Identification of de Novo Germline Mutations in the HRPT2 Gene in Two Apparently Sporadic Cases with Challenging Parathyroid Tumor Diagnoses

The diagnosis of parathyroid carcinomas is often difficult. HRPT2 mutations have been identified in familial [hyperparathyroidism-jaw tumor (HPT-JT) syndrome] and sporadic parathyroid carcinomas, supporting that HRPT2 mutations may confer a malignant potential to parathyroid tumors. In this study, we report the clinical, histopathological, and genetic investigation of two unrelated cases, whom had apparently sporadic malignant parathyroid tumors, initially diagnosed as adenomas. In one case, the differential diagnosis was complicated by cervical seeding of parathyroid tumor cells. Genetic studies identified de novo HRPT2 germline mutations in cases 1 (c.518_521delTGTC [p.Ser174LysfsX27]) and 2 (c.226 C > T [p.Arg76X]), unveiling the hereditary HPT-JT syndrome in both patients. Furthermore, the identification of somatic mutations in the patients‟ parathyroid tumors provided evidence for complete inactivation of the HRPT2 gene, which was consistent with the tumor malignant features. The sensitivity of parafibromin immunostaining to detect HRPT2 mutations was limited. The present data suggests that patients with apparently sporadic parathyroid carcinomas, or parathyroid tumors with atypical histological features, should undergo molecular genetic testing, as it may detect germline HRPT2 mutations. Establishing the diagnosis of hereditary HPT-JT syndrome is relevant for clinical counseling and management of the carriers and their relatives.

Clinical and Genetic Characterization of Portuguese Patients with Pseudohypoparathyroidism Type Ib

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G-protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)α), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia-related complications.

PROP1 Gene Analysis in Portuguese Patients with Combined Pituitary Hormone Deficiency

OBJECTIVE: Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. DESIGN, PATIENTS AND MEASUREMENTS: A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. RESULTS: PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. CONCLUSIONS: This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.

The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

Signal transduction pathways involving the hypertension-related WNK1 and WNK4 protein kinases

Dissertação apresentada para obtenção do Grau de Doutor em Biologia, na especialidade de Genética Molecular, pela Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia

Envelhecimento ativo, capacidade funcional e atividade física: análise de fatores que contextualizam o processo de envelhecimento e sua percepção por parte de pessoas idosas

