ESR and cell culture studies on free radical-scavenging and antioxidant activities of isoflavonoids

Isoflavonoids are thought to be the biologically active components in soy that play a role in the prevention of coronary heart disease and breast and prostate cancer. Mechanisms to explain how isoflavonoids mediate beneficial effects have not yet been clearly established. This study was undertaken to investigate the free radical-scavenging and antioxidant activities of various structure-related isoflavonoids including genistein, daidzein, biochanin A, and genistin in a cell-free and an endothelial cell model system. Electron spin resonance spectroscopy and spin trapping techniques were applied to evaluate the ability of isoflavonoids to scavenge hydroxyl, superoxide, nitric oxide, diphenylpicrylhydrazyl, galvinoxyl, and lipid-derived radicals. All isoflavonoids tested had no significant scavenging effects on the aforementioned radicals in concentrations up to 1.0 mM. However, at a physiologically achievable concentration of 5 nM, both genistein and daidzein slightly increased intracellular-reduced glutathione levels approximately by 10 and 30%, respectively, in human endothelial cells, whereas cellular alpha-tocopherol and uric acid remained unchanged by the isoflavonoid treatments. Present data indicate that free radical-scavenging activities of the isoflavonoids tested probably do not substantially contribute to their antioxidant properties. The ability of genistein and daidzein to increase cellular GSH (reduced glutathione) might be important for their action in biological system.     

Do beta-blockers prolong survival in heart failure only by inhibiting the beta1-receptor? A perspective on the results of the COMET trial

Experimental and clinical studies indicate that carvedilol exerts multiple antiadrenergic effects in addition to beta(1)-receptor blockade, but the prognostic importance of these actions has long been debated. This controversy has now been substantially advanced by the results of the recently completed Carvedilol Or Metoprolol European Trial (COMET), which showed that carvedilol (25 mg twice daily) reduced mortality by 17% when compared with metoprolol (50 mg twice daily), P=.0017--a result that was consistent with the differences seen across earlier controlled trials with beta-blockers in survivors of an acute myocardial infarction and in patients with chronic heart failure. Questions have been raised about the interpretation of these findings in view of the fact that the trial did not use the dose or formulation of metoprolol that was shown to prolong life in a placebo-controlled trial (ie, Metoprolol CR/XL [Controlled Release] Randomized Intervention Trial in Heart Failure). Pharmacokinetic and pharmacodynamic analyses, however, indicate that the dosing regimen of metoprolol selected for use in the COMET trial produces a magnitude and time course of beta(1)-blockade during a 24-hour period that is similar to the dose of carvedilol targeted for use in the trial. These analyses suggest that the observed difference in the mortality effects of metoprolol and carvedilol is not related to a difference in the magnitude or time course of their beta(1)-blocking effects but instead reflect antiadrenergic effects of carvedilol in addition to beta(1)-blockade.     

S-Adenosylmethionine: molecular,biological, and clinical aspects--an introduction

In clinical research, a novel approach has emerged: some of the essential nutrients are being used to treat pathologic conditions. Many of these nutrients, including methionine, must first be activated in the liver or in other tissues before they can exert their key functions. However, this activating process is impaired in disease states and, as a consequence, nutritional requirements change. For instance, for methionine to act as the main cellular methyl donor, it must first be activated to S-adenosylmethionine (SAMe; also known as ademethionine). SAMe is required and is of fundamental importance for the metabolism of nucleic acids and polyamines, the structure and function of membranes, and as a precursor of glutathione. These processes are often seriously altered in various pathologic states addressed in this symposium, but they cannot be restored by simply administering methionine. For instance, in liver disease associated with impairment of the enzyme that activates methionine to SAMe, supplementation with methionine is useless and may even become toxic as it accumulates because it is not used. Accordingly, one must correct the lack of SAMe by bypassing the deficiency in enzyme activation; this is done by providing the product of the defective reaction, namely SAMe. Under these pathologic conditions, SAMe becomes crucial for the functioning of the cell. Thus SAMe, which is found in all living organisms, becomes the essential nutrient instead of methionine. This symposium reviewed the biological and corresponding molecular aspects of SAMe metabolism and the clinical consequences of its deficiency or supplementation in various tissues.     

