α1- and α2-Adrenoceptors are involved in various physiological events in the eye: blood flow regulation, aqueous humor dynamics and pupil regulation. The α1- and α2-adrenoceptors can be further subdivided into six subtypes (α1A, α1B, α1D, α2A , α2B, and α2C ). Currently available α1- and α2-adrenergic drugs are not selective for the different subtypes and some ocular adrenergics have undesirable side-effects, both local and systemic. A better understanding of the subtype distribution in the eye would be useful when designing new drugs with greater efficacy and fewer adverse effects; this applies especially to the treatment of glaucoma. The purpose of the thesis was therefore to identify and localize the different subtypes of α1- and α2-adrenoceptors in the eye. The identities of the α1-adrenoceptor subtypes were studied in various parts of pig and albino rabbit eyes by radioligand binding. In the pig retina and in the albino rabbit iris, ciliary body and retina, mixed populations of α1A- and α1B-adrenoceptors were localized. In the rabbit choroid only the α1A-adrenoceptor subtype was detected. The α2-adrenoceptor subtypes were also characterized by radioligand binding, in different parts of the pig eye. In the iris, ciliary body and choroid, only α2A-adrenoceptors were localized, while in the retina, mostly α2A-adrenoceptors and a minor population of α2C-adrenoceptors were identified. High densities of α2A-adrenoceptors were found in the ciliary body and choroid. The effect of α2-adrenoceptor agonists on the porcine ciliary artery was studied on a small-vessel myograph. α2-Adrenoceptor agonists proved to be potent vasoconstrictors in the porcine ciliary artery and it was found that the vasoconstriction induced by brimonidine was mediated by the αA-adrenoceptor.

The objective of the present study was to investigate Amen's formulations of subtypes of AD/HD initially identified by brain imaging techniques, through the use of behavioral checklist data. And in testing Amen's theory of six separate subtypes of AD/HD, to identify and differentiate the subtypes based on symptom presentation. Data was obtained through retrospective chart reviews (N=161) of children between the ages of 5 and 12 who met the criteria for the major symptoms observed in AD/HD and were referred for a previous comprehensive AD/HD evaluation. Data from behavioral checklist (CBCL and DBRS-IV) were matched to Amen's Subtype Symptom Checklist and each subject was given a percentage score for six subtype symptoms. Cluster analysis reliably found six clusters and each subject was labeled according to their symptom presentation. The clusters found were labeled as AD/HD - Combined Type, AD/HD - Predominately Inattentive Type, AD/HD - Predominately Hyperactive-Impulsive Type, Ad/HD - Combined Type with Obsessive-Compulsive features, AD/HD - Combined Type with Obsessive/Compulsive and Conduct Disorder features and Undifferentiated AD/HD. However, the present study did not find evidence of subtypes that corresponded to Amen's Temporal Lobe ADD or Limbic ADD. Discriminant function analysis of the six clusters found that the variables in the model (symptom percentage scores) significantly discriminated the subtype classification. Also, 76% of all cases were correctly classified according to their symptom presentation. Potential limitations of the sample and the data used for interpretation were discussed. Limitations of the study warrant further investigation making use of multi-modal assessment tools which relate well with brain imaging techniques, such as neuropsychological measures of attention and concentration, laboratory based measures of activity, continuous performance tests measuring inattention and impulsivity, and QEEG data measuring brain wave information. A multi-modal approach to investigating symptom subtypes of AD/HD would likely provide increased reliability and validity of differential diagnosis, and therefore, more effective treatment of children with the presenting symptomology of AD/HD. The diagnostic and clinical implications' of each cluster subtype symptomology found in the present study was discussed as well.