RESUMO: O envelhecimento populacional saudável ocupa parte da agenda do processo do envelhecimento humano, retratando uma preocupação social com repercussões nas economias societárias. O processo de envelhecimento, quando abordado fora do paradigma do envelhecimento saudável, desconsidera socialmente o potencial humano das pessoas idosas, promovendo a segregação e motivando atitudes de preconceito e discriminação, além de desperdiçar a experiência, o saber, a cultura e a capacidade de participação da pessoa idosa como contributo para a sociedade a que ela está inserida. O foco central da Política Nacional de Saúde do Idoso brasileira se inscreve na promoção de um envelhecimento saudável, nomeadamente por meio da manutenção da capacidade funcional ao valorizar a autonomia, a independência física e a integridade mental da pessoa idosa. O desafio para a viabilização do processo de envelhecimento ativo e bem-sucedido consiste na maximização das capacidades, potencialidades e recursos pessoais, comunitários e políticos. Pressupõe, também, uma concepção ampliada de viver, contextualizada no contínuo da vida, capaz de externar a preocupação com a saúde e o bem-estar, integrando as pessoas em fase de envelhecimento no contexto do ciclo de vida. Diante do exposto, a presente investigação objetivou conhecer os determinantes de envelhecimento ativo e bem-sucedido, numa população em processo de envelhecimento e relacioná-los com as ―práticas/conteúdos‖ e representações / significados‖ sobre o envelhecimento, as atividades físicas e a capacidade funcional. A investigação foi estruturada em três estudos: no primeiro foi criado e testado o instrumento ―Envelhecimento ativo, capacidade funcional e atividade física‖, na cidade de Lisboa, Portugal, e posteriormente realizada sua adaptação cultural e linguística do português de Portugal para o do Brasil. No segundo foi feita uma pesquisa observacional do tipo survey, descritiva e exploratória com o objetivo de conhecer as relações esteabelecidas entre o envelhecimento bem-sucedido, ativo, a atividade física e a capacidade funcional de uma população em processo de envelhecimento; e no terceiro momento foi realizado um estudo de cariz qualitativo com o objetivo de captar as percepções e comportamentos dos entrevistados diante do fato de se sentirem ou não pessoas idosas ou envelhecidas. Foram adotados os seguintes referenciais teóricos: envelhecimento ativo, envelhecimento bem sucedido, concepção muldidimensional do processual do envelhecimento (determinantes pessoais, familiares, sociais, psicocomunicacionais, econômicos e de saúde), atividade física e capacidade funcional e abordados à luz do perfil demográfico e da experiência das realidades européias, americana e brasileira. Foram triagulados métodos e técnicas (entrevista individual gravada, mensurações e questionário). Participaram pessoas com 60 anos de idade ou mais vinculadas que frequentam dois programas públicos destinados às pessoas idosas na cidade de Juiz de Fora, Minas Gerais, Brasil e foram excluidas as participações de pessoas com dependência para atividades da vida diária, para as atividades instrumentais da vida diária e com alteração do nível de consciência. Amostra aleatória estratificada composta por 326 participantes na qual foram realizadas mensurações e amostra por tipicidade construída a partir da base amostral composta de 87 participantes na qual foi realizada entrevista individual gravada. Atendidos todos os requisitos éticos e legais de pesquisa envolvendo seres humanos, segundo legislação brasileira. Aplicada Análise Fatorial e selecionados 11 fatores com 31 variáveis que contemplaram os determinantes do processo de envelhecimento ativo. Realizado reajustamento da análise fatorial,por questão de coerência conceptual, sendo selecionado oito fatores nomeados de acordo com o referencial teórico adotado que resultou em 25 variáveis que abordaram a participação em atividades e acesso aos serviços de saúde; à atividade física; à convivência, interação e avaliação do contato social; à escolaridade e renda; à saúde percebida e ao voluntariado. Utilizado como marcador para a atividade aeróbia o perfil da sobrecarga da atividade física semanal em consonância com diretrizes e recomendações de atividades aeróbias de intensidade moderada para as pessoas idosas. Identificado que 60,7% dos entrevistados realizam atividade física insuficiente. Os indicadores antropométricos utilizados evidenciaram índices de sobrepeso e de obesidade tanto entre os homens quanto entre as mulheres. Houve correlação do índice de massa corporal (IMC) com as medidas efetuadas segundo as faixas etárias. A análise inferencial possibilitou relacionar os