Master regulators of FGFR2 signalling and breast cancer risk.

The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk.This is the final version of the article. It was originally published in Nature Communications here: http://www.nature.com/ncomms/2013/130917/ncomms3464/full/ncomms3464.html

Comorbidade de sintomas ansiosos e depressivos em pacientes com dor crônica e o impacto sobre a qualidade de vida

BACKGROUND: Pain is an unpleasant sensory and emotional experience. Both chronic pain and depression result in substantial disability reduced HRQoL and increased health care costs and utilization. OBJECTIVES: To evaluate the strength of the association between depressive and anxiety symptoms and chronic pain, and to investigate the impact of these symptoms on health-related quality of life (HRQoL) in chronic pain individuals. METHODS: Pain was assessed by means of a Visual Analogue Scale (VAS). Depressive and anxiety symptoms were assessed by the Hospital Anxiety and Depression (HAD) scale. Quality of life was assessed by means of the SF-36. RESULTS: Four hundred patients were studied, mean age 45.6 ± 11.4 years and 82.8% female gender. According to HAD, 70% had anxiety and 60% depression symptoms. SF-36 showed mean scores < 50% for all the domains. Patients with severe pain/extreme (70.4%) had a higher frequency of anxiety than those with pain selvagem/moderada (59,5%). This was a statistically significant (p = 0.027). However, the frequency of depression did not reach statistical significance when both groups were compared p = 0.109). DISCUSSION: Depressive/anxiety symptoms and pain together have worse clinical outcomes than each condition alone.CONTEXTO: Dor é uma experiência emocional e sensorial desagradável. Tanto a dor crônica como a depressão reduzem de forma significativa a qualidade de vida, além de aumentar muito os custos dos cuidados com a saúde. OBJETIVOS: Analisar a associação entre sintomas depressivos e de ansiedade em relação à dor crônica e investigar o impacto desses sintomas na saúde e na qualidade de vida em indivíduos com dor crônica. MÉTODOS: A dor foi avaliada por meio de uma Escala Analógica Visual (VAS). Os sintomas depressivos e a ansiedade foram avaliados pela Escala Hospitalar de Ansiedade e Depressão (HAD). A qualidade de vida foi avaliada por meio do SF-36. RESULTADOS: Quatrocentos pacientes foram estudados, com idade média de 45,6 ± 11,4 anos e 82,8% são do sexo feminino. De acordo com a HAD, 70% tinham ansiedade e 60%, os sintomas de depressão. A SF-36 apresentou escores < 50% para todos os domínios. Os pacientes com dor intensa/ extrema apresentaram maior frequência (70,4%) de ansiedade do que aqueles com dor selvagem/moderada (59,5%). Essa foi uma associação estatisticamente significante (p = 0,027). No entanto, a frequência de depressão não atingiu significância estatística quando ambos os grupos foram comparados (p = 0,109). CONCLUSÃO: Os sintomas depressivos/ansiedade e dor, em conjunto, apresentaram piores desfechos clínicos de cada estado sozinho. É necessária mais investigação para determinar se o tratamento da dor ajuda os sintomas dos pacientes depressivos e se o alívio dos sintomas depressivos melhora a dor e sua morbidade

Treatment of developmental dyslexia: A review

Remarkably few research articles on the treatment of developmental dyslexia were published during the last 25 years. Some treatment research arose from the temporal processing theory, some from the phonological deficit hypothesis and some more from the balance model of learning to read and dyslexia. Within the framework of that model, this article reviews the aetiology of dyslexia sub-types, the neuropsychological rationale for treatment, the treatment techniques and the outcomes of treatment research. The possible mechanisms underlying the effects of treatment are discussed. © 2005 Informa UK Ltd All rights reserved

In Vitro and In Vivo Investigation of the Efficacy of Arylimidamide DB1831 and Its Mesylated Salt Form - DB1965 - against Trypanosoma cruzi Infection

Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA - DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T.cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC50 value/48 h of 5–40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T.cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T.cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole

European registry on helicobacter pylori management: Effectiveness of first and second-line treatment in Spain

The management of Helicobacter pylori infection has to rely on previous local effectiveness due to the geographical variability of antibiotic resistance. The aim of this study was to evaluate the effectiveness of first and second-line H. pylori treatment in Spain, where the empirical prescription is recommended. A multicentre prospective non-interventional registry of the clinical practice of European gastroenterologists concerning H. pylori infection (Hp-EuReg) was developed, including patients from 2013 until June 2019. Effectiveness was evaluated descriptively and through a multivariate analysis concerning age, gender, presence of ulcer, proton-pump in-hibitor (PPI) dose, therapy duration and compliance. Overall, 53 Spanish hospitals were included, and 10, 267 patients received a first-line therapy. The best results were obtained with the 10-day bismuth single-capsule therapy (95% cure rate by intention-to-treat) and with both the 14-day bismuth-clarithromycin quadruple (PPI-bismuth-clarithromycin-amoxicillin, 91%) and the 14-day non-bismuth quadruple concomitant (PPI-clarithromycin-amoxicillin-metronidazole, 92%) therapies. Second-line therapies were prescribed to 2448 patients, with most-effective therapies being the triple quinolone (PPI-amoxicillin-levofloxacin/moxifloxacin) and the bismuth-levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-amoxicillin) prescribed for 14 days (92%, 89% and 90% effective-ness, respectively), and the bismuth single-capsule (10 days, 88.5%). Compliance, longer duration and higher acid inhibition were associated with higher effectiveness. “Optimized” H. pylori therapies achieve over 90% success in Spain

