OBJECTIVE

Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3.

METHODS

Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 μg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration.

RESULTS

At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported.

CONCLUSIONS

(1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

OBJECTIVE

We and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (L-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established.

METHODS

We retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental L-T4 (+L-T4) group (n=103); the HT+L-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels.

RESULTS

The TT+L-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+L-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls.

CONCLUSIONS

The presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels.

The involvement of FSH and triiodothyronine (T(3)) in circadian clocks was investigated using immature granulosa cells of ovaries during the progress of cell maturation. Granulosa cells were prepared from preantral follicles of mouse Period2 (Per2)-dLuc reporter gene transgenic rats injected subcutaneously with the synthetic nonsteroidal estrogen diethylstilbestrol. Analysis of the cellular clock of the immature granulosa cells was performed partly using a serum-free culture system. Several bioluminescence oscillations of Per2-dLuc promoter activity were generated in the presence of FSH + fetal bovine serum, but not in the presence of either FSH or serum. As revealed by bioluminescence recording and analysis of clock gene expression, the granulosa cells lack the functional cellular clock at the immature stage, although Lhr was greatly expressed during the period of cell maturation. The granulosa cells gained a strong circadian rhythm of bioluminescence during stimulation with FSH, whereas LH reset the cellular clock of matured granulosa cells. During strong circadian rhythms of clock genes, the Star gene showed significant expression in matured granulosa cells. In contrast, T(3) showed an inhibitory effect on the development of the functional cellular clock during the period of cell maturation. These results indicate that FSH provides a cue for the development of the functional cellular clock of the immature granulosa cells, and T(3) blocks the development of the cellular clock.

Selenium (Se) influences the metabolism of thyroid hormones in mammals. However, the role of Se deficiency in the regulation of thyroid hormones in chickens is not well known. In the present study, we examined the levels of thyroidal triiodothyronine (T3), thyroidal thyroxine (T4), free triiodothyronine, free thyroxine (FT4), and thyroid-stimulating hormone in the serum and the mRNA expression levels of 25 selenoproteins in chicken thyroids. Then, principal component analysis (PCA) was performed to analyze the relationships between the selenoproteins. The results indicated that Se deficiency influenced the conversion of T4 to T3 and induced the accumulation of T4 and FT4. In addition, the mRNA expression levels of the selenoproteins were generally decreased by Se deficiency. The PCA showed that eight selenoproteins (deiodinase 1 (Dio1), Dio2, Dio3, thioredoxin reductase 2 (Txnrd2), selenoprotein i (Seli), selenoprotein u (Selu), glutathione peroxidase 1 (Gpx1), and Gpx2) have similar trends, which indicated that they may play similar roles in the metabolism of thyroid hormones. The results showed that Se deficiency inhibited the conversion of T4 to T3 and decreased the levels of the crucial metabolic enzymes of the thyroid hormones, Dio1, Dio2, and Dio3, in chickens. In addition, the decreased selenoproteins (Dio1, Dio2, Dio3, Txnrd2, Seli, Selu, Gpx1, and Gpx2) induced by Se deficiency may indirectly limit the conversion of T4 to T3 in chicken thyroids. The information presented in this study is helpful to understand the role of Se in the thyroid function of chickens.

One member in each of 15 parabiosed pairs of rats was fed twice its normal food intake as four tube-fed meals per day. Seven other pairs ate ad libitum. Partners of overfed rats ate approximately 90% of the intake of individual members of ad libitum pairs. After 46 days of overfeeding, blood samples were taken and the rats were killed for carcass analysis. Tube-fed parabiotic rats had gained a considerable amount of fat and some protein. Their partners had a normal lean body mass but very little fat. Serum corticosterone, reverse triiodothyronine, free fatty acids, and beta-hydroxybutyrate were the same in all parabionts. Serum triiodothyronine and insulin were increased and growth hormone was decreased in obese rats. Serum thyroxine and triiodothyronine were increased and glucose was decreased in their parabiotic partners. The results are discussed as evidence for a humoral factor that crossed the parabiotic union and acted as a "lipid-depleting" agent in the partners of overfed rats.

