Query: blood clots

Relevant passages:
The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives <=SEP=> Summary Grapefruit is a popular, tasty and nutritive fruit enjoyed globally. Biomedical evidence in the last 10 years has, however, shown that consumption of grapefruit or its juice is associated with drug interactions, which, in some cases, have been fatal. Grapefruit-induced drug interactions are unique in that the cytochrome P450 enzyme CYP3A4, which metabolises over 60% of commonly prescribed drugs as well as other drug transporter proteins such as P-glycoprotein and organic cation transporter proteins, which are all expressed in the intestines, are involved. However, the extent to which grapefruit–drug interactions impact on clinical settings has not been fully determined, probably because many cases are not reported. It has recently emerged that grapefruit, by virtue of its rich flavonoid content, is beneficial in the management of degenerative diseases such as diabetes and cardiovascular disorders. This potentially explosive subject is reviewed here.

Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study <=SEP=> In vitro and in vivo studies have shown that cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of oestrogens. There is evidence that grapefruit, an inhibitor of CYP3A4, increases plasma oestrogen concentrations. Since it is well established that oestrogen is associated with breast cancer risk, it is plausible that regular intake of grapefruit would increase a woman's risk of breast cancer. We investigated the association of grapefruit intake with breast cancer risk in the Hawaii–Los Angeles Multiethnic Cohort Study, a prospective cohort that includes over 50 000 postmenopausal women from five racial/ethnic groups. A total of 1657 incident breast cancer cases were available for analysis. Grapefruit intake was significantly associated with an increased risk of breast cancer (relative risk=1.30, 95% confidence interval 1.06–1.58) for subjects in the highest category of intake, that is, one-quarter grapefruit or more per day, compared to non-consumers (Ptrend=0.015). An increased risk of similar magnitude was seen in users of oestrogen therapy, users of oestrogen+progestin therapy, and among never users of hormone therapy. Grapefruit intake may increase the risk of breast cancer among postmenopausal women.

Effects of grapefruit, grapefruit juice and water preloads on energy balance, weight loss, body composition, and cardiometabolic risk in free-living obese adults <=SEP=> Background Reducing dietary energy density has proven to be an effective strategy to reduce energy intakes and promote weight control. This effect appears most robust when a low energy dense preload is consumed before meals. Yet, much discussion continues regarding the optimal form of a preload. The purpose of the present study was to compare effects of a solid (grapefruit), liquid (grapefruit juice) and water preload consumed prior to breakfast, lunch and dinner in the context of caloric restriction. Methods Eighty-five obese adults (BMI 30-39.9) were randomly assigned to (127 g) grapefruit (GF), grapefruit juice (GFJ) or water preload for 12 weeks after completing a 2-week caloric restriction phase. Preloads were matched for weight, calories, water content, and energy density. Weekly measures included blood pressure, weight, anthropometry and 24-hour dietary intakes. Resting energy expenditure, body composition, physical performance and cardiometabolic risk biomarkers were assessed. Results The total amount (grams) of food consumed did not change over time. Yet, after preloads were combined with caloric restriction, average dietary energy density and total energy intakes decreased by 20-29% from baseline values. Subjects experienced 7.1% weight loss overall, with significant decreases in percentage body, trunk, android and gynoid fat, as well as waist circumferences (-4.5 cm). However, differences were not statistically significant among groups. Nevertheless, the amount and direction of change in serum HDL-cholesterol levels in GF (+6.2%) and GFJ (+8.2%) preload groups was significantly greater than water preload group (-3.7%). Conclusions These data indicate that incorporating consumption of a low energy dense dietary preload in a caloric restricted diet is a highly effective weight loss strategy. But, the form of the preload did not have differential effects on energy balance, weight loss or body composition. It is notable that subjects in GF and GFJ preload groups experienced significantly greater benefits in lipid profiles. Trial registration ClinicalTrials.gov NCT00581074

Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. <=SEP=> 1. The effects of grapefruit juice and naringenin on the activity of the human cytochrome P450 isoform CYP1A2 were evaluated using caffeine as a probe substrate. 2. In vitro naringin was a potent competitive inhibitor of caffeine 3-demethylation by human liver microsomes (Ki = 7-29 microM). 3. In vivo grapefruit juice (1.2 l day-1 containing 0.5 g l-1 naringin, the glycone form of naringenin) decreased the oral clearance of caffeine by 23% (95% CI: 7%-30%) and prolonged its half-life by 31% (95% CI: 20%-44%) (n = 12). 4. We conclude that grapefruit juice and naringenin inhibit CYP1A2 activity in man. However, the small effect on caffeine clearance in vivo suggests that in general the ingestion of grapefruit juice should not cause clinically significant inhibition of the metabolism of other drugs that are substrates of CYPIA2.

Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. <=SEP=> The contents of the bioactive compounds in red and blond grapefruits and their influence on humans suffering from hypertriglyceridemia were studied. It was found that red grapefruit has a higher content of bioactive compounds and a higher antioxidant potential than blond grapefruit, determined by oxygen radical scavenging capacity, 1,1-diphenyl-2-picrylhydrazyl, carotenoid bleaching, and Folin-Ciocalteu assays. Fifty-seven hyperlipidemic patients, ages 39-72 years, after coronary bypass surgery, recruited from the Institute's pool of volunteers, were randomly divided into three equal in number (19) groups: two experimental (red and blond groups) and one control group (CG). During 30 consecutive days of the investigation the diets of the patients of the red and blond dietary groups were daily supplemented with one equal in weight fresh red or blond grapefruit, respectively. Before and after this trial, serum lipid levels of all fractions and serum antioxidant activity were determined. It was found that serum lipid levels in patients of the red and blond groups versus the CG after treatment were decreased: (a) total cholesterol, 6.69 versus 7.92 mmol/L, 15.5%, and 7.32 versus 7.92 mmol/L, 7.6%, respectively; (b) low-density lipoprotein cholesterol, 5.01 versus 6.29 mmol/L, 20.3%, and 5.62 versus 6.29 mmol/L, 10.7%, respectively; (c) triglycerides, 1.69 versus 2.32 mmol/L, 17.2%, and 2.19 versus 2.32 mmol/L, 5.6%, respectively. No changes in the serum lipid levels in patients of the CG were found. In conclusion, fresh red grapefruit contains higher quantities of bioactive compounds and has significantly higher antioxidant potential than blond grapefruit. Diet supplemented with fresh red grapefruit positively influences serum lipid levels of all fractions, especially serum triglycerides and also serum antioxidant activity. The addition of fresh red grapefruit to generally accepted diets could be beneficial for hyperlipidemic, especially hypertriglyceridemic, patients suffering from coronary atherosclerosis.

Can grapefruit juice influence ethinylestradiol bioavailability? <=SEP=> The effects of grapefruit juice on the bioavailability of 17 alpha-ethinylestradiol (EE2) after a single oral administration of 50 micrograms EE2 have been investigated. The pharmacokinetics of EE2 were studied in an open, randomized, cross-over study in which 13 healthy volunteers were administered the drug with herbal tea or grapefruit juice (naringin, 887 mg/ml). In contrast to herbal tea, grapefruit juice increased the peak plasma concentration (Cmax) significantly to 137% (mean; range 64% to 214%, p = 0.0088) and increased the area under plasma concentration-time curve from 0 to 8 hours (AUC0-8) to 128% (mean; range 81% to 180%, p = 0.0186). This study shows that grapefruit juice increases the bioavailable amount of EE2. A possible explanation may be that grapefruit juice inhibits the metabolic degradation of EE2. Whether the increased bioavailability of EE2 following grapefruit juice administration is of clinical importance should be investigated in long-term studies.

