BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.

BACKGROUND: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis. METHODS: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes. RESULTS: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies. CONCLUSIONS: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients.

Prostate cancer (PrCa) is one of the three most frequent and deadliest cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors with deleterious variants in homologous recombination repair (HRR) genes has placed PrCa on the roadmap of precision medicine. However, the overall contribution of HRR genes to the 10%-20% of carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used targeted next-generation sequencing (T-NGS) covering eight HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, and RAD51C) and an analysis pipeline querying both small and large genomic variations to clarify their global and relative contribution to hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and finally by BRCA2, RAD51C, and BRIP1 (5.6% of the carriers, each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1. These results contribute to clarify the genetic heterogeneity that underlies PrCa predisposition in the early-onset and familial disease, respectively.

Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene.

BACKGROUND: Prostate cancer (PrCa) is one of the most hereditable human cancers, however, only a small fraction of patients has been shown to carry deleterious variants in known cancer predisposition genes. METHODS: Whole-exome sequencing was performed in multiple affected members of 45 PrCa families to select the best candidate genes behind part of the PrCa missing hereditability. Recurrently mutated genes were prioritised, and further investigated by targeted next-generation sequencing in the whole early-onset and/or familial PrCa series of 462 patients. RESULTS: PRUNE2 stood out from our analysis when also considering the available data on its association with PrCa development. Ten germline pathogenic/likely pathogenic variants in the PRUNE2 gene were identified in 13 patients. The most frequent variant was found in three unrelated patients and identical-by-descent analysis revealed that the haplotype associated with the variant is shared by all the variant carriers, supporting the existence of a common ancestor. DISCUSSION: This is the first report of pathogenic/likely pathogenic germline variants in PRUNE2 in PrCa patients, namely in those with early-onset/familial disease. Importantly, PRUNE2 was the most frequently mutated gene in the whole series, with a deleterious germline variant identified in 2.8% of the patients, representing a novel prostate cancer predisposition gene.

Two-dimensional vector bending sensor based on Fabry-Pérot cavities in a multicore fiber.

In this work we demonstrate the fabrication and characterization of a temperature insensitive, two-dimensional curvature sensor using a resin based Fabry-Pérot interferometer, constructed using a multicore fiber (MCF). The fabrication simplicity makes this fiber device very attractive compared to the already reported technologies. Furthermore, the sensitivity reached (>400 pm/m-1), 7 times higher than the one reported for fiber Bragg gratings written on a similar MCF. The reconstruction of the amplitude and curvature has been performed for, showing errors lower than 4%. A numerical study has also been developed, allowing us to understand the sensor response at different fiber sensor geometries.

Truncating and missense PPM1D mutations in early-onset and/or familial/hereditary prostate cancer patients.

Truncating activating mutations in the last exon of PPM1D have been described in patients with breast, ovarian, colorectal and non-small cell lung cancer, but recent data indicate that they may be associated with previous chemotherapy. In this study we evaluated the prevalence of PPM1D mutations in white blood cells (WBC) of 462 patients with early-onset and/or familial/hereditary prostate cancer (PrCa) by sequencing the coding region of exon 6. Two truncating mutations were found in two patients (0.4%), both treated with androgen-ablation therapy but no chemotherapy prior to blood collection. Next generation sequencing analysis showed that the truncating variants were present in 21.4% and 32.4% of the reads, indicating that they were in mosaic in WBC, something that was confirmed by its absence in a different tissue from one of these patients. Additionally, nine patients (1.95%) were found to harbor non-synonymous germline mutations, with three patients sharing the same missense variant, c.1607G > A, p.Arg536Lys. This variant was predicted to be deleterious by different in silico tools and was not found in the 293 male control subjects tested. Large cohorts and/or functional evaluation are needed to clarify the nature of the truncating mosaic mutations in PrCa patients treated with and without androgen-ablation therapy and to evaluate the contribution of the recurrent missense variant to the risk of developing PrCa. © 2016 Wiley Periodicals, Inc.

Barriers and Proposed Solutions to a Successful Implementation of Pediatric Sepsis Protocols.

