Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS

Full-Exon Pyrosequencing Screening of BRCA Germline Mutations in Mexican Women with Inherited Breast and Ovarian Cancer

Hereditary breast cancer comprises 10% of all breast cancers. The most prevalent genes causing this pathology are BRCA1 and BRCA2 (breast cancer early onset 1 and 2), which also predispose to other cancers. Despite the outstanding relevance of genetic screening of BRCA deleterious variants in patients with a history of familial cancer, this practice is not common in Latin American public institutions. In this work we assessed mutations in the entire exonic and splice-site regions of BRCA in 39 patients with breast and ovarian cancer and with familial history of breast cancer or with clinical features suggestive for BRCA mutations by massive parallel pyrosequencing. First we evaluated the method with controls and found 41–485 reads per sequence in BRCA pathogenic mutations. Negative controls did not show deleterious variants, confirming the suitability of the approach. In patients diagnosed with cancer we found 4 novel deleterious mutations (c.2805_2808delAGAT and c.3124_3133delAGCAATATTA in BRCA1; c.2639_2640delTG and c.5114_5117delTAAA in BRCA2). The prevalence of BRCA mutations in these patients was 10.2%. Moreover, we discovered 16 variants with unknown clinical significance (11 in exons and 5 in introns); 4 were predicted as possibly pathogenic by in silico analyses, and 3 have not been described previously. This study illustrates how massive pyrosequencing technology can be applied to screen for BRCA mutations in the whole exonic and splice regions in patients with suspected BRCA-related cancers. This is the first effort to analyse the mutational status of BRCA genes on a Mexican-mestizo population by means of pyrosequencing

Patients’ views of treatment focused genetic testing (TFGT): some lessons for the mainstreaming of BRCA1 and BRCA2 testing

This paper explores patients' views and experiences of undergoing treatment-focused BRCA1 and BRCA2 genetic testing (TFGT), either offered following triaging to clinical genetics (breast cancer) or as part of a mainstreamed care pathway in oncology (ovarian cancer). Drawing on 26 in-depth interviews with patients with breast or ovarian cancer who had undergone TFGT, this retrospective study examines patients' views of genetic testing at this point in their care pathway, focusing on issues, such as initial response to the offer of testing, motivations for undergoing testing, and views on care pathways. Patients were amenable to the incorporation of TFGT at an early stage in their cancer care irrespective of (any) prior anticipation of having a genetic test or family history. While patients were glad to have been offered TFGT as part of their care, some questioned the logic of the test's timing in relation to their cancer treatment. Crucially, patients appeared unable to disentangle the treatment role of TFGT from its preventative function for self and other family members, suggesting that some may undergo TFGT to obtain information for others rather than for self

Mating dances and the evolution of language: What’s the next step?

The Darwinian protolanguage hypothesis is one of the most popular theories of the evolution of human language. According to this hypothesis, language evolved through a three stage process involving general increases in intelligence, the emergence of grammatical structure as a result of sexual selection on protomusical songs, and finally the attachment of meaning to the components of those songs. The strongest evidence for the second stage of this process has been considered to be birdsong, and as a result researchers have investigated the existence of various forms of grammar in the production and comprehension of songs by birds. Here, we argue that mating dances are another relevant source of sexually-selected complexity that has until now been largely overlooked by proponents of Darwinian protolanguage, focusing especially on the dances of long-tailed manakins. We end by sketching several lines of research that should be pursued to determine the relevance of mating dances to the evolution of language

O potencial pedagógico da Hora do Conto para o desenvolvimento da Comunicação Oral

O presente relatório é produto de um projeto de investigação que pretendeu caracterizar a adequação e dinamização da hora do conto com a finalidade de promover o desenvolvimento da comunicação oral, implementada numa sala de 3/4 anos e a adequação didática de um processo de intervenção educativa de estratégias para a promoção do desenvolvimento da Oralidade (incidindo na dinamização da hora conto) implementado numa turma de 3.º ano do 1.º Ciclo do Ensino Básico. Tendo consciência da desvalorização que é atribuída à temática em análise, acreditamos que os profissionais de educação se tornam responsáveis pelo desenvolvimento e aperfeiçoamento das capacidades de comunicação das crianças/alunos. Neste sentido, consideramos que foi extremamente importante investir neste domínio e nas competências a ele associado, nas vertentes de compreensão e expressão orais. Para atingir os objetivos delineamos, planificamos, construímos, aplicamos e avaliamos em sala de aula, um conjunto de intervenções educativas adotando como estratégia principal a dinamização da hora do conto. Assim sendo, podemos verificar através dos resultados obtidos, que efetivamente, a hora do conto e a utilização de diferentes estratégias para a dinamização da mesma, contribuíram positivamente para o desenvolvimento das competências orais dos intervenientes, potenciando melhorias, a vários níveis, nomeadamente na vertente de compressão e de expressão oral dos dois grupos de aplicação.This report is the product of a research project that aimed to characterize the adequacy and dynamization of the story time with the purpose of promoting the development of oral communication, implemented in a 3/4 year classroom and the didactic adequacy of a process of educational intervention strategies to promote the development of Orality (focusing on the dynamization of the story time) implemented in a 3rd year class of the 1st Cycle of Basic Education. Being aware of the devaluation that is attributed to the theme under analysis, we believe that education professionals become responsible for the development and improvement of communication skills of children/students. In this sense, we believe that it was extremely important to invest in this field and in the skills associated with it, in the areas of understanding and oral expression. In order to achieve the objectives, we delineate, plan, build, apply and evaluate in the classroom, a set of educational interventions adopting as the main strategy the dynamization of the story time. Therefore, we can verify through the results obtained, that effectively, the story time and the use of different strategies for the dynamization of the tale, contributed positively to the development of the oral skills of the participants, enhancing improvements, at various levels, particularly in the compression and oral expression of the two groups of application. Keywords: Oral Communication; Compression and Oral Expression; Story Time; Pre-School; 1st Cycle of Basic Education

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers