Thyroid-Friendly Soft Materials as 3D Cell Culture Tool for Stimulating Thyroid Cell Function.

The disruption of thyroid hormones because of chemical exposure is a significant societal problem. Chemical evaluations of environmental and human health risks are conventionally based on animal experiments. However, owing to recent breakthroughs in biotechnology, the potential toxicity of chemicals can now be evaluated using 3D cell cultures. In this study, the interactive effects of thyroid-friendly soft (TS) microspheres on thyroid cell aggregates are elucidated and their potential as a reliable toxicity assessment tool is evaluated. Using state-of-the-art characterization methods coupled with cell-based analysis and quadrupole time-of-flight mass spectrometry, it is shown that TS-microsphere-integrated thyroid cell aggregates exhibit improved thyroid function. Specifically, the responses of zebrafish embryos, which are used for thyroid toxicity analysis, and the TS-microsphere-integrated cell aggregates to methimazole (MMI), a known thyroid inhibitor, are compared. The results show that the thyroid hormone disruption response of the TS-microsphere-integrated thyroid cell aggregates to MMI is more sensitive compared with those of the zebrafish embryos and conventionally formed cell aggregates. This proof-of-concept approach can be used to control cellular function in the desired direction and hence evaluate thyroid function. Thus, the proposed TS-microsphere-integrated cell aggregates may yield new fundamental insights for advancing in vitro cell-based research.

Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors.

Modern anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of androgen receptor, estrogen receptor α (ERα), glucocorticoid receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1-5 µM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.

Current approach to surgical management of hyperthyroidism.

Hyperthyroidism is a set of disorders that involve excess synthesis and secretion of thyroid hormones by the thyroid gland, which leads to thyrotoxicosis. The most common forms of hyperthyroidism include diffuse toxic goiter (Graves' disease), toxic multinodular goiter (Plummer disease), and a solitary toxic adenoma. The most reliable screening measure of thyroid function is the thyroid-stimulating hormone (TSH) level. Options for treatment of hyperthyroidism include: antithyroid drugs, radioactive iodine therapy (the preferred treatment of hyperthyroidism among US thyroid specialists), or thyroidectomy. Massive thyroid enlargement with compressive symptoms, a suspicious nodule, Graves' orbitopathy, and patient preference are indications for surgical treatment of thyrotoxicosis. This paper reviews the current literature and controversies on the surgical approach to the management of hyperthyroidism.

Medical treatment of thyrotoxicosis.

Medical treatment is the primary therapeutic option for thyrotoxicosis/hyperthyroidism. Two groups of causes of thyrotoxicosis (i.e. thyrotoxicosis with hyperthyroidism and thyrotoxicosis without hyperthyroidism) need to be considered for therapeutic reasons. Herein we provide an updated review on the role of conventional medical therapies (i.e. ß-blockers, antithyroid drugs [ATDs], corticosteroids, inorganic iodide, perchlorate, cholecystographic agents, lithium, cholestyramine) in the main causes of thyrotoxicosis, starting from the rationale subtending their clinical application.

The role of laboratory medicine in the diagnosis of the hyperthyroidism.

Hyperthyroidism is a clinical condition characterized by inappropriately high synthesis and secretion of thyroid hormones by the thyroid gland. It has multiple aetiologies, manifestations and potential therapies. Graves' disease is the most common form of hyperthyroidism, due to the production of autoantibodies against thyrotropin receptor, capable of over-stimulating thyroid function. A reliable diagnosis of hyperthyroidism can be established on clinical grounds, followed by the evaluation of serum thyroid function tests (thyrotropin first and then free thyroxine, adding the measurement of free triiodothyronine in selected specific situations). The recent guidelines of both the American and European Thyroid Associations have strongly recommended the measurement of thyrotropin receptor autoantibodies for the accurate diagnosis and management of Graves' disease. If autoantibody test is negative, a radioiodine uptake should be performed. Considering the most recent laboratory improvements, binding assays can be considered the best first solution for the measurement of thyrotropin receptor autoantibodies in diagnosis and management of overt cases of Graves' disease. In fact, they have a satisfactory clinical sensitivity and specificity (97.4% and 99.2%, respectively) being performed in clinical laboratories on automated platforms together with the other thyroid function tests. In this setting, the bioassays should be reserved for fine and complex diagnoses and for particular clinical conditions where it is essential to document the transition from stimulating to blocking activity or vice versa (e.g. pregnancy and post-partum, related thyroid eye disease, Hashimoto's thyroiditis with extrathyroidal manifestations, unusual cases after LT4 therapy for hypothyroidism or after antithyroid drug treatment for Graves' disease). Undoubtedly, technological advances will help improve laboratory diagnostics of hyperthyroidism. Nevertheless, despite future progress, the dialogue between clinicians and laboratory will continue to be crucial for an adequate knowledge and interpretation of the laboratory tests and, therefore, for an accurate diagnosis and correct management of the patient.

