Thyroid hormone can increase estrogen-mediated transcription from a consensus estrogen response element in neuroblastoma cells

Thyroid hormones (T) and estrogens (E) are nuclear receptor ligands with at least two molecular mechanisms of action: (i) relatively slow genomic effects, such as the regulation of transcription by cognate T receptors (TR) and E receptors (ER); and (ii) relatively rapid nongenomic effects, such as kinase activation and calcium release initiated at the membrane by putative membrane receptors. Genomic and nongenomic effects were thought to be disparate and independent. However, in a previous study using a two-pulse paradigm in neuroblastoma cells, we showed that E acting at the membrane could potentiate transcription from an E-driven reporter gene in the nucleus. Because both T and E can have important effects on mood and cognition, it is possible that the two hormones can act synergistically. In this study, we demonstrate that early actions of T via TRalpha1 and TRbeta1 can potentiate E-mediated transcription (genomic effects) from a consensus E response element (ERE)-driven reporter gene in transiently transfected neuroblastoma cells. Such potentiation was reduced by inhibition of mitogen-activated protein kinase. Using phosphomutants of ERalpha, we also show that probable mitogen-activated protein kinase phosphorylation sites on the ERalpha, the serines at position 167 and 118, are important in TRbeta1-mediated potentiation of ERalpha-induced transactivation. We suggest that crosstalk between T and E includes potential interactions through both nuclear and membrane-initiated molecular mechanisms of hormone signaling.

Estrogens and thyroid hormone: Non-genomic effects are coupled to transcription.

Estrogens and thyroid hormones are regulators of important diverse physiological processes such as reproduction, thermogenesis, neural development, neural differentiation and cardiovascular functions. Both are ligands for receptors in the nuclear receptor superfamily, which act as ligand-dependent transcription factors, regulating transcription. However, estrogens and thyroid hormones also rapidly (within minutes or seconds) activate kinase cascades and calcium increases, presumably initiated at the cell membrane. We discuss the relevance of both modes of hormone action, including the membrane estrogen receptor, to physiology, with particular reference to lordosis behavior. We first showed that estrogen restricted to the membrane can, in fact, lead to subsequent increases in transcription from a consensus estrogen response element-based reporter in the neuroblastoma cell line, SK-N-BE(2)C. Using a novel hormonal paradigm, we also showed that the activation of protein kinase A, protein kinase C, mitogen activated protein kinase and increases in calcium were important in the ability of the membrane-limited estrogen to potentiate transcription. We discuss the source of calcium important in transcriptional potentiation. Since estrogens and thyroid hormones have common effects on neuroprotection, cognition and mood, we also hypothesized that crosstalk could occur between the rapid actions of thyroid hormones and the genomic actions of estrogens. In neural cells, we showed that triiodothyronine acting rapidly via MAPK can increase transcription by the nuclear estrogen receptor ERa from a consensus estrogen response element, possibly by the phosphorylation of the ERa. Novel mechanisms that link signals initiated by hormones from the membrane to the nucleus are physiologically relevant and can achieve neuroendocrine integration

Distinct behavioral phenotypes in male mice lacking the thyroid hormone receptor alpha1 or beta isoforms

Thyroid hormones influence both neuronal development and anxiety via the thyroid hormone receptors (TRs). The TRs are encoded by two different genes, TRalpha and TRbeta. The loss of TRalpha1 is implicated in increased anxiety in males, possibly via a hippocampal increase in GABAergic activity. We compared both social behaviors and two underlying and related non-social behaviors, state anxiety and responses to acoustic and tactile startle in the gonadally intact TRalpha1 knockout (alpha1KO) and TRbeta (betaKO) male mice to their wild-type counterparts. For the first time, we show an opposing effect of the two TR isoforms, TRalpha1 and TRbeta, in the regulation of state anxiety, with alpha1 knockout animals (alpha1KO) showing higher levels of anxiety and betaKO males showing less anxiety compared to respective wild-type mice. At odds with the increased anxiety in non-social environments, alpha1KO males also show lower levels of responsiveness to acoustic and tactile startle stimuli. Consistent with the data that T4 is inhibitory to lordosis in female mice, we show subtly increased sex behavior in alpha1KO male mice. These behaviors support the idea that TRalpha1 could be inhibitory to ERalpha driven transcription that ultimately impacts ERalpha driven behaviors such as lordosis. The behavioral phenotypes point to novel roles for the TRs, particularly in non-social behaviors such as state anxiety and startle.

