Camargo CA Jr; Stampfer MJ; Glynn RJ; Gaziano JM; Manson JE; Goldhaber SZ ; Hennekens CH
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215-1204, USA.
Circulation (United States) Feb 4 1997, 95 (3) p577-80

BACKGROUND: Moderate alcohol consumption decreases the risk of coronary heart disease, but its relation to peripheral arterial disease (PAD) is uncertain.

METHODS AND RESULTS: In the Physicians' Health Study, a randomized trial of the use of aspirin and beta-carotene in 22071 apparently healthy men, we documented 433 incident cases of PAD during 11 years of follow-up. After we controlled for age and treatment assignment, daily drinkers (> or = 7 drinks per week) had a relative risk (RR) of PAD of 0.92 (95% confidence interval, 0.72 to 1.17) compared with the reference group (< 1 drink per week). After additional control for smoking, however, the RR was 0.68 (0.52 to 0.89). Further control for exercise, diabetes mellitus, and parental history of myocardial infarction revealed an RR of 0.74 (0.57 to 0.97).

CONCLUSIONS: Moderate alcohol consumption appears to decrease the risk of PAD in apparently healthy men.

Devaraj S; Jialal I
Center for Human Nutrition and Department of Internal Medicine. University of Texas Southwestern Medical Center, Dallas 75235-9052, USA.
Int J Clin Lab Res (Germany) 1996, 26 (3) p178-84

Atherosclerosis is the leading cause of morbidity and mortality in western society. The most important risk factiabetes and a family history of premature atherosclerosis. Several studies indicate that an increased plasma low density lipoprotein (LDL) cholesterol constitutes a major risk factor for atherosclerosis. Many data support a proatherogenic role for oxidized LDL, and its in vivo existence. The oxidative susceptibility of LDL is increased with established cardiovascular risk factors, such as diabetes, smoking and dyslipidemia. Supplementation with antioxidants such as ascorbate and alpha to copherol can decrease LDL oxidation as well as cardiovascular mortality and thus shows promise in the prevention of atherosclerosis (86 Refs.)

Kim SY; Lee-Kim YC; Kim MK; Suh JY; Chung EJ; Cho SY; Cho BK; Suh I
Department of Food and Nutrition, Yonsei University, Seoul, Korea.
Biomed Environ Sci (United States) Sep 1996, 9 (2-3) p229-35

With the changes in trends of disease pattern from infectious to chronic degenerative disease, cardiovascular disease has been considered as the major cause of death in Korea. Numerous studies have been done on the antioxidant effects of some vitamins in the prevention of chronic illness, but not many in relation to the cardiovascular disease. Therefore, the relation between antioxidant vitamins, mainly alpha-tocopherol (alpha-T) and beta-carotene (beta-C), and coronary artery disease (CAD) such as angina pectoris and myocardial infarction has been investigated in this study. The blood samples were obtained from the CAD patients who were angiographically diagnosed within a month (100 case group). Patients who had an experience of PTCA or CABG were excluded from the study. Control subjects were healthy adults who had normal EKG values, no chest pain and no past history of cardiac disease (100 control group). All subjects were free for serum lipid lowering drugs. Serum alpha-T and beta-C were analysed using HPLC. In addition to antioxidant vitamins, serum lipids (total cholesterol, HDL, TG) were also measured. Each case and control was matched in terms of age and sex. And all the CAD risk factors such as blood pressure, smoking, alcohol, serum lipid profile and BMI were adjusted to determine pure effect(s) of alpha-T and beta-C on the CAD. The concentrations of both alpha-T and beta-C were significantly lower in the CAD group than those in control group (P < 0.05); in CAD group, mean values of alpha-T and beta-C were 11.9 +/- 7.2 (micrograms/ml), 35.8 +/- 3.1 (micrograms/dl) respectively. As for the levels of beta-C, it shows inverse relation with age, but not for the alpha-T levels. Serum levels of both vitamins did not show any significant differences in terms of sex, but men have a tendency o higher levels of beta-C, but lower levels of alpha-T.

Candlish JK; Das NP
Biochemistry Department, National University of Singapore, Singapore.
Biomed Environ Sci (United States) Sep 1996, 9 (2-3) p117-23

Both preventive and chain breaking antioxidants have a role in the limitation of free radical damage. Some of these may be regarded as "classical", like vitamins E and C but others are more recently discovered, such as the flavonoids, widespread in plant tissues, and the muscle constituents anserine and carnosine. The major conditions in which the role of antioxidants is under intense investigation include coronary artery disease, cancer and diabetes. There are theoretical underpinnings for the efficacy of antioxidants in each of these, with the protection of low density lipoprotein (in respect of the first) being exceptionally persuasive. Much attention is now being focussed on the flavonoids, which are surprisingly pleiotropic in their effects. For one of them, quercetin, over a dozen seemingly independent biological effects can be listed, including the inhibition of low density lipoprotein oxidation. Flavonoids also inhibit peroxidation in foodstuffs, as opposed to tissues. Tersy over antioxidant supplementation policies, some authorities recommending a massive programme of supplementation for all ages and classes, others stressing the value of the traditional mixed diet. This matter is unlikely to be resolved soon, but in the meantime sensible supplementation policies should be continued for those most vulnerable, that is, babies and the aged.