The implementation of managed protocols contributes to a systematized approach to the patient and continuous evaluation of results, focusing on improving clinical practice, early diagnosis, treatment, and outcomes. Advantages to the adoption of a pediatric sepsis recognition and treatment protocol include: a reduction in time to start fluid and antibiotic administration, decreased kidney dysfunction and organ dysfunction, reduction in length of stay, and even a decrease on mortality. Barriers are: absence of a written protocol, parental knowledge, early diagnosis by healthcare professionals, venous access, availability of antimicrobials and vasoactive drugs, conditions of work, engagement of healthcare professionals. There are challenges in low-middle-income countries (LMIC). The causes of sepsis and resources differ from high-income countries. Viral agent such as dengue, malaria are common in LMIC and initial approach differ from bacterial infections. Some authors found increased or no impact in mortality or increased length of stay associated with the implementation of the SCC sepsis bundle which reinforces the importance of adapting it to most frequent diseases, disposable resources, and characteristics of healthcare professionals. Conclusions: (1) be simple; (2) be precise; (3) education; (5) improve communication; (5) work as a team; (6) share and celebrate results.

Atherosclerosis: The cost of illness in Portugal.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease is the leading cause of death in Portugal and atherosclerosis is the most common underlying pathophysiological process. The aim of this study was to quantify the economic impact of atherosclerosis in Portugal by estimating disease-related costs. METHODS: Costs were estimated based on a prevalence approach and following a societal perspective. Three national epidemiological sources were used to estimate the prevalence of the main clinical manifestations of atherosclerosis. The annual costs of atherosclerosis included both direct costs (resource consumption) and indirect costs (impact on population productivity). These costs were estimated for 2016, based on data from the Hospital Morbidity Database, the health care database (SIARS) of the Regional Health Administration of Lisbon and Tagus Valley including real-world data from primary care, the 2014 National Health Interview Survey, and expert opinion. RESULTS: The total cost of atherosclerosis in 2016 reached 1.9 billion euros (58% and 42% of which was direct and indirect costs, respectively). Most of the direct costs were associated with primary care (55%), followed by hospital outpatient care (27%) and hospitalizations (18%). Indirect costs were mainly driven by early exit from the labor force (91%). CONCLUSIONS: Atherosclerosis has a major economic impact, being responsible for health expenditure equivalent to 1% of Portuguese gross domestic product and 11% of current health expenditure in 2016.

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

Da exclusão social ao desalento: um olhar "decolonial" / From social exclusion to discouragement: a decolonial look

RESUMO: O objeto central deste artigo, fundamentado na psicanálise, é a problemática da exclusão social. Trata-se de mostrar a importância desse saber em uma reflexão dedicada a situações de precariedade social. Um de seus eixos principais concerne à dimensão de pertencimento, própria ao laço social, tendo em vista, em particular, vividos subjetivos marcados por significativas falhas quanto a essa dimensão. A questão da colonialidade é um operador de relevo neste trabalho, visando ao aprofundamento da relação exclusão/pertencimento. A noção de desamparo e sua modalidade extrema, o desalento, têm grande relevância neste estudo, o qual se ancora na articulação entre subjetividade e universo sócio-cultural.

ABSTRACT: From social exclusion to discouragement: a "decolonial" look. The central object of this article, based on psychoanalysis, is the issue of social exclusion. It is about showing the importance of this knowledge in a reflection dedicated to situations of social precariousness. One of its main axes concerns the dimension of belonging, specific to the social bond, taking into account, in particular, subjective experiences marked by significant flaws in this dimension. The issue of coloniality is a relevant operator in this work, aiming to deepen the relationship of exclusion/belonging. The notion of helplessness and its extreme modality, discouragement, has great relevance in this study, which is anchored in the articulation between subjectivity and the socio-cultural universe.