Radioiodine therapy of thyroid autonomy.

Radioiodine therapy (RIT) of thyroid functional autonomy (TFA) is rapidly evolving, though it has been recognized for decades as a very effective treatment of toxic nodular varieties. Indeed, TFA is a frequent cause of persistent subclinical hyperthyroidism, which should be regarded as a new metabolic syndrome, with well-established adverse cardio-vascular consequences. Sensitive TSH assays and multiparametric ultrasounds are not accurate enough to reliably diagnose TFA and identify its main variants, unifocal, multifocal (UFA/MFA) and disseminated autonomy (DISA). Modern diagnostic tools are extensively presented and rely upon Thyroid Scan imaging and quantification. A new relationship allows predicting at baseline, an excess of 123I uptake as compared to the TSH stimulation in compensated TFA. Suppressed TS are useful with either isotope, otherwise. Diagnosis of the DISA variant is presented as compared to Graves' disease. Dosimetry has some specificity in TFA work-up. Indeed, the spatial distribution of the dose is as important as the mean value itself and can be eventually controlled by adjusting the TSH level with the smart use of LT3 or antithyroid drug therapy (ATD). A review of the different ways to determine the target mass from anatomical to functional approaches is presented. Main clinical and dosimetric published results of RIT are summarized according to clinical goals. Endogenous TSH stimulation using an ATD preparation has promising results in reducing big autonomously functioning goiters. Finally, we report preliminary successful results of preventive RIT using short term LT3 suppression in compensated TFA, with low administered activities and low rate of hypothyroidism.

Graves' orbitopathy: a multidisciplinary approach.

Orbitopathy is the main extra thyroidal manifestation of Graves' disease. It is a very challenging condition, which requires a cooperation between many specialists (endocrinologists, ophthalmologists, radiologists, radiotherapeutic, orbital surgeons) for an optimal clinical management. An accurate diagnostic assessment is required, in order to plan an adequate treatment of Graves' orbitopathy. Medical therapy, radiotherapy or surgery may be necessary to control the disease. In this review, the authors analyze the various therapeutic strategies, as well the more recent therapies based on pharmacologic immunomodulation.

RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures.

Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.

Increasing Use of Thyroidectomy as Definitive Treatment for Hyperthyroidism.

BACKGROUND: Thyroidectomy is a definitive treatment for hyperthyroidism. The purpose of this study is to examine how often patients with hyperthyroidism are referred for thyroidectomy and what are the common reasons for referral. MATERIALS AND METHODS: We identified 864 patients with hyperthyroidism diagnosis. A total of 237 patients underwent thyroidectomy from January 2011 to December 2016. Patients were divided into six groups according to the year of thyroidectomy, group 1 to group 6, from 2011 to 2016, respectively. Primary and secondary outcomes: reasons why patient was referred for thyroidectomy, time from diagnosis, and/or start of antithyroid drugs (ATDs) to thyroidectomy as well as the trend and total number of thyroidectomies each surgeon did during the study period. RESULTS: The mean age was 44 ± 15 y, 73% were women, and 54% were African American. A significant increase in the rate of thyroidectomy over the study period was observed where 31 patients underwent thyroidectomy in 2011 compared with 61 patients in 2016. The most common reasons patients were referred for thyroidectomy were resistance or intolerance to ATDs followed by patient's preference, and presentation with obstructive symptoms with no statistically significant difference between groups. The median time from diagnosis to surgery was 8 mo (0 to 204 mo) and 7 mo from initiation of ATDs to thyroidectomy with no significant difference between groups. CONCLUSIONS: An increase of thyroidectomy rate was observed at our institution over the last 6 y. Patients were mostly referred due to resistance or intolerance to antithyroid medications, patients' preference of surgery, and presentation with obstructive symptoms.

Inhibitory effects of methimazole and propylthiouracil on iodotyrosine deiodinase 1 in thyrocytes.