Use of a state inpatient forensic system under managed mental health care

OBJECTIVES: One of the goals of managed mental health care has been to lower the use of inpatient psychiatric treatment. In the past, interventions that have limited hospitalization for persons with severe mental illness have led to greater involvement of these individuals with the criminal justice and forensic mental health systems. The authors examined associations between Medicaid managed mental health care in Massachusetts and rates of admission to the inpatient forensic mental health service maintained by the state's mental health department. METHODS: A total of 7,996 persons who were receiving services from the department before and after the introduction of managed care were studied. A logistic regression model based on generalized estimating equations was used to identify associations between Medicaid beneficiary status and forensic hospitalization before and after the introduction of managed care. RESULTS: The overall rate of forensic hospitalization declined in the study cohort in both periods. However, no significant decline was observed in the risk of forensic hospitalization among Medicaid beneficiaries whose care had become managed. CONCLUSIONS: Although the results of this study warrant further exploration, the risk of forensic hospitalization among Medicaid beneficiaries should be considered by policy makers in the design of mental health system interventions.     

The aging baboon: comparative demography in a non-human primate

Why do closely related primate genera vary in longevity, and what does this teach us about human aging? Life tables of female baboons (Papio hamadryas) in two wild populations of East Africa and in a large captive population in San Antonio, Texas, provide striking similarities and contrasts to human mortality patterns. For captive baboons at the Southwest Foundation for Biomedical Research, we estimate the doubling time of adult mortality rate as 4.8 years. Wild females in free-living populations in Tanzania and in Kenya showed doubling times of 3.5 and 3.8 years, respectively. Although these values are considerably faster than the estimates of 7-8 years for humans, these primates share a demographic feature of human aging: within each taxon populations primarily vary in the level of Gompertz mortality intercept (frailty) and vary little in the demographic rate of aging. Environmental and genetic factors within taxa appear to affect the level of frailty underlying senescence. In contrast, primate taxa are differentiated by rates of demographic aging, even if they cannot be characterized by species-specific lifespan.     

From Case Management to Court Clinic: Examining Forensic System Involvement of Persons with Severe Mental Illness

The study examined the flow of a state mental health agency's case-managed clients into its forensic mental health court clinic systems for evaluation of competency to stand trial (CST) for a criminal offense. An analysis of merged encounter data from the case management and court clinic systems revealed that roughly 2% of the case-managed population were referred to court clinics for evaluation of CST during a 1-year period, but that these 2% represented roughly one eighth of that year's court clinic evaluees. The likelihood of this involvement was higher for males, African-Americans, and Latinos, and for persons with a history of substance abuse, and also was associated with higher levels of previous hospitalization. In addition, CST evaluees were more likely to be non-White, male, and uninsured than were case-managed evaluees. These data indicate that demographic characteristics, substance abuse, and lack of insurance are potential risk factors for forensic and, by inference, criminal justice system involvement among persons with mental illness.     

Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers.

Free radicals in cigarette smoke (CS) cause oxidative damage to proteins, DNA, and lipids, contributing to the pathobiology of atherosclerosis, heart disease, and cancer. In vitro studies have shown that antioxidants quench free radicals and ameliorate certain aspects of biomolecular damage caused by CS. It is hypothesized that a combination of antioxidants is more effective than a single antioxidant, due to their interactions. To investigate whether supplemental antioxidants reduce CS-related lipid peroxidation in vivo and whether they are more effective in combination, we conducted an intervention study in smokers. In a randomized double-blind placebo-controlled trial, we investigated whether vitamin C or an antioxidant mixture containing vitamin C, alpha-lipoic acid, and vitamin E decreases plasma F(2)-isoprostane levels, an index of oxidant stress, in smokers. Plasma of 126 smokers (mean age, 46 years; age range, 20-78 years) was analyzed for F(2)-isoprostanes at baseline and after intervention with antioxidants and placebo. In smokers with a body mass index (BMI) above the median, 2 months of daily supplementation with 500 mg of vitamin C decreased plasma F(2)-isoprostane levels by 28.8 pmol/liter when compared with the placebo group (P = 0.001); levels in the mixture group were 7.45 pmol/liter lower after treatment, but this difference was not statistically significant (P = 0.14). There was no treatment effect in smokers with a low BMI. BMI was significantly positively associated with plasma F(2)-isoprostane levels (trend P = 0.001). Antioxidants decrease smoking-related lipid peroxidation markers of oxidative stress in humans with high BMI. Our results do not indicate that an antioxidant combination is more effective than vitamin C alone. The intake of antioxidants may help prevent smoking-related diseases. Smoking cessation should still be considered the most effective way to prevent smoking-related diseases.