William J. Oliver

A familial disorder of uric acid metabolism and central nervous system function. II

A syndrome of mental retardation, spastic cerebral palsy, choreoathetosis, and self-destructive biting has been observed in a 22-month-old boy, who is described as the third and youngest patient studied. Hyperuricemia was found at 4 months of age. The excretion of uric acid in the urine was considerably higher than that of controls and was in the range of values found in those adults with gout who are classified as hyperexcretors. The conversion of C 14 -labeled glycine to uric acid exceeded that of controls by a factor of 200 times. These data provide confirmation for a chemical deviation from normality that is as striking as the clinical manifestations of the disorder. They suggest the possibility that intermediates of purine metabolism may be of importance for the integrity of the developing nervous system.

Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?

Uric acid has historically been viewed as a purine metabolic waste product excreted by the kidney and gut that is relatively unimportant other than its penchant to crystallize in joints to cause the disease gout. In recent years, however, there has been the realization that uric acid is not biologically inert but may have a wide range of actions, including being both a pro- and anti-oxidant, a neurostimulant, and an inducer of inflammation and activator of the innate immune response. In this paper, we present the hypothesis that uric acid has a key role in the foraging response associated with starvation and fasting. We further suggest that there is a complex interplay between fructose, uric acid and vitamin C, with fructose and uric acid stimulating the foraging response and vitamin C countering this response. Finally, we suggest that the mutations in ascorbate synthesis and uricase that characterized early primate evolution were likely in response to the need to stimulate the foraging “survival” response and might have inadvertently had a role in accelerating the development of bipedal locomotion and intellectual development. Unfortunately, due to marked changes in the diet, resulting in dramatic increases in fructose- and purine-rich foods, these identical genotypic changes may be largely responsible for the epidemic of obesity, diabetes and cardiovascular disease in today’s society.

Genetic studies on the Ticuna, an eniǵmatic tribe of Central Amazonas

The Ticuna are an Amerindian tribe of Central Amazonas, a key location in theories of the peopling of eastern South America. The results of typing some 1760 members of the tribe with respect to 37 different genetic systems are reported, as are the results of HLA typings on a subsample of 129 persons. Salient findings include the following. (1) Except for a high frequency of the LMsallele and an unusual combination of HLA allele frequencies, there are no notable findings with respect to the commonly studied polymorphic systems. A multivariate treatment of six of the most commonly studied genetic polymorphisms accords the Ticuna an ‘average’ position among Amerindian tribes. (2) There is much less intervillage heterogeneity than usually encountered in Amerindian tribes; this is attributed to recent high rates of intervillage migration due to religious developments. (3) A thus‐far unique polymorphism of ACP1was identified, the responsible allele having a frequency of 0.111. (4) In proportion to the size of the tribe, there was a relative paucity of ‘private’ genetic variants, the ACP1 allele being the only one. This discrepancy is attributed to a relatively recent numerical expansion of the tribe; effective population size over the past several thousand years is thought to have been well below what present numbers would suggest. (5) The thesis is again advanced that ‘private variants’ (alleles not occurring as polymorphisms of wide distribution) are more common in Amerindian than in Caucasian or Japanese populations.

Genetic studies of the Macushi and Wapishana Indians

SummaryBlood samples from 509 Macushi and 623 Wapishana Amerindians of Northern Brazil and Southern Guyana have been analyzed with reference to the occurrence of rare variants and genetic polymorphisms of the following 25 systems: (i) Erythrocyte enzymes: acid phosphatase-1, adenosine deaminase, adenylate kinase-k, carbonic anhydrase-1, carbonic anhydrase-2, esterase A1,2,3, esterase D, galactose-1-phosphate uridyltransferase, isocitrate dehydrogenase, lactate dehydrogenase, malate dehydrogenase, nucleoside phosphorylase, peptidase A, peptidase B, phosphoglucomutase 1, phosphoglucomutase 2, phosphogluconate dehydrogenase, phosphohexoseisomerase, triosephosphate isomerase and (ii) Serum proteins: albumin, ceruloplasmin, haptoglobin, hemoglobin A, hemoglobin A2 and transferrin. Fifteen different rare variants were detected, involving 11 of these systems. In addition, a previously undescribed variant of ESA1,2,3 which achieves polymorphic proportions in both these tribes is described. Excluding this variant, the frequency of rare variants is 1.1/1000 in 12510 determinations in the Macushi and 4.7/1000 in 15 396 determinations in the Wapishana. The ESA1,2,3, polymorphism was not observed in 382 Makiritare, 232 Yanomama, 146 Piaroa, 404 Cayapo, 190 Kraho and 112 Moro. Irregularities in the intratribal distribution of this polymorphism in the Macushi and Wapishana render a decision as to the tribe of origin impossible at present. Gene frequencies are also given for previosly described polymorphisms of 5 systems: haptoglobin, phosphoglucomutase 1, erythrocyte acid phosphatase, esterase D, and galactose-1-phosphate-uridyl-transferase.

