Revisiting the utility of identifying nuclear grooves as unique nuclear changes by an object detector model.

BACKGROUND: Among other structures, nuclear grooves are vastly found in papillary thyroid carcinoma (PTC). Considering that the application of artificial intelligence in thyroid cytology has potential for diagnostic routine, our goal was to develop a new supervised convolutional neural network capable of identifying nuclear grooves in Diff-Quik stained whole-slide images (WSI) obtained from thyroid fineneedle aspiration. METHODS: We selected 22 Diff-Quik stained cytological slides with cytological diagnosis of PTC and concordant histological diagnosis. Each of the slides was scanned, forming a WSI. Images that contained the region of interest were obtained, followed by pre-formatting, annotation of the nuclear grooves and data augmentation techniques. The final dataset was divided into training and validation groups in a 7:3 ratio. RESULTS: This is the first artificial intelligence model based on object detection applied to nuclear structures in thyroid cytopathology. A total of 7,255 images were obtained from 22 WSI, totaling 7,242 annotated nuclear grooves. The best model was obtained after it was submitted 15 times with the train dataset (14th epoch), with 67% true positives, 49.8% for sensitivity and 43.1% for predictive positive value. CONCLUSIONS: The model was able to develop a structure predictor rule, indicating that the application of an artificial intelligence model based on object detection in the identification of nuclear grooves is feasible. Associated with a reduction in interobserver variability and in time per slide, this demonstrates that nuclear evaluation constitutes one of the possibilities for refining the diagnosis through computational models.

Phosphate induces inflammation and exacerbates injury from cigarette smoke in the bronchial epithelium.

An elevation in serum phosphate-also called hyperphosphatemia-is associated with reduced kidney function in chronic kidney disease (CKD). Reports show CKD patients are more likely to develop lung disease and have poorer kidney function that positively correlates with pulmonary obstruction. However, the underlying mechanisms are not well understood. Here, we report that two murine models of CKD, which both exhibit increased serum levels of phosphate and fibroblast growth factor (FGF) 23, a regulator of phosphate homeostasis, develop concomitant airway inflammation. Our in vitro studies point towards a similar increase of phosphate-induced inflammatory markers in human bronchial epithelial cells. FGF23 stimulation alone does not induce a proinflammatory response in the non-COPD bronchial epithelium and phosphate does not cause endogenous FGF23 release. Upregulation of the phosphate-induced proinflammatory cytokines is accompanied by activation of the extracellular-signal regulated kinase (ERK) pathway. Moreover, the addition of cigarette smoke extract (CSE) during phosphate treatments exacerbates inflammation as well as ERK activation, whereas co-treatment with FGF23 attenuates both the phosphate as well as the combined phosphate- and CS-induced inflammatory response, independent of ERK activation. Together, these data demonstrate a novel pathway that potentially explains pathological kidney-lung crosstalk with phosphate as a key mediator.

ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a systemic disease strongly associated with cigarette smoking, airway inflammation, and acute disease exacerbations. Changes in terminal sialylation and fucosylation of asparagine (N)-linked glycans have been documented in COPD, but the role that glycosyltransferases may play in the regulation of N-linked glycans in COPD has not been fully elucidated. Recent studies suggest that modulation of ST6GAL1 (ST6 beta-galactoside alpha-2,6-sialyltransferase-1), which catalyzes terminal α2-6 sialylation of cellular proteins, may regulate inflammation and contribute to COPD phenotype(s). Interestingly, it has been previously demonstrated that ST6GAL1, a Golgi resident protein, can be proteolytically processed by BACE1 (beta-site amyloid precursor protein cleaving enzyme-1) to a circulating form that retains activity. In this study, we showed that loss of ST6GAL1 expression increased interleukin (IL)-6 expression and secretion in human bronchial epithelial cells (HBECs). Furthermore, exposure to cigarette smoke medium/extract (CSE) or BACE1 inhibition resulted in decreased ST6GAL1 secretion, reduced α2-6 sialylation, and increased IL-6 production in HBECs. Analysis of plasma ST6GAL1 levels in a small COPD patient cohort demonstrated an inverse association with prospective acute exacerbations of COPD (AECOPD), while IL-6 was positively associated. Altogether, these results suggest that reduced ST6GAL1 and α2-6 sialylation augments IL-6 expression/secretion in HBECs and is associated with poor clinical outcomes in COPD.