determinantes do envelhecimento ativo, as medidas antropométricas e as variáveis sociodemográficas (escolaridade e idade), sendo obtidos os seguintes destaques: 1) à medida em que a idade aumenta, diminuem os níveis de prática da atividade física, dos contatos com as pessoas para conversar (das relações de convivência), dos trabalhos de voluntariado e das relações familiares e intergeracionais; 2) foi identificado um alinhamento conceptual dos diferentes determinantes concorrentes para um envelhecimento ativo à luz da prática da atividade física com a convivência e interação com os familiares e com auto-avaliação positiva da saúde percebida e atividade física; 3) quanto maior a idade menor os anos de escolaridade; 4) a diminuição da área transversa do braço e do IMC à medida que a idade aumenta, retratou diminuição da adiposidade corporal que está associada à perda da massa magra. A categorização do discurso dos 87 entrevistados permitiu captar a percepção do processo de envelhecimento por dois critérios antagônicos: preservação da autonomia e presença da deterioração. Foi caracterizado o sistema de crenças dos participantes com 1090 emissões de crenças. Houve tendência do sistema de crenças à centralidade com 638 (58,6%) crenças retratando concepções e situações difíceis de serem modificadas por processos educacionais. Os resultados obtidos diagnosticaram e reiteraram a tendência de incremento numérico de pessoas com 60 anos de idade ou mais na cidade brasileira de Juiz de Fora. Embora o estatuto do idoso esteja alicerçado em princípios do envelhecimento saudável e ativo ficou evidenciado a necessidade de estratégias para implementá-la com vistas a impactos sociais, econômicas e de saúde na perspectiva da prática de atividade física e da preservação da capacidade funcional. Constituem contribuição da presente investigação: 1) fundamentos teóricos e informação sobre juiz-foranos com 60 anos de idade ou mais segundo dimensões social, econômica, cultural e espiritual numa concepção ampliada de saúde; 2) abordagem do envelhecimento de forma processual e integrada, multidimensional e articulada com o ciclo da vida; 3) diagnóstico do grau de autonomia dos participantes permitindo subsidiar decisões para melhorar a capacidade funcional dos mesmos; 4) processo investigativo utilizando modelos teóricos que permitiram estabelecer um diagnóstico local e contextualizar o processo de envelhecimento para os participantes e 5) sobrecarga semanal de atividade física e os indicadores antropométricos dos participantes a ponto de subsidiar parâmetros de indicação terapêutica para manutenção da capacidade funcional.-------- ABSTRACT: The populational healthy aging holds part of the process of the human aging agenda, portraying a social concern with the repercussion in societary economies. The aging process when addressed out of the healthy aging paradigm socially disregard the human potential of the elderly, promoting segregation and motivating acts of prejudice and discrimination, in addition to the waste of experience, knowledge, culture and the participatory capacity of an older person in contributting to the society they are a part of. The Brazilian National Health Policy for the Elderly has its main focus in promoting the healthy aging, namely through the maintenance of the functional capacity by valuing the autonomy, physical independence and the mental integrity of the elderly person. The challenge of enabling the process of a successful and active aging lays in maximazing the capabilities, potencialities and personal, communitary and political resources. It infers additionaly a broad view of living, contextualized in the continuum of life, able to express concern with health and well-being, integrating the people in aging phase to the context of the life cycle. Hence, this research aimed to learn the determinants of active and successful aging in a population in aging process and relate them with the "practices/contents" and "representations/meanings" about aging, the physical activities and functional capacity. The investigation was structured in three studies: in the first it was developed and tested the instrument "Active Aging, Functional Capacity and Physical Activity" in the city of Lisboa, Portugal, and afterwards it was culturally and linguistically adapted from Portugal Portuguese to Brazilian Portuguese. The second study was an observational research with survey, descriptive and exploratory methods which aimed to learn the relations established between the successful aging, active aging, the physical activity and the functional capacity of a population in aging process; and the third comprised a qualitative study with the objective to