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Background: The Thr92Ala-DIO2 polymorphism has been associated with clinical outcomes in hospitalized patients with COVID-19 and neuropsychiatric diseases. This study examines the impact of the Thr92Ala-DIO2 polymorphism on neuropsychological symptoms, particularly depressive symptoms, in patients who have had moderate to severe SARS-CoV-2 infection and were later discharged. Methods: Our prospective cohort study, conducted from June to August 2020, collected data from 273 patients hospitalized with COVID-19. This included thyroid function tests, inflammatory markers, hematologic indices, and genotyping of the Thr92Ala-DIO2 polymorphism. Post-discharge, we followed up with 68 patients over 30 to 45 days, dividing them into depressive (29 patients) and non-depressive (39 patients) groups based on their Beck Depression Inventory scores. Results: We categorized 68 patients into three groups based on their genotypes: Thr/Thr (22 patients), Thr/Ala (41 patients), and Ala/Ala (5 patients). Depressive symptoms were less frequent in the Thr/Ala group (29.3%) compared to the Thr/Thr (59.1%) and Ala/Ala (60%) groups (p = 0.048). The Thr/Ala heterozygous genotype correlated with a lower risk of post-COVID-19 depression, as shown by univariate and multivariate logistic regression analyses. These analyses, adjusted for various factors, indicated a 70% to 81% reduction in risk. Conclusion: Our findings appear to be the first to show that heterozygosity for Thr92Ala-DIO2 in patients with COVID-19 may protect against post-COVID-19 depression symptoms up to 2 months after the illness.

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Introduction: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). Objective: The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. Methods: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. Results: In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. Conclusion: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

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Background: Type 2 Deiodinase (DIO2) converts thyroxine (T4) into the active hormone triiodothyronine (T3). Thr92Ala DIO2 polymorphism has been associated with reduced conversion of T4 into T3 and central nervous system hypothyroidism. However, how Thr92Ala DIO2 polymorphism affects cognitive function is still unclear. Objective: To assess the association between Thr92Ala DIO2 polymorphism and cognitive performance in older adults. Design: Cross-sectional study. Setting: University-based tertiary hospital in Brazil. Patients: > 65-year-old with no limiting clinical disease. Interventions: All participants answered a standard questionnaire before undergoing thyroid function laboratory evaluation and genotyping of the Thr92Ala DIO2 polymorphism. Main Outcomes: Cognitive impairment measured by the Word List Memory task from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) and the Brief Cognitive Screening Battery (BCSB). Results: A hundred individuals were included. Clinical and laboratory characteristics were similar among DIO2 genotypes (all p > 0.05). No differences were found in the Word List Memory, recall, or recognition tests of the CERAD-NB assuming a recessive model for the Ala/Ala vs. Thr/Ala-Thr/Thr genotypes. Results of Clock Drawing Test, Animal Fluency Test, Mini-Mental State Exam, and Figure Memory Test of the BCSB were similar between groups. Conclusions: These findings suggest that Thr92Ala DIO2 polymorphism is not associated with relevant cognitive impairment in older adults.

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OBJECTIVE: We aimed to investigate the role of DIO2 polymorphisms rs225014 and rs12885300 in Graves' disease patients, mainly for controlling body weight following treatment. METHODS: We genotyped 280 GD patients by the time of diagnosis and 297 healthy control individuals using a TaqMan SNP Genotyping technique. We followed up 141 patients for 18.94 ± 6.59 months after treatment. RESULTS: There was no relationship between the investigated polymorphisms with susceptibility to GD and gain or loss of weight after GD treatment. However, the polymorphic inheritance (CC+CT genotype) of DIO2 rs225014 was associated with a lower body weight variation after GD treatment (4.26 ± 6.25 kg) when compared to wild type TT genotype (6.34 ± 7.26 kg; p = 0.0456 adjusted for the follow-up time). This data was confirmed by a multivariate analysis (p = 0.0138) along with a longer follow-up period (p = 0.0228), older age (p = 0.0306), treatment with radioiodine (p-value = 0.0080) and polymorphic inheritance of DIO2 rs12885300 (p = 0.0306). CONCLUSION: We suggest that DIO2 rs225014 genotyping may have an auxiliary role in predicting the post-treatment weight behavior of GD patients.