Congenital hypothyroidism as a risk factor for hearing and parents' knowledge about its impact on hearing.

AIM: To evaluate the hearing of children with congenital hypothyroidism (CH) and to analyze the knowledge that parents' have on the possible auditory impacts of the disease. METHODS: A total of 263 parents/guardians were interviewed about aspects of CH and hearing. Audiological evaluation was performed on 80 participants, divided into two groups: with CH (n= 50) and without CH (n=30). Clinical and laboratory CH data were obtained from medical records, pure tone auditory thresholds and acoustic reflexes were analyzed. The auditory data was compared between groups. Student's t-test and Chi-square were used for statistical analysis at a significance level of 5% (p ≤0.05). RESULTS: The majority (78%), of the parents were unaware that CH when not treated early is a potential risk to hearing. There was no correlation between socioeconomic class and level of information about CH and hearing (p>0,05; p=0.026). There was a statistically significant difference between the auditory tone thresholds of the groups and between the levels of intensity necessary for the triggering of the acoustic reflex. The group with CH presented the worst results (p≤0.05) and absence of acoustic reflex in a normal tympanometric condition. CONCLUSIONS: Children with CH are more likely to develop damage to the auditory system involving retrocochlear structures when compared to healthy children, and that the disease may have been a risk factor for functional deficits without deteriorating hearing sensitivity. The possible impacts of CH on hearing, when not treated early, should be more publicized among the parents/guardians of this population.

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.

Glial-derived neurotrophic factor is essential for blood-nerve barrier functional recovery in an experimental murine model of traumatic peripheral neuropathy.

There is emerging evidence that glial-derived neurotrophic factor (GDNF) is a potent inducer of restrictive barrier function in tight junction-forming microvascular endothelium and epithelium, including the human blood-nerve barrier (BNB) in vitro. We sought to determine the role of GDNF in restoring BNB function in vivo by evaluating sciatic nerve horseradish peroxidase (HRP) permeability in tamoxifen-inducible GDNF conditional knockout (CKO) adult mice following non-transecting crush injury via electron microscopy, with appropriate wildtype (WT) and heterozygous (HET) littermate controls. A total of 24 age-, genotype- and sex-matched mice >12 weeks of age were injected with 30 mg/kg HRP via tail vein injection 7 or 14 days following unilateral sciatic nerve crush, and both sciatic nerves were harvested 30 minutes later for morphometric assessment by light and electron microscopy. The number and percentage of HRP-permeable endoneurial microvessels were ascertained to determine the effect of GDNF in restoring barrier function in vivo. Following sciatic nerve crush, there was significant upregulation in GDNF protein expression in WT and HET mice that was abrogated in CKO mice. GDNF significantly restored sciatic nerve BNB HRP impermeability to near normal levels by day 7, with complete restoration seen by day 14 in WT and HET mice. A significant recovery lag was observed in CKO mice. This effect was independent on VE-Cadherin or claudin-5 expression on endoneurial microvessels. These results imply an important role of GDNF in restoring restrictive BNB function in vivo, suggesting a potential strategy to re-establish the restrictive endoneurial microenvironment following traumatic peripheral neuropathies.

The Human Blood-Nerve Barrier Transcriptome.

The blood-nerve barrier (BNB), formed by tight junction-forming microvessels within peripheral nerve endoneurium, exists to regulate its internal microenvironment essential for effective axonal signal transduction. Relatively little is known about the unique human BNB molecular composition. Such knowledge is crucial to comprehend the relationships between the systemic circulation and peripheral nerves in health, adaptations to intrinsic or extrinsic perturbations and alterations that may result in disease. We performed RNA-sequencing on cultured early- and late-passage adult primary human endoneurial endothelial cells and laser-capture microdissected endoneurial microvessels from four cryopreserved normal adult human sural nerves referenced to the Genome Reference Consortium Human Reference 37 genome browser, using predefined criteria guided by known transcript or protein expression in vitro and in situ. We identified 12881 common transcripts associated by 125 independent biological networks, defined as the normal adult BNB transcriptome, including a comprehensive array of transporters and specialized intercellular junctional complex components. These identified transcripts and their interacting networks provide insights into peripheral nerve microvascular morphogenesis, restrictive barrier formation, influx and efflux transporters with relevance to understanding peripheral nerve homeostasis and pharmacology, including targeted drug delivery and the mediators of leukocyte trafficking in peripheral nerves during normal immunosurveillance.