We describe for the first time the successful organ culture, in a serum-free chemically defined medium, of hind limb buds from stage 54/55 Xenopus laevis tadpoles in which 2 x 10(-9) M triiodothyronine (T3) precociously induces morphogenesis to give rise to morphologically normal limbs within 7 days. It was important to retain the mesenchymal tissue joining the two limb buds in order to obtain limb development in culture. T3 added to tail explants from the same larvae, cultured in parallel with limb buds, induced regression and cell loss at rates comparable to those seen during T3-induced metamorphosis in intact tadpoles. We also demonstrate for the first time that 0.2 units of prolactin (PRL) added at the same time as 2 x 10(-9) M T3 totally blocked both limb development and tail regression over 8 days in culture. When added after T3 had initiated its metamorphic action. PRL arrested further morphogenesis and regression of these two tissues, respectively. Retinoic acid at 10(-7) M had only a marginal effect. Histological examination showed that T3 added to limb buds produced normal chondrogenesis and osteogenesis in vitro as well as skin, muscle, and digit formation, while it produced a rapid and marked histolysis of fin and connective tissue of the tail. The ease of hormonally manipulating both morphogenesis and cell death in culture in opposite directions offers a simple, effective model system for molecular analysis of mechanisms underlying hormone-regulated postembryonic developmental processes.

A double-stranded cDNA library constructed from the total poly(A+) RNA of goose uropygial gland was screened for recombinants containing sequences complementary to malic enzyme mRNA. Replicate arrays of 1400 colonies were hybridized independently with 32P-labeled cDNAs copied from two populations of hepatic RNA derived from tissues which differed by about 35-fold with respect to the relative synthesis of malic enzyme. Forty-eight of the colonies which gave differential signals were further screened by hybrid-selected translation. DNA from one of these contained an insert of 970 base pairs and selected an mRNA which directed the synthesis of malic enzyme in a cell-free system. The malic enzyme sequences were subcloned into the single-stranded bacteriophage M13mp8. The subclones were used to prepare 32P-labeled single-stranded hybridization probe. Northern analysis indicated that malic enzyme mRNA from both goose and chicken is about 2100 bases in length. Hepatic malic enzyme mRNA concentration is stimulated 30- to 50-fold or more when neonatal chicks or goslings, respectively, are fed for 24 h. When added to chick embryo hepatocytes in culture, triiodothyronine stimulated malic enzyme mRNA accumulation by more than 100-fold. Glucagon inhibited the thyroid hormone-stimulated accumulation of malic enzyme mRNA by 99%. In all instances, malic enzyme mRNA concentration was closely correlated with the relative rate of malic enzyme synthesis. These results suggest that nutritional and hormonal regulation of malic enzyme synthesis occurs at the pretranslational level.

The physiological consequences and mechanism(s) for thyroid hormone-induced alterations in serum leptin are not known. To address this, leptin expression in rats was evaluated in relationship to food intake, fat mass, and body temperature in rats with pharmacologically altered thyroid status. Total body weight, food intake, and temperature were decreased in hypothyroid rats. Fat weight was decreased in both chronically hypothyroid and hyperthyroid rats (n = 6/group). Serum leptin was linearly correlated with fat weight, epididymal and retroperitoneal fat leptin mRNA concentration, but not total body weight. Serum leptin was decreased in the chronically hyperthyroid rats. When fat weight was used as a covariant, serum leptin was not different between the three groups. Epididymal fat leptin mRNA was higher in euthyroid (n = 7) than in hypothyroid and hyperthyroid rats. Retroperitoneal fat leptin mRNA was not affected by thyroid status. A positive linear relationship between food intake and free triiodothyronine (FT3) index was observed, but not between food intake and serum leptin alone. In a time course study, serum leptin, epididymal fat leptin mRNA content, and fat weight did not change within 24 hours of high-dose triiodothyronine (T3) (n = 6/group), but both temperature and epididymal fat S14 mRNA content rapidly increased. These findings demonstrate that thyroid state influences circulating leptin levels, but primarily does so indirectly through the regulation of fat mass. Leptin does not influence core body temperature across thyroidal state. Finally, thyroid state is more important to regulate food intake, through an as yet undefined mechanism, than are thyroid state-associated changes in serum leptin.

