Perceptions of genetic discrimination among people at risk for Huntington’s disease: a cross sectional survey

Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington’s disease who had undergone genetic testing or remained untested

Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing

MicroRNAs (miRNAs) are prevalent regulatory RNAs that mediate gene silencing and play key roles in diverse cellular processes. While synthetic RNA-based regulatory systems that integrate regulatory and sensing functions have been demonstrated, the lack of detail on miRNA structure–function relationships has limited the development of integrated control systems based on miRNA silencing. Using an elucidated relationship between Drosha processing and the single-stranded nature of the miRNA basal segments, we developed a strategy for designing ligand-responsive miRNAs. We demonstrate that ligand binding to an aptamer integrated into the miRNA basal segments inhibits Drosha processing, resulting in titratable control over gene silencing. The generality of this control strategy was shown for three aptamer–small molecule ligand pairs. The platform can be extended to the design of synthetic miRNAs clusters, cis-acting miRNAs and self-targeting miRNAs that act both in cis and trans, enabling fine-tuning of the regulatory strength and dynamics. The ability of our ligand-responsive miRNA platform to respond to user-defined inputs, undergo regulatory performance tuning and display scalable combinatorial control schemes will help advance applications in biological research and applied medicine

Strangeness Production close to Threshold in Proton-Nucleus and Heavy-Ion Collisions

We discuss strangeness production close to threshold in p+A and A+A collision. Comparing the body of available K+, K0, K-, and Lambda data with the IQMD transport code and for some key observables as well with the HSD transport code, we find good agreement for the large majority of the observables. The investigation of the reaction with help of these codes reveals the complicated interaction of the strange particles with hadronic matter which makes strangeness production in heavy-ion collisions very different from that in elementary interactions. We show how different strange particle observables can be used to study the different facets of this interaction (production, rescattering and potential interaction) which finally merge into a comprehensive understanding of these interactions. We identify those observables which allow for studying (almost) exclusively one of these processes to show how future high precision experiments can improve our quantitative understanding. Finally, we discuss how the K+ multiplicity can be used to study the hadronic equation of state.Comment: 134 pages, pdf 3.3MB, version to be published in Physics Report

The Initial Response to the Boston Marathon Bombing

We discuss the strengths of the medical response to the Boston Marathon bombings that led to the excellent outcomes. Potential shortcomings were recognized, and lessons learned will provide a foundation for further improvements applicable to all institutions

Older people's preferences regarding programme formats for managing concerns about falls

Objective: to explore the preferences of community-dwelling older persons regarding different programme formats for managing concerns about falls

Teste rápido para o HIV como estratégia de prevenção da transmissão vertical no Brasil