collect the understanding and behavior of the interviewees based on the fact of either they saw themselves as elder or aged person or not. As theoretical framework were explored: active aging, successful aging, multidimensional concept of aging process (personal, familial, social, psycho-communicational, economic determinants), physical activity and functional capacity and explored based in demographic profile and in the European, American a Brazilian realities. Performed triangulation of methods and tecniques (recorded individual interviews, measurements and questionnaires). Participants were aged 60 or older included in two public services for the elderly population in the city of Juiz de Fora, Minas Gerais, Brazil and were excluded persons with dependency in both daily activities and instrumental daily activities and the persons with altered level of conciousness. Stratified ramdon sample of 326 participants in which were performed the measurements and typicality sample constructed from the sample basis of 87 participants whereupon the recorded individual interview was performed. Conforming to all the ethical and legal requirements of research with human beings according to the Brazilian legislation. Applied Factor Analysis and selected 11 factors and 31 variables that convey the determinants of the active aging process. Executed reajustment of factor analysis, for conceptual coherence, being selected eight factors named accordingly to the theoretical framework that resulted in 25 variables which approached the participation in activities and access to health care services; to physical activity; to coexistence, interaction and evaluation of social contact; to scholarity and income; to perceived health and volunteering. Used as marker to aerobic activity the profile of weekly physical activity overload in accordance with guidelines and reccomendations for moderate-intensity aerobic activities for older people. Identified that 60,7% of interviewees practice enough physical activity. Anthropometric markers evidence overweight and obesity levels both within men and women. There was correlation between body mass index (BMI) and measures carried out according to age ranges. The inferential analysis allowed relating the active aging determinants, the anthropometric measurements and sociodemographic variables (scholarity and age), obtaining the following highlights: 1) to the extent that age increases, lowers the levels of physical activity practice, of contact with people to talk to (social relationships), of volunteering work and familial and intergenerational relationships; 2) it was identified a conceptual alignment of diferent determinants concurrent to an active aging in light of the physical activity practice with the relationship and interaction of family and with positive self-assessment of perceived health and physical activity; 3) the older the person, lower are scholarity levels; 4) the decrease of the cross-sectional area of the arm and BMI as the age increases portrayed decreased adiposity of the body that is associated with loss of lean body mass. The categorization of the speech of 87 interviewees allowed to collect the understanding of the aging process by two opposite criteria: preservation of autonomy and existance of decline. It marked the belief system of participants with 1090 beliefs expressed. With tendency of the belief system to centrality with 638(58,6%) beliefs showing concepts and dificult situations to be changed through educational processes. The results diagnosed and reiterated the tendency of increase in the number of people aged 60 or older in the Brazilian city of Juiz de Fora. Although the elderly statute is built upon principles of healthy and active aging it was evident the need of strategies to implement it aiming at social, economic and health impacts in the perspective of physical education and preservation of the functional capacity. Constitute contributions of this study: 1) theoretical fundaments and data about Juiz de Fora citizens aged 60 or more according to social, economic, cultural and spiritual dimensions in a broad concept of health; 2) approach of aging in a procedural and integrative, multidimensional manner, articulated with the life cycle; 3) diagnosis of degree of autonomy of participants enabling decisions on how to improve their functional capacities; 4) investigative process using theoretical models which permit to stablish a local diagnosis and contextualize the aging process of participants and 5) weekly overload of physical activity and anthropometric indexes of participants as to subsidize parameters to therapeutic indication to the maintainence of functional capacity.

