Tamotu Sato

Periodic ACTH discharge

A 9 1/2-year-old girl is presented who had cyclical attacks of abdominal pain, vomiting, emotional disturbance, and marked weight change for two years. Associated findings were facial plethora, hypertension, transient hyperglycemia and glycosuria, elevated plasma ACTH, cortisol, and urinary 17-OHCS excretion, and low plasma osmolality with hyponatremia. Urinary excretion of catecholamines and porphyrin metabolites was not increased. Between episodes, she showed no abnormal clinical signs or laboratory data. The attacks were effectively suppressed with the administration of chlorpromazine. The disorder appears to be due to the periodic release of excessive ACTH; the cause remains unknown.

Bloom's syndrome in a Japanese girl

Clinical, cytogenetic, and immunological data of a 5‐year‐old Japanese girl with Blooms syndrome are described. Growth deficiency, photosensitivity, and a very mild facial telangiectatic erythema were present. Cytological studies revealed chromosomal aberrations and the characteristic high frequency in sister chromatid exchanges. Immunological studies showed that the serum levels of IgM and IgA, but not IgG, were abnormally low as compared to the agematched control values and that the generation of cytoplasmic immunoglobulin‐producing cells in the peripheral blood lymphocytes, which was evaluated in the in vitro pokeweed mitogen‐stimulated cultures, was markedly reduced.

Dopaminergic Instability in Children with Orthostatic Dysregulation

Effects of postural change on plasma catecholamine levels were examined in 53 children with orthostatic dysregulation (OD). Special interest was focused on plasma dopamine and dopamine‐β‐hydroxylase (DBH) activity, since one patient showed a prominent rise in plasma dopamine from 822 pmol/L to 126 nmol/L in postural change. She had a wide fluctuation of plasma dopamine from 209 pmol/L to 305 nmol/L during 12 hours of observation period, but plasma norepinephrine and epinephrine remained within the normal range as well as urinary excretion of catecholamines. Of 52 children with OD, 11 had a marked increase in plasma dopamine, whereas 11 showed a reduction of it by postural change. Plasma DBH activity was significantly decreased in the former (81±14 nmol/h/ml), while it was elevated in the latter (320±48 nmol/h/ml, P<0.001 vs the former), although DBH activity in individuals was not affected by postural change. These results indicate the involvement of dopaminergic instability as a cause of OD in childhood.

Correlation between pituitary growth hormone reserve and degree of growth failure in children with short stature

The correlation between a releasable pituitary growth hormone (GH) pool and degree of growth failure was examined in 30 children with GH deficiency (group I) and 19 children with normal short stature (group II). Based on the responsiveness of GH to GH-releasing hormone (GHRH), group I, with low GH responses (below 7 ng/ml) to both insulin and arginine, was classified into three subgroups; Ia (peak value less than 10 ng/ml, n=19), Ib (10–20 ng/ml, n=5) and Ic (above 20 ng/ml, n=6). Group II, with a GH response above 10 ng/ml to either insulin or arginine, was also divided into IIa (below 20 ng/ml, n=5) and IIb (above 20 ng/ml, n=14). Body length and growth velocity in Ia and Ib were significantly reduced vs Ic; bone age in Ia was retarded vs Ic; plasma somatomedin C (Sm-C) levels in Ia and Ib were decreased vs Ic, who had almost normal levels (0.90±0.55 U/ml). The incidence of other combined pituitary hormone deficiencies and previous perinatal distress was definitely high in Ia and Ib, but zero in Ic. In group II also, body length and growth velocity were significantly decreased in IIa vs IIb (P<0.01). These results indicate that [1] the pituitary reserve of GH estimated by GHRH is a good reflection of the degree of growth failure in GH-deficient children as well as in those of normal short stature, [2] hypothalamic GHRH deficiency tends to have a milder effect on growth retardation than pituitary GH deficiency, and [3] normal short children with a diminished GH reserve may be potential candidates for the GH treatment.

Maturational Changes in the Regulatory Mechanisms of Hepatic Thyroxine 5'-Monodeiodination in Growing Rats

Summary: Changes in the regulatory mechanisms of hepatic thyroxine (T4) 5′-monodeiodination during maturational process were studied in rats aged 1,3, and 6 wk and in adults. Despite low T4 5′-deiodinase activity in the neonates, a similar degree of activation in older rats was obtained with graded doses of dithiothreitol. Lineweaver-Burk plot analysis showed that Vmax increased 1–3 wk of age, decreasing with age thereafter, whereas a high Km value in young rats (7.0–7.8 × 10−4 M) fell to a level of 4.8 × 10−4 ? by 6 wk of age. T4 5′-deiodinase at 3 wk of age was relatively resistant to iodoacetamide, a SH blocking agent (11% inhibition at 10−6 M versus 47% in adult). Furthermore, it was markedly enhanced with 3 mM EDTA (125% versus 10–20% in older rats). Among various bivalent cations tested, Cu++ and Zn++ had a strong inhibitory effect on the reaction, whereas livers from 3-wk-old rats were less sensitive to Zn++ (7% inhibition at 10−6 M versus 40% in adult). Responses to graded doses of reduced glutatbione (GSH) or to its blocker, diamide, suggest that GSH exerts its promoting effect through preservation of protein SH radicals in reduced form. In contrast, NADPH stimulates the reaction directly, and a marked increase in the sensitivity to NADPH was observed 1–3 wk of age. Dose-response relation to methylene blue (MB), inhibitor of NADPH, exhibited a biphasic effect on the reaction: stimulatory at smaller dose and inhibitory at larger dose. The critical dose of MB producing this reversal shifted to a lower level with advancing age, which appears to be due to the content of endogenous NADPH as well as to the reactivity of the enzyme to it. These results indicate that (1) protein SH radicals appear to change from a relatively inactive to an active state with age, in which an interaction with Zn++ might be involved; (2) GSH is probably associated with the conversion of SH groups; (3) NADPH enhances directly the enzyme activity, playing a pivotal role in the regulation of the reaction; and (4) maturation of T4 5′-deiodination includes changes in the protein SH groups and GSH-NADPH generating system.

