DISEASE PREVENTION
Page 9

Jain SK; McVie R; Jaramillo JJ; Palmer M; Smith T; Meachum ZD; Little RL
Department of Pediatrics, Louisiana State University Medical Center, Shreveport 71130, USA.
Lipids (United States) Mar 1996, 31 Suppl pS87-90

Among many factors, elevated lipids and lipid peroxide levels in blood are major risk factors in the development of cardiovascular disease in diabetic patients. This study has examined whether oral supplementation of vitamin E, an antioxidant, has any effect on blood of diabetic patients. Thirty-five diabetics(D) were supplemented with DL-alpha-tocopherol (E) capsule (orally, 100 IU/d) or placebo (P) for three months in double-blind clinical trials. Plasma E was analyzed by HPLC and LP by the thiobarbituric acid-reactivity; serum lipids by auto-analyzer. Data were analyzed using paired t-test and Wilcoxon Signed Rank Test. Vitamin E supplementation significantly lowered LP and lipid levels in diabetic patients; there were no differences in these parameters after P supplementation. There were no differences in the duration of diabetes and ages of D between P- and E- supplemented groups. This study suggests that vitamin E supplementation significantly lowers blood LP and lipid levels in diabetic patients.

Berliner JA; Heinecke JW
Department of Pathology, University of California Los Angeles 90024, USA.
Free Radic Biol Med (United States) 1996, 20 (5) p707-27

This article reviews our current understanding of the mechanisms of low-density lipoprotein (LDL) oxidation and the potential role of oxidized lipoproteins in atherosclerosis. Studies in hypercholesterolemic animal models indicate that oxidation of LDL is likely to play an important role in atherogenesis. Epidemiological investigations further suggest that the dietary intake of antioxidants is inversely associated with the risk of vascular disease, suggesting that oxidized LDL may be important in human atherosclerosis. By activating inflammatory events, oxidized lipoproteins may contribute to all stages of the atherosclerotic process. Lipoprotein oxidation is promoted by several different systems in vitro, including free and protein-bound metal ions, thiols, reactive oxygen intermediates, lipoxygenase, peroxynitrite, and myeloperoxidase. Intracellular proteins that bind iron or regulate iron metabolism might also play an important role. The physiologically relevant pathways have yet to be identified, however. We assess recent findings on the effects of antioxidants in vivo and suggest potential strategies for inhibiting oxidation in the vessel wall. (265 Refs.)

Lou MF; Xu GT; Zigler S Jr; York B Jr
Department of Veterinary and Biomedical Sciences, University of Nebraska-Lincoln 68583, USA.
Curr Eye Res (England) Apr 1996, 15 (4) p423-32

Naphthalene-induced cataract in rat lenses can be completely prevented by AL01576, an aldose reductase inhibitor (ARI). In an attempt to understand the mechanism of this inhibition, several ARIs were examined to compare their efficacies in preventing naphthalene cataract, using both in vitro and in vivo models. Two classes of ARIs were tested: One group including AL01576, AL04114 (a AL01576 analog) and Sorbinil contained the spirohydantoin group, while Tolrestat contained a carboxylic acid group. Furthermore, to clarify if aldose reductase played a role in naphthalene-induced cataractogenesis in addition to its role in sugar cataract formation, a new dual cataract model was established for ARI evaluations. This was achieved by feeding rats simultaneously with high galactose and naphthalene or incubating rat lenses in culture media containing high galactose and naphthalene dihydrodiol. Under these conditions, both cortical cataract and perinuclear cataract developed in the same lens. It was found that at the same dosage of 10 mg/kg/day, both AL01576 and AL04114 completely prevented all morphological and biochemical changes in the lenses of naphthalene-fed rats. Sorbinil was less efficacious, while Tolrestat was inactive. AL01576 showed a dose-response effect in preventing naphthalene cataract and at 10 mg/kg/day, it was also effective as an intervention agent after cataractogenesis had begun. With the dual cataract model, Tolrestat prevented the high galactose-induced cortical cataract but showed no protection against the naphthalene-induced perinuclear cataract. AL01576, on the other hand, prevented both cataract formations. Results for dulcitol and glutathione levels were in good agreement with the morphological findings. AL04114, and ARI as potent as AL01576 but without its property for cytochrome P-450 inhibition, displayed similar efficacy in preventing naphthalene cataract. Based on these results, it was concluded that the prevention of the naphthalene cataract probably results from inhibition of the conversion of naphthalene dihydrodiol to 1,2-dihydroxynaphthalene and that the effect of the ARIs cannot be explained by their inhibition of the dihydrodiol dehydrogenase activity of aldose reductase.

Borghi C; Ambrosioni E
Department of Internal Medicine, University of Bologna, Italy.
Clin Exp Hypertens (United States) Apr-May 1996, 18 (3-4) p547-58

The prevention of coronary artery disease (CHD) and particularly of myocardial infarction (MI) is based on some well designed strategies aimed at treating both asymptomatic high-risk patients (primary prevention) and patients with established CHD (secondary prevention). A positive impact from primary prevention can be basically achieved trough a reduction in high blood pressure and by correcting dyslipidemia. The benefit can be substantially increased by smoking cessation, increasing physical exercise, reduction of body weight, use of post-menopausal oestrogen, moderate alcohol consumption and use of high doses of vitamin E in those patients who are compliant with the specific strategies. Secondary prevention of MI can be again obtained by controlling blood pressure and reducing serum cholesterol in patients surviving acute MI who can also benefit from the administration of beta-blockers, aspirin and probably ace-inhibitors particularly in presence of left ventricular dysfunction. We suggest that in both arms of prevention, significant results can be achieved mainly by a multifactorial approach capable of correcting all the modifiable risk factors that contribute to the rather complex pathogenesis of CHD. (22 Refs.)

Drobniewski F; Tayler E; Ignatenko N; Paul J; Connolly M; Nye P; Lyagoshina T; Besse C
Regional Tuberculosis Centre, Dulwich Public Health Laboratory, London, UK.
Tuber Lung Dis (Scotland) Aug 1996, 77

OBJECTIVE: To assess tuberculosis diagnosis, chemoprophylaxis and therapy in Siberia as a paradigm for the Russian Federation.

DESIGN: Data was obtained from official sources and through visits to dispensaries and hospitals in 1994.

RESULTS: Tuberculosis disease and cure is classified according to a Dispensary Group Register based principally on clinical and radiological criteria. Isoniazid is widely used for chemoprophylaxis and post-therapy and may be linked to high levels of isoniazid resistance. Combination drug therapy is individualized, frequently changed, and given orally, parenterally or intra-bronchially. Galvanization, autotransfusion of ultra-violet irradiated blood, antioxidants and steroids are used as adjunct treatment. Ambulatory treatment is uncommon. Surgical treatments including lobectomy and pneumonectomy are used in 5-10% of patients.

CONCLUSION: Tuberculosis is increasing in Siberia. An improved drug supply using short course standardized regimens is required supported by high quality co-ordinated bacteriological services. Surgery retains a useful role, but many adjunct therapies should be abandoned.

Singh RB; Niaz MA
Heart Research Laboratory, Medical Hospital and Research Centre, Moradabad, India.
J Assoc Physicians India (India) Jan 1996, 44 (1) p43-8

No abstract.

Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
Int J Food Sci Nutr (England) May 1996, 47 (3) p233-61

In this review the process of lipid peroxidation and the atherogenicity of peroxidied lipids are discussed. Recent findings with regard to the effect of selected dietary factors on susceptibility of lipids to oxidative stress and on antioxidant defences are analysed with particular reference to their potential use in the prevention and treatment of atherogenesis and, by extension, coronary heart disease. Laboratory methods of assessing antioxidant defences, lipid peroxidation and the effects of lipid peroxidation are also reviewed and discussed with particular reference to their ability to assess in vivo oxidative stress and lipid peroxidation status. A range of oxidative stress indices are presented and their limitations discussed, but the main focus is on the most commonly used laboratory test for lipid peroxidation, the thiobarbituric acid reacting substances (TBARS) test. Finally, the influence of selected dietary factors on measured peroxidation status is discussed, with particular reference to the antioxidant vitamins C (ascorbic acid) and E (alpha tocopherol) and the type of fatty acids (mono- and poly-unsaturated) in the diet. (222 Refs.)