Aberturas na técnica psicanalítica: uma intervenção social clínica com educadores / Openings in the psychoanalytic technique: a clinical social intervention with educators

Exploramos questões da clínica psicanalítica numa proposta de intervenção social clínica junto a educadores. Nossa atuação é orientada por uma abertura do manejo clínico visando possibilitar um espaço de escuta para professores de escolas municipais do Rio de Janeiro. Esses educadores vivem situações geradoras de sofrimento psíquico nem sempre passível de compartilhamento entre pares. Abordamos a singularidade da técnica na realização de uma clínica ampliada. Ao proporcionar espaços sustentados pela psicanálise extramuros, torna-se possível um melhor enfrentamento da precária realidade das referidas escolas, o que dá contorno político a essa prática.(AU)

We explore issues of the psychoanalytic clinic in a proposal for clinical social intervention with educators. Our work is guided by an openness to clinical management in order to provide a listening space for teachers from municipal schools in Rio de Janeiro. These educators experience situations that generate psychic suffering that are not always liable to be shared among peers. We approach the uniqueness of the technique in carrying out an expanded clinic. By providing spaces supported by extramural psychoanalysis, it becomes possible to better face the precarious reality of the referred schools, which gives a political contour to this practice.(AU)

Comparing follow-up of patients with vitamin K antagonists in a health center: pre- and post-COVID-19 pandemic / Comparação do seguimento de doentes hipocoagulados com antagonistas da vitamina K numa unidade de saúde: pré e pós pandemia COVID-19

Introduction and objectives: During the COVID-19 pandemic, the follow-up of patients treated with vitamin K antagonists (VKAs) may have been affected. This study aims to compare how these patients were monitored pre- and post-COVID-19 pandemic and understand the impact of non-face-to-face appointments on their follow-up. Methods: We conducted a retrospective cohort study in a Portuguese Health Center. The study included patients treated with VKAs and followed at the Health Center for international normalized ratio (INR) monitoring between March 2019 and March 2021. Data collected: sex, age, type of VKA; INR; date of INR assessment, type of appointment (face-to-face or phone/e-mail). Rosendaal's method was used to calculate pre-COVID-19 and post-COVID-19 time in therapeutic range (TTR). Good TTR control was defined if values ≥ 70%. Results: 44 patients were included. The mean TTR in the pre-COVID-19 period was 64.55% (95% CI: 58.10 - 71.00%). The post-COVID-19 mean was slightly higher (+ 2.26%), 66.81% (95% CI: 59.66 - 73.97%), but the difference was not statistically significant (p = 0.576). The use of non-face-to-face appointments did not contribute to worsening post-pandemic TTR, show-ing no lower follow-up than during pre-pandemic period in which all contacts were face-to-face [CI (95%) -0.397 - 0.196 for a reference range -0.489 - 0.693]. Conclusions: The TTR value in both periods was similar and lower than the value defined for effective hypocoagulation. The use of non-face-to-face consultation in the post-COVID-19 period does not seem to have influenced the quality of hypocoagulation (AU).

Introdução e objetivos: Durante a pandemia COVID-19 o acompanhamento de doentes medicados com antagonistas da vitamina K (AVKs) pode ter sido afetado. Este estudo pretende comparar a forma como estes doentes foram monitorizados antes e depois da pandemia COVID-19 e compreender o impacto da consulta não presencial no seu seguimento. Métodos: Estudo de coorte retrospetivo num Centro de Saúde em Portugal. O estudo incluiu doentes tratados com AVKs e seguidos no Centro de Saúde para monitorização do International Normalized Ratio(INR) entre março de 2019 e março de 2021. Dados recolhidos: sexo, idade, tipo de AVK; INR; data da avaliação do INR, tipo de consulta (presencial ou por telefone/e-mail). Foi utilizado o método de interpolação linear de Rosendaal para calcular o tempo em intervalo terapêutico (TTR) pré- e pós-COVID-19. Foi definido um bom controle se valores de TTR ≥ 70%. Resultados: Foram incluídos 44 doentes. A média de TTR no período pré-COVID-19 foi de 64,55% (95% IC: 58,10 - 71,00%). A média pós-COVID-19 foi ligeiramente superior (+ 2,26%), 66,81% (95% IC: 59,66 - 73,97%), mas a diferença não foi estatisticamente significativa (p = 0,576). A utilização da consulta não presencial não contribuiu para o agravamento do TTR no período pós-pandemia, não mostrando um seguimento inferior ao do período pré-pandemia em que todos os contatos foram presenciais [IC (95%) -0,397 - 0,196 para um intervalo de referência -0,489 - 0,693]. Conclusões: O valor de TTR em ambos os períodos foi semelhante e inferior ao valor definido para hipocoagulação eficaz. A utilização da consulta não presencial no período pós-COVID-19 não parece ter influenciado a qualidade da hipocoagulação (AU).

