Juan F. Sotos

Rapid determination of picomole quantities of ATP with a liquid scintillation counter

Abstract A rapid method for the determination of picomole quantities of ATP by the use of firefly lantern extract and the liquid scintillation counter is presented. The luminescence rate at 7 sec after the addition of ATP was found to be proportional to the picomoles of ATP added.

Familial holoprosencephaly with endocrine dysgenesis

Two siblings with holoprosencephaly are presented. The first infant died at 1 day of age. Absence of the pituitary and hypoplasia of the adrenals were observed at autopsy. The thyroid and ovaries were normal. Endocrine function was evaluated during life in the second sibling. Diminished reserve of pituitary adrenocorticotropic hormone, secondary adrenal insufficiency, and Pitressin-responsive diabetes insipidus were demonstrated. There was no evidence of abnormalities of the release of growth hormone or of thyroid-stimulating hormone. The thyroid and parathyroid functions were normal. The clinical and postmortem findings suggest similar endocrine abnormalities in both siblings.

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subjects bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.

Diabetes responsive to intravenous but not subcutaneous insulin: effectiveness of aprotinin.

Patients with diabetes that is insensitive to subcutaneous insulin but sensitive to intravenous insulin have recently been described. We have studied this phenomenon is five female diabetics (14 to 31 years of age) who required excessive amounts of insulin (2.5 to 30.0 units per kilogram of body weight per day) to avoid recurrent ketoacidosis. Known causes of insulin resistance were excluded. All patients had normal responses to conventional doses of intravenous insulin (0.35 to 0.9 unit per kilogram per day). Four patients required continuous intravenous infusion of insulin for one to six months. When a mixture of aprotinin (a protease inhibitor) and regular porcine insulin was given subcutaneously, conventional doses (0.7 to 1.4 units per kilogram per day) produced euglycemia; plasma levels of free insulin rose, and ketonuria disappeared. Four patients had episodes of spontaneous, severe hypoglycemia before and during aprotinin therapy, necessitating continuous infusion of glucose for two to 14 days. Although no insulin was administered, hyperinsulinemia (50 to 2000 muU of free insulin per milliliter [359 to 14,350 pmol per liter]) was present. These findings suggest excessive degradation or sequestration of insulin at the site of injection.

X-linked hypogonadism, gynecomastia, mental retardation, short stature, and obesity--a new syndrome.

Five male members in four generations of the same family had hypogonadism, gynecomastia, mentalretardation, obesity, and short stature. The X-linked mode of inheritance, the distinctive facies, the normal size of the hands and feet, and the true gynecomastia are the main characteristics. Endocrine evaluation and histologic studies of the testes suggest partial hypogonadotropic hypogonadism. This disorder represents a new syndrome distinct from others previously described.

Rumination — A Near Fatal Psychiatric Disease of Infancy

Abstract A six-and-a-half-month-old male infant received an intensive diagnostic evaluation for life-threatening persistent vomiting. The correct diagnosis of rumination was missed for a month. His mother was found to be schizophrenic. Striking improvement resulted from kindness and affectionate care. The observations confirm that a disturbed emotional maternal-child relation is the cause of this disorder.

Multiple endocrine neoplasia type 2A: A 25-year review

BACKGROUND/PURPOSE Before 1970, treatment decisions for the thyroid lesions in patients with multiple endocrine neoplasia (MEN) were based on physical findings. For the next 20 years, biological markers assumed a preeminent role, and at present, DNA testing is being used to define the need for therapeutic intervention. This report presents a 25-year review of 22 children with MEN-2A, with a mean follow-up of 12.5 years. METHODS All 22 children underwent a total thyroidectomy, and four (18%) were rendered permanently hypoparathyroid. Since 1976, however, only one patient (6.7%) has lost parathyroid function. Despite the fact that biological screening studies routinely were performed once a year in the majority of our patients and surgery was recommended for any elevation in the serum calcitonin (CT) levels, medullary carcinoma of the thyroid (MTC) developed in 17 children (77%) and only five had C cell hyperplasia (CCH). Thirteen of the 17 had macroscopic tumor described by the pathologist, evidence of recurrent disease (MTC-REC) has developed in four children (24%). RESULTS There was considerable overlap in both the basal and stimulated CT levels among the five children with CCH, the 13 with localized MTC (MTC-NED), and the four who later had recurrent MTC. The basal calcitonin levels were between 25 and 110 (mean, 58) in the CCH patients, 30 to 1,130 (mean, 184) in the MTC-NED group, and 108 to 201 (mean, 140) in those with recurrent MTC. The corresponding stimulated calcitonin levels were 45 to 417 (mean, 179) in CCH, 111 to 9,510 (mean, 1,407) in MTC-NED, and 449 to 5,093 (mean, 3,383) in MTC-REC. CONCLUSIONS (1) Basal and pentagastrin-stimulated CT levels did not reliably discriminate between CCH and MTC and should not be used to define the timing of thyroid surgery in children with MEN-2A. (2) Surgical therapy should be undertaken early in childhood on the basis of molecular genetic testing. (3) Postoperative complications are infrequent in the modern era.

