações humanas.

Contribution of conservation genetics in assessing neotropical freshwater fish biodiversity

Human activities have a considerable impact on hydrographic systems and fish fauna. The present review on conservation genetics of neotropical freshwater fish reveals that DNA analyses have been promoting increased knowledge on the genetic structure of fish species and their response to environmental changes. This knowledge is fundamental to the management of wild fish populations and the establishment of Evolutionary Significant Units capable of conserving genetic integrity. While population structuring can occur even in long-distance migratory fish, isolated populations can show reduced genetic variation and be at greater risk of extinction. Phylogeography and phylogeny have been powerful tools in understanding the evolution of fish populations, species and communities in distinct neotropic environments. Captive fish can be used to introduce new individuals and genes into the wild and their benefits and disadvantages can be monitored through genetic analysis. Understanding how fish biodiversity in neotropical freshwaters is generated and maintained is highly important, as these habitats are transformed by human development and fish communities are increasingly exploited as food sources to sustain a growing human population.

Atividades humanas têm um grande impacto sobre os sistemas hidrográficos e a fauna de peixes. A presente revisão em genética da conservação dos peixes de água doce neotropicais revela que as análises de DNA têm promovido um crescimento no conhecimento da estrutura genética das espécies e suas respostas às alterações ambientais. Este conhecimento é fundamental para o manejo das populações de peixes nativos e para o estabelecimento de Unidades Evolutivas Significantes capazes de conservar a integridade genética dessas populações. Enquanto o fenômeno de estruturação de populações pode ocorrer mesmo em peixes migradores de longas distâncias, populações isoladas podem mostrar reduzida variação genética e apresentar grande risco de extinção. Em adição, a filogeografia e a filogenia têm dado importantes contribuições para o entendimento da evolução das populações, espécies e comunidades de peixes em distintos ambientes neotropicais. Populações de cativeiro podem ser utilizadas como fonte de introdução de novos indivíduos e genes no ambiente natural e seus benefícios e desvantagens podem ser monitorados por meio de análises genéticas. É altamente importante, portanto, entender como é gerada e mantida a biodiversidade de peixes de água doce neotropicais, uma vez que os habitats são transformados pelo desenvolvimento humano e as comunidades de peixes têm sido intensamente exploradas como alimento de sustentação desse crescimento das populações humanas.

Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

O câncer de tiróide é habitualmente raro em crianças, mas em indivíduos expostos a radiação o risco da doença aumenta consideravelmente. Cerca de uma década após o acidente de Chernobil, em 1986, foi registrado um aumento de mais de 10 vezes na incidência de câncer de tiróide, resultando cumulativamente em mais de mil novos casos diagnosticados em crianças que viviam nos territórios da Bielorrússia, Russia, e Ucrânia, afetadas pela chuva radioativa. A experiência com essa epidemia resultou em conhecimento substancial de oncologia pediátrica clínica, patologia e ciências básicas. Este artigo analisa a epidemiologia, os achados clínicos, os resultados do tratamento e a evolução de pacientes pediátricos com câncer de tiróide induzido pela radiação de Chernobil, em comparação com casos esporádicos diagnosticados atualmente. Adicionalmente, serão discutidos tópicos de patologia e achados moleculares no carcinoma de tiróide infantil.

Congenital adrenal hyperplasia clinical: characteristics and genotype in newborn, childhood and adolescence / Hiperplasia suprarrenal congenital: características clínicas, seguimiento y genotipo en la etapa perinatal, la niñez y la adolescencia

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a disorder which can adopt three clinical expressions: two classical forms –salt-wasting (SW), with residual enzymatic activity (EA) < 1% and simple virilizing (SV), with EA 1-2%– and a mild late onset or nonclassical (NC) form, with EA 10-60%. Our objective is to describe clinical characteristics, growth, and bone mass in a group of patients affected by 21-hydroxylase deficiency. Besides, molecular genetics studies were performed in patients, and also when available in their parents and siblings. Nine patients with neonatal diagnosis and 8 with pre or postpubertal diagnosis were studied. Analyses of 10-point mutations in the CYP21A2 gene were performed. We found that all the patients with the classical expression, except one with a de novo mutation R356W in one allele, were fully genotyped with predictive < 2% EA mutations. Signs of hyperandrogenism were present in 5/6 NC patients; one was diagnosed by searching for mutations in asymptomatic siblings. All the NC patients were compound heterozygotes carrying V281L mutation in one allele and a predictive low EA in the other, except for one not yet determined. In patients with neonatal diagnosis, mean height was low at one year of age, though it showed a significant increase before the onset of puberty. We conclude that neonatal diagnosis of classical CAH allows an adequate follow up enhancing growth. Molecular analyses of all members of an affected family may disclose asymptomatic patients. The presence of de novo mutations, as well as, the presence of mutations with low predicted EA in NC patients reinforces the importance of genotyping for appropriate genetic counseling. In fully genotyped NC patients, the lowest value of ACTH-stimulated 17OHP was 14 ng/ml. Lower cut-off values might overestimate the diagnosis of the NC form.

La hiperplasia suprarrenal congénita por déficit de 21-hidroxilasa presenta tres formas clínicas: dos clásicas, perdedora de sal, con actividad enzimática (AE) < 1% y virilizante simple, con AE 1-2% y una no clásica, con AE 10-60%. Nuestro objetivo es describir las características clínicas y el genotipo de un grupo de pacientes con hiperplasia suprarrenal congénita; este último también sedeterminó en todos los miembros de la familia. Se estudiaron 9 pacientes diagnosticados en la etapa perinatal y 8 durante la etapa pre y postpuberal. Se analizaron diez mutaciones en el gen CYP21A2 y se evaluó crecimiento y densidad mineral ósea. Once pacientes presentaron la forma clásica: 9 con diagnóstico perinatal y 2 diagnosticados más tardíamente, uno de ellos con agrandamiento testicular por restos adrenales. Todos los pacientes, salvo 1 con una mutación de novo R356W en un alelo, presentaron ambos alelos mutados con un genotipo que predice AE < 2%. Seis pacientes presentaron la forma no clásica, todos con signos clínicos de hiperandrogenismo salvo un familiar asintomático que se diagnosticó por el estudio molecular. Todos, a excepción de uno con un alelo aún no determinado, presentaron la mutación V281L acompañada de otra que predice AE < 2%. Durante la evolución de los pacientes de diagnóstico perinatal se observó talla baja al año con recuperación de la misma en la etapa prepuberal. La densidad mineral ósea fue normal. Podemos concluir que el diagnóstico en la etapa perinatal en pacientes con la forma clásica posibilita un mejor seguimiento y crecimiento. La genotipificación de todos los miembros de una familia permite el diagnóstico de formas asintomáticas. La presencia de mutaciones de novo y de un alelo con una mutación que predice baja AE en los pacientes con forma no clásica, refuerza la importancia de la genotipificación para un adecuado asesoramiento genético.