Comparing the effects and potencies of perchlorate and nitrate on amphibian metamorphosis using a modified amphibian metamorphosis assay (AMA).

A modified amphibian metamorphosis assay was performed in which Nieuwkoop and Faber (NF) stage 47 Xenopus laevis larvae were exposed to different concentrations of either perchlorate (ClO4 -) or nitrate (NO3 -) for 32 days. Larvae were exposed to 0.0 (control), 5, 25, 125, 625, and 3125 µg/L ClO4 -, or 0 (control), 23, 71, 217, 660, and 2000 mg/L NO3 -. The primary endpoints were survival, hind limb length (HLL), forelimb emergence and development, developmental stage (including time to NF stage 62 [MT62]), thyroid histopathology, wet weight, and snout-vent length (SVL). Developmental delay as evidenced by altered stage distribution and increased MT62, a higher degree of thyroid follicular cell hypertrophy, and an increase in the prevalence of follicular cell hyperplasia was observed at concentrations ≥125 µg/L ClO4 -. The no observed effect concentration (NOEC) for developmental endpoints was 25.0 µg/L ClO4 - and the NOEC for growth endpoints was 3125 µg/L ClO4 -. Exposure to nitrate did not adversely affect MT62, but a decreasing trend in stage distribution and median developmental stage at ≥217 mg/L NO3 - was observed. No histopathologic effects associated with nitrate exposure were observed. An increasing trend in SVL-normalized HLL was observed at 2000 mg/L NO3 -. Nitrate did not alter larval growth. The NOEC for developmental endpoints was 71 mg/L NO3 -, and 2000 mg/L NO3 - for growth endpoints. The present study provided additional evidence that the effects and potency of nitrate and perchlorate on metamorphosis and growth in X. laevis are considerably different.

Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis.

PURPOSE: Congenital hypothyroidism (CH) is a common congenital endocrine disorder in humans. CH-related diseases such as athyreosis, thyroid ectopy, and hypoplasia are primarily caused by dysgenic thyroid development. However, the underlying molecular mechanisms remain unknown. METHODS: To identify novel CH candidate genes, 192 CH patients were enrolled, and target sequencing of 21 known CH-related genes was performed. The remaining 98 CH patients carrying no known genes were subjected to exome sequencing (ES). The functions of the identified variants were confirmed using thyroid epithelial cells in vitro and in zebrafish model organisms in vivo. RESULTS: Four pathogenic GBP1 variations from three patients were identified. In zebrafish embryos, gbp1 knockdown caused defective thyroid primordium morphogenesis and hypothyroidism. The thyroid cells were stuck together and failed to dissociate from each other to form individual follicles in gbp1-deficient embryos. Furthermore, defects were restored with wild-type human GBP1 (hGBP1) messenger RNA (mRNA) except for mutated hGBP1 (p.H150Y, p.L187P) overexpression. GBP1 promoted ß-catenin translocation into the cytosol and suppressed the formation of cellular adhesion complexes. Suppression of cell-cell adhesion restored the thyroid primordium growth defect observed in gbp1-deficient zebrafish embryos. CONCLUSION: This study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism.

Xenopus laevis tadpoles exposed to metamifop: Changes in growth, behavioral endpoints, neurotransmitters, antioxidant system and thyroid development.

Pesticides are a major cause of the reduction in the global amphibian population. In this study, the acute toxicity and chronic effects of metamifop on Xenopus laevis (X. laevis) tadpoles were investigated. The 96 h-LC50 value of metamifop on X. laevis tadpoles was 0.634 mg/L, which indicated that metamifop was highly toxic to tadpoles. In the chronic toxicity study, tadpoles were exposed to 0.063 mg/L of metamifop. After 14, 21 and 35 d of exposure, metamifop significantly inhibited the body weight and neurotransmitter synthesis of tadpoles, caused abnormal behavior and interfered with fat metabolism. According to the results of antioxidant enzymes and malondialdehyde (MDA), tadpoles exposed to 0.063 mg/L metamifop suffered severe lipid oxidative damage. Compared with the control group, the thyroid hormone (TH) levels and related gene expression in tadpoles in the treatment group were affected, reflecting the endocrine interference effect of metamifop. The data of this study can enrich our knowledge of the effects of aryloxyphenoxy propionate pesticides on amphibians and highlight the role of metamifop and other pesticides play in global decline of amphibians.

