A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant.

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.

Uso de medicamentos off-label e não licenciados em unidade de tratamento intensivo neonatal e sua associação com escores de gravidade / Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores

OBJETIVO: Avaliar a frequência da prescrição de medicamentos de uso não licenciado (UL) e off-label (OL) em recém-nascidos internados em unidade de tratamento intensivo neonatal de hospital de nível terciário e verificar a associação do seu uso com a gravidade dos pacientes. MÉTODOS: Estudo observacional de coorte dos medicamentos prescritos no período de 6 semanas da internação de neonatos, entre julho e agosto de 2011. Os medicamentos foram classificados em UL e OL para dose, frequência, apresentação, faixa etária e indicação, de acordo com bulário eletrônico aprovado pela Food and Drug Administration. Os pacientes foram acompanhados até alta hospitalar ou 31 dias de internação, com registro diário do Neonatal Therapeutic Intervention Scoring System. RESULTADOS: Foram identificados 318 itens de prescrição para 61 pacientes (média de cinco itens/paciente) e apenas 13 pacientes com uso de medicamentos adequados (21%). Identificaram-se prevalências de 7,5% para prescrições UL e de 27,7% para OL. O uso OL mais prevalente foi para medicamentos não padronizados para faixa etária - 19,5%. Computaram-se 57 medicações - um paciente recebeu 10 fármacos UL/OL na internação. A prevalência de usos OL foi maior em prematuros < 35 semanas e nos com escores de gravidade mais elevados (p = 0,00). CONCLUSÕES: A prevalência de neonatos expostos a medicamentos UL/OL durante a internação hospitalar foi elevada, especialmente naqueles com maior escore de gravidade no Neonatal Therapeutic Intervention Scoring System. Embora haja apreciação geral de que neonatos, especialmente pré-termo, tenham alta taxa de uso de medicamentos, uma avaliação incluindo diferentes culturas e países é necessária para priorizar áreas de pesquisa futura na farmacoterapêutica dessa população vulnerável.

OBJECTIVE: To analyze the frequency of unlicensed (UL) and off-label (OL) prescriptions in neonates admitted to the neonatal intensive care unit of a tertiary care hospital and to determine their association with patients' severity. METHODS: Observational cohort study including drugs prescribed during hospitalization of neonates over a 6-week period between July and August 2011. The drugs were classified as UL and OL for dose, frequency, presentation, age group, or indication, according to an electronic list of drugs approved by the Food and Drug Administration. Patients were followed until hospital discharge or 31 days of hospitalization, with daily records of the Neonatal Therapeutic Intervention Scoring System (NTISS). RESULTS: We identified 318 prescription items for 61 patients (average of five items/patient); there were only 13 patients with appropriate use of medications (21%). A prevalence of 7.5% was identified for UL prescriptions and 27.7% for OL, and the most prevalent OL use was that related to age group - 19.5%. Fifty-seven medications were computed - one patient received 10 UL/OL drugs during hospitalization. The prevalence of OL uses was higher in preterm infants < 35 weeks and in those with higher severity scores (p = 0.00). CONCLUSIONS: The prevalence of neonates exposed to UL/OL drugs during hospitalization was high, especially for those with higher NTISS scores. Although there is general appreciation that neonates, especially preterm infants, have a high rate of drug use, an assessment including different cultures and countries is still needed to prioritize areas for future research in the pharmacotherapy of this vulnerable population.

Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores.

OBJECTIVE: To analyze the frequency of unlicensed (UL) and off-label (OL) prescriptions in neonates admitted to the neonatal intensive care unit of a tertiary care hospital and to determine their association with patients' severity. METHODS: Observational cohort study including drugs prescribed during hospitalization of neonates over a 6-week period between July and August 2011. The drugs were classified as UL and OL for dose, frequency, presentation, age group, or indication, according to an electronic list of drugs approved by the Food and Drug Administration. Patients were followed until hospital discharge or 31 days of hospitalization, with daily records of the Neonatal Therapeutic Intervention Scoring System (NTISS). RESULTS: We identified 318 prescription items for 61 patients (average of five items/patient); there were only 13 patients with appropriate use of medications (21%). A prevalence of 7.5% was identified for UL prescriptions and 27.7% for OL, and the most prevalent OL use was that related to age group - 19.5%. Fifty-seven medications were computed - one patient received 10 UL/OL drugs during hospitalization. The prevalence of OL uses was higher in preterm infants < 35 weeks and in those with higher severity scores (p = 0.00). CONCLUSIONS: The prevalence of neonates exposed to UL/OL drugs during hospitalization was high, especially for those with higher NTISS scores. Although there is general appreciation that neonates, especially preterm infants, have a high rate of drug use, an assessment including different cultures and countries is still needed to prioritize areas for future research in the pharmacotherapy of this vulnerable population.

DNA damage in leukocytes from pretreatment mucopolysaccharidosis type II patients; protective effect of enzyme replacement therapy.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Enzyme replacement therapy reduces the storage of these substances in the lysosomes. Oxidative stress is related to the pathophysiology of many disorders, including inborn errors of metabolism. Oxidative damage to protein and lipid has been described in MPS types I and III. The aim of this study was to analyze DNA damage, as determined by the alkaline comet assay using silver staining, in peripheral leukocytes from MPS II patients before treatment and during the first six months of enzyme replacement therapy. We also correlated DNA damage with lipid and protein oxidative damages, analyzed by plasma malondialdehyde levels and carbonyl group content, respectively. We found a significant increase in lipid and protein damage in MPS II patients before treatment when compared to controls. Also, our results showed greater DNA damage in terms of damage index (DI) in pretreatment MPS II patients (DI=18.0 ± 2.4) when compared to controls (DI=66.0 ± 2.0). Enzyme replacement therapy led to a significant decrease in levels of malondialdehyde and DNA damage when compared to pretreatment, but did not reach control values. Significant positive correlations between DNA damage and malondialdehyde levels, as well as carbonyl group content, were observed. Our findings indicate that MPS II patients are subject to DNA damage and that enzyme replacement therapy is able to protect against this process.

