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

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loc

Supporting MANOaaS and Heterogenous MANOaaS Deployment Within the Zero-Touch Network and Service Management Framework

With the deployment of network slicing in fifth generation (5G) systems, telecom operators can partition their physical infrastructure into a number of distinct network services. However, the advantages of network slicing come at the price of higher complexity in operating and managing telecom networks. To cope with such complexity, the ETSI zero-Touch network and service management (ZSM) framework is designed as a next-generation management system that aims to ideally have all operational processes and tasks executed automatically. ETSI has defined a procedure to deploy the network-slice-As-A-service (NSaaS) scenario using the ZSM reference architecture. Two important use-cases for a more ambitious NSaaS model are MANO-As-A-service (MANOaaS) and heterogeneous MANO-As-A-service (H-MANOaaS), where multiple instances of the same (MANOaaS) or different (H-MANOaaS) MANO frameworks are deployed over the same physical substrate. We propose a conceptual model for supporting the never-Addressed H-MANOaaS use-case. We also offer a blueprint to integrate the MANOaaS and H-MANOaaS use-cases into the ZSM procedures and mechanisms. We then validate the H-MANOaaS deployment use-case with a proof-of-concept where our proposed solution is instantiated using a real-world slice-As-A-service platform and some relevant implementations of different MANO frameworks

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

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Parameters in panoramic radiography for differentiation of radiolucent lesions

OBJECTIVE: The aims of this study were to establish parameters in panoramic radiography for interpretation of unilocular radiolucent lesions, and to compare the accuracy of diagnoses given by examiners before and after using these parameters. MATERIAL AND METHODS: In Part I, 12 specialists analyzed 24 images and the diagnostic criteria used by each examiner to make correct diagnoses were used to build a list of basic radiographic parameters for each pathology (ameloblastoma, keratocystic odontogenic tumor, dentigerous cyst, and idiopathic bone cavity). In Part II, this list was used by 6 undergraduate students (Un), 8 recently graduated dentists (D), 3 oral pathologists, 3 stomatologists, 3 oral radiologists, and 3 oral surgeons to diagnose the corresponding pathologies in the other set of 24 panoramic radiographs (T2). The same analysis occurred without using this list (T1). The method of generalized estimating equations (GEE) was used in order to estimate the probability of making a correct diagnosis depending on the specialty of the examiner, type of lesion, and moment of the evaluation, T1 or T2 (before or after they had access to the list of parameters, respectively). RESULTS: Higher values were obtained for the probability (GEE) of making a correct diagnosis on T2; the group Un presented the highest improvement (14.6 %); no differences between the probabilities were observed either between Un and D, or among the different groups of specialists. CONCLUSIONS: The use of panoramic radiographic parameters did allow improving the diagnostic accuracy for all groups of examiners

A Cholinergic-Regulated Circuit Coordinates the Maintenance and Bi-Stable States of a Sensory-Motor Behavior during Caenorhabditis elegans Male Copulation

Penetration of a male copulatory organ into a suitable mate is a conserved and necessary behavioral step for most terrestrial matings; however, the detailed molecular and cellular mechanisms for this distinct social interaction have not been elucidated in any animal. During mating, the Caenorhabditis elegans male cloaca is maintained over the hermaphrodite's vulva as he attempts to insert his copulatory spicules. Rhythmic spicule thrusts cease when insertion is sensed. Circuit components consisting of sensory/motor neurons and sex muscles for these steps have been previously identified, but it was unclear how their outputs are integrated to generate a coordinated behavior pattern. Here, we show that cholinergic signaling between the cloacal sensory/motor neurons and the posterior sex muscles sustains genital contact between the sexes. Simultaneously, via gap junctions, signaling from these muscles is transmitted to the spicule muscles, thus coupling repeated spicule thrusts with vulval contact. To transit from rhythmic to sustained muscle contraction during penetration, the SPC sensory-motor neurons integrate the signal of spicule's position in the vulva with inputs from the hook and cloacal sensilla. The UNC-103 K+ channel maintains a high excitability threshold in the circuit, so that sustained spicule muscle contraction is not stimulated by fewer inputs. We demonstrate that coordination of sensory inputs and motor outputs used to initiate, maintain, self-monitor, and complete an innate behavior is accomplished via the coupling of a few circuit components

The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected Mice

Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5×106 trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1+, CD8+ and CD4+ cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4+ and CD8+ cells were activated, increased frequencies of CD69+CD8+, CD69+CD4+ and CD25+CD122+CD4+ cells were observed at 24 and 48 h after challenge, and of CD25−CD122+CD4+ cells at 48 h. The major role of CD4+ cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-γ-producing CD4+ cells 24 h after challenge. In contrast, liver CD8+ cells produced little IFN-γ, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge

Inducible Nitric Oxide Synthase in Heart Tissue and Nitric Oxide in Serum of Trypanosoma cruzi-Infected Rhesus Monkeys: Association with Heart Injury

