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Background/Objective: Autoimmune thyroid diseases (AITD) affect 2 to 5% of the general population. This study aimed to determine changes in activity of A-Tg and A-TPO antibodies before, during, and after pregnancy in women with previous AITD. Methods: This was a single-center study with a retrospective review of the medical records of 30 female patients aged 25-41 years who came to our endocrinology service in the city of Santo André, state of São Paulo, Brazil, to investigate thyroid diseases. The following data were reviewed: total triiodothyronine (totalT3), total thyroxine (totalT4), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and anti-TSH receptor antibodies (anti-TSH receptor or anti-thyrotropin receptor antibodies (TRAb), anti-thyroid peroxidase (A-TPO), and anti-thyroglobulin (A-Tg)). These data were reviewed for 30 patients before and during the three trimesters of pregnancy and during the three months after pregnancy. Results: During gestation, we observed a progressive decrease in the blood values of A-TPO and A-Tg, which reached their lowest values in the third trimester of pregnancy, but after birth, they returned to values statistically equivalent to those before pregnancy. Analyzing the three trimesters and the post-pregnancy period, A-TPO increased 192% between the first trimester and postpartum (p = 0.009); it increased 627% between the second trimester and postpartum (p < 0.001); and it increased >1000% between the third trimester and postpartum (p < 0.001). There was no significant difference in the A-TPO values between the pre- and post-gestational periods (p = 1.00), between the first and second trimesters (p = 0.080), or between the second and third trimesters (p = 0.247). Conclusions: According to the results presented here, we observed changes in the activities of A-Tg and A-TPO antibodies during and after pregnancy in women with previous AITD. In women who intend to become pregnant, are pregnant, or have given birth within three months, it is essential to monitor A-TPO, A-Tg, and thyroid function as well as serum thyroid hormones and TSH to identify thyroid dysfunction in a timely manner and adjust the treatment strategy to avoid the deleterious effects of hypothyroidism on both mother and baby during and after pregnancy.
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PURPOSE: This article aims to describe the presentation of Plummer disease and its evolution after radioiodine treatment and determine factors that may influence treatment efficacy. PATIENTS AND METHODS: The sample included retrospective medical records of 165 adult patients with toxic nodular goiter treated with radioiodine between 1997 and 2017, followed up at a single thyroid center. RESULTS: The efficacy of treatment with a single dose of radioiodine was higher than 90%. The mean radioiodine activity was 28.9 ± 3.4 mCi. The mean time between radioiodine performance and hyperthyroidism resolution was 3.6 ± 3.0 months, ranging from 1-12 months. After the first year, 33.9% of the patients were under hypothyroidism, 59.4% under euthyroidism, and 6.7% under hyperthyroidism. Among the nonresponders, the variables that showed statistical difference were the presence of multinodular goiter and the radioiodine activity (mean, 25.5 ± 6.5 mCi; median, 30 [15-30 mCi]). The cumulative rate of hypothyroidism was 48.9% over 20 years of follow-up. CONCLUSIONS: Radioiodine therapy is an effective and safe treatment. In Plummer disease, high rates of euthyroidism are expected after the radioiodine treatment. Therapeutic failure was observed mainly in patients with larger multinodular goiters treated with lower doses of radioiodine. The evolution to hypothyroidism was mostly observed in younger patients with larger and uninodular goiters.
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Radioisótopos do Iodo , Nódulo da Glândula Tireoide , Humanos , Radioisótopos do Iodo/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Nódulo da Glândula Tireoide/radioterapia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Seguimentos , Adulto , Idoso , Estudos Retrospectivos , Resultado do Tratamento , Fatores de Tempo , Idoso de 80 Anos ou maisRESUMO
Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.