Methimazole (MMI) and propylthiouracil (PTU) are commonly used for the treatment of Graves' disease. They share similar inhibitory effects on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation and organification of iodine. However, their potential effects on other thyroid functional molecules have not been explored in depth. To identify novel effects of MMI and PTU, DNA microarray analysis, real-time PCR, Western blotting, immunofluorescence staining and confocal laser scanning microscopy were performed using FRTL-5 rat thyroid cells. DNA microarray analysis indicated that both MMI and PTU suppress iodotyrosine deiodinase 1 (Iyd, Dehal1) mRNA levels. Further studies revealed that Dehal1 mRNA levels was stimulated by TSH, insulin and serum, while it was suppressed by iodine and a follicular concentration of thyroglobulin. MMI and PTU significantly suppressed Dehal1 expression induced by TSH, insulin and serum. On the other hand, although MMI suppressed Dehal1 expression in the absence of TSH, PTU only weakly suppressed Dehal1 without TSH. These results suggest that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. The drugs also inhibited re-distribution of Dehal1 protein into newly formed lysosomes following thyroglobulin endocytosis. These findings imply complex and multifaceted regulation of Dehal1 in the thyroid and suggest that MMI and PTU modulate Dehal1 expression and distribution of the protein in thyrocytes to exert their effect.

Number, Proliferative Activity, and Expression of Thyroid Hormone Receptors in Dermal Fibroblasts in Mice with Changed Thyroid Status.

We studied the intensity of age-specific changes in the dermis (number and proliferative activity of fibroblasts) in mice with normal and experimentally changed level of thyroid hormones. Receptors of thyroid hormones, TR-α and TR-ß, in mouse dermal fibroblasts were identified by immunohistochemical methods. The relative expression of Thra, Thrb, and Dio2 genes was assessed by real-time PCR analysis. From the second to fifth month of life, the number of fibroblasts in the connective tissue layer of mouse skin decreased by 42.3%. The number of fibroblasts in the dermis of 5-month-old mice treated with Thyrozol significantly decreases by 25.9% (p<0.05), and vice versa, in mice receiving thyroxin this parameter increased by 4.7% in comparison with the control (p>0.05). TR-α and TR-ß were identified in dermal fibroblasts in all groups of mice. No differences in the content TR-α and Thra gene expression in 2- and 5-month-old mice of the control and experimental were revealed. TR-ß content in dermal fibroblasts of 2-month-old animals was maximum and exceeded this value in 5-month-old control mice by 25%. The number of these receptors decreased by 33.3% in mice treated with Thyrozol and increased by 25% in animals receiving thyroxin injection in comparison with the control. Relative expression of Thrb gene significantly increased only in mice treated with thyroxin. Comparative analysis of the relative expression of Dio2 gene revealed no differences between the experimental and control groups. Changes in the level of thyroid hormones, content of TR-ß, and relative Thrb gene expression contribute to agerelated shifts in the number and proliferative activity of mouse dermal fibroblasts.

Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30-40% in the Rpe65-/- mouse model of Leber congenital amaurosis and reduced the number of TUNEL+ cells. Cone survival was significantly improved in Rpe65-/- and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2-/- and Rpe65-/- /Thrb2-/- mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.-Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

A patient-specific treatment model for Graves' hyperthyroidism.

BACKGROUND: Graves' is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves' disease. METHODS: We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients' progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients. RESULTS: When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism. CONCLUSION: We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients' data including loading and maintenance doses and describe the mechanism, hyperthyroidism→euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.

The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies.