BACKGROUND: The benefits of the Mediterranean-style dietary pattern in mitigating cancer risk among Americans is unclear and its role in obesity-related cancer risk has not been evaluated. OBJECTIVES: This study examines the prospective association between adherence to a Mediterranean style dietary pattern and cancer risk (including total, obesity related, breast and colorectal cancers) among men and women in the Framingham Offspring (FOS) cohort. In secondary analyses for breast cancer, we explore stratifying by hormone receptor status and menopausal status. METHODS: The Mediterranean style dietary pattern (MSDP) score was derived from a semi-quantitative food frequency questionnaire taken at examination visit 5 in the prospective FOS cohort. Subjects included 3199 participants (1703 women and 1496 men), aged 30 years old and older, who were free of prevalent cancer. The MSDP score was classified into tertiles and also dichotomized (MSDP score <19 vs. ≥19) to evaluate the association between the MSDP and cancer risk through the ninth examination cycle (2014). Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all subjects and for men and women separately, adjusting for confounding by age, physical activity, body mass Index, pack-years of cigarette smoking, supplement use, diabetes status and sex (for all subjects models). In the breast cancer model, we adjusted for age, waist-to-height ratio height ratio, pack-years, physical activity, diabetes, supplement use age at menopause. Factors found not to confound the effects of the MSDP on cancer risk were excluded from final models. RESULTS: During a median follow-up of approximately 18 years, 377 and 273 cancer cases were documented among men and women, respectively. Women in the upper two tertiles of the MSDP score had approximately 30% lower lower total cancer risks than women in the lowest tertile (tertile 2: HR, 0.69, 95% CI: 0.50-0.94; tertile 3: HR, 0.73; 95% CI: 0.54-0.99). Effects in men were weaker. Higher adherence to a MSDP was somewhat more strongly protective against total cancer risk among lower-risk individuals such as those who were leaner (BMI <25), drank less alcohol (<14 g/d), and did not currently smoke cigarettes. The association between MSDP adherence and total cancer risk was also modified by waist circumference and WHtR. We also observed a non-statistically significant protective effect of higher MSDP conformity and obesity-related cancer risk (tertile 3: HR, 0.80, 95% CI: 0.60-1.07). The association was present especially among women (tertile 2: HR, 0.76, 95% CI 0.53-1.09; tertile 3: HR, 0.73, 95% CI: 0.51-1.05). In analyses of effect modification by anthropometric measures of body fat, the combined effect estimates for higher adherence to the MSDP in women and body fat were more than additive for BMI and WHtR. The MSDP adherence was also inversely associated with BrCa risk (tertile 3 vs tertile 1: HR: 0.58, 95% CI: 0.34-0.98) especially in post-menopausal women (HR: 0.51, 95% CI: 0.29-0.91) and among those with any positive Estrogen Receptor/Progesterone Receptor BrCa (HR: 0.58, 95% CI: 0.31-1.06). We found no association between MSDP and colorectal cancer in these analyses. CONCLUSIONS: In this large cohort study, higher adherence to MSDP was associated with lower cancer risk (including total, obesity-related and breast cancers), among women aged 30 years old or older in the FOS study.

Made available in DSpace on 2015-04-11T13:38:39Z (GMT). No. of bitstreams: 1 Dissertacao Final Luana Karen.pdf: 1636172 bytes, checksum: c9eb81400c0c198ae103082ad8f70318 (MD5) Previous issue date: 2007-11-16 / Fundação de Amparo à Pesquisa do Estado do Amazonas / The Human Immunodeficiency Virus (HIV) is characterized by a wide genetic diversity. Two types of HIV are recognized at present: HIV-1 and HIV-2. The HIV-1, responsible for most of the cases of AIDS in the world, is divided in three groups denominated M (Major), O (Outlier) and N (Non-M/Non-O), and until this moment nine subtypes of the group M (A-D, F-H, J-K) were already identified. Beyond of those subtypes, the HIV-1 also have been classified in circulating recombinant forms (CRFs) and unique recombinant forms (URFs). In Brazil, a pattern complex of distribution of those subtypes has been described in their different geographical areas. In search of elucidating the predominant subtypes of HIV-1 in the city of Manaus, this study had as objective to analyze blood samples of subjects that presented results positive or indeterminate for HIV, in the systematic selection of blood donors of the Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM). In the moment of the collect, the donors