Ernster VL
Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco 94143-0560, USA.
Annu Rev Public Health (United States) 1996, 17 p97-114

Female lung cancer death rates increased by more than 550 percent between 1950 and 1991. In 1986 lung cancer surpassed breast cancer to become the leading cause of cancer death in women in the United States. The lung cancer epidemic is primarily attributable to cigarette smoking, which is responsible for at least 80% of the disease in women. There are gender differences in the distribution of lung cancer by histologic type, even controlling for smoking, and some data suggest greater female than male susceptibility to lung cancer at a given leves risk of lung cancer in nons moking women. Family history of lung cancer, personal history of lung disease (e.g. asthma, chronic bronchitis, pneumonia, or tuberculosis), and a history of radiotherapy also appear to be associated with increased risk. Data specific to women on the role of household radon exposures or of specific occupational or environmental exposures are relatively sparse and inconsistent. Finally, many studies have reported a decreased risk of lung cancer in individuals who consume high levels of fruits and vegetables; however, clinical trials fail to support a beneficial effect of beta-carotene supplementation. Since cigarette smoking accounts for the vast majority of lung cancer cases in women, efforts to prevent adolescent girls from starting to smoke and to encourage cessation among established smokers have the greatest potential for reducing the female lung cancer burden. (94 Refs.)

Arora AS; Gores GJ
Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Semin Liver Dis (United States) Feb 1996, 16 (1) p31-8

Based on current information, we have described the role that metals play in potentiating and ameliorating liver I/R injury. To date, most of the data have focused on the deleterious effects of free iron in mediating I/R injury. Several therapeutic strategies have proven useful in animal models to counteract the effect of iron as a potentiator of I/R injury. These approaches have predominantly centered on the role of iron chelation using DFO and DFO conjugates. The data suggest that chelation of iron may prove useful in preventing I/R injury such as occurs in liver transplantation. Indeed, enough data are now available to initiate and support clinical trials (e.g., addition of DFO conjugates to explant storage solutions). The role of copper, however, is less well defined. Copper is important for the function of copper-zinc SOD. However, free copper may be as injurious as free iron. Further studies are needed to clarify the role of copper in I/R-induced hepatocellular necrosis. Selenium has a well-defined antioxidant role as part of GSH peroxidase (GSH antioxidant pathway). More recent data suggest that selenium may also act as an antioxidant through selenoprotein P, but the role of selenoprotein P in I/R injury remains to be defined. Finally, zinc appears to function as an antioxidant in less well-defined pathways. Further studies are needed to identify the fundamental mechanisms by which zinc may ameliorate oxidative damage during I/R injury. These data demonstrate that metals play a critical role in I/R injury of the liver and remain a fruitful area for investigation and development of therapeutic strategies. (65 Refs.)

Clement A
Service de Physiologie, Hopital Trousseau, Paris.
Rev Mal Respir (France) Jul 1996, 13 (3) p243-9

Bronchopulmonary dysplasia (BPD), a respiratory disorder first described in prematurely born infants with respiratory distress syndrome (RDS) treated with mechanical ventilation and oxygen supplementation, is the most common cause of chronic lung disease in infants. It is defined as the need for increased inspired oxygen at 28 days of age, and is observed with the highest frequency following premature delivery of very low birth weight infants. Indeed, an incidence of 48% has been recently reported in a population with a mean gestational age of 27 weeks. The etiology of BPD is multifactorial including lung immaturity, respiratory distress, oxygen therapy, and mechanical ventilation. Based on the current understanding of the pathogenesis of the disease, several therapeutical strategies are used. One of them is focused on the prevention of BPD by correcting surfactant deficiency in premature infants with RDS using exogenous surfactant, and also by improving the techniques of mechanical ventilation used for the management of RDS. Another approach which is being deveon the factors involved in the processes of repair of the injured immature lung. These factors include the use of inhibitors of the inflammatory cascade, antioxidants, and inhibitors of fibrosis. (42 Refs.)

Napoli C; Postiglione A; Scarpato N; Corso G; Ambrosio G; Condorelli M; Mancini M; Chiariello M
Cattedra di Cardiologia, Universita degli Studi, Federico II, Napoli.
Cardiologia (Italy) May 1996, 41 (5) p435-9

Homozygous familial hypercholesterolemia (HFH) results from a mutation affecting both the structure and function of a cell surface receptor that removes low density lipoproteins (LDL) from plasma. The disorder is characterized by autosomal dominant inheritance, a lifelong elevation in the concentration of LDL-bound cholesterol in blood and by cholesterol deposits that form xanthomas and early coronary artery disease. HFH patients, as a result of the increased levels and prolonged residence time of LDL in plasma, have a strong tendency toward accumulation of LDL-cholesterol in the arterial wall causing premature atherosclerosis. Selective LDL-apheresis (LA) on dextran/sulphate cellulose columns is the best therapy reducing mortality of these patients. We previously showed that prolonged lifelong enhanced LDL oxidation in HFH. LDL undergo oxidation before being taken up by macrophages then transformed into foam cells. At the present time, the relevance of the in vitro macrophages studies to the accumulation of cholesterol esters in scavenger cells of HFH patients is not yet established. The aim of this study was to investigate LDL oxidation, induced by xanthine (2 mM)+xanthine oxidase (100 mU), and cholesterol esterification in macrophages, in 8 HFH patients before and after LA. LDL peroxidation by conjugated-diene absorbance showed an increased resistance against oxidation after LA: lag time 129 +/- 25 vs 112 +/- 27 min, p < 0.05; diene 1 vs 13.9 +/- 2.5 nM/min/mg LDL, p < 0.01. Peroxidation was also evaluated from lipid peroxides (158 +/- 34 vs 57 +/- 18 nM/mg protein after LA, p < 0.05) and malonyldialdehyde (38 +/- 12 vs 27 +/- 8 nM/mg protein after LA, p < 0.05) content. When oxidized LDL was run on polyacrylamide gel extensive apo-B100 fragmentation was observed in LDL before LA, vs a less fragmentation after LA. A similar reduction was obtained in LDL agarose mobility after LA (1.7 +/- 0.2 vs 2.5 +/- 0.2, p < 0.05). Cholesterol esterification in mouse peritoneal macrophages was also decreased after LA (8.5 +/- 1.8 vs 14.6 +/- 2.7 nM/mg cell protein/12 hours, p < 0.05). Vitamin E content of LDL (mg/g protein) was increased after LA (4.44 +/- 1.0 vs 3.9 +/- 1.2, p < 0.05). Thus, selective LA, not only decreases the pool of LDL, but it also induces changes that render LDL less susceptible to oxidation and decreased high cholesterol esterification in macrophages. The prevention of these mechanisms by LA contributes actively to retard atherogenesis in HFH patients.

Gordon M
Department of Food Science & Technology, University of Reading, UK.
Nat Prod Rep (England) Aug 1996, 13 (4) p265-73

No abstract.

Prasad K; Gupta JB; Kalra J; Lee P; Mantha SV; Bharadwaj B
Department of Physiology, University of Saskatchewan, Saskatoon, Canada.
J Mol Cell Cardiol (England) Feb 1996, 28 (2) p375-85

We investigated the effects of chronic volume overload in the absence or presence of vitamin E supplements on the cardiac function and contractility, cardiac malondialdehyde (MDA)--a lipid peroxidation product--cardiac antioxidant enzyme activity and antioxidant reserve in canine model. The dogs were divided into three groups of seven dogs each: group I, control; group II, mitral regurgitation (MR) of 4 months duration; and group III, MR of 4 months duration receiving vitamin E (40 U/kg/daily) orally. MR was created by detaching two or more chordae tendinae to raise left atrial pressure to 2.5 to three times normal. MR produced a decrease in the index of myocardial contractility with little change in myocardial function. Decrease in myocardial (left and right ventricles) contractility was associated with an increase in cardiac MDA, and a decrease in cardiac antioxidant reserve and antioxidant enzyme activity. Prevention of volume overload-induced decrease in myocardial contractility by vitamin E was associated with a decrease in cardiac MDA and an increase in cardiac antioxidant reserve and glutathione peroxidase activity towards control levels. Superoxide dismutase and catalase activity remained depressed in vitamin E-treated group. The results indicate that chronic volume overload decreases the contractility of both right and left ventricles and is associated with oxidative stress in both ventricles. These results support the hypothesis that oxygen free radicals are involved in the chronic volume overload-induced cardiac depression.

