Malcolm M. Martin

Measles vaccine failures : lack of sustained measles-specific immunoglobulin G responses in revaccinated adolescents and young adults

The measles-specific antibody responses of seronegative adolescents and young adults were evaluated after revaccination. Of 1650 previously vaccinated healthy volunteers between the ages of 10 and 30 years, 4.4% were found to be seronegative for measles antibodies and 9.9% had equivocal titers. Seronegative volunteers were revaccinated to measles and followed serially for development of measles-specific IgG. Of 43 subjects followed for at least 1 year, only 58% developed and maintained positive antibody titers; 12% never developed positive titers and 30% initially developed titers that fell below positive levels within 1 year. The peak titers achieved by those subjects who responded transiently were lower than those achieved by subjects who developed sustained responses. Thus even after the recommended two dose schedule of the current measles vaccine, some adolescents and young adults lack protective titers of measles-specific antibody.

Continuous low-dose infusion of insulin in the treatment of diabetic ketoacidosis in children.

Twelve diabetic children--eight in ketoacidosis, three with insulin refractory hyperglycemia, and one postoperative patient--were treated with continuous, low-dose, intravenous infusion of insulin. The eight ketoacidotic children with a mean serum glucose concentration on admission of 631 mg/dl and bicarbonate value of 6.8 mM/1 were given regular insulin, 0.1 U/kg, slowly by bolus injection followed by a sustaining infusion of 0.1 U/kg/hour. Plasma glucose concentration fell at a mean rate of 82 mg/dl/hour. Euglycemia with concomitant improvement in the metabolic disorder was achieved with a mean dose of insulin, 0.68 U/kg, given over four to 10 hours. Mean plasma insulin in those children who had not previously received insulin was 55 muU/ml, well within the normal physiologic range. Growth hormone and serum triglyceride levels, low initially, rose with insulin therapy before returning to control values. Continuous low-dose insulin infusion is simple, safe, and effective, avoids confusion and empiricism, and appears to be the method of choice for the treatment of diabetic ketoacidosis or insulin resistance.

Obesity, hyperinsulinism, and diabetes mellitus in childhood

Plasma glucose, immunoreactive insulin, and growth hormone following oral glucose were compared in 42 obese and 30 normal-weight children. Twelve (28 per cent) of the obese children had chemical diabetes, and a further 11 (26 per cent) had significant impairment of mean carbohydrate tolerance. All but the youngest exhibited hyperinsulinemia. There was no clear division between normal and abnormal carbohydrate tolerance or insulin response in the obese children, but there was a general tendency toward increasing hyperinsulinemia and decreasing carbohydrate tolerance with age and duration of obesity. Age of onset or degree of obesity did not relate to carbohydrate intolerance, and hyperinsulinemia did not relate to a family history of diabetes. Significant carbohydrate intolerance was seen only in association with a delay in the attainment of peak insulin concentration. Growth hormone was lower in the obese children than in the normal-weight control subjects, but the rise during the latter part of the glucose tolerance test was significantly greater in the obese children with chemical diabetes than in those with normal carbohydrate tolerance.

Constitutional Delayed Puberty in Males and Hypogonadotropic Hypogonadism: A Reliable and Cost Effective Approach to Differential Diagnosis

