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BackgroundThe association between dental status and mortality in community-dwelling older adults has been documented by several studies. The aim of this study was to analyze the contribution of self-assessed chewing ability, number of remaining teeth and serum albumin levels to mortality and the interactions between the three factors.MethodsA 20-year follow-up study was conducted with 666 subjects aged 80 years (from 1996 to 2017) who resided in the 8 areas served by one health center in Iwate Prefecture. Health check-ups including physical fitness measurements were conducted at a meeting place or gymnasium. Medical interview and blood sampling were conducted by physician. Oral examination was examined by dentist. The number of remaining teeth, serum albumin levels, and self-assessed chewing ability were used as predictors of mortality.ResultsAmong the 608 subjects (233 men and 375 women) included in this study, only 12 subjects (1.97%) survived after 20 years of follow-up. For men, dental status and serum levels of albumin were significantly associated with mortality. The hazard ratios of self-assessed chewing ability calculated by item response theory analysis and the inability to chew at least one food adjusted for serum albumin and tooth conditions were statistically significant in men. When adjusted by health status evaluated by blood tests, self-assessed chewing ability was statistically significant in men. According to path analysis, self-assessed chewing ability and serum albumin independently affected mortality in men.ConclusionMasticatory dysfunction may be an important risk factor for mortality in men, even though it was self-assessed. Retaining chewing ability might be a useful predictor of longevity in older male adults.

Telomerase activity (TA) and apoptosis were analysed in placenta with and without intrauterine growth retardation (IUGR). Thirty-one specimens were taken from chorionic villi in the first trimester (Group A), 32 placenta specimens were obtained from cases without IUGR in second and third trimester (Group B) and 12 specimens of placenta tissue were obtained from cases of asymmetric IUGR between 26 and 39 weeks of gestation (Group C). TA was analysed by the Telomeric Repeat Amplification Protocol (TRAP) and in situ TRAP assay. Apoptotic changes were assessed by immunohistochemical staining using Bcl-2 monoclonal antibody and by terminal transferase-mediated in situ end-labelling (TUNEL). TA was detected in 29 of the 31 (93.5 per cent) chorionic villi (Group A) and in 20 of the 32 (62.5 per cent) placenta without IUGR (Group B), whereas weak TA was observed in the placenta of all 12 asymmetric IUGR cases (Group C). Significantly higher Bcl-2 immunoreactivity was observed in trophoblastic cells of Group A (85.9+/-4.2 per cent) and Group B (72.8+/-7.2 per cent) than Group C (54.84+/-4.83 per cent), while TUNEL positive cells were identified at a significantly higher frequency in the trophoblastic cells of Group C (9.7+/-7.4 per cent) than Group A (1.1+/-1.9 per cent) or Group B (2.9+/-3.7 per cent).

Telomerase activity (TA) was analysed in human chorionic villi and placenta in normal and abnormal pregnancy using the telomeric repeat amplification protocol (TRAP) and in situ TRAP assay. Twenty chorionic villi specimens and 25 placenta specimens from normal pregnancies were examined as well as placenta specimens from 10 cases of intrauterine growth retardation (IUGR; nine asymmetric and one symmetric). TA was detected in 18 of the 20 (90 per cent) chorionic villi specimens and in 18 of the 25 (72 per cent) placenta specimens from normal pregnancy. However, no or only weak TA was exhibited in the placenta specimens of the nine asymmetric IUGR cases. In situ TRAP assay detected TA in trophoblastic cells from normal pregnancy, but not in trophoblastic cells from cases of asymmetric IUGR.

Our previous study demonstrated that the serum IL-6 correlated inversely with serum T3 and the T3/T4 ratio in children with acute respiratory infection during the acute phase of illness. To investigate whether serum IL-6 inversely correlates with serum thyroid hormone during not only the active stage of the disease but also in the follow-up period in nonthyroidal illness, we measured serum levels of IL-6, T3 and T4 in 31 children from the acute to the convalescent phase. They were divided into 3 groups; 7 patients with Kawasaki disease, 16 patients with infectious disease and 8 patients with non-inflammatory disease. In the follow-up of patients with Kawasaki disease, a marked inverse relationship was observed between serum IL-6 and T3 (r = -0.844, P < 0.001) or the T3/T4 ratio (r = -0.863, P < 0.001). Serum T4 showed a weak but significant negative correlation with serum IL-6 (r = -0.474, P = 0.035) only in this situation. There was also a significant negative correlation between serum IL-6 and T3 (r = -0.582, P < 0.001) or the T3/T4 ratio (r = -0.660, P < 0.001) during the follow-up of children with infectious disease. In the follow-up study of patients with non-inflammatory disease, however, no significant relationships were observed between serum thyroid hormones and IL-6. IL-6 may be one important factor involved in the decrease in the serum T3 level and the T3/T4 ratio in patients with nonthyroidal illness particularly characterized by strong inflammation and activation of the immune system as observed in Kawasaki and infectious disease.