Supplementation of a western diet with golden kiwifruits (Actinidia chinensis var.'Hort 16A':) effects on biomarkers of oxidation damage and antioxidant protection <=SEP=> Background The health positive effects of diets high in fruits and vegetables are generally not replicated in supplementation trials with isolated antioxidants and vitamins, and as a consequence the emphasis of chronic disease prevention has shifted to whole foods and whole food products. Methods We carried out a human intervention trial with the golden kiwifruit, Actinidia chinensis, measuring markers of antioxidant status, DNA stability, plasma lipids, and platelet aggregation. Our hypothesis was that supplementation of a normal diet with kiwifruits would have an effect on biomarkers of oxidative status. Healthy volunteers supplemented a normal diet with either one or two golden kiwifruits per day in a cross-over study lasting 2 × 4 weeks. Plasma levels of vitamin C, and carotenoids, and the ferric reducing activity of plasma (FRAP) were measured. Malondialdehyde was assessed as a biomarker of lipid oxidation. Effects on DNA damage in circulating lymphocytes were estimated using the comet assay with enzyme modification to measure specific lesions; another modification allowed estimation of DNA repair. Results Plasma vitamin C increased after supplementation as did resistance towards H2O2-induced DNA damage. Purine oxidation in lymphocyte DNA decreased significantly after one kiwifruit per day, pyrimidine oxidation decreased after two fruits per day. Neither DNA base excision nor nucleotide excision repair was influenced by kiwifruit consumption. Malondialdehyde was not affected, but plasma triglycerides decreased. Whole blood platelet aggregation was decreased by kiwifruit supplementation. Conclusion Golden kiwifruit consumption strengthens resistance towards endogenous oxidative damage.

Platelets and atherogenesis: Platelet anti-aggregation activity and endothelial protection from tomatoes (Solanum lycopersicum L.) <=SEP=> In recent years, it has been shown that platelets are not only involved in the arterial thrombotic process, but also that they play an active role in the inflammatory process of atherogenesis from the beginning. The interaction between platelets and endothelial cells occurs in two manners: activated platelets unite with intact endothelial cells, or platelets in resting adhere to activated endothelium. In this context, inhibition of the platelet function (adhesion/aggregation) could contribute to the prevention of atherothrombosis, the leading cause of cardiovascular morbidity. This can be achieved with antiplatelet agents. However, at the public health level, the level of primary prevention, a healthy diet has also been shown to exert beneficial effects. Among those elements of a healthy diet, the consumption of tomatoes (Solanum lycopersicum L.) stands out for its effect on platelet anti-aggregation activity and endothelial protection, which may be beneficial for cardiovascular health. This article briefly discusses the involvement of platelets in atherogenesis and the possible mechanisms of action provided by tomatoes for platelet anti-aggregation activity and endothelial protection.

Strawberry extract presents antiplatelet activity by inhibition of inflammatory mediator of atherosclerosis (sP-selectin, sCD40L, RANTES, and IL-1β... <=SEP=> Cardiovascular disease prevention is of high priority in developed countries. Healthy eating habits including the regular intake of an antithrombotic diet (fruit and vegetables) may contribute to prevention. Platelet function is a critical factor in arterial thrombosis and the effect strawberries have is still unclear. Therefore, the aim of this study was to systematically examine the action of strawberries in preventing platelet activation and thrombus formation. Strawberry extract concentration-dependently (0.1-1 mg/ml) inhibited platelet aggregation induced by ADP and arachidonic acid. At the same concentrations as strawberry inhibits platelet aggregation, it significantly decreased sP-selectin, sCD40L, RANTES, and IL-1β levels. The strawberry may exert significant protective effects on thromboembolic-related disorders by inhibiting platelet aggregation. Also, this suggests that antithrombotic activity may have novel anti-inflammatory effects.

Effects of tomato extract on human platelet aggregation in vitro. <=SEP=> Among all fruits tested in vitro for their anti-platelet property, tomato had the highest activity followed by grapefruit, melon, and strawberry, whereas pear and apple had little or no activity. Tomato extract (20-50 microl of 100% juice) inhibited both ADP- and collagen-induced aggregation by up to 70% but could not inhibit arachidonic acid-induced platelet aggregation and concomitant thromboxane synthesis under similar experimental conditions. The anti-platelet components (MW <1000 Da) in tomatoes are water soluble, heat stable and are concentrated in the yellow fluid around the seeds. The active fractions were separated using gel filtration and HPLC. The aqueous fraction (110 000 xg supernatant) of tomatoes containing anti-platelet activity was subjected to gel filtration column chromatography (Biogel P2 column). The activity was fractionated into two peaks, peak-3 and peak-4 (major peak). Subsequently, peak-4 was further purified by HPLC using a reversed-phase column. NMR and mass spectroscopy studies indicated that peak F2 (obtained from peak 4) contained adenosine and cytidine. Deamination of peak F2 with adenosine deaminase almost completely abolished its anti-platelet activity, confirming the presence of adenosine in this fraction. In comparison, deamination of peak-4 resulted in only partial loss of inhibitory activity while the activity of peak-3 remained unaffected. These results indicate that tomatoes contain anti-platelet compounds in addition to adenosine. Unlike aspirin, the tomato-derived compounds inhibit thrombin-induced platelet aggregation. All these data indicate that tomato contains very potent anti-platelet components, and consuming tomatoes might be beneficial both as a preventive and therapeutic regime for cardiovascular disease.

Cardioprotective properties of kiwifruit. <=SEP=> Beneficial effects of consumption of fruit and vegetables on the cardiovascular system have been reported. Fruit and vegetable components affect the cardiovascular system in both antioxidant and nonantioxidant ways. The mechanisms of their actions are, however, still not well understood. The compounds present in fruits and vegetables may function individually or in concert to protect lipoproteins and vascular cells from oxidation or by other mechanisms such as reducing plasma lipid levels, high blood pressure, and platelet hyperactivity. Emerging data indicate that kiwifruit is beneficial in the prevention of cardiovascular disease, as consumption of two or three fruit per day for 28 days or more lowers platelet hyperactivity, plasma lipids, and blood pressure in human volunteers. These studies suggest that kiwifruit may provide a new dietary means as part of a preventive or therapeutic strategy to favorably modify cardiovascular risk factors. The relevance of lowering the cardiovascular risk factors by kiwifruit in human health is discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro. <=SEP=> Effect of aqueous extract of several herbs on human platelet aggregation in vitro was investigated. Out of 28 herbs/nutriceuticals investigated, camomile, nettle alfalfa, garlic and onion exhibited most significant anti-platelet activity (>or=45% inhibition). Aqueous extracts of alfalfa, fresh nettle, and camomile inhibited ADP induced-platelet aggregation by 73, 65 and 60%, respectively, compared with control (P < 0.05). Camomile and alfalfa inhibited collagen-induced platelet aggregation by 84 and 65%, respectively, but nettle could not inhibit collagen-induced aggregation. In contrast, nettle was the most potent inhibitor (66%) of whole blood aggregation induced by collagen, followed by alfalfa (52%), and camomile (30%) compared with control (P < 0.05). None of these three herbs however could inhibit arachidonic acid or thrombin induced platelet aggregation. Camomile and alfalfa strongly inhibited thromboxane B2 synthesis induced by ADP or collagen, but nettle had no effect. Alfalfa and nettle increased cGMP levels in platelets by 50 and 35%, respectively, compared with the control (1.85 +/- 0.23 nM) (P < 0.005). All these data indicate that camomile, nettle and alfalfa have potent anti-platelet properties, and their inhibitory actions are mediated via different mechanisms.

Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans. <=SEP=> BACKGROUND: Aqueous extracts from tomatoes display a range of antiplatelet activities in vitro. We previously showed that the active components also alter ex vivo platelet function in persons with a high response to ADP agonist. OBJECTIVE: The objective was to evaluate the suitability of a tomato extract for use as a dietary supplement to prevent platelet activation. DESIGN: A randomized, double-blinded, placebo-controlled crossover study was conducted in 90 healthy human subjects selected for normal platelet function. Changes from baseline hemostatic function were measured 3 h after consumption of extract-enriched or control supplements. RESULTS: Significant reductions in ex vivo platelet aggregation induced by ADP and collagen were observed 3 h after supplementation with doses of tomato extract equivalent to 6 (6TE) and 2 (2TE) tomatoes [3 micromol ADP/L: 6TE (high dose), -21.3%; 2TE (low dose), -12.7%; P < 0.001; 7.5 micromol ADP/L: 6TE, -7.8%, 2TE, -7.6%; P < 0.001; 3 mg collagen/L: 6TE, -17.5%; 2TE, -14.6%; P = 0.007]. No significant effects were observed for control supplements. A dose response to tomato extract was found at low levels of platelet stimulation. Inhibition of platelet function was greatest in a subgroup with the highest plasma homocysteine (P < 0.05) and C-reactive protein concentrations (P < 0.001). CONCLUSION: As a functional food or dietary supplement, tomato extract may have a role in primary prevention of cardiovascular disease by reducing platelet activation, which could contribute to a reduction in thrombotic events.

