Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals

Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction

Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

PMCID: PMC3579848This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Comprehensiveness and programmatic vulnerability to stds/hiv/aids in primary care

This study aimed to identify programmatic vulnerability to STDs/HIV/AIDS in primary health centers (PHCs). This is a descrip - tive and quantitative study carried out in the city of São Paulo. An online survey was applied (FormSUS platform), involving administrators from 442 PHCs in the city, with responses received from 328 of them (74.2%), of which 53.6% were nurses. At - tention was raised in relation to program - matic vulnerability in the PHCs regarding certain items of infrastructure, prevention, treatment, prenatal care and integration among services on STDs/HIV/AIDS care. It was concluded that in order to reach comprehensiveness of actions for HIV/ AIDS in primary health care, it is necessary to consider programmatic vulnerability, in addition to more investment and reor - ganization of services in a dialogue with the stakeholders (users, multidisciplinary teams, and managers, among others)

Exploring Tai Chi in rheumatoid arthritis: a quantitative and qualitative study

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) is a chronic, inflammatory and systemic disease which affects the musculoskeletal system. Exercise programmes are reported to improve physical functioning in patients with RA. Tai Chi is a traditional Chinese martial art which combines slow and gentle movements with mental focus. The purpose of this study was to study in which way Tai Chi group exercise impacted on disease activity, physical function, health status and experience in RA patients, applying quantitative and qualitative methods.</p> <p>Methods</p> <p>Fifteen patients with RA (13 females, age 33-70 years) were recruited from a rheumatology department into a single group study. The patients were instructed in Tai Chi exercise twice weekly for 12 weeks. Assessments at baseline, 12 weeks, and 12 weeks follow-up were performed with a wide range of measures, including disease activity, self-reported health status, physical performance tests (Walking in Figure of Eight, Timed-Stands Test, and Shoulder Movement Impairment Scale). Qualitative data were obtained from a focus group interview conducted after completed intervention with taping and verbatim transcription. Review of the transcripts identified themes important to patients practicing Tai Chi.</p> <p>Results</p> <p>Within the group, Tai Chi practice lead to improved lower-limb muscle function at the end of intervention and at 12 weeks follow-up. Qualitative analyses showed that patients experienced improved physical condition, confidence in moving, balance and less pain during exercise and in daily life. Other experience included stress reduction, increased body awareness, confidence in moving and indicated that Tai Chi was a feasible exercise modality in RA.</p> <p>Conclusions</p> <p>Improved muscle function in lower limbs was also reflected when patient experiences with Tai Chi were studied in depth in this explorative study. The combination of qualitative and quantitative research methods shows that Tai Chi has beneficial effects on health not related to disease activity and standardised health status assessment, and may contribute to an understanding of how Tai Chi exerts its effects.</p> <p>Trial registration</p> <p>NCT00522054</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Emergent Orthotopic Liver Transplantation for Hemorrhage from a Giant Cavernous Hepatic Hemangioma: Case Report and Review

IntroductionCavernous hemangiomas represent the most common benign primary hepatic neoplasm, often being incidentally detected. Although the majority of hepatic hemangiomas remain asymptomatic, symptomatic hepatic hemangiomas can present with abdominal pain, hemorrhage, biliary compression, or a consumptive coagulopathy. The optimal surgical management of symptomatic hepatic hemangiomas remains controversial, with resection, enucleation, and both deceased donor and living donor liver transplantation having been reported.Case reportWe report the case of a patient found to have a unique syndrome of multiorgan cavernous hemangiomatosis involving the liver, lung, omentum, and spleen without cutaneous involvement. Sixteen years following her initial diagnosis, the patient suffered from intra-abdominal hemorrhage due to her giant cavernous hepatic hemangioma. Evidence of continued bleeding, in the setting of Kasabach-Merritt Syndrome and worsening abdominal compartment syndrome, prompted MELD exemption listing. The patient subsequently underwent emergent liver transplantation without complication.ConclusionAlthough cavernous hemangiomas represent the most common benign primary hepatic neoplasm, hepatic hemangioma rupture remains a rare presentation in these patients. Management at a center with expertise in liver transplantation is warranted for those patients presenting with worsening DIC or hemorrhage, given the potential for rapid clinical decompensation

Antimalarial Activity of Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase Enzyme Selected by Docking Studies

The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH) all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH) and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2). The IC50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM) and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use