The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothy...

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This study was undertaken to address the effects of fetal mesencephalic tissue transplantation on the serotonin system in a rat model of Parkinson's disease (PD) while also investigating the usefulness of 4-[18 F]-ADAM (a serotonin transporter imaging agent) coupled with micro-PET for imaging serotonin transporters (SERTs). A PD model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of the nigrostriatal pathway, while cell transplantation was performed via intrastriatal injection of mesencephalic brain tissue dissected from embryonic (E14) rats. The 4-[18 F]-ADAM/micro-PET scanning was performed following both 6-OHDA lesioning and transplantation. Immunohistochemistry (IHC) studies were also performed following the final PET scan, and the results were compared to show a 17-43% decrease in the specific uptake ratio (SUR) and a 23-52% decrease in serotonin transporter immunoreactivity (SERT-ir) within various brain regions on the lesioned side. The number of methamphetamine-induced rotations also decreased significantly at the 4th week postgraft. In addition, striatal SUR and the SERT-ir levels were restored to 77% and 83% 5 weeks postgraft. These results suggest that Parkinson's disease also affects the serotonergic system, while both the dopaminergic and serotonergic systems can be partially restored in a rat model of PD after E14 mesencephalic tissue transplantation. In addition, we have also determined that 4-[ 18 F]-ADAM/micro-PET can be used to detect serotonergic neuron loss, monitor the progress of Parkinson's disease, and oversee the effectiveness of therapy.

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(131)I therapy insignificantly increased the risk of salivary gland dysfunction and second primary malignancy. In patients with higher cumulative doses, an increase in the incidence of salivary gland dysfunction was observed. By contrast, we did not find an association between (131)I treatment and KCS development.

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Compound W, a 3,3=-diiodothyronine sulfate (T 2 S) cross-reactive material in maternal serum, was found to be useful as a marker for fetal hypothyroidism. In the present report, we explored its biochemical properties and studied its concentrations in cord and in maternal serum obtained from various gestational periods and at term from different continents. Mean W concentrations, expressed as nmol/L T 2 S-equivalent, in maternal serum during gestation showed a moderate increase at 20 -26 wk (1.57 nmol/L) and an accelerated increase to 34 -40 wk (3.59 nmol/L). The mean serum level was relatively low in nonpregnant women (0.17 nmol/L). Compound W levels in cord and maternal serum at term were not significantly different among samples obtained from Taiwan compared with samples from the United States. The mean cord serum "corrected" (by hot acid digestion) concentrations of W were significantly higher than maternal serum concentrations at birth and were also higher in venous than in paired arterial samples, suggesting that the placenta may play a role in its production. We compared a total of 45 iodothyronine analogs by antibody, gel filtration, and HPLC chromatographic studies and found only one compound, N,N-dimethyl- E mploying a sensitive RIA for T 2 S, we found high concentrations in fetal and pregnant serum in humans (1). We further identified that this T 2 S-cross-reactive material is not authentic T 2 S and does not co-chromatograph with synthetic T 2 S on HPLC. Thus, the name Compound W was coined to represent this material in fetal and maternal serum (1). Levels increased with the progression of pregnancy and rapidly peaked before parturition. At delivery, a 20-fold increase in "T 2 S" was found compared with nonpregnant women and returned to baseline within 7-10 d. Serial measurements of serum W in pregnant women have been found to be useful as a noninvasive technique for the diagnosis of fetal hypothyroidism (2,3).The present study was undertaken to determine the normal distribution of elevated Compound W levels in different stages of pregnancy as well as from various geographic areas and correlate between paired maternal and cord blood samples, and to explore its origin and chemical structure. MATERIALS AND METHODS T 2 S RIA. 3,3=-T 2 S and [125 I]T 2 S were prepared by the method of Eelkman-Rooda and co-workers (4,5). T 2 S was further purified and quantitatively recovered by reverse-phase HPLC with a preparative column, as described previously (1,2,4).The T 2 S RIA procedure was a modification of the RIA described previously (1,2). Serum samples (0.2-1.0 mL) were extracted with 2 vol 95% ethanol (final concentration, 63%) before assay. Preliminary experiments showed that the extraction efficiency of T 2 S in serum exceeded 96%. Final T 2 S concentrations were not corrected for recovery. The lower limit of detection of the assay was 3.3 fmol (2 pg), or 33.1 pmol/L in a 300 L ethanol extract of serum. Intra-assay variations were 1.9 -9.1% and interassay variations were 6.0 -19.5%, depending on ...

An increased risk of second primary malignancy after 131 I therapy has been reported. The objective of this study was to determine the risk of breast cancer in patients with thyroid cancer receiving or not receiving radioiodine treatment in Taiwan. Methods: This nationwide population-based cohort study was conducted using data obtained from the Taiwan National Health Insurance Database from 2000 to 2011. A total of 10,361 female patients with thyroid cancer (3,292 did not receive 131 I treatment and 7,069 received 131 I treatment) were enrolled, and 41,444 female controls were frequency-matched to the thyroid cancer patients in a 1:4 ratio by age (5-y age group). A Cox proportional hazards model was applied to estimate the risk of breast cancer in thyroid cancer patients receiving or not receiving 131 I treatment in terms of hazard ratios and 95% and 98% confidence intervals. Results: The incidence rates of breast cancer in patients with thyroid cancer receiving 131 I therapy, those not receiving 131 I therapy, and controls were 18.9, 17.7, and 13.1 per 10,000 person-years, respectively. Compared with patients with thyroid cancer treated with a cumulative 131 I dose of 4.44 GBq or less, the risk of breast cancer was not significantly increased in those treated with a cumulative 131 I dose of more than 4.44 GBq (adjusted hazard ratio, 0.78; 95% confidence interval, 0.50-1.21, P 5 0.26; 98% confidence interval, 0.45-1.33, P . 0.02). Conclusion: The greatest increased risk of breast cancer in patients with thyroid cancer is associated with the fact that the patient has thyroid cancer regardless of 131 I administration. However, 131 I further increased that risk but not as much as just having thyroid cancer.