Thyroid hormones regulate anxiety in the male mouse

Thyroid hormone levels are implicated in mood disorders in the adult human but the mechanisms remain unclear partly because, in rodent models, more attention has been paid to the consequences of perinatal hypo and hyperthyroidism. Thyroid hormones act via the thyroid hormone receptor (TR) alpha and beta isoforms, both of which are expressed in the limbic system. TR's modulate gene expression via both unliganded and liganded actions. Though the thyroid hormone receptor (TR) knockouts and a transgenic TRalpha1 knock-in mouse have provided us valuable insight into behavioral phenotypes such as anxiety and depression, it is not clear if this is because of the loss of unliganded actions or liganded actions of the receptor or due to locomotor deficits. We used a hypothyroid mouse model and supplementation with tri-iodothyronine (T3) or thyroxine (T4) to investigate the consequences of dysthyroid hormone levels on behaviors that denote anxiety. Our data from the open field and the light-dark transition tests suggest that adult onset hypothyroidism in male mice produces a mild anxiogenic effect that is possibly due to unliganded receptor actions. T3 or T4 supplementation reverses this phenotype and euthyroid animals show anxiety that is intermediate between the hypothyroid and thyroid hormone supplemented groups. In addition, T3 but not T4 supplemented animals have lower spine density in the CA1 region of the hippocampus and in the central amygdala suggesting that T3-mediated rescue of the hypothyroid state might be due to lower neuronal excitability in the limbic circuit.

Cognition and anxiety are regulated by thyroid hormone signaling

Anxiety and cognition are both linked to deficits in thyroid hormone concentrations in humans and in rodent models. Both processes have also been shown to be affected by the loss of the thyroid hormone receptors (TR) or by mutant transgenic TRs. Specifically, the unbalanced action of the unliganded TRα1 is thought to be important in the memory deficit and extreme anxiety seen in transgenic mice. The contribution of TRβ is less well defined and the molecular mechanisms that underlie these deficits are also unknown. We review the literature that demonstrates the importance of the thyroid hormone (TH) and the TR in these processes and focus on the mechanisms, in particular adult hippocampal neurogenesis in the dentate gyrus, that might be important in mediating both state anxiety and cognition by thyroid hormone.

Analyses of cataract surgery performed by the Unified Health System in Brazil, 2006-2007

Objective. Estimate cataract surgical rates (CSR) for Brazil and each federal unit in 2006 and 2007 based on the number of surgeries performed by the Unified Health System to help plan a comprehensive ophthalmology network in order to eliminate cataract blindness in compliance with the target set by the World Health Organization (WHO) of 3 000 cataract surgeries per million inhabitants per year. Methods. This descriptive study calculates CSR by using the number of cataract surgeries carried out by the Brazilian Unified Health System for each federal unit and estimates the need for cataract surgery in Brazil for 2006-2007, with official population data provided by the Brazilian Institute of Geography and Statistics. The number of cataract surgeries was compared with the WHO target. Results. To reach the WHO goal for eliminating age-related cataract blindness in Brazil, 560 312 cataract surgeries in 2006 and 568 006 surgeries in 2007 needed to be done. In 2006, 179 121 cataract surgeries were done by the Unified Health System, corresponding to a CSR of 959 per million population; in 2007, 223 317 were performed, with a CSR of 1 179. With the Brazilian Council of Ophthalmology estimation of 165 000 surgeries each year by the non-public services, the CSR for Brazil would be 1 842 for 2006 and 2 051 for 2007. The proportions needed to achieve the proposed target were 38.6% in 2006 and 31.6% in 2007. Conclusions. Human resources, technical expertise, and equipment are crucial to reach the WHO goal. Brazil has enough ophthalmologists but needs improved planning and infrastructure in order to eliminate the problem, aspects that require greater financial investment and stronger political commitment.

Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: the Japanese-Brazilian thyroid study

Objective: The currently available data concerning the influence of subclinical thyroid disease (STD) on morbidity and mortality are conflicting. Our objective was to investigate the relationships between STD and cardiometabolic profile and cardiovascular disease at baseline, as well as with all-cause and cardiovascular mortality in a 7.5-year follow-up. Design: Prospective, observational study. Methods: An overall of 1110 Japanese-Brazilians aged above 30 years, free of thyroid disease, and not taking thyroid medication at baseline were studied. In a cross-sectional analysis, we investigated the prevalence of STD and its relationship with cardiometabolic profile and cardiovascular disease. All-cause and cardiovascular mortality rates were assessed for participants followed for up to 7.5 years. Association between STD and mortality was drawn using multivariate analysis, adjusting for potential confounders. Results: A total of 913 (82.3%) participants had euthyroidism, 99 (8.7%) had subclinical hypothyroidism, and 69 (6.2%) had subclinical hyperthyroidism. At baseline, no association was found between STD and cardiometabolic profile or cardiovascular disease. Multivariate-adjusted hazard ratios (HRs (95% confidence interval)) for all-cause mortality were significantly higher for individuals with both subclinical hyperthyroidism (HR, 3.0 (1.5-5.9); n=14) and subclinical hypothyroidism (HR, 2.3 (1.2-4.4); n=13) than for euthyroid subjects. Cardiovascular mortality was significantly associated with subclinical hyperthyroidism (HR, 3.3 (1.4-7.5); n=8), but not with subclinical hypothyroidism (HR, 1.6 (0.6-4.2); n=5). Conclusion: In the Japanese-Brazilian population, subclinical hyperthyroidism is an independent risk factor for all-cause and cardiovascular mortality, while subclinical hypothyroidism is associated with all-cause mortality.