Polychlorinated biphenyls (PCBs) are known to reduce serum thyroxine (T(4)) in rats, but the relative effects of individual PCB congeners on thyroid hormones are not known. Thus, male Sprague-Dawley rats were administered Aroclor 1254, Aroclor 1242 (4, 8, 16, or 32 mg/kg/day), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 99 (2,2',4,4',5-pentachlorobiphenyl), PCB 118 (2,3',4,4',5-pentachlorobiphenyl) (2, 4, 8, or 16 mg/kg/day), PCB 126 (3,3'4,4',5-pentachlorobiphenyl) (2.5, 5, 10, 20, or 40 microg/kg/day), TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) (0.14, 0.43, 1.3, or 3.9 microg/kg/day), or corn oil via oral gavage for 7 days. Rats were necropsied 24 h after the last dose. Serum thyroid hormone levels were evaluated by radioimmunoassay, and induction of hepatic Cyp1a (a TCDD-inducible protein) and Cyp2b (a phenobarbital [PB]-inducible protein) activity was determined by ethoxyresorufin-O-deethylase and pentoxyresorufin-O-deethylase assays, respectively. Significant increases in Cyp1a activity occurred in response to PCBs, except PCB 95 and PCB 99. Aroclor 1254, PCB 99, and PCB 118 significantly induced Cyp2b activity. Serum total T(4) and free T(4) were dramatically reduced in response to each of the seven treatments in a dose-dependent manner. The marked T(4) reductions occurred in response to Aroclor 1254, PCB 99 (a PB-type congener), and PCB 118 (a mixed-type congener). In contrast, reductions in serum triiodothyronine (total and free) were variable and mild, and serum thyroid-stimulating hormone was not significantly affected by any of the compounds. These data indicate that the PB and mixed-type PCB congeners are more effective than the TCDD-type PCB congeners at reducing serum T(4).

An extract of Citrus sinensis (CS) peel was evaluated for its efficacy in ameliorating L-thyroxine (L-T(4)) induced tissue lipid peroxidation (LPO), hyperthyroidism and hyperglycemia in mice. In a preliminary investigation, of the three different doses of CS (12.5 mg/kg, 25 mg/kg and 50.0 mg/kg) peel extract, 25 mg/kg was found to be the most effective and antiperoxidative, while 50 mg/kg was proved to be hepatotoxic. Therefore in the pilot experiment the effects of 25 mg/kg/day of CS for 10 days were studied in L-T(4) induced hyperthyroid animals. L-T(4) (500 microg/kg/day for 10 days) increased the levels of thyroxine (T(4)) and triiodothyronine (T(3)) with a concomitant increase in serum glucose concentration, alpha-amylase activity, heart/body weight ratio (HW/BW), kidney/body weight ratio (KW/BW) and cardiac as well as hepatic LPO. However, it decreased the concentration of different serum lipids such as total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C). Administration of CS extract (25 mg/kg/day) in hyperthyroid animals reversed most of these observations revealing the ameliorating potential of CS extract against various adverse effects of hyperthyroidism. It appears that the test extract primarily acts through its antioxidative/free radical-scavenging, antithyroidal and HDL-C stimulating properties.

BACKGROUND

The clinical value of free thyroxine (FT(4)) and free triiodothyronine (FT(3)) analysis depends on the reference intervals with which they are compared. We determined age- and sex-specific reference intervals for neonates, infants, and children 0-18 years of age for FT(4) and FT(3) using tandem mass spectrometry.

METHODS

Reference intervals were calculated for serum FT(4) (n = 1426) and FT(3) (n = 1107) obtained from healthy children between January 1, 2008, and June 30, 2008, from Children's National Medical Center and Georgetown University Medical Center Bioanalytical Core Laboratory, Washington, DC. Serum samples were analyzed using isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) with deuterium-labeled internal standards.

