THYROSIM App for Education and Research Predicts Potential Health Risks of Over-the-Counter Thyroid Supplements

Background: Computer simulation tools for education and research are making increasingly effective use of the Internet and personal devices. To facilitate these activities in endocrinology and metabolism, a mechanistically based simulator of human thyroid hormone and thyrotropin (TSH) regulation dynamics was developed and further validated, and it was implemented as a facile and freely accessible web-based and personal device application: the THYROSIM app. This study elucidates and demonstrates its utility in a research context by exploring key physiological effects of over-the-counter thyroid supplements. Methods: THYROSIM has a simple and intuitive user interface for teaching and conducting simulated ?what-if? experiments. User-selectable ?experimental? test-input dosages (oral, intravenous pulses, intravenous infusions) are represented by animated graphical icons integrated with a cartoon of the hypothalamic?pituitary?thyroid axis. Simulations of familiar triiodothyronine (T3), thyroxine (T4), and TSH temporal dynamic responses to these exogenous stimuli are reported graphically, along with normal ranges on the same single interface page; and multiple sets of simulated experimental results are superimposable to facilitate comparative analyses. Results and Conclusions: This study shows that THYROSIM accurately reproduces a wide range of published clinical study data reporting hormonal kinetic responses to large and small oral hormone challenges. Simulation examples of partial thyroidectomies and malabsorption illustrate typical usage by optionally changing thyroid gland secretion and/or gut absorption rates?expressed as percentages of normal?as well as additions of oral hormone dosing, all directly on the interface, and visualizing the kinetic responses to these challenges. Classroom and patient education usage?with public health implications?is illustrated by predictive simulated responses to nonprescription thyroid health supplements analyzed previously for T3 and T4 content. Notably, it was found that T3 in supplements has potentially more serious pathophysiological effects than does T4?concomitant with low-normal TSH levels. Some preparations contain enough T3 to generate thyrotoxic conditions, with supernormal serum T3-spiking and subnormal serum T4 and TSH levels and, in some cases, with normal or low-normal range TSH levels due to thyroidal axis negative feedback. These results suggest that appropriate regulation of these products is needed.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140268/1/thy.2015.0373.pd

Long-term, treatment-free survival in select patients with distant metastatic papillary thyroid cancer

Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary

The Type 2 Iodothyronine Deiodinase is Essential for Adaptive Thermogenesis in Brown Adipose Tissue

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3′-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2–/–) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2–/– brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O2 consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor β (TRβ) while the normal sympathetic response of brown adipocytes requires TRα. Intracellularly generated T3 may be required to saturate the TRα, which has an approximately fourfold lower T3-binding affinity than does TRβ. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals

Thyroid Hormone Promotes Postnatal Rat Pancreatic β-Cell Development and Glucose-Responsive Insulin Secretion Through MAFA

Neonatal β cells do not secrete glucose-responsive insulin and are considered immature. We previously showed the transcription factor MAFA is key for the functional maturation of β cells, but the physiological regulators of this process are unknown. Here we show that postnatal rat β cells express thyroid hormone (TH) receptor isoforms and deiodinases in an age-dependent pattern as glucose responsiveness develops. In vivo neonatal triiodothyronine supplementation and TH inhibition, respectively, accelerated and delayed metabolic development. In vitro exposure of immature islets to triiodothyronine enhanced the expression of Mafa, the secretion of glucose-responsive insulin, and the proportion of responsive cells, all of which are effects that were abolished in the presence of dominant-negative Mafa. Using chromatin immunoprecipitation and electrophoretic mobility shift assay, we show that TH has a direct receptor-ligand interaction with the Mafa promoter and, using a luciferase reporter, that this interaction was functional. Thus, TH can be considered a physiological regulator of functional maturation of β cells via its induction of Mafa

Localization of nonlinear excitations in curved waveguides

Motivated by the example of a curved waveguide embedded in a photonic crystal, we examine the effects of geometry in a ``quantum channel'' of parabolic form. We study the linear case and derive exact as well as approximate expressions for the eigenvalues and eigenfunctions of the linear problem. We then proceed to the nonlinear setting and its stationary states in a number of limiting cases that allow for analytical treatment. The results of our analysis are used as initial conditions in direct numerical simulations of the nonlinear problem and localized excitations are found to persist, as well as to have interesting relaxational dynamics. Analogies of the present problem in contexts related to atomic physics and particularly to Bose-Einstein condensation are discussed.Comment: 14 pages, 4 figure