registered their authorization by the signature of the free consent and knowledge term and they answered a questionnaire used for epidemic data investigation. DNA proviral extracted of the samples with indeterminate/positive resulted in Western Blot was submitted a Polimerase Chain Reaction in two stages (Nested PCR) for the confirmation of the HIV-I infection. The amplified products (regions gag, pol and env) of the 31 samples reactivate for PCR were automatically sequencing and analyzed phylogenetically by the Phylip program. All of the indeterminate samples for the confirmatory test presented negative amplification pattern. Of the reactivates samples for HIV in the confirmatory test and PCR, it was observed male predominance (77,4%) and in the donors of first time (67,7%). Among the repetition donors, 60% presented seroconvertion in up to 20 months. Of the total of samples, was identified the predominance of the subtype B (87,1%), following by the subtype C (6,5%), F (3,2%) and recombinant BF (3,2%). The amino acids sequences of 19 isolated were analyzed for the genetic variability characterization of the region of the loop V3. Among the isolated of the subtype B, the tetrapeptide more prevalente was GPGR (68,4%), following by the Brazilian variant B" GWGR (15,8%). The Subtype C occurrence in the North Region still was not reported in the literature. The analyses of similarity of the isolated of the subtype C in this study demonstrated larger similarity of these with other isolated ones brazilian, in relation to isolated in other parts of the world. Our results can contribute to a better understanding of the characteristics of the lineages of the HIV-1 circulating in Brazil, information that can be used in benefit of the diagnosis, treatment, control of the disease and preparation of vaccines. / O Vírus da Imunodeficiência Humana (HIV) é caracterizado por uma ampla diversidade genética. Dois tipos de HIV são reconhecidos atualmente: HIV-1 e HIV-2. O HIV-1, responsável pela maioria dos casos de aids no mundo, é dividido em três grupos denominados M (Major), O (Outlier) e N (Non-M/Non-O). Para o grupo M, nove subtipos foram identificados até o momento: A-D, F-H, J, K. Além desses subtipos, o HIV-1 também tem sido classificado em formas recombinantes circulantes (CRFs) e formas recombinantes únicas (URFs). No Brasil, um complexo padrão de distribuição desses subtipos tem sido descrito em suas diferentes regiões geográficas. Buscando esclarecer a distribuição dos subtipos de HIV-1 predominantes na cidade de Manaus, este estudo teve como objetivo analisar amostras de sangue de indivíduos candidatos a doadores de sangue que apresentaram resultados positivo ou indeterminado para HIV-1, na triagem sistemática para doação de sangue da Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM). Na ocasião da coleta, os doadores registraram a sua autorização através da assinatura do termo de consentimento livre e esclarecido e responderam a um questionário utilizado para investigação de dados epidemiológicos. O DNA proviral extraído das amostras com resultados indeterminado/positivo no Wersten Blot foi submetido a uma Reação em Cadeia da Polimerase em duas etapas (Nested PCR) para a confirmação da infecção pelo HIV-1. Os produtos amplificados (regiões gag, pol e env) das 31 amostras reativas por PCR foram seqüenciados e analisados por métodos filogenéticos usando o programa Phylip. Todas as amostras indeterminadas para o teste confirmatório apresentaram padrão de amplificação negativo. Das amostras reativas para HIV-I no teste confirmatório e PCR, observou-se predominância do sexo masculino (77,4%) e de doadores de primeira vez (67,7%). Entre os doadores de repetição, 60 % apresentaram soroconversão em até 20 meses. Do total de amostras, identificou-se a predominância do subtipo B (87,1%), seguida do subtipo C (6,5%), F (3,2%) e recombinante BF (3,2%). As seqüências de aminoácidos de 19 isolados foram analisadas para a caracterização da variabilidade genética da região da alça V3. Dentre os isolados do subtipo B, o tetrapeptídeo mais prevalente foi o GPGR (68,4%), seguido pelo variante brasileiro B GWGR (15,8%). A ocorrência do Subtipo C na região Norte, ainda não foi relatada na literatura. As análises de similaridade dos isolados do subtipo C nesse estudo demonstraram maior semelhança destes com outros isolados brasileiros, em relação a isolados de outras partes do mundo. Nossos resultados contribuem para uma melhor compreensão das características dos isolados do HIV-1 circulantes no Brasil, informações que poderão ser utilizados em benefício do diagnóstico, tratamento, controle da doença e preparação de vacinas.