HTLV-I associated myelopathy in the northern region of Brazil (Belém-Pará): serological and clinical features of three cases

Three patients (males, black, ages 37, 40 and 57) attended a university clinic with a progressive paraparesis of obscure origin. One patient who referred disease duration of more than 16 years, showed diminished deep reflexes, bilateral Babinski's sign, diminished sensation of vibration, abnormal bladder function and back pain. The other two patients (with one and six years of disease duration) complained of weakness in one leg, increased deep reflexes and back pain. Babinski's sign and bladder disturbance were also present in the patient with six years of disease. Blood samples tested by an enzyme immune assay and a discriminatory Western blot were positive for HTLV-I. The familial analysis of one patient showed a possible pattern of sexual and vertical transmission of the virus. To the best of our knowledge, these are the first cases of a proven association between HTLV-I and TSP/HAM in Belem, Para, and emphasize the need to actively look for cases of neurological disease associated to the virus.

Autoantibody profile in individuals with chronic hepatitis C

IntroductionAutoantibodies are often produced during infection with chronic hepatitis C virus (HCV), but it remains controversial whether they influence the biochemical profile and histological features of this disease. Therefore, this current study sought to describe these autoantibodies and evaluate their impact on the clinical and histological presentation of hepatitis C.MethodsThis cross-sectional analytical study assessed patients with HCV (RNA+) from October 2011 to July 2012.ResultsThis study included 66 patients, with a mean age of 53.2±10.5 years. Of these patients, 60.6% were male, and 54.3% presented with genotype 1. Non-organ-specific autoantibodies (NOSA) were detected in 24% of the patients; of these, 7.6% were anti-mitochondrial antibodies (AMA+), 26.7% were anti-smooth muscle antibodies (SMA+) and 6.8% were liver kidney microsomal type 1 antibodies (LKM1+). With respect to the thyroid autoantibodies, 7.4% were anti-peroxidase (ATPO+) antibodies, and none were anti-thyroglobulin (ATG+) antibodies. Regarding celiac disease autoantibodies, 5.8% were endomysial antibodies (EMA+), and no transglutaminase (TTG+) antibodies were detected. Cryoglobulins were found in 2.1% of patients. When NOSA+ individuals were compared to patients without the presence of NOSAs, they exhibited higher median alkaline phosphatase (0.7 vs. 0.6 xULN; p=0.041), lower median platelet counts (141,500.0 vs. 180,500.0/mm3; p=0.036), lower mean prothrombin activity (72.6±11.5% vs. 82.2±16.0%; p=0.012) and an increased prevalence of significant fibrosis (E≥2) (45.5% vs. 18.2%; p=0.012). There was also a tendency for a greater proportion of NOSA+ cases to have marked periportal activity (APP≥3) (44.5% vs. 15.6%; p=0.087).ConclusionsIn addition to the high prevalence of autoantibodies associated with HCV infection, it was observed that NOSA positivity was associated with a more severe histological and biochemical profile of hepatitis C infection.

Laparoscopic versus open splenectomy in the management of hematologic diseases

Splenectomy is the best available treatment for severe forms of hereditary spherocytosis, idiopathic thrombocytopenic purpura, and other hematologic conditions when these prove refractory to conservative management. It has been employed for many decades with low mortality and favorable remission rates. The use of laparoscopic splenectomy in recent years has been rapidly and even enthusiastically adopted in this field. However, the exact role of laparoscopic versus open surgery for hematologic diseases is still debated. In this study of 58 adult patients, laparoscopic procedures were compared with conventional splenectomies for similar indications. METHODS: All patients were operated on within an 8-year period. Subjects underwent similar procedures under the supervision of the same surgical school and were compared regarding age, gender, body mass index, and diagnosis. Laparoscopically managed cases (Group I, n = 30) were prospectively followed according to a written protocol, whereas the same investigation was retrospectively done with regard to traditional laparotomy (Group II, n = 28). Methods included general and demographic findings, duration and technical steps of operation, blood loss, weight of spleen, need for conversion (in minimally invasive subjects), intraoperative and postoperative complications, time until realimentation, postoperative hospitalization, mortality, and late follow-up including recurrence rate. RESULTS: Idiopathic thrombocytopenic purpura was the surgical indication in over 50% of the patients in both groups, but familial spherocytosis, thalassemia, myelodysplasia, and lymphomas were also represented in this series. Laparoscopic procedures took more time to perform (P = 0.004), and postoperative hospitalization was 2 days shorter, but this difference was not statistically significant. Postoperative hematocrit and volume of blood transfusions was equivalent, although the laparoscopic cases had a somewhat lower preoperative hematocrit (NS) and displayed better recovery for this measurement (P = 0.03). More patients in Group I were able to accept oral food on the first day than subjects undergoing conventional operations (P < 0.05). Relatively few conversions were necessary during the minimally invasive surgeries (13.3%), and postoperative early and late complications as well as recurrences occurred in similar proportions. Also, the mean weight of the spleen was not statistically different between the groups, although there was a marked numerical tendency toward larger masses in conventional procedures. No spleen in Group I exceeded 2.0 kg, whereas in Group II values up to 4.0 kg occurred, and the mean weight was 50% higher in the latter group. CONCLUSIONS: 1) Minimally invasive splenectomy was essentially comparable to open surgery with regard to safety, efficacy, and late results; 2) Advantages concerning shorter postoperative hospitalization could not be shown, despite earlier food intake and a non-significant tendency toward earlier discharge; 3) This new modality should be considered an option in cases of hematologic conditions whenever the spleen is not hugely enlarged.

