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

Understory Bird Communities in Amazonian Rainforest Fragments: Species Turnover through 25 Years Post-Isolation in Recovering Landscapes

Inferences about species loss following habitat conversion are typically drawn from short-term surveys, which cannot reconstruct long-term temporal dynamics of extinction and colonization. A long-term view can be critical, however, to determine the stability of communities within fragments. Likewise, landscape dynamics must be considered, as second growth structure and overall forest cover contribute to processes in fragments. Here we examine bird communities in 11 Amazonian rainforest fragments of 1–100 ha, beginning before the fragments were isolated in the 1980s, and continuing through 2007. Using a method that accounts for imperfect detection, we estimated extinction and colonization based on standardized mist-net surveys within discreet time intervals (1–2 preisolation samples and 4–5 post-isolation samples). Between preisolation and 2007, all fragments lost species in an area-dependent fashion, with loss of as few as <10% of preisolation species from 100-ha fragments, but up to 70% in 1-ha fragments. Analysis of individual time intervals revealed that the 2007 result was not due to gradual species loss beginning at isolation; both extinction and colonization occurred in every time interval. In the last two samples, 2000 and 2007, extinction and colonization were approximately balanced. Further, 97 of 101 species netted before isolation were detected in at least one fragment in 2007. Although a small subset of species is extremely vulnerable to fragmentation, and predictably goes extinct in fragments, developing second growth in the matrix around fragments encourages recolonization in our landscapes. Species richness in these fragments now reflects local turnover, not long-term attrition of species. We expect that similar processes could be operating in other fragmented systems that show unexpectedly low extinction

Changes in the Brain Microstructure of Children with Primary Monosymptomatic Nocturnal Enuresis: A Diffusion Tensor Imaging Study

Background: Primary monosymptomatic nocturnal enuresis (PMNE) is a common disorder in school-aged children. Previous studies have suggested that a developmental delay might play a role in the pathology of children with PMNE. However, microstructural abnormalities in the brains of these children have not been thoroughly investigated. Methodology/Principal Findings: In this work, we evaluated structural changes in the brains of children with PMNE using diffusion tensor imaging (DTI). Two groups consisting of 26 children with PMNE and 26 healthy controls were scanned using magnetic resonance DTI. The diffusion parameters of fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain, voxel-wise group comparisons using statistical parametric mapping (SPM). When compared to healthy subjects, children with PMNE showed both a decrease in FA and an increase in MD in the thalamus. MD also increased in the frontal lobe, the anterior cingulate cortex and the insula; these areas are all involved in controlling micturition. The significant changes seen in the thalamus could affect both urine storage and arousal from sleep. Conclusions/Significance: The microstructure abnormalities were observed in the thalamus, the medial frontal gyrus, the anterior cingulate cortex and the insula, which are involved in micturition control network. This indicates developmenta

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals

The application of omics in ruminant production: a review in the tropical and sub-tropical animal production context

The demand for animal products (e.g. dairy and beef) in tropical regions is expected to increase in parallel with the public demand for sustainable practices, due to factors such as population growth and climate change. The necessity to increase animal production output must be achieved with better management and production technologies. For this to happen, novel research methodologies, animal selection and postgenomic tools play a pivotal role. Indeed, improving breeder selection programs, the quality of meat and dairy products as well as animal health will contribute to higher sustainability and productivity. This would surely benefit regions where resource quality and quantity are increasingly unstable, and research is still very incipient, which is the case of many regions in the tropics. The purpose of this review is to demonstrate how omics-based approaches play a major role in animal science, particularly concerning ruminant production systems and research associated to the tropics and developing countriesinfo:eu-repo/semantics/acceptedVersio

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362