Gaziano JM
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215-1204, USA.
J Cardiovasc Risk (England) Aug 1996, 3 (4) p368-71

The hypothesis that antioxidant vitamins might reduce cardiovascular disease risk is based on a large body of basic and human epidemiologic research. Basic research provides a plausible mechanism by which antioxidants might reduce the risk of atherosclerosis. A large number of descriptive, case-control and cohort studies provide data suggesting that consumption of antioxidant vitamins is associated with reduced risks of cardiovascular disease. These data raise the question of a role of antioxidants, such as vitamins C and E, and beta-carotene, in the primary prevention of cardiovascular disease, but do not provide a definitive answer. Randomized trial data will be essential in establishing whether or not there is a causal effect of antioxidants in reducing the risk of cardiovascular disease. For many hypotheses randomized trials are neither necessary nor desirable; however, when searching for small to moderate effects, large-scale randomized trials of adequate dose and duration, in which investigators allocate subjects at random to either active treatment or placebo will provide valuable information about whether there is a causal relationship, and provide reliable estimates of effect size. Results from several large-scale randomized trials of antioxidants are summarized in this paper. At present, there is not sufficient data available to define clearly the role of antioxidants in primary or secondary prevention of cardiovascular disease. Additional trial data should be forthcoming in the near future which will aid in individual clinical decision-making and in the establishment of guidelines for the general public. (19 Refs.)

Gokce N; Frei B
Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Massachusetts 02118, USA.
J Cardiovasc Risk (England) Aug 1996, 3 (4) p352-7

Oxidised low-density lipoprotein (LDL) contributes to atherogenesis by a number of mechanisms, and antioxidants may act as anti-atherogens. LDL oxidation is inhibited by LDL-associated antioxidants, particularly alpha-tocopherol (vitamin E), and water-soluble antioxidants present in LDL's biologic milieu, especially ascorbate (vitamin C). In addition to protecting LDL against oxidation, antioxidants may act at the level of the vascular cell by limiting cellular production of reactive oxygen species, and, thus, cell-mediated LDL oxidation. Cellular antioxidants can also protect against vascular cell dysfunction that would otherwise promote atherogenesis, such as increased adhesion molecule expression and monocyte recruitment, impaired production or release of nitric oxide, or both, and the proliferation of smooth muscle cells. Some of these processes are regulated by nuclear factor-kappa B or related transcription factors, which are redox-sensitive and inhibited by antioxidants. Furthermore, cellular antioxidants can limit cytotoxic effects of oxidised LDL and other oxidant insults, inhibiting vascular cell necrosis and lesion progression. Finally, some antioxidants, in particular alpha-tocopherol, may affect atherogenesis by inhibiting platelet function and mural thrombosis, although this effect appears to be explained by the inhibition of protein kinase C independent of alpha-tocopherol's antioxidant activity. (65 Refs.)

Hill MJ
ECP (UK) Headquarters, Lady Sobell GI Unit, Wexham Park Hospita 1996, 5 (5) p 413-4

No abstract.

Croft KD; Puddey IB; Rakic V; Abu-Amsha R; Dimmitt SB; Beilin LJ
Department of Medicine, Royal Perth Hospital, University of Western Australia.
Alcohol Clin Exp Res (United States) Sep 1996, 20 (6) p980-4

In population studies, a low-to-moderate intake of alcohol has been consistently linked to a lower risk of coronary artery disease. The recent suggestion that alcoholic beverages may be conferring this decrease in risk because they contain antioxidant phenolic compounds that reduce the oxidizability of low-density lipoprotein (LDL) has to be reconciled with the possible counteracting influence of a pro-oxidant effect of alcohol. In a controlled crossover study, we have now measured the oxidizability of LDL in 27 regular beer drinkers during consecutive 4-week periods, wherein they consumed a high versus low alcohol beer (4.9 vs. 0.9% alcohol v/v, respectively), with the two beers being similar in phenolic content. This resulted in a decrease in alcohol consumption by approximately 80% (408 +/- 25 ml/week vs. 75 +/- 11 ml/week). During the low alcohol period, there was no change in LDL vitamin E or its cholesterol or protein content. Analysis of LDL oxidation kinetics revealed an increase in oxidizability during the high alcohol phase. This was despite a decrease in arachidonic acid content of LDL and a corresponding increase in palmitic acid during high alcohol intake--a change in fatty acid composition that has the potential to favor a decrease in oxidizability. Our results suggest that alcohol ingestion increases LDL oxidation, despite reducing the polyunsaturated fatty acid composition. The overall effect of alcoholic beverages on LDL oxidation may be a balance between the pro-oxidant and antioxidant activity of its various constituents. The predominant pro-oxidant effect demonstrated in these beer drinkers, although not relevant to any potential decrease in coronary artery disease, may be important in the pathogenesis of alcohol-related

Khuri FR; Lippman SM; Spitz MR; Lotan R; Hong WK
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
J Natl Cancer Inst (United States) Feb 5 1997, 89 (3) p199-211

Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions. (116 Refs.)

Howard AN; Williams NR; Palmer CR; Cambou JP; Evans AE; Foote JW; Marques-Vidal P; McCrum EE; Ruidavets JB; Nigdikar SV; Rajput-Williams J; Thurnham DI
Department of Pathology, Papworth Hospital NHS Trust, Cambridge, UK.
Int J Vitam Nutr Res (Switzerland) 1996, 66 (2) p113-8

High intakes of antioxidants in fruit, vegetables and wine are thought to protect against coronary heart disease (CHD). Because people in Toulouse have a much lower incidence of CHD compared with Belfast, the plasma concentrations of antioxidant vitamins and carotenoids in the two populations have been compared. The major difference was in some of the plasma carotenoids. Hydroxy-carotenoids were twice as high in Toulouse in both sexes, notably lutein which occurs principally in dark green vegetables and beta-cryptoxanthin which occurs chiefly in citrus fruits. In addition, alpha-carotene was 50% higher in Toulouse, gamma-tocopherol was 50% higher in Belfast. Other plasma vitamins and carotenoids were not significantly different. If antioxidants play a role in preventing CHD, then the hydroxy-carotenoids are major candidates for further investigation.

Wiseman H
Department of Nutrition and Dietetics, King's College London, U.K.
Biochem Soc Trans (England) Aug 1996, 24 (3) p795-800

No abstract.