<p>For several decades, researchers have sought to fully understand the nature of the relationship between depression and weight. To date, the research in this area has yielded highly inconsistent results, with some identifying null (Crumpton, Wine, & Groot, 1966; Moore, Stunkard, & Srole, 1962), positive (R. E. Roberts, Kaplan, Shema, & Strawbridge, 2000), negative (Silverstone, 1968; Simon, 1963) and gender specific relationships (DiPietro, Anda, Williamson, & Stunkard, 1992; Istvan, Savela, & Weidner, 1992; Onyike, Crum, Lee, Lyketsos, & Eaton, 2003). The author suggests that these inconsistencies can be explained by the use of measures of depression used which do not differentiate between various subtypes of depression associated with divergent somatic symptoms; including atypical depression (AD) and melancholic depression (MD). Adolescence may be an important intervention point to avert adult obesity and identification of subtypes may identify those at greatest risk. Yet, the characteristics of depression subtypes among adolescents are unknown. In order to identify subtypes of depression among adolescents that are differentially associated with weight, Latent Class Analysis (LCA) was conducted and resulting classes were tested for associations with weight. Six latent classes were identified. Four were uniquely associated with somatic symptoms including hyper- and hypophagia, suggesting that somatic symptoms play an important role in the distinction between depressive subtypes. Analyses showed an association with BMI for the 2 hyperphagic classes but not for the 2 hypophagic classes. The inclusion of depression class improved the fit of regression models for depression predicting BMI. This suggests that the inclusion of depression subtype in analyses may clarify the association between weight and depression.</p> / Dissertation

The mammalian neocortex is an exquisite, highly organized brain structure composed of hundreds of subpopulations of neurons and glia, precisely connected to enable motor control, sensory perception, information integration, and planning. Unique molecular, structural, and anatomical neuronal properties underlie diverse functionality, endowing much of the neocortex’s complex processing power. Neocortical size correlates with information processing capacity, suggesting that increased neuronal number and diversity begets increased sophistication. One excitatory projection neuron type, callosal projection neurons (CPN), has disproportionately expanded with cortical size increase. CPN directly connect homotypic regions of the two neocortical hemispheres by sending axons via the largest white matter fiber tract in the brain, the corpus callosum (CC), allowing quick relay, integration, and comparison of information. In humans, the CC contains over 300,000 axons, CPN have been centrally implicated in autism spectrum disorders, and absence or surgical disruption of CPN connectivity in humans is associated with defects in abstract reasoning, problem solving, and generalization. Therefore, CPN are critical to complex brain functions, and their diversity likely contributes to these roles. Work presented in this dissertation addresses molecular controls over CPN development, specifically genes that are expressed by, and function in, particular subpopulations of CPN. While much progress has been made in identifying molecular controls over neocortical arealization, lamination, and broad subtype specification, CPN diversity has remained largely unaddressed. Therefore, this work begins by identifying genes more highly expressed in CPN than other closely related projection neuron populations, and uncovers molecular diversity within CPN. From this molecular diversity, functional analysis of three candidate molecular controls over CPN subtype diversity follows. Cited2 acts broadly in neocortical progenitor development and postnatally in refining somatosensory CPN identity. Caveolin1 identifies a population of CPN with dual axonal projections. Tmtc4 is mutated in human CC disease and can function in CPN axonal development. These analyses of CPN molecular diversity in mouse then expand to an investigation of which molecular subpopulations are conserved, expanded, or uncommon between rodent and primate, allowing both for comparative evolutionary theories of CPN function, and indicating which CPN populations critical for human brain function can be best studied in rodent models.