RESULTS

FT(4) reference intervals were very similar for males and females of all ages and ranged between 1.3 and 2.4 ng/dL for children 1 to 18 years old. FT(4) reference intervals for 1- to 12-month-old infants were 1.3-2.8 ng/dL. These 2.5 to 97.5 percentile intervals were much tighter than reference intervals obtained using immunoassay platforms 0.48-2.78 ng/dL for males and 0.85-2.09 ng/dL for females. Similarly, FT(3) intervals were consistent and similar for males and females and for all ages, ranging between 1.5 pg/mL and approximately 6.0 pg/mL for children 1 month of age to 18 years old.

CONCLUSIONS

This is the first study to provide pediatric reference intervals of FT(4) and FT(3) for children from birth to 18 years of age using LC/MS/MS. Analysis using LC/MS/MS provides more specific quantification of thyroid hormones. A comparison of the ultrafiltration tandem mass spectrometric method with equilibrium dialysis showed very good correlation.

BACKGROUND

Fetal alcohol exposure causes in the offspring a collection of permanent physiological and neuropsychological deficits collectively termed Fetal Alcohol Spectrum Disorder (FASD). The timing and amount of exposure cannot fully explain the substantial variability among affected individuals, pointing to genetic influences that mediate fetal vulnerability. However, the aspects of vulnerability that depend on the mother, the father, or both, are not known.

RESULTS

Using the outbred Sprague-Dawley (SD) and inbred Brown Norway (BN) rat strains as well as their reciprocal crosses, we administered ethanol (E), pair-fed (PF), or control (C) diets to the pregnant dams. The dams' plasma levels of free thyroxine (fT4), triiodothyronine (T3), free T3 (fT3), and thyroid stimulating hormone (TSH) were measured to elucidate potential differences in maternal thyroid hormonal environment, which affects specific aspects of FASD. We then compared alcohol-exposed, pair fed, and control offspring of each fetal strain on gestational day 21 (G21) to identify maternal and paternal genetic effects on bodyweight and placental weight of male and female fetuses.

CONCLUSIONS

SD and BN dams exhibited different baseline hypothalamic-pituitary-thyroid function. Moreover, the thyroid function of SD dams was more severely affected by alcohol consumption while that of BN dams was relatively resistant. This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to FASD. The fetal vulnerability to decreased bodyweight after alcohol exposure depended on the genetic contribution of both parents, not only maternal contribution as previously thought. In contrast, the effect of maternal alcohol consumption on placental weight was consistent and not strain-dependent. Interestingly, placental weight in fetuses with different paternal genetic contributions exhibited opposite responses to caloric restriction (pair feeding). In summary, these novel findings demonstrate both maternal and paternal genetic contributions to in utero vulnerability to alcohol, refining our understanding of the genetically-based heterogeneity seen in human FASD.

In an effort to assess the impact of moderate iodine deficiency on maternal thyroid function during pregnancy, we measured serum thyrotropin, total and free thyroid hormones, thyroid-binding globulin (TGB) at 8, 14, 20, 29, and 36 weeks of gestation, along with urinary iodide excretion, in 10 healthy women from a moderately iodine deficient region (group A), and compared them with 6 women from an iodine sufficient region (group B). Serum total thyroxine (T4) fell significantly in group A, and was significantly lower than in group B at 29 and 36 weeks (p<0.05). TBG saturation was significantly lower in group A throughout pregnancy, and declined in both groups as pregnancy progressed. Free thyroxine (T4) and triiodothyronine (T3) concentrations fell in both groups, and FT4 values were significantly lower in group A than group B in the third trimester (p<0.05). Urinary iodine excretion was lower in group A women with respect to group B and did not vary significantly in either group as gestation progressed. The serum T3/T4 molar ratio increased through pregnancy only in group B. Thyrotropin concentrations rose in both groups through pregnancy, and were higher in group A at term (p< 0.01). The incidence of isolated hypothyroxinemia or biochemical hypothyroidism doubled (30% to 70%) between midgestation and term in group A, suggesting that moderate iodine deficiency may result in maternal thyroid failure during the later stages of pregnancy.