OBJECTIVE: To assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission. METHODS: Study based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIV-DNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied. RESULTS: HIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV-infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79). CONCLUSIONS: The strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this population access to health care services after hospital discharge.OBJETIVO: Analizar la viabilidad de evaluación rápida del HIV entre gestantes en la admisión en la maternidad y de intervenciones para reducir la transmisión perinatal del HIV. MÉTODOS: Muestra de conveniencia de mujeres que desconocían su situación serológica para el HIV al ser admitidas para el parto en maternidades públicas de Rio de Janeiro (Sureste) y de Porto alegre (Sur de Brasil), entre marzo de 2000 y abril de 2002. Las mujeres fueron aconsejadas y evaluadas con prueba rápida Determine HIV1/2 en la maternidad. Infección por el HIV fue confirmada por el algoritmo brasilero para el diagnóstico de la infección por el HIV. La transmisión intra- útero fue determinada por el PCR-DNA-HIV. Fueron realizados análisis descriptivos de los datos sociodemográficos, número de gestaciones y de abortos previos, número de visitas de prenatal, momento de la evaluación para el HIV, resultado de la prueba rápida para el HIV, intervenciones recibidas por los recién nacidos y de transmisión vertical del HIV, de acuerdo con cada ciudad. RESULTADOS: La prevalencia de HIV entre las mujeres fue de 6,5% (N=1.439) en Porto Alegre y 1,3% (N=3,778) en Rio de Janeiro. La mayoría fue evaluada durante el trabajo de parto en Porto Alegre y en el postparto, en Rio de Janeiro. Ciento y cuarenta y cuatro niños nacieron de 143 mujeres infectadas por el HIV. Todos los recién nacidos recibieron al menos la profilaxia con zidovudina oral, excepto uno en cada ciudad. Fue posible evitar cualquier exposición a la leche materna en 96,8% y 51,1% de los recién nacidos en Porto Alegre y en Rio de Janeiro, respectivamente. La zidovudina inyectable fue administrada durante el trabajo de parto a 68,8% de los recién nacidos en Porto Alegre y 27,7% en Rio de Janeiro. Entre aquellos con muestras de sangre colectadas hasta 48 horas de nacimiento, la transmisión intra-útero fue confirmada en cuatro casos en Rio de Janeiro (4/47) y en seis casos en Porto Alegre (6/79). CONCLUSIONES: La estrategia se mostró factible en las maternidades de Rio de Janeiro y de Porto Alegre. Esfuerzos deben ser emprendidos para maximizar la evaluación durante el trabajo de parto. Fuerte soporte social precisa ser acoplado a esa estrategia para garantizar el acceso de dicha población al sistema de salud posterior a ser dado de alta de la maternidad.OBJETIVO: Analisar a viabilidade da testagem rápida para o HIV entre gestantes na admissão à maternidade e de intervenções para reduzir a transmissão perinatal do HIV. MÉTODOS: Amostra de conveniência de mulheres que desconheciam sua situação sorológica para o HIV quando admitidas para o parto em maternidades públicas do Rio de Janeiro, RJ, e de Porto Alegre, RS, entre março de 2000 e abril de 2002. As mulheres foram aconselhadas e testadas com teste rápido Determine HIV1/2 na maternidade. Infecção pelo HIV foi confirmada pelo algoritmo brasileiro para o diagnóstico da infecção pelo HIV. A transmissão intra-útero foi determinada pelo PCR-DNA-HIV. Foram realizadas análises descritivas dos dados sociodemográficos, número de gestações e de abortos prévios, número de visitas de pré-natal, momento da testagem para o HIV, resultado do teste rápido para o HIV, intervenções recebidas pelos recém-natos e de transmissão vertical do HIV, de acordo com cada cidade. RESULTADOS: A prevalência de HIV entre as mulheres foi 6,5% (N=1.439) em Porto Alegre e 1,3% (N=3.778) no Rio de Janeiro. A maioria foi testada durante o trabalho de parto em Porto Alegre e no pós-parto, no Rio de Janeiro. Cento e quarenta e quatro crianças nasceram de 143 mulheres infectadas pelo HIV. Todos os recém-natos receberam ao menos a profilaxia com zidovudina oral, exceto um em cada cidade. Foi possível evitar qualquer exposição ao leite materno em 96,8% e 51,1% dos recém-natos em Porto Alegre e no Rio de Janeiro, respectivamente. A zidovudina injetável foi administrada durante o trabalho de parto para 68,8% dos recém-natos em Porto Alegre e 27,7% no Rio de Janeiro. Entre aqueles com amostras de sangue coletadas até 48 horas do nascimento, a transmissão intra-útero foi confirmada em quatro casos no Rio de Janeiro (4/47) e em seis casos em Porto Alegre (6/79). CONCLUSÕES: A estratégia mostrou-se factível nas maternidades do Rio de Janeiro e de Porto Alegre. Esforços devem ser empreendidos para maximizar a testagem durante o trabalho de parto. Forte suporte social precisa ser acoplado a essa estratégia para garantir o acesso dessa população ao sistema de saúde após a alta da maternidade

Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial

Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)-based testing

Increased copy number at 3p14 in breast cancer

INTRODUCTION: The present study was conducted to investigate if chromosome band 3p14 is of any pathogenic significance in the malignant process of breast cancer. Genetic studies have implicated a tumour suppressor gene on chromosome arm 3p and we have proposed LRIG1 at 3p14 as a candidate tumour suppressor. The LRIG1 gene encodes an integral membrane protein that counteracts signalling by receptor tyrosine kinases belonging to the ERBB family. LRIG1 mRNA and protein are expressed in many tissues, including breast tissue. METHODS: In the present report we analysed the LRIG1 gene by fluorescence in situ hybridisation (FISH), LRIG1 mRNA by quantitative RT-PCR, and LRIG1 protein by western blot analysis. Two tumour series were analysed; one series consisted of 19 tumour samples collected between 1987 and 1995 and the other series consisted of 9 tumour samples with corresponding non-neoplastic breast tissues collected consecutively. RESULTS: The LRIG1 gene showed increased copy number in 11 out of 28 tumours (39%) and only one tumour showed a deletion at this locus. Increased LRIG1 copy number was associated with increased levels of LRIG1 mRNA (two of three tumours) and protein (four of four tumours) in the tumours compared to matched non-neoplastic breast tissue, as assessed by RT-PCR and western blot analysis. CONCLUSION: The molecular function of LRIG1 as a negative regulator of ERBB receptors questions the biological significance of increased LRIG1 copy number in breast cancer. We propose that a common, but hitherto unrecognised, breast cancer linked gene is located within an amplicon containing the LRIG1 locus at 3p14.3

Challenges in Whole Exome Sequencing: An Example from Hereditary Deafness

Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same ∼6 Mb autozygous region on chromosome 19 in affected members of the family. Both variants co-segregated with the phenotype and were absent in 335 ethnicity-matched controls. Biallelic GIPC3 mutations have recently been reported to cause autosomal recessive nonsyndromic sensorineural hearing loss. Thus we conclude that the hearing loss in the family described in this report is caused by a novel missense mutation in GIPC3. Identified variant in GIPC3 had a low read depth, which was initially filtered out during the analysis leaving ZNF57 as the only potential causative gene. This study highlights some of the challenges in the analyses of whole exome data in the bid to establish the true causative variant in Mendelian disease