Forty-six male teenagers 13-19 years old with delayed puberty (DP) underwent gonadotropin releasing hormone (GnRH) and human chorionic gonadotropin (HCG) stimulation as part of their work-up. All were followed to age 18 and beyond. Thirty-seven had constitutional delayed puberty (CDP). Nine had hypogonadotropic hypogonadism (HH). At referral 34 youngsters with CDP were properly diagnosed when the lower limit for the luteinizing hormone (LH) response to GnRH (Factrel 0.1 mg i.v.) was set at 12 IU/l. Three boys with CDP failed to reach that level and were not assigned appropriately. All nine patients with HH had basal serum testosterone (T) < 50 ng/dl when first seen and LH responses to GnRH stimulation < 8.0 IU/l. In the late 1970s, five subjects with DP were given HCG 3,000 IU (two patients daily for 5 days; three on 3 alternate days). Serum T was measured before the first, and 48 hours after the last injection (day 7). With recognition of the long biological half-life of injected HCG and receptor downregulation by daily doses, the protocol was changed. In the early 1980s, the dose of HCG was randomized to either 500 IU or 1,000 IU given on 3 alternate days. T was measured before the first injection (basal), 48 hours later (day 3) and 48 hours after the third injection (day 7). At referral 35 patients with CDP, including one GnRH failure, met the criterion for a positive response to HCG stimulation based on their own reactions (T > 170 ng/dl on day 3; > 200 on day 7). Eleven patients with DP failed the test. Nine had HH and two had CDP. The nine patients with HH included the two given daily injections and the three given HCG 3,000 IU on 3 alternate days. Of the two with CDP, one, an obese boy with a normal GnRH test, only received 500 IU HCG (5.6 IU/kg), which may have been inadequate. The other failed both tests. Of the 35 responders, 17 (group 1) were given HCG 500 IU and 18 (group 2) were given 1,000 IU i.m. on 3 alternate days. Seven boys in group 1 and 12 in group 2 had serum T determined on day 3, and all 35 had T measured on day 7. There was no significant difference between the basal T levels in the two groups or in their responses to HCG, and the results were pooled. The combined data in the patients with CDP were then compared with those of the nine patients with HH, recognizing that the result on day 7 in the two patients given daily injections may reflect receptor down-regulation. Setting the limit for a normal T response at > 170 ng/dl 48 hours after a single injection of HCG and > 200 ng/dl after the third injection assigned all the patients with CDP appropriately. The data on the patients with HH are less complete, with only three T values 48 hours after the first injection However, even after three injections of HCG on alternate days, only one of nine patients with HH approached the lowest level achieved by the patients with CDP after a single injection. The data confirm that a basal serum T 50 ng/dl is evidence of the onset of puberty. In those with serum T < 50 ng/ dl our data suggest that a single injection of HCG 15 IU/kg, with serum T determined 48 hours later, is more discriminatory and offers the most reliable, easy to perform, least painful, and by far the most cost effective test to differentiate CDP from HH.

ENDOCRINOLOGY: Idiopathic hypoglycemia-a defect in hypothalamic ACTH-releasing factor secretion

Corticotropin releasing factor (CRF) deficiency has not previously been demonstrated as a cause of hypoglycemic convulsions. We have recently stuided 3 children who justify such a diagnosis. One child moreover has an identical twin who provided the ideal control in the various test situations. The presence of the a disorder in ACTH release was suggested by the absence of a response in plasma cortisol and plasma ACTH to insulin induced hypoglycemia as measured by radioimmunoassay, impaired prompt water diuresis, lack of elevation in urinary 17-OHCS following metyrapone administration despite adequate 11-B-hydroxylase inhinition and normal adrenocortial activation by exogenous ACTH. Normal insuline and growth hormone responses to glucose, arginine, tolbutamide and glucagon adminstration as well as catecholamine release by insulin induced hypoglycemia confirmed the isolated nature of the defect in keeping with the presence of a normal growth pattern and normal thyroid indices. That the defeat is one of hypothalamic activation of ACTH release rather than isolated ACTH deficiency was confirmed by the release of ACTH and rise in plasma cortisol following vasopressin administration. Two children had a history of low birth weight for gestation age. The third infant was born postmaute with respiratory distress. The available evidence suggests that this is an acquired defect rather than a genetically determined abnormality. Hypoglycemia due to a defect in hypothalamic activation of ACTH release may provide the explanation for fasting hypoglycemia and convulsions in children otherwise unexplained or masquerading as ketotic hypoglycemia.

Direct spectrophotometric quantitation of steroid chromatograms: 1. The measurement of corticosteroids

Abstract In recent years, thin-layer chromatography (TLC) has become recognized as a valuable method for the separation and identification of closely related compounds. The development of a versatile spectrophotometric scanning device (1) has led us to evaluate the many factors involved in direct spectrophotometric quantitation of thin-layer chromatograms. In the past, direct spectrophotometric quantitation of paper chromatograms has been regarded, generally, as inferior to elution methods (2–6). However, the data to be presented suggest that, with the scanning arrangement to be described and careful planimetry, accurate, sensitive, and reproducible direct spectrophotometric measurements can be obtained.

The syndrome of congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism.