Hollman PC; Hertog MG; Katan MB
DLO State Institute for Quality Control of Agricultural products (RIKILT-DLO) Wageningen, The Netherlands.
Biochem Soc Trans (England) Aug 1996, 24 (3) p785-9

No abstract.

Sanderson J; McLauchlan WR; Williamson G
School of Biological Sciences, University of East Anglia, Norwich, U.K.
Biochem Soc Trans (England) Aug 1996, 24 (3) p385S

No abstract.

Gerstein HC; Bosch J; Pogue J; Taylor DW; Zinman B; Yusuf S
McMaster University, Hamilton, Ontario, Canada.
Diabetes Care (United States) Nov 1996, 19 (11) p1225-8

OBJECTIVE: To describe the rationale and design of a large international study (microalbuminuria, cardiovascular, and renal outcomes [MICRO] in the HOPE [Heart Outcomes Prevention Evaluation] study) of an ACE inhibitor and vitamin E for the prevention of diabetic nephropathy (DN) and cardiovascular disease (CVD) in patients with diabetes and microalbuminuria (MA).

RESEARCH DESIGN AND METHODS: A total of 3,657 diabetic subjects, including 1,129 with MA, are randomly allocated to receive the ACE inhibitor ramipril (or placebo) and vitamin E (or placebo) for 4 years in a two-by-two factorial design. Diabetic subjects are a subset of the 9,541 subjects enrolled in the HOPE study.

RESULTS: The development of DN in microalbuminuric diabetic subjects and the development of MA in normoalbuminuric subjects, as well as cardiovascular death, myocardial infarction, and storke, are the main outcomes. The correlation of changes in albuminuria with changes in carotid atherosclerosis documented in a subset of subjects will also be analyzed.

CONCLUSIONS: The effect of both an ACE inhibitor and vitamin E on the progression of renal and CVD in patients with diabetes is being assessed in the MICRO-HOPE study.

Trachtman H; Chan JC; Chan W; Valderrama E; Brandt R; Wakely P; Futterweit S; Maesaka J; Ma C
Department of Pediatrics (Division of Nephrology), Schneider Children's Hospital, New Hyde Park New York 11040, USA.
Pediatr Res (United States) Oct 1996, 40 (4) p620-6

IgA nephropathy is one of the most common forms of glomerular disease. Nearly 25% of affected patients progress to end-stage renal disease over a 20-25-y follow-up period. IgA-containing immune complexes stimulate oxygen-free radical production by mesangial cells in vitro. The excessive oxidant stress may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal disease in an experimental model of incipient IgA nephropathy with mild kidney inflammation. IgA nephropathy was induced in male Lewis rats by oral immunization with 0.1% bovine gamma-globulin (BGG)-containing drinking water for 8 wk. At the completion of this period, animals received BGG, 1 mg/dose i.v., on three successive days. Experimental rats (n = 10) received a specially formulated diet containing 100 IU of vitamin E/kg of chow, whereas control animals (n = 10) were fed chow containing 30 IU of vitamin/kg of chow. The BGG immunization regimen induced mesangial IgA deposition in all rats. Vitamin E supplementation resulted in a nearly 5-fold increase in the serum vitamin E concentration. Vitamin E-treated rats gained more weight and had a lower incidence of hematuria, 20% versus 80% (p < 0.03). Moreover, proteinuria was decreased by 50%, and reduced renal plasma flow was restored to normal, compared with untreated rats with IgA nephropathy. Glomerular hypertrophy occurred in animals with IgA nephropathy, but less so in those receiving vitamin E supplementation. Renal cortical malondialdehyde content was reduced from 1.55 +/- 0.10 to 1.22 +/- 0.09 nmol/mg of protein (p < 0.01) in rats fed the vitamin E-enriched diet. Finsforming growth factor-beta 1 gene expression was reduced by 34% in rats with IgA nephropathy receiving vitamin E treatment (p < 0.05). We conclude that experimental IgA nephropathy is associated with increased renal oxidant injury. Dietary treatment with the antioxidant agent, vitamin E, attenuated renal functional and structural changes in this experimental glomerulopathy. These studies support the importance of clinical trials for the evaluation of the efficacy of antioxidant therapy in patients with IgA nephropathy.

Tsuda H; Iwahori Y; Asamoto M; Baba-Toriyama H; Hori T; Kim DJ; Uehara N; Iigo M; Takasuka N; Murakoshi M; Nishino H; Kakizoe T; Araki E; Yazawa K
National Cancer Center Research Institute, National Cancer Center Hospital, Tokyo, Japan.
IARC Sci Publ (France) 1996, (139) p143-50

Organotropic chemopreventive effects of three (pro)vitamins and three unsaturated fatty acids were examined using mouse and rat multiorgan carcinogenesis models. For the study of (pro)vitamins, male and female B6C3F1 mice were treated with N,N-diethylnitrosamine (DEN) and N-methyl-N-nitrosourea (MNU) during the first 11 weeks, then from weeks 12 to 32 they received alpha-carotene (0.4 mg/mouse), beta-carotene (0.4 mg/mouse) or alpha-tocopherol (40 mg/mouse) three times a week by gavage; control mice received vehicle alone. In male mice, alpha-carotene significantly reduced liver weights, representing a reduced tumour mass (P < 0.001), and alpha-carotene, beta-carotene and alpha-tocopherol significantly reduced the numbers of liver tumours (adenomas a0.01) as compared with control mice, the effects being greatest with alpha-carotene. In female mice, alpha-carotene significantly decreased the number of liver tumours (P < 0.001). In the lung, alpha-carotene and alpha-tocopherol reduced the area of lesions (hyperplasias and adenomas combined) only in males (P < 0.05). For the study of unsaturated fatty acids, F344 male rats were treated with DEN, MNU, N-butyl-N-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and N,N-bis(2-hydroxy)propylnitrosamine during the first 5 weeks, then from weeks 6 to 36 they were given docosahexaenoic acid (C22:6), eicosapentaenoic acid (C20:5) or linoleic acid (C18:2) at 1.0 g/rat, three times a week by gavage; control rats were treated with oleic acid (C18:1) using the same protocol. All animals were fed a low linoleic acid and calorie-adjusted basal diet during fatty acid administration. Docosahexaenoic acid and linoleic acid reduced tumours in the large and small intestines, respectively. However, they did not influence the yield of preneoplastic liver, lung, kidney, forestomach and urinary bladder lesions. The data thus provide evidence for organotropic effects of carotenoids and unsaturated fatty acids on carcinogenesis.

