Heart protective effects of cardioactive drugs associated with antineoplastic treatment against breast cancer.

The prevalence of breast cancer in women is a fundamental problem in public health worldwide. There is consensual evidence that many chemotherapeutic agents might have harmful effects on the cardiovascular system of patients. The cardiotoxicity of chemotherapeutic drugs might lead to ventricular systolic dysfunction and heart failure, and consequently cardioactive drugs, such as antihypertensive, might mitigate those cardiac dysfunctions. Thus, this study carried out an integrative literature review on the potential benefits of cardioactive drugs in cardiovascular repercussions resulting from chemotherapy (CT), especially in women with breast cancer. The research involved articles available on the PubMed, LILACS, and MedLine databases, using as descriptors "breast cancer", "chemotherapy", "cardiotoxicity", and "antihypertensive"; 11 articles were selected. The data corroborate an association between the use of antineoplastic drugs (anthracyclines, fluorouracil, and anti-HER2 monoclonal antibody, trastuzumab) and cardiotoxic effects, and anthracyclines are the most studied CT drugs in relation to cardiac dysfunction. The cardioprotective effect of cardioactive drugs, including non-selective and selective beta-blockers classes, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, could be observed in clinical outcomes. Nonetheless, the drugs have different cardioprotective effects on breast cancer patients and left ventricular ejection fraction; the serum concentrations of troponins and brain natriuretic peptide were the most frequent parameters analysed in selected articles. In summary, cardiovascular parameters should be followed-up in patients undergoing oncology treatment in all stages, regardless of the therapeutic scheme carried out, given the risk of developing and worsening such heart conditions.

Immersive Virtual Tasks With Motor and Cognitive Components: A Feasibility Study With Young and Older Adults.

OBJECTIVE: To analyze the feasibility, safety, and acceptability of immersive virtual tasks. METHODS: The authors recruited 11 young adults and 10 older adults. The participants performed three virtual reaching tasks while walking on a virtual path. The descriptive analysis and comparison between participants were performed using the Mann-Whitney U test and chi-square test for nonparametric and nominal variables, respectively. The authors also used analysis of variance for a between-groups comparison for normal variables. RESULTS: Twenty percent of older adults and 81.8% of young adults completed all three tasks (chi-square test; p = .005). Both groups reported minor symptoms, with no significant differences. The older adults were more motivated to practice the tasks (Mann-Whitney U test; p = .015) and would be more likely to suggest them to others (chi-square test; p = .034). CONCLUSION: All three tasks were feasible for young adults. All participants, except for one, had cybersickness. The symptoms were mostly mild and subsided once the interaction was complete.

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis.

BACKGROUND: A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein. METHODS: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. RESULTS: The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH. CONCLUSIONS: EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.

Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity.

Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.

Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling.

BACKGROUND: Thyroid hormone signaling is critical for development, growth and metabolic control in vertebrates. Although serum concentration of thyroid hormone is remarkable stable, deiodinases modulate thyroid hormone signaling on a time- and cell-specific fashion by controlling the activation and inactivation of thyroid hormone. SCOPE OF THE REVIEW: This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold-containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner. MAJOR CONCLUSIONS: D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic- and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis. GENERAL SIGNIFICANCE: Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling.

Thyroid hormone interacts with the sympathetic nervous system to modulate bone mass and structure in young adult mice.