Two brothers are reported with congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism, who experienced difficulties in the neonatal period, with electrolyte disturbances suggestive of adrenal insufficiency in the younger sibling. They thrived nevertheless until age 5 to 6 years when they presented with unequivocal evidence of primary adrenocortical failure. Upon reaching the age of puberty spontaneous sexual maturation failed to occur despite normal gonadotropin levels. Lack of LH response to LHRH but normal elevation in plasma testosterone following HCG stimulation suggested GnRH deficiency. Ten other patients with congenital hereditary adrenal hypoplasia and pubertal failure reported in the literature are reviewed. All are males with histological confirmation of adrenal agenesis or hypoplasia in 7 siblings. Eight of the twelve patients presented with signs and symptoms of adrenocortical insufficiency in the neonatal period; three were treated temporarily and thrived without therapy for years before becoming symptomatic again. None of the patients experienced a normal puberty though five showed some elevation in plasma testosterone and two had gonadotropins in the pubertal range early on. Both the onset of adrenal failure and of gonadotropin deficiency are variable in this disorder. The presence of the syndrome in three half-brothers with the same mother but different fathers suggests X-linked inheritance. Although the exact nature of the genetic defect remains unknown, the association of congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism is now sufficiently well documented to establish it as a recognizable inherited syndrome.

Steroid reactions on thin-layer films

Abstract Steroids with a Δ4 or Δ5-3β-hydroxy configuration have bean found to develop a distinctive pink color on thin films of silica gel or alumina when treated with ethanolic sulfuric acid. In combination with in situ borohydride reduction this color test can be extended to the identification of Δ 4-3 ketones. Oxidation of 17–20 glycols derived from borohydride reduction of 17-hydroxycorticosteroids to 17-oxosteroids with sodium metaperiodate can also be employed for further characterization. The combination of chemical transformation, chromatography and specific color tests on the same chromatogram without the need for elution furnishes a valuable technique for steroid identification with much saving in time and effort.

Continuous infusion of insulin vs repeated S.C. injections in the treatment of diabetic ketoacidosis in children

SummaryThirty-two episodes of diabetic ketoacidosis in 30 children treated with conventional repeated s.c. injections of insulin every 4 h are compared with 18 episodes in 14 children treated with continuous i.v. insulin infusion. Fluid therapy, bicarbonate and potassium supplementation were essentially the same for both groups. Recovery as reflected in serum glucose, bicarbonate and the rate of rehydration, was smoother and more rapid in the children receiving continuous i.v. insulin, though the difference just failed to attain statistical significance in this small series of cases. There was, however, a marked difference in insulin administered (0.58 U/kg ± 0.05 SEM in the children treated with continuous i.v. insulin infusionvs 2.54 ± 0.27 SEM in the children treated with repeated s.c. injections). Hypoglycemia was noted in 11 and hypokalemia in 10 children on conventional insulin therapy given every 4 h s.c. In contrast, there was no hypoglycemia and only one case of hypokalemia with the i.v. insulin infusion.

Autonomous Hyperfunctioning Thyroid Nodules in Childhood and Adolescence.

Over the past five years the criteria for the diagnosis of an autonomous hyperfunctioning thyroid nodule were met by seven patients referred for evaluation of thyroid enlargement. There were 6 females and 1 male ranging in age from 4 to 19 years. Six of the patients were asymptomatic and clinically euthyroid with normal thyroid function studies. One patient had symptoms of thyrotoxicosis confirmed by elevated hormone levels and thyroidal radioactive iodine uptake. Serum T-3 elevated in 3 of the clinically euthyroid patients when first seen, showed variability on serial determinations suggesting that a single high level may not be diagnostic for T 3 toxicosis. Thyroid antibodies were absent from the sera of all patients. TRH stimulation showed a normal response in one and a blunted response in another patient. Sonography in 5 of the 6 euthyroid subjects proved valuable not only in determining the size of the nodule but also in demonstrating in addition the presence of smooth-walled cysts in all cases which appears to be a hallmark. One patient had the nodule ablated because of hyperthyroidism. Four others elected to have surgery for cosmetic reasons. Two patients with nodules less than 2.5 cm are being managed conservatively with careful observation of thyroid status and serial sonograms in view of the experience in adults that nodules less than 3.0 cm in diameter are less at risk of becoming toxic.