Keaney JF Jr; Guo Y; Cunningham D; Shwaery GT; Xu A; Vita JA
Evans Memorial Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118, USA.
J Clin Invest (United States) Jul 15 1996, 98 (2) p386-94

Excess vascular oxidative stress has been linked to impaired endlemia. alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known. We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 microg/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction. Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014). These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy. Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL. Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL.

Hansen PR
Medicinsk afdeling B, Rigshospitalet, Kobenhavn.
Ugeskr Laeger (Denmark) May 6 1996, 158 (19) p2706-10

The "oxidation hypothesis" states that oxidised low-density lipoprotein (ox-LDL) plays a central role in atherogenesis. LDL oxidation is a chaotic process initiated by reactive oxygen species. Enhanced uptake of ox-LDL in macrophages leads to foam cell formation in vitro, and ox-LDL has a variety of other experimental proatherogenic effects, e.g., endothelial cell activation, immunogenicity, platelet aggregation, and inhibition of endothelium-dependent vaso-relaxation. There are methodological limitations in the current laboratory methods aimed at characterization of the oxidative state of LDL. However, considerable evidence indicates that ox-LDL is found in plasma, arteries, and atheromatous plaques of humans, although the significance of this phenomenon is unknown. Antioxidants may inhibit atherosclerosis in experimental animals, and epidemiological data suggest an inverse relation between the intake of antioxidant vitamins and the risk of coronary artery disease. Randomised prospective trials are in progress, and until their conclusion, the clinical effect of antioxidant therapy in man remains unknown. (40 Refs.)

Harbige LS
Division of Immunology, United Medical School of Guy's and St. Thomas's Hospital, Rayne Institute, London, UK.
Nutr Health (England) 1996, 10 (4) p285-312

Nutrition and nutritional status can have profound effects on immune functions, resistance to infection and autoimmunity in man and other animals. Nutrients enhance or depress immune function depending on the nutrient and level of its intake. Protein-energy malnutrition and vitamin A deficiency are strongly associated with impaired immunity and infectious disease. The essential role vitamin A plays in infection and maintenance of mucosal surfaces has long been known. Recent evidence shows that T-cell subpopulations, cytokines and antibody subclasses are all affected by vitamin A. In animal studies supplementation with vitamin E protects against infection and is linked to stimulatory effects on the immune system. In man vitamin E and other anti-oxidants increase the number of CD4+ cells. Dietary lipids and zinc have a substantial impact on autoimmunity from protective to potentiation of immuno-pathological processes in animals. There is considerable potential to modify human autoimmune disease by manipulation of lipid nutrition. Deficiency of pyridoxine induces atrophy of lymphoid organs, marked reduction in lymphocyte numbers, impairs antibody responses and IL-2 production. Dietary copper is important in the prevention of infection in some animal species and T-cell function is defective under deficiency states due to an inability to produce IL-2. Selenium has been linked to viral infection, enhanced T-cell functions and TNF beta induced increase in natural killer cell activity. Understanding the molecular and cellular immunological mechanisms involved in nutrient-immune interactions will increase our applications for nutrition of the immune system in health and in disease.

Blackwell TS; Blackwell TR; Holden EP; Christman BW; Christman JW
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 27232, USA.
J Immunol (United States) Aug 15 1996, 157 (4) p1630-7

We hypothesized that endotoxin injection in rats would stimulate in vivo nuclear factor-kappa B (NF-kappa B) activation in lung tissue and that antioxidant treatment before endotoxin injection would attenuate endotoxin-induced NF-kappa B activation, chemokine gene expression, and neutrophilic lung inflammation. We studied NF-kappa B activation in rat lung tissue following a single i.p. injection of endotoxin (6 mg/kg). After in vivo endotoxin treatment, lung NF-kappa B activation peaked at 2 h and temporall the expression of cytokine-induced neutrophil chemoattractant mRNA in lung tissue. Treatment with the antioxidant N-acetylcysteine (NAC) 1 h before endotoxin resulted in decreased lung NF-kappa B activation in a dose-dependent manner (from 200-1000 mg/kg) and diminished cytokine-induced neutrophil chemoattractant mRNA expression in lung tissue. Treatment with NAC significantly suppressed endotoxin-induced neutrophilic alveolitis. The average total lung lavage neutrophil count was 5.5 x 10(6) with endotoxin treatment vs 0.9 x 10(6) with NAC treatment before endotoxin. The NF-kappa B pathway represents an attractive therapeutic target for strategies to control neutrophilic inflammation and lung injury.

Katz D; Mazor D; Dvilansky A; Meyerstein N
Dr. Joseph Kaufmann Hematology Laboratory, Corob Medical Research Center, Faculty of Health Sciences, Ben-Gurion, University of the Negev, Beer-Sheva, Israel.
Free Radic Res (Switzerland) Mar 1996, 24 (3) p199-204

Ionizing radiation is currently used for prevention of transfusion associated graft versus host disease (TAGVHD). As radiation damage is associated with the production of activated oxygen species, the aim of this study was to observe the immediate effect of ionizing radiation on red cell membrane and intracellular oxidative defense systems. Neonatal and iron deficiency (IDA) cells, known for their increased sensitivity to oxidative stress, were chosen and compared with normal cells. Irradiation was performed in doses of 1500 cGy, 3000 cGy and 5000 cGy. GSH and methemoglobin levels and the activity of different antioxidant enzymes, measured under optimal in vitro conditions, were preserved in all cells after irradiation. Only radiation at the highest does of 5000 cGy, caused significant potassium leakage in neonatal cells and insignificant increase in IDA cells. Thus, cells with increased sensitivity to oxidative stress are more susceptible to damage by ionizing radiation than normal cells.

Jialal I; Fuller CJ
Center for Human Nutrition, University of Texas--Southwestern Medical Center, Dallas 75235-9052, USA.
Crit Rev Food Sci Nutr (United States) Apr 1996, 36 (4) p341-55

Much evidence has accumulated that implicates the oxidative modification of low-density lipoprotein (LDL) in the early stages of atherogenesis. The , they have nutrients alpha-tocopherol, ascorbic acid, and betacarotene been shown to increase the resistance of LDL to oxidation when given to animals and humans. Because plasma levels of these nutrients can be increased by dietary supplementation with minimal side effects, they may show promise in the prevention of coronary artery disease. (115 Refs.)

Devaraj S; Li D; Jialal I
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9052, USA.
J Clin Invest (United States) Aug 1 1996, 98 (3) p756-63

Low levels of alpha tocopherol are related to a higher incidence of cardiovascular disease and increased intake appears to afford protection against cardiovascular disease. In addition to decreasing LDL oxidation, alpha tocopherol may exert intracellular effects on cells crucial in atherogenesis, such as monocytes. Hence, the aim of this study was to test the effect of alpha tocopherol supplementation on monocyte function relevant to atherogenesis. Monocyte function was assessed in 21 healthy subjects at baseline, after 8 wk of supplementation with d-alpha tocopherol (1,200 IU/d) and after a 6-wk washout phase. The release of reactive oxygen species (superoxide anion, hydrogen peroxide), lipid oxidation, release of the potentially atherogenic cytokine, interleukin 1 beta, and monocyte-endothelial adhesion were studied in the resting state and after activation of the monocytes with lipopolysaccharide at 0, 8, and 14 wk. There was a 2.5-fold increase in plasma lipid-standardized and monocyte alpha tocopherol levels in the supplemented phase. After alpha tocopherol supplementation, there were significant decreases in release of reactive oxygen species, lipid oxidation, IL-1 beta secretion, and monocyte-endothelial cell adhesion, both in resting and activated cells compared with baseline and washout phases. Studies with the protein kinase C inhibitor, Calphostin C, suggest that the inhibition of reactive oxygen species release and lipid oxidation is due to an inhibition of protein kinase C activity by alpha tocopherol. Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic.