Freud e a arte: uma postura estética / Freud and art: an aesthetic posture

O artigo desenvolve a hipótese de que haveria no discurso freudiano sobre a criatividade artística a presença de uma postura estética subentendida no próprio encontro de Freud com as obras de arte de seu tempo. O argumento expõe alguns dados históricos sobre o panorama artístico da época; algumas referências do arquivo epistolar do autor; e um recorte da metapsicologia. Sugerimos que o trilho da estética possibilitou a emergência do emblemático texto O estranho, em 1919, que antecede a formalização da segunda tópica. O artigo consiste numa adaptação da primeira parte de uma tese que versa sobre o aspecto estranho e regressivo da criação artística ­ inscrito, portanto, numa dimensão além do princípio do prazer ­ de modo que o discurso que articula a arte ao sonho, o devaneio e a brincadeira é aqui apresentado como base, portanto, de uma estranheza esteticamente marcada na obra freudiana.

Precariedade social e exclusão em tempos de Covid-19: um olhar psicanalítico / Social precariousness and exclusion during Covid-19: a psychoanalytic look / Precariedad social y exclusión en tiempos de Covid-19: una mirada psicoanalítica

Neste artigo, é analisada a questão do impacto psicológico produzido pela coronavirus disease 2019 (Covid-19) tendo em vista sua incidência num contexto de exclusão e precariedade social. Trata-se de experiências subjetivas de ruptura de laços sociais e simbólicos que são relativas a diferentes planos de pertencimento coletivo: econômico, político, racial e cultural. Os modos de enfrentamento e a própria ameaça que a pandemia representa são reveladores da sociedade atual considerando-se, particularmente, a singularidade de suas diferentes camadas. A partir de um referencial psicanalítico, com ênfase na articulação subjetividade/laço social, é explorada a ideia de que o fenômeno da Covid-19 produz efeitos de aprofundamento de processos de exclusão, já existentes na cena social contemporânea, com consequências nefastas para o psiquismo de sujeitos cuja existência é marcada pela invisibilidade social. Diante de uma crescente situação de desproteção, acirrada pela crise econômica, política e sanitária, o sujeito luta diariamente pela sobrevivência física, o que pode resultar em uma traumática situação de urgência subjetiva

In this article, we analyze the issue of the psychological impact of the coronavirus disease 2019 (Covid-19) in view of its incidence in a context of exclusion and social precariousness. We refer to subjective experiences of rupture of social and symbolic bonds that are related to different forms of belonging: economic, political, racial, and cultural. The threat that the pandemic represents and the ways of coping with it reveal central aspects of society nowadays, considering the singularity of its different layers. From a psychoanalytical point of view, stressing the articulation of subjectivity/social bond, we study the idea that the phenomenon of Covid-19 intensifies the processes of exclusion, already present in the contemporary social scene, with nefarious consequences for the psyche of subjects whose existence is marked by social invisibility. In the context of a situation of social insecurity, exacerbated by unprecedented economic, political, and health crisis, individuals face a daily struggle for survival, which can result in a traumatic experience of subjective urgency

En este artículo, analizamos el tema del impacto psicológico de la coronavirus disease 2019 (Covid-19) en vista de su incidencia en un contexto de exclusión y precariedad social. Se trata de experiencias subjetivas de ruptura de vínculos sociales y simbólicos que se relacionan con diferentes planes de pertenencia colectiva: económico, político, racial y cultural. Las formas de enfrentamiento y la propia amenaza que representa la pandemia revelan la sociedad actual, teniendo especialmente en cuenta la singularidad de sus diferentes estratos. Desde un punto de vista psicoanalítico, destacando la articulación subjetividad/vinculo social, exploramos la idea de que el fenómeno de Covid-19 produce efectos de profundización de los procesos de exclusión, ya existentes en la escena social contemporánea, con consecuencias nefastas para la psique de sujetos cuya existencia está marcada por la invisibilidad social. Ante una situación creciente de desprotección, agravada por la crisis económica, política y sanitaria, el sujeto enfrenta una lucha diaria por la supervivencia, lo que puede resultar en una experiencia traumática de urgencia subjetiva.