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ABSTRACT Objective: We aimed to investigate the role of DIO2 polymorphisms rs225014 and rs12885300 in Graves' disease patients, mainly for controlling body weight following treatment. Subjects and methods: We genotyped 280 GD patients by the time of diagnosis and 297 healthy control individuals using a TaqMan SNP Genotyping technique. We followed up 141 patients for 18.94 ± 6.59 months after treatment. Results: There was no relationship between the investigated polymorphisms with susceptibility to GD and gain or loss of weight after GD treatment. However, the polymorphic inheritance (CC+CT genotype) of DIO2 rs225014 was associated with a lower body weight variation after GD treatment (4.26 ± 6.25 kg) when compared to wild type TT genotype (6.34 ± 7.26 kg; p = 0.0456 adjusted for the follow-up time). This data was confirmed by a multivariate analysis (p = 0.0138) along with a longer follow-up period (p = 0.0228), older age (p = 0.0306), treatment with radioiodine (p-value = 0.0080) and polymorphic inheritance of DIO2 rs12885300 (p = 0.0306). Conclusion: We suggest that DIO2 rs225014 genotyping may have an auxiliary role in predicting the post-treatment weight behavior of GD patients.

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Some endocrine-disrupting chemicals (EDCs) can affect the endocrine system through covalent interactions with specific sites, leading to deregulation of physiological homeostasis. The acrylamide (AA) present in some fried or baked foods is an example of an electrophile molecule that is able to form adducts with nucleophilic regions of nervous system proteins leading to neurological defects. A positive correlation between increased urinary AA metabolite concentration and reduced levels of thyroid hormones (TH) was described in adolescents and young adults. Thus, this study aimed to evaluate whether AA affects the physiology of the hypothalamus-pituitary-thyroid (HPT) axis and the possible repercussions in peripheral TH-target systems. For this, male Wistar rats were exposed to doses of 2.5 or 5.0 mg AA/Kg/day, based on the LOAEL (Lowest Observed Adverse Effect Level) during prepubertal development. The expression of molecular markers of HPT functionality was investigated in the hypothalamus, pituitary, thyroid, heart and liver, as well as the hormonal and lipid profiles in blood samples. Herein, we showed that AA acts as EDCs for thyroid gland function, increasing the transcript expression of several proteins related to TH synthesis and altering hypothalamus-pituitary-thyroid axis homeostasis, an effect evidenced by the higher levels of THs in the serum. Compensatory mechanisms were observed in TH-target tissues, such as an increase in Dio3 mRNA expression in the liver and a reduction in Mct8 transcript content in the hearts of AA-treated rats. Together, these results pointed out an allostatic regulation of the HPT axis induced by AA and suggest that chronic exposure to it, mainly associated with food consumption, might be related to the higher prevalence of thyroid dysfunctions.

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Molecular mechanisms responsible for the initiation of primate spermatogenesis remain poorly characterized. Previously, 48 h stimulation of the testes of three juvenile rhesus monkeys with pulsatile LH and FSH resulted in down-regulation of a cohort of genes recognized to favor spermatogonia stem cell renewal. This change in genetic landscape occurred in concert with amplification of Sertoli cell proliferation and the commitment of undifferentiated spermatogonia to differentiate. In this report, the non-protein coding small RNA transcriptomes of the same testes were characterized using RNA sequencing: 537 mature micro-RNAs (miRNAs), 322 small nucleolar RNAs (snoRNAs) and 49 small nuclear RNAs (snRNAs) were identified. Pathway analysis of the 20 most highly expressed miRNAs suggested that these transcripts contribute to limiting the proliferation of the primate Sertoli cell during juvenile development. Gonadotrophin treatment resulted in differential expression of 35 miRNAs, 12 snoRNAs and four snRNA transcripts. Ten differentially expressed miRNAs were derived from the imprinted delta-like homolog 1-iodothyronine deiodinase 3 (DLK1-DIO3) locus that is linked to stem cell fate decisions. Four gonadotrophin-regulated expressed miRNAs were predicted to trigger a local increase in thyroid hormone activity within the juvenile testis. The latter finding leads us to predict that, in primates, a gonadotrophin-induced selective increase in testicular thyroid hormone activity, together with the established increase in androgen levels, at the onset of puberty is necessary for the normal timing of Sertoli cell maturation, and therefore initiation of spermatogenesis. Further examination of this hypothesis requires that peripubertal changes in thyroid hormone activity of the testis of a representative higher primate be determined empirically.

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