Fernandez-Pol JA
Department of Veterans Affairs Medical Center, St. Louis, MO 63106, USA.
Anticancer Res (Greece) Jul-Aug 1996, 16 (4B) p2177-85

Metallopanstimulin (MPS) is a 9.5-kDal subunit "zinc finger" protein which is expressed in a wide variety of actively proliferating cells and tumor tissues (J. Biol. Chem. 268:21198-21204, 1993; Cell Growth & Diff. 5:811-825, 1994). A sensitive and specific radioimmunoassay (RIA) has been developed to measure circulating levels of MPS and MPS-like proteins. The RIA was evaluated for its ability to detect accurately elevations of MPS-immunoreactive material in the blood of patients with various types of neoplastic diseases. MPS concentrations were determined in the blood of 147 healthy subjects having no evidence of neoplastic disease, in 260 patients with nonmalignant diseases, and in 225 patients diagnosed with various types of cancer such as prostate, colorectal, lung, head and neck (epithelial malignancies), neuroendocrine, central nervous system, etc. Elevated MPS levels identified patients with neoplasias with greater than 90% confidence. In patients, not having neoplastic disease the MPS levels were lower than 10 ng/mL (82% of the population). In untreated patients with cancer, the MPS level range was 20-50 ng/mL and in stage M1b (metastasis to the bones) the MPS levels were extremely high (100 to 1000 ng/mL). In M1b patients that did not respond to therapy, the MPS levels remained very high ( > 100 ng/mL). In M1b patients that went into remission after treatment, the MPS levels were reduced. The MPS test may be useful as an aid in: 1) the early detection of a wide variety of neoplastic conditions and 2) the prognosis and management of cancer patients by following the changes in the concentrations of MPS in sera. Moreover, the results suggest that the combined use of the MPS test with other currently available tumor maker tests may significantly improve the chances of identifying a large proportion of active oncogenic processes by serodiagnosis.

Christen WG; Glynn RJ; Hennekens CH
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Ann Epidemiol (United States) Jan 1996, 6 (1) p60-6

Oxidative mechanisms may play an important role in the pathogenesis of age-related eye disease, in particular cataract and macular degeneration, the two most important causes of visual impairment in older adults. For this reason, there is considerable interest in determining whether vitamins and trace minerals with antioxidant properties can be of benefit in preventing the onset or progression of disabling eye disease. Basic research studies have shown that antioxidants can protect against the cumulative effects of oxidative stress in animal models of cataract and macular degeneration. Data from observational epidemiological studies in humans, however, are inconclusive. While results from several studies, primarily cross-sectional and case-control, are compatible with a possible protective role for micronutrients in disease development, data for specific nutrients or specific disease types have often been inconsistent. Further, these observational studies are limited because of the inherent imprecision of dietary exposure data and the likely effects of uncontrolled confounding. Thus, reliable data regarding a potentially important benefit of vitamin supplementation in eye disease will emerge mainly from well-designed, large-scale, randomized trials. (79 Refs.)

Wise GR; Schultz TT
Division of General Internal Medicine and Geriatric Medicine, Loma Linda University Medical Center, CA 92350, USA.
Postgrad Med (United States) Jul 1996, 100 (1) p138-49

A high serum cholesterol level is regarded as a major contributor to the development of coronary atherosclerosis. Screening for hyperlipidemia should begin no later than age 35 for men and age 45 for women. Individuals with additional risk factors for coronary artery disease should be screened earlier. When values are not within a desirable range, further assessment should be done by determining high-density lipoprotein and triglyceride levels. The initial approach to treatment of hyperlipidemia includes diet, exercise, and weight loss. Smoking should be proscribed. When nonpharmacologic intervention fails, "statins" are increasingly being selected as agents of first choice. Recommendations for the busy practitioner include consistently identifying the hyperlipidemic patient, setting target goals for lipid values, addressing modifiable risk factors, and providing appropriate pharmacologic intervention (eg, aspirin, antioxidants, and beta blockers in patients with established disease; angiotensin-converting enzyme inhibitors in patients with systolic dysfunction; estrogen replacement in selected patients) and treatment to attain target goals in lowering cholesterol. (17 Refs.)

Rokyta R; Racek J; Holecek V
Ustav fyziologie a klinicke fyziologie 3. lekarske fakulty UK, Praha.
Cesk Fysiol (Czech Republic) Mar 1996, 45 (1) p4-12

Central nervous system has a low antioxidative capacity, which is formed mainly by ascorbic acid. Therefore the cerebral tissue is threatened by the increased formation of free radicals and their metabolites (ROS--reactive oxygen species). ROS are formed such as in reperfusion phase after ischemia and in catecholamine metabolism, in oxidative stress due to hyperglycaemia. Polyunsaturated fatty acids (PUFA) are peroxidased by ROS; proteins and DNK are damaged as well. Free radicals are involved in etiology and pathogenesis of many CNS diseases, such as neuritis, Alzheimer disease, Parkinson disease, Huntington disease, aging and atherosclerosis of the brain, epilepsy, etc. During the antioxidant therapy it is necessary to consider the types of ROS, their origin and their mode of action, whether to administer hydrophilic or lipophilic antioxidants, eventually chelate agents, etc. Hydrophylic antioxidants are acting very soon after the administration, whereas the lipophilic ones reach their target tissues with a great delay. Therefore it is better to apply them preferentially like a prevention, if possible. Enzymatic antioxidants (SOD, GSPHx and catalase and others) are usually acting only for a short time. The methods of estimation of free radicals attacks are discussed as well their possible pathophysiological effects. (34 Refs.)

Nguyen KN; Landmark K
Institutt for farmakoterapi, Universitetet i Oslo.
Tidsskr Nor Laegeforen (Norway) Mar 30 1996, 116 (9) p1109-13

Oxidation of low-density lipoprotein (LDL) probably plays an important part in atherosclerosis. Vitamin E (alpha-tocopherol) is a potent antioxidant carried in LDL. It increases the resistance of LDL to oxidation, thereby, among other things, inhibiting foam cell formation and proliferation of smooth muscle cells. Some animal experiments have indicated that vitamin E retards the development of atherosclerotic lesions. Observational studies (case-control and cohort) have shown that long-term treatment with vitamin E is associated with lower incidence of coronary heart disease introlled trial gave a nonsignificant reduction in mortality from ischemic heart disease. Although vitamin E seems to reduce the risk of coronary heart disease, randomised trials of adequate size are necessary in both secondary and primary prevention in order to test this. Such trials are in progress. (61 Refs.)

Chen H; Tappel A
Department of Pharmacology, School of Medicine, University of Washington, Seattle, USA.
Lipids (United States) Jan 1996, 31 (1) p47-50

The purpose of this study was to test the hypothesis that multiple antioxygenic nutrients provide increased protection against lipid peroxidative damage to rat liver. Rats were fed diets (i) deficient in vitamin E and selenium (Diet 1), (ii) supplemented with vitamin E and selenium (Diet 2), (iii) supplemented with (ii) and in addition trolox C, N-acetylcysteine, coenzyme Q0, and (+)-catechin (Diet 3), or (iv) supplemented with (iii) and in addition beta-carotene, ascorbic acid palmitate, canthaxanthin, and coenzyme Q10 (Diet 4). Liver homogenates were obtained from three rats fed each of the diets for six weeks and were incubated at 37 degrees C up to two hours with and without exogenous tertiary-butyl hydroperoxide (TBHP) or Cu2+. Lipid peroxidation was determined by measurement of thiobarbituric acid substances. Diets 2 and 3 significantly protected against in vivo hepatic lipid peroxidation, and this protection was augmented by Diet 4. Diets 2, 3, and 4 were protective against mild oxidation induced by TBHP or Cu2+. During incubations with exogenous TBHP and Cu2+, there were only small differences between diets supplemented with antioxidants in inhibition of lipid peroxidation, indicating that diets supplemented with vitamin E and selenium (Diet 2) may have provided the maximal protection for liver. The possible mechanisms of protection provided by multiple antioxidants in diets were discussed. Protection by multiple antioxidants against lipid peroxidation may translate to prevention of peroxidative damage to human tissue, a factor in human disease.

Jao SW; Shen KL; Lee W; Ho YS
Division of Colon and Rectal Surgery, National Defense Medical Center, Tri-Service General Hospital Taipei, Taiwan, Republic of China.
Dis Colon Rectum (United States) Jun 1996, 39 (6) p628-31

PURPOSE: This study was designed to determine the cancer prevention and therapeutic effects of selenium on rats treated with 1,2-dimethylhydrazine (DMH).