Comparison between clinical diagnoses and autopsy findings in a pediatric intensive care unit in São Paulo, Brazil.

OBJECTIVE: To verify the frequency of discrepancies between clinical diagnoses and autopsy findings in patients from a pediatric intensive care unit and to look for predictive factors of the discrepancies. DESIGN: Prospective evaluation performed between September 1996 and December 1998. SETTING: Eight-bed pediatric intensive care unit of a university hospital. PATIENTS: One hundred and two autopsies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Disagreements between autopsy and antemortem diagnoses were classified as proposed by Goldman. Patient age, presence of underlying disease, and length of stay were studied as possible predictive factors for diagnosis discrepancies. During the 28 months of study there were 779 admissions to the pediatric intensive care unit; the death rate was 26% and the autopsy rate was 55%. One hundred and two of 114 (89.5%) autopsies were evaluated. The median age of the patients was 21 months, and 85% of them had a previous underlying disease. One third of patients died before 24 hrs of admission to the pediatric intensive care unit. The autopsy revealed unexpected findings in 73 study patients (72%), 33 of which were related to "major diagnoses" (Goldman's classes I or II), either causes of death or main underlying disease. In 12 patients (12%), the correct diagnosis, if known before death, might have led to a change in the patient's therapy or outcome (class I). Unexpected findings in this group included viral or fungal infection and pulmonary embolism. None of the possible predictive factors that we studied showed significant statistical association between clinical and autopsy discrepant diagnoses in the univariate analysis. CONCLUSIONS: Although diagnoses of both cause of death and underlying disease were accurate in most cases before death, some autopsies revealed findings that would have changed intensive care unit therapy. Nonbacterial infections and pulmonary thromboembolism should always be considered when managing critically ill patients with underlying disease. Autopsy examinations continue to provide important information, especially in the pediatric intensive care unit setting, despite the advances in diagnostic technology.

Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis.

The recurrent germline mutation HOXB13 p.(Gly84Glu) (G84E) has recently been identified as a risk factor for prostate cancer. In a recent study, we have performed full sequencing of the HOXB13 gene in 462 Portuguese prostate cancer patients with early-onset and/or familial/hereditary disease, and identified two novel missense mutations, p.(Ala128Asp) (A128D) and p.(Phe240Leu) (F240L), that were predicted to be damaging to protein function. In the present work we aimed to investigate the potential oncogenic role of these mutations, comparing to that of the recurrent G84E mutation and wild-type HOXB13. We induced site-directed mutagenesis in a HOXB13 expression vector and established in vitro cell models of prostate carcinogenesis with stable overexpression of either the wild-type or the mutated HOXB13 variants. By performing in vitro assays we observed that, while the wild-type promotes proliferation, also observed with the F240L variant along with a decrease in apoptosis, the A128D mutation decreases apoptosis and promotes anchorage independent growth. No phenotypic impact was observed for the G84E mutation in the cell line model used. Our data show that specific HOXB13 mutations are involved in the acquisition of different cancer-associated capabilities and further support an oncogenic role for HOXB13 in prostate carcinogenesis.

Pecado, crime e patologia: produções discursivas acerca da perversão / Sin, crime and pathology: discursive productions on perversion / Péché, crime et pathologie: productions discursives sur la perversion / Pecado, crimen y patología: producciones discursivas acerca de la perversión

Baseando-nos nas análises genealógica e epistemológica propostas por Foucault e Lantéri-Laura, nosso objetivo principal é discernir quais são as principais linhas discursivas que constituíram o saber em torno da perversão, produzindo um sujeito dito perverso. Emerge de maneira fundamental dessa leitura como a ideia de transgressão de limites acompanha a história dos perversos: seja o limite moral imposto pela autoridade divina, seja o limite jurídico determinado pela lei penal, seja o limite do normal definido pela medicina, a perversão sempre aponta para o excesso transgressor. Tais leituras constituem o solo epistemológico sobre o qual Freud se apoia na concepção de uma metapsicologia cujo eixo central é a sexualidade. O discurso freudiano subverte o estatuto da perversão ao afirmá-la como dimensão inescapável da sexualidade e da constituição da subjetividade humana.