Diplock AT
Division of Biochemistry and Molecular Biology, UMDS Guy's Hospital, London, UK.
Food Chem Toxicol (England) Oct 1996, 34 (10) p1013-20

No abstract.

Ashakumary L; Vijayammal PL
Department of Biochemistry, University of Kerala, India.
Pharmacology (Switzerland) Mar 1996, 52 (3) p153-8

Nicotine, a major component of cigarette smoke, plays an important role in the development of cardiovascular disease and lung cancer in smokers. Lipid peroxidation is a process associated with the pathogenesis of atherosclerosis and the level of lipid peroxides is increased in smokers. In rats fed a high-fat diet, the tissue concentration of lipid peroxides was found to be increased. On nicotine administration along with a high-fat diet an additive effect was observed in lipid peroxidation and free radical scavengers. The activities of scavenging enzymes superoxide dismutase, catalase and glutathione reductase were found to be decreased, while the glutathione concentration and activity of glutathione peroxidase were enhanced.

Ritenbaugh C; Peng YM; Aickin M; Graver E; Branch M; Alberts DS
Department of Family and Community Medicine, University of Arizona Health Sciences Center, Tucson 85724, USA.
Cancer Epidemiol Biomarkers Prev (United States) Nov 1996, 5 (11) p907-12

Carotenoid consumption is of great interest in disease prevention studies. Until recently, carotenoid food composition data have not been available from a single laboratory source with high validity/reliability characteristics. With the availability of a new carotenoid food composition data base, we examined the impact of the new data base on the intake estimates as measured by a food frequency questionnaire and on the relationship of those estimates to pes to ascertain what, if any, improvement is achieved through use of the new values. Plasma samples were available for 162 healthy adults participating in cancer prevention studies at the Arizona Cancer Center, including men and women, smokers and nonsmokers. A single laboratory analyzed plasma samples for beta-carotene, alpha-carotene, lutein, and lycopene. All subjects had completed a modified version of the Block food frequency questionnaire, which calculates carotenoids using a literature-based algorithm. A new carotenoid composition data base using recently published data (A.R. Mangels et al., J. Am. Diet. Assoc., 93: 284-296, 1993) was then directly substituted for the Block data base. There were high correlations between intake estimates derived from the two data bases for all four carotenoids (range, r = 0.76-0.96). Average intake estimates based on the Mangels et al. data base were significantly higher for beta-carotene and lycopene; however, correlations between intakes and plasma values were significantly different only for beta-carotene (r = 0.44 for Mangels versus 0.32 for Block, P = 0.015).

Hubner C; Lehr HA; Bodlaj R; Finckh B; Oexle K; Marklund SL; Freudenberg K; Kontush A; Speer A; Terwolbeck K; Voit T; Kohlschutter A
Department of Neuropediatrics, Virchow Medical Center, Humboldt University, Berlin, Germany.
Pediatr Res (United States) Sep 1996, 40 (3) p444-9

A simple, reproducible test was used to quantify muscle weakness in mdx mice, an animal model of Duchenne muscular dystrophy. The effect of bedding on wheat kernels and of dietary supplementation of alpha-tocopherol on the progression of muscle weakness was investigated in mdx mice. When measured during the first 200 d of life, mdx mice developed muscle weakness, irrespective of bedding and diet. When kept on wood shavings and fed a conventional rodent diet, mdx mice showed progressive muscle weakness over the consecutive 200 d, and eventually showed a significant weight loss during the next 200-d observation period. Progression of muscle weakness and weight loss were almost completely prevented in mdx mice that were kept on wheat kernel bedding. In contrast, only incomplete maintenance of muscle strength and body weight was observed in mdx mice kept on wood shavings and fed the alpha-tocopherol-supplemented diet. It is concluded from these experiments that a component of wheat kernels other than alpha-tocopherol is essential to prevent the progression of muscle weakness in mdx mice.

Bagenholm R; Andine P; Hagberg H
Department of Physiology and Pharmacology, Goteborg University, Sweden.
Pediatr Res (United States) Sep 1996, 40 (3) p399-403

Using 7-d-old rat pups, the neuroprotective efficacy of the lipid peroxidation inhibitor tirilazad mesylate (U-74006F) was tested in a model of perinatal hypoxic-ischemic (HI) brain damage. The experimental protocol was divided into five parts: 1) pre- plus post-HI treatment or 2) only post-HI treatment with tirilazad (7.5 mg/kg intraperitoneally) or vehicle with evaluation of hemispheric weight deficit 14 d after the insult; 3) post-HI treatment with tirilazad or vehicle with histopathologic evaluation 14 d after the insult; 4) pre- plus post-HI treatment; or 5) posthypoxic treatment with tirilazad or vehicle with evaluation of brain edema 20 h after the insult. In the pre- plus post-HI treatment group, the mean left hemispheric weight deficit was 20.7% +/- 17.8 (mean +/- SD) in tirilazad-treated rats and 27.5% +/- 20.4 in vehicle-treated rats (p = 0.032). Corresponding values for the post-HI treated animals were 19.6% +/- 16.0 and 28.6% +/- 15.4 (p = 0.043). Histopathologic injury assessed as pathology score on a scale of 0-5 was less extensive in tirilazad-treated animals compared with controls (p = 0.038). There was a significant increase in water content in the HI hemisphere compared with the contralateral (hypoxic) hemispheres in tirilazad- and vehicle-treated animals. This increase of water content in the HI hemispheres did not differ between tirilazad- and vehicle-treated animals. The lipid peroxidation inhibitor tirilazad administered after perinatal HI reduced brain damage by 30%, but no effect was found on early postinsult edema.