Shaping the thyroid: From peninsula to de novo lumen formation.

A challenging and stimulating question in biology deals with the formation of organs from groups of undifferentiated progenitor cells. Most epithelial organs indeed derive from the endodermal monolayer and evolve into various shape and tridimensional organization adapted to their specialized adult function. Thyroid organogenesis is no exception. In most mammals, it follows a complex and sequential process initiated from the endoderm and leading to the development of a multitude of independent closed spheres equipped and optimized for the synthesis, storage and production of thyroid hormones. The first sign of thyroid organogenesis is visible as a thickening of the anterior foregut endoderm. This group of thyroid progenitors then buds and detaches from the foregut to migrate caudally and then laterally. Upon reaching their final destination in the upper neck region on both sides of the trachea, thyroid progenitors mix with C cell progenitors and finally organize into hormone-producing thyroid follicles. Intrinsic and extrinsic factors controlling thyroid organogenesis have been identified in several species, but the fundamental cellular processes are not sufficiently considered. This review focuses on the cellular aspects of the key morphogenetic steps during thyroid organogenesis and highlights similarities and common mechanisms with developmental steps elucidated in other endoderm-derived organs, despite different final architecture and functions.

Novel insights into di­(2­ethylhexyl)phthalate activation: Implications for the hypothalamus­pituitary­thyroid axis.

Di (2­ethylhexyl) phthalate (DEHP), an environmental pollutant, is widely used as a plasticizer and causes serious pollution in the ecological environment. As previously reported, exposure to DEHP may cause thyroid dysfunction of the hypothalamic­pituitary­thyroid (HPT) axis. However, the underlying role of DEHP remains to be elucidated. The present study performed intragastrical administration of DEHP (150, 300 and 600 mg/kg) once a day for 90 consecutive days. DEHP­stimulated oxidative stress increased the thyroid follicular cavity diameter and caused thyrocyte oedema. Furthermore, DEHP exposure altered mRNA and protein levels. Thus, DEHP may perturb TH homeostasis by affecting biosynthesis, biotransformation, bio­transportation, receptor levels and metabolism through disruption of the HPT axis and activation of the thyroid­stimulating hormone (TSH)/TSH receptor signaling pathway. These results identified the formerly unappreciated endocrine­disrupting activities of phthalates and the molecular mechanisms of DEHP­induced thyrotoxicity.

In Vivo Generation of Lung and Thyroid Tissues from Embryonic Stem Cells Using Blastocyst Complementation.

Rationale: The regeneration and replacement of lung cells or tissues from induced pluripotent stem cell- or embryonic stem cell-derived cells represent future therapies for life-threatening pulmonary disorders but are limited by technical challenges to produce highly differentiated cells able to maintain lung function. Functional lung tissue-containing airways, alveoli, vasculature, and stroma have never been produced via directed differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells. We sought to produce all tissue components of the lung from bronchi to alveoli by embryo complementation.Objectives: To determine whether ESCs are capable of generating lung tissue in Nkx2-1-/- mouse embryos with lung agenesis.Methods: Blastocyst complementation was used to produce chimeras from normal mouse ESCs and Nkx2-1-/- embryos, which lack pulmonary tissues. Nkx2-1-/- chimeras were examined using immunostaining, transmission electronic microscopy, fluorescence-activated cell sorter analysis, and single-cell RNA sequencing.Measurements and Main Results: Although peripheral pulmonary and thyroid tissues are entirely lacking in Nkx2-1 gene-deleted embryos, pulmonary and thyroid structures in Nkx2-1-/- chimeras were restored after ESC complementation. Respiratory epithelial cell lineages in restored lungs of Nkx2-1-/- chimeras were derived almost entirely from ESCs, whereas endothelial, immune, and stromal cells were mosaic. ESC-derived cells from multiple respiratory cell lineages were highly differentiated and indistinguishable from endogenous cells based on morphology, ultrastructure, gene expression signatures, and cell surface proteins used to identify cell types by fluorescence-activated cell sorter.Conclusions: Lung and thyroid tissues were generated in vivo from ESCs by blastocyst complementation. Nkx2-1-/- chimeras can be used as "bioreactors" for in vivo differentiation and functional studies of ESC-derived progenitor cells.

The Impact of Bisphenol A on Thyroid Function in Neonates and Children: A Systematic Review of the Literature.

BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical widely used in plastic products that may have an adverse effect on several physiologic functions in children. The aim of this systematic review is to summarize the current knowledge of the impact of BPA concentrations on thyroid function in neonates, children, and adolescents. METHODS: A systematic search of Medline, Scopus, Clinical Trials.gov, Cochrane Central Register of Controlled Trials CENTRAL, and Google Scholar databases according to PRISMA guidelines was performed. Only case-control, cross-sectional, and cohort studies that assessed the relationship between Bisphenol A and thyroid function in neonates and children aged <18 years were included. Initially, 102 articles were assessed, which were restricted to 73 articles after exclusion of duplicates. A total of 73 articles were assessed by two independent researchers based on the title/abstract and the predetermined inclusion and exclusion criteria. According to the eligibility criteria, 18 full-text articles were selected for further assessment. Finally, 12 full-text articles were included in the present systematic review. RESULTS: The presented studies offer data that suggest a negative correlation of BPA concentrations with TSH in children, a gender-specific manner of action, and a potential effect on proper neurodevelopment. However, the results are inconclusive with respect to specific thyroid hormone concentrations and the effect on thyroid autoimmunity. CONCLUSION: The potential negative effect of BPA in the developing thyroid gland of children that may affect proper neurodevelopment, suggesting the need to focus future research on designing studies that elucidate the underlying mechanisms and the effects of BPA in thyroid function in early life.

Liver at the nexus of rat postnatal HPA axis maturation and sexual dimorphism.

Normal function of the hypothalamic-pituitary-adrenal (HPA) axis is critical for survival, and its development is choreographed for age-, sex- and context-specific actions. The liver influences HPA ontogeny, integrating diverse endocrine signals that inhibit or activate its development. This review examines how developmental changes in the expression of genes in the liver coordinate postnatal changes in multiple endocrine systems that facilitate the maturation and sexual dimorphism of the rat HPA axis. Specifically, it examines how the ontogeny of testicular androgen production, somatostatin-growth hormone activities, and hypothalamic-pituitary-thyroid axis activity intersect to influence the hepatic gene expression of insulin-like growth factor 1, corticosteroid-binding globulin, thyroxine-binding globulin, 11ß-hydroxysteroid dehydrogenase type 1 and 5α-reductase type 1. The timing of such molecular changes vary between mammalian species, but they are evolutionarily conserved and are poised to control homeostasis broadly, especially during adversity. Importantly, with the liver as their nexus, these diverse endocrine systems establish the fundamental organization of the HPA axis throughout postnatal development, and thereby ultimately determine the actions of glucocorticoids during adulthood.

Generation of Thyroid Tissues From Embryonic Stem Cells via Blastocyst Complementation In Vivo.

The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, but in vitro differentiation remains difficult. We earlier reported the in vivo generation of lung organs via blastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10 Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids of Fgf10 Ex1mut/Ex3mut mice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) in Fgf10 Ex1mut/Ex3mut mice via blastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells of Fgf10 Ex1mut/Ex3mut chimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generation in vivo via blastocyst complementation will aid functional thyroid regeneration.

Peripheral T3 signaling is the target of pesticides in zebrafish larvae and adult liver.

The intra-tissue levels of thyroid hormones (THs) regulate organ functions. Environmental factors can impair these levels by damaging the thyroid gland and/or peripheral TH metabolism. We investigated the effects of embryonic and/or long-life exposure to low-dose pesticides, ethylene thiourea (ETU), chlorpyrifos (CPF) and both combined on intra-tissue T4/T3 metabolism/signaling in zebrafish at different life stages. Hypothyroidism was evident in exposed larvae that showed reduced number of follicles and induced tshb mRNAs. Despite that, we found an increase in free T4 (fT4) and free T3 (fT3) levels/signaling that was confirmed by transcriptional regulation of TH metabolic enzymes (deiodinases) and T3-regulated mRNAs (cpt1, igfbp1a). Second-generation larvae showed that thyroid and TH signaling was affected even when not directly exposed, suggesting the role of parental exposure. In adult zebrafish, we found that sex-dependent damage of hepatic T3 level/signaling was associated with liver steatosis, which was more pronounced in females, with sex-dependent alteration of transcripts codifying the key enzymes involved in 'de novo lipogenesis' and ß-oxidation. We found impaired activation of liver T3 and PPARα/Foxo3a pathways whose deregulation was already involved in mammalian liver steatosis. The data emphasizes that the intra-tissue imbalance of the T3 level is due to thyroid endocrine disruptors (THDC) and suggests that the effect of a slight modification in T3 signaling might be amplified by its direct regulation or crosstalk with PPARα/Foxo3a pathways. Because T3 levels define the hypothyroid/hyperthyroid status of each organ, our findings might explain the pleiotropic and site-dependent effects of pesticides.