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Mutação em Linhagem Germinativa , Mosaicismo , Neoplasia Endócrina Múltipla Tipo 2a , Linhagem , Proteínas Proto-Oncogênicas c-ret , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Mutação em Linhagem Germinativa/genética , Feminino , Masculino , Adulto , Substituição de Aminoácidos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Genótipo , Sequenciamento do ExomaRESUMO
Objective: The risk of malignancy and diagnostic accuracy of fine-needle aspiration biopsy (FNAB) of thyroid nodules (TN) with diameters ≥ 3-4 cm remains controversial. However, some groups have indicated surgical treatment in these patients regardless of the FNAB results. We aimed to evaluate the diagnostic accuracy of the FNAB in systematically resected ≥4 cm TN and if the risk of malignancy is higher in these patients. Subjects and methods: We retrospectively evaluated 138 patients (142 nodules) with TN with diameters ≥4 cm who underwent thyroidectomy. Results: The FNAB results were nondiagnostic/unsatisfactory (ND/UNS) in 2.1% of the cases and benign in 51.4%. They indicated atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 23.9% of cases, follicular neoplasia/suspicious for a follicular neoplasm (FN/SFN) in 9.2%, suspicion of malignancy (SUS) in 8.5%, and malignant in 4.9%. The histopathological analysis after thyroidectomy revealed a thyroid cancer rate of 100% in the FNABs classified as malignant, 33.3% in SUS cases, 7.7% in FN/SFN, 17.6% in AUS/FLUS, and 4.1% in benign FNABs. None of the ND/UNS FNABs were malignant. The global malignancy diagnosis was 14.8% (n = 21). However, the rate of false negatives for FNAB was low (4.1%). Conclusion: We showed that the risk of malignancy in nodules with diameters ≥4 cm was higher compared to the risk of thyroid cancer in TN in general. However, we found a low rate of false-negative cytological results; therefore, our data do not justify the orientation of routine resection for these larger nodules.
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Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina/métodos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/cirurgiaRESUMO
CONTEXT: Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. OBJECTIVE: This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. METHODS: This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. RESULTS: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. CONCLUSION: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.
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Tiroxina , Tri-Iodotironina , Humanos , Estudos Transversais , Testes de Função Tireóidea , TireotropinaRESUMO
ABSTRACT Objective: The risk of malignancy and diagnostic accuracy of fine-needle aspiration biopsy (FNAB) of thyroid nodules (TN) with diameters ≥ 3-4 cm remains controversial. However, some groups have indicated surgical treatment in these patients regardless of the FNAB results. We aimed to evaluate the diagnostic accuracy of the FNAB in systematically resected ≥4 cm TN and if the risk of malignancy is higher in these patients. Subjects and methods: We retrospectively evaluated 138 patients (142 nodules) with TN with diameters ≥4 cm who underwent thyroidectomy. Results: The FNAB results were nondiagnostic/unsatisfactory (ND/UNS) in 2.1% of the cases and benign in 51.4%. They indicated atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 23.9% of cases, follicular neoplasia/suspicious for a follicular neoplasm (FN/SFN) in 9.2%, suspicion of malignancy (SUS) in 8.5%, and malignant in 4.9%. The histopathological analysis after thyroidectomy revealed a thyroid cancer rate of 100% in the FNABs classified as malignant, 33.3% in SUS cases, 7.7% in FN/SFN, 17.6% in AUS/FLUS, and 4.1% in benign FNABs. None of the ND/UNS FNABs were malignant. The global malignancy diagnosis was 14.8% (n = 21). However, the rate of false negatives for FNAB was low (4.1%). Conclusion: We showed that the risk of malignancy in nodules with diameters ≥4 cm was higher compared to the risk of thyroid cancer in TN in general. However, we found a low rate of false-negative cytological results; therefore, our data do not justify the orientation of routine resection for these larger nodules.
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Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.
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Doença de Alzheimer , Tri-Iodotironina , Animais , Camundongos , Masculino , Tri-Iodotironina/farmacologia , Tri-Iodotironina/uso terapêutico , Doença de Alzheimer/metabolismo , Depressão/tratamento farmacológico , Quinase 3 da Glicogênio Sintase , Camundongos Transgênicos , Hormônios Tireóideos/metabolismo , Modelos Animais de DoençasRESUMO
Recurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFNγ) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19.
