A study of twins and stroke.

BACKGROUND AND PURPOSE: Although there are strong genetic contributions to coronary artery disease, only a few studies have considered heritable influences on stroke. METHODS: We investigated the role of genetic factors in stroke using the Twin Registry maintained by the National Academy of Sciences-National Research Council. The registry includes 15,948 male twin pairs born between 1917 and 1927. In 1985, 9,475 twins responded to a mailed questionnaire, which covered vascular risk factors, cardiac events, and stroke. RESULTS: Analysis of twin pairs in which both responded to the questionnaire, and a question on stroke, indicated proband concordance rates of 17.7% for monozygotic pairs and 3.6% for dizygotic pairs (relative risk = 4.3; chi 2 = 4.94, df = 1; p less than 0.05). CONCLUSIONS: This nearly fivefold increase in the prevalence of stroke among the monozygotic compared with the dizygotic twin pairs suggests that genetic factors are involved in the etiology of stroke. The twin study paradigm holds considerable promise for identifying both genetic and environmental influences on stroke.     

Localized proton NMR observation of [3-13C]lactate in stroke after [1-13C]glucose infusion.

To assess whether elevated lactate in stable stroke is being actively produced from blood glucose localized 1H NMR stimulated echo spectra were obtained from a patient in the region of a 32-day-old cortical infarct before and 60-100 min after infusion of [1-13C]glucose. Prior to the infusion the spectrum from the region of the infarct contained an elevated resonance from C3 lactate and a greatly reduced resonance from N-acetyl groups relative to an unaffected contralateral region. After the infusion two additional resonances were observed at 62 and -64 Hz relative to the unlabeled resonance of C3 lactate which were assigned on the basis of chemical shift and relative intensity to [3-13C]lactate. The [3-13C]lactate fractional enrichment in the infarct region was measured to be 32% which is within error one-half the average [1-13C]plasma glucose enrichment during the postinfusion NMR measurement. The result suggests that the stroke lactate pool was completely derived from infused glucose.     

Identification of antibody epitopes within the CB-11 peptide of type II collagen. I: Detection of antibody binding sites by epitope scanning.

Using epitope scanning, the precise location of antibody binding sites on the CB-11 peptide of bovine type II collagen have been identified for the first time. Two hundred and seventy two peptides (8 amino acids in length and overlapping by seven amino acids), representing the complete CB-11 sequence, were synthesised on solid phase supports, in duplicate, and were screened with sera from arthritic and non-arthritic, bovine type II collagen-immunised rats. A total of twenty one different antibody binding sites were identified with no epitope being uniquely recognised by sera from arthritic, as compared to non-arthritic, rats although differences in the relative amount of antibody binding were seen. Individual sera identified between two and thirteen epitopes with one epitope being recognised by all sera. Some of the amino acid sequences, of the CB-11 region of bovine type II collagen, recognised by the rat sera are identical to the sequences in human type II collagen and thus these epitopes may be relevant to autoimmunity to type II collagen in patients with rheumatoid arthritis.     

Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia

PURPOSE: Eicosanoids with vasodilating and angiogenic properties have been postulated to be effective therapies for critical leg ischemia (CLI) secondary to atherosclerotic peripheral arterial disease. The ability to deliver active drug to the site of action at adequate doses for sufficient duration has been a major limitation in the clinical development of such therapies. Lipo-ecraprost is a lipid-encapsulated prostaglandin E1 prodrug with the potential to deliver active prostaglandin to the site of critical arterial ischemia. The current trial was designed to test the hypothesis that lipo-ecraprost would improve amputation-free survival in patients with CLI who had no revascularization options. METHODS: The study was randomized, multicenter, double blind, and placebo controlled. Patients who met clinical and hemodynamic criteria were randomized to receive placebo or lipo-ecraprost (60 microg) administered intravenously on each of 5 days per week, for a total of 8 weeks. The study's primary endpoint was the rate of a composite end point of death or amputation above the level of the ankle at 180 days (6 months). RESULTS: The study was terminated on a recommendation from the Data and Safety Monitoring Board after the completion of a protocol-specified interim analysis for futility. At the time of termination, 383 of the planned 560 patients had been randomized, of which 379 received at least one dose of study medication and thus were included in the intention-to-treat population. Twenty-three patients were lost to follow-up and were not available for 6-month assessments. At 6 months of follow-up, there were 23 amputations in the 177 patients who received placebo, and 29 amputations in the 179 patients randomized to lipo-ecraprost. At 6 months, 10 deaths had occurred in the placebo group and 18 deaths had occurred in the lipo-ecraprost arm. Changes in lower-extremity hemodynamics over the 6-month study period did not differ between the placebo and lipo-ecraprost treatment arms. CONCLUSION: Intensive treatment with lipo-ecraprost failed to modify the 6-month amputation rate in patients with CLI who were not candidates for revascularization.     

Administration of dexamethasone induces proteinuria of glomerular origin in mice

The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.