Our aim was to assess the risk of fractures or low bone mineral density (BMD) associated with subclinical thyroid dysfunction among cohorts. We systematically searched Medline (via PubMed), EMBASE, Cochrane Library, Web of Science, CENTRAL and SinoMed up to 31 July 2016 to identify cohort studies which have analyzed associations between subclinical thyroid dysfunction and fracture or BMD. A total of 19 population-based cohorts including 79,368 participants with relationships between subclinical thyroid dysfunction and fractures or BMD were identified as eligible for this meta-analysis. Subclinical hypothyroidism was associated with relative risks (RRs) of 1.34 (95% confidence interval [CI] 1.14, 1.58; I 2 = 32%) for hip fracture, 1.27 (95% CI 1.02, 1.58; I 2 = 51.9%) for any location of fracture, and 1.25 (95% CI 1.04, 1.50) for forearm fracture. Subclinical hyperthyroidism was associated with RRs of 1.71 (95% CI 1.06, 2.76; I 2 = 0.0%) for spine fracture, 1.20 (95% CI 1.03, 1.39; I 2 = 0.0%) for non-spine fracture, 1.44 (95% CI 1.21, 1.71; I 2 = 0.0%) for hip fracture, and 1.38 (95% CI 1.21, 1.58; I 2 = 0.0%) for any location of fracture. Subgroup analysis was conducted according to whether thyroid/anti-thyroid drug users were excluded or not and the results were similar. The change in BMD at the hip (weighted mean difference [WMD] = -0.060, 95% CI -0.116, -0.004; I 2 = 0.0%) and femoral neck (WMD = -0.046, 95% CI -0.077, -0.015; I 2 = 0.0%) was significantly decreased in the subclinical hyperthyroidism group compared with the euthyroidism groups in females. We failed to find any associations between the change in BMD and subclinical hypothyroidism. The overall quality of evidence was low in all outcomes. Subclinical hyperthyroidism and subclinical hypothyroidism were associated with an increased risk of fractures. Although subclinical hyperthyroidism was related to reduced BMD, no evidence could prove a definite association between subclinical hypothyroidism and the risk of low BMD.

Developmental expression profiles and thyroidal regulation of cytokines during metamorphosis in the amphibian Xenopus laevis.

Early life-stages of amphibians rely on the innate immune system for defense against pathogens. While thyroid hormones (TH) are critical for metamorphosis and later development of the adaptive immune system, the role of TH in innate immune system development is less clear. An integral part of the innate immune response are pro-inflammatory cytokines - effector molecules that allow communication between components of the immune system. The objective of this study was to characterize the expression of key pro-inflammatory cytokines, tumor necrosis factor-α (TNFα), interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ), throughout amphibian development and determine the impacts of thyroidal modulation on their expression. Xenopus laevis were sampled at various stages of development encompassing early embryogenesis to late prometamorphosis and cytokine expression was measured by real-time PCR. Expression of TNFα and IL-1ß were transient over development, increasing with developmental stage, while IFN-γ remained relatively stable. Functionally athyroid, premetamorphic tadpoles were exposed to thyroxine (0.5 and 2 µg/L) or sodium perchlorate (125 and 500 µg/L) for seven days. Tadpoles demonstrated characteristic responses of advanced development with thyroxine exposure and delayed development (although to a lesser extent) and increased thyroid gland area and follicular cell height with sodium perchlorate exposure. Exposure to thyroxine for two days resulted in decreased expression of IL-1ß in tadpole trunks. Sodium perchlorate had negligible effects on cytokine expression. Overall, these results demonstrate that cytokine transcript levels vary with stage of tadpole development but that their ontogenic regulation is not likely exclusively influenced by thyroid status. Understanding the direct and indirect effects of altered hormone status may provide insight into potential mechanisms of altered immune function during amphibian development.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents.

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents.

Thyroid Hormone Acts Locally to Increase Neurogenesis, Neuronal Differentiation, and Dendritic Arbor Elaboration in the Tadpole Visual System.

Thyroid hormone (TH) regulates many cellular events underlying perinatal brain development in vertebrates. Whether and how TH regulates brain development when neural circuits are first forming is less clear. Furthermore, although the molecular mechanisms that impose spatiotemporal constraints on TH action in the brain have been described, the effects of local TH signaling are poorly understood. We determined the effects of manipulating TH signaling on development of the optic tectum in stage 46-49 Xenopus laevis tadpoles. Global TH treatment caused large-scale morphological effects in tadpoles, including changes in brain morphology and increased tectal cell proliferation. Either increasing or decreasing endogenous TH signaling in tectum, by combining targeted DIO3 knockdown and methimazole, led to corresponding changes in tectal cell proliferation. Local increases in TH, accomplished by injecting suspensions of tri-iodothyronine (T3) in coconut oil into the midbrain ventricle or into the eye, selectively increased tectal or retinal cell proliferation, respectively. In vivo time-lapse imaging demonstrated that local TH first increased tectal progenitor cell proliferation, expanding the progenitor pool, and subsequently increased neuronal differentiation. Local T3 also dramatically increased dendritic arbor growth in neurons that had already reached a growth plateau. The time-lapse data indicate that the same cells are differentially sensitive to T3 at different time points. Finally, TH increased expression of genes pertaining to proliferation and neuronal differentiation. These experiments indicate that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting cell proliferation and differentiation and by acting on neurons to increase dendritic arbor elaboration. SIGNIFICANCE STATEMENT: Thyroid hormone (TH) is a critical regulator of perinatal brain development in vertebrates. Abnormal TH signaling in early pregnancy is associated with significant cognitive deficits in humans; however, it is difficult to probe the function of TH in early brain development in mammals because of the inaccessibility of the fetal brain in the uterine environment and the challenge of disambiguating maternal versus fetal contributions of TH. The external development of tadpoles allows manipulation and direct observation of the molecular and cellular mechanisms underlying TH's effects on brain development in ways not possible in mammals. We find that endogenous TH locally regulates neurogenesis at developmental stages relevant to circuit assembly by affecting neural progenitor cell proliferation and differentiation and by acting on neurons to enhance dendritic arbor elaboration.

