Phyllis E. Bowen

National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline.

The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panels assessment of the available evidence.

Maintenance of lower proportions of (n − 6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n − 3) fatty acids

Competition between the (n - 3) and (n - 6) types of highly unsaturated fatty acids can diminish the abundance of (n - 6) eicosanoid precursors in a tissue, which in turn can diminish the intensity of tissue responses that are mediated by (n - 6) eicosanoids. The mixture of 20- and 22-carbon highly unsaturated fatty acids maintained in the phospholipids of human plasma is related to the dietary intake of 18:2 (n - 6) and 18:3 (n - 3) by empirical hyperbolic equations in a manner very similar to the relationship reported for laboratory rats (Lands, W.E.M., Morris, A. and Libelt, B. (1990) Lipids 25, 505-516). Analytical results from volunteers ingesting self-selected diets showed an inter-individual variance for the proportion of (n - 6) eicosanoid precursors in the fatty acids of plasma phospholipids of about 5%, but the variance among multiple samples taken from the same individual throughout the day was less (about 3%), closer to the experimental variance of the analytical procedure (about 1%). The reproducibility of the results makes it likely that analysis of fatty-acid composition of plasma lipids from individuals will prove useful in estimating the diet-related tendency for severe thrombotic, arthritic or other disorders that are mediated by (n - 6) eicosanoids. Additional constants and terms were included in the equations to account for the effects of 20- and 22-carbon highly unsaturated (n - 3) fatty acids in the diet. A lower constant for the 20- and 22-carbon (n - 3) fatty acids compared to that for the 18-carbon (n - 3) fatty acid in decreasing the ability of dietary 18:2 (n - 6) to maintain 20:4 (n - 6) in tissue lipids confirmed the greater competitive effectiveness of the more highly unsaturated n - 3 fatty acids in the elongation/desaturation process. Also, a lower constant for direct incorporation of 20-carbon fatty acids of the n - 6 vs. the n - 3 type indicated a greater competitive effectiveness of 20:4 (n - 6) relative to 20:5 (n - 3) in reesterification after release from tissue lipids. The equations may be used in reverse to estimate the dietary intakes of the (n - 3) and (n - 6) fatty acids by using the composition of the fatty acids that had been maintained in plasma lipids.

Update on the Biological Characteristics of the Antioxidant Micronutrients: Vitamin C, Vitamin E, and the Carotenoids

Under normal circumstances, free radicals that are produced through biological processes and in response to exogenous stimuli are controlled by various enzymes and antioxidants in the body. Laboratory evidence suggests that oxidative stress, which occurs when free radical formation exceeds the ability to protect against them, may form the biological basis of several acute medical problems, such as tissue injury after trauma, and chronic conditions, such as atherosclerosis and cancer. A potential role for the antioxidant micronutrients (vitamin C, vitamin E, and the carotenoids) in modifying the risk for conditions that may result from oxidative stress has stimulated intense research efforts, increased interest in micronutrient supplements, and heightened consumer interest in these compounds. Much remains to be learned, however, about the bioavailability, tissue uptake, metabolism, and biological activities of these micronutrients. These biological characteristics will ultimately determine their clinical usefulness in modulating oxidative stress. Also, whether the antioxidant mechanism explains their relationship with risk for acute and chronic disease in epidemiologic studies remains to be determined. Increased knowledge in this area of nutrition science will have an impact on both clinical dietetics practice and public health nutrition guidelines.

Risk Factors and Preventive Interventions for Alzheimer Disease: State of the Science

BACKGROUND Numerous studies have investigated risk factors for Alzheimer disease (AD). However, at a recent National Institutes of Health State-of-the-Science Conference, an independent panel found insufficient evidence to support the association of any modifiable factor with risk of cognitive decline or AD. OBJECTIVE To present key findings for selected factors and AD risk that led the panel to their conclusion. DATA SOURCES An evidence report was commissioned by the Agency for Healthcare Research and Quality. It included English-language publications in MEDLINE and the Cochrane Database of Systematic Reviews from 1984 through October 27, 2009. Expert presentations and public discussions were considered. STUDY SELECTION Study inclusion criteria for the evidence report were participants aged 50 years and older from general populations in developed countries; minimum sample sizes of 300 for cohort studies and 50 for randomized controlled trials; at least 2 years between exposure and outcome assessment; and use of well-accepted diagnostic criteria for AD. DATA EXTRACTION Included studies were evaluated for eligibility and data were abstracted. Quality of overall evidence for each factor was summarized as low, moderate, or high. DATA SYNTHESIS Diabetes mellitus, hyperlipidemia in midlife, and current tobacco use were associated with increased risk of AD, and Mediterranean-type diet, folic acid intake, low or moderate alcohol intake, cognitive activities, and physical activity were associated with decreased risk. The quality of evidence was low for all of these associations. CONCLUSION Currently, insufficient evidence exists to draw firm conclusions on the association of any modifiable factors with risk of AD.