Using a functioning rat thyroid cell line (FRTL-5), we studied the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) on thyroidal type I iodothyronine 5'-deiodination (I-5'-deiodination) and on the expression of I-5'-deiodinase (I-5'-D) mRNA. After 24 h incubation in medium containing 0.5 microM rT3 with a tracer amount of [125I]rT3, radioactivity of released 125I- was counted. Deiodination in live FRTL-5 cells was enhanced about three times from the basal level by the addition of TSH and was inhibited markedly by propylthiouracil and dose dependently by T4. These results suggest the suitability of this model for investigating I-5'-deiodination in live thyroid tissue. Basal and TSH-induced I-5'-deiodination were significantly inhibited by 100 ng/liter of IL-1 beta and IL-6, and the inhibitory effect of TNF-alpha was seen over 1 microgram/liter. I-5'-deiodination was restored by removal of the cytokines. TSH-induced cAMP production and (Bu)2cAMP-induced I-5'-deiodination were also inhibited by the cytokines. Catalase, dexamethasone, and indomethacin did not abolish the inhibitory effects of the cytokines. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a marked suppression of I-5'-D mRNA expression by IL-1 beta and IL-6. We conclude that these cytokines inhibit the thyroidal type I I-5'-deiodination in the order of potency IL-1 betaIL-6TNF-alpha, probably by decreasing the I-5'-D mRNA level.(ABSTRACT TRUNCATED AT 250 WORDS)

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85024290405&doi=10.1297%2fcpe.2.Supple2_79&partnerID=40&md5=12626aca76eb2a4e78f5240390705369, Insulin-like growth factor-II (IGF-II) and its specific receptor are present in the central nervous system (CNS) of experimental animal models, where this peptide has unique roles in neuronal growth and differentiation. IGF-II in the cerebrospinal fluid (CSF), as well as in plasma, is bound to specific binding protein (IGFBP). In this study we examined CSF IGF-II levels and IGFBP patterns in children with various physiological and pathological states. IGF-II, dissociated from IGFBP by acid gel chromatography, was measured by RIA, and IGFBP analyzed by western-ligand blotting. CSF IGF- II levels were 16.7±4.9 ng/ml in control subjects and there were no age-related variations. In some cases with CNS tumor, hydrocephalus and inflammatory conditions, their CSF IGF-II levels were increased. CSF IGFBP mainly consisted of 34kd, 31kd and 24kd protein. In contrast to serum IGFBP, CSF IGFBP patterns were almost unaffected by age, and were increased in some CNS inflammatoryconditions. Although the specific role of IGF-II in the human CNS remains to be defined, our results suggest that the regulatory mechanisms for the IGF-II /IGFBP system are present in the human CNS as well as in animal models.

Six hundred one patients with histologically proven "chronic thyroiditis" were assessed for the correlation of thyroid function to histologic findings. The histology of chronic thyroiditis was classified into four groups (oxyphilic, mixed, focal, and hyperplastic), and the thyroid function of patients was divided into hyperthyroid, euthyroid, latent hypothyroid, and overt hypothyroid, based on the laboratory data of serum triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) levels, as well as thyrotropin-releasing hormone (TRH) tests. In the oxyphilic group (137 cases), 116 (85%) of the patients were classified as hypothyroid: 52 (38%) as latent hypothyroid and 64 (47%) as overt hypothyroid. In the mixed group (161 cases), the thyroid function of the patients varied. Thirty-seven (23%) of the patients were classified as hyperthyroid, 61 (39%) as euthyroid, 54 (33%) as latent hypothyroid, and nine (5%) as overt hypothyroid. In this group thyroid function was intimately related to the ratio of replacement by hyperplastic-changed follicles and oxyphilic-changed follicles. In the focal group (149 cases), 123 (83%) of the patients were classified as euthyroid, while 22 (14%) were classified as latent hypothyroid. The frequency of latent hypothyroid patients increased in parallel with the severity of cell infiltration. In the hyperplastic group (154 cases), 130 (85%) of the patients were classified as hyperthyroid. In this series 19 patients under 10 years of age were included, and no difference in the distribution of histologic varieties was observed between juvenile and adult patients. Thyroid needle biopsy is a useful and safe tool, not only for the histologic diagnosis of chronic thyroiditis, but also for the evaluation of thyroid function and the identification of causes for hyperthyroidism or hypothyroidism.