An Assessment of Imaging Informatics for Precision Medicine in Cancer.

Objectives: Precision medicine requires the measurement, quantification, and cataloging of medical characteristics to identify the most effective medical intervention. However, the amount of available data exceeds our current capacity to extract meaningful information. We examine the informatics needs to achieve precision medicine from the perspective of quantitative imaging and oncology. Methods: The National Cancer Institute (NCI) organized several workshops on the topic of medical imaging and precision medicine. The observations and recommendations are summarized herein. Results: Recommendations include: use of standards in data collection and clinical correlates to promote interoperability; data sharing and validation of imaging tools; clinician's feedback in all phases of research and development; use of open-source architecture to encourage reproducibility and reusability; use of challenges which simulate real-world situations to incentivize innovation; partnership with industry to facilitate commercialization; and education in academic communities regarding the challenges involved with translation of technology from the research domain to clinical utility and the benefits of doing so. Conclusions: This article provides a survey of the role and priorities for imaging informatics to help advance quantitative imaging in the era of precision medicine. While these recommendations were drawn from oncology, they are relevant and applicable to other clinical domains where imaging aids precision medicine.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

PURPOSE OF REVIEW: The purpose of this review is to present an overview regarding the renaming of encapsulated follicular variant of papillary thyroid cancer as 'noninvasive follicular thyroid neoplasm with papillary-like nuclear features'. RECENT FINDINGS: A recent retrospective study has shown the excellent clinical outcomes of noninvasive encapsulated follicular variant of papillary thyroid cancer, for which the diagnosis is based on a thorough examination of all tumor tissue and its capsule to exclude any vascular or capsular invasion. Given the extremely low malignant potential of this entity, the term cancer was eliminated from its name, as this tumor requires less aggressive follow-up and treatment. SUMMARY: The low-risk tumor was previously treated conservatively prior to its renaming. However, elimination of the term cancer from its name may decrease the psychological and social consequences of its diagnosis.

Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy.

The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2mg/kg FNCS1 peptide for 5days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25µM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of inflammatory demyelination. Microvessels demonstrating FNCS1 expression and CD49d+ leukocytes were seen within the endoneurium of patient nerve biopsies. Taken together, these results imply a role for FNCS1 in pathogenic leukocyte trafficking in CIDP, providing a potential target for therapeutic modulation.

Dysregulation of Systemic and Mucosal Humoral Responses to Microbial and Food Antigens as a Factor Contributing to Microbial Translocation and Chronic Inflammation in HIV-1 Infection.

HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4+ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4+ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.

A novel method for measuring hydraulic conductivity at the human blood-nerve barrier in vitro.

Microvascular barrier permeability to water is an essential biophysical property required for the homeostatic maintenance of unique tissue microenvironments. This is of particular importance in peripheral nerves where strict control of ionic concentrations is needed for axonal signal transduction. Previous studies have associated inflammation, trauma, toxin exposure and metabolic disease with increases in water influx and hydrostatic pressure in peripheral nerves with resultant endoneurial edema that may impair axonal function. The regulation of water permeability across endoneurial microvessels that form the blood-nerve barrier (BNB) is poorly understood. Variations exist in apparatus and methods used to measure hydraulic conductivity. The objective of the study was to develop a simplified hydraulic conductivity system using commercially available components to evaluate the BNB. We determined the mean hydraulic conductivity of cultured confluent primary and immortalized human endoneurial endothelial cell layers as 2.00×10-7 and 2.17×10-7cm/s/cm H2O respectively, consistent with restrictive microvascular endothelial cells in vitro. We also determined the mean hydraulic conductivity of immortalized human brain microvascular endothelial cell layers, a commonly used blood-brain barrier (BBB) cell line, as 0.20×10-7cm/s/cm H2O, implying a mean 10-fold higher resistance to transendothelial water flux in the brain compared to peripheral nerves. To our knowledge, this is the first reported measurement of human BNB and BBB hydraulic conductivities. This model represents an important tool to further characterize the human BNB and deduce the molecular determinants and signaling mechanisms responsible for BNB hydraulic conductivity in normal and disease states in vitro.

Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway.

HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1) on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR-7/8 ligand, bacterial lipopolysaccharide (LPS), and IFNα. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs) expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function.

The Brazilian consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism.

INTRODUCTION: Hyperthyroidism is characterized by increased synthesis and release of thyroid hormones by the thyroid gland. Thyrotoxicosis refers to the clinical syndrome resulting from excessive circulating thyroid hormones, secondary to hyperthyroidism or due to other causes. This article describes evidence-based guidelines for the clinical management of thyrotoxicosis. OBJECTIVE: This consensus, developed by Brazilian experts and sponsored by the Department of Thyroid Brazilian Society of Endocrinology and Metabolism, aims to address the management, diagnosis and treatment of patients with thyrotoxicosis, according to the most recent evidence from the literature and appropriate for the clinical reality of Brazil. MATERIALS AND METHODS: After structuring clinical questions, search for evidence was made available in the literature, initially in the database MedLine, PubMed and Embase databases and subsequently in SciELO - Lilacs. The strength of evidence was evaluated by Oxford classification system was established from the study design used, considering the best available evidence for each question. RESULTS: We have defined 13 questions about the initial clinical approach for the diagnosis and treatment that resulted in 53 recommendations, including the etiology, treatment with antithyroid drugs, radioactive iodine and surgery. We also addressed hyperthyroidism in children, teenagers or pregnant patients, and management of hyperthyroidism in patients with Graves' ophthalmopathy and various other causes of thyrotoxicosis. CONCLUSIONS: The clinical diagnosis of hyperthyroidism usually offers no difficulty and should be made with measurements of serum TSH and thyroid hormones. The treatment can be performed with antithyroid drugs, surgery or administration of radioactive iodine according to the etiology of thyrotoxicosis, local availability of methods and preferences of the attending physician and patient.

Consenso brasileiro para o diagnóstico e tratamento do hipertireoidismo: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia / The Brazilian consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism

INTRODUÇÃO: O hipertireoidismo é caracterizado pelo aumento da síntese e liberação dos hormônios tireoidianos pela glândula tireoide. A tireotoxicose refere-se à síndrome clínica decorrente do excesso de hormônios tireoidianos circulantes, secundário ao hipertireoidismo ou não. Este artigo descreve diretrizes baseadas em evidências clínicas para o manejo da tireotoxicose. OBJETIVO: O presente consenso, elaborado por especialistas brasileiros e patrocinado pelo Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia, visa abordar o manejo, diagnóstico e tratamento dos pacientes com tireotoxicose, de acordo com as evidências mais recentes da literatura e adequadas para a realidade clínica do país. MATERIAIS E MÉTODOS: Após estruturação das questões clínicas, foi realizada busca das evidências disponíveis na literatura, inicialmente na base de dados do MedLine-PubMed e posteriormente nas bases Embase e SciELO - Lilacs. A força das evidências, avaliada pelo sistema de classificação de Oxford, foi estabelecida a partir do desenho de estudo utilizado, considerando-se a melhor evidência disponível para cada questão. RESULTADOS: Foram definidas 13 questões sobre a abordagem clínica inicial visando ao diagnóstico e ao tratamento que resultaram em 53 recomendações, incluindo investigação etiológica, tratamento com drogas antitireoidianas, iodo radioativo e cirurgia. Foram abordados ainda o hipertireoidismo em crianças, adolescentes ou pacientes grávidas e o manejo do hipertireoidismo em pacientes com oftalmopatia de Graves e com outras causas diversas de tireotoxicose. CONCLUSÕES: O diagnóstico clínico do hipertireoidismo, geralmente, não oferece dificuldade e a confirmação diagnóstica deverá ser feita com as dosagens das concentrações séricas de TSH e hormônios tireoidianos. O tratamento pode ser realizado com drogas antitireoidianas, administração de radioiodoterapia ou cirurgia de acordo com a etiologia da tireotoxicose, as características clínicas, disponibilidade local de métodos e preferências do médico-assistente e paciente.