Simons LA; Von Konigsmark M; Balasubramaniam S
University of New South Wales Lipid Research Department, St Vincent's Hospital, Sydney, NSW.
Aust N Z J Med (Australia) Aug 1996, 26 (4) p496-503

BACKGROUND: Oxidation modification of low density lipoprotein (LDL) may play a role in the pathogenesis of atherosclerosis. Ingestion of vitamin E in high dosage has been shown to reduce the susceptibility of LDL to copper-induced oxidation, as assessed ex vivo. AIM: To determine a minimum dose of supplementary vitamin E which will significantly reduce the susceptibility of LDL to oxidation.

METHODS: A single centre, double-blind, parallel placebo-controlled trial. Healthy volunteers (total n = 42) were randomised to receive placebo, 500, 1000 or 1500 IU/day of vitamin E (D-alpha-tocopherol) for a period of six weeks. Primary outcomes were change in lag time or oxidation rate to copper-induced LDL oxidation. Secondary outcomes were changes in plasma vitamin E levels and clinical tolerance.

RESULTS: Lag time to LDL oxidation was significantly prolonged and oxidation rate significantly slowed at all dose levels of vitamin E, indicating a threshold effect from 500 IU/day. Compared to placebo, the median prolongation in lag time on 500 IU/day was 26%, on 1000 IU/day 24% and on 1500 IU/day 35%. The corresponding slowing in oxidation rates was 14%, 19% and 25% respectively. The per cent change in plasma vitamin E concentration was highly correlated with the change in lag time (r = 0.61, p < 0.001) and oxidation rate (r = 0.55, p < 0.001). Vitamin E was generally well tolerated.

CONCLUSIONS: Vitamin E in a dose of 500 IU/day will significantly reduce the susceptibility of LDL to oxidation. Whether or not this treatment will consistently reduce the future incidence of coronary artery disease will only be answered by further clinical trials.

Lombardo ME; Meyer-Siegler K; Hakky SI; Hudson PB
Department of Veterans Affairs Medical Center, Bay Pines Flo) Dec 1996, 2 9 (6) p381-5

BACKGROUND: The increasing incidence of prostate cancer demands that we give our full attention not only to the etiology and prevention of this common type of cancer, but also to the diagnosis and prognostic course of this disease. In an effort to develop new prostatic tumor markers that could be useful to the physician at the current state of our knowledge in the diagnosis and prognosis of this disease, our laboratories have undertaken an effort to isolate and characterize the nature of the major proteins in the normal prostate and in prostatic neoplasia.

METHODS: In this preliminary study, tissue was obtained from open prostatic surgery in patients with a pre- and postoperative diagnosis of benign prostatic hyperplasia. The initial fractionation and separation of the proteins was achieved through the use of ultrafiltration of homogenates followed by SDS-PAGE. Initial analysis of four prominent protein bands was accomplished by amino acid sequencing, and identified by a search in GeneBank data base.

RESULTS: Two proteins previously identified in prostatic tissue were prostate specific antigen (M(r) 26,496) with 240 amino acid residues and beta-inhibin (M(r) 10,704) with 94-amino acid residues. A third protein was identified as human cysteine rich protein (hCRP). This protein functions as a DNA binding protein and has previously been postulated to contain four putative zinc fingers and to play a fundamental role in cellular function. Ubiquitin, the fourth major protein identified was a 76-amino acid polypeptide whose function is to target other proteins for destruction.

CONCLUSIONS: hCRP and ubiquitin are reported as being found in high levels in prostatic tissue for the first time.

Wilcox JG; Hwang J; Hodis HN; Sevanian A; Stanczyk FZ; Lobo RA
University of Southern California School of Medicine, Los Angeles, California, USA.
Fertil Steril (United States) Jan 1997, 67 (1) p57-62

OBJECTIVE: To examine the independent effects on insulin sensitivity and antioxidative activity of the three most prevalent constituents in Premarin (Wyeth-Ayerst Laboratories, Philadelphia, PA): estrone sulfate (E1S), 50%; equilin sulfate (EqS), 25%, and 17 alpha-dihydroequilin sulfate (17 alpha-ES), 15%.

DESIGN: Prospective randomized cross-over study. SETTING: University of Southern California Medical Center.

PATIENT(S): Eight healthy postmenopausal women, mean age 53 +/- 2 years, and mean body mass index, 26 +/- 2 kg/m2, were enrolled.

INTERVENTION(S): Each woman received, in randomized succession, daily oral doses of 17 alpha-ES (0.2 mg), E1S (0.625 mg), and EqS (0.3 mg) for 30 days.

MAIN OUTCOME MEASURE(S): Oxidation of low-density lipoprotein (LDL) by negatively charged LDL (LDL-) and lag phase duration and measured the plasma glucose disappearance after insulin administration (K(itt)).

RESULT(S): All three estrogen preparations demonstrated antioxidant effects with E1S demonstrating the most significant changes, followed by EqS and 17 alpha-ES. Using E1S, LDL-levels decreased from a baseline of 3.91 +/- 0.9 to 2.05 +/- 0.32 mg/dL and the lag time increased from 24.5 +/- 6.0 to 87.8 +/- 11.8 minutes. Changes in insulin tolerance tests revealed improved insulin action with the various estrogens. With EqS, K(itt) increased from 3.1% +/- 0.3% to 4.3% +/- 0.3% glucose/min, was intermediate with E1S and was least with 17 alpha-ES.