To clarify whether serum free fatty acid (FFA) is an inhibitor of extrathyroidal conversion (IEC) of thyroxine (T4) to thyronine (T3), we measured the concentration of FFA, IEC activity and thyroid hormones in normal subjects, acute ketotic children and children with low T3 syndrome due to nonthyroidal illness (NTI). Iodothyronine (I) 5'-deiodinase activity was assayed with reverse triiodothyronine (rT3) as substrate and liberated 125I-was measured. The IEC was determined by the inhibition of I 5'-deiodination by ether extract of sera or standard oleate solution. IEC values were represented as mM oleate. The serum concentration of FFA was 0.470 +/- 0.117 (SD) mM in 11 normal subjects, and it was significantly higher (1.242 +/- 0.248 mM; P0.01) in 10 acute ketotic children and in 7 samples from 6 NTI children (0.904 +/- 0.530 mM; P0.05). In contrast, there was no difference in IEC among three groups (normal subject, 0.451 +/- 0.069 mM; acute ketosis, 0.437 +/- 0.040 mM; NTI, 0.465 +/- 0.224 mM). No correlations were found between IEC activity and the serum FFA concentration or thyroid hormones in 28 samples from three groups. The sequential changes in serum thyroid hormones, FFA and IEC in 3 of 6 NTI children revealed no consistent relationship. Furthermore, one NTI child had significantly high IEC (1.000 mM) but its serum FFA (1.182 mM) was below the mean value for the acute ketotic group. These results indicate that 1) many NTI patients may bear no relation to IEC and 2) IEC may not be caused by serum FFA only but includes several factors.

Background There have been no studies in which fasting serum ionic fluoride (SIF) concentrations in a general population were investigated despite the fact that SIF has various activities in humans. Methods A total of 332 healthy subjects (167 men and 165 women aged 40 to 69 years) were selected from residents of 2 towns in Iwate Prefecture, Japan using sex-specific and age-specific stratified random sampling methods. Overnight fasting blood samples were collected from all subjects. Serum levels of creatinine, bone alkaline phosphatase and urinary deoxypyridinoline levels were determined in one laboratory. SIF concentrations were measured using highly sensitive methods. Estimated glomerular filtration rate (eGFR) was calculated using serum creatinine level, age and sex. Results Mean SIF concentrations were 0.495 μmol/l in men and 0.457 μmol/l in women. SIF concentrations were independently related to eGFR in both sexes and to menopause status in women. SIF concentrations in women were significantly higher in the post-menopausal group than in the pre-menopausal group. Conclusion SIF concentrations in middle-aged healthy subjects were increased with an age-related degeneration in renal function. SIF concentrations in post-menopausal women arise from the increased fluoride release from bone after menopause. Age is not related to SIF concentrations.

The effects of fetal androgen excess or deficiency on postnatal behavior were examined in 7 males and 14 females with congenital adrenal hyperplasia or hypoplasia aged 3 to 21 years. The subjects were divided into 3 groups: those with androgen excess (A+) comprised a group of 13 patients with classical 21-hydroxylase deficiency and one with 11-beta-hydroxylase deficiency; a normal or reduced androgen (a+) group was represented by one patient with late-onset 21-hydroxylase deficiency and one with congenital adrenal hypoplasia; and a group with absent androgen (A-) consisted of 5 patients with a cholesterol side-chain cleaving-enzyme deficiency. Behavior was evaluated as male (M) or female (F) according to the pattern of play, classification of which was based on data of prevalent play in 1,275 preschool and 400 school boys and girls. Play prevalent in both sexes was classified as neutral (N). The mothers of the patients were requested to check the preferred play during childhood from a randomized play list. The androgen excess group showed M or bisexual (M/F) type, whereas all of the androgen deficient group revealed F type irrespective of gender. In preschool children, coincidence of M or F play type with genetic sex, social sex and androgen exposure was 38%, 53% and 90%, respectively, indicating androgen-dependency of playing patterns. This persisted into school age, although the coincidence rate was slightly changed by environmental effects. These results suggest that fetal androgen plays a role in the sexual differentiation of the central nervous system.

To evaluate the effect of human growth hormone (hGH) on the growth of children with achondroplasia, three patients with achondroplasia and one patient with hypochondroplasia were treated with 0.5 IU/kg/W of pituitary-extracted hGH for 6-12 months. Mean height velocity was significantly increased from 4.0 +/- 0.4 to 7.5 +/- 0.7 cm/year (P less than 0.05) by hGH. The tibial index, defined as the length/width ratio of left tibia, did not change during the treatment, indicating that hGH promotes growth without exaggeration of tubular bone deformity. Case 2, who had atlantoaxial dislocation, developed sleep apnea and neurological deficits during the second hGH treatment, but these were cured by operation. Thus, hGH therapy is effective in promoting growth in patients with achondroplasia, but the complication of atlantoaxial dislocation should be explored and corrected before the treatment.