To exploit the antiarrhythmic effect of amiodarone when patients develop the side effect of thyrotoxicosis three patients with hyperthyroidism induced by amiodarone were given simultaneously 1 g potassium perchlorate a day for 40 days and a starting dose of 40 mg methimazole a day while they continued to take amiodarone. As hyperthyroidism might have recurred after potassium perchlorate treatment was stopped the dose of methimazole was not reduced until biochemical hypothyroidism (raised thyroid stimulating hormone concentrations) was achieved. The patients became euthyroid (free triiodothyronine concentration returned to normal values) in two to five weeks and hypothyroid in 10 to 14 weeks. One patient became euthyroid while taking 5 mg methimazole a day and 600 mg amiodarone weekly; the two others required substitution treatment with thyroxine sodium while taking 5 mg methimazole or 50 mg propylthiouracil (because of an allergic reaction to methimazole) and 2100 or 1400 mg amiodarone weekly. Hyperthyroidism induced by amiodarone may be treated with potassium perchlorate and methimazole given simultaneously while treatment with amiodarone is continued.

Several in-vivo studies have shown a procoagulant state in both overt and subclinical hyperthyroidism and in subclinical hypothyroidism. Insofar, no clinical studies have ever evaluated the relationship between thyroid dysfunction and clinically deep venous thrombosis (DVT). A pilot cross-sectional study aimed at assessing the frequency of overt and subclinical thyroid dysfunction patients with DVT was carried out. Fifty consecutive adult outpatients with a previous diagnosis of provoked DVT (pDVT), and 50 consecutive adult outpatients with a previous diagnosis unprovoked DVT (unDVT), both of the lower legs, who were followed at the Thrombosis Unit of the University Hospital of Varese, Italy, were enrolled after written informed consent. Fifty subjects, in whom such a diagnosis could be ruled out, served as controls. In each patient serum free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH), anti-thyroid peroxidase (AbTPO), and anti-thyroglobulin (AbTg) antibodies were assayed. Previously unrecognised subclinical hypothyroidism was diagnosed in seven (14.0%) unDVT patients, one (2%) pDVT patient, and one (2%) control (odds ratio at multivariate analysis, 5.54; 95% confidence interval, 0.6-52.6); one new case of subclinical hyperthyroidism was diagnosed in each group; only one case (in the control group) of clinical overt hyperthyroidism was observed. The prevalence of thyroid autoantibodies, including both euthyroid and subclinical hypothyroid patients, did not differ in the three groups. The results of this pilot study suggest an increased prevalence of subclinical hypothyroidism in patients with unDVT. The clinical relevance of these preliminary findings needs to be addressed in larger prospective studies.

A serum-free hormone-supplemented medium able to support the growth of rodent adipose precursor cells has been used to characterize additional components from serum required for the differentiation of preadipose Ob17 cells into adipose-like cells. Fetuin is shown to behave as a growth-promoting agent for these cells. In addition to growth hormone, triiodothyronine and a low-molecular weight component(s) also purified from serum, fetuin is required for the full expression of the differentiation program. Other serum proteins as well as other mitogenic factors are unable to substitute for fetuin. A possible role of fetuin in the development of adipose tissue is discussed.

