Poverty, primary care and age-specific mortality.

An important area of concern among rural health researchers and policy analysts is the social and ecological correlates of mortality levels. This research is concerned with the empirical relationship between the prevalence of poverty and the mortality experience of different age groups within the population. Poverty is viewed as a characteristic of the social organization of local areas and operationalized by employing several indicators, including a measure of rurality. The empirical results indicate that the magnitude of the association between the prevalence of poverty and mortality varies among different age groups. The impact of rurality, while being consistently positive, is shown to be statistically nonsignificant. The research also shows that the availability of primary care is associated with lower mortality.

Corn oil ketogenic diet for children with intractable seizures.

The ketogenic diet is a well-established, but relatively infrequently used, therapy for intractable seizures in children. Currently, the standard ketogenic diet is formulated using medium chain triglyceride (MCT) oil as its major caloric source. Cost, availability, and gastrointestinal side effects limit its use in some cases. We report the successful substitution of corn oil for MCT oil in six children treated with the ketogenic diet for intractable seizures. In each case, the corn oil ketogenic diet was effective, well-tolerated by the patient and parents, and free of clinical toxicity. Corn oil also has the major advantages of being much less expensive and more available that MCT oil. Its use in the ketogenic diet appears to be effective, safe, and practical.

The Prader-Willi syndrome: a study of 40 patients and a review of the literature.

Forty patients with the Prader-Willi syndrome have been examined. The typical features begin in gestational life with poor fetal vigor and difficulties with birth and post-partum feeding. The classical features of hypotonia, small hands and feet, cryptorchidism can be identified at this time. The delayed milestones, mental retardation and obesity become more prominent later. The average height of the patients in this series who were admitted to the Clinical Study Center was 149 cm and their weight was 114 kg. The weight and height curves show that Prader-Willi individuals are consistently shorter and heavier than normal children. Tests of endocrine function showed normal glucose tolerance. Insulin secretion was increased in relation to obesity. The rise in growth hormone (hGH) after injecting insulin to induce hypoglycemia and after the infusion of arginine was comparable to other obese individuals but was low in comparison to normal weight subjects. There was no rise in growth hormone with L-dopa administration, but there was a rise in hGH with the administration of 2-deoxy-D-glucose. The hypoglycemia produced by insulin was greater in the Prader-Willi patient than in obese controls. The rise in TRH (thyrotropin-releasing hormone) following the injection of TSH (thyrotropin stimulating hormone) was greater in the Prader-Willi patients than in the obese controls. Hypogonadism was routine in this series, and the response to LRH (luteinizing releasing hormone) was absent in all tested subjects. Treatment with clomiphene for 30 to 90 days significantly increased the response to LRH in three adult individuals who had not been treated with gonadal steroids previously and who were hypogonadal. Rectal temperature declined in three of the five Prader-Willi patients during exposure to an ambient temperature of 4 degrees C, but none of the three obese controls showed a decline. Food intake averaged 5167 kcal/d when six patients were given trays containing more food than they could eat. Food intake was not reduced when tryptophan was added to the diet. Salivary secretion was reduced in the Prader-Willi patients. A number of pulmonary function tests were significantly reduced in the study patients compared to obese or normal weight controls. The anatomic findings in four autopsied patients with the Prader-Willi syndrome showed no significant differences from those of obese subjects without this syndrome. The chromosomal pattern showed a deletion or translocation at chromosome 15 in 3 of 12 patients in whom this test was performed. These findings in 40 patients with the Prader-Willi syndrome have been compared with the information contained in 159 reports published in the medical literature.

Endocrine-metabolic relationships in patients with leprechaunism.