We observed the sequential changes in serum thyroid hormones and thyroid-stimulating hormone receptor antibodies in an infant born at 30 weeks of gestation to a mother with florid Graves disease. Transient central hypothyroidism caused by pituitary suppression was observed after the resolution of peripheral thyrotoxicosis induced by thyroid-stimulating antibody. Central hypothyroidism became overt when the suppression of the pituitary gland after fetal thyrotoxicosis was combined with weak activity of thyroid-stimulating antibody after birth.

Objective: To analyze telomerase and proliferative activity in placenta from women with and without fetal growth restriction (FGR). Methods: Telomerase activity was analyzed in 30 first-trimester chorionic villi specimens (group A) and in 28 second- and third-trimester placenta specimens (group B) from women without FGR. Telomerase activity also was analyzed in 11 placenta specimens from women with asymmetric FGR (group C). The proliferative activity of these 69 specimens was assessed by immunohistochemical staining, using the MIB-1 monoclonal antibody. Results: Telomerase activity was detected in 28 (93.3%) of 30 chorionic villi specimens and in 18 (64.3%) of 28 placenta specimens without FGR. In contrast, no telomerase activity was exhibited in the placenta specimens from any of the 11 women with asymmetric FGR by telomeric repeat amplification protocol assay. Telomerase activity also was detected by in situ telomeric repeat amplification protocol assay in trophoblastic cells from women without FGR but not in trophoblastic cells from women with asymmetric FGR. Thus, telomerase activity was detected significantly more often in groups A and B than in group C (P < .01). The rate of proliferative activity, evident as positive MIB-1 staining in trophoblastic cells, in groups A and B (28.1 ± 1.7% and 7.0 ± 2.9%, respectively) was significantly higher than that in group C (1.9 ± 0.6%; P < .01). Conclusion: Telomerase and proliferative activity were minimal in placenta from women with asymmetrical FGR, suggesting placental senescence with asymmetrical FGR.

We examined serum-free carnitine (SFC) concentrations and serum acylcarnitine (SAC)/SFC ratios in 40 severely handicapped patients, aged 2 to 36 years, and 69 age-matched control subjects. SFC levels in the patients treated with valproic acid (VPA) and/or receiving carnitine-deficient elemental diets (ED) were significantly lower, and their SAC/SFC ratios were significantly higher than in the other patients or in control subjects. There were 6 patients whose SFC levels were less than the -2SD level (15.8 +/- 6.7 microM, range 6.3-25.5) of those in control subjects (52.1 +/- 11.5 microM). They had no clinical symptoms of carnitine deficiency such as non-ketotic hypoglycemia, hepatomegaly, muscle weakness or cardiac function impairment, and showed normal transaminase, lipid and ammonia levels. In two cases (SFC = 11.0, 13.4 microM), the ketogenic responses to intravenous administration of fat-emulsion were impaired, but they were restored after D-,L-carnitine supplementation (30 mg/kg/day, po) for 1 month. However, in one case with the lowest SFC level (6.3 microM), the ketogenic responses to fat-emulsion infusion or fasting were normal, and dicarboxylic aciduria was not detected. These results indicate that 1) SFC levels are reduced in handicapped patients receiving VPA and/or ED, although clinical symptoms of carnitine deficiency do not easily develop, 2) some of these hypocarnitinemic cases show a subclinical impairment of hepatic fatty acid metabolism, not always correlated with the degree of SFC reduction, which can be restored by exogenous carnitine supplements, and therefore 3) in patients with acquired hypocarnitinemia, carnitine therapy should be considered, although a low SFC level alone may not imply an immediate indication.

A girl aged 4 years with goiter and accelerated physical and skeletal growth was found to be hyperthyroid on the basis of elevated serum thyroid hormone level, nevertheless both the basal TSH and TSH responsiveness to TRH were maintained within the normal range. Serum TSH was suppressed by exogenous T3 and dexamethasone administration, but not significantly changed after propylthiouracil (PTU) treatment. The diurnal rhythmicity of anterior pituitary hormones was preserved with the high nocturnal peak of TSH and prolactin. Clinically, neither thyrotoxic signs nor evidences of pituitary tumor were observed. Her accelerated growth and elevated thyroid hormone level appeared to be induced by inappropriate secretion of TSH. In view of the literature, this is the first case of the syndrome of inappropriate secretion of TSH excluding the neoplastic origin in Japan.

