Effects of the calcineurin inhibitor FK506, the platelet-activating factor (PAF) antagonist, and free radical scavenger Ginkgo biloba extract, EGb 761, and their combination on reperfusion-induced ventricular fibrillation (VF), ventricular tachycardia (VT), and recovery of cardiac function were studied after 30 min of global ischemia followed by 2 h of reperfusion in isolated rat hearts. In the first series of studies, rats received a daily (oral) dose of 0, 1, 5, 10, 20, or 40 mg/kg/day FK506 for 10 days. FK506 dose-dependently reduced the incidence of reperfusion-induced total (irreversible plus reversible) VF from a value of 92% for untreated animals to 92% (NS), 83% (NS), 67% (NS), 33% (p<0.05), and 25% (p<0.05), for doses of 1-40 mg/kg/day, respectively, with effects on incidence of VT showing the same pattern. FK506, between 20 and 40 mg/kg/day, also resulted in significant recovery of postischemic cardiac function. In the second series of studies, rats were treated with EGb 761 alone or in combination with FK506. Whereas no significant reduction in arrhythmias or improvement in cardiac function resulted from a single intervention of EGb 761 at 25 mg/kg/day, combined treatment of rats with 25 mg/kg/day of EGb 761 and 1 or 5 mg/kg/day of FK506 resulted in a reduction in total and irreversible VF of 92% and 92% to 42% (p<0.05) and 33% (p<0.05), 25% (p<0.05) and 8% (p<0.05), respectively, versus untreated control animals, paralleled by similar effects on the incidence of VT and accompanied by significant improvements in postischemic cardiac function. Our results demonstrate a novel cardioprotective characteristic of FK506 and suggest that combination therapy by using FK506 plus EGb 761 synergistically improves postischemic cardiac function, while reducing the incidence of reperfusion-induced VF and VT, which may expand the clinical utility of FK506 and allow therapy with FK506 at lower doses than are currently useful.
A random sample of 457 neonates was prospectively studied in order to identify the incidence, common types, and risk factors for arrhythmias in the neonatal intensive care unit (NICU). A 12-lead EKG was studied in all neonates (n = 457). A total of 139 Holter studies was done in every fourth baby with a normal EKG (n = 100) and in all babies with an abnormal EKG (n = 39). Of the 100 infants who were thought to be arrhythmia-free by EKG, nine infants demonstrated an arrhythmia on Holter studies. When we correlated screening results with maternal, obstetrical, and neonatal risk factors; arrhythmias were significantly associated with male gender, more mature gestational age, lower glucose levels, maternal smoking, high umbilical artery lines, and the use of the nebulized beta-2 adrenergic treatment, whereas umbilical venous lines and dopamine infusion did not relate to arrhythmia. We conclude that arrhythmias are more common in the NICU than in the general neonatal population. Compared to Holter monitoring, the sensitivity of the EKG was only 89%.
This study evaluates peripheral blood T lymphocyte expression of inflammatory and proinflammatory cytokines as well as T regulatory (Treg) (FOXP3+CD25+CD4+) cells in type 2 diabetes (T2DM). Participants included 40 T2DM and 30 healthy control subjects. Twenty-four patients had no complications while 16 were afflicted with coronary heart disease (CHD). Relative to healthy subjects, all T2DM patients showed a significant increase in expression of CD4+IFN-ϒ+, CD4+TNF-α+, and CD4+IL-8+ T cells (P < 0.001) as well as CD4+IL-6+, CD4+IL-1β+, and IL-17+ T cells (P < 0.05) while the ratios of Treg/Th1(CD4+IFN-ϒ+) and Treg/Th-17(CD4+IL-17+) cells were significantly decreased (P < 0.05 and P < 0.01). T2DM patients with CHD showed a significant increase in CD4+IFN-ϒ+, CD4+TNF-α+, and CD4+IL-17+ T cells and a significant decrease in Treg/Th1 and Treg/IL-17 cells compared to T2DM patients without CHD (P < 0.05). In CHD-afflicted T2DM, HbA1c correlated positively with CD4+IFN-ϒ+ T cells (P < 0.01), HDL correlated negatively with each of CD4+IL-8+ T cells and CD4+IL-17+ T cells (P < 0.05), and LDL correlated positively with CD4+IL-1β+ T cells (P < 0.05). Conclusion. This study shows that hyperglycemia and dyslipidemia correlate with increased inflammatory cytokine expression and suggests the involvement of T cells in the development of diabetes and its complications.
Vitiligo is a disorder involving progressive skin depigmentation caused by host mediated destruction of melanocytes. Its pathogenesis is known to correlate with elevated levels of activated skin-infiltrating T lymphocytes and is presumed to be autoimmune in nature. In the present study, we characterize the immunophenotype of peripheral blood T cells from vitiligo patients, with the objective of developing an investigative and diagnostic tool for the disease, using analysis of peripheral blood. Subjects for this investigation included 32 patients diagnosed with non-segmental vitiligo and 28 age-and gender-matched, normal, healthy control participants. Whole venous blood taken from each subject was analyzed using 2-color flow cytometry for immunologically-relevant lymphocyte subsets. When compared with healthy control subjects, peripheral blood from individuals with vitiligo was found to have lower total numbers of lymphocytes (p<0.039). Vitiligo patients also had elevated percentages of memory (CD4+CD45RO+) T cells; (p<0.05), but NK-T cells (CD3+CD16+CD56+) and naive T cells (CD4+CD45RA+) were present at lower total numbers and percentages than in healthy controls (p<0.01 and 0.05 respectively). Blood from severely afflicted subjects exhibited elevated CD3+HLADR+ and CD4+CD45RO+ as well as lower percentages of NK-T cells (p<0.05) when compared with mild cases. In conclusion, disease-associated, peripheral blood lymphocyte immunophenotypic profiles of vitiligo patients are consistent with the hypothesis of T cell activation as a major feature of the disorder. These include elevated memory and reduced naive T cell percentages and increased expression of the activation-associated surface antigen CD25. These changes presumably reflect increased antigen-mediated activation. Moreover, because a corollary effect is increased activation-induced cell death (AICD), lower overall lymphocyte counts observed in vitiligo-afflicted subjects is also expected.
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