METHODS: One hundred sixty Spraque-Dawley male rats were divided into seven groups and received 20 mg/kg/week DMH, subcutaneously for 20 weeks. Two different dosages of selenium (8 and 4 ppm) were administered to the rats through drinking water during DMH treatment (B and C groups) or one month before and during DMH treatment (D and E groups). The rats of Groups A (control group), B, C, D, and E were killed immediately after the last DMH injection. The incidence of intestinal cancer in each group was compared. Eight ppm selenium was also administered to rats after DMH treatment (Group F), and survival times were observed and compared with Group G (treated with DMH only).

RESULTS: Rats of Groups B and D received 8 ppm selenium and had a significantly decreased incidence of intestinal cancer (from 65.8 percent (Group A) to 33.3 percent (Group B) and 27.8 percent (Group D); P = 0.0225 and 0.0038). Rats receiving 4 ppm selenium had a relatively decreased incidence of intecent (Group A) to 44.4 percen t (Group C) and 47.1 percent (Group E) but P > 0.05). Survival time of Groups F and G showed no difference.

CONCLUSIONS: Eight ppm selenium provided via drinking water has a significant intestinal cancer prevention effect in the presence of a high dose of DMH (20 mg/kg x 20 weeks), and the cancer therapeutic effect of selenium is doubtful in this animal model.

Paunio M; Virtamo J; Gref CG; Heinonen OP
University of Helsinki, Department of Public Health, Finland.
BMJ (England) May 11 1996, 312 (7040) p1200-3

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake.

DESIGN--Cohort study.

SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland.

PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s.

MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups.

RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward.

CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also.

O'Keefe JH Jr; Nelson J; Harris WS
Mid America Heart Institute, Kansas City, MO 64111, USA.
Postgrad Med (United States) Feb 1996, 99 (2) p89-92, 95-6, 102-6

Heart-healthy living is a wise choice for anyone, but it assumes even greater importance in persons who have or are at risk for coronary artery disease. Such patients need to know which measures have proved most effective in the prevention and treatment of the disease. This article reviews the data regarding risk factor reduction and offers recommendations for effective lifestyle modifications. (34 Refs.)

Rohn TT; Hinds TR; Vincenzi FF
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Biochem Pharmacol (England) Feb 23 1996, 51 (4) p471-6

Preincubation of red blood cell (RBC) membranes with a model system known to generate reactive oxygen species (ROS) and free radicals (200 microM ferrous sulfate and 200 microM EDTA, Fe2+/EDTA) resulted inhibition of the Na+/K+ -pump ATPases was also associated with membrane protein crosslinking and lipid peroxidation, the latter as monitored by the formation of thiobarbituric acid reactive substances (TBARS). Inhibition of the ion transport ATPases, protein cross-linking and formation of TBARS were prevented by U-89843D in a concentration-dependent manner, with half-maximal protection seen at 0.3 microM. U-89843D was more potent than the classical antioxidant butylated hydroxytoluene. Neither U-89843D nor the solvent DMSO had any effect on the assay of TBARS. U-89843D exerted only minimal inhibitory activity on ATPase activities. Thus, U-89843D was potent in vitro in preventing a variety of membrane-damaging reactions mediated by ROS. It is suggested that protection of membranes from ROS-mediated damage is of potential usefulness in the prevention and treatment of certain disease processes.

Winklhofer-Roob BM; van't Hof MA; Shmerling DH
Division of Gastroenterology and Nutrition, Department of Pediatrics, University of Zurich, Switzerland.
Am J Clin Nutr (United States) May 1996, 63 (5) p722-8

To investigate the efficacy of three different vitamin E preparations for optimizing vitamin E status in cystic fibrosis (CF patients long-term, 29 patients (aged 0.7-29.8 y) were randomly assigned to receive 400 IU of either RRR-alpha-tocopherol (A: 268 mg, n = 10) or all rac-alpha-tocopheryl acetate as a fat-soluble (B: 400 mg, n = 10) or water-miscible preparation (C: 400 mg, n = 9) and were followed for 6 wk. In the whole study group, plasma alpha-tocopherol concentrations increased from baseline (10.5 +/- 4.6 micromol/L) to 3 wk (25.7 +/- 6.5 micromol/L; P < 0.001), but not further between 3 and 6 wk; concentrations at 3 and 6 wk did not differ from those of age-matched control subjects (23.6 +/- 3.9 micromol/L). There was no significant difference in the increase from baseline to 6 wk among preparations A (17.75 +/- 8.43 micromol/L), B (14.0 +/- 9.4 micromol/L), and C (15.5 +/- 7.1 micromol/L). Because of differences in body weight, the dose administered ranged from 5.5 to 47.4 IU x kg-1 x d-1; it correlated positively with the increase in plasma alpha-tocopherol concentrations (P < 0.001). There was no significant difference in the increase in plasma alpha-tocopherol concentrations between patients with CF-associated liver disease (n = 8) who received 10.2 +/- 3.8 IU x kg-1 x d-1 and those without liver disease taking comparable doses. We conclude that CF patients can be efficiently supplemented with 400 IU/d of any one of the three vitamin E preparations and plasma values of healthy control subjects can be achieved.

The HOPE study investigators.
Can J Cardiol (Canada) Feb 1996, 12 (2) p127-37

OBJECTIVE: To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) study.

DESIGN: Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments--ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin--in the prevention of myocardial infarction, stroke or cardiovascular death.

SETTING: Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America.

PATIENTS: Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months.

INTERVENTIONS: A 2X2 factorial design with ramipril and vitamin E with follow-up for up to four years.

CONCLUSIONS: HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.

Kushi LH; Folsom AR; Prineas RJ; Mink PJ; Wu Y; Bostick RM
Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis 55454-1015, USA.
N Engl J Med (United States) May 2 1996, 334 (18) p1156-62

BACKGROUND: The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that oxidative modification of low-density lipoprotein may promote atherosclerosis.

METHODS. We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease.

RESULTS. In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend, 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitely addressed. Intake of vitamins A and C did not appear to be associated with the risk of death form coronary heart disease.

CONCLUSIONS. These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.

Greenberg ER; Baron JA; Karagas MR; Stukel TA; Nierenbel and Norris Cotton Cancer Center, Lebanon, NH, USA.
JAMA (United States) Mar 6 1996, 275 (9) p699-703

OBJECTIVE: To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes.

DESIGN: Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation.

SETTING: Medical school-affiliated dermatology practices.

PATIENTS: A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer.

INTERVENTION: Oral beta carotene, 50 mg per day for a median of 4.3 years.

MAIN OUTCOME MEASURES: All-cause mortality and mortality from cardiovascular disease and cancer.

RESULTS: During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 micromol/L [27.7 microg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 micromol/L [11.2 microg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group.

CONCLUSIONS: These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.

Rapola JM; Virtamo J; Haukka JK; Heinonen OP; Albanes D; Taylor PR; Huttunen JK
National Public Health Institute, Helsinki, Finland.
JAMA (United States) Mar 6 1996, 275 (9) p693-8

OBJECTIVE: To examine the effect of supplementation with vitamin E (alpha tocopherol), beta carotene, or both on the incidence of angina pectoris in men without known previous coronary heart disease.

DESIGN: Randomized, double-blind, placebo-controlled trial.

SETTING AND PARTICIPANTS: Participants in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study (N=29133) were male smokers aged 50 through 69 years who were living in southern and western Finland. Of these men, 22269 were considered free of coronary heart disease at baseline and were followed up for the incidence of angina pectoris.

INTERVENTION: Participants were randomized to receive 50 mg/d of alpha tocopherol, 20 mg/d of beta carotene, both, or placebo in a 2x2 design.

OUTCOME MEASURES: An incident case was defined as the first occurrence of typical angina pectoris identified in administering the annually repeated World Health Organization (Rose) Chest Pain Questionnaire.