CONCLUSION(S): All three conjugated equine estrogens demonstrated antioxidant activity. Also, some improved insulin action was demonstrated. To our knowledge, this is the first in vivo study to examine the effects of these components which may help explain, in part, some of the cardioprotective properties ascribed to Premarin.

Gaziano JM
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215-1204, USA.
Nutrition (United States) Sep 1996, 12 (9) p583-8

The hypothesis that antioxidant vitamins might reduce cardiovascular disease risk is based on a large body of both basic and human epidemiologic research. One of the most consistent findings in dietary research is that those who consume higher amounts of fruits and vegetables have lower rates of heart disease and stroke as well as cancer. Recent attention has focused on the antioxidant content of fruits and vegetables as a possible explanation for the apparent protective effects. Basic research provides a plausible mechanism by which antioxidants might reduce the risk of atherosclerosis. A large number of descriptive, case-control and cohort studies provide data suggesting that consumption of antioxidant vitamins is associated with reduced risks of cardiovascular disease. These data raise the question of a possible role of antioxidants, such as vitamins C and E, and beta carotene, in the primary prevention of cardiovascular disease but do not provide a definitive answer. Results from several large-scale randomized trials of antioxidant supplements are now available; however, results are not entirely consistent. The results of the major trials do not prove or disprove the value of antioxidant vitamins, nor do they incriminate them as harmful. They do, however, raise the possibility that some of the benefits from observational epidemiology may have been overestimated and that there may be some adverse effects. At this point randomized trial data are not yet sufficient to fully assess the risk-to-benefit ratios for antioxidant supplements. More reliable data should be forthcoming in the near future which will better define the role of antioxidants in the primary and secondary prevention of atherosclerotic disease as well as cancer. (59 Refs.)

Wong ND; Detrano RC; Diamond G; Rezayat C; Mahmoudi R; Chong EC; Tang W; Puentes G; Kang X; Abrahamson D
Heart Disease Prevention Program, University of California, Irvine 92697, USA.
Am J Cardiol (United States) Dec 1 1996, 78 (11) p1220-3, Comment in Am J Cardiol 1996 Dec 1;78(11):1265-6

We evaluated the extent to which cardiovascular risk-reducing behaviors are initiated as a result of knowledge of newly detected coronary artery disease, based on test results from noninvasive electron beam computed tomography (EBCT). A total of 703 men and women, aged 28 to 84 years, asymptomatic and without prior coronary disease, who had a baseline EBCT coronary artery scan and basic medical history and risk factor information completed a follow-up survey questioning them about health behaviors undertaken since their scan. Baseline calcium scores were significantly higher in those who subsequently reported consulting with a physician, or reported new hospitalization, coronary revascularization, beginning aspirin usage, blood pressure medications, cholesterol-lowering therapy, decreasing dietary fat, losing weight, beginning vitamin E, and under more worry (all p <0.01). Other factors, including reducing time worked, obtaining life insurance, losing empld work absenteeism, increasing exercise, or stopping smoking were not associated with coronary calcium. In logistic regression, after adjusting for age, gender, pre-existing high cholesterol, high blood pressure, cigarette smoking, and a positive family history of coronary disease, the natural log of total calcium score remained associated with new aspirin usage, new cholesterol medication, consulting with a physician, losing weight, decreasing dietary fat, new coronary revascularization (all p <0.01), but also new hospitalization (p <0.05) and increased worry (p <0.001). The results suggest that potentially important risk-reducing behaviors may be reinforced by the knowledge of a positive coronary artery scan, independent of preexisting coronary risk factor status.

Kojima M; Shui YB; Murano H; Sasaki K
Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan.
Ophthalmic Res (Switzerland) 1996, 28 Suppl 2 p64-71

The efficacy of a vitamin-E (VE) ophthalmic solution was evaluated on a newly developed rat steroid-induced cataract model. Brown Norway rats irradiated with 2 Gy X-ray, right eyes only, were divided into 5 groups: the control group; 2 steroid (1 mg/kg/day)-treated groups with topic (Top) and systemic (Sys) administration, and 2 VE-treated groups, 1 with the same treatment as the Top group with the addition of 5% VE twice a day (Top + VE) and 1 with the same treatment as the Sys group with 5% VE twice a day (SYS + VE). The lens changes were documented with a Scheimpflug camera and changes in light scattering were evaluated quantitatively. The VE-treated groups (Top + VE and Sys + VE) showed a significant inhibition of the increase in the opaque area compared with each of the non-VE-treated groups. The VE ophthalmic solution was strong enough to prevent steroid-induced cataract in rats.

Ohta Y; Okada H; Majima Y; Ishiguro I
Department of Biochemistry, School of Medicine, Fujita Health University, Aichi, Japan.
Ophthalmic Res (Switzerland) 1996, 28 Suppl 2 p16-25

The aim of this study was to estimate the anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a decrease in vitamin E content and an increase in water content in addition to further increases in LPO content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane function.

Stern F; Dror Y; Eliraz A; Barg J; Zimlichman R
Harefuah (Israel) Nov 15 1996, 131 (10) p408-12

No abstract.

Evans DA; Morris MC
Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois 60612, USA.
Alzheimer Dis Assoc Disord (United States) Fall 1996, 10 Suppl 1 p45-9

Alzheimer disease is a common condition that severely affects both persons with the illness and their families. Prevention of Alzheimer disease is an urgent priority, but study of potentially modifiable risk factors for the illness is at an early stage. Laboratory studies suggest that oxidative mechanisms may be involved in the pathogenesis of Alzheimer disease and raise the possibility that antioxidant nutrients could be used in disease prevention. Observational studies suggest that antioxidant nutrients may have protective effects against a number of other common chronic diseases, including cardiovascular disease and cancer. Because the protective effects, if any, of antioxidant nutrients are likely to be small to moderate in magnitude, large-scale randomized trials of primary prevention will likely be necessary to resolve this issue, and a major question is how quickly to progress to expensive and time consuming trials needed to provide more definitive evidence. This is a difficult question, but the severity of the disease, the current absence of preventive strategies and the likelihood that observational studies alone will not provide clear resolution of the issue all suggest that it may be prudent to strongly consider such trials in the near future.