Chagas disease, a neglected tropical disease caused by the protozoan Trypanosoma cruzi, afflicts from 8 to 15 million people in the Latin America. Chronic chagasic cardiomyopathy (CCC) is the most frequent manifestation of Chagas disease. Currently, patient management only mitigates CCC symptoms. The pathogenic factors leading to CCC remain unknown; therefore their comprehension may contribute to develop more efficient therapies. In patients, high nitric oxide (NO) levels have been associated with CCC severity. In T. cruzi-infected mice, NO, mainly produced via inducible nitric oxide synthase (iNOS/NOS2), is proposed to work in parasite control. However, the participation of iNOS/NOS2 and NO in T. cruzi control and heart injury has been questioned. Here, infected rhesus monkeys and iNOS/NOS2-deficient mice were used to explore the participation of iNOS/NOS2-derived NO in heart injury in T. cruzi infection. Chronically infected monkeys presented electrical abnormalities, myocarditis and fibrosis, resembling the spectrum of human CCC. Moreover, cardiomyocyte lesion correlated with iNOS/NOS2+ cells infiltrating the cardiac tissue. Our findings support that parasite-driven iNOS/NOS2+ cells accumulation in the cardiac tissue and NO overproduction contribute to cardiomyopathy severity, mainly disturbing the pathway involved in electrical synchrony in T. cruzi infection

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Diagnosis and management of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is probably one of the most prevalent diseases in the world that also compromises the quality of life of the affected significantly. Its incidence in Brazil is 12%, corresponding to 20 million individuals. OBJECTIVE: To update the GERD management and the new trends on diagnosis and treatment, reviewing the international and Brazilian experience on it. METHOD: The literature review was based on papers published on Medline/Pubmed, SciELO, Lilacs, Embase and Cochrane crossing the following headings: gastroesophageal reflux disease, diagnosis, clinical treatment, surgery, fundoplication. RESULTS: Various factors are involved on GERD physiopathology, the most important being the transient lower esophageal sphincter relaxation. Clinical manifestations are heartburn, regurgitation (typical symptoms), cough, chest pain, asthma, hoarseness and throat clearing (atypical symptoms), which may be followed or not by typical symptoms. GERD patients may present complications such as peptic stenosis, hemorrhage, and Barrett's esophagus, which is the most important predisposing factor to adenocarcinoma. The GERD diagnosis must be based on the anamnesis and the symptoms must be evaluated in terms of duration, intensity, frequency, triggering and relief factors, pattern of evolution and impact on the patient's quality of life. The diagnosis requires confirmation with different exams. The goal of the clinical treatment is to relieve the symptoms and surgical treatment is indicated for patients who require continued drug use, with intolerance to prolonged clinical treatment and with GERD complications. CONCLUSION: GERD is a major digestive health problem and affect 12% of Brazilian people. The anamnesis is fundamental for the diagnosis of GERD, with special analysis of the typical and atypical symptoms (duration, intensity, frequency, triggering and relief factors, evolution and impact on the life quality). High digestive endoscopy and esophageal pHmetry are the most sensitive diagnosctic methods. The clinical treatment is useful in controlling the symptoms; however, the great problem is keeping the patients asymptomatic over time. Surgical treatment is indicated for patients who required continued drug use, intolerant to the drugs and with complicated forms of GERD.A doença do refluxo gastroesofágico (DRGE) é, provavelmente, uma das doenças mais prevalentes no mundo que compromete significativamente a qualidade de vida. Sua incidência no Brasil é de 12%, o que corresponde a 20 milhões de indivíduos. OBJETIVO: Atualizar o manuseio da DRGE e as novas tendências no diagnóstico e tratamento, revendo as experiências internacional e brasileira sobre o tema. MÉTODO: Foi realizada revisão da literatura baseada em artigos publicados no Medline/Pubmed, SciELO, Lilacs, Embase e Cochrane cruzando os seguintes descritores: doença do refluxo gastroesofágico, diagnóstico, tratamento clínico, cirurgia, fundoplicatura. RESULTADOS: Vários fatores estão envolvidos na fisiopatologia da DRGE, sendo o mais importante o relaxamento transitório do esfíncter inferior do esôfago. As manifestações clínicas são azia, regurgitação (sintomas típicos), tosse, dor torácica, asma, rouquidão e pigarro (sintomas atípicos), que podem ser seguidos ou não de sintomas típicos. Pacientes com DRGE podem apresentar complicações como estenose péptica, hemorragia e esôfago de Barrett, que é o fator predisponente mais importante para adenocarcinoma. O diagnóstico deve ser baseado na anamnese e os sintomas devem ser avaliados em termos de duração, intensidade, frequência, fatores precipitantes e relevância, padrão de evolução e impacto na qualidade de vida do paciente. O diagnóstico exige confirmação com exames diferentes. O objetivo do tratamento clínico é aliviar os sintomas e o tratamento cirúrgico é indicado para os que necessitam de uso contínuo de drogas, com intolerância ao tratamento clínico prolongado e com complicações. CONCLUSÃO: A anamnese é fundamental para o diagnóstico de DRGE, com análise especial dos sintomas típicos e atípicos. Endoscopia digestiva alta e pHmetria esofágica são os métodos diagnósticos mais sensíveis. O tratamento clínico é útil no controle dos sintomas; no entanto, o grande problema é manter os pacientes assintomáticos ao longo do tempo. O tratamento cirúrgico é indicado para pacientes que necessitaram o uso contínuo de drogas, intolerantes às drogas e com formas complicadas da DRGE.Universidade Estadual Paulista Júlio de Mesquita Filho, Departamento de Cirurgia e Ortopedia, Faculdade de Medicina de Botucatu, Botucatu, Anexo Verde, Rubião Junior s/n, CEP 18605-970, SP, BrasilUniversidade Estadual Paulista Júlio de Mesquita Filho, Departamento de Cirurgia e Ortopedia, Faculdade de Medicina de Botucatu, Botucatu, Anexo Verde, Rubião Junior s/n, CEP 18605-970, SP, Brasi