RESULTS: During a median follow-up time of 4.7 years (96427 person-years), 1983 new cases of angina pectoris were detected. Comparing alpha tocopherol-supplemented subjects with non-alpha tocopherol-supplement ed subjects showed a relative risk (RR) of angina pectoris incidence of 0.91 (95% confidence interval[CI], 0.83 to 0.99; P=.04). The RR for incidence of angina pectoris for the beta carotene- supplemented subjects compared with those not receiving beta carotene was 1.06 (95% CI, 0.97 to 1.16; P=.19). Compared with those receiving placebo, the RRs for incidence of angina pectoris were 0.97 (95% CI, 0.85 to 1.10) and 0.96 (95% CI, 0.85 to 1.09) in the alpha tocopherol and alpha tocopherol plus beta carotene groups, respectively, and 1.13 (95% CI, 1.00 to 1.27) in the beta carotene group (P=.06). Baseline dietary intakes and serum levels of alpha tocopherol and beta carotene did not predict incidence of angina pectoris.

CONCLUSIONS: Supplementation with alpha tocopherol was associated with only a minor decrease in the incidence of angina pectoris. Beta carotene had no preventive effect and was associated with a slight increase of angina.

Saito N
Nippon Rinsho (Japan) Jan 1996, 54 (1) p59-66

It is known that the peroxidation of LDL is a trigger for developing arteriosclerosis. The oxidized LDL is produced by either oxidative stress or a few oxidant. Selenium decreased in serum and some organs of stroke-prone spontaneously hypertensive rats (SHRSP), which is a cofactor of glutamine peroxidase. Serum magnesium decreased in patients with diabetes mellitus, with ischemic heart disease, with essential hypertension and with cerebral vascular lesions. Calcium to magnesium ratio was higher in some organs of SHRSP as compared to Wistar Kyoto rats (WKY). These changes accelerated vascular lesions in SHRSP. (21 Refs.)

Kozluca O; Olcay E; Surucu S; Guran Z; Kulaksiz T; Uskent N
Radiation Oncology Department, Kartal State Hospital, Istanbul, Turkey.
Cancer Lett (Ireland) Jan 19 1996, 99 (1) p1-6

Doxorubicin (dox) is an anthracycline antibiotic which is broadly used in solid tumors. Long-term therapy with this drug is accompanied by potentially lethal, dose-dependent side effects. Several reports suggest that oxygen free radicals produced during the metabolic activation of dox may have toxic effects on heart muscle. We tried to protect dox cardiotoxicity in rats using catechin which is a known antioxidant and iron chelating agent. Different dose levels and combinations of catechin and doxorubicin have been studied in different experimental groups. Electrocardiograms, myocardial contractility, body weight and the electron microscope were used to assess the cardioprotective effect of catd animals. We found significant prevention of dox-induced cardiotoxicity by catechin in rats.

Stein O; Dabach Y; Hollander G; Halperin G; Thiery J; Stein Y
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Biochim Biophys Acta (Netherlands) Jan 19 1996, 1299 (2) p216-22

Male golden hamsters were rendered hypercholesterolemic by feeding diets enriched with cholesterol and fat. In the first series of experiments, 5% butter and 1% cholesterol were added to a chow diet and plasma cholesterol levels were maintained at 350-390 mg/dl over the entire experimental period. Groups of hamsters and their age controls consuming the chow diet, were killed after 7, 15 and 20 months when the aorta was examined for atherosclerosis by determination of cholesterol mass. In the controls, aortic total cholesterol (TC) increased with age by 28% and esterified cholesterol increased to 11% of TC. In the hypercholesterolemic animals aortic TC was only 28% higher than in the controls and cholesteryl ester was also 11.5% of TC. In the second series, one group of hamsters were fed a semi-purified diet deficient in vitamin E, containing 1% cholesterol and 10% lard; a second group received the same diet, but supplemented with vitamin E. Controls consumed local chow. After 7 months on the vitamin E deficient diet plasma alpha-tocopherol was 0.05 mg/l, in those supplemented with vitamin E it was 20 mg/l, while in the controls it was 3.3 mg/l. Plasma thiobarbituric acid reactive substances (TBARS) were higher in the vitamin E deficient group and there was a greater propensity of lipoproteins (d < 1.063 g/ml) to peroxidation in vitro than in the vitamin E supplemented group. Plasma cholesterol was 366 mg/dl in the vitamin E deficient, 336 mg/dl in the vitamin E supplemented group, and 64 mg/dl in controls. Aortic cholesterol was 79.1 in vita0 mg dry weight in vitamin E def icient hamsters. In both series of experiments, HDL amounted to 36-41% of plasma TC in the hypercholesterolemic animals and 59-62% in the controls. In conclusion: the hamster appears to be quite resistant to atherosclerosis in face of sustained hypercholesterolemia, even in the presence of increased peroxidative stress caused by vitamin E deficiency. This relative resistance could be related to commensurate increase in plasma HDL which was observed in both series of experiments. Since vitamin E deficiency did not enhance aortic cholesteryl ester deposition, the protective effect of HDL seems to be related to its role in reverse cholesterol transport, rather than in prevention of peroxidation.

Konturek PC; Konturek SJ; Brzozowski T; Dembinski A; Zembala M; Mytar B; Hahn EG
Dept. of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
Scand J Gastroenterol (Norway) May 1997, 32 (5) p433-8

BACKGROUND: Melatonin, a pineal hormone that is biosynthesized from L-tryptophan, is known to scavenge oxygen free radicals and to be present in the gut, but little is known about the role of this hormone and its precursor, L-tryptophan, in protecting the gastric mucosa from damage accompanied by increase in the generation of oxygen radicals.

METHODS: This study was designed to determine the effects of melatonin and L-tryptophan on the formation of acute gastric lesions induced by stress and ischaemia reperfusion and, for comparison, by topical irritants such as 100% ethanol or acidified acetylsalicylic acid.

RESULTS: It was found that pretreatment with melatonin in doses ranging from 1.2 to 10 mg/kg dose-dependently reduced the stress-induced gastric lesions and was accompanied by a reduction in blood-free radicals and by attenuation of the fall in gastric blood flow. L-tryptophan applied intragastrically in doses ranging from 1 to 100 mg/kg also reduced dose-dependently the lesions induced by stress; this effect too was accompanied by a rise in gastric blood flow. Pretreatment with indomethacin, to block the biosynthesis of prostaglandins, significantly augmented the lesions produced by stress and completely abolished the protective effects of melatonin or L-tryptophan. Both melatonin and tryptophan reduced the formation of acute gastric lesions provoked by ischaemia reperfusion; this was accompanied by an increase in gastric blood flow. In contrast, melatonin and L-tryptophan failed to influence acute gastric lesions induced by topical irritants such as 100% ethanol or acidified aspirin.

CONCLUSIONS: Melatonin and L-tryptophan protect the gastric mucosa from damage by stress and ischaemia reperfusion, and this action is mediated, at least in part, by the limitation in the free radicals, the stimulation of mucosal generation of PG and by the increase in gastric blood flow.

Sakono M; Fukuyama T; Ni WH; Nagao K; Ju HR; Sato M; Sakata N; Iwamoto H; Imaizumi K
Department of Food Science and Technology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Biosci Biotechnol Biochem (Japan) Mar 1997, 61 (3) p514-9

Atherosclerotic lesions of the thoracic aorta were induced in exogenously hypercholesterolemic (ExHC) rats by treating initially with hypervitamin D2 and subsequently feeding on hypercholesterolemic diets for 180 days. Dietary soybean protein, in comparison with casein, substantially decreased the degree of atherosclerotic lesions, which was evaluated by intimal thickening, although with a similar topographical distribution. The casein-fed rats tended to maintain a high concentration of serum cholesterol, particularly in triacylglycerol-rich lipoproteins. The concentrations of apo A-I and TBARS in the serum was comparable between the dietary protein groups. The data suggest that dietary soybean protein, compared to casein, produced lipoproteins which were less atherosclerotic by partitioning cholesterol in the triacylglycerol-poor lipoproteins.

Kendler BS
Manhattan College, Riverdale, N.Y., USA.
Nurse Pract (United States) Feb 1997, 22 (2) p66-7, 71-2, 77

Currently available as a dietary supplement, the pineal hormone melatonin is portrayed by the media as a formidable weapon against disease and aging. Accordingly, primary health care providers should be cognizant of which of its proposed uses are supported by biomedical research and which are, as yet, unproven. Melatonin entrains circadian rhythms and, thus, can treat jet lag, delayed sleep phase syndrome, and sleep disorders in the blind and in some neurologically impaired children. By virtue of its hypnotic effect, melatonin can mitigate insomnia in the elderly. Reductions in melatonin secretion have been associated with many disorders, including cardiovascular disease, Alzheimer's, diabetes, SIDS, and aging; however, melatonin's role in their athophysiology is unproven. Preliminary studies suggest a possible adjuvant therapeutic role for melatonin in cancer therapy. Melatonin secretion is reduced by alcohol, caffeine, and some commonly prescribed drugs. Since tolerance, fatigue, and other side effects have been reported, melatonin use on consecutive nights should be avoided and only the lowest effective hypnotic dose should be taken. (75 Refs.)