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies.

"Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5µg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically - and toxicologically - relevant.

Effect of melatonin on gonad and thyroid development of offspring of hypothyroid pregnant rats.

We investigated the effects of melatonin on rats with induced hypothyroidism during gestation as well as its effect on the development of the gonads of their offspring. Fifteen pregnant rats were divided into three groups: GC, rats without induced hypothyroidism; GH, rats with induced hypothyroidism; GHM, rats with induced hypothyroidism plus melatonin. Hypothyroidism was induced by oral administration of 6-propyl-2-thiouracil and melatonin was applied subcutaneously. Treatments were performed during gestation and lactation. For the matrices, we evaluated the number of pups, body weight gain, ovarian weight, thyroid weight, organosomatic index, thyroid stimulating hormone (TSH) dose and thyroid morphometry. For the pups, weight gain, TSH, weight, morphometry of the gonads and organosomatic index were analyzed, as well as the cell proliferation index. TSH was elevated only in the matrices of GH animals. Melatonin prevented reduction of ovarian and thyroid weight, number of pups, follicular diameter and thyroid epithelial proportion of the matrices with hypothyroidism. The offspring of rats of the GH group exhibited less body weight gain, gonad and thyroid weight, and gonad cell proliferation index compared to the offspring born of rats of the GC and GHM groups. Melatonin prevented the effects of maternal hypothyroidism on the offspring of rats.

Thyroid Function During the Fetal and Neonatal Periods.

Thyroid hormones are essential during infancy and childhood for growth and brain development. The formation and maturation of the newborn's hypothalamic-pituitary-thyroid axis begin in utero with fetal dependence on maternal thyroid hormones early in the pregnancy. As the fetal thyroid gland begins to produce thyroid hormones in the second trimester, the reliance decreases and remains at lower levels until birth. After birth, the detachment from the placenta and the change in thermal environment lead to a rapid increase in circulating thyroid-stimulating hormone in the neonate within hours, resulting in subsequent increases in thyroxine and triiodothyronine concentrations. Preterm infants may have lower thyroxine concentrations because of an immature hypothalamic-pituitary-thyroid axis at the time of birth and premature discontinuation of transference of maternal thyroid hormones. Similarly, infants with critical illness unrelated to the thyroid gland may have lower thyroxine levels. Infants born to mothers with Graves' disease are at risk for hypothyroidism and hyperthyroidism, which is related to the placental transfer of maternal autoantibodies, as well as antithyroid medications. An understanding of the normal embryology and physiology of the fetal and neonatal thyroid will help in evaluating a newborn for thyroid disorders.

A Stem Cell Surge During Thyroid Regeneration.

Background: Many tissues, including the thyroid, contain resident (adult) stem cells that are responsible for regeneration and repair after injury. The mechanisms of thyroid regeneration and the role of thyroid stem cells and thyroid progenitor cells in this process are not well understood. We have now used a new mouse thyroid injury model to gain insight into this phenomenon. Methods: Tamoxifen induced TPO-Cre mice (TPOCreER2) were crossed with inducible Diphtheria Toxin Receptor homozygous mice (ROSA26iDTR) to give rise to TPOCreER2/iDTR mice, allowing for the Cre-mediated expression of the DTR and rendering TPO expressing thyroid cells highly sensitive to diphtheria toxin (DT). This model of TPOCreER2/iDTR mice allowed us to study the repair/regeneration of thyroid follicles after diphtheria toxin induced thyroid damage by measuring serum thyroid hormones and cell fate. Results: In TPOCreER2/iDTR double transgenic mice we observed severe thyroid damage as early as 2 weeks after initiating intraperitoneal DT injections. There was marked thyroid tissue apoptosis and a ~50% drop in serum T4 levels (from 5.86 to 2.43 ug/dl) and a corresponding increase in serum TSH (from 0.18 to 8.39 ng/dl). In addition, there was a ~50% decrease in transcription of thyroid specific genes (thyroglobulin, TSH receptor, and sodium-iodide symporter). After suspending the DT administration, the thyroid rapidly recovered over a 4-week period during which we observed a transient surge in stem cell marker expression (including Oct4, Nanog, Sox2, and Rex1). In addition, cells immunostaining with stem cell markers Oct4 and Ssea-1 were found in clusters around new thyroid follicles in TPOCreER2/iDTR double transgenic mice. Furthermore, the presence of clusters of thyroid progenitor cells was also identified by Pax8 staining of thyroglobulin negative cells. This recovery of the injured gland was followed by a rapid and sequential restoration of thyroid function. Conclusion: These data demonstrate that a new model of thyroid cell damage induced by DT can be used to study the mobilization of resident adult stem cells. Furthermore, the model clearly demonstrates the involvement of both stem and progenitor cells in the in vivo regeneration of the thyroid after severe destruction.