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COVID-19/imunologia , Epitopos de Linfócito T/imunologia , Imunidade Celular , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Gêmeos Monozigóticos , Adolescente , Adulto , Feminino , Humanos , Masculino , RecidivaRESUMO
Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.
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Analgésicos Opioides/farmacologia , Hipertensão/metabolismo , Bulbo/metabolismo , Neurônios/efeitos dos fármacos , Condicionamento Físico Animal , Receptores Opioides mu/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Bulbo/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neurônios/metabolismo , Oligopeptídeos/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , NataçãoRESUMO
Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.
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Carcinoma Neuroendócrino/epidemiologia , Carcinoma Neuroendócrino/genética , Perfil Genético , Variação Genética/genética , Saúde Global , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Carcinoma Neuroendócrino/diagnóstico , Bases de Dados Genéticas , Geografia , Humanos , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as "discordant couples". We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
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Infecções Assintomáticas , COVID-19 , Antígenos de Histocompatibilidade , Complexo Principal de Histocompatibilidade , SARS-CoV-2 , Adulto , Idoso , Brasil , COVID-19/genética , COVID-19/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Humanos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Sequenciamento do ExomaRESUMO
CONTEXT: Treatment with levothyroxine (LT4) that normalize serum thyrotropin (TSH) is expected to restore lipid metabolism. OBJECTIVE: To assess statin utilization in LT4-treated patients through an observational drug utilization study. METHODS: Three sites were involved: (1) 10 723 outpatients placed on LT4 during 2006-2019 identified from the Clinical Research Data Warehouse of the University of Chicago; (2) ~1.4 million LT4 prescriptions prepared by primary care physicians during January-December 2018, identified from the IQVIA™ database of medical prescriptions in Brazil; (30 ~5.4 million patient interviews during 2009-2019, including ~0.32 million patients on LT4, identified from the Fleury Group database in Brazil. RESULTS: On site 1, initiation of therapy with LT4 increased the frequency of statin utilization (19.1% vs 24.6%), which occurred ~1.5 years later (median 76 weeks) and, among those patients that were on statins, increased intensity of treatment by 33%, despite normalization of serum TSH levels; on site 2, after matching for sex and age, the frequency of statins prescription was higher for those patients using LT4: females, 2.1 vs 3.4% (odds ratio [OR] 1.656 [1.639-1.673]); males, 3.1 vs 4.4% (OR 1.435 [1.409-1.462]); and, on site 3, after matching for sex and age, the frequency of statin utilization was higher in those patients using LT4: females, 10 vs 18% (OR 2.02 [2.00-2.04]); males, 15 vs 25% (OR 1.92 [1.88-1.96]); all P values were <.0001. CONCLUSION: Prescription and utilization of statins were higher in patients taking LT4. The reasons for this association should be addressed in future studies.
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PURPOSE: The aims of this study were to assess the role of an in-house competitive thyroglobulin assay (Tg-c) in the follow-up of metastatic differentiated thyroid carcinoma (DTC) patients who presented underestimated Tg measurements by immunometric assays (Tg-IMA) and to compare the results with IMA and LC-MS/MS Tg methods. METHODS: This prospective study included 40 patients. Twenty-one with metastatic disease: 14 had Tg-IMA levels inappropriately low or undetectable (eight patients with positive and six with borderline TgAb) and seven had high Tg-IMA levels. Nineteen had an excellent response to therapy. The competitive assay employs a polyclonal antibody produced in rabbits immunized with human Tg, Tg labeled with biotin, and for the solid phase separation, a monoclonal anti-rabbit IgG antibody adsorbed to microtiter plates. RESULTS: All 14 patients with structural disease and underestimated levels of Tg-IMA presented detectable Tg-c levels. The median Tg-c level in the group with positive TgAb was 183 µg/L (range: 22-710 µg/L), and 58 µg/L (range 23-148 µg/L) in the borderline TgAb group. The levels of Tg-LC-MS/MS were detectable in some patients (range < 0.5-18 µg/L). All seven patients with high Tg-IMA presented also high levels of Tg-c. Only 2/19 patients with excellent response had Tg-c levels above the functional sensitivity. CONCLUSIONS: The competitive assay was able to detect Tg in all patients, even in the presence of serum TgAb, and may be an option in patients with underestimated Tg-IMA and relevant structural disease.