To investigate whether thyroid hormone (TH) interacts with the sympathetic nervous system (SNS) to modulate bone mass and structure, we studied the effects of daily T3 treatment in a supraphysiological dose for 12 wk on the bone of young adult mice with chronic sympathetic hyperactivity owing to double-gene disruption of adrenoceptors that negatively regulate norepinephrine release, α(2A)-AR, and α(2C)-AR (α(2A/2C)-AR(-/-) mice). As expected, T3 treatment caused a generalized decrease in the areal bone mineral density (aBMD) of WT mice (determined by DEXA), followed by deleterious effects on the trabecular and cortical bone microstructural parameters (determined by µCT) of the femur and vertebra and on the biomechanical properties (maximum load, ultimate load, and stiffness) of the femur. Surprisingly, α(2A/2C)-AR(-/-) mice were resistant to most of these T3-induced negative effects. Interestingly, the mRNA expression of osteoprotegerin, a protein that limits osteoclast activity, was upregulated and downregulated by T3 in the bone of α(2A/2C)-AR(-/-) and WT mice, respectively. ß1-AR mRNA expression and IGF-I serum levels, which exert bone anabolic effects, were increased by T3 treatment only in α(2A/2C)-AR(-/-) mice. As expected, T3 inhibited the cell growth of calvaria-derived osteoblasts isolated from WT mice, but this effect was abolished or reverted in cells isolated from KO mice. Collectively, these findings support the hypothesis of a TH-SNS interaction to control bone mass and structure of young adult mice and suggests that this interaction may involve α2-AR signaling. Finally, the present findings offer new insights into the mechanisms through which TH regulates bone mass, structure, and physiology.

Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.

Six weeks of aerobic training improves VO2max and MLSS but does not improve the time to fatigue at the MLSS.

The purpose of this study was to investigate the effects of a 6-week aerobic training period on the time to fatigue (t lim) during exercise performed at the maximal lactate steady state (MLSS). Thirteen untrained male subjects (TG; age 22.5 ± 2.4 years, body mass 72.9 ± 6.7 kg and VO2max 44.9 ± 4.8 mL kg(-1) min(-1)) performed a cycle ergometer test until fatigue at the MLSS power output before and after 6 weeks of aerobic training. A group of eight control subjects (CG; age 25.1 ± 2.4 years, body mass 70.1 ± 9.8 kg and VO2max 45.2 ± 4.1 mL kg(-1) min(-1)) also performed the two tests but did not train during the 6-week period. There were no differences between the groups with respect to the VO2max or MLSS power output (MLSSw) before the treatment period. The VO2max and the MLSSw of the TG increased by 11.2 ± 7.2 % (pre-treatment = 44.9 ± 4.8 vs. post-treatment = 49.8 ± 4.5 mL kg(-1) min(-1)) and 14.7 ± 8.9 % (pre-treatment = 150 ± 27 vs. post-treatment = 171 ± 26 W), respectively, after 6 weeks of training. The results of the CG were unchanged. There were no differences in t lim between the groups or within groups before and after training. Six weeks of aerobic training increases MLSSw and VO2max, but it does not alter the t lim at the MLSS.

Localized T3 production modifies the transcriptome and promotes the hepatocyte-like lineage in iPSC-derived hepatic organoids.

Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.

Different Hypothalamic Mechanisms Control Decreased Circulating Thyroid Hormone Levels in Infection and Fasting-Induced Non-Thyroidal Illness Syndrome in Male Thyroid Hormone Action Indicator Mice.

Background: Non-Thyroidal Illness Syndrome (NTIS) caused by infection or fasting is hallmarked by reduced circulating thyroid hormone (TH) levels. To better understand the role of local TH-action in the development of NTIS, we assessed tissue-specific changes of TH signaling in Thyroid Hormone Action Indicator (THAI) mice. Methods: NTIS was induced in young adult THAI mice by bacterial lipopolysaccharide (LPS)-administration or by 24 or 48 hours' fasting. Tissue-specific TH-action was assessed by the detection of changes of the Luciferase reporter of THAI mice with quantitative polymerase chain reaction along with tissue-specific examination of regulators of TH metabolism and signaling. Age dependence of revealed alterations of hypothalamic TH-action was also studied in 1-year-old male THAI mice. Results: LPS-treatment increased TH-action in the hypothalamic arcuate nucleus-median eminence (ARC-ME) region preceded by an increase of type 2 deiodinase (D2) expression in the same region and followed by the suppression of proTrh expression in the hypothalamic paraventricular nucleus (PVN). In contrast, LPS decreased both TH-action and D2 activity in the pituitary at both ages. Tshß expression and serum free thyroxine (fT4) and free triiodothyronine (fT3) levels decreased in LPS-treated young adults. Tshß expression and serum fT4 levels were not significantly affected by LPS treatment in aged animals. In contrast to LPS treatment, TH-action remained unchanged in the ARC-ME of 24 and 48 hours fasted animals accompanied with a modest decrease of proTrh expression in the PVN in the 24-hour group. Tshß expression and fT3 level were decreased in both fasted groups, but the fT4 decreased only in the 48 hours fasted animals. Conclusions: Although the hypothalamo-pituitary-thyroid (HPT) axis is inhibited both in LPS and fasting-induced NTIS, LPS achieves this by centrally inducing local hyperthyroidism in the ARC-ME region, while fasting acts without affecting hypothalamic TH signaling. Lack of downregulation of Tshß and fT4 in LPS-treated aged THAI mice suggests age-dependent alterations in the responsiveness of the HPT axis. The LPS-induced tissue-specific hypo-, eu-, and hyperthyroidism in different tissues of the same animal indicate that under certain conditions TH levels alone could be a poor marker of tissue TH signaling. In conclusion, decreased circulating TH levels in these two forms of NTIS are associated with different patterns of hypothalamic TH signaling.