On the basis of low specificity, poor positive predictive value, and cost, there is at present no basis for routine assessment of thyroid function in acutely hospitalized patients, unless clinical features suggest the possibility of thyroid dysfunction, or a patient's background increases the likelihood of thyroid dysfunction. When used in severely ill patients, estimates of both thyroxine (T4) and thyrotropin (TSH) show a high prevalence of abnormal results, but lack specificity and have poor positive predictive value for true thyroid disease. When thyroid function is tested in the critically ill, the positive predictive value for true thyroid disease of both free T4 and TSH measurements could be improved by using wider reference intervals than for unselected populations. The knowledge of nonspecific disease-related abnormalities of triiodothyronine, T4, and TSH is not currently likely to yield useful prognostic information or to alter management for individual patients. Thyroid testing should be readily available for any acutely ill patient with any clinical features that suggest thyroid dysfunction, and for groups at increased risk of thyroid dysfunction. An initial abnormal result for either TSH or free T4 estimate should be followed by combined analysis of free T4 and TSH with the best available methodology. Diagnosis of thyroid dysfunction should be based on the T4-TSH relation rather than either value alone. Persistence of an apparent diagnostic abnormality should be confirmed before therapy is commenced.

For the purpose of investigating a possible correlation between the genesis of breast cancer and the levels of serum thyroid hormones or the estrogen status, which is one of the potential risk factors for breast cancer in Japanese women, we measured the percentage of free estradiol (E2) and the amounts of sex hormone-binding globulin (SHBG) and thyroid hormones in serum samples from Japanese patients with breast cancer (N = 39) and normal controls (N = 36). The patients were found to have significantly higher free E2 and significantly lower SHBG than controls. Moreover, the serum levels of free triiodothyronine (FT3) and free thyroxine (FT4) were lower in the patients than in controls, while the serum levels of TSH and TBG in the patients were not significantly different from those in controls. The percentage of free E2 in serum was not significantly correlated with the level of any one of FT3, FT4, TSH, and TBG either in the patients or in controls regardless of menstrual status. These results suggest the possibility that the reduction in the serum FT3 and FT4 levels, which is independent of changes in the serum level of free E2, may be one of the risk factors for breast cancer in Japanese women.

This study examines relationships between hormonal levels and novelty seeking in a group of 27 Vietnam veterans with combat-related posttraumatic stress disorder (PTSD). Novelty seeking in the veteran sample, measured by the Cloninger Tridimensional Personality Questionnaire (TPQ), was almost twice as high as previously published norms. A distinctive pattern of significant positive correlations was found between novelty seeking scores and serum total triiodothyronine (T3), free T3, the T3/free thyroxine (FT4) ratio, urinary norepinephrine and the norepinephrine/cortisol ratio, while a negative correlation was found between novelty seeking scores and urinary cortisol levels. The findings were confirmed by t test analyses of high vs low novelty seeking subgroups and do not appear to be related simply to the severity of PTSD. These preliminary findings indicate the need to include measures of characterological traits in psychoendocrine studies of PTSD and to investigate their possible usefulness in subtyping this disorder.

BACKGROUND

Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain.

OBJECTIVE

The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans.

METHODS

Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed.

RESULTS

RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly.

CONCLUSIONS

These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

A total of 14,740 schoolchildren in seven provinces of Shoa Administrative Region in Central Ethiopia were surveyed for the prevalence of goitre, xerophthalmia and anaemia. Haemoglobin and packed cell volume were assessed in 966 children in one province while an in-depth study was conducted on 344 children in the same province and two others. Goitre, xerophthalmia (Bitot's spots) and clinical anaemia were observed in 34.2, 0.91 and 18.6% respectively of the children. Most biochemical variables were within the normal range while those of haemoglobin (Hb), mean corpuscular Hb concentration (MCHC) and urinary I excretion were lower, and mean corpuscular volume, mean corpuscular Hb (MCH), and immunoglobulins G and M were higher. Hb was strongly correlated with retinol, ferritin, MCHC, MCH, packed cell volume and erythrocyte count while retinol formed a triad with transthyretin (TTR) and retinol-binding protein (RBP) which were all correlated with one another. Total and free thyroxin and total and free triiodothyronine were positively correlated as were the concentrations of the total and free hormones. Thyrotropin (TSH) was negatively correlated with total and free thyroxin and positively correlated with free triiodothyronine. Thyroxin and triiodothyronine in both free and combined forms were all correlated with thyroxin-binding globulin which in turn was negatively correlated with the triad retinol, RBP and TTR. The triad was also negatively correlated with C-reactive protein. Urinary I excretion was positively associated with total thyroxin and negatively associated with TSH. The anaemia found was not nutritional in origin but due to the effect of infestation with intestinal parasites and malaria.