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Tireoglobulina , Neoplasias da Glândula Tireoide , Animais , Autoanticorpos , Cromatografia Líquida , Seguimentos , Humanos , Estudos Prospectivos , Coelhos , Espectrometria de Massas em TandemRESUMO
Urinary bladder dysfunction affects several people worldwide and shows higher prevalence in women. Micturition is dependent on the Barrington's nucleus, pontine urine storage center and periaqueductal gray matter, but other brain stem areas are involved in the bladder regulation. Neurons in the medulla oblongata send projections to hypothalamic nuclei as the supraoptic nucleus, which synthetizes oxytocin and in its turn, this peptide is released in the circulation. We investigated the effects of intravenous injection of oxytocin (OT) on the urinary bladder in sham and ovariectomized rats. We also evaluated the topical (in situ) action of OT on intravesical pressure (IP) as well as the existence of oxytocin receptors in the urinary bladder. In sham female Wistar rats, anesthetized with isoflurane, intravenous infusion of OT (10 ng/kg) significantly decreased the IP (-47.5 ± 1.2%) compared to saline (3.4 ± 0.7%). Similar effect in IP was observed in ovariectomized rats after i.v. OT (-41.9 ± 2.9%) compared to saline (0.5 ± 0.6%). Topical administration (in situ) of 0.1 mL of OT (1.0 ng/mL) significantly reduced the IP (22.3.0 ± 0.6%) compared to saline (0.9 ± 0.7%). We also found by qPCR that the gene expression of oxytocin receptor is present in this tissue. Blockade of oxytocin receptors significantly attenuated the reduction in IP evoked by oxytocin i.v. or in situ. Therefore, the findings suggest that (1) intravenous oxytocin decreases IP due to bladder relaxation and (2) OT has local bladder effect, binding directly in receptors located in the bladder.
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Background: The basis for the treatment of hypothyroidism with levothyroxine (LT4) is that humans activate T4 to triiodothyronine (T3). Thus, while normalizing serum thyrotropin (TSH), LT4 doses should also restore the body's reservoir of T3. However, there is evidence that T3 is not fully restored in LT4-treated patients. Summary: For patients who remain symptomatic on LT4 therapy, clinical guidelines recommend, on a trial basis, therapy with LT4+LT3. Reducing the LT4 dose by 25 mcg/day and adding 2.5-7.5 mcg liothyronine (LT3) once or twice a day is an appropriate starting point. Transient episodes of hypertriiodothyroninemia with these doses of LT4 and LT3 are unlikely to go above the reference range and have not been associated with adverse drug reactions. Trials following almost a 1000 patients for almost 1 year indicate that similar to LT4, therapy with LT4+LT3 can restore euthyroidism while maintaining a normal serum TSH. An observational study of 400 patients with a mean follow-up of â¼9 years did not indicate increased mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures after adjusting for age when compared with patients taking only LT4. Desiccated thyroid extract (DTE) is a form of combination therapy in which the LT4/LT3 ratio is â¼4:1; the mean daily dose of DTE needed to normalize serum TSH contains â¼11 mcg T3, but some patients may require higher doses. The DTE remains outside formal FDA oversight, and consistency of T4 and T3 contents is monitored by the manufacturers only. Conclusions: Newly diagnosed hypothyroid patients should be treated with LT4. A trial of combination therapy with LT4+LT3 can be considered for those patients who have unambiguously not benefited from LT4.