Tomato sauce supplementation and prostate cancer: lycopene accumulation and modulation of biomarkers of carcinogenesis.

As part of a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage in men with prostate cancer, a nonrandomized 5th arm using tomato sauce was included and reported here. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical prostatectomy. Prostate tissue was obtained as biopsies at baseline and as resected tissue at the time of the prostatectomy. Serum and prostate lycopene, serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH-deoxyguanosine/deoxyguanosine (80HdG) were measured at baseline and at the end of the intervention. Cancer cells in paraffin sections of prostate biopsies and postintervention resected tissue were compared for 80HdG staining and for apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6% of the intended dose, and serum and prostate lycopene concentrations increased 1.97- and 2.92-fold (P< 0.001), respectively. Mean serum PSA concentrations decreased by 17.5% (P< 0.002) and leukocyte 80HdG decreased by 21.3% (P< 0.005) after tomato sauce consumption. Resected tissues from tomato sauce-supplemented patients had 28.3% lower prostate 80HdG compared with the nonstudy control group (P < 0.03). Cancer cell 80HdG staining of Gleason Score-matched resected prostate sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic index was higher in hyperplastic and neoplastic cells in the resected tissue after supplementation. These data taken as a whole indicate significant uptake of lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and prostate tissue. Whether reduction in DNA. damage to prostate cancer cells is beneficial awaits further research, although reduction in serum PSA concentrations is promising.

Oxidative Stress in Critical Care: Is Antioxidant Supplementation Beneficial?

Reactive oxygen species (ROS) are constantly produced in human beings under normal circumstances. Antioxidant systems help defend the body against ROS but may be overwhelmed during periods of oxidative stress, which can cause lipid peroxidation, damage to DNA, and cell death. Critical illness, such as sepsis or adult respiratory distress syndrome, can drastically increase the production of ROS and lead to oxidative stress. Sources of oxidative stress during critical illness include activation of the phagocytic cells of the immune system (the respiratory burst), the production of nitric oxide by the vascular endothelium, the release of iron and copper ions and metalloproteins, and the vascular damage caused by ischemia reperfusion. Only indirect measurements of ROS are available, but the presence of oxidative stress in critical illness is supported by clinical studies. In general, serum antioxidant vitamin concentrations seem to decrease and measures of oxidative stress seem to increase in critically ill populations. Oxidative stress has been associated with sepsis, shock, a need for mechanical ventilation, organ dysfunction, acute respiratory distress syndrome, disseminated intravascular coagulation, surgery, and the presence of an acute-phase response. In addition, higher levels of oxidative stress seem to occur in patients with more notable injuries. Dietary supplementation with antioxidant vitamins seems to be the logical answer to decreasing serum antioxidant concentrations, but antioxidants may have adverse effects. The benefit of supplementing antioxidants in critically ill populations has not been shown and requires further study.

Cigarettes and alcohol as independent risk factors for colonic adenomas

Healthy adults completed smoking and alcohol consumption questionnaires before colonoscopies, which were performed because of occult blood in the stool or prior barium enema suggesting polyps. Subjects with adenomas at colonoscopy (n = 102) were compared with colonoscopy-negative controls (n = 89). In univariate analyses, age (p less than 0.05), male sex (p less than 0.005), cumulative smoking (p less than 0.0001), and cumulative beer consumption (p less than 0.005) were associated with adenomas. The association of smoking with adenomas was stronger in younger subjects. The association of beer with adenomas was stronger in older subjects. Logistic regression confirmed statistically significant associations of smoking (odds ratio for greater than 40 pack-years = 3.31; confidence intervals 1.41, 7.81) and beer consumption (odds ratio for greater than 40 beer-years = 2.64; confidence intervals 1.10, 6.32) with adenomas. These results suggest that smoking and beer consumption are independent risk factors for colonic adenomas.

