AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma

A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo

Avaliação dos padrões de uso de álcool em usuários de serviços de Atenção Primária à Saúde de Juiz de Fora e Rio Pomba (MG) Evaluation of the patterns of alcohol consumption at Primary Health Care services in Juiz de Fora and Rio Pomba (MG)

Uma parte significativa da população brasileira apresenta padrões de consumo de álcool associados a alto risco de desenvolvimento de problemas. Por tal razão, é fundamental avaliá-los na população para traçar estratégias de prevenção primária e secundária ao seu uso. O objetivo deste estudo foi avaliar esse padrão de consumo dos usuários de serviços da Atenção Primária à Saúde das cidades de Juiz de Fora e Rio Pomba, Minas Gerais. Foi aplicado um instrumento de rastreamento -o AUDIT- a 921 sujeitos recrutados durante as consultas de rotina. Considerando os dados em conjunto, 18,3% das pessoas avaliadas encontravam-se na faixa de uso de risco, 77,9% da amostra faziam uso de baixo risco ou eram abstêmios, e 3,8% pontuaram na faixa sugestiva de dependência. De modo geral, os homens apresentaram comportamento de risco em maior freqüência do que as mulheres, sendo mais prevalente na faixa etária dos 38 aos 47 anos de idade.<br>A significant part of the Brazilian population presents alcohol consumption patterns associated with high risk of development problems. Therefore, it is fundamental to verify the patterns of alcohol consumption among the population in order to outline primary and secondary prevention strategies. The aim of this study is to verify the patterns of alcohol consumption among the users of Primary Health Care in the cities of Juiz de Fora and Rio Pomba, in the state of Minas Gerais. We applied a screening test -the AUDIT- in a sample of 921 people selected during routine consultations. Considering data as a whole, 18.3% of the evaluated people were at the risk use zone; 77.9% had low hazardous alcohol use or were abstemious and 3.8% pointed toward the suggestive dependence zone. In general, men more frequently demonstrated hazardous behavior compared to women, which was also more prevalent in the 38 to 47 year-old-age group

Hypersensitivity reactions to antiepileptic drugs in children

Background: Antiepileptic drugs (AEDs) can cause hypersensitivity reactions in children. These reactions are mainly cutaneous, self-limiting, and benign, but life-threatening severe cutaneous adverse reactions can occur. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions, if a drug is taken at the same time. The aims of our study were to confirm or rule out the diagnosis of hypersensitivity reactions to AEDs in children and to detect an infection which mimics these reactions. Methods: A prospective survey was conducted in a group of 100 children with histories of hypersensitivity reactions to AEDs by performing patch tests, delayed-reading intradermal test, and, in case of negative results, challenge test. In all children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae. Results: Maculopapular exanthema and delayed-appearing urticaria were the most reported hypersensitivity reactions to AEDs. Sixty-six (66%) of 100 children had confirmed hypersensitivity reactions to AEDs. Fifty-nine children had positive patch test. No children had positive challenge tests. The most common AEDs causing hypersensitivity reactions were carbamazepine (45.4%) and lamotrigine (43.6%). Thirty-two children had positive tests for viruses or M pneumoniae, and nine of them had also a positive allergy work-up. Conclusion: Considering that there are no specific tests to distinguish between a viral infection and hypersensitivity reactions to AEDs in the acute phase, a diagnostic work-up should be performed in all children with suspected hypersensitivity reactions to AEDs, as well as infectious agent study, to remove a false label of hypersensitivity