Schneider HA
Institute of Nutrition, University of North Carolina, Chapel Hill, USA.
Perspect Biol Med (United States) Autumn 1996, 40 (1) p1-6

No abstract.

Ohnishi Y; Fujii H; Kimura F; Mishima T; Murata J; Tazawa K; Fujimaki M; Okada F; Hosokawa M; Saiki I
Department of Pathogenic Biochemistry, Research Institute for Wakan-Yaku, Toyama, Japan.
Jpn J Cancer Res (Japan) Oct 1996, 87 (10) p1039-44

We have investigated the inhibitory effect of oral administration of Juzen-taiho-to, a Kampo (Chinese herbal) medicine, on progressive growth of a mouse fibrosarcoma. Spontaneously regressive QR-32 tumor cells were able to grow progressively in vivo when coimplanted s.c. with a foreign body, gelatin sponge, whereas QR-32 cells alone gradually grew for over 15 days after inoculation and thereafter regressed for up to 25 days. Oral administration of Juzen-taiho-to (40 mg/day/mouse) for 7 days after inoculation of QR-32 cells with gelatin sponge resulted in significant inhibition of tumor growth and prolongation of the survival of the tumor-bearing mice. This growth-inhibitory effect of Juzen-taiho-to observed on day 25 was dose-dependent over the dose range from 4 to 40 mg/day. Treatment with Juzen-taiho-to for 7 days before tumor inoculation with gelatin sponge also significantly suppressed tumor growth examined on day 25, as did the administration of bismuth subnitrate, which is well known to induce metallothionein, an antioxidant. On the other hand, inoculation of progressed tumor cells (QRsP) resulted in growth without gelatin sponge, leading to death in syngeneic mice. Administration of Juzen-taiho-to for 7 days after inoculation of QRsP cells resulted in a decrease of the tumor growth and prolongation of the survival of mice, but the effect was less than that on the growth of QR-32 regressor tumor after coimplantation with gelatin sponge. These results suggest that the inhibitory effect of Juzen-taiho-to is partly associated with prevention of gelatin sponge-elicited progressive growth, probably mediated by endogenous factors including antioxidant substances, in addition to the augmentation of host-mediated antitumor activity.

Nicholson A
Physicians Committee for Responsible Medicine, Washington, DC, USA.
Altern Ther Health Med (United States) Nov 1996, 2 (6) p32-8

The role of diet in breast cancer has been considered since the 1940s. However, most epidemiological studies on the incidence of the disease have been limited by their focus on one dietary component-fat-at the expense of a balanced consideration of the effect of the total diet. Further, only the intercultural comparison studies examine a wide range of fat intakes. These studies indicate a dearth of breast cancer in populations with diets in which less than 10% of calories are from fat. Although dietary fat, estrogenic food additives, and alcohol increase the risk of breast cancer, fiber, indoles, flavonols, vitamins C and E, beta carotene, and selenium are associated with a decreased risk. Except for alcohol, factors that increase risk predominate in animal products, whereas those that decrease risk abound in plant products. These factors have similar effects on progression and prognosis in breast cancer. Mechanistically, higher serum levels of estrogen have been linked with risk of breast cancer. Dietary fat, insecticide residues, and alcohol result in higher estrogen activity. A variety of plant nutrients have estrogen-blocking activity. Current evidence justifies recommending that women of all ages follow a plant-based diet in which fat provides no more than 10% of calories, with the goals of preventing breast cancer and improving its prognosis in a low-cost, safe manner. (80 Refs.)

Cockcroft J; Chowienczyk P
Heart (England) Oct 1996, 76 (4) p293-4

No abstract.

Klosterhalfen B; Tons C; Hauptmann S; Tietze L; Offner FA; Kupper W; Kirkpatrick CJ
Department of Surgery, Technical University of Aachen, Germany.
Biochem Pharmacol (England) Oct 25 1996, 52 (8) p1201-10

The manipulation of stress gene expression by heavy metals provides protection against the lethal effects of endotoxemia in murine models of septic shock. Recent in vitro studies with alveolar macrophages or monocytes show that induction of the stress response in these cells is followed by a decreased liberation of major cytokines [tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1)] after endotoxin challenge. These findings suggest eased resistance to endotoxin in vivo after stress protein induction could be explained by an altered pattern of inflammatory mediator release. Therefore, we measured the time course of thromboxane-B2 (TxB2), 6-keto-PGF1 alpha, platelet activating factor (PAF), TNF alpha, interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) formation with and without induction of the stress response in an established porcine model of recurrent endotoxemia (Klosterhalfen et al., Biochem Pharmacol 43: 2103-2109, 1992). Induction of the stress response was done by a pretreatment with Zn2+ (25 mg/kg zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn2+). Pretreatment with Zn2+ prior to lipopolysaccharide (LPS) infusion induced an increased heat shock protein 70 and metallothionein expression in the lungs, liver, and kidneys and increased plasma levels of TNF alpha, IL-1 beta, IL-6, and TxB2 as opposed to untreated controls. After LPS infusion, however, pretreated animals showed significantly decreased peak plasma levels of all mediators as opposed to the untreated group. The time course of mediator release was identical with the decreasing and increasing three peak profiles described previously. Hemodynamic data presented significantly decreased peak pulmonary artery pressures and significantly altered hypodynamic/hyperdynamic cardiac output levels in the pretreated group. In conclusion, the data show that the induction of stress proteins by Zn2+ could be a practicable strategy to prevent sepsis.