We describe a 12-year-old boy with acquired von Willebrand's syndrome, who also had various autoantibodies. He presented with recent hemorrhagic symptoms and a prolonged bleeding time. Hemostatic studies revealed severely reduced levels of factor VIII procoagulant activity (VIII:C), von Willebrand's factor (vWF) antigen (vWF:Ag), and ristocetin cofactor activity (RCoF). An inhibitor that could be detected in the patient's plasma moderately decreased the levels of vWF:Ag in normal plasma, but did not interfere with the measurement of VIII:C or RCoF. Following the infusion of cryoprecipitate, half-lives of VIII:C, vWF:Ag, and RCoF were markedly reduced. 1-Deamino-8-D-arginine vasopressin infusion induced normalization of the prolonged bleeding time and caused a marked increase in VIII:C, vWF:Ag, and RCoF. Prior to treatment, there was a uniform reduction of all the multimers of plasma vWF in sodium dodecyl sulfate agarose gel electrophoresis. Following prednisone therapy, clinical and hemostatic findings were improved, and the multimeric patterns of vWF were normalized. These findings suggest that the low levels of all three parameters of factor VIII and all the multimers of plasma vWF in the patient are caused by rapid elimination of factor VIII complex from the circulation.

To investigate the regulatory role of head activator (HA) and its synthetic analogue, (Arg1,Phe5)-HA(AHA) on brain cell growth, we measured serial uptakes of [3H]thymidine, [3H]uridine and [3H]leucine and changes in cyclic AMP content in cultured chick embryo brain cells. HA stimulated all of these uptakes at a concentration of 10−10m, while 10−9m AHA suppressed them. The stimulatory effect of HA on [3H]thymidine uptake was observed after 4 h of the treatment, reached a maximum of 200% of the initial value at 8 h and declined to the pre-treatment level at 14 h. [3H]uridine uptake began to increase after 6 h of HA treatment, and the effect lasted for 4 h. Increase in [3H]leucine followed after 12 h and sustained for 4 h. Prior to the initiation of HA stimulation, cyclic AMP also began to rise, reaching 170% of the pre-treatment level at 6 h. In contrast, depression of [3H]thymidine uptake by AHA was noted at 6 h and continued for 8 h. Uptake of [3H]uridine and [3H]leucine showed similar tendency. Cyclic AMP in AHA-treated cells at 6 h was significantly lower than that in non-treated cells. These results indicate that HA stimulates DNA, RNA and protein synthesis in an early stage of growing brain cells, in which cAMP may be involved as a regulator of nerve cell growth.

The effect of therapeutic doses of theophylline on the pituitary-thyroid axis was studied in four normal adults and in 15 asthmatic children on theophylline treatment. In the four normal adults, sustained-release theophylline was administered every 12 hr for 60 hr, and serial determinations of serum theophylline, thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3), thyrotropin (TSH), and cyclic AMP (cAMP) were done. In all four cases, serum T4 increased significantly (134% +/- 4% vs basal level) with significant correlation to plasma cAMP level (r = 0.67, p less than 0.05). Changes in T3 and rT3 showed a marked individuality; an increase in T3 occurred in a subject with severe side effects, while the increase in rT3 was observed in a subject with mild side effects. Of the 15 children on theophylline treatment, a higher T4 level was found in 12 and a lower T3 level in nine at 1 wk, but these values returned to the previous level after 4 wk. These results indicate that the therapeutic doses of theophylline significantly but transiently increased the serum T4 level. In most cases, T4 is metabolized to rT3, an inactive metabolite of T4, but in a few cases it is metabolized to T3, which might double the side effects of theophylline.

Alterations in catecholamine (CA) and thyroid hormone metabolism were examined in a 12-year-old girl with anorexia nervosa during 3 months of treatment. According to her body weight change, the observation period was divided into 3 stages: initial emaciation (stage 1), stable maintenance of the -30% level of the previous weight (stage 2) and convalescent stage (stage 3). Stage 1 was characterized by relatively high urinary norepinephrine (NE) and epinephrine (E) but low dopamine (DA) excretion, elevated plasma DA-beta-hydroxylase (DBH) activity and reduced serum thyroid hormones, especially the triiodothyronine (T3) level. In stage 2, urinary CAs were markedly suppressed, while serum thyroid hormones gradually increase. In stage 3, a great increase in DA excretion, a fall in plasma DBH activity and normalization of thyroid hormones were observed. In the low T3 state below 60 ng/dl, urinary NE + E/DA ratios were elevated and widely fluctuated (0.58 +/- 0.30, SD), but were gradually decreased and completely stabilized in the normal T3 state (0.07 +/- 0.02, P less than 0.001). These results indicate that (1) although total CA production was depressed in anorexia nervosa, a change from an adrenergic-dominant to a dopaminergic-dominant state occurs in accordance with body weight gain, and (2) this shift in the CA profile is associated with concomitant recovery of reduced thyroid hormone concentrations. Thus, as for the energy expenditure, compensatory changes were observed in CAs and thyroid hormones in relation to caloric restriction.