Προδρομικές και αναδρομικές μελέτες έχουν κατά το παρελθόν αναδείξει ένα ευρύ φάσμα προδρόμων συμπτωμάτων. Ωστόσο η σχέση των προδρόμων αυτών συμπτωμάτων με αυτά της ενεργού ψύχωσης δεν έχει διερευνηθεί επαρκώς. Σε 73 νοσηλευθέντες ασθενείς με σχιζοφρένεια στο πρώτο ή το δεύτερο ψυχωτικό επεισόδιο και με διάρκεια νόσου ≤ 3 έτη (DSM-IV-TR, Axis I διάγνωση), μετρήθηκε η βαρύτητα του επεισοδίου με τη χρήση της Κλίμακας για το Αρνητικό και το Θετικό σύνδρομο (PANSS), εντός 5 ημερών από τη έναρξη του επεισοδίου. Αναζητήθηκαν επίσης αναδρομικά τα πρόδρομα συμπτώματα της νόσου. Η ανάλυση με κατά βήματα παλινδρόμηση έδειξε ότι 8 πρόδρομα συμπτώματα έφεραν αυξημένο κίνδυνο για υψηλή τιμή PANSS (ολική ή/και υποκλίμακες ), ανεξάρτητα του φύλου, ενώ ένα σύμπτωμα συσχετίστηκε με ήπια ψυχοπαθολογία. Ωστόσο τα αρνητικά και τα θετικά-αποδιοργανωτικά πρόδρομα συμπτώματα δεν συσχετίζονταν με τα αντίστοιχα συστατικά της PANSS. Παρόμοια ευρήματα παρατηρήθηκαν στους μη παρανοϊκούς ασθενείς, ενώ στους παρανοϊκούς μόνο 2 μη ειδικά πρόδρομα συμπτώματα συσχετίστηκαν με υψηλή ψυχοπαθολογία. Επίσης υπήρξαν σημαντικές συσχετίσεις ανάμεσα στον αριθμό των προδρόμων συμπτωμάτων και στα σκορ της PANSS (ολικής κλίμακας, θετικής και γενικής υποκλίμακας) στους ασθενείς με μη παρανοϊκό υπότυπο όχι όμως και στους ασθενείς με παρανοϊκό υπότυπο. Συμπερασματικά αρκετά πρόδρομα συμπτώματα, αλλά και ο αριθμός των συμπτωμάτων της πρόδρομης φάσης σχετίζεται με τη σοβαρότητα της ψυχοπαθολογίας της ενεργού ψύχωσης. Στους μη παρανοϊκούς ασθενείς υπάρχει συνέχεια στη μετάβαση από την προψυχωτική στη ψυχωτική φάση, ενώ στους παρανοϊκούς η μετάβαση αυτή διακόπτεται. / Both retrospective and prospective studies have identified a broad spectrum of ‘‘prodromal’’ symptoms, but their relationship to those of frank psycho¬sis remains largely unexplored. In 73 successive hospitalized schizophrenia patients in the first or second psychotic episode and with duration of illness ≤ 3years from the onset of psychosis were made DSM-IV-TR, Axis I, diagnoses. Also, within the first 5 days from the psychotic episode’s onset, symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS). Patients were interviewed for the presence of ‘‘prodromal’’ symptoms retrospectively. Stepwise regression analyses showed that 8 prodromal symptoms carried an increased risk for high total PANSS and the components of the PANSS scores, independently of gender; one symptom was associated with mild psychopathology. However, the categories of negative and positive-disorganization prodromal symptoms were not associated with the corresponding PANSS components. Similar findings were observed in the nonpa¬ranoid patients, whereas in the paranoid only 2 nonspecific symptoms were associated with high PANSS psychopathology. Also, there were significant associations between number of prodromal symptoms and total PANSS and the subscales positive and general scores in the patients with the nonparanoid subtypes, but there were not such associations in those with the paranoid. In conclusion several prodromal symptoms as well as the number of symptoms are associated with the severity of the psychopathology of frank psychosis. In the nonpa¬ranoid subtypes there is a continuance in the transition from the prepsychotic to the psychotic stage, whereas in the paranoid the transition appears to be disrupted.