Outcome Analysis of Immediate and Delayed Conservative Breast Surgery Reconstruction With Mastopexy and Reduction Mammaplasty Techniques

Background: Bilateral mammaplasty or mastopexy is frequently used for oncoplastic objectives. However, little information has been available regarding outcome following immediate and delayed reconstruction. Method: Patients were divided into Group I (immediate reconstruction) and Group II (delayed reconstruction). Retrospective review was performed to compare complications, length of hospital stay, revision surgeries, and satisfaction. The associations between the complications with potential risk factors (timing, age, body mass index, smoking, and comorbid medical conditions) were analyzed. Results: There were a total of 144 patients with a mean follow-up of 47 months. Of the 106 patients in Group I, complications occurred in 24 (22.6%), skin necrosis was observed in 7.5%, fat necrosis in 5.6%, and 6.6% patients developed local recurrence. Mean period of hospitalization was 1.89 days. Of the 38 patients of the Group II, complications occurred in 12 (31.5%), skin necrosis was observed in 7 (18.4%), fat necrosis in 4 (10.5%), and 5.2% patients developed local recurrence. Mean period of hospitalization was 1.35 days. Increased length of hospital stay greater than 1 day (P < 0.001) and the number of revision surgeries (P = 0.043) were associated with the timing of the reconstruction. In univariate analysis, no difference between groups was found with respect to complication incidence (P = 0.275); however, after adjusting for other risk factors, the probability of complications tend to be higher for Group II (OR = 2.65; 95% confidence interval - 1.01-7.00; P = 0.049). Conclusions: On the basis of the results of our study, the probability of complications tends to be higher for delayed reconstructions, and it is demonstrated that obesity and smoking are risk factors for complications. Ultimately, these data may facilitate the provision of individualized risk information for shared medical decision-making.

Immediate reconstruction following breast-conserving surgery: Management of the positive surgical margins and influence on secondary reconstruction

The efficacy of breast-conserving Surgery for the local control of early breast cancer has been repeatedly evidenced. Although immediate reconstruction following breast-conserving Surgery has been described, little information is available regarding surgical management in reoperative settings due to positive margins. We studied the influence of intraoperatively assessed and postoperatively controlled Surgical margin status on the type of breast-conserving Surgery and report our results regarding complications in a reoperative breast reconstruction scenario. All patients were seen by a multidisciplinary team who recommended breast-conserving surgery. According to the breast volume, ptosis and tumor size/location, the patients were also evaluated by a plastic Surgeon, who recommended reconstruction with the appropriate technique. Intraoperative assessment Of Surgical margins was determined by histological examination of frozen sections. The mean follow-up time was 48 months. Two hundred and eighteen patients (88.5%) underwent breast-conserving Surgery and immediate reconstruction. Twelve (5.5%) patients had a positive tumor margin after review of the permanent section. All patients underwent re-exploration. In 1.3%, a second reconstructive technique was indicated and in 2.2% a skin-sparing mastectomy with total reconstruction was performed. Our findings support the important role of the intraoperative assessment of surgical margins and its interference in the selection of reconstruction techniques and negative margins: however, it will not guarantee complete excision of the tumor. Success depends on coordinated planning with the oncologic Surgeon and careful intraoperative management, (C) 2008 Elsevier Ltd. All rights reserved.

Immediate conservative breast surgery reconstruction with perforator flaps: New challenges in the era of partial mastectomy reconstruction?