Effect of tomato industrial processing on phenolic profile and antiplatelet activity. <=SEP=> BACKGROUND: Regular consumption of fruits and vegetables (e.g., tomatoes) has been shown to be beneficial in terms of reducing the incidence of cardiovascular diseases. The industrial processing of tomatoes into tomato-based products includes several thermal treatments. Very little is known on the effect of tomato industrial processing on antiaggregatory activity and phenolic profile. METHODS: It was assessed the effect of tomato and by-products extracts on platelet aggregation induced by ADP, collagen, TRAP-6 and arachidonic acid. These in vitro antithrombotic properties were further supported in an in vivo model of thrombosis. A set of antiplatelet compounds has been selected for HPLC analysis in the different extracts. RESULTS: Some natural compounds such as chlorogenic, caffeic, ferulic and p-coumaric acids were identified by HPLC in tomatoes and its products may inhibit platelet activation. Red tomatoes, tomato products (sauce, ketchup and juice) and by-products extracts inhibited platelet aggregation induced adenosine 5'-diphosphate, collagen, thrombin receptor activator peptide-6 and arachidonic acid, but to a different extent. Also, pomace extract presents antithrombotic activity. CONCLUSIONS: Processed tomatoes may have a higher content of health-benefiting compounds than fresh ones. Pomace even presents the best antiplatelet activity. Finally, tomato products may be used as a functional ingredient adding antiplatelet activities to processed foods.

Effects of antiplatelet components of tomato extract on platelet function in vitro and ex vivo: a time-course cannulation study in healthy humans. <=SEP=> BACKGROUND: Natural antithrombotic agents that influence platelet function are of potential interest for primary prevention of cardiovascular disease. Previous reports showed that tomato extracts inhibit platelet aggregation in vitro, but little is known of the active components, their mode of action, or their efficacy in vivo. OBJECTIVE: The objectives of the study were to examine the antiplatelet activity of specific tomato components by in vitro experimentation and to establish their ex vivo efficacy in healthy humans. DESIGN: The mechanisms of action of antiplatelet components isolated from tomato extracts were examined in vitro. A 7-h time-course study was carried out in cannulated human subjects (n = 23) to determine the ex vivo efficacy of a supplement drink containing tomato extract and the onset and duration of antiplatelet effects. RESULTS: The inhibition of ADP-, collagen-, thrombin-, and arachidonate-mediated platelet aggregation by tomato extract components appears to be linked to the inhibition of glycoprotein IIb/IIIa and platelet secretory mechanisms. We found a significant inhibition of baseline platelet function, from 2.9 +/- 1.4% (optimal ADP concentrations; P = 0.03) to 20.0 +/- 4.9% (suboptimal ADP concentrations; P < 0.001), 3 h after supplementation with a dose of tomato extract equivalent to 6 tomatoes. The observed effects persisted for >12 h. Coagulation variables were not affected. CONCLUSIONS: The ingestion of tomato components with in vitro antiplatelet activity significantly affects ex vivo platelet function. The reported cardioprotective effects of tomatoes are potentially linked to a modulation of platelet function.

Diet and thrombosis risk: nutrients for prevention of thrombotic disease. <=SEP=> An increased prothrombotic state is a major risk factor for the development of heart attacks, strokes, and venous thromboembolism. Platelet activation and aggregation play an important role in determining a prothrombotic state. Although pharmaceutical agents such as aspirin, heparin, and warfarin are able to reduce prothrombotic tendency, long-term drug treatment may produce a variety of side effects, including bleeding. Diet is generally recognized to be significantly involved in modifying the individual risk for the development of thrombotic diseases, although its influence during the treatment of these disorders is probably less important. Dietary intervention has proven effective in lowering serum lipid levels, which are otherwise essential elements in the pathogenesis of cardiovascular disease. Likewise, certain dietary components have also been proven effective in decreasing platelet activation through various mechanisms and therefore may contribute to attenuating the future risk of thrombosis. This article provides an up-to-date review of the role of nutrient and nonnutrient supplements on platelet aggregation and risk of thrombosis. © Thieme Medical Publishers.

Platelet dysfunction in vascular pathologies and how can it be treated. <=SEP=> Cardiovascular diseases are one of the leading causes of morbidity and mortality in industrialized countries, and although many processes play a role in the development of vascular disease, thrombosis is the primary event that precipitates stroke and acute coronary syndromes. The blood platelets are of significant importance in medicine. These cells are involved in many physiological processes, particularly haemostasis through their ability to aggregate and form clots in response to activation. In addition, these dynamic cells display activities that extend beyond thrombosis, including an important role in initiating and sustaining vascular inflammation. The expansion of knowledge from basic and clinical research has highlighted the critical position of platelets in several inflammatory diseases such as arthritis and atherosclerosis. Platelets are emerging as important mediators of inflammation and provide important signals to mediate phenotype of other blood and vascular cells. The important role of platelets in arterial thrombosis and the onset of acute myocardial infarction after atherosclerotic plaque rupture make inhibition of platelet aggregation a critical step in preventing thrombotic events associated with stroke, heart attack, and peripheral arterial thrombosis. However, the use of platelet inhibitors for thrombosis prevention must seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. The aim of this review is to up-date the knowledge on platelets physiology and dysfunction in pathologies, such as diabetes mellitus, hypercholesterolemia, and hypertension, emphasizing the link between platelets and the inflammation-related atherosclerosis. The review evaluates the opportunities offered by the novel platelet inhibitors to efficiently alleviate the thrombotic events. Copyright © 2011 Elsevier Ltd. All rights reserved.

Tomatoes and cardiovascular health. <=SEP=> Diet is believed to play a complex role in the development of cardiovascular disease, the leading cause of death in the Western world. Tomatoes, the second most produced and consumed vegetable nationwide, are a rich source of lycopene, beta-carotene, folate, potassium, vitamin C, flavonoids, and vitamin E. The processing of tomatoes may significantly affect the bioavailability of these nutrients. Homogenization, heat treatment, and the incorporation of oil in processed tomato products leads to increased lycopene bioavailability, while some of the same processes cause significant loss of other nutrients. Nutrient content is also affected by variety and maturity. Many of these nutrients may function individually, or in concert, to protect lipoproteins and vascular cells from oxidation, the most widely accepted theory for the genesis of atherosclerosis. This hypothesis has been supported by in vitro, limited in vivo, and many epidemiological studies that associate reduced cardiovascular risk with consumption of antioxidant-rich foods. Other cardioprotective functions provided by the nutrients in tomatoes may include the reduction of low-density lipoprotein (LDL) cholesterol, homocysteine, platelet aggregation, and blood pressure. Because tomatoes include several nutrients associated with theoretical or proven effects and are widely consumed year round, they may be considered a valuable component of a cardioprotective diet.

Dietary components and human platelet activity. <=SEP=> Platelet hyperactivity is one of the most important factors responsible for the incidence of cardiovascular disease. There are many nutritive and non-nutritive compounds present in the diet which may affect platelet function in various ways. Recent discovery of anti-platelet factors in plants, vegetables and fruits provides a new dietary means for a long-term strategy to favorably modify human blood platelet activity. This review summarises the effects of these dietary components on human platelet function both in vitro and in vivo.