Postpartum depression in rats causes poor maternal care and neurochemical alterations on dams and long-lasting impairment in sociability on the offspring.

Postpartum depression is a mentally disabling disease with multifactorial etiology that affects women worldwide. It can also influence child development and lead to behavioral and cognitive alterations. Despite the high prevalence, the disease is underdiagnosed and poorly studied. To study the postpartum depression caused by maternal separation model in rats, dams were separated from their litter for 3 h daily starting from lactating day (LD) 2 through LD12. Maternal studies were conducted from LD5 to LD21 and the offspring studies from postnatal day (PND) 2 through PND90. The stress caused by the dam-offspring separation led to poor maternal care and a transient increase in anxiety in the offspring detected during infancy. The female offspring also exhibited a permanent impairment in sociability during adult life. These changes were associated with neurochemical alterations in the prefrontal cortex and hippocampus, and low TSH concentrations in the dams, and in the hypothalamus, hippocampus and striatum of the offspring. These results indicate that the postpartum depression resulted in a depressive phenotype, changes in the brain neurochemistry and in thyroid economy that remained until the end of lactation. Changes observed in the offspring were long-lasting and resemble what is observed in children of depressant mothers.

Inactivation of Type 3 Deiodinase Results in Life-long Changes in the Brown Adipose Tissue Transcriptome in the Male Mouse.

Adaptive thermogenesis in small mammals and infants takes place in brown adipose tissue (BAT). Heat is produced via uncoupling protein 1 (UCP1)-mediated uncoupling between oxidation of energy substrates and adenosine 5'-triphosphate synthesis. Thyroid hormone (TH) signaling plays a role in this process. The deiodinases activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3) (D2) or inactivate T4 and T3 to 3,3,5'-triiodothyronine and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 × UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (embryonic days 16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, including Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA sequencing, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by more than 1.5-fold, 36 of which play a role in metabolic/thermogenic processes. BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22 °C) and in the cold (4 °C). They also defend their core temperature more effectively and do not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in the BAT transcriptome.

Improvement of depression in a patient with hypothyroidism and deiodinase polymorphism with LT3 Therapy.

We report a 54-year-old man with treatment-resistant depression (TRD) and hypothyroidism who responded to LT3/LT4 combination, rather than LT4 alone. He was able to discontinue all antidepressant medications eventually. Interestingly, the patient has a DIO2 polymorphism.

Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism.

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.

What changed between the peak and plateau periods of the first COVID-19 pandemic wave? A multicentric Portuguese cohort study in intensive care. / O que mudou entre os períodos de pico e de platô durante a primeira onda do SARS-CoV-2? Estudo multicêntrico português em unidades de cuidados intensivos.