Introduction Recent advances in microarray technology have allowed more understanding of the complex molecular biology of breast cancer. The traditional prognostic information afforded by hormone receptor status and pathology variables is being supplemented and superseded by gene signatures predictive of risk of recurrence and response to treatments. Approximately 75% of breast cancers are oestrogen receptor positive (ER+) and can be treated by drugs that block oestrogen production such as letrozole. However not all ER+ tumours respond and even those that initially respond can develop resistance. Treating patients with neoadjuvant letrozole affords a unique opportunity to sample the same tumour in vivo at different time points reducing any potential inter-patient and inter-tumour variability. The molecular effects of drugs can be assessed long before clinical outcome is apparent. Underlying genetic differences or characteristics of the patient, tumour or sample may affect the molecular response to treatment. This project set out to use sequential patient-matched samples to evaluate molecular changes in breast tumours in the presence or absence of endocrine treatment in different subtypes, defined by histology or mutation status and to assess molecular variation between primary tumour and nodal metastasis. Methods RNA was extracted and processed to generate whole transcriptome Illumina Beadarray gene expression data from four unique cohorts of patients. Clinical data on treatments, recurrence and survival was collected from medical records. The first cohort compared 25 breast cancer patients with matched samples at diagnosis and at surgery, 14-35 (median 23) days later, with no intervening treatment; with 36 patients treated with neoadjuvant letrozole. A PCR assay to detect 8 known PIK3CA mutations and assessment of PTEN status was performed at both the primary and secondary event in a second cohort of 120 patients with endocrine treated disease who relapsed with either recurrence, lymph node metastases, a new second primary or progression of disease on primary endocrine therapy. The third cohort compared the molecular response to neoadjuvant letrozole in 14 patients with invasive lobular cancer (ILC) and 14 patients with invasive ductal cancer (IDC). A fourth cohort of women with node positive disease at diagnosis were assessed for variations in gene expression profiles between primary tumour and synchronous metastatic axillary lymph nodes (68 samples from 31 patients). Results The genomic profile of the no intervening treatment cohort did not differ significantly. Some changes in inflammatory genes were evident. This reassures us that changes seen during treatment are truly due to drug effect. This validates the use of a second biopsy to explore prediction of response. PIK3CA mutation status is maintained in the majority of patients with endocrine resistant disease and changed in only 15.7%. Where there was a change in PIK3CA this was significantly more likely to be a second primary breast cancer rather than a recurrence or progression of the primary cancer. PTEN status was also maintained in most patients. This does not support the theory that acquisition of a PIK3CA mutation is responsible for developing endocrine resistance. Novel PI3K inhibitor drugs may still be suitable in endocrine-resistant disease if activation of the pathway develops by other mechanisms. Consistent with previous studies, significant molecular differences were observed between ILC and IDC pre-treatment. Over half of these molecular differences were maintained after 3 months of letrozole. However, changes over time in individual tumours in response to letrozole were highly consistent in both ILC and IDC. When comparing primary with synchronous metastatic nodes only 39% of tumours clustered together with their matched primary or node. The molecular subtype of the node was often a poorer prognosis than the primary. There were also differences in subtype between nodes in a small cohort of patients with 2 involved nodes. Conclusions We have demonstrated that neoadjuvant window studies are a valid model for assessment of drug effects and evaluated differences in histology and mutation status. Endocrine resistance in breast cancer is rarely related to acquisition of PIK3CA mutations. Synchronous lymph node metastases can differ greatly from their matched primary. These findings are highly relevant when considering prescribing (neo)/adjuvant therapy and have significantly improved our understanding of breast cancer as we strive towards personalised medicine.