Effects of kiwi fruit consumption on platelet aggregation and plasma lipids in healthy human volunteers. <=SEP=> Fruits and vegetables have been thought to be beneficial in cardiovascular disease. The beneficial effects of fruits and vegetables may be explained by the antioxidants and other components contained therein. These nutrients may function individually or in concert to protect lipoproteins and vascular cells from oxidation, or by other mechanisms such as reducing plasma lipid levels (LDL cholesterol, triglycerides), and platelet aggregation response. Kiwi fruit which contains high amounts of vitamin C, vitamin E and polyphenols may be beneficial in cardiovascular disease; however very little is known about its cardioprotective effects. Platelets are involved in atherosclerotic disease development and the reduction of platelet activity by medications reduces the incidence and severity of disease. To this end, we evaluated whether consuming kiwi fruit modulated platelet activity and plasma lipids in human volunteers in a randomized cross-over study. We report that consuming two or three kiwi fruit per day for 28 days reduced platelet aggregation response to collagen and ADP by 18% compared with the controls (P < 0.05). In addition, consumption of kiwi fruit lowered blood triglycerides levels by 15% compared with control (P < 0.05), whereas no such effects were observed in the case of cholesterol levels. All these data indicate that consuming kiwi fruit may be beneficial in cardiovascular disease.

Gender, Race, and Diet Affect Platelet Function Tests in Normal Subjects Contributing to a High Rate of Abnormal Results <=SEP=> Summary To assess sources of variability in platelet function tests in normal subjects, 64 healthy young adults were tested on 2–6 occasions at 2 week intervals using 4 methods: platelet aggregation (AGG) in platelet-rich plasma (PRP) in the Bio/Data PAP-4 Aggregometer (BD) and Chrono-Log Lumi-Aggregometer (CL); and AGG in whole blood (WB) in the CL and Multiplate Platelet Function Analyzer (MP), with ATP release (REL) in CL-PRP and CL-WB. Food and medication exposures were recorded prospectively for 2 weeks prior to each blood draw. At least one AGG abnormality was seen in 21% of 81 drug-free specimens with CL-PRP, 15% with CL-WB, 13% with BD-PRP, and 6% with MP-WB, increasing with inclusion of REL to 28% for CL-PRP and 30% for CL-WB. Epinephrine AGG and REL were significantly reduced in males (P<0.0001). Ristocetin AGG and collagen and thrombin REL were significantly reduced in Blacks (P<0.0001). One-third of specimens drawn following flavonoid-rich food exposures had aberrant results, compared to 8.5% of specimens without such exposures (P=0.0035). PRP tests had less intra-individual variation than WB tests. Gender, race, diet, and test system affected results of platelet function testing in healthy subjects, suggesting caution when interpreting the results of platelet function testing in patients.

Effect of Tomato Industrial Processing (Different Hybrids, Paste, and Pomace) on Inhibition of Platelet Function In Vitro, Ex Vivo, and In Vivo <=SEP=> Cardiovascular disease (CVD) is the leading cause of death worldwide. Healthy eating is among its safeguards, especially the daily intake of fruits and vegetables. In this context it has been shown that tomato (Solanum lycopersicum) presents antiplatelet activity. In the present study, we evaluated in vitro antiplatelet activity of fresh hybrid tomato process (nine hybrids: Apt 410, H 9888, Bos 8066, Sun 6366, AB3, HMX 7883, H 9665, H 7709, and H 9997), paste and its by-product of industrial processes (pomace). We assessed antiplatelet activity ex vivo and bleeding time in rats that ingested 0.1 and 1.0 g/kg of pomace each day. In studies in vitro, no significant differences in antiplatelet activity was observed in fresh tomato hybrids. Furthermore, the agro-industrial process did not affect the antiplatelet activity of paste and pomace. Likewise, pomace intake of 1.0 g/kg per day prolonged bleeding time and reduced ex vivo platelet aggregation in rats. The data obtained indicate that tomato has one or more compounds that caused antiplatelet activity. Regular consumption of tomato and its industrial derivatives could be part of a CVD prevention regimen.

Reduction in Ki-67 in Benign Breast Tissue of High Risk Women with the Lignan Secoisolariciresinol Diglycoside (SDG) <=SEP=> Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a greater than 3-fold increase in 5 year risk, and baseline Ki-67 ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG 50 mg daily was given for 12 months, followed by repeat RPFNA. The primary endpoint was change in Ki-67. Secondary endpoints included change in cytomorphology, mammographic breast density, serum bioavailable estradiol, and testosterone IGF-I and IGFBP-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~ 9-fold, and total lignans 16 fold. Thirty-six (80%) of the 45 evaluable subjects demonstrated a decrease in Ki-67, from a median of 4% (range 2–16.8 %) to 2% (range 0–15.2%) (p<0.001 by Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (p=0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG vs. placebo in premenopausal women.

Antiproliferative activity of lignans against the breast carcinoma cell lines MCF 7 and BT 20. <=SEP=> PURPOSE: Phytoestrogens are plant-derived, non-steroidal phytochemicals with anticarcinogenic potential. The major structural classes are the isoflavones and lignans. The aim of this study was to compare the effect of the plant-derived lignans secoisolariciresinol and matairesinol with the human lignans enterodiol and enterolactone as well as with 17β estradiol and tamoxifen on cell proliferation of breast carcinoma cell lines. METHODS: The influence of the lignans, 17β estradiol and tamoxifen on cell proliferation was determined using the BrdU test in MCF 7 and BT 20 cell lines. RESULTS: Enterodiol and enterolactone induced a stronger inhibition of cell growth in MCF 7 and BT 20 cells than secoisolariciresinol and matairesinol. The inhibition effects were less expressed in the BT 20 than in the MCF 7 cells. CONCLUSIONS: The human lignans enterodiol and enterolactone are more biologically active than their precursors secoisolariciresinol and matairesinol, and may be defined as the real drugs in cancer prevention.

Role of dietary lignans in the reduction of breast cancer risk. <=SEP=> Lignans are a large group of fiber-associated phenolic compounds widely distributed in edible plants. Some of the ingested plant lignans are converted by intestinal microbiota to enterolignans, enterodiol (END) and enterolactone (ENL), the latter of which has been thought to be the major biologically active lignan, and suggested to be associated with low risk of breast cancer. In line with this, administration of plant lignans which are further metabolized to ENL, or ENL as such, have been shown to inhibit or delay the growth of experimental mammary cancer. The mechanism of anticarcinogenic action of ENL is not yet fully understood, but there is intriguing evidence for ENL as a modulator of estrogen signaling. These findings have generated interest in the use of lignans as components of breast cancer risk reducing functional foods. Identification of target groups, who would benefit most, is of pivotal importance. Therefore, further identification and validation of relevant biomarkers, which can be used as indicators of lignan or ENL action and breast cancer risk reduction at different stages of the disease, are of importance.

Dietary lignan intakes in relation to survival among women with breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study <=SEP=> Dietary lignan intakes have been associated with reduced breast cancer risks; however, no previous studies have investigated whether lignan intake might be associated with breast cancer survival. We examined the association of dietary lignan intakes with survival in 1122 women with primary, incident, histologically confirmed breast cancer identified between 1996 and 2001, and with vital status determined through December 31, 2006. Diet in the 12–24 months before diagnosis was assessed with an extensive food frequency questionnaire, and potential confounders assessed from an extensive epidemiologic interview and abstracted clinical data. Lignan intake was calculated using published food composition data. Hazard ratios (HR), and 95% confidence intervals (CIs) for dietary lignan intakes with all cause, and breast cancer mortality were estimated using Cox proportional hazards adjusting for age, education, race, total energy intake, tumor stage, and body mass index. Of the 1122 women with complete dietary data, 160 had died by the end of follow-up. Among postmenopausal women only, those in the highest versus lowest quartile of lignan intakes had a statistically significant reduction in the risk of all cause mortality (HR 0.49, 95% CI 0.26–0.91) and a significantly reduced risk of breast cancer mortality (HR 0.29, 95% CI 0.11–0.76). Higher intakes of dried beans (HR 0.61, 95% CI 0.36–1.03), but not fruits, vegetables, or grains, were also weakly associated with overall mortality. In summary, our results suggest that higher lignan intakes may be associated with improved survival among postmenopausal women with breast cancer.