Prevalence of antinuclear autoantibodies in the serum of normal blood dornors

OBJECTIVE:To examine the presence of serum antinuclear autoantibodies in a healthy population. METHODS: Serum of 500 normal blood donors between 18 and 60 years of age were tested for the presence of autoantibodies. Antinuclear antibodies were detected by indirect immunofluorescence technique using HEp-2 epithelial cells as the substrate. The presence of dnaN was detected by indirect immunofluorescence technique using Critidia lucillae as the substrate. Anti-SSA (RO), anti-SSB (LA), anti-Sm, and anti-RNP were determined by double radial immunodiffusion. RESULTS: In the evaluation of the presence of serum antibodies, antinuclear antibodies were detected in 22.6% of the sera. The presence of other antibodies was not significant. The majority of the titers were 1:40. CONCLUSION: The presence of autoantibodies is not necessarily pathologic and has to be related to the age group, gender, and clinical condition of the patient.

Endemic pemphigus foliaceus (fogo selvagem) and pemphigus vulgaris: immunoglobulin G heterogeneity detected by indirect immunofluorescence

Pemphigus are autoimmune intraepidermal blistering diseases in which immunoglobulin G (IgG) autoantibodies are directed against desmosomal glycoproteins. The aim of this study was to determine the IgG subclass profile of endemic pemphigus foliaceus (fogo selvagem) and pemphigus vulgaris utilizing indirect immunofluorescence. PATIENTS AND METHODS: Twenty-five patients with pemphigus vulgaris, 25 with endemic pemphigus foliaceus (fogo selvagem), and 25 healthy controls were analyzed by indirect immunofluorescence for circulating autoantibodies (total IgG and its subclasses). RESULTS: Our data revealed a significant correlation (P <.05) of disease activity and autoantibody levels in both forms of pemphigus, i.e., negative titers related to clinical remission, whereas positive results related to active disease. Immunoglobulin G subclass analysis in fogo selvagem demonstrated that in patients in remission, 56% showed positive immunoglobulin G4; in active disease, immunoglobulin G4 was the predominant subclass (100% positive in all cases). The IgG subclass profile in pemphigus vulgaris showed that in patients in remission, only 10% were positive for immunoglobulin G4; in active disease, positivity for immunoglobulin G4 was present in 78% to 88% of the cases. CONCLUSION: Subclass characterization of immunoglobulin G autoantibodies is a useful tool for pemphigus follow-up, since immunoglobulin G4 (IgG4) is the subclass that is closely related to recognition of pathogenic epitopes, and consequently with disease activity. Careful monitoring should be performed for fogo selvagem in clinical remission with a homogeneous IgG4 response, since this may indicate more frequent relapses.

Para cá e para lá dos muros: relações familiares na interface entre o interior e o exterior da prisão

Tese de Doutoramento em Sociologia

Aging and Alzheimer's disease: Searching for novel molecular cues

Tese de Doutoramento em Ciências da Saúde

ADHD: the impact when not diagnosed

ADHD is a highly prevalent disorder in childhood with social, academic and familial difficulties when not diagnosed and treated correctly. The aim of this case report is to demonstrate the impairment of ADHD among generations of the same family.

Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) founder mutation : clues from haplotyping of short tandem repeats on Chromosome 17p

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial his- tory. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Ibe- ric origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenera- tional distance) and thus pre-dating European migration to Brazil. So far, the founder p. Arg337His haplotype has not been detected outside Brazil, with the exception of two resi- dents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.