Towards the elimination of dog-mediated rabies: development and application of an evidence-based management tool

Abstract: Background: International organizations advocate for the elimination of dog-mediated rabies, but there is only limited guidance on interpreting surveillance data for managing elimination programmes. With the regional programme in Latin America approaching elimination of dog-mediated rabies, we aimed to develop a tool to evaluate the programme’s performance and generate locally-tailored rabies control programme management guidance to overcome remaining obstacles. Methods: We developed and validated a robust algorithm to classify progress towards rabies elimination within sub-national administrative units, which we applied to surveillance data from Brazil and Mexico. The method combines criteria that are easy to understand, including logistic regression analysis of case detection time series, assessment of rabies virus variants, and of incursion risk. Subjecting the algorithm to robustness testing, we further employed simulated data sub-sampled at differing levels of case detection to assess the algorithm’s performance and sensitivity to surveillance quality. Results: Our tool demonstrated clear epidemiological transitions in Mexico and Brazil: most states progressed rapidly towards elimination, but a few regressed due to incursions and control lapses. In 2015, dog-mediated rabies continued to circulate in the poorest states, with foci remaining in only 1 of 32 states in Mexico, and 2 of 27 in Brazil, posing incursion risks to the wider region. The classification tool was robust in determining epidemiological status irrespective of most levels of surveillance quality. In endemic settings, surveillance would need to detect less than 2.5% of all circulating cases to result in misclassification, whereas in settings where incursions become the main source of cases the threshold detection level for correct classification should not be less than 5%. Conclusion: Our tool provides guidance on how to progress effectively towards elimination targets and tailor strategies to local epidemiological situations, while revealing insights into rabies dynamics. Post-campaign assessments of dog vaccination coverage in endemic states, and enhanced surveillance to verify and maintain freedom in states threatened by incursions were identified as priorities to catalyze progress towards elimination. Our finding suggests genomic surveillance should become increasingly valuable during the endgame for discriminating circulating variants and pinpointing sources of incursions

Arbóreas forrageiras: pastagem o ano todo na Caatinga Sergipana

A Caatinga é o bioma predominante no Nordeste do país e o único exclusivamente brasileiro. No estado de Sergipe, a área de influencia desse bioma é conhecida pela forte presença de assentamentos de reforma agrária e se destaca como região produtora de leite. As longas secas vêm prejudicando significativamente a criação de gado nessa região, tornando os agricultores altamente dependentes de insumos externos a suas propriedades. Há, entretanto, espécies arbóreas nativas que podem ser utilizadas como forragem durante o período de seca, objeto deste estudo. O trabalho foi realizado no Assentamento Florestan Fernandes, localizado no Município de Canindé de São Francisco, estado de Sergipe. O estudo da vegetação foi realizado através de levantamento fitossociológico em 30 parcelas de 400m², mensurando-se indivíduos com circunferênciaà altura do peito acima de 6 cm. Registraram-se 2.057 indivíduos, pertencentes a 26 espécies e 16 famílias. A abundância foi de 1.714,2 indivíduos/ha e a área basal de 10,9 m²/ha. As espécies que apresentaram o maior índice de valor de importância ecológica no ambiente estudado foram a Catingueira (28,9%), a Imbura-na-de-cambão (9,7%) e o Pinhão (7,2 %). Nove das 16 espécies apontadas como forrageiras pelos assentados já são apontadas na literatura como forrageiras. Entrevistas realizadas com os assentados revelaram o seu conhecimento dessas espécies como forrageiras, mas ao mesmo tempo evidenciaram que o recurso é pouco utilizado. Assim, o potencial das forrageiras arbóreas contrasta com a sua baixa utilização, o que sugere a oportunidade de programas para promover o uso adequado dessas espécies

HIV-1-Transmitted Drug Resistance and Transmission Clusters in Newly Diagnosed Patients in Portugal Between 2014 and 2019

Objective: To describe and analyze transmitted drug resistance (TDR) between 2014 and 2019 in newly infected patients with HIV-1 in Portugal and to characterize its transmission networks. Methods: Clinical, socioepidemiological, and risk behavior data were collected from 820 newly diagnosed patients in Portugal between September 2014 and December 2019. The sequences obtained from drug resistance testing were used for subtyping, TDR determination, and transmission cluster (TC) analyses. Results: In Portugal, the overall prevalence of TDR between 2014 and 2019 was 11.0%. TDR presented a decreasing trend from 16.7% in 2014 to 9.2% in 2016 (p for-trend = 0.114). Multivariate analysis indicated that TDR was significantly associated with transmission route (MSM presented a lower probability of presenting TDR when compared to heterosexual contact) and with subtype (subtype C presented significantly more TDR when compared to subtype B). TC analysis corroborated that the heterosexual risk group presented a higher proportion of TDR in TCs when compared to MSMs. Among subtype A1, TDR reached 16.6% in heterosexuals, followed by 14.2% in patients infected with subtype B and 9.4% in patients infected with subtype G. Conclusion: Our molecular epidemiology approach indicates that the HIV-1 epidemic in Portugal is changing among risk group populations, with heterosexuals showing increasing levels of HIV-1 transmission and TDR. Prevention measures for this subpopulation should be reinforced.info:eu-repo/semantics/publishedVersio