Pietinen P; Rimm EB; Korhonen P; Hartman AM; Willett WC; Albanes D; Virtamo J
Department of Nutrition, National Public Health Institute, Helsinki, Finland. Pirjo.Pietinen ktl.fi
Circulation (United States) Dec 1 1996, 94 (11) p2720-7

BACKGROUND: Even though dietary fiber has been hypothesized to reduce the risk of coronary heart disease, few large epidemiological studies have examined this relation with good methodology.

METHODS AND RESULTS: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was a randomized, double-blind, placebo-controlled trial with daily supplementation of alpha-tocopherol and/or beta-carotene. Of the participants, 21930 smoking men aged 50 to 69 years who were free of diagnosed cardiovascular disease and had completed a validated dietary questionne monitored the incidence o f major coronary events (a combination of first nonfatal myocardial infarction and coronary heart disease death; n = 1399) and mortality from coronary heart disease (n = 635). Both entities had a significant inverse association with dietary fiber, but the association was stronger for coronary death. For men in the highest quintile of total dietary fiber intake (median, 34.8 g/d), the relative risk for coronary death was 0.69 (95% confidence interval, 0.54 to 0.88; P < .001 for trend) compared with men in the lowest quintile of intake (median, 16.1 g/d). With an adjustment for known cardiovascular risk factors, intake of saturated fatty acids, beta-carotene, vitamin C, and vitamin E did not materially change the result. Water-soluble fiber was slightly more strongly associated with reduced coronary death than water-insoluble fiber, and cereal fiber also had a stronger association than vegetable or fruit fiber.

CONCLUSIONS: These findings suggest that independent of other risk factors, greater intake of foods rich in fiber can substantially reduce the risk of coronary heart disease, and particularly coronary death, in middle-aged, smoking men.

Hsia SL; He JL; Nie Y; Fong K; Milikowski C
Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Florida 33101, USA.
Artery (United States) 1996, 22 (1) p1-23

To test possible hypocholesterolemic and antiatherogenic effects of transdermally administered phosphatidylcholine (PC), we applied a 33% solution of PC in ethanol containing 0.01% butylated hydroxytoluene as antioxidant, to the shaved back of a strain of inbred rabbits which spontaneously developed hypercholesterolemia (serum cholesterol above 110 mg/dl) and severe atherosclerotic lesions especially in the aortic arch. After the topical application of PC, increases of choline-containing phospholipids in blood were observed, reaching a plateau in 24-48 hr. There were significant reductions in serum cholesterol and LDL cholesterol in thesions in the aortic arch were clearly less severe in the animals repeatedly treated with topical PC. The hypocholesterolemic and antiatherogenic effects of topical PC could be the result of increased cholesterol efflux from extrahepatic tissues and enhanced reverse cholesterol transport.

Clifford AJ; Ebeler SE; Ebeler JD; Bills ND; Hinrichs SH; Teissedre PL; Waterhouse AL
Department of Nutrition, University of California, Davis 95616, USA
Am J Clin Nutr (United States) Nov 1996, 64 (5) p748-56

Increased consumption of vegetable foods (cereals, legumes, fruits) and some beverages (tea, cider, wine) is associated with reduced risk of cancer. Polyphenols in these foods and beverages are thought to be responsible, based on data from in vitro assays and from in vivo studies that used animals pretreated with carcinogen and given tea or polyphenol-spiked water to drink. We tested the hypothesis that dehydrated-dealcoholized red wine (wine solids), when consumed as part of a precisely defined complete diet, would delay tumor onset in transgenic mice that spontaneously develop externally visible tumors without carcinogen pretreatment. Sibling transgenic mice were weaned onto an amino acid-based diet alone or supplemented with red wine solids. Mice were examined daily; the age at which a first tumor appeared was recorded as the age of tumor onset. The concentration of the major polyphenol of red wine (cate in blood serum was also measured at the end of the study. The supplemented diet was fed continuously for three generations to ensure that it supported normal growth and reproduction. We discovered that the wine solid supplement delayed tumor onset, that intact catechin was absorbed, and that the supplemented diet supported normal growth and reproduction for three generations. Also, our simple experimental protocol offers an alternate and/or complementary way to identify foods, beverages, and their constituents that delay tumor onset and to investigate possible mechanisms involved.

Lonn EM; Yusuf S; Doris CI; Sabine MJ; Dzavik V; Hutchison K; Riley WA; Tucker J; Pogue J; Taylor W
Division of Cardiology and Preventive Cardiology, Hamilton Civic Hospitals Research Center, McMaster University, Ontario, Canada.
Am J Cardiol (United States) Oct 15 1996, 78 (8) p914-9

Atherosclerotic cardiovascular disease remains a major cause of mortality and morbidity in most developed countries. Experimental and clinical evidence suggests that angiotensin-converting enzyme inhibitors and vitamin E therapy may retard the atherosclerotic process; however, definitive proof in humans is lacking. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) is designed to assess the effects of ramipril--an angiotensin-converting enzyme inhibitor, at 2 doses: 2.5 mg daily (which has little effect oure) and 10 mg daily--and the antioxidant vitamin E, 400 IU daily, on atherosclerosis progression in 732 patients using a factorial 3 x 2 study design. High-risk patients with a documented history of significant cardiovascular disease or with diabetes and additional risk factors were enrolled and will be followed for 4 years. The extent and progression of atherosclerosis are assessed noninvasively by B-mode carotid ultrasonography. The SECURE trial is a substudy of the larger Heart Outcomes Prevention Evaluation (HOPE) study of 9,541 high-risk patients evaluating the effects of ramipril and vitamin E on major cardiovascular events (cardiovascular death, myocardial infarction, and stroke). The 2 studies are complementary. Whereas HOPE is expected to provide information on major clinical outcomes, SECURE will shed light on the mechanisms by which these effects may be mediated.

Continued on the next page...