Effects of Tomato Sauce Consumption on Apoptotic Cell Death in Prostate Benign Hyperplasia and Carcinoma

Population studies have suggested that lycopene, which is mostly found in tomato and tomato products, may reduce the risk of prostate cancer. We previously found that tomato sauce consumption prior to prostatectomy for prostate cancer decreased serum prostate specific antigen, decreased oxidative DNA damage, and increased lycopene concentrations in prostate tissue (Chen et al., 2001). Here, we extended those investigations to determine whether apoptotic cell death and associated Bcl-2 and Bax proteins were modulated by tomato sauce intervention. Thirty-two patients diagnosed by biopsy with prostate carcinoma were given tomato sauce pasta entrees (30 mg lycopene/day) for 3 wk before prostatectomy. Thirty-four patients with prostate cancer who did not consume tomato sauce and underwent prostatectomy served as controls. When tumor areas with the most apoptotic cells were compared in the biopsy (before) and resected prostate tissue (after), tomato sauce consumption increased apoptotic cells in benign prostate hyperplasia (BPH) from 0.66 ± 0.10% to 1.38 ± 0.31% (P = 0.013) and in carcinomas from 0.84 ± 0.13% to 2.76 ± 0.58% (P = 0.0003). When comparable morphological areas were counted, apoptotic cell death in carcinomas increased significantly with treatment, from 0.84 ± 0.13% to 1.17 ± 0.19% (P = 0.028), and apoptotic cell death in BPH showed a tendency toward an increase from 0.66 ± 0.10% to 1.20 ± 0.32% (P = 0.20). When the values of apoptotic cells in BPH and carcinomas of patients who consume tomato sauce were compared with corresponding control lesions of the patients who did not consume tomato sauce in resected prostate tissue, the differences of values were not significant [BPH 1.38 ± 0.31% vs. 1.14 ± 0.32% (P= 0.97); carcinomas 2.76 ± 0.58% vs. 1.91 ± 0.32% (P = 0.24)]. Tomato sauce consumption did not affect Bcl-2 expression but decreased Bax expression in carcinomas. These data provide the first in vivo evidence that tomato sauce consumption may suppress the progression of the disease in a subset of patients with prostate cancer by increasing apoptotic cell death. However, because of the relatively small number of control and tomato sauce-supplemented patients and the variability in the values of apoptotic cells in BPH and carcinomas, a much larger number of patients needs to be examined to support the data generated in this study.

Pharmacokinetics of beta-carotene and canthaxanthin after ingestion of individual and combined doses by human subjects.

OBJECTIVE This study investigated effects of ingestion of a combined dose of beta-carotene and canthaxanthin on their individual pharmacokinetics in serum. METHODS During three 5-day study periods, two subjects ingested either a 25 mg dose of beta-carotene, a 25 mg dose of canthaxanthin, or a combined dose of 25 mg each of beta-carotene and canthaxanthin. Pharmacokinetics of the individual and combined doses were compared within subjects. RESULTS Ingestion of a concurrent beta-carotene dose reduced the peak serum canthaxanthin concentration by 38.8 +/- 6.5%, and the 24- and 72-hour areas under the serum canthaxanthin concentration-time curves by 38.1 +/- 6.4 and 34.4 +/- 7.4%, respectively. The suggested antagonism between beta-carotene and canthaxanthin was not reciprocal; beta-carotene inhibited the appearance of canthaxanthin in serum but canthaxanthin did not inhibit the appearance of beta-carotene. CONCLUSION Our data suggest that ingestion of a combined pharmacologic dose of beta-carotene and canthaxanthin reduces the bioavailability of the canthaxanthin dose.

Effects of β-carotene repletion on β-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men.

Abstract The chemopreventive effects of s‐carotene are usually attributed to its antioxidant properties. To determine the effects of s‐carotene supplementation on different parameters of oxidative metabolism, 15 normal young male subjects (18–30 yrs) were placed on a carotenoid‐free liquid diet for two weeks prior to entry into the study. Blood was then measured for five carotenoids, retinol, retinyl palmitate, retinol‐binding protein, α‐tocopherol, vitamin C, zinc, lipid peroxides, and neutrophil Superoxide production. Absorption tests were performed with 15 mg of s‐carotene to determine absorption curves for each subject. Subjects were then divided into two groups and given either 15 (n = 7) or 120 (n = 8) mg of s‐carotene daily for four weeks along with the same carotenoid‐free liquid diet. The absorption test and the blood measurements were repeated. After repletion with s‐carotene, serum lipid peroxide levels decreased in both groups (p < 0.05), but no other changes were noted in either the neutrophi...