In order to define humoral growth factors which may regulate mammalian renal development, the growth requirements of fetal metanephric organogenesis were studied in serum-free murine organ culture. Metanephric growth, determined by cell proliferation and protein content, and metanephric differentiation, determined morphometrically as epithelial glomerular formation, were compared and contrasted following 144 hours of organ culture incubation in basal medium, basal medium supplemented with 10% fetal bovine serum, and basal medium supplemented with various combinations of growth factors. The basal medium was composed of equal volumes of Dulbecco's modified Eagle's medium and Ham's F-12 medium. Five humoral growth factors were studied in the following concentrations: selenium, 6.8 X 10(-9) M; insulin, 8.3 X 10(-7) M; triiodothyronine, 2 X 10(-9) M; transferrin, 6.2 X 10(-8) M; and prostaglandin E1, 7.1 X 10(-8) M. Results showed that transferrin and prostaglandin E1 were necessary for optimal growth in the system and that prostaglandin E1 was necessary for maximal metanephric differentiation. Such data provide guidelines for the creation of serum-free medium for future fetal renal cell and tissue culture systems, and provide insight into the factors which may regulate normal and abnormal renal embryogenesis and the reparative processes of renal hyperplasia and hypertrophy which follow renal injury.

The acute effect of triiodothyronine (T3) on mobilization of fat and protein energy stores has been measured in five fasting, normal men. Fasting subjects were chosen for this study to amplify catabolic effects occurring during brief thyroid hormone treatment. Subjects were fasted for 72 hr on two occasions with admintration of T3, 150 mug every 12 hr, for 72 hr before and during the second fast. Plasma beta hydroxybutyrate, acetoacetate, and free fatty acid levels as well as ketone, creatine, and urea excretion were measured during control and T3 fasts. T3 enhances catabolism of protein stores as indicated by the doubling of urea excretion during the T3 fasts. Likewise, creatine excretion is increased six to ninefold during the T3 fasts. Catabolism of fat stores is enhanced during the T3 fasts as shown by increased plasma free fatty acid and ketone levels, and increased ketone excretion. Brief T3 treatment for 3 days augments the expected protein and fat catabolism of starvation without causing subjective changes of hyperthyroidism. Much of the catabolic expression of hyperthyroidism may simply reflect inadequate caloric intake to fuel energy requiring processes stimulated by thyroid hormone such as cell membrane sodium pumping and protein synthesis.

BACKGROUND

Abnormalities in cardiac function, eg, arrhythmias and congestive heart failure, often accompany thyrotoxicosis. A relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction (MI) remains largely speculative.

METHODS

The results of thyroid function studies on blood samples drawn from a total of 1049 patients (aged 40 years or older) immediately on emergency medical admission were related to frequencies of angina pectoris and myocardial infarction as determined according to current diagnostic algorithms. After 3 years, those patients who had initially presented with angina pectoris or acute MI were observed for subsequent coronary events; of these (n=185), 98% of the subjects (n=181) could be reevaluated.

RESULTS

On hospital admission, the relative rate of angina pectoris and MI was markedly high (odds ratio, 2.6; 95% confidence interval, 1.3-5.2; P=.007) in patients with elevated serum free and total triiodothyronine (T(3)) levels. An initially elevated free T(3) level was a risk factor for subsequent coronary events during the 3-year follow-up (adjusted odds ratio, 4.8; 95% confidence interval, 1.3-17.4; P=.02).

CONCLUSIONS

An elevation of serum free T(3) levels at hospital admission is associated with a 2.6-fold greater likelihood of the presence of a coronary event. Moreover, an initially elevated T(3) level is associated with a 3-fold higher risk of developing a subsequent coronary event during the next 3 years. Excess T(3) seemed to be a factor associated with the development and progression of acute myocardial ischemia.