On Minisuperspace Models of S-branes

In this note we reconsider the minisuperspace toy models for rolling and bouncing tachyons. We show that the theories require to choose boundary conditions at infinity since particles in an exponentially unbounded potential fall to infinity in finite world-sheet time. Using standard techniques from operator theory, we determine the possible boundary conditions and we compute the corresponding energy spectra and minisuperspace 3-point functions. Based on this analysis we argue in particular that world-sheet models of S-branes possess a discrete spectrum of conformal weights containing both positive and negative values. Finally, some suggestions are made for possible relations with previous studies of the minisuperspace theory.Comment: 24 pages, 3 figure

Natural boundaries for the Smoluchowski equation and affiliated diffusion processes

The Schr\"{o}dinger problem of deducing the microscopic dynamics from the input-output statistics data is known to admit a solution in terms of Markov diffusions. The uniqueness of solution is found linked to the natural boundaries respected by the underlying random motion. By choosing a reference Smoluchowski diffusion process, we automatically fix the Feynman-Kac potential and the field of local accelerations it induces. We generate the family of affiliated diffusions with the same local dynamics, but different inaccessible boundaries on finite, semi-infinite and infinite domains. For each diffusion process a unique Feynman-Kac kernel is obtained by the constrained (Dirichlet boundary data) Wiener path integration.As a by-product of the discussion, we give an overview of the problem of inaccessible boundaries for the diffusion and bring together (sometimes viewed from unexpected angles) results which are little known, and dispersed in publications from scarcely communicating areas of mathematics and physics.Comment: Latex file, Phys. Rev. E 49, 3815-3824, (1994

The fitness consequences of inbreeding in natural populations and their implications for species conservation – a systematic map

Background: Threatened species often have small and isolated populations where mating among relatives can result in inbreeding depression increasing extinction risk. Effective management is hampered by a lack of syntheses summarising the magnitude of, and variation in inbreeding depression. Here we describe the nature and scope of the literature examining phenotypic/fitness consequences of inbreeding, to provide a foundation for future syntheses and management. Methods: We searched the literature for articles documenting the impact of inbreeding in natural populations. Article titles, abstracts and full-texts were assessed against a priori defined criteria, and information relating to study design, quality and other factors that may influence inbreeding responses (e.g. population size) was extracted from relevant articles. Results: The searches identified 11457 articles, of which 614 were assessed as relevant and included in the systematic map (corresponding to 703 distinct studies). Most studies (663) assessed within-population inbreeding resulting from self-fertilisation or consanguineous pairings, while 118 studies assessed among-population inbreeding due to drift load. Plants were the most studied taxon (469 studies) followed by insects (52 studies) and birds (43 studies). Most studies investigated the effects of inbreeding on components of fitness (e.g. survival or fecundity; 648 studies) but measurements were typically under laboratory/greenhouse conditions (486 studies). Observations were also often restricted to the first inbred generation (607 studies) and studies frequently lacked contextual information (e.g. population size). Conclusions: Our systematic map describes the scope and quality of the evidence describing the phenotypic consequences of inbreeding. The map reveals substantial evidence relating to inbreeding responses exists, but highlights information is still limited for some aspects, including the effects of multiple generations of inbreeding. The systematic map allowed us to define several conservation-relevant questions, where sufficient data exists to support systematic reviews, e.g. How do inbreeding responses vary with population size? However, we found that such syntheses are likely to be constrained by incomplete reporting of critical contextual information. Our systematic map employed the same rigorous literature assessment methods as systematic review, including a novel survey of study quality and thus provides a robust foundation to guide future research and syntheses seeking to inform conservation decision-making

Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity

The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding.After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and β-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance.We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity

Thyroid nodularity after childhood irradiation for lymphoid hyperplasia: a comparison of questionnaire and clinical findings

Ionizing radiation is a well-established cause of thyroid cancer and modularity, however, important questions relating to the magnitude of the risk following low-dose medical exposures remain unresolved. To address these issues, we conducted a follow-up study of 1590 individuals treated between 1938 and 1969 with X-rays for childhood lymphoid hyperplasia (av. thyroid DOSE = 24 cGy) and 1499 individuals treated with surgery only. Thyroid nodularity was determined from self-administered questionnaires completed by 1195 irradiated and 1063 surgically-treated subjects and from clinical examinations of 602 irradiated and 457 non-irradiated subjects. A much higher relative risk (RR) for radiation-induced thyroid nodules was estimated from the questionnaire than from the clinical examination data, 15.8 and 2.7, respectively. (The corresponding estimates of excess RR per cGy were 64 and 7%). Analysis of the examination data revealed a strong dose-response relationship, similar excess RR/cGy for males and females, and an inverse relationship with age at exposure. Although the thyroid gland is one of the most sensitive organs to the neoplastic effects of radiation, the radiation-induced risk of thyroid nodularity reported from questionnaire studies may over-estimate the true risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28887/1/0000723.pd