Base teórica: Nas últimas décadas, o prognóstico do câncer inicial da mama tem sido baseado nas características clínicas das pacientes e em aspectos histológicos dos tumores. Nos últimos anos, subtipos moleculares de carcinoma de mama foram identificados através de estudos de perfil genético por “DNA microarray”. Esta nova classificação pode melhorar a avaliação prognóstica, porém ainda não está disponível e é de alto custo. A possibilidade de identificar subtipos moleculares através de métodos mais simples e de menor custo é particularmente importante em países com recursos limitados. A identificação de subtipos do câncer de mama é particularmente importante pelas implicações clínicas e pelas opções de tratamento. Métodos: Uma coorte retrospectiva de 71 pacientes consecutivas com carcinoma primário de mama de estágio clínico I e II, tratadas no Serviço de Mastologia do HCPA entre os anos de 1993 e 1997 com um seguimento mínimo de 5 anos.Foram revisados dados sobre características clínicas, histopatológicas, evolução clínica e desfechos apresentados no período. Foi realizada uma análise imunoistoquímica de blocos representativos dos tumores, avaliando-se o Receptor Estrogênico (RE), o Receptor de Progesterona (RP), o HER2, o Ki-67, o Bcl-2, o p53, o p63 e o CK8. Os objetivos foram determinar a prevalência do perfil molecular nesta população e em seus desfechos clínicos. Resultados: 39 tumores (54,9 %) foram luminal A; 15 tumores (21,1%) foram luminal B; 15 tumores (21,1) foram basais ou triplo negativos e somente 2 tumores (2,8%) foram HER2. Não houve diferença no prognóstico entre os subtipos de câncer de mama: luminal A (RH positivo e HER2 negativo); luminal B (RH positivo e HER2 positivo); HER2 (HER2 positivo) e basal (RH negativo, HER2 negativo) em relação à sobrevida livre de doença e à sobrevida global, embora apresentassem uma forte correlação com a diferenciação e com o grau tumoral. Provavelmente, isto se deve ao pequeno número de pacientes e ao prognóstico de pacientes com estágios iniciais da doença. Conclusões: Nossos resultados sugerem que é possível identificar os subtipos do câncer de mama pela análise imunoistoquímica de RE, RP e HER2, e que a adição de outros marcadores não melhora a estimativa de prognóstico. O perfil molecular pode ser um instrumento valioso para o manejo do câncer de mama em países com recursos limitados. / Background: In the last decades, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available and it’s too expensive. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising especially in countries with limited resorts. The identification of breast cancer subtypes is particularly important because it has clinical implications and for treatment options. Methods: A retrospective cohort of 71 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the HCPA Breast Unit, between 1993 and 1997 with a minimum follow up of 5 years , was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER),Progesterone Receptor (PR), Human Epidermal Growth Receptor – type 2 (HER2), Ki-67, Bcl-2, p53, p63 and CK8. The endpoints were to determine the prevalence the molecular portrait in this population and its clinical outcomes. Results: 39 tumors (54,9 %) were Luminal A, 15 tumors (21,1%) were Luminal B, 15 tumors (21,1) were Basal or triple negative and only 2 tumors (2,8%) were HER2. There was no prognostic difference among the breast cancer subtypes: luminal A (HR-positive and HER2 negative); luminal B (HR positive and HER2 positive); HER2 overexpressing (HER2 positive) and basal (HR negative, HER2 negative) relating to disease-free and overall survival, although there was a robust correlation with tumor grade and differentiation. This is probably related to limited number of patients in this study and prognosis of initial-stage patients. Conclusions: Our results suggest that it is possible to identify breast cancer subtypes by immunohistochemical analysis of ER, EP, HER2, and that the addition of other markers didn’t improve the prognosis estimates. The molecular profile may be a very useful instrument for breast cancer managing in countries with limited resorts.