Flax and Breast Cancer: A Systematic Review. <=SEP=> Background. Flax is a food and dietary supplement commonly used for menopausal symptoms. Flax is known for its lignan, α-linolenic acid, and fiber content, components that may possess phytogestrogenic, anti-inflammatory, and hormone modulating effects, respectively. We conducted a systematic review of flax for efficacy in improving menopausal symptoms in women living with breast cancer and for potential impact on risk of breast cancer incidence or recurrence. Methods. We searched MEDLINE, Embase, the Cochrane Library, and AMED from inception to January 2013 for human interventional or observational data pertaining to flax and breast cancer. Results. Of 1892 records, we included a total of 10 studies: 2 randomized controlled trials, 2 uncontrolled trials, 1 biomarker study, and 5 observational studies. Nonsignificant (NS) decreases in hot flash symptomatology were seen with flax ingestion (7.5 g/d). Flax (25 g/d) increased tumor apoptotic index (P < .05) and decreased HER2 expression (P < .05) and cell proliferation (Ki-67 index; NS) among newly diagnosed breast cancer patients when compared with placebo. Uncontrolled and biomarker studies suggest beneficial effects on hot flashes, cell proliferation, atypical cytomorphology, and mammographic density, as well as possible anti-angiogenic activity at doses of 25 g ground flax or 50 mg secoisolariciresinol diglycoside daily. Observational data suggests associations between flax and decreased risk of primary breast cancer (adjusted odds ratio [AOR] = 0.82; 95% confidence interval [CI] = 0.69-0.97), better mental health (AOR = 1.76; 95% CI = 1.05-2.94), and lower mortality (multivariate hazard ratio = 0.69; 95% CI = 0.50-0.95) among breast cancer patients. Conclusions. Current evidence suggests that flax may be associated with decreased risk of breast cancer. Flax demonstrates antiproliferative effects in breast tissue of women at risk of breast cancer and may protect against primary breast cancer. Mortality risk may also be reduced among those living with breast cancer. © The Author(s) 2013.

Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. <=SEP=> PURPOSE: To investigate the association between intake of flaxseed-the richest source of dietary lignans (a class of phytoestrogens)-and breast cancer risk. METHODS: A food frequency questionnaire was used to measure the consumption of flaxseed and flax bread by 2,999 women with breast cancer and 3,370 healthy control women who participated in the Ontario Women's Diet and Health Study (2002-2003). Logistic regression was used to investigate associations between consumption of flaxseed and flax bread and breast cancer risk. Confounding by established and suspected breast cancer risk factors, as well as dietary factors, was assessed. RESULTS: Flaxseed or flax bread was consumed at least weekly by 21 % of control women. None of the 19 variables assessed were identified as confounders of the associations between flaxseed or flax bread and breast cancer risk. Consumption of flaxseed was associated with a significant reduction in breast cancer risk (odds ratio (OR) = 0.82, 95 % confidence interval (CI) 0.69-0.97), as was consumption of flax bread (OR = 0.77, 95 % CI 0.67-0.89). CONCLUSIONS: This Canadian study is, to our knowledge, the first to report on the association between flaxseed alone and breast cancer risk and has found that flaxseed intake is associated with a reduction in breast cancer risk. As dietary intake of flaxseed is modifiable, this finding may be of public health importance with respect to breast cancer prevention.

In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases i... <=SEP=> BACKGROUND: Actin cytoskeleton is involved in actin-based cell adhesion, cell motility, and matrix metalloproteinases(MMPs) MMP2, MMP9, MMP11 and MMP14 are responsible for cell invasion in breast cancer metastasis. The dietary intake of lignan from flax seed gets converted to enterolactone (EL) and enterodiol in the human system. Here we show that the enterolactone has a very significant anti-metastatic activity as demonstrated by its ability to inhibit adhesion and invasion and migration in MCF-7 and MDA MB231 cell lines. MATERIALS AND METHODS: Migration inhibition assay, actin-based cell motility assay along with reverse transcriptase polymerase chain reaction (RT-PCR) for MMP2, MMP9, MMP11 and MMP14 genes were performed in MCF-7 and MDA MB 231 cell lines. RESULTS: Enterolactone seems to inhibit actin-based cell motility as evidenced by confocal imaging and photo documentation of cell migration assay. The results are supported by the observation that the enterolactone in vitro significantly down-regulates the metastasis-related metalloproteinases MMP2, MMP9 and MMP14 gene expressions. No significant alteration in the MMP11 gene expression was found. CONCLUSIONS: Therefore we suggest that the anti-metastatic activity of EL is attributed to its ability to inhibit cell adhesion, cell invasion and cell motility. EL affects normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby inhibits actin-based cell adhesion and cell motility. The process involves multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction. By down-regulating the metastasis-related MMP2, MMP9 and MMP14 gene expressions, EL may be responsible for cell invasion step of metastasis.

Quantitative determination of lignans and isoflavonoids in plasma of omnivorous and vegetarian women by isotope dilution gas chromatography-mass sp... <=SEP=> The first quantitative method for the determination of both lignans and isoflavonoid phytoestrogens in plasma is presented. Using ion-exchange chromatography the diphenols are separated into two fractions 1) the biologically "active" fraction containing the free compounds + mono- and disulfates and 2) the biologically "inactive" fraction containing the mono- and diglucuronides and the sulfoglucuronides. After hydrolysis the fractions are further purified by solid phase extraction and ion exchange chromatography. Losses during the complete procedure are corrected for using radioactive estrogen conjugates during the first steps and later by adding deuterated internal standards of all compounds measured (matairesinol, enterodiol, enterolactone, daidzein, O-desmethylangolensin, equol, and genistein). The final determination is carried out by isotope dilution gas chromatography-mass spectrometry in the selected ion monitoring mode (GC/MS/SIM). The diphenols may be measured at concentrations as low as 0.2 to 1.0 nmol/l. Results of plasma analyses of all compounds in 27 pre- and postmenopausal omnivorous and vegetarian women are presented for the first time. The most important findings are that the free+sulfate fraction is low for genistein (3.8% of total), but as much as 21-25% of enterolactone and enterodiol occurs in this fraction. A good correlation between plasma and urine values was found. Total concentrations of individual compounds vary greatly between the subjects (from pmol/l to mumol/l), the vegetarians having higher values, particularly one vegan subject. The highest total enterolactone concentration value exceeded 1 mumol/l. It is concluded that a highly specific method for the assay of 3 lignans and 4 isoflavonoids in plasma has been developed. This method will be useful in future studies of lignan and isoflavonoid metabolism.

Estradiol, tamoxifen, and flaxseed alter IL-1β and IL-1Ra levels in normal human breast tissue in vivo. <=SEP=> INTRODUCTION: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1α and IL-1β. OBJECTIVE: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. DESIGN AND METHODS: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. RESULTS: We show a significant positive correlation between estradiol and in vivo levels of IL-1β in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1β were significantly higher compared with normal adjacent breast tissue. CONCLUSION: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1β in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

Exploration of 100 commonly used drugs and supplements on cognition in older adults <=SEP=> Background There are conflicting reports and a lack of evidence-based data regarding effects of medications on cognition in cognitively normal older adults. We explored whether use of 100 common medications taken by older adults is associated with longitudinal cognitive performance. Methods A longitudinal observational cohort was used with analysis of data collected September 2005 through May 2011 and maintained in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. Participants were aged 50 years or older and cognitively normal (N=4414). Composite scores were constructed from 10 psychometric tests. Scores for each participant reflecting change in the psychometric composite score from the baseline clinical assessment to the next assessment were calculated. General linear models were used to test whether the mean composite change score differed for participants who reported starting, stopping, continuing, or not taking each of the 100 most frequently-used medications in the NACC sample. Results The average time between assessments was 1.2 years (SD=0.42). Nine medications showed a difference (p<0.05) across the four participant groups in mean psychometric change scores from the first to the second assessment. Medications associated with improved psychometric performance were: naproxen, calcium-vitamin D, ferrous sulfate, potassium chloride, flax, and sertraline. Medications associated with declining psychometric performance were: bupropion, oxybutynin, and furosemide. Conclusions Reported use of common medications is associated with cognitive performance in older adults, but studies are needed to investigate the mechanisms underlying these effects.

Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. <=SEP=> BACKGROUND: Berries are a particularly rich source of polyphenols. They also contain other bioactive substances, such as vitamin C. Previous studies indicated that the consumption of polyphenol-rich foods (eg, cocoa, tea, and red wine) may induce beneficial changes in pathways related to cardiovascular health. Whether the consumption of berries has similar effects is unknown. OBJECTIVE: We aimed to investigate the effects of berry consumption on hemostatic function, serum lipids, and blood pressure (BP). DESIGN: Middle-aged unmedicated subjects (n = 72) with cardiovascular risk factors consumed moderate amounts of berry or control products for 8 wk in a single-blind, randomized, placebo-controlled intervention trial. RESULTS: Berry consumption inhibited platelet function as measured with a platelet function analyzer (using collagen and ADP as platelet activator) [changes: 11% and -1.4% in the berry and control groups, respectively; P = 0.018, analysis of covariance (ANCOVA)]. Plasma biomarkers of platelet activation, coagulation, and fibrinolysis did not change during the intervention. Serum HDL-cholesterol concentrations increased significantly more (P = 0.006, ANCOVA) in the berry than in the control group (5.2% and 0.6%, respectively), but total cholesterol and triacylglycerol remained unchanged. Systolic BP decreased significantly (P = 0.050, ANCOVA); the decrease mostly occurred in subjects with high baseline BP (7.3 mm Hg in highest tertile; P = 0.024, ANCOVA). Polyphenol and vitamin C concentrations in plasma increased, whereas other nutritional biomarkers (ie, folate, tocopherols, sodium, and potassium) were unaffected. CONCLUSION: The consumption of moderate amounts of berries resulted in favorable changes in platelet function, HDL cholesterol, and BP. The results indicate that regular consumption of berries may play a role in the prevention of cardiovascular disease.

One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans. <=SEP=> Strawberries are an important fruit in the Mediterranean diet because of their high content of essential nutrients and beneficial phytochemicals, which seem to exert beneficial effects in human health. Healthy volunteers were supplemented daily with 500 g of strawberries for 1 month. Plasma lipid profile, circulating and cellular markers of antioxidant status, oxidative stress and platelet function were evaluated at baseline, after 30 days of strawberry consumption and 15 days after the end of the study. A high concentration of vitamin C and anthocyanins was found in the fruits. Strawberry consumption beneficially influenced the lipid profile by significantly reducing total cholesterol, low-density lipoprotein cholesterol and triglycerides levels (-8.78%, -13.72% and -20.80%, respectively; P<.05) compared with baseline period, while high-density lipoprotein cholesterol remained unchanged. Strawberry supplementation also significant decreased serum malondialdehyde, urinary 8-OHdG and isoprostanes levels (-31.40%, -29.67%, -27.90%, respectively; P<.05). All the parameters returned to baseline values after the washout period. A significant increase in plasma total antioxidant capacity measured by both ferric reducing ability of plasma and oxygen radical absorbance capacity assays and vitamin C levels (+24.97%, +41.18%, +41.36%, respectively; P<.05) was observed after strawberry consumption. Moreover, the spontaneous and oxidative hemolysis were significant reduced (-31.7% and -39.03%, respectively; P<.05), compared to the baseline point, which remained stable after the washout period. Finally, strawberry intake significant decrease (P<.05) the number of activated platelets, compared to both baseline and washout values. Strawberries consumption improves plasma lipids profile, biomarkers of antioxidant status, antihemolytic defenses and platelet function in healthy subjects, encouraging further evaluation on a population with higher cardiovascular disease risk. Copyright © 2014 Elsevier Inc. All rights reserved.

Platelets in atherosclerosis. <=SEP=> Beyond obvious functions in haemostasis and thrombosis, platelets are considered to be essential in proinflammatory surroundings such as atherosclerosis, allergy, rheumatoid arthritis and even cancer. In atherosclerosis, platelets facilitate the recruitment of inflammatory cells towards the lesion sites and release a plethora of inflammatory mediators, thereby enriching and boosting the inflammatory milieu. Platelets do so by interacting with endothelial cells, circulating leukocytes (monocytes, neutrophils, dendritic cells, T-cells) and progenitor cells. This cross-talk enforces leukocyte activation, adhesion and transmigration. Furthermore, platelets are known to function in innate host defense through the release of antimicrobial peptides and the expression of pattern recognition receptors. In severe sepsis, platelets are able to trigger the formation of neutrophil extracellular traps (NETs), which bind and clear pathogens. The present antiplatelet therapies that target key pathways of platelet activation and aggregation therefore hold the potential to modulate platelet-derived immune functions by reducing cellular interactions of platelets with other immune components and by reducing the secretion of inflammatory proteins into the milieu. The objective of this review is to update and discuss the current perceptions of the platelet immune constituents and their prospect as therapeutic targets in an atherosclerotic setting.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 <=SEP=> Summary Background Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. Methods We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. Findings In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. Interpretation Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. Funding Bill & Melinda Gates Foundation.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease S... <=SEP=> BACKGROUND: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. METHODS: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. FINDINGS: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. INTERPRETATION: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. FUNDING: Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. <=SEP=> Coronary artery disease is responsible for much mortality and morbidity around the world. Platelets are involved in atherosclerotic disease development and the reduction of platelet activity by medications reduces the incidence and severity of disease. Red wine and grapes contain polyphenolic compounds, including flavonoids, which can reduce platelet aggregation and have been associated with lower rates of cardiovascular disease. Citrus fruits contain different classes of polyphenolics that may not share the same properties. This study evaluated whether commercial grape, orange and grapefruit juices, taken daily, reduce ex vivo platelet activity. In a randomized cross-over design, ten healthy human subjects (ages 26-58 y, five of each gender) drank 5-7.5 mL/(kg. d) of purple grape juice, orange juice or grapefruit juice for 7-10 d each. Platelet aggregation (whole blood impedance aggregometry, Chronolog Model #590) at baseline was compared to results after consumption of each juice. Drinking purple grape juice for one week reduced the whole blood platelet aggregation response to 1 mg/L of collagen by 77% (from 17.9 +/- 2.3 to 4.0 +/- 6.8 ohms, P = 0.0002). Orange juice and grapefruit juice had no effect on platelet aggregation. The purple grape juice had approximately three times the total polyphenolic concentration of the citrus juices and was a potent platelet inhibitor in healthy subjects while the citrus juices showed no effect. The platelet inhibitory effect of the flavonoids in grape juice may decrease the risk of coronary thrombosis and myocardial infarction.

The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. <=SEP=> IMPORTANCE: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS: US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE: From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Antiplatelet, anticoagulant, and fibrinolytic activity in vitro of extracts from selected fruits and vegetables. <=SEP=> A diet rich in fruits and vegetables is known to decrease the risk of cardiovascular disease. However, the information regarding the antithrombotic activity (antiplatelet, anticoagulant, and fibrinolytic) of fruits and vegetables is scarce. The aim of this study was to assess the antithrombotic activity of extracts from fruits and vegetables widely consumed in central Chile. The study included samples of 19 fruits and 26 vegetables, representative of the local diet. The extracts prepared from each sample included an aqueous (juice or pressed solubles) and/or methanol-soluble fraction. The extracts were evaluated for antiplatelet, anticoagulant, and fibrinolytic activity in vitro at a final concentration of 1 mg/ml. The antiplatelet activity was assessed by platelet aggregation inhibition; anticoagulant activity was measured by the prothrombin time (PT), diluted prothrombin time (dPT), activated partial thromboplastin time (APTT), kaolin clotting time (KCT), and thrombin time. The fibrinolytic effect was determined with the euglobin clot lysis time and fibrin plate methods. Extracts of green beans and tomatoes inhibited platelet aggregation induced by ADP and arachidonic acid, in a concentration-dependent manner. The methanolic extracts of grapes prolonged the PT and dPT. Finally, extracts of raspberry prolonged the APTT and also presented fibrinolytic activity. In conclusion, from a screening that included a variety of fruits and vegetables, we found antiplatelet activity in green beans and tomatoes, anticoagulant activities in grapes and raspberries, whereas fibrinolytic activity was observed only in raspberries. Further investigations are necessary to advance in knowledge of the active compounds of these fruits and vegetables and their mechanisms of action.