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration.

Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.

Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) levels in patients with overt and subclinical hyperthyroidism: effects of treatment.

BACKGROUND AND OBJECTIVES: Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1) has been shown to increase in parallel with platelet activation in acute ischaemic and thrombotic diseases. There has been no study evaluating SCUBE1 levels in patients with overt hyperthyroidism (OHyper) and subclinical hyperthyroidism (SHyper), conditions which are known to show impairment of both endothelial and platelet function. This study sought to evaluate SCUBE1 concentrations in patients with SHyper and OHyper, and assessed the effects of antithyroid drug (ATD) therapy on circulating SCUBE1 levels. DESIGN AND METHODS: Forty-five untreated patients with OHyper, 20 untreated patients with SHyper and 30 age- and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. RESULTS: Compared with the control subjects, SCUBE1 levels were significantly increased in patients with SHyper and OHyper (P < 0·0001 and P = 0·002, respectively). SCUBE1 levels were not significantly different in patients with OHyper compared with patients with SHyper. There was no significant correlation between serum thyroid hormones and SCUBE1 levels. Plasma SCUBE1 levels decreased significantly in both OHyper and SHyper after ATD treatment (P < 0·05). CONCLUSIONS: Increased SCUBE1 levels in both SHyper and OHyper patients may reflect increased platelet activation and possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. SCUBE1 may be used as a reliable marker of endothelial damage in hyperthyroidism, especially in the subclinical period.

Thyroid antagonists and thyroid indicators in U.S. pregnant women in the Vanguard Study of the National Children's Study.

The sodium iodide-symporter (NIS) mediates uptake of iodide into thyroid follicular cells. This key step in thyroid hormone synthesis is inhibited by perchlorate, thiocyanate (SCN) and nitrate (NO3) anions. When these exposures occur during pregnancy the resulting decreases in thyroid hormones may adversely affect neurodevelopment of the human fetus. Our objectives were to describe and examine the relationship of these anions to the serum thyroid indicators, thyroid stimulating hormone (TSH) and free thyroxine (FT4), in third trimester women from the initial Vanguard Study of the National Children's Study (NCS); and to compare urine perchlorate results with those in pregnant women from the National Health and Nutritional Examination Survey (NHANES). Urinary perchlorate, SCN, NO3, and iodine, serum TSH, FT4, and cotinine were measured and a food frequency questionnaire (FFQ) was administered to pregnant women enrolled in the initial Vanguard Study. We used multiple regression models of FT4 and TSH that included perchlorate equivalent concentration (PEC, which estimates combined inhibitory effects of the anions perchlorate, SCN, and NO3 on the NIS). We used multiple regression to model predictors of each urinary anion, using FFQ results, drinking water source, season of year, smoking status, and demographic characteristics. Descriptive statistics were calculated for pregnant women in NHANES 2001-2012. The geometric mean (GM) for urinary perchlorate was 4.04µg/L, for TSH 1.46mIU/L, and the arithmetic mean for FT4 1.11ng/dL in 359 NCS women. In 330 women with completed FFQs, consumption of leafy greens, winter season, and Hispanic ethnicity were significant predictors of higher urinary perchlorate, which differed significantly by study site and primary drinking water source, and bottled water was associated with higher urinary perchlorate compared to filtered tap water. Leafy greens consumption was associated with higher urinary NO3 and higher urinary SCN. There was no association between urinary perchlorate or PEC and TSH or FT4, even for women with urinary iodine <100µg/L. GM urinary perchlorate concentrations in the full sample (n=494) of third trimester NCS women (4.03µg/L) were similar to pregnant women in NHANES (3.58µg/L).