Based on the genealogical and epistemological analyzes proposed by Foucault and Lanteri-Laura, we aim to discern which are the main discursive lines that constituted the knowledge around perversion, producing a so-called perverse subject. It emerges in a fundamental way from this reading how the idea of transgression of limits accompanies the history of the perverse: whether the moral limit imposed by divine authority, whether the legal limit determined by criminal law, or the normal limit defined by medicine, perversion always points towards the transgressive excess. Such readings constitute the epistemological ground on which Freud relies to develop the conception of a metapsychology whose central axis is sexuality. The Freudian discourse subverts the status of perversion by affrming it as an inescapable dimension of sexuality and of the constitution of human subjectivity.

Sur la base des analyses généalogique et épistémologique proposées par Foucault et Lanteri-Laura, notre objectif principal est de discerner quelles sont les principales lignes discursives qui constituaient les connaissances autour de la perversion, produisant un sujet dit pervers. Il ressort de manière fondamentale de cette lecture comment l'idée de transgression des limites accompagne l'histoire du pervers : soit la limite morale imposée par l'autorité divine, soit la limite légale déterminée par le droit pénal, ou la limite normale définie par la médecine, la perversion pointe toujours dans la direction de l'excès transgressif. Ces lectures constituent le terrain épistémologique sur lequel Freud s'appuie pour la conception d'une métapsychologie dont l'axe central est la sexualité. Le discours freudien subvertit le statut de perversion en l'affrmant comme une dimension incontournable de la sexualité et de la constitution de la subjectivité humaine.

Basado en los análisis genealógico y epistemológico propuestos por Foucault y por Lanteri-Laura, nuestro principal objetivo es discernir cuáles son las principales líneas discursivas que constituyeron el conocimiento en materia de perversión, produciendo un sujeto denominado perverso. De esta lectura surge de manera fundamental la idea de que la transgresión de los límites acompaña la historia de lo perverso: ya sea el límite moral impuesto por la autoridad divina, el límite legal determinado por el derecho penal o el límite normal definido por la medicina, la perversión siempre señala el exceso transgresor. Tales lecturas constituyen el fundamento epistemológico en el que Freud se basa para la concepción de una metapsicología cuyo eje central es la sexualidad. El discurso freudiano trastorna el estatuto de la perversión al afirmarla como una dimensión ineludible de la sexualidad y de la constitución de la subjetividad humana.

The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer.

Prostate cancer (PrCa) is one of the most common cancers diagnosed worldwide and 5-10 % of all cases are estimated to be associated with inherited predisposition. Even though there is strong evidence that the genetic component is significant in PrCa, the genetic etiology of familial and early-onset disease is largely unknown. Although it has been suggested that men from families with hereditary breast/ovarian cancer (HBOC) and, more recently, with Lynch syndrome may have an increased risk for PrCa, the contribution of these syndromes to PrCa predisposition in families ascertained for early-onset and/or familial PrCa, independently of the presence of other cancers in the family, is uncertain. To quantify the contribution of genes associated with HBOC and Lynch syndromes to PrCa predisposition, we have tested for germline mutations 460 early-onset and/or familial PrCa patients. All patients were screened for the six mutations that are particularly common in Portugal and 38 of them were selected for complete sequencing of BRCA1/2 and/or MLH1, MSH2 and MSH6. Two patients were found to harbor the same MSH2 mutation and a third patient carried a Portuguese BRCA2 founder mutation. None of the alterations were identified in 288 control subjects. Furthermore, we reviewed the 62 PrCa diagnoses in all HBOC (n = 161) and Lynch syndrome (n = 124) families previously diagnosed at our department, and found five other BRCA2 mutation carriers and two additional MSH2 mutation carriers. The clinicopathological characteristics of mutation carriers are in concordance with earlier data suggesting an aggressive PrCa phenotype and support the hypothesis that mutation carriers might benefit from targeted screening according to the gene mutated in the germline.