Potential risks resulting from fruit/vegetable-drug interactions: effects on drug-metabolizing enzymes and drug transporters. <=SEP=> It has been well established that complex mixtures of phytochemicals in fruits and vegetables can be beneficial for human health. Moreover, it is becoming increasingly apparent that phytochemicals can influence the pharmacological activity of drugs by modifying their absorption characteristics through interactions with drug transporters as well as drug-metabolizing enzyme systems. Such effects are more likely to occur in the intestine and liver, where high concentrations of phytochemicals may occur. Alterations in cytochrome P450 and other enzyme activities may influence the fate of drugs subject to extensive first-pass metabolism. Although numerous studies of nutrient-drug interactions have been published and systematic reviews and meta-analyses of these studies are available, no generalizations on the effect of nutrient-drug interactions on drug bioavailability are currently available. Several publications have highlighted the unintended consequences of the combined use of nutrients and drugs. Many phytochemicals have been shown to have pharmacokinetic interactions with drugs. The present review is limited to commonly consumed fruits and vegetables with significant beneficial effects as nutrients and components in folk medicine. Here, we discuss the phytochemistry and pharmacokinetic interactions of the following fruit and vegetables: grapefruit, orange, tangerine, grapes, cranberry, pomegranate, mango, guava, black raspberry, black mulberry, apple, broccoli, cauliflower, watercress, spinach, tomato, carrot, and avocado. We conclude that our knowledge of the potential risk of nutrient-drug interactions is still limited. Therefore, efforts to elucidate potential risks resulting from food-drug interactions should be intensified in order to prevent undesired and harmful clinical consequences. © 2011 Institute of Food Technologists®

Management of grapefruit-drug interactions. <=SEP=> Grapefruit is a healthy addition to a well-balanced diet. However, the fruit has been shown to affect the metabolism of many medications, increasing the risk of toxicity and adverse effects. Characteristics of oral medications that may interact with grapefruit include extensive metabolism through the intestinal cytochrome P450 3A4 system, low bioavailability, and a narrow therapeutic index. Prominent medications known to interact with grapefruit include statins, antiarrhythmic agents, immunosuppressive agents, and calcium channel blockers. There are equally effective alternatives to these drug classes that do not have the potential to interact with grapefruit. These alternative drugs may be substituted if a patient experiences or is at risk of a grapefruit-drug interaction. Patients also may choose to exclude grapefruit from their diets and consume other fruits, including other types of citrus, to avoid an interaction.

Prospective study of the association between grapefruit intake and risk of breast cancer in the European Prospective Investigation into Cancer and ... <=SEP=> Grapefruit inhibits cytochrome P450 3A4 and may affect estrogen metabolism. In the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the relationships of grapefruit intake with risk of breast cancer and with serum sex hormone levels. 114,504 women with information on dietary intake of grapefruit and on reproductive and lifestyle risk factors were followed for a median 9.5 years and 3,747 incident breast cancers were identified. Fifty-nine percent of women reported eating grapefruit, 4% ate > or = 60 g/day. Cox proportional hazard models were used to estimate the hazard ratio (HR) for breast cancer according to grapefruit intake, adjusting for study centre, reproductive factors, body mass index, energy intake, and alcohol intake. Grapefruit intake was not related to the risk of breast cancer: compared with women who ate no grapefruit, women with the highest intake of > or =60 g/day had a HR of 0.93 (95% CI 0.77-1.13), p for linear trend = 0.5. There was no relationship between grapefruit intake and breast cancer risk among premenopausal women, all postmenopausal women, or postmenopausal women categorized by hormone replacement therapy use (all p>0.05). There was no association between grapefruit intake and estradiol or estrone among postmenopausal women. In this study, we found no evidence of an association between grapefruit intake and risk of breast cancer.

The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. <=SEP=> To study the effects of grapefruit and grapefruit products on body weight and metabolic syndrome, 91 obese patients were randomized to either placebo capsules and 7 ounces (207 mL) of apple juice, grapefruit capsules with 7 ounces (207 mL) of apple juice, 8 ounces (237 mL) of grapefruit juice with placebo capsule, or half of a fresh grapefruit with a placebo capsule three times a day before each meal. Metabolic syndrome parameters were measured at the beginning and end of 12 weeks. After 12 weeks, the fresh grapefruit group had lost 1.6 kg, the grapefruit juice group had lost 1.5 kg, the grapefruit capsule group had lost 1.1 kg, and the placebo group had lost 0.3 kg. The fresh grapefruit group lost significantly more weight than the placebo group (P < .05). A secondary analysis of those with the metabolic syndrome in the four treatment groups demonstrated a significantly greater weight loss in the grapefruit, grapefruit capsule, and grapefruit juice groups compared with placebo (P < .02). There was also a significant reduction in 2-hour post-glucose insulin level in the grapefruit group compared with placebo. Half of a fresh grapefruit eaten before meals was associated with significant weight loss. In metabolic syndrome patients the effect was also seen with grapefruit products. Insulin resistance was improved with fresh grapefruit. Although the mechanism of this weight loss is unknown it would appear reasonable to include grapefruit in a weight reduction diet.

The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives <=SEP=> Summary Grapefruit is a popular, tasty and nutritive fruit enjoyed globally. Biomedical evidence in the last 10 years has, however, shown that consumption of grapefruit or its juice is associated with drug interactions, which, in some cases, have been fatal. Grapefruit-induced drug interactions are unique in that the cytochrome P450 enzyme CYP3A4, which metabolises over 60% of commonly prescribed drugs as well as other drug transporter proteins such as P-glycoprotein and organic cation transporter proteins, which are all expressed in the intestines, are involved. However, the extent to which grapefruit–drug interactions impact on clinical settings has not been fully determined, probably because many cases are not reported. It has recently emerged that grapefruit, by virtue of its rich flavonoid content, is beneficial in the management of degenerative diseases such as diabetes and cardiovascular disorders. This potentially explosive subject is reviewed here.

A low-energy-dense diet adding fruit reduces weight and energy intake in women. <=SEP=> This study evaluated the effect of adding fruit or oats to the diet of free-living women on energy consumption and body weight. Fruit and oat cookies had the same amount of fiber and total calories ( approximately 200 kcal), but differed in energy density. We analyzed data from a clinical trial conducted in a primary care unit in Rio de Janeiro, Brazil. Forty-nine women, ages ranging from 30 to 50 years, with body mass index (BMI)>25 kg/m2, were randomly chosen to add three apples (0.63 kcal/g energy density) or three pears (0.64 kcal/g energy density) or three oat cookies (3.7 kcal/g energy density) to their usual diet for 10 weeks. Fiber composition was similar ( approximately 6g). Statistical analysis of the repeated measures of dietary composition and body weight were analyzed using mixed model procedures. Results showed a significant decrease in the energy density during the follow-up (-1.23 kcal/g, p<0.04, and -1.29 kcal/g, p<0.05) for apples and pears, respectively, compared to the oat group. The energy intake also decreased significantly (-25.05 and -19.66 kcal/day) for the apple and pear group, respectively, but showed a small increase (+0.93) for the oat group. Apples and pears were also associated (p<0.001) with weight reduction (-0.93 kg for the apple and -0.84 for the pear group), whereas weight was unchanged (+0.21; p=0.35) in the oat group. Results suggest that energy densities of fruits, independent of their fiber amount can reduce energy consumption and body weight over time.