OBJECTIVE: To analyze and compare COVID-19 patient characteristics, clinical management and outcomes between the peak and plateau periods of the first pandemic wave in Portugal. METHODS: This was a multicentric ambispective cohort study including consecutive severe COVID-19 patients between March and August 2020 from 16 Portuguese intensive care units. The peak and plateau periods, respectively, weeks 10 - 16 and 17 - 34, were defined. RESULTS: Five hundred forty-one adult patients with a median age of 65 [57 - 74] years, mostly male (71.2%), were included. There were no significant differences in median age (p = 0.3), Simplified Acute Physiology Score II (40 versus 39; p = 0.8), partial arterial oxygen pressure/fraction of inspired oxygen ratio (139 versus 136; p = 0.6), antibiotic therapy (57% versus 64%; p = 0.2) at admission, or 28-day mortality (24.4% versus 22.8%; p = 0.7) between the peak and plateau periods. During the peak period, patients had fewer comorbidities (1 [0 - 3] versus 2 [0 - 5]; p = 0.002) and presented a higher use of vasopressors (47% versus 36%; p < 0.001) and invasive mechanical ventilation (58.1 versus 49.2%; p < 0.001) at admission, prone positioning (45% versus 36%; p = 0.04), and hydroxychloroquine (59% versus 10%; p < 0.001) and lopinavir/ritonavir (41% versus 10%; p < 0.001) prescriptions. However, a greater use of high-flow nasal cannulas (5% versus 16%, p < 0.001) on admission, remdesivir (0.3% versus 15%; p < 0.001) and corticosteroid (29% versus 52%, p < 0.001) therapy, and a shorter ICU length of stay (12 days versus 8, p < 0.001) were observed during the plateau. CONCLUSION: There were significant changes in patient comorbidities, intensive care unit therapies and length of stay between the peak and plateau periods of the first COVID-19 wave.

OBJETIVO: Analisar e comparar as características de pacientes críticos com a COVID-19, a abordagem clínica e os resultados entre os períodos de pico e de platô na primeira onda pandêmica em Portugal. MÉTODOS: Este foi um estudo de coorte multicêntrico ambispectivo, que incluiu pacientes consecutivos com a forma grave da COVID-19 entre março e agosto de 2020 de 16 unidades de terapia intensiva portuguesas. Definiram-se as semanas 10 - 16 e 17 - 34 como os períodos de pico e platô. RESULTADOS: Incluíram-se 541 pacientes adultos com mediana de idade de 65 [57 - 74] anos, a maioria do sexo masculino (71,2%). Não houve diferenças significativas na mediana de idade (p = 0,3), no Simplified Acute Physiology Score II (40 versus 39; p = 0,8), na pressão parcial de oxigênio/fração inspirada de oxigênio (139 versus 136; p = 0,6), na terapia com antibióticos na admissão (57% versus 64%; p = 0,2) ou na mortalidade aos 28 dias (24,4% versus 22,8%; p = 0,7) entre o período de pico e platô. Durante o período de pico, os pacientes tiveram menos comorbidades (1 [0 - 3] versus 2 [0 - 5]; p = 0,002); fizeram mais uso de vasopressores (47% versus 36%; p < 0,001) e ventilação mecânica invasiva na admissão (58,1% versus 49,2%; p < 0,001), e tiveram mais prescrição de hidroxicloroquina (59% versus 10%; p < 0,001), lopinavir/ritonavir (41% versus 10%; p < 0,001) e posição prona (45% versus 36%; p = 0,04). Entretanto, durante o platô, observou-se maior uso de cânulas nasais de alto fluxo (5% versus 16%; p < 0,001) na admissão, remdesivir (0,3% versus 15%; p < 0,001) e corticosteroides (29% versus 52%; p < 0,001), além de menor tempo de internação na unidade de terapia intensiva (12 versus 8 dias; p < 0,001). CONCLUSÃO: Houve mudanças significativas nas comorbidades dos pacientes, nos tratamentos da unidade de terapia intensiva e no tempo de internação entre os períodos de pico e platô na primeira onda da COVID-19.

Neonatal thyroxine activation modifies epigenetic programming of the liver.

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1-5 (P1-P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.

Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism.

INTRODUCTION: Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. METHODOLOGY: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. RESULTS: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). CONCLUSIONS: As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.