Thyroxine (T4), triiodothyronine (T3) and reverse triodothyronine (rT3) concentrations in human milk were measured by radioimmunoassay in 114 samples obtained from 1 week to 8 months postpartum. Several assay systems applied for the determination of serum thyroid hormone concentration were proved to be unsuitable for human milk, and the method of separating free and antibody-bound hormone by polyethylene glycol was also inappropriate for milk specimens, which tended to give a falsely high value. The binding of finity of T4 to milk was lower than that to serum protein, on which 8-anilino-1-naphthalene sulfonic acid showed no remarkable effect. In spite of the high sensitivity of 100 pg/tub in T4 assay system, no immunoassayable T4 was detected in all samples with or without ethanol extraction and trypsin hydrolysates of milk. In contrast, T3 was present in a measurable amount in most of the samples, the mean +/- SD value of which was 10 +/- 9 ng/100 ml, and those in colostrum were significantly higher than those in matured milk (P less than 0.01), whereas rT3 was not detectable in 76 samples tested. These results indicate that permeability of thyroid hormones through the mammary gland is different between T4 and T3 as well as in placental transport, and human milk can not be a source of thyroxine supply for the breast-fed infant.

The effects of thyrotropin-releasing hormone (TRH) and its putative metabolite, cyclo-histidine-proline (cHP), on the homeothermic development of neonatal rats were studied. The daily intrathecal administration of 10−11–10−9 moles of TRH during the second week of age produced a significant rise in body temperature by 3 weeks of age and was followed by a transient period of hypothermia. This effect, which could not be produced by an intraperitoneal injection of 10−7 moles of TRH, was abolished by the simultaneous administration of 6-hydroxydopamine (6OHD). In contrast, intrathecally administered cHP decreased thermogenesis. During TRH treatment, brain norepinephrine (NE) and dopamine (DA) release was accelerated 2- to 4-fold. Two weeks after either TRH or cHP treatment, brain NE and DA were significantly reduced; adrenal NE in cHP-treated rats increased. The weight of the interscapular brown adipose tissue (BAT) was decreased by both cHP and 6OHD. At 3 weeks of age, [3H]guanosine diphosphate binding capacity in BAT mitochondria was reduced by 60% in TRH-treated rats and was associated with reduced mitochondrial levels of α-glycerophosphate dehydrogenase and liver cytochrome C reductase. These results indicate that 1) TRH stimulates central NE release thereby enhancing thermogenesis, 2) cHP decreases heat production, and 3) TRH-induced hyperthermia is associated with changes in mitochondrial exothermic processes. The central TRH-cHP system may modulate the maturation of homeothermic mechanism in neonatal rats.

Effects of the inhibition of maternal phenylalanine (Phe) or tyrosine (Tyr) hydroxylase on the postnatal maturation of catecholamine, thyroxine and amino acid metabolisms were examined in young rats. The intraperitoneal injections of 100 mg/kg p-chlorophenylalanine three times during the second gestational week together with 0.2% Phe solution as drinking water produced marked reduction in birth weight, body weight gain, brain weight, cerebral Tyr hydroxylase activity, adrenal epinephrine, renal norepinephrine and free amino acids in plasma and brain as well as delayed maturation of thermoregulation in the offspring. In contrast, the administration of 100 mg/kg α-methyl-p-tyrosine with 0.2% Tyr supplementation did not affect general growth, but only decreased cerebral Tyr hydroxylase and serum thyroxine level, while cerebral dopamine was increased. These results indicate that maternal Phe hydroxylase inhibition induces more severe growth failure including catecholamine and amino acid metabolism than Try hydroxylase inhibition in postnatal development.

