Lack of Autoimmune Serological Reactions in Rodent Models of Insulin Dependent Diabetes Mellitus

Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to β islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the ‘IDDM-relevant’ autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.     

Associations between Family-Based Stress and Dietary Inflammatory Potential among Families with Preschool-Aged Children

Chronic stress is known to influence dietary choices, and stressed families often report poorer diet quality; however, little is known about how family-based stress is linked with dietary patterns that promote inflammation. This study investigated associations between family-based stress and the inflammatory potential of the diet among preschool-aged children and their parents. Parents (n = 212 mothers, n = 146 fathers) and children (n = 130 girls, n = 123 boys; aged 18 months to 5 years) from 241 families participating in the Guelph Family Health Study were included in the analyses. Parents reported levels of parenting distress, depressive symptoms, household chaos, and family functioning. The inflammatory potential of parents’ and children’s diets was quantified using the Dietary Inflammatory Index (DII^®), adjusted for total energy intake (i.e., the E-DII^TM). E-DII scores were regressed onto family stress using generalized estimating equations to account for shared variance among family clusters. Compared to those in homes with low chaos, parents in chaotic homes had significantly more proinflammatory dietary profiles (β = 0.973; 95% CI: 0.321, 1.624, p = 0.003). Similarly, compared to those in well-functioning families, parents in dysfunctional families had significantly more proinflammatory dietary profiles (β = 0.967; 95% CI: 0.173, 1.761, p = 0.02). No significant associations were found between parents’ E-DII scores and parenting distress or depressive symptoms, nor were any associations found for children’s E-DII scores. Results were not found to differ between males and females. Parents in chaotic or dysfunctional family environments may be at increased risk of chronic disease due to proinflammatory dietary profiles. Children’s dietary inflammatory profiles were not directly associated with family stress; however, indirect connections through family food-related behaviours may exist. Future research should prioritize elucidating these mechanisms.     

Ontogeny of J chain expression in pig lymphocytes

The ontogeny of lymphocytes expressing J chain in the cytoplasm (J+) was studied in pig foetuses by the immunofluorescent technique. Peripheral blood lymphocytes were the first J+ cells in prenatal life. The spleen and lymph nodes contained J+ cells in the last days of gestation. J+ cells were found in the lamina propria of the gut and some glands of conventional but not of germ-free piglets. J chain was not detected on or in cell membranes at any developmental stage.     

Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.     

Free amino acid pool in the brain of mice homozygous for the gene "dilute lethal"

The neurologic mutant "dilute lethal" (dl) mice, which reveal several neurologic and biochemical disturbances similar to human phenylketonuria, were used to investigate some aspects of amino acid disorder. We have studied the free amino pool in the brain of "dl" mice and of their control littermates as well as phenylalanine and tyrosine levels in brain and liver as a function of age and after phenylalamine overload. The tyrosine level decreased in brain and liver of affected mice whereas the phenylalanine/tyrosine ratio increased as a function of age. The significantly higher phenylalanine level and phenylalanine/tyrosine ratio in the liver of 20-day-old "dl" mice suggest a lower liver phenylalanine hydroxylase activity. After phenylalanine overload, the impairment of phenylalanine metabolism is predominant in the brain of "dl" mice, suggesting a disturbance in phenylalanine hydroxylation. A decrease in the level of several amino acids occurs in the brains of "dl" mice without or after phenylalanine overload; these facts might correspond to a disturbance in the transfer of amino acids to the brain and may lead to impairment in protein synthesis.     

Glutaric aciduria type I

Summary Serial CT findings in an infant with glutaric aciduria type I (GA-I) are reported. The major CT features were dilatation of the insular cisterns, regression of the temporal lobes, with bat wings dilatation of the Sylvian fissures and hypodensity of the lenticular nuclei. CT changes preceded the onset of symptoms by 3 months. An improvement in the temporal lobe atrophy was seen after a period of treatment, coinciding with marked clinical improvement. A peculiar feature was the presence of external hydrocephalus, which diverted the attention from manifestations of the primary disease and thus consitituted a diagnostic pitfall. The delineation and recognition of the characteristic radiologic manifestations of GA-I are essential for allowing an adequate radiologist/clinican interaction in diagnosing this inborn error of metabolism.