[Prescription of drugs not appropriate for children in a Pediatric Intensive Care Unit]. / Identificação de medicamentos "não apropriados para crianças" em prescrições de unidade de tratamento intensivo pediátrica.

OBJECTIVE: To assess the extent of use of drugs not appropriate for children in prescriptions issued in a tertiary pediatric intensive care unit (PICU), according to FDA standards. METHODS: Observational cross-sectional study. The prescriptions issued to all patients admitted to the PICU at Hospital de Clínicas de Porto Alegre, Brazil, over a six-week period were assessed. Patients' age, sex, weight, prior disease, reason for admission to the PICU and pediatric index of mortality (PIM) were recorded, as were all drugs prescribed, their indications, presentations, doses, frequencies and means of administration. Adequacy for prescription of drugs in three pediatric age ranges was defined according to USA Food and Drug Administration (FDA) approval classification, based on the USP DI 2001 drug reference database. RESULTS: Data were obtained in the months of July and August 2002, on different days, for six consecutive weeks, based on prescriptions issued to 51 patients in 54 admissions to the PICU. Median patient age was 10.5 months; 61% of patients were male. Two thirds of patients (65%) presented prior disease. 87% of admissions were due to clinical reasons, of which 57% were respiratory complaints. A total of 747 prescription items were registered, with prevalence of 10.5% for non-approved uses and 49.5% for off-label uses. No statistically significant difference was found in the distribution of prevalence of irregular prescription either by the three age ranges or by level of severity of disease at admission (according to PIM risk categories). CONCLUSIONS: The high prevalence of prescription of drugs not appropriate for children confirms, in the Brazilian context, the inadequate and inadvertent use of drugs either not approved or off-label for PICU use. This demonstrates the need to encourage further studies on the quality, efficacy and safety of drugs for pediatric use.

Identificaçäo de medicamentos "näo apropriados para crianças" em prescriçöes de unidade de tratamento intensivo pediátrica / Prescription of drugs not appropriate for children in a pediatric intensive care unit

OBJETIVO: Avaliar a extensäo do uso de medicamentos näo apropriados para crianças em prescriçöes de uma unidade de tratamento intensivo pediátrica (UTIP) terciária, de acordo com os padröes estabelecidos pela FDA. MÉTODOS: Estudo transversal, observacional, baseado na avaliaçäo das prescriçöes de todos os pacientes admitidos na UTIP do Hospital de Clínicas de Porto Alegre, no período de seis semanas consecutivas. Foram considerados idade, sexo, peso, doença prévia, motivo de admissäo na UTIP, e PIM (pediatric index of mortality) dos pacientes, e todos os medicamentos prescritos e suas indicaçöes, com as respectivas apresentaçöes, doses, freqüências e vias de administraçäo. O critério de adequaçäo na prescriçäo dos medicamentos seguiu a classificaçäo de aprovaçäo da FDA, baseada no catálogo de informaçöes de medicamentos USP DI 2001, em três faixas etárias pediátricas. RESULTADOS: Os dados foram obtidos nos meses de julho e agosto de 2002, em diferentes dias, de seis semanas consecutivas, baseados nas prescriçöes de 51 pacientes em 54 admissöes de UTIP. A mediana de idade dos pacientes foi 10,5 meses, sendo 61 por cento do sexo masculino. Dois terços (65 por cento) dos pacientes apresentavam doença prévia, e 87 por cento das admissöes ocorreram por motivos clínicos, sendo 57 por cento por causas respiratórias. Foram registrados 747 itens de prescriçäo, com prevalências de 10,5 por cento para medicamentos näo aprovados e 49,5 por cento para medicamentos näo padronizados. A distribuiçäo das prevalências de prescriçäo, tanto pela faixa etária quanto pelo nível de gravidade dos pacientes na admissäo (de acordo com as categorias de risco do PIM), nas três classes de medicamentos, näo mostrou diferença estatística entre os grupos. CONCLUSÄO: A alta prevalência de prescriçöes com medicamentos näo apropriados para crianças confirma, também no nosso meio, o uso inadequado e inadvertido de medicamentos näo testados ou de apresentaçöes näo padronizadas para crianças em UTIP. Isso aponta para a necessidade de estimular a realizaçäo de estudos sobre qualidade, eficácia e segurança de medicamentos para uso pediátrico

Association between mental health screening by self-report questionnaire and insomnia in medical students

Epidemiological research points to the high prevalence of psychiatric disorders among insomniacs. We carried out a cross-sectional study with medical students with the aim of evaluating the association between insomnia and suspicion of psychiatric disorder; 302 medical students were included (184 males and 118 females; mean age = 20.47Ý1.89 years). The main association was tested by logistic regression analysis. The overall prevalence of positivity in a screening test for psychiatric disorder was 22.19 percent; and of insomnia, 28.15 percent. Difficulty initiating sleep (OR=3.45), difficulty maintaining sleep (OR=7.61), falling asleep later (OR=1.99) and waking up earlier (OR=1.91) were associated with suspicion of psychiatric disorder. As a group, the variables difficulty initiating sleep, difficulty maintaining sleep, falling asleep after 11 pm, and waking up before 6 am presented an odds ratio of 5.96 for positivity in the screening for psychiatric disorder. Furthermore, difficulty maintaining sleep (OR=2.24) was associated with "being female," and falling asleep later (OR=0.43) was associated with "being male". These results underscore the importance of determining in what cases difficulty sleeping may have severe clinical repercussions or affect performance