We describe the fatty acid (FA) and prostaglandin (PG) metabolism in two Japanese cases of cystic fibrosis (CF) with or without pancreatic insufficiency (PI). The diagnosis of CF was based on the elevated sweat chloride concentration by pilocarpine iontophoresis. A 1-month-old boy (case 1) showed poor weight gain, steatorrhea and scaly dermatitis, but no respiratory symptoms were noted. He had decreased levels of serum linoleate and arachidonate, and increased palmitoleate and oleate levels, indicating essential fatty acid (EFA) deficiency. Supplementation of fat-emulsion improved his skin lesions and the altered FA pattern within a few months, associated with the definite reduction of the urinary PG F2 alpha levels. Until two years of age, he has been free from respiratory symptoms. A 12-year-old girl (case 2) had had recurrent respiratory tract infections due to Pseudomonas aeruginosa and Staphylococcus aureus for several years, and her pancreatic functions were preserved. The FA patterns of her serum lipid were almost within the normal range. These results indicate that 1) the altered FA composition appeared to be a secondary consequence of PI commonly complicating CF and 2) the correction of the altered FA and PG metabolism might have a beneficial effect on the respiratory function of CF patients with EFA deficiency.

The effects of TRH and its metabolite, histidyl-proline diketopiperazine (cyclo(His-Pro] on catecholamine metabolism in the central nervous system, peripheral tissues and plasma were examined in adult and young Wistar rats aged 3 weeks. The intravenous administration of 50 micrograms of TRH produced an increase in plasma epinephrine, cerebral dopamine and a reciprocal decrease in norepinephrine and dopamine in diencephalon and midbrain. In contrast, 50 micrograms of cyclo(His-Pro) induced a rise in plasma dopamine and a decrease of dopamine in cerebellum, pons and medulla oblongata. After intraperitoneal injection of 3 mg of alpha-methyl-p-tyrosine, which blocked re-uptake of catecholamines in synapses, intrathecal administration of 30 ng TRH accelerated 2 times metabolic turnover of norepinephrine and dopamine in cerebral hemisphere, diencephalon and midbrain as well as norepinephrine turnover in cerebellum, pons, medulla oblongata, heart and brown adipose tissue. Consecutive intrathecal administration of TRH for 6 days enhanced cerebral catecholamine content. These results indicate that (1) TRH accelerates metabolic rate of catecholamine in the central nervous system as well as peripheral tissues, and (2) TRH acts on both noradrenergic and dopaminergic neurons in cerebral hemisphere, diencephalon and midbrain, whereas cyclo(His-Pro) acts mainly on dopaminergic neurons in cerebellum, pons and medulla oblongata.

Unique association of hypothyrotropinemia with euthyroidism was described in 2 children of short stature. Both had a history of intrauterine growth retardation (IUGR), but showed an appropriate growth rate after infancy (5 cm/y). Growth hormone secretion after provocation tests was normal, whereas TSH response to TRH was absent. With a highly sensitive TSH radioimmunoassay (RIA) and a specific RIA for TSH-alpha-subunit, both responded to a high dose of TRH stimulation. Serum thyroid hormones were within the normal range, while prolactin response to TRH was exaggerated. Exogenous thyroxine (T4) supplement in case 1 did not improve his growth rate, indicating absence of hypothyroidism. Case 2 was treated with stanozolol, which accelerated his growth velocity to 8 cm/y. During the treatment, serum T4 gradually decreased to 50% of the initial level, but blunted TSH response to TRH remained unchanged. These results indicate that their thyrotrophs are resistant to TRH stimulation and the pituitary setpoint of TSH release is unusually high. The exact mechanism involved in maintaining euthyroidism despite hypothyrotropinemia remains to be elucidated, but a common history of IUGR appears to play a role in producing this pituitary-thyroid state.

An epidemiological survey on the incidence of juvenile chronic lymphocytic thyroiditis was performed in 10,220 apparently healthy school children in Ishikawa district, Japan. The subject of present study included 6,244 school children (2,831 boys and 3,413 girls, ages 6-18 yrs.) in Kanazawa City and 3,976 children (2,055 boys and 1,921 girls, ages 6-18 yrs.) in Wajima City. The first group was selected as a representative of urban area and the second group as that of seaside area. Children who have goiter or firm thyroid were selected for testing antithyroglobulin and anti-microsomal antibodies in sera. Final diagnosis of chronic lymphocytic thyroiditis was made on histological specimen obtained by needle biopsy on the antibody positive subjects. The overall incidence of chronic lymphocytic thyroiditis in these children was 3.0 per 1,000, whereas the incidence in adolescent girls was as high as 8.2 per 1,000. There was a considerable sex difference in the prevalence, the ratio of female to male was 6.5:1, and the incidence increased with age. The incidence in seaside area was 5.3 per 1,000 that was significantly higher than in urban area, 1.4 per 1,000 (p less than 0.005). Histologically, 26 of 30 cases (87%) were classified as focal thyroiditis and 4 cases (13%) were diffuse thyroiditis. Serum T4-I and T3 values within normal range in all patients, but resting TSH was elevated in 1 of 23 cases and TSH response to TRH was exaggerated in 3 of 23 cases. Impaired organification of iodide was observed in 6 of 32 cases by iodide-perchlorate discharge test. The present study demonstrates that juvenile chronic lymphocytic thyroiditis is highly prevalent among apparently healthy school children and early recognition of the disease with preventive care for hypothyroidism in future should be stressed.