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Hipotireoidismo/tratamento farmacológico , Glândula Tireoide/patologia , Tireotropina/uso terapêutico , Tri-Iodotironina/uso terapêutico , Quimioterapia Combinada , Feminino , Terapia de Reposição Hormonal , Humanos , Masculino , Modelos Teóricos , Guias de Prática Clínica como Assunto , Valores de Referência , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos , Tireotropina/sangue , Tri-Iodotironina/sangue , Estados UnidosRESUMO
BACKGROUND: Different pathogenic germline mutations in the RET oncogene are identified in MEN 2, a hereditary syndrome characterized by medullary thyroid carcinoma (MTC) and other endocrine tumors. Although genetic predisposition is recognized, not all RET mutation carriers will develop the disease during their lifetime or, likewise, RET mutation carriers belonging to the same family may present clinical heterogeneity. It has been suggested that a single germline mutation might not be sufficient for development of MEN 2-associated tumors and a somatic bi-allelic alteration might be required. Here we investigated the presence of somatic second hit mutation in the RET gene in MTC. METHODS: We integrated Multiplex Ligation-dependent Probe Amplification (MLPA) and whole exome sequencing (WES) to search for copy number alteration (CNA) in the RET gene in MTC samples and medullary thyroid cell lines (TT and MZ-CR-1). We next found reads spanning exon-exon boundaries on RET, an indicative of retrocopy. We subsequently searched for RET retrocopies in the human reference genome (GRCh37) and in the 1000 Genomes Project data, by looking for reads reporting joined exons in the RET locus or distinct genomic regions. To determine RET retrocopy specificity and recurrence, DNA isolated from sporadic and MEN 2-associated MTC (n = 37), peripheral blood (n = 3) and papillary thyroid carcinomas with RET fusion (n = 10) samples were tested using PCR-sequencing methodology. RESULTS: Through MLPA we have found evidence of CNA in the RET gene in MTC samples and MTC cell lines. WES analysis reinforced the presence of the CNA and hinted for a retroposed copy of RET not found in the human reference genome and 1.000 Genomes Project. Extended analysis confirmed the presence of a somatic MTC-related retrocopy of RET in both sporadic and hereditary tumors. We further unveiled a recurrent (28%) novel point mutation (p.G548 V) found exclusively in the retrocopy of RET. The mutation was also found in cDNA of mutated samples, suggesting it might be functional. CONCLUSION: We here report a somatic specific RET retroposed copy in MTC samples and cell lines. Our results support the idea that generation of retrocopies in somatic cells is likely to contribute to MTC genesis and progression.
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Carcinoma Neuroendócrino/genética , Dosagem de Genes/genética , Proteínas Proto-Oncogênicas c-ret/genética , Retroelementos/genética , Neoplasias da Glândula Tireoide/genética , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Neoplasias da Glândula Tireoide/patologiaRESUMO
MeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neuronal progenitor cells and adult neurons. Using this cellular model, we then investigated the expression of genes associated with TH homeostasis, such as the TH transporters (LAT1, LAT2, MCT8, MCT10, and OATP4A1) and deiodinases (DIO1, 2, and 3). Then, we treated the neural cells with THs and analyzed the expression of several genes related to neurodevelopment and functional maintenance. Our results showed that several TH-related genes, such as deiodinases, are altered in RTT samples when compared to WT cells. Moreover, the treatment of the neural cells with THs increased the amount of MAP2 and synapsin-1 expression in RTT cells. Our work provided evidences that TH homeostasis is compromised in RTT-derived neural cells, which could be an important factor to contribute to the imbalance in the neurodevelopmental phenotype presented in this syndrome and can lead us to better understand other neurodevelopmental diseases.
Assuntos
Regulação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/metabolismo , Iodeto Peroxidase/genética , Proteínas de Membrana Transportadoras/genética , Proteína 2 de Ligação a Metil-CpG/deficiência , Neurônios/metabolismo , Hormônios Tireóideos/metabolismo , Humanos , Iodeto Peroxidase/metabolismo , Cariotipagem , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Redes e Vias Metabólicas , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Síndrome de Rett/enzimologia , Síndrome de Rett/genéticaRESUMO
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.
RESUMO
BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.
Assuntos
Insuficiência Renal Crônica/epidemiologia , Doenças da Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Estudos Longitudinais , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Doenças da Glândula Tireoide/metabolismo , Testes de Função TireóideaRESUMO
ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.