Histology and microscopic anatomy of the thyroid gland during the larval development of Pseudis platensis (Anura, Hylidae).

Several hormones regulate anuran larval development, most notably thyroid hormones (THs). In anurans, metamorphosis fails when the thyroid gland is absent or inactivated, resulting in giant tadpoles. Larval gigantism occurs naturally in neotropical frogs of the genus Pseudis as a result of a prolonged larval period. Its thyroid function is poorly investigated and the focus of this study. We describe qualitative and quantitative variations in larval development for field-captured specimens of Pseudis platensis and compare those to the development of two sympatric species, Phyllomedusa sauvagii and Pithecopus azureus, which have small tadpoles and a shorter larval period. We describe morphological changes in the thyroid glands of larval and adult specimens. In contrast to other species with similar ecological requirements, P. platensis exhibits distinct glandular activity. During premetamorphosis, there was little or no thyroid activity, a period in which the tadpole reached 70% of its maximum size. Development and degree of activity of the thyroid gland determine the duration of the early stages of the larval period. Thyroid gland histology in tadpoles appears to correlate with the TH activity, and in turn with the diversity in anuran life history transitions.

Differences in responsiveness and sensitivity to exogenous disruptors of the thyroid gland in three anuran species.

Anuran larval development comprises tissues/organs/systems that are: exclusively of larvae, able to be remodelled, and those of postmetamorphic stages. Also, the anuran larval development is characterized by inter-related parameters: time, size and shape forming part of growth and differentiation. The anuran metamorphosis starts when growth and differentiation achieve a threshold that differs among species since it is regulated by a number of external (environmental) and internal (hormonal) processes. Here we explore the consequences of exogenous disruptors on the thyroid gland (e.g., methimazole and thyroxine as T4) of three species by immersing premetamorphic tadpoles in predetermined concentrations of the disruptors for short periods (10 or 16 days). The species were Pleurodema borellii, Leptodactylus chaquensis, and Dermatonotus muelleri, which all breed in small temporary ponds during the summer, but differ in their ecomorphology. The experiments were conducted to evaluate the effects of these substances on larval development (based in Gosner larval stages), morphometric variation in body parameters (snout-vent and total length by larval stages), and thyroid gland histopathology at the end of the assays. In P. borelli and L. chaquensis, methimazole produces significant increment of size measurements (nonparametric Kruskal-Wallis, p < .05) during stages of digit differentiation and induced thyroid gland hypertrophy. In the three species, T4 exposure accelerated limb development and caused atrophy of thyroid gland. Prolonged T4 exposure in L. chaquensis and D. muelleri triggered metamorphic transformation in the gut and skull cartilages. Discussion about interspecific differences in responsiveness and sensitivity elucidates the importance of hormonal signals to morphological evolution.

Exposure to humidifier disinfectants induces developmental effects and disrupts thyroid endocrine systems in zebrafish larvae.

