Complete XY gonadal dysgenesis due to p.D293N homozygous mutation in the NR5A1 gene: a case study

The SRY gene (sex-determining region on the Y chromosome; MIM *480000) is responsible for initiating male gonadal development. However, only 15-20% of the cases of XY gonadal dysgenesis are due to mutations in its sequence. Recently, heterozygous mutations in the NR5A1 gene (nuclear receptor subfamily 5, group A. member 1; MIM +184757) have been described in association with ovarian failure and disorders of testis development with or without adrenal failure. Here we describe a case of XY complete gonadal dysgenesis due to a p.D293N homozygous mutation in the NR5A1 gene, with normal SRY and no adrenal failure.51222322

Inducible nitric oxide synthase haplotype associated with hypertension and responsiveness to antihypertensive drug therapy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Hypertension is a multifactorial disorder associated with increased inducible nitric oxide synthase (iNOS) expression and activity. While genetic polymorphisms affect iNOS expression, it is not known whether iNOS gene polymorphisms affect the susceptibility to hypertension and the responses to antihypertensive therapy. This study aimed at assessing whether iNOS polymorphisms ((CCTTT)(n), g.-1026C>A, and g.2087G>A) and haplotypes are associated with hypertension and with responsiveness to drug therapy. We studied 115 well controlled hypertensive patients (HTN), 82 hypertensive patients resistant to optimized antihypertensive therapy (RHTN), and 113 normotensive healthy subjects (NT). Genotypings were carried out using real-time polymerase chain reaction (PCR) and PCR amplification followed by capillary electrophoresis. The software PHASE 2.1 was used to estimate the haplotype frequencies in each group. Variant genotypes (GA + AA) for the g.2087G>A polymorphism were more commonly found in hypertensive patients (HTN + RHTN) than in normotensives (P=0.016; OR=2.05). We found no associations between genotypes and responsiveness to therapy (P>0.05). The S-C-A haplotype was more commonly found in hypertensive patients (HTN + RHTN) than in normotensives (P=0.014; OR=6.07). Interestingly, this haplotype was more commonly found in the HTN group than in the RHTN group (P=0.012; OR=0.14). Our findings indicate that the g.2087G>A polymorphism in the iNOS gene affects the susceptibility to hypertension. Moreover, while the S-C-A haplotype is associated with hypertension, it is also associated with responsiveness to antihypertensive therapy. (C) 2012 Elsevier B.V. All rights reserved.5152391395Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Hip fracture in the elderly: does counting time from fracture to surgery or from hospital admission to surgery matter when studying in-hospital mortality?

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)This study aims to analyze whether the interval from hospital admission to surgery may be used as a surrogate of the actual gap from fracture to surgery when investigating in-hospital hip fracture mortality. After analyzing 3,754 hip fracture admissions, we concluded that those intervals might be used interchangeably without misinterpretation bias. The debate regarding the influence of time to surgery in hip fracture (HF) mortality is one of the most controversial issues in the HF medical literature. Most previous investigations actually analyzed the time from hospital admission to surgery as a surrogate of the less easily available gap from fracture to surgery. Notwithstanding, the assumption of equivalency between those intervals remains untested. We analyzed 3,754 hospital admissions of elderly patients due to HF in Quebec, Canada. We compared the performance as predictors of in-hospital mortality of the delay from admission to surgery and the actual gap from fracture to surgery using univariate and multiple logistic regression analysis. The mean times from fracture to surgery and from admission to surgery were 1.84 and 1.02 days (P < 0.001), respectively. On univariate logistic regression, both times were slightly significant as mortality predictors, yielding similar odds ratios of 1.08 (P < 0.001) for time from fracture to surgery and 1.11 (P < 0.001) for time from admission to surgery. After accounting for other covariates, neither times remained significant mortality predictors. The gap from admission to surgery may be used as a surrogate of the actual delay from fracture to surgery when studying in-hospital HF mortality.205723729Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Delay from fracture to hospital admission: a new risk factor for hip fracture mortality?