Leprechaunism is a rare, heritable syndrome, associated with multiple dysmorphic and pathologic features, suggestive of an endocrine dysfunction. Few endocrine and metabolic studies have been obtained because of the rarity of the syndrome, and the small size and early demise of these infants. The authors present here the clinical, anatomic, and endocrine-metabolic studies of three patients, with a view toward careful delineation of the syndrome and further characterization of the metabolic defect.The most striking and consistent metabolic derangements present in all of these patients were fasting hypoglycemia (less than 20 mg/dL), postprandial hyperglycemia (more than 250 mg/dL), marked hyperinsulinemia (more than 2000 µU/mL), and severe insulin resistance (less than a 20 percent decrease in blood sugar with 0.3 to 1.0 U/kg of regular insulin IV). Hyperinsulinemia was observed in response to oral feedings and glucose infusion, and after tolbutamide. Insulin secretion was less marked with amino acid infusions. Normal increments in blood glucose occurred following alanine, galactose, and glycerol. Glucagon caused a rise in glucose 4 hours after a meal, but no response was seen after a 12-hour fast. Pituitary, gonadal, and adrenal hormone levels were normal, and there was a normal response pattern to GnRH and TRH. Hyperinsulinemia would appear to be the biochemical hallmark of this disease. Our previous studies were suggestive of a postreceptor defect in insulin action. The present endocrine-metabolic studies are compatible with this hypothesis. Interaction of supraphysiologic concentrations of plasma insulin with growth factor receptors, this may provide a partial explanation for some of the dysmorphic features seen in the disorder.

Glycogenosis type IB: possible membrane transport defect.

We have described a 20-month-old child with type IB glycogen storage disease, based on clinical and biochemical manifestations. Functional testing data were similar to those found in glucose-6-phosphatase deficiency, but in vitro studies showed normal hepatic glucose-6-phosphatase activity. Disruption of membranes with deoxycholic acid was followed by an increase in enzyme activity compared to a control liver tissue, suggesting "latency" of enzyme. We suggest that this patient had glycogen storage type IB and that this disorder may represent a specific glucose-6-phosphate transport defect.

Rapid glucose disappearance in infants with infection.

Altered carbohydrate metabolism has been reported during episodes of neonatal infection. To document that there is more rapid glucose disappearance during infection, intravenous glucose tolerance tests (IVGTT) and serial plasma growth hormone and insulin levels were determined in eight full-term neonates during the first three days of an acute episode of infection and during convalescence, 5 to 15 days later. Eight healthy infants were each studied once using the same study protocol. Glucose disappearance rates, measured as K1 of glucose, were increased (p less than 0.01) during both the acute septic period (3.7 +/- 0.3% disappearance/min; mean +/- S.E.M.) and convalescent period (2.5 +/- 0.2% min) when compared with values in control infants (1.3 +/- 0.3%/min). Gram-negative, gram-positive, and viral infections were all associated with rapid glucose disposal. The abnormality in carbohydrate homeostasis persisted for at least 5 to 15 days after treatment was begun. Baseline and stimulated (20-minutes post bolus glucose infusion) plasma insulin and growth hormone levels did not differ among the groups. Thus, there is no evidence that hyperinsulinism produced the rapid glucose disappeared rate and enhanced glucose utilization. The reason for the disturbed carbohydrate metabolism in neonatal infections remains unknown.

Glucose perturbation in experimental hyperviscosity.

Hyperviscosity was produced in one member of each of 7 sets of twin newborn lambs by an exchange transfusion with 500 ml maternal packed red blood cells. The remaining seven control twin lambs underwent an identical exchange with maternal whole blood. Postexchange hematocrits were 63 +/- 6 and 29.0 +/- 3% (mean +/- S.E.), respectively (P less than 0.01). Whole blood viscosity measured at 3 rpm increased from 3.2 +/- 0.4 centipoise (cps) to 14.4 +/- 6.1 cps in the lambs made hyperviscous (P less than 0.01) and remained unchanged in the control lambs (2.2 +/- 0.1 versus 2.8 +/- 0.3 cps). A 2-hr steady state glucose infusion was performed on each lamb before and after the packed cell or whole blood exchange transfusion. Mean steady state plasma glucose concentrations were significantly decreased from pre-exchange steady state glucose infusion levels in the same lambs made hyperviscous (P less than 0.05), whereas steady state glucose levels increased from preexchange levels in the twin lambs exchanges with maternal whole blood. Mean plasma insulin and glucagon values for the hyperviscous and control lambs remained unchanged during the glucose infusion.

Glucose kinetics in leprechaunism: accelerated fasting due to insulin resistance.