Humidifier disinfectants have been widely used in Korea to prevent the growth of microorganisms in humidifier water. However, their use has been banned since 2011 after epidemiological studies reported humidifier disinfectant induced lung injury. In the present study, the developmental effects of exposure to two humidifier disinfectants (Oxy® and Wiselect) and their main component, polyhexamethylene guanidine (PHMG)-phosphate, were investigated in zebrafish embryos/larvae for seven days. The effects on triiodothyronine (T3) and thyroxine (T4) hormones, reactive oxygen species (ROS) generation, antioxidant enzyme activities, and changes in expression of the genes related to the hypothalamus-pituitary-thyroid (HPT) axis and oxidative stress were also investigated. Zebrafish embryos exposed to the highest concentration (amounts recommended for use by the manufacturers) of all tested humidifier disinfectants showed an increase in embryo coagulation, leading to death without hatching. Exposure to Oxy® and Wiselect resulted in significantly decreased body length, increased ROS generation and antioxidant enzyme activities, decreased T4, and up-regulated genes related to the HPT axis (trh, trß, and tpo) and oxidative damage (sod2 and gpx1b). The humidifier disinfectants and PHMG-phosphate could induce oxidative stress and disrupt thyroid hormone systems in zebrafish, leading to developmental retardation when used at sub-lethal concentrations. Potential effects of long-term exposure to humidifier disinfectants and mixture effects of several major components deserve further investigation.

Aging Is Associated with Low Thyroid State and Organ-Specific Sensitivity to Thyroxine.

Background: Serum thyroid state in older adults correlates with extended longevity. We hypothesized that age impacts not only systemic but also organ-specific thyroid state and response to thyroxine (T4). Methods: Young (3 months) and old (23 months) male mice were analyzed at baseline and after acute T4 challenge. Age effects on circulating thyrotropin (TSH) and thyroid hormone (TH) concentrations, transcript expression in the pituitary and thyroid were compared with organ-specific responses characterized by hepatic and cardiac content of TH and TH metabolites and expression of TH-target genes, as well as hepatic deiodinase 1 activity. Results: Circulating TH concentrations and hepatic and cardiac TH content were lower in old versus young mice. After injection with T4, conversion of T4 to triiodothyronine was decreased in old mice while TH transport in liver and heart was not affected. Organ-specific TH response was augmented in old mice in liver but not heart, indicating age- and tissue-specific sensitivity to TH. A compensatory increase of thyroid stimulating hormone subunit beta expression in the pituitary and increased serum TSH concentrations, but reduced expression of thyroid differentiation markers were found in old mice. Conclusions: We suggest that a reduced activity of the aged thyroid is responsible for the systemic low TH state in old mice. Further, divergent TH metabolism and tissue response in liver and heart occur after T4 treatment in an aged organism. These rodent data are in agreement with a much narrower window for T4 substitution in the older adults to avoid overtreatment.

Indications, benefits and risks of transoral thyroidectomy.

The advancement of minimally invasive surgery in the field of endocrine surgery over the last 2 decades has fostered the attempt of natural orifice transluminal endoscopic surgery (NOTES) for thyroidectomy and parathyroidectomy via oral incisions. This technically demanding surgery is currently being evaluated in a number of specialised centres. The procedure has gained popularity worldwide and is performed in more than 50 centres. By retrieving information from published or presented articles and direct personal communications, this study reports several issues to enable and optimise correct patient and surgeon candidacy, present the advantages and prevent novel complications under the standards of open thyroid surgery. Not all patients are eligible for the transoral approach. Transoral endoscopic and robotic procedures were described and critically analysed in this study.

Thyroid Rosai-Dorfman disease with infiltration of IgG4-bearing plasma cells associated with multiple small pulmonary cysts.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare histiocytosis which involves principally lymph nodes. Thyroid involvement in RDD is a very rare situation, and lung involvement is even rarer. CASE PRESENTATION: We report the case of a 46-year-old woman presenting a painless mass in the right side of the neck and subacute dyspnoea. Computerised tomography (CT) scans of the neck and thorax showed a large thyroid mass causing tracheal stenosis and multiple cystic lesions in both lungs. Subtotal thyroidectomy with a tracheal segment resection and histological analysis confirmed the diagnosis of nodal and extranodal (thyroid, tracheal and probably lung) Rosai-Dorfman disease (RDD) with the presence of increased numbers of IgG4-bearing plasma cells. Clinical, functional and radiological follow up 4 years after surgery without medical treatment did not show any disease progression. CONCLUSIONS: This case report indicates a benign course of nodal RDD with thyroid and tracheal infiltration following surgical resection, association of typical histological signs of RDD (emperipolesis) with IgG4-related disease features, and that lung cysts might be a manifestation of RDD.