Yanagisawa N
Department of Medicine (Neurology), Shinshu University School of Medicine.
Nippon Rinsho (Japan) Jan 1997, 55 (1) p52-7

Treatment of Parkinson's disease has progressed steadily for the last decades after introduction of levodopa. For recovery of striatal dysfunction caused by loss of projecting nigral cells, supplementation of neurotransmitter dopamine (DA), facilitation of neural transmission by DA agonists and amantadine, suppression of acetyl-choline neurons, having antagonistic action to DA cells, are all effective especially at the early to middle stages of illness. As prevention of neuronal cell death in parkinsonian brain has not yet been succeeded, difficulties in treatment with symptom fluctuation and CNS side effects such as dyskinesia or psychic symptoms develop inevitably in the long course of evodopa treatment. Proper choice of drugs for parkinsonian core and accompanying symptoms and selection of methods of medication for maintenance of natural daily life activities are necessary for attainment of good QOL for whole time course of the disease. (11 Refs.)

Welt K; Fitzl G; Schaffranietz L
Institute of Anatomy, University Leipzig, Germany.
Exp Toxicol Pathol (Germany) Jan 1996, 48 (1) p81-6

Aim of this electron microscopic morphomere protective properties of Gin kgo biloba extract EGb 761 on myocardial microvessels of old rats during acute hypoxic stress. Hypoxia of 20 minutes duration with N2O/O2 mixture (5 vol% O2) was performed using a hypoxia chamber combined with a commercial narcosis apparatus. EGb 761-pretreatment diminished significantly the percentage of endothelial cells exhibiting edema, luminal blebs and of capillaries surrounded by pericapillary debris. Hypoxia-related decrease in plasmalemmal vesicle frequency was prevented by EGb 761, formation of vacuoles non significantly diminished against the hypoxic group. Volume density of mitochondrial cristae was significantly less diminished, the volume fraction of degenerated areas less increased in the EGb 761-protected group. The results give some evidence that EGb 761 protects endothelial cell ultrastructure of myocardial microvasculature against hypoxic alterations, probably by its radical scavenging properties.

Fitzl G; Welt K; Schaffranietz L
Institute of Anatomy, University Leipzig, Germany.
Exp Toxicol Pathol (Germany) Jan 1996, 48 (1) p33-9

Ginkgo biloba extract EGb 761 was used in hypoxia experiments with old rats to investigate its ultrastructure-preserving effects on the myocardium. Hypoxia was performed by means of a hypoxia chamber combined with a commercial narcosis apparatus. N2O/O2-mixture was applied with O2 at 5 vol.% for 20 minutes under normobaric conditions. Ultrastructural-morphometric analysis revealed that EGb 761-pretreatment was able to diminish hypoxic damage at mitochondrial cristae and matrix and also distension of the sarcoplasmic reticulum during acute hypoxic stress. Whereas formation of vacuoles was depressed below thed. The preservation of mitochondrial cristae was confirmed by independent secondary morphometric parameters and by cytophotometrically measured activities of mitochondrial enzymes.

Birnbaum Y; Hale SL; Kloner RA
Heart Institute, Good Samaritan Hospital, Los Angeles, CA 90017, USA.
Cardiovasc Res (Netherlands) Nov 1996, 32 (5) p861-8

OBJECTIVE: Coenzyme Q10 has been found to enhance recovery of function after reperfusion in numerous experimental acute ischemia-reperfusion models. We assessed whether coenzyme Q10, administered intravenously either during or 1 h before ischemia, can limit infarct size in the rabbit.

METHODS: Anesthetized open-chest rabbits were subjected to 30 min of coronary artery occlusion and 4 h of reperfusion. In Protocol 1, 12 min after beginning of ischemia rabbits were randomized to intravenous infusion of 30 mg coenzyme Q10 (Eisai Co., Japan) (n = 10) or vehicle (n = 10). In Protocol 2, rabbits were randomized to 30 mg coenzyme Q10 (n = 6) or vehicle (n = 6) treatment 60 min before ischemia. Ischemic zone at risk (IZ) was assessed by blue dye and necrotic zone (NZ) by tetrazolium staining.

RESULTS: In both protocols, coenzyme Q10 did not alter heart rate, mean blood pressure, or regional myocardial blood flows in either the ischemic or non-ischemic zones during ischemia or reperfusion. No difference was found in IZ (as fraction of LV weight) (Protocol 1: 0.24 +/- 0.02 vs. 0.25 +/- 0.02; Protocol 2: 0.28 +/- 0.02 vs. 0.28 +/- 0.03, in the control vs. coenzyme Q10 groups, respectively). The NZ/IZ ratio was comparable between the groups in both protocols (Protocol 1: 0.22 +/- 0.04 vs. 0.26 +/- 0.04; Protocol 2: 0.21 +/- 0.06 vs. 0.30 +/- 0.06, in the control vs. coenzyme Q10 groups, respectively).

CONCLUSIONS: Coenzyme Q10, administered acutely either during or 60 min before myocardial ischemia, does not attenuate infarct size in the rabbit.

Lissoni P; Pittalis S; Ardizzzzoni F; Maestroni GJ; Zubelewicz B; Braczkowski R
Division of Radiation Oncology, S. Gerardo Hospital, (Milan), Italy.
Support Care Cancer (Germany) Jul 1996, 4 (4) p313-6

Hypotension is a frequent side-effect of cancer biotherapies with cytokines. Cytokine-induced hypotension would mainly depend on the stimulation of nitric oxide (NO) production, which represents the most effective endogenous vasodilator. Moreover, it has been proven that both biological activity and toxicity of cytokines are influenced by the psychoneuroendocrine system, in particular by the pineal hormone melatonin. To investigate the possible modulatory effect of melatonin on cytokine cardiovascular toxicity, we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis-factor -alpha(TNF)-induced hypotension in advanced cancer patients. The study included 116 patients with advanced solid tumour, for whom no effective standard anticancer therapy was available, who underwent cancer biotherapy with IL-2 (3 x 10(6) IU/ day s.c. every day, 6 days/week for 4 weeks) or with TNF (0.75 mg/day i.v. for 5 days) as compassionate treatment for their disease. Patients were randomized to be treated with or without a concomitant melatonin administration (40 mg/day orally in the evening, starting 7 days prior to cytokine injection). The occurrence of hypotension was significantly less frequent in patients concomitantly treated by melatonin than in those who received the cytokine alone, during either IL-2: or TNF immunotherapy (IL-2; 11/45 versus 2/46, P < 0.05; TNF: 10/23 versus 1/12, P < 0.01). This study shows that melatonin may prevent hypotension occurring during cancer immunotherapy with IL-2 or TNF. Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells, we suggest that melatonin may prevent cytokine-induced hypotension by inhibiting NO production, which plays an essential role in inducing hypotension during IL-2 and TNF biotherapies.

Chello M; Mastroroberto P; Romano R; Castaldo P; Bevacqua E; Marchese AR
Medical School of Catanzaro, Italy.
J Cardiovasc Surg (Torino) (Italy) Jun 1996, 37 (3) p229-35

PURPOSE: To evaluate the effect of coenzyme Q10 in reducing the skeletal muscle reperfusion injury following clamping and declamping the abdominal aorta.

METHODS: 30 patients undergoing elective vascular surgery for abdominal aortic aneurysm or obstructive aorto-iliac disease were randomly divided into two groups: patients in group I were treated with coenzyme Q10 (150 mg/day) for seven days before operation, and those in group II received a placebo. We studied the hemodynamic profile in each patient during clamping and declamping of the abdominal aorta. The plasma concentrations of thiobarbituric acid reactive substances (malondialdhehyde), conjugated dienes, creatine kinase and lactate dehydrogenase were measured in samples from both arterial and inferior vena cava sites. Serial sampling was performed after induction of anesthesia, 5 and 30 minutes after abdominal aortic cross clamping, 5 and 30 minutes after aortic cross-clamp removal.