INTRODUCTION: Hyperthyroidism is characterized by increased synthesis and release of thyroid hormones by the thyroid gland. Thyrotoxicosis refers to the clinical syndrome resulting from excessive circulating thyroid hormones, secondary to hyperthyroidism or due to other causes. This article describes evidence-based guidelines for the clinical management of thyrotoxicosis. OBJECTIVE: This consensus, developed by Brazilian experts and sponsored by the Department of Thyroid Brazilian Society of Endocrinology and Metabolism, aims to address the management, diagnosis and treatment of patients with thyrotoxicosis, according to the most recent evidence from the literature and appropriate for the clinical reality of Brazil. MATERIALS AND METHODS: After structuring clinical questions, search for evidence was made available in the literature, initially in the database MedLine, PubMed and Embase databases and subsequently in SciELO - Lilacs. The strength of evidence was evaluated by Oxford classification system was established from the study design used, considering the best available evidence for each question. RESULTS: We have defined 13 questions about the initial clinical approach for the diagnosis and treatment that resulted in 53 recommendations, including the etiology, treatment with antithyroid drugs, radioactive iodine and surgery. We also addressed hyperthyroidism in children, teenagers or pregnant patients, and management of hyperthyroidism in patients with Graves' ophthalmopathy and various other causes of thyrotoxicosis. CONCLUSIONS: The clinical diagnosis of hyperthyroidism usually offers no difficulty and should be made with measurements of serum TSH and thyroid hormones. The treatment can be performed with antithyroid drugs, surgery or administration of radioactive iodine according to the etiology of thyrotoxicosis, local availability of methods and preferences of the attending physician and patient.

Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms.

Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.

New cases of isolated congenital central hypothyroidism due to homozygous thyrotropin beta gene mutations: a pitfall to neonatal screening.

BACKGROUND: Congenital central hypothyroidism (CCH) is a rare condition that is often diagnosed in late childhood in countries where neonatal screening programs rely solely on detecting thyrotropin (TSH) elevation. TSHbeta gene mutation is one of the causes of CCH. We describe two cases of c.Q49X mutation and three cases of c.C105Vfs114X mutation in exon 3 of the TSH beta-subunit gene. SUMMARY: We found two different TSHbeta gene mutations in two families. In one family, we identified a missense mutation in exon 3 leading to a premature stop at position 49 (c.Q49X) in the two affected twins. In the other family, the three affected siblings had a 313delT nucleotide deletion leading to a frame shift responsible for premature termination at codon 114 (c.C105Vfs114X); neonatal screening showed very low TSH levels in all three patients. The presence of inappropriately low TSH levels at birth in the three affected members of the second family raises questions about the value of the TSH level for CCH screening. CONCLUSIONS: The marked phenotypic variability in patients with the c.Q49X mutation suggests modulation by interacting genes and/or differences in the genetic background. TSHbeta gene mutations should be suspected in neonates with inappropriately low TSH levels.

Clinical and molecular analysis of thyroid hypoplasia: a population-based approach in southern Brazil.

BACKGROUND: Congenital hypothyroidism (CH) is mainly due to developmental abnormalities leading to thyroid dysgenesis (TD). TD encompasses very distinct morphologic subtypes of disease. This study examined and compared the phenotype in TD variants and searched for genetic alterations in sporadic thyroid hypoplasia (TH), the most misdiagnosed form of CH. This was a longitudinal study over a 14-year period (1990-2004). METHODS: A continuous series of 353 children with TD was identified using thyroid function tests [thyroxine (T4) and TSH], scintigraphy, and ultrasound as diagnostic tools. Individual phenotypes were analyzed in 253 children with TD. Mutations in the most likely candidate genes were studied in 35 cases of TH. RESULTS: The overall birth prevalence of permanent CH was 1:4795. Ectopy represented 37% of all cases of permanent primary CH, dyshormonogenesis 28%, agenesis 24%, hypoplasia 10%, and hemiagenesis 1%. The lowest screening T4 level and the highest TSH level were in the agenetic group, followed by TH. The TH group had an improvement in the thyroid function showing less-severe phenotype with aging. In the molecular analysis, one patient was identified with a mutation in the PAX8 gene (155G>C; R52P); four patients had a heterozygous G>C substitution in position -569; two patients showed a (234C>A; P52T) or (2181C>G; D727E) polymorphic variants of the TSH-R gene; and one patient presented a novel heterozygous nonsynonymous substitution, 293G>A; S98N, in the NKX2.5 gene. CONCLUSIONS: The prevalence of CH was within the previously reported range of 1:3000-4000. Ectopy was the most common etiology. Clinical analysis revealed distinct hormonal patterns in TH subgroup when compared with other variants of TD, with genetic abnormalities identified only in few cases in the TSH-R, PAX8, and NKX2.5 genes.