Introdução: Resistência aos antirretrovirais pode limitar opções de tratamento, principalmente em pacientes com acúmulo de falhas terapêuticas, o que pode comprometer resultados clínicos. Objetivos: caracterizar o perfil de mutações na transcriptase reversa e protease do HIV-1 de pacientes em falha ao tratamento. Secundariamente, avaliar associação entre mutações e número de falhas terapêuticas, associação entre mutações e subtipos do HIV-1 e apresentar a evolução temporal da prevalência dos subtipos do HIV-1, no estado do Pará, ao Norte do Brasil. Método: Estudo transversal, no qual se avaliam genotipagens, entre janeiro de 2004 a dezembro de 2013, com dados obtidos de formulário de solicitação do exame padronizado pela RENAGENO e de impressos dos resultados, ambos arquivados em quatro serviços de atendimento especializados. Foram incluídos os testes realizados por laboratório da RENAGENO, em maiores de 18 anos, e o primeiro exame daqueles que o realizaram em mais de um momento, totalizando 377 amostras. As mutações são descritas de acordo com o banco de dados de resistência do HIV da Universidade de Stanford (http://hivdb.stanford.edu), estimam-se suas prevalências e avaliam-se mutações de resistência de acordo com o número de falhas no momento da genotipagem, bem como diferenças de mutações entre subtipos B e não-B do HIV-1. Resultados: A mutação M184V foi a mais prevalente (80,1%), seguida da K130N (40,6%) e TAM. Em pacientes multiexperimentados previamente à genotipagem, resistência a ZDV, d4T e TDF foi associada às mutações M41L, D67N, V118I, L210W, K219Q e T69D; bem como resistência a todos os IP/r associou-se às mutações principais M46I, V82A, L90M, I54V, I84V, M46L e L76V. O subtipo B é o predominante no Pará (90,7%) e diferenças de prevalência de mutações entre subtipos ocorreram entre as mutações L63P e A71T versus subtipo B, enquanto as mutações L76V, M36I, K20R, L10V, L89M e F53L associaram-se ao subtipo não-B. Conclusão: A seleção de mutações de resistência do HIV-1 relacionada aos antirretrovirais é similar ao descrito em literatura. O acúmulo de falhas ao tratamento favorece a emergência de mutações, o que reforça o monitoramento de falha virológica, seguida de genotipagem para minimizar o impacto de resistência. Estudos adicionais de epidemiologia molecular são necessários para avaliar melhor a questão da prevalência de subtipos de HIV-1 no estado e possíveis associações com mutações de resistência do HIV-1. / Introduction: Resistance to antiretroviral treatment can limit treatment options, especially in patients with accumulation of therapeutic failures, which may compromise clinical outcomes. Objectives: characterizing the profile of mutations in the protease and reverse transcriptase of HIV-1 patients in the treatment failure. Secondarily to evaluate the association between mutations and the number of treatment failures, association between mutations and subtypes of HIV-1 and present the temporal evolution of the prevalence of subtypes of HIV-1 in the state of Pará in northern Brazil. Method: cross-sectional study in which genotyping is evaluated between January, 2004 and December, 2013 with data obtained from the standardized application form for the examination RENAGENO and printed the results, both filed in four specialty care services. We included those by laboratory RENAGENO in 18 years and the first examination in those who underwent more than one time, totaling 377 samples. Mutations are described according to the database of HIV resistance at Stanford University (http://hivdb.stanford.edu), estimated their prevalence and resistance is evaluated according to the number of failures at the time of genotyping as well as differences between mutations and subtype B and non-B HIV-1. Results: The M184V mutation was the most prevalent (80.1%), followed by K130N (40.6%) and TAM. In patients who received at least three treatments prior to genotyping, resistance to ZDV, d4T and TDF was associated with mutations M41L, D67N, V118I, L210W, K219Q and T69D; well as resistance to all PI / r was associated with the major mutations M46I, V82A, L90M, I54V, I84V M46L and L76V. HIV-1 subtype B was the most prevalent (90.7%) and there were differences between subtypes B versus mutations: L63P and A71T were more frequent in the subtype B, whereas mutations L76V, K20R, L10V, L89M and F53L were in non-B subtypes. Conclusion: The selection of resistance mutations in HIV-1 related to antiretroviral is similar to that described in the literature. The accumulation of failures to treatment favors the emergence of mutations, reinforcing the monitoring and evaluation of virologic failure by genotyping to minimize the impact resistance. Additional molecular epidemiological studies are needed to better assess the issue of prevalence of subtypes of HIV-1 in the state and possible associations with resistance mutations in HIV-1.