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The relationship between surgical timing and hip fracture mortality is unknown in the context of developing countries where large delays to surgery are common. We observed that delay from fracture to hospital admission is associated with decreased survival after a hip fracture. To examine the relationship between the time interval from fracture to surgery as well as its subcomponents (time from fracture to hospital admission and time from admission to surgery) and hip fracture survival. The medical records of all patients aged 60 years and older admitted to a public university hospital in the city of Rio de Janeiro with a primary diagnosis of hip fracture between 1995 and 2000 were reviewed. Survival to hospital discharge and at 1 year were examined. Among 343 patients included in the study, there were 18 (5.3%) in-hospital deaths, and 297 (86.6%) patients remained alive 1 year after surgery. Very long delays from the time of fracture to hospital admission (mean 3 days) and from hospital admission to surgery (mean 13 days) were identified. Increased time from fracture to hospital admission was associated with reduced survival to hospital discharge (hazard ratio [HR] 1.09, 95% CI 1.03-1.15, p = 0.005) and reduced survival at 1 year after surgery (HR 1.07, 95% CI 1.03-1.10, p < 0.001). The interval of time from hospital admission to surgery was not associated with reduced survival to hospital discharge (HR 1.03, 95% CI 0.96-1.10, p = 0.379) or at 1 year after surgery (HR 1.03, 95% CI 0.99-1.07, p = 0.185). If the association estimated in our study is causal, our results provide evidence that some hip fracture-related deaths could be prevented by improved patient access to appropriate and timely hospital care in the context of a developing country.231228472853Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Novel DMRT1 3 ' UTR+11insT mutation associated to XY partial gonadal dysgenesis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA-binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis. Several sex-determining genes direct the fate of the bipotential gonad to either testis or ovary. In addition, heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis. In this report we describe a nucleotide insertion in DMRT1 3'UTR in a patient of XY partial gonadal dygenesis. The 3'UTR+11insT is located within a conserved motif important for mRNA stabilization. Arq Bras Endocrinol Metab. 2010;54(8):749-53548SI749753Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundo de Apoio ao Ensino e a Pesquisa da Universidade Estadual de Campinas (FAEP-Unicamp)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2007/57818-4

Screening for the GJB2 c.-3170 G > A (IVS 1+1 G > A) Mutation in Brazilian Deaf Individuals Using Multiplex Ligation-Dependent Probe Amplification

Mutations in GJB2 gene are the most common cause of nonsyndromic sensorineural recessive hearing loss. One specific mutation, c.35delG, is the most frequent in the majority of Caucasian populations and may account for up to 70% of all GJB2 mutations. However, 10-40% of the patients carry only one pathogenic mutation in the GJB2 gene. Deletions del(GJB6-D13S1830) and del(GJB6-D13S1854), truncating the GJB6 gene, have been detected in GJB2 heterozygous patients in different populations. The IVS 1+1 G > A splice site mutation in the noncoding region of the GJB2 gene has been found in heterozygous state in addition to c.35delG mutation. This mutation has not been reported in Brazilian deaf patients. In the present study we investigated the presence of the IVS 1+1 G > A mutation by multiplex ligation-dependent probe amplification in 185 unrelated Brazilian patients with autosomal recessive nonsyndromic sensorineural hearing loss (43 heterozygous patients and 142 without any pathogenic mutation in the GJB2-coding region). We have found two patients (4.6%) carrying the IVS 1+1 G > A mutation in compound heterozygous with c.35delG mutation.13570170

OCT4 immunohistochemistry may be necessary to identify the real risk of gonadal tumors in patients with Turner syndrome and Y chromosome sequences

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)BACKGROUND: The aim of this study was to investigate the frequency of gonadal tumors among patients with Turner syndrome (TS) carrying Y-derivative sequences in their chromosomal constitution. METHODS: Six out of 260 patients with TS were selected based on mosaicism of the entire Y chromosome; 10 were included because Y-derivative sequences have been detected by PCR with specific oligonucleotides (sex-determining region on the Y, testis specific-protein, Y and DYZ3) and further confirmed by FISH. The 16 patients were subjected to bilateral gonadectomy at ages varying from 8.7 to 18.2 years. Both histopathological investigation with hematoxylin and eosin (H&E) and immunohistochemical analysis with anti-octamer-binding transcription factor 4 (OCT4) antibody were performed. RESULTS: Gonadal neoplasia was not detected in any of the 32 gonads evaluated by H & E; however, four gonads (12%) from three patients (19%) had positive OCT4 staining in 50-80% of nuclei, suggesting the existence of germ cell tumors (gonadoblastoma or in situ carcinoma). CONCLUSIONS: Evaluation of the real risk of development of gonadal tumors in TS patients with Y-derivative sequences in their chromosomal constitution may require a specific histopathological study, such as immunohistochemistry with OCT4.261234503455Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CNPq [500446/2007-5]FAPESP [07/00520-3