Novos aspectos da genética e dos mecanismos moleculares da morfogênese da tiróide para o entendimento da disgenesia tiroidiana: [revisão] / New aspects of genetics and molecular mechanisms on thyroid morphogenesis for the understading of thyroid dysgenesia: [review]

A organogênese da tiróide ainda não está completamente elucidada, assim como também não se conhece o mecanismo patogenético da maioria dos casos de disgenesias tiroidianas. Vários genes têm sido identificados como importantes para a sobrevivência, a proliferação e a migração dos precursores das células tiroidianas e tem-se demonstrado que eles atuam de modo integrado. Além disso, por meio da geração de camundongos geneticamente modificados, diversos estudos têm trazido melhor entendimento para o papel destes genes na morfogênese tiroidiana. Finalmente, tem-se também evidenciado que mutações em alguns destes genes são responsáveis pelo desenvolvimento de disgenesias tiroidianas em crianças com hipotiroidismo congênito. O objetivo desta revisão é sumarizar os aspectos moleculares do desenvolvimento tiroidiano, descrever os modelos animais e respectivos fenótipos e oferecer novas informações sobre a ontogenia e a patogênese das disgenesias tiroidianas humanas.

The elucidation of the molecular mechanisms underlying the very early steps of thyroid organogenesis and the etiology of most cases of thyroid dysgenesis are poorly understood. Many genes have been identified as important contributors to survival, proliferation and migration of thyroid cells precursors, acting as an integrated and complex regulatory network. Moreover, by generation of mouse mutants, the studies have provided better knowledge of the role of these genes in the thyroid morphogenesis. In addition, it is likely that a subset of patients has thyroid dysgenesis as a result of mutations in regulatory genes expressed during embryogenesis. This review summarizes molecular aspects of thyroid development, describes the animal models and phenotypes known to date and provides information about novel insights into the ontogeny and pathogenesis of human thyroid dysgenesis.

Management of Graves' orbitopathy in Latin America: an international questionnaire study compared with Europe.

CONTEXT: Management of Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON) continues to be challenging. Other surveys have been successful in elucidating trends in GO management. Knowledge of current practice by members of the Latin American Thyroid Society (LATS) who manage patients with GO was targeted by distribution of a questionnaire. We compared our results with a previously reported European Thyroid Association (ETA) survey. OBJECTIVES: To determine how endocrinologists in Latin America access and treat patients with GO and compare the results with the same European survey. RESULTS: One hundred and two responders representing endocrinologists from 10 countries participated in the survey. Most (57%) participate in a multidisciplinary setting for GO management. Access to a surgeon for orbital decompression was available only 'within months' according to 48.3% of responders. Despite suspected DON, 32.4% were reluctant to recommend urgent referral to an eyecare physician. Steroids were preferred as the first-option therapy by 88.2% of responders (by intravenous route by 57.8% of these). The presence of diabetes reduced the use of steroids to 64.7% (P < 0.001) and increased the use of other immunosuppressive agents (from 1% to 9.8%, P < 0.01). Development of cushingoid features resulted in a reduction in steroid use to 40.2% (P < 0.001), with increased preference for irradiation (from 23.5% to 52.9%, P < 0.001) and nonsteroidal immunosuppressive drugs (from 1% to 10.8%, P < 0.01), along with a nonsignificant trend to higher indication of orbital surgery (from 24.5% to 34.3%). CONCLUSION: Some potential deficiencies in the diagnosis and management of DON and hyperthyroidism were observed in our survey, highlighting the need for improvement in specialist education and the quality of care offered to patients with GO in Latin America.