RESULTS: The concentrations of malondialdehyde, conjugated dienes, creatine kinase and lactate dehydrogenase in patients who received CoQ10 were significantly lower than in the placebo group. Decrease of plasma malondialdehyde concentrations correlated positively (p < 0.01) with decrease of both creatine kinase and lactate dehydrogenase release in samples from the inferior vena cava. The hemodynamic profile during clamping and declamping the abdominal aorta was similar in both groups.

CONCLUSIONS: Our findings suggest that pre-treatment with coenzyme Q10 may play a protective role during routine vascular procedures requiring abdominal aortic cross clamping by attenuating the degree of peroxidative damage.

Knight DC; Eden JA
Royal Hospital for Women, New South Wales, Australia.
Obstet Gynecol (United States) May 1996, 87 (5 Pt 2) p897-904

OBJECTIVE: To review the sources, metabolism, potencies, and clinical effects of phytoestrogens on humans.

DATA SOURCES: The MEDLINE data base for the years 1980-1995 and reference lists of published articles were searched for relevant English-language articles concerning phytoestrogens, soy products, and diets with high-phytoestrogen content.

METHODS OF STUDY SELECTION: We identified 861 articles as being relevant. Human cell line studies, human epidemiologic studies (case-control or cohort), randomized trials, and review articles were included. Animal studies regarding phytoestrogens were included when no human data were available concerning an important clinical area.

TABULATION, INTEGRATION, AND RESULTS: Included were studies containing information considered pertinent to clinical practice in the areas of growth and development, menopause, cancer, and cardiovascular disease. When findings varied, those presented in this study reflect consensus. All studies concurred that phytoestrogens are biologically active in humans or animals. These compounds inhibit the growth of different cancer cell lines in cell culture and animal models. Human epidemiologic evidence supports the hypothesis that phytoestrogens inhibit cancer formation and growth in humans. Foods containing phytoestrogens reduce cholesterol levels in humans, and cell line, animal, and human data show benefit in treating osteoporosis.

CONCLUSION: This review suggests that phytoestrogens are among the dietary factors affording protection against cancer and heart disease in vegetarians. With this epidemiologic and cell line evidence, intervention studies are now an appropriate consideration to assess the clinical effects of phytoestrogens because of the potentially important health benefits associated with the consumption of foods containing these compounds. (90 Refs.)

Gardner DM; Shulman KI; Walker SE; Tailor SA
Department of Pharmacy, Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada.
J Clin Psychiatry (United States) Mar 1996, 57 (3) p99-104

BACKGROUND: Many monoamine oxidase inhibitor (MAOI) diets are considered to be excessively restrictive and founded on poor scientific evidence. We present a safe and practical MAOI diet based on the related clinical and analytic data.

METHOD: We used a critical review of the literature and our own tyramine assay results to categorize foods to be restricted absolutely, taken in moderation only, or unrestricted.

RESULTS: We recommend that users avoid aged cheese; aged or cured meats (e.g., air-dried sausage); any potentially spoiled meat, poultry, or fish; broad (fava) bean pods; Marmite concentrated yeast extract; sauerkraut; soy sauce and soy bean condiments; and tap beer. Wine and domestic bottled or canned beer are considered safe when consumed in moderation. Other foods not mentioned are considered unrestricted.

CONCLUSION: The concerns about perpetuating an overly restrictive MAOI diet include the avoidance by prescribers of a potentially useful treatment option, excessive limitations on lifestyle for patients, and increased risk to patients secondary to noncompliance with the diet. We propose an MAOI diet that has a solid scientific and clinical basis and that is, above all, practical. (53 Refs.)

Gozes I; Bardea A; Reshef A; Zamostiano R; Zhukovsky S; Rubinraut S; Fridkin M; Brenneman DE
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
Proc Natl Acad Sci U S A (United States) Jan 9 1996, 93 (1) p427-32

Neurodegenerative diseases, in which neuronal cell disintegrate, bring about deteriorations in cognitive functions as is evidenced in millions of Alzheimer patients. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective and to play an important role in the acquisition of learning and memory. A potent lipophilic analogue to VIP now has been synthesized, [stearyl-norleucine17]VIP ([St-Nle17]VIP), that exhibited neuroprotection in model systems related to Alzheimer disease. The beta-amyloid peptide is a major component of the cerebral amyloid plaque in Alzheimer disease and has been shown to be neurotoxic. We numb er of neurons in rat cerebral cortical cultures treated with the beta-amyloid peptide (amino acids 25-35) in comparison to controls. This cell death was completely prevented by cotreatment with 0.1 pM [St-Nle17]VIP. Furthermore, characteristic deficiencies in Alzheimer disease result from death of cholinergic neurons. Rats treated with a cholinergic blocker (ethylcholine aziridium) have been used as a model for cholinergic deficits. St-Nle-VIP injected intracerebroventricularly or delivered intranasally prevented impairments in spatial learning and memory associated with cholinergic blockade. These studies suggest both an unusual therapeutic strategy for treatment of Alzheimer deficiencies and a means for noninvasive peptide administration to the brain.

Takabayashi F; Harada N
Hamamatsu College, University of Shizuoka, Japan.
Pancreas (United States) Apr 1997, 14 (3) p276-9

Effects of green tea catechins (GTC) on cerulein-induced acute pancreatitis in rats were examined. The acute pancreatitis induced by cerulein (cerulein pancreatitis) was characterized by interstitial edema and vacuolation. When cerulein pancreatitis was induced, prior administration of 0.1% GTC in drinking water for 1 week before the induction significantly decreased the wet weight of the pancreas, the serum level of amylase, and the tissue concentration of lipid peroxides in the pancreas compared with those in nonmedicated rats supplied with plain tap water only. Furthermore, the pancreatic tissue alterations of the medicated rats were milder than those of the nonmedicated rats. These data suggest that GTC have a protective effect on the pathogenesis of cerulein pancreatitis.

Yang G; Wang ZY; Kim S; Liao J; Seril DN; Chen X; Smith TJ; Yang CS
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA.
Cancer Res (United States) May 15 1997, 57 (10) p1889-94

The pathogenesis of pulmonary tumors induced by a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its inhibition by black tea have been characterized. Female A/J mice (6 weeks old) were treated with a single dose of NNK (103 mg/kg of body weight, i.p.) on day 0, and the cell proliferation index was measured by the incorporation of bromodeoxyuridine (BrdUrd) immunohistochemically. The number of BrdUrd-labeled cells increased in the bronchiolar epithelium from day 2 to day 14, with the highest proliferation rate observed on day 5. By day 35, the BrdUrd-labeling index returned to the level of the control group. Further examination of the day 35 samples revealed the presence of foci of hyperproliferative cells in the bronchiolar epithelium, particularly in the bronchiolalveolar regions. These proliferating bronchiolar epithelial cells (Clara cells) may be the initiated sites for pulmonary tumorigenesis. In this short-term model, administration of black tea polyphenols (0.3%) through the drinking water starting 24 h after NNK treatment significantly inhibited NNK-induced early bronchiolar cell proliferation on day 5. In long-term studies, adenomas were observed in 100% (15 of 15) of the mice at week 16, with 7.8 +/- 0.8 tumors per mouse. At week 52, a malignant tumor incidence of 80% (41 of 51 mice) and a malignant tumor multiplicity of 2.39 +/- 0.19 were observed. The growth patterns of the malignant tumors, which included solid, papillary, and mixed types, may be associated with the cellular origin of the tumor. The cell proliferation indices, as measured by proliferating cell nuclear antigen immunohistochemistry, were significantly higher in dysplasia within adenoma than in adenoma, and significantly higher in adenoma at week 52 than in adenoma at week 16. Administration of black tea, starting 16 weeks after a single dose of NNK, inhibited the progression of adenoma to adenocarcinoma as determined by both malignant tumor incidence and multiplicity. The cell proliferation rate in adenomas was also suppressed by black tea treatment. The present work demonstrates the antiproliferative activities of black tea and its polyphenols. Such activities, at the early and late stages be important for the cancer-chemopreventive activities of black tea.