Diagnostic significance of urinary growth hormone measurements in children with growth failure: correlation between serum and urine growth hormone.

ABSTRACT: Twelve-h overnight urine and serum samples obtained simultaneously at 20-min intervals were assayed for growth hormone (GH). Ninety-one children, 5 to 16 y (Tanner stage 1 to 3) participated; group 1 were healthy children, group 2 were children with organic GH deficiency, and group 3 had idiopathic growth failure and normal GH stimulation tests. Serum pool GH concentrations in group 1 were similar to those in group 3 (3.3 ± 0.3 versus 3.4 ± 0.2 μg/L); group 2 had significantly lower GH concentrations (1.6 ± 0.2 μg/L). Plasma IGF-I levels were significantly greater in groups 1 (14.2 ± 2.6 nmol/L, p < 0.001) than in groups 2 and 3 (2.6 ± 0.5 and 5.5 ± 0.7 nmol/L, respectively). Urinary GH (mean ± SEM) standardized for body weight (μg/kg) in group 1 (0.31 ± 0.02) was significantly greater than in group 2 (0.14 ± 0.01) and group 3 (0.20 ± 0.01). However, when expressed as μg/mol creatinine, the output of GH was similar in group 1 (4.0 ± 0.3) and group 3 (3.4 ± 0.3); both groups had significantly greater output compared to group 2 (1.3 ± 0.2). Urinary IGF-I (nmol/kg) in group 1 (0.22 ± 0.02) was significantly greater than in group 2 (0.12 ± 0.01) or group 3 (0.07 ± 0.01). Urinary GH correlated with serum pool GH concentration (r = 0.64, p < 0.001). Although urinary GH output reflects endogenous GH secretion, the overlap between groups 1 and 3 precludes using urinary GH measurements as a diagnostic test for GH deficiency in children with idiopathic growth failure.

Prognostic and etiologic factors in hypoglycemia.

The outcome and the developmental status of the survivors among 71 children who in their earlier years had laboratory evidence of hypoglycemia have been analyzed. For the purposes of this study, the children were assigned to three main groups: (1) neonatal symptomatic hypoglycemia (subdivided into infants of both diabetic and nondiabetic mothers); (2) postneonatal symptomatic hypoglycemia; (3) postneonatal asymptomatic hypoglycemia. The observations and interpretations are summarized.

Extracellular correction of the androgen-receptor transformation defect in two families with complete androgen resistance

We have characterized the cellular and extracellular phenotype of the mutant androgen receptor (AR) from two families who have complete androgen resistance despite a normal androgen-binding capacity (Bmax) in their genital skin fibroblasts (GSF). The cellular receptors fail to up-regulate their basal AR activity in response to prolonged incubation with 5 alpha-dihydrotestosterone (DHT), or with two synthetic androgens, methyltrienolone (MT) and mibolerone (MB), and form A-R complexes with increased equilibrium (Kd) and non-equilibrium (k) dissociation constants. In addition, they are thermolabile when recently dissociated, but not in their native state. A-R complexes made in normal or mutant cytosol at 4 degrees C elute from DEAE-Sephacel at approximately 0.25 M KCl (untransformed), with or without prior passage through Sephadex G-25; when made in cells at 37 degrees C, extracted with 0.4 M KCl in a buffer containing 10 mM Na2MoO4, and desalted by G-25, they elute at less than or equal to 0.1 M KCl. Normal KCl-extracted DHT- and MB-R complexes dissociate (37 degrees C) at the same slow, linear rate as their in-cell counterparts (transformed); the mutant ones dissociated more slowly than their rapidly-dissociating in-cell counterparts and, to a variable extent, nonlinearly-an early faster phase, a later slower (transformed). Thus, as judged by two conventional criteria of steroid-R complex transformation, the mutant A-R complexes can transform, possibly in two steps, under certain cell-free conditions. This behavior differentiates a class of structural AR mutations whose molecular definition awaits application of recombinant DNA techniques to the X-linked AR locus.