Introduction: Although the use of local flaps in conservative breast surgery (CBS) reconstruction is a reliable technique, little information has been available regarding outcome following the use of perforator flaps. The purpose of this study is to analyze the feasibility, surgical planning and outcome following CBS reconstruction with intercostal artery perforator (ICAP) flap. Patients/methods: Thirteen patients underwent CBS reconstructions with an ICAP flap. These flaps were raised from adjacent tissue located on the lateral and thoracic region and based on perforators originating from the costal and muscular segment of the intercostal vessels. The technique was indicated in patients with small/moderate volume breasts. Results: Mean time of follow-up was 32 months. Flap complications were evaluated and information on patient satisfaction were collected. 61.5 percent had tumors located in the lower-outer quadrants and 69.2 percent had tumors measuring 2 cm or less (T1). Complications occurred in 3 patients (23%), including wound dehiscence in 2 patients and fat necrosis in one. All cases were treated by conservative approach with a good result. No flap loss or wound infection were reported. 90 percent were either satisfied or very satisfied with their result. Conclusion: The ICAP flap is a reliable technique for immediate CBS reconstruction. The technique is advantageous because it does not require the use of muscle transfer, with minimum donor site morbidity. Success depends on patient selection, coordinated planning with the oncological surgeon and careful intra-operative management. (C) 2011 Elsevier Ltd. All rights reserved.

Reactive oxygen and nitrogen species balance in the determination of thyroid hormones-induced cardiac hypertrophy mediated by renin-angiotensin system

Role of reactive oxygen species (ROS)/nitric oxide (NO) balance and renin-angiotensin system in mediating cardiac hypertrophy in hyperthyroidism was evaluated in an in vivo and in vitro experimental model. Male Wistar rats were divided into four groups: control, thyroid hormone, vitamin E (or Trolox, its hydrosoluble analogue), thyroid hormone + vitamin E. Angiotensin II receptor (AT1/AT2) gene expression, immunocontent of AT1/AT2 receptors, angiotensinogen, NADPH oxidase (Nox2), and nitric oxide synthase isoforms, as well as ROS concentration (hydrogen peroxide and superoxide anion) were quantified in myocardium. Thyroid hormone increased ROS and NO metabolites, iNOS, nNOS and eNOS isoforms and it was accompanied by cardiac hypertrophy. AT1/AT2 expression and the immunocontent of angiotensinogen and Nox2 were enhanced by thyroid hormone. Antioxidants reduced ROS levels, Nox2, AT1/AT2, NOS isoforms and cardiac hypertrophy. In conclusion, ROS/NO balance may play a role in the control of thyroid hormone-induced cardiac hypertrophy mediated by renin-angiotensin system. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Thyroid hormones alter the adenine nucleotide hydrolysis in adult rat blood serum

The effects of ATP, ADP, and adenosine in the processes of platelet aggregation, vasodilatation, and coronary flow have been known for many years. The sequential hydrolysis of ATP to adenosine by soluble nucleotidases constitutes the main system for rapid inactivation of circulating adenine nucleotides. Thyroid disorders affect a number of biological factors including adenosine levels in different fractions. Then, we intend to investigate if the soluble nucleotidases responsible for the ATP, ADP, and AMP hydrolysis are affected by variations in the thyroid hormone levels in blood serum from adult rats. Hyperthyroidism was induced by daily intraperitoneal injections of L-thyroxine (T4) (2.5 and 10.0 mu g/100 g body weight, respectively) for 7 or 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water during 7 or 14 days. The treatments efficacy was confirmed by determination of hemodynamic parameters and cardiac hypertrophy evaluation. T4 treatment predominantly inhibited, and hypothyroidism (14 days after thyroidectomy) predominantly increased the ATP, ADP, and AMP hydrolysis in rat blood serum. These results suggest that both excess and deficiency of thyroid hormones can modulate the ATP diphosphohydrolase and 5`-nucleotidase activities in rat blood serum and consequently modulate the effects mediated by these enzymes and their products in vascular system. (C) 2010 International Union of Biochemistry and Molecular Biology, Inc.

Acute actions of thyroid hormone on blood vessel biochemistry and physiology

Purpose of review Description of the progress about the vascular effects promoted by thyroid hormones. Recent findings Over the past few years, a number of studies have shown that in addition to genomic effects on blood vessels, thyroid hormones exert extranuclear nongenomic effects on vascular smooth muscle cells and endothelium. These nongenomic effects occur rapidly and do not involve thyroid hormone response elements-mediated transcriptional events. In this context, the genomic and nongenomic events promoted by thyroid hormones act in concert to control the vascular hemodynamic and regulate the cardiovascular function. Summary Considering the antiatherogenic property of thyroid hormones and the rapid effects produced by this molecule as a vasodilator, including that in the coronary bed, a better understanding of the molecular mechanisms involved in its action may contribute to the development of drugs that can be clinically used to increase the known benefits promoted by thyroid hormones in cardiovascular physiology.