Hypothyroidism Impairs Human Stem Cell-Derived Pancreatic Progenitor Cell Maturation in Mice.

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer ß-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of ß-cell formation.

A behavioral and micro positron emission tomography imaging study in a rat model of hypothyroidism.

Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.

Feed and forage toxicants affecting embryo survival and fetal development.

Early embryonic and fetal development in mammals is sensitive to deficiencies and excesses of specific nutrients and toxicants. Operating directly and/or indirectly, these deficiencies and excesses can result in embryonic death or, in less severe circumstances, disruption of normal embryo and fetal growth. This paper explores the threats posed by feed and forage toxicants to the developing embryo and their impact on early programming of fetal development. Using significant examples, we consider the relevance of temporal sensitivities during early development in utero, and their implications for the morphology and functional competence of specific organs and tissues.

[Rapeseed poisoning of wild herbivores]. / Rapsvergiftung wildlebender Pflanzenfresser.

Beginning with the simultaneous occurrence of the first extensive sowing of 00-rape and local increased losses among hares and roe deer in Western Germany and Austria at the end of 1986, the clinical and morphological symptoms of rape poisoning are discussed. They consist of damage to endo- and epithelium, cell membranes, blood, liver and in the so called "rape-blindness". Subsequently, the most important toxic agents of rape including their metabolites are presented. They consist in alkenyl- and indolyl-glucosinolates, leading to isothiocyanates (mustard oils), thiocyanates or thiocyanate ions resp., nitriles and antithyroid agents (e.g. goitrin) as well as S-methylcysteine sulphoxide and its metabolites, particularly dimethyl disulphide. Finally, the activity spectrum of the toxic agents or the metabolites and the clinical picture of the affected wildlife in 1986 are compared with the result that the losses of that period are most likely to be traced back to rape poisoning and that the rape-blindness mentioned is to be interpreted as a thiocyanate-psychosis.

Clinical features and management of overdosage with thyroid drugs.

Accidental ingestion and overdose of medications used in thyroidal illnesses may occur because of the frequency of these diagnoses. This review discusses acute overdosage of 4 groups of medicines. Acute ingestion of thyroid replacement medications occurs very frequently. Overdosage in children is usually asymptomatic and a benign condition; after evacuation of the stomach, propranolol may be used to treat symptomatic children. Other therapeutic regimens are rarely indicated in this age group. Ingestions of large amounts of antithyroid medications occur very rarely and limited information regarding treatment is available in the medical literature. Acute ingestion of iodine often results in corrosive injury of the gastrointestinal tract and renal damage. Cardiopulmonary collapse secondary to circulatory failure, oedema of the epiglottis and aspiration pneumonias may cause death. Administration of starch and sodium thiosulphate, maintenance of airway and stabilisation of circulation are the major components of therapy. Acute overdosage of beta-blockers is uncommon but can be lethal. Patients may appear well initially but they can suddenly develop convulsions and profound cardiovascular collapse requiring instant aggressive therapy. Potassium and glucose concentrations should be monitored. The usage of atropine, isoprenaline (isoproterenol), glucagon and prenalteral is discussed.

Biochemical changes in layer and broiler chickens when fed on a high-glucosinolate rapeseed meal.

Diets containing 500 g high-glucosinolate rapeseed meal/kg or an equivalent amount of soybean meal as the only protein supplement were fed to layer-type chickens and two broiler strains from 1 to 56 d of age. Additional groups of the former were maintained on the diets until they were 16 and 28 d old. The rapeseed meal produced thyroid hypertrophy in all strains but reduced the growth rate of only one of the broiler strains. The livers of chickens fed on rapeseed meal were enlarged and DNA analysis indicated hyperplasia, but no macroscopic lesions were found. The activities of aspartate transaminase, lactate dehydrogenase and alkaline phosphatase in the plasma were increased by rapeseed meal, suggesting liver damage. In all strains, feeding rapeseed meal increased plasma total protein, albumin and cholesterol and decreased urate. Hyperglycaemia accompanied by a decrease in plasma triglycerides occurred in the layer strain. Through its extra-thyroidal toxicity (-)5-vinyl-oxazolidine-2-thione (goitrin) was probably responsible for most of these changes.

[Development of follicular and parafollicular adenomas in the thyroid of rats treated with thiamazole (author's transl)]. / Les adénomes à cellules folliculaires et parafolliculaires de la thyroïde du rat soumis au thiamazole.

Hypothyroidism is induced in rats treated with thiamazole, an antithyroid drug. If this phase lasts long enough, the follicular cells develop adenomas. Within the same period, the number of parafollicular or C cells increases threefold on an average, but without producing corresponding adenomas, the formation of which is inhibited. When treatment is stopped, a second phase appears during which thyroid function reverts to normal. The previously observed inhibition disappears, and, after a period of latency, the hyperplastic C cells develop parafollicular adenomas. The type of tumors to be found in treated rats (either of them, or both simultaneously) is determined by respective durations of the two phases. The endocrine mechanisms of these phenomena are discussed.