Cardioprotective effects of diltiazem when given before, during or delayed after infusion of norepinephrine in anesthetized dogs

Catecholamine excess has been shown to produce 2 distinct forms of irreversible myocardial necrosis termed contraction band lesions. Calcium channel blocking agents provided a variable protective effect from these contraction band lesions. The purpose of this study was to determine the temporal responses of the most effective of these blocking agents, diltiazem, when given before, simultaneous with or after an initial exposure to a necrogenic infusion of norepinephrine (NE). Forty-one adult mongrel dogs were anesthetized with sodium pentobarbital (32 mg/kg) and infused with saline solution or NE (4 micrograms/kg/min) for 60 minutes or diltiazem at a rate of 20 micrograms/kg/min for the first 5 minutes and 10 micrograms/kg/min for the remaining 70 minutes. Diltiazem was infused as pretreatment 15 minutes before continued infusion with NE for 60 minutes, simultaneously infused with NE for 60 minutes or delayed 30 minutes after the start of NE infusion. Diltiazem alone exhibited no significant effect on hemodynamics, but pretreatment with diltiazem was able to moderate the rapid NE-induced increases in heart rate. NE infusion produced significant numbers of the 2 forms of contraction band lesions: (1) paradiscal contraction band lesions involving a small portion of the cell adjacent to the disc, and (2) holocytic contraction band lesions involving the entire cell. Diltiazem reduced the number of contraction band lesions, particularly the holocytic contraction band lesions, provided diltiazem was available before the insult and massive influx of calcium with a pharmacologic dose of NE. Although the exact mechanism of diltiazem's cardioprotective properties is not known, the timing of drug administration does appear to affect the degree of protection.     

Evidence for a Type 1 diabetes‐specific mechanism for the insulin gene‐associated IDDM2 locus rather than a general influence on autoimmunity

Aims The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5′ upstream of the insulin (INS) and insulin‐like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self‐tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes‐specific locus or acting as a general autoimmunity gene. Methods We genotyped the INS‐IGF2 VNTR [using the surrogate INS?23 HphI single nucleotide polymorphism (SNP)] in 823 Graves’ disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. Results We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case–control dataset showed no genotypic or allelic difference between the two populations. Conclusions These data suggest that the INS‐IGF2 VNTR is acting as a Type 1 diabetes‐specific susceptibility gene rather than as an influence on general autoimmunity.     

Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

AIMS: Autoimmune disorders co-exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population. METHODS: Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population. RESULTS: The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P-value = 1.98 x 10(-5) (female), P-value = 1.1 x 10(-8) (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01). CONCLUSION: These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.