Postprandial and postabsorptive glucose metabolism was studied in a 3-yr-old girl with leprechaunism by substrate and hormonal measurements and by quantifying hepatic glucose output during continuous infusion of D-[6-6-2H2]-glucose. Hepatic glucogen content and the activity of glycogen synthase and phosphorylase were also measured in the post-prandial state on a separate occasion. During the 4-h postprandial state, plasma glucose, alanine, lactate, beta-hydroxybutyrate, and glycerol were normal, as were hepatic glycogen, glycogen synthase, phosphorylase, and hepatic glucose output of 7.5 mg kg-1 min-1. Intravenous injection of glucagon (30 micrograms kg-1) caused an immediate almost 3-fold rise in glucose production consistent with brisk glycogenolysis. During the 8- to 12-h postabsorptive state, however, the patient had elevated levels of glycerol (330-508 microM) and beta-hydroxybutyrate (3291-3801 microM) and decreased levels of glucose 24-29 mg/dl) and alanine (121-135 microM) consistent with a much longer period of fasting in the normal child. Furthermore, hepatic glucose output was reduced to 3.9 mg kg-1 min-1, and iv glucagon injection failed to increase this rate; both of these observations are consistent with a hepatic state generally found only later in fasting in the normal child. From these observations we conclude that the hypoglycemia reported in the leprechaunism syndrome is due to an accelerated fasting state secondary to insulin resistance. As with long-fasted, glycogen-depleted normal children, gluconeogenesis alone is often not capable of adequately meeting the child's large noninsulin-dependent cerebral glucose requirements.

Insulin resistance due to a defect distal to the insulin receptor: demonstration in a patient with leprechaunism.

We have studied a 2-year-old girl with acanthosis nigricans, glucose intolerance, marked hyperinsulinemia, and somatic features characteristic of the leprechaunism syndrome. Circulating plasma insulin levels were increased up to 50-fold and the patient showed a blunted hypoglycemic response to an injection of exogenous insulin (0.2 units/kg), indicating the presence of severe insulin resistance. Insulin purified from the patient's plasma was normal on the basis of chromatographic, electrophoretic, and immunologic criteria. Furthermore, the purified insulin competed effectively with (125)I-labeled insulin for binding to insulin receptors on cultured IM-9 lymphocytes and rat fat cells and also exhibited normal biological potency when tested on rat fat cells. Anti-insulin receptor and anti-insulin antibodies were not detected in the patient's plasma, and plasma levels of glucagon, growth hormone, and cortisol were normal. Insulin binding to the patient's circulating monuclear leukocytes was only slightly depressed into the low normal range and could not account for the severe insulin resistance. Studies on the patient's fibroblasts revealed normal levels of insulin receptors but a total absence of insulin's ability to accelerate glucose transport. Because rates of glucose transport and metabolism were normal in the basal state in the absence of insulin, we conclude that this patient's insulin resistance is due to an inherited cellular defect in the coupling mechanism between occupied insulin receptors and the plasma membrane glucose transport system.

Differential effects of cranial radiation on growth hormone response to arginine and insulin infusion.

The growth hormone responses to arginine infusion and to insulin-induced hypoglycemia were studied in 13 patients with neoplastic disease after treatment with radiation and chemotherapy. Patients who received intensive cranial radiation (greater than 2,400 rads) had no response to either arginine or insulin; those who received moderate cranial radiation (greater than or equal to 2,400 rads) had GH response to arginine but not to insulin; patients receiving no cranial radiation responded to both arginine and insulin. These data support the hypothesis that GH secretion in response to arginine infusion has a different mechanism in contrast to the response to insulin-induced hypoglycemia and that the latter is more vulnerable to cranial radiation.

Chronic disease and short stature.

Careful graphing of the anthropometric measurements of children with chronic disease and short stature should be done to determine height and weight growth velocities. In addition, a detailed history can provide information helpful in determining the expected growth curve. If the chronic disease can be effectively treated (eg, malnutrition, emotional deprivation, celiac disease, asthma, rheumatoid arthritis), a period of rapid "catch-up" growth can be anticipated. The prognosis with regard to adult stature depends on the timing, duration, and severity of the growth-inhibiting influence.

Rare occurrence of Addison's disease and diabetes mellitus in children.

We report on two children with both Addison's disease and diabetes mellitus, a rare occurrence in children. One of the children first developed Addison's disease and later developed diabetes mellitus, while the other had the onset of diabetes mellitus first and later Addison's disease. In the latter patient a direct relationship was shown between the insulin dose and adrenal cortical hormone. Organ-specific antibody studies are reported and the diagnosis and management of these combined endocrinopathies are discussed.