A syndrome of periodic ACTH and ADH discharge

A girl aged 8 yrs had suffered from periodic attacks of vomiting, psychotic depression and hypertension lasting for 5 to 6 days at monthly intervals since 16 months before admission. At the initiation of the attack, serum corticotropin (ACTH) and vaso-pressin (ADH) levels were prominently increased (610 pg/ml and 41 uU/ml respectively) despite normal plasma osmolality, which consequently produced hypertension (160/110 mmHg), hypercortisolemia and hyponatremia. Serum prolactin was also increased (91 ng/ml). During the attack, urinary excretion of epinephrine (E) and nor-epinephrine (NE) was elevated while that of dopamine (D) was reduced, resulting in marked rise in E+NE/D ratio (0.8 − 4.5), which decreased to normal level when symptoms disappeared (0.08 − 0.17). Provocation of the attack by hypertonic saline infusion or by metyrapone administration was not successful. Infusion of somatostatin at early stage of the attack suppressed the symptoms and chronic administration of methyl-DOPA with reserpine effectively inhibited the recurrence of the episodes. Her symptoms appear to be induced by periodic discharge of ACTH and ADH. Although the exact cause of this syndrome is unknown, disturbance in catechol-aminergic mechanism in hypothalamus is postulated.

67 The Role of Thyrotropin-releasing Hormone(TRH) and Histidyl-proline Diketopiperazine(HPD) in the Maturation of Thermogenesis in Growing Rats

Effects of TRH and its metabolite, histidyl-proline diketopi-perazine (HPD) on the maturation of thermogenesis were examined. Week old Wistar rats were administered 0.04, 0.4 or 4 nmoles of TRH or HPD intrathecally for 7 days. Half of the litters served as saline-treated controls. Body temperature upon cold exposure (5°C, 1-3 hrs) was measured weekly. On the 4th week of age, catecholamines in forebrain, midbrain, cerebellum, brain stem and adrenal glands were measured by HPLC with an EC detector. NADPH-dependent cytochrome C reductase(CCR) and ATPase activities were determined in liver mitochondria and microsomes. TRH showed a dose-dependent thermogenic effect while HPD potentiated hypothermia. This was associated with an elevated or reduced mitochondrial CCR activity in the TRH and HPD groups respectively. No significant differences were noted in either mitochondrial ATPase or microsomal CCR activity. Norepinephrine(NE) and dopamine in midbrain, cerebellum and brain stem were decreased in both groups but adrenal NE was increased in the HPD group. Dose-related changes were not apparent at 4 weeks of age. These results indicate that TRH and HPD exert antagonistic effects on thermogenesis and mitochondrial NADPH-dependent CCR activity and that these changes may be mediated by central and adrenal catecholamine release.

Creatine Metabolism during Growth

Premature infants on a low protein formula (2 g/kg/day) excrete small amounts of creatine (Cr) and urea (U) in the urine. The administration of a high protein formula (6 g/kg/day) resulted in an abrupt rise in creatine and guanidino-acetic acid (GAA) excretion during the first few days of adaptation, followed by a variable drop, while urinary excretion of urea increased gradually over the following two weeks. The ratio of Cr to U in the urine which elevated at the onset of the high protein period returned to the previous level of low protein formula by the end of the 2nd week of adaptation. A similar phenomenon was observed in the weanling rat whose dietary protein was raised abruptly from a low intake to high intake. Furthermore, the initial creatinuria was more exaggerated when the rats were injected with 50 mg of ethionine intraperitoneally for two consecutive days of dietary change. The urinary urea excretion was smaller and liver ornithine carbamyltransferase and arginase activities were lower in the ethionine treated rats than those of uninjected rats on the same diet. But after one week of adaptation to the high protein intake, the ethionine treatment (75 mglrat) produced no increase of creatine excretion. On a high protein ingestion, ethionine appeared to depress the enzyme induction of the urea cycle in the liver, and urinary excretion of Cr regressed inversely in relation to the amounts of urea excreted. Feeding of the high protein diet led to from a 2 to 3-fold increase in Cr and GAA content of the liver and kidneys within 48 hours, and marked activation of creatine synthesis was observed. These results suggested that guanidinium compounds seemed to be one of the compensatory metabolic products in amidine group transfer and excretion when urea synthesis was relatively repressed or enzyme activities of urea cycle were not adequately elevated.