To elucidate the mechanism by which TRH and its metabolite, histidyl-proline diketopiperazine (cyclo(His-Pro)), act on the maturation of homoiothermy, the chronic effects of intrathecal administration of the peptides on body temperature, serum thyroid hormone levels, and mitochondrial energy-producing enzyme activities were examined in neonatal rats. The two peptides or an equimolar mixture of both were injected intrathecally at a dose of 3, 6 and 9 nmol for 7 consecutive days during the 1st, 2nd or 3rd week of life, respectively. Control rats were treated with saline and they were sacrificed at 6 weeks of age. Although food and water intake were not decreased, body weight gain was slightly reduced in the rats treated with TRH or cyclo(His-Pro) during the 1st and 2nd week of life, whereas the mixturetreated rats showed normal weight gain. Body temperature at 25°C was not different in the TRH- and cyclo(HisPro)-treated groups, whereas after cold exposure (5°C for 3 h), the groups treated with TRH during the 1st and 2nd week of life had an impaired thermoregulation at 5 weeks of age. Serum T4 and T3 concentrations were similar in all groups, except in the rats treated with TRH during the 2nd week of life; their thyroid hormone levels were slightly reduced. The TRH treatment suppressed mitochondrial cytochrome c reductase and glucose-6-phosphatase activities, whereas cyclo(His-Pro) reduced cytochrome c reductase and malic enzyme activities. In contrast, α-glycerophosphate dehydrogenase was enhanced by both treatments. These results suggest that TRH and cyclo(His-Pro) modulate the central thermoregulatory mechanism and produce particular changes in the mitochondrial respiratory chains in peripheral thermogenic tissues.

To elucidate catecholamine (CA) secretory dynamics in neuroblastoma, urinary excretion of CAs and their metabolites was serially measured in 6 patients aged 3 months to 3 years before and during treatment. After tumor extirpation, increased urinary CAs were promptly normalized; the reduction reflected the amount of CA production from the tumor. Urinary dopamine (DA) showed the most prominent reduction, whereas DA content in the tumor was very small, indicating that the DA produced was immediately released from the tumor and metabolized in extra-tumor tissues. In contrast, patients receiving chemotherapy continued to excrete excess DA and homovanillic acid (HVA), which were increased further at recidivation. One patient showed an inverse correlation between DA and norepinephrine (NE) excretion; a decrease in DA was associated with an increase in NE and plasma DA-beta-hydroxylase (DBH) activity. A similar inverse correlation was also noted between NE and vanillylmandelic acid (VMA) or 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, while HVA and dihydroxyphenylacetic acid (DOPAC) were positively correlated with DA excretion. Urinary HVA and VMA were lineally correlated but in a patient excreting an enormous amount of DA, urinary VMA was markedly suppressed in terms of HVA excretion. Excessive DA induced an increase in renal water output but did not enhance Na and K excretion. These results indicate that endogenous DA overload in neuroblastoma inhibits NE production by suppressing DBH activity as well as by forming VMA and MHPG. This precursor regulation appears to be the characteristic of the CA metabolic pathway.

The present study was designed to investigate the relation between endogenous dopamine and natriuresis during the early postnatal days in term infants. Urinary dopamine levels were measured by high-performance liquid chromatography in the initial urines of 61 full-term male infants and in serial collected urines at 3-hour intervals during the first three days in five full-term male. infants. Dopamine excretion rate (ng/mgCr or ng/hr) correlated significantly with sodium excretion rate in both the initial urines (mEq/mgCr) and serial collected urines (mEq/hr). In the initial urines, dopamine excretion rate (ng/mgCr) did not correlate with aldosterone excretion rate (ng/mgCr), which showed an inverse relation with sodium excretion rate (mEq/mgCr), but with cyclic AMP values (nmol/mgCr). In addition, dopamine excretion rate (ng/hr) significantly correlated with cyclic AMP excretion rate (nmol/hr) in one infant. Although the significance of the direct relation between urinary dopamine and sodium output needs to be further investigated, it is possible that endo-genously produced dopamine may play a role in natriuresis, via the cyclic AMP producing system, during the early neonatal period.