Differential binding kinetics of cholera toxin to intestinal microvillus membrane during development

A complete randomized block design was used to compare the binding kinetics of cholera toxin to developing rat enterocyte microvillus membranes prepared from newborn, 2-week-old, 4-week-old, and adult animals. Saturation-binding isotherms were generated on 16 independent samples (four blocks) under steady-state and reversible conditions. Scatchard analyses suggested positive cooperative binding to a single class of receptors, and the isotherms were analyzed by both the Hill-Waud and Michaelis-Menten functions. Receptor density varied significantly with age (P = 0.013). An abrupt rise in receptor density occurred after the neonatal period and normalized in the adult animal. The half-dissociation constant also varied significantly with age (P = 0.019). Microvillus membranes from suckling animals had a slightly higher apparent affinity than those from weaned animals. Neither receptor concentration nor membrane purity confounded these observations. Whereas age-related changes in apparent affinity correlated with cellular responses, changes in receptor density did not. This study suggests that developmental changes in membrane structure which influence binding affinity but not receptor density may, in part, contribute to the increased sensitivity of suckling rats to cholera toxin exposure.     

Excess of DR3/4 in type I diabetes. What does it portend?

The HLA-DR genotypes of 158 new type I diabetic probands from simplex families are compared with those of 43 multiply affected sibships. There were no significant differences in the gene frequencies of the insulin-dependent diabetes mellitus (IDDM)-associated alleles, DR3 and DR4, and whereas the DR3/4 heterozygotes were as frequent among simplex probands as among the first affected of multiplex sibships, subsequently affected sibs displayed lower frequencies of this genotype in this as well as in previously reported samples, indicating that the excessive risk associated with DR3/4 heterozygosity depends on the order of affection and thus on environmental factors. It is proposed that the penetrance of the susceptibility gene is enhanced by epistatic effects of this genotype and that this enhancement is strongest under conditions of low environmental liability. Thus, the excessive risk for DR3/4 individuals appears to depend on secondary interactions between DR and the environmental factors that trigger the onset of this disease and does not in itself indicate the existence of distinct susceptibility alleles in coupling with these genes, i.e., of genetic heterogeneity or overdominance.     

Renal disease and syphilis: a report of nephrotic syndrome with minimal change disease

A case of nephrotic syndrome and acute renal failure in a 74-year-old man with latent syphilis is described. A renal biopsy demonstrated focal global sclerosis in three of nine glomeruli, however, the remaining glomeruli revealed typical lesions of minimal change disease. Previous reports of renal involvement in syphilis have described membranous glomerulonephritis, mesangial and endothelial cell proliferative glomerulonephritis, and, recently, rapidly progressive glomerulonephritis. The proteinuria and renal failure resolved after penicillin therapy alone. This response strongly suggested that there was a causal relationship between the syphilis and the nephrotic syndrome. This is the first report of such a relationship.     

Dithiocarbamate-induced biliary platinum excretion and the control of cis-platinum nephrotoxicity

Treatment with any one of six different dithiocarbamates subsequent to the administration of cis-platinum (CDDP) is shown to promote the biliary excretion of platinum. The administration of the most effective of these compounds, sodium diethyldithiocarbamate (DDTC) at 1.57 mmol/kg, led to a 30-fold increase in the biliary excretion of platinum. For the other dithiocarbamates investigated, a similar dosage led to increases ranging from approximately 5-fold for sodium iminodiacetic acid dithiocarbamate, to 26-fold for sodium sarcosine dithiocarbamate. The presence of alkyl groups on the nitrogen of the dithiocarbamate increased the effectiveness of the compounds. There is no increase in the platinum levels of the brain when DDTC is used in this manner. A histopathological evaluation of the kidneys of rats given 15 mg CDDP/kg in 6.3% saline with and without the use of dithiocarbamates for renal protection shows significant additional protection due to the use of the dithiocarbamates. Dithiocarbamates given at an appropriate dosing schedule can lead to a significant reduction in the renal damage which is revealed by microphotographs. It is suggested that part of the renal protection obtained by the use of dithiocarbamates may be due to this shift of platinum excretion to the bile which obviates additional renal exposure to platinum. It was also found that the simultaneous injection of a dithiocarbamate with the cis-platinum has no obvious effect on the anti-cancer action of cis-platinum against the Walker 256 carcinosarcoma in rats.     

Effect of cholesterol deprivation on piglet small intestine and serum lipids

Using the neonatal piglet, the effects of dietary cholesterol deprivation on growth, intestinal enzyme activity, intestinal and hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and serum lipid were studied. Six litters of piglets were randomly assigned to one of two feeding regimens: restricted (800 ml of formula/24 h) versus unrestricted (1,200 ml of formula/24 h). Within litters, piglets were separated by sex, then randomly assigned to a formula containing low cholesterol (less than 2 mg/dl) or high cholesterol (145 mg/dl). Piglets were fed for 2 weeks. Male piglets in the restricted low cholesterol group gained significantly less weight per milliliter of formula than the restricted high cholesterol males. No effect was observed in the females. Microvillus membrane lactase activity was greater in males fed a high versus low cholesterol diet. Intestinal and hepatic HMG-CoA reductase activities and serum lipid profiles showed a trend toward compensation for dietary cholesterol deprivation but did not differ statistically between the cholesterol-fed versus -deprived groups. It is concluded that dietary cholesterol deprivation in the male neonatal pig causes alterations in growth, but no other statistically significant responses were detectable in this study.