Family Structure and Child Abuse

Knowledge of the characteristics of family structure may be helpful to the pediatrician for predicting child abuse. During the past several decades progressive shifts from the classic family unit of two biological parents and their children to a variety of parental living arrangements have occurred. Most notable are the increases in teenage pregnancies, unmarried motherhood, divorce rates approximating 50% of marriage rates, and frequency of unrelated surrogate parents, most often male, cohabitating in the home. In these settings, identifiable characteristics of the mother, the father or surrogate, the child, the family history, and the immediate neighborhood of the family have been associated with a greater likelihood of child and/or spousal abuse. The accumulated information may be used for preventative intervention.

The predicted increased cancer risk associated with a single computed tomography examination for calculus detection in pediatric patients compared with the natural cancer incidence.

Objectives: The objective of the study was to estimate the increased lifetime cancer risk associated with a single computed tomography (CT) examination for calculus detection in pediatric patients and compare it with the lifetime natural cancer risk. Methods: We used the program CT-Expo to calculate the radiation doses to various abdominal and pelvic organs for age-appropriate pediatric renal stone CT examination protocols used at our institution. Using the Biological Effects of Ionizing Radiation (BEIR) VII report, we estimated the lifelong cancer risk for these organs and compared it with the natural cancer risk for the same organs as predicted by the Surveillance, Epidemiology and End Results data from the National Cancer Institute. Results: For children 10 years or younger at the time of the examination, about 3 radiation-induced cancers are predicted for every 1000 naturally occurring cancers, and for children 15 years old, about 2 radiation-induced cancers are predicted for every 1000 naturally occurring cancers. The radiation dose from this examination is approximately equivalent to 1 to 2 years of background radiation. Conclusions: The ratio of the risk for any abdominal and pelvic cancer due to a single CT examination for calculus detection to the risk of a naturally occurring cancer over the lifetime of a child is estimated to be 2/1000 to 3/1000. With this information, the emergency department pediatrician can more effectively counsel parents about the risk-benefit aspects of the CT examination for renal calculus disease in their children.

Factors contributing to Severity of Herpes Zoster in Children.

Herpes zoster is typically a benign disease in children. Three patients were observed in whom unusually severe herpes zoster was present. Among the factors which may have contributed to the gravity of the illness were the presence of malignancy, debility, and therapy with immune-suppressive agents.

Effect of Prolonged Hypoxia Upon Granularity of Renal Juxtaglomerular Cells

The various experimental models used in previous studies of the juxtaglomerular apparatus do not permit the effect of changes in oxygen tension of the renal parenchyma to be separated from that of changes in distension of the renal arterial bed. To study the isolated effect of prolonged hypoxia, three groups of rats, matched for weight, were kept in low oxygen, room air, and high oxygen environment for two weeks. The animals were pair-fed with the hypoxic rats serving as the determinant group. Supplemental injections of sodium chloride were given daily to avoid the effect of sodium deprivation on the juxtaglomerular cells. It was found that the hematocrits and also the granularity of the juxtaglomerular cells were significantly increased in the hypoxic rats as compared to the other two groups. Blood pressures, serum sodium levels, and urinary excretion of sodium were comparable among the three groups. These findings demonstrate that increased granularity of the renal juxtaglomerular cells can be induced by prolonged hypoxia.

Studies on dietary correction of metabolic abnormalities in hepatorenal glycogenosis.

Extract: This study reports the effects of frequent glucose feeding on the metabolic abnormalities observed in a patient with hepatorenal glycogenosis. Use of this diet resulted in correction of metabolic acidosis and hyperlacticacidemia. External calcium balance became positive secondary to a decrease in the loss of calcium in urine. Long-term use of the diet caused a reduction to normal values of triglyceride and cholesterol levels in serum. Continued use of the diet for nine months resulted in increased growth rate and increased calcification of bone. Evidence based on excretion of epinephrine and 17-hydroxy-corticosteroids in urine did not indicate that an increased excretion of these hormones occurred in response to hypoglycemia. Concentrations of growth hormone were low despite hypoglycemia; however, after nine months of treatment, the patient showed a rapid decline in the levels of blood sugar with an increase in the levels of growth hormone in blood.Speculation: Partially controlled hepatorenal glycogenosis is in some ways similar to juvenile diabetes mellitus since patients with this disease sustain intermittent starvation of the peripheral tissues for glucose. Study of the metabolic sequellae of peripheral glucose deprivation and repletion in some forms of glycogenosis may lead to a better understanding of the complications of juvenile diabetes mellitus.

Demonstration of Increased Catecholamine Excretion in the Nephrotic Syndrome.

Summary In 7 edematous nephrotic children, the mean excretion of norepinephrine was significantly greater than in these children during remission or in 7 control subjects. The increased excretion did not correlate with glomerular filtration rate or quantity of urine protein but correlated with magnitude of sodium retention. Steroid therapy caused a prompt decrease of excretion of catecholamines and their metabolites. These findings may relate to circulatory changes or to other unrecognized abnormalities.