The effects of daily consumption of grapefruit on body weight, lipids, and blood pressure in healthy, overweight adults. <=SEP=> Folklore has suggested that consuming grapefruit may promote weight control. Sparse data exist to support this hypothesis, although there is some evidence of health promotion effects with regard to blood pressure control and modulation of circulating lipids. The aim of this randomized controlled trial was to prospectively evaluate the role of grapefruit in reducing body weight and blood pressure and in promoting improvements in the lipid profile in overweight adults (N = 74). Following a 3-week washout diet low in bioactive-rich fruits and vegetables, participants were randomized to either the control diet (n = 32) or daily grapefruit (n = 42) in the amount of one half of a fresh Rio-Red grapefruit with each meal (3× daily) for 6 weeks. No differences between group in weight, blood pressure, or lipids were demonstrated. Grapefruit consumption was associated with modest weight loss (-0.61 ± 2.23 kg, P = .097), a significant reduction in waist circumference (-2.45 ± 0.60 cm, P = .0002), and a significant reduction in systolic blood pressure (-3.21 ± 10.13 mm Hg, P = .03) compared with baseline values. Improvements were observed in circulating lipids of those consuming grapefruit, with total cholesterol and low-density lipoprotein significantly decreasing by -11.7 mg/dL (P = .002) and -18.7 mg/dL (P < .001), respectively, compared with baseline values. This study suggests that consumption of grapefruit daily for 6 weeks does not significantly decrease body weight, lipids, or blood pressure as compared with the control condition. However, the improvements in blood pressure and lipids demonstrated in the intervention group suggest that grapefruit should be further evaluated in the context of obesity and cardiovascular disease prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of dietary protein on composition and metabolism of plasma lipoproteins in rabbits. <=SEP=> Changes in the concentration and composition of serum VLDL, LDL, and HDL were studied in rabbits transferred from Chow diets to cholesterol-free, semipurified diets containing casein or isolated soy protein. During the first week on the casein diet, there was a marked increase in LDL-cholesterol and these higher levels were maintained during the subsequent 3 weeks of the study. Similar but less marked changes were obtained with the soy protein diet. When the percent composition of the particles was determined, both VLDL and LDL had a higher proportion of cholesterol. Turnover studies indicated that the FCRs for radiolabelled VLDL and LDL were reduced in casein-fed animals compared to those fed soy protein. The elevated LDL levels in casein-fed rabbits were primarily due to a reduction in receptor-mediated catabolism of LDL-apo B. Receptor-independent removal in the two groups was similar. These studies show that the hypercholesterolemia in casein-fed rabbits, compared to those fed soy protein, is associated with cholesterol enrichment of LDL and impaired receptor-dependent removal of LDL-apo B.

Effects of dietary proteins on plasma lipoprotein levels in normal subjects: interaction with dietary cholesterol. <=SEP=> We have compared the effects of dietary soy protein and casein in diets low in cholesterol (less than 100 mg/d) and in diets enriched in cholesterol (500 mg/d) to examine whether the level of cholesterol intake affects the response of plasma lipoproteins to dietary proteins of plant and animal origin. Normal men and women consumed formula diets containing 20% of calories as soy protein or casein, 27% as fat and 53% as carbohydrate in 2 crossover studies. The dietary periods lasted for 31 days and were separated by a month-long interim period on self-chosen food. Following an initial reduction of plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels on all diets, the plasma lipid and lipoprotein concentrations stabilized. On low-cholesterol diets the concentration of each of the major lipoprotein classes were similar during the soy and the casein dietary periods. On cholesterol-enriched diets, the concentration of LDL-C stabilized at a 16% lower level on soy protein than on the casein diet (p less than 0.02), while the concentration of high-density lipoprotein-cholesterol (HDL-C) was 16% higher (p less than 0.01). Since the difference in LDL-C (p less than 0.05) and in HDL-C (p less than 0.025) levels on casein and on soy protein diets were significantly greater on the high than on the low cholesterol intake, the findings indicate that the level of dietary cholesterol may determine whether plant and animal dietary proteins have similar or different effects on plasma LDL-C and HDL-C concentrations.

Structural basis for androgen specificity and oestrogen synthesis in human aromatase <=SEP=> Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens1–3. Aromatase inhibitors therefore constitute a front-line therapy for oestrogen-dependent breast cancer3,4. In a three-step process, each step requiring 1 mol of O2, 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively1–3. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme’s androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

Phytochemicals for breast cancer prevention by targeting aromatase. <=SEP=> Aromatase is a cytochrome P450 enzyme (CYP19) and is the rate limiting enzyme in the conversion of androgens to estrogens. Suppression of in situ estrogen production through aromatase inhibition is the current treatment strategy for hormone-responsive breast cancers. Drugs that inhibit aromatase have been developed and are currently utilized as adjuvant therapy for breast cancer in post-menopausal women with hormone dependent breast cancer. Natural compounds have been studied extensively for important biologic effects such as antioxidant, anti-tumor and anti-viral effects. A significant number of studies have also investigated the aromatase inhibitory properties of a variety of plant extracts and phytochemicals. The identification of natural compounds that inhibit aromatase could be useful both from a chemopreventive standpoint and in the development of new aromatase inhibitory drugs. This review will discuss whole food extracts and the common classes of phytochemicals which have been investigated for potential aromatase inhibitory activity. We will review reported aromatase inhibition, kinetic data and possible structural variations that may inhibit or enhance the interaction of phytochemicals with the aromatase enzyme.

Breast cancer incidence rates in U.S. women are no longer declining. <=SEP=> BACKGROUND: Several publications reported breast cancer incidence rates continued to decrease among white women, following the decline of about 7% from 2002 to 2003. However, none of these reports exclusively examined the trend after 2003. In this paper, we examined breast cancer incidence rates among non-Hispanic (NH) white women from 2003 to 2007 to determine whether the decrease in breast cancer incidence rates indeed persisted through 2007. In addition, we present breast cancer incidence trends for NH black and Hispanic women and postmenopausal hormone use for all three racial/ethnic groups. METHODS: Breast cancer incidence rates were calculated by race/ethnicity, age and ER status using data from the Surveillance, Epidemiology, and End Results (SEER) 12 registries for 2000 to 2007. Prevalence of postmenopausal hormone use was calculated using National Health Interview Survey data from 2000, 2005, and 2008. RESULTS: From 2003 to 2007, overall breast cancer incidence rates did not change significantly among NH white women in any age group. However, rates increased (2.7% per year) for ER+ breast cancers in ages 40 to 49, and decreased for ER- breast cancers in ages 40 to 49 and 60 to 69. Similarly, overall breast cancer incidence rates did not change significantly for black and Hispanic women. Hormone use continued to decrease from 2005 to 2008 in all groups, although the decreases were smaller compared to those from 2000 to 2005. CONCLUSIONS: The sharp decline in breast cancer incidence rates that occurred from 2002 to 2003 among NH white women did not continue through 2007. IMPACT: Further studies are needed to better understand the recent breast cancer trends. ©2011 AACR.

Laboratory, Epidemiological, and Human Intervention Studies Show That Tea (Camellia sinensis) May Be Useful in the Prevention of Obesity <=SEP=> Tea (Camellia sinensis, Theaceae) and tea polyphenols have been studied for the prevention of chronic diseases, including obesity. Obesity currently affects >20% of adults in the United States and is a risk factor for chronic diseases such as type II diabetes, cardiovascular disease, and cancer. Given this increasing public health concern, the use of dietary agents for the prevention of obesity would be of tremendous benefit. Whereas many laboratory studies have demonstrated the potential efficacy of green or black tea for the prevention of obesity, the underlying mechanisms remain unclear. The results of human intervention studies are mixed and the role of caffeine has not been clearly established. Finally, there is emerging evidence that high doses of tea polyphenols may have adverse side effects. Given that the results of scientific studies on dietary components, including tea polyphenols, are often translated into dietary supplements, understanding the potential toxicities of the tea polyphenols is critical to understanding their potential usefulness in preventing obesity. In this review, we will critically evaluate the evidence for the prevention of obesity by tea, discuss the relevance of proposed mechanisms in light of tea polyphenol bioavailability, and review the reports concerning the toxic effects of high doses of tea polyphenols and the implication that this has for the potential use of tea for the prevention of obesity. We hope that this review will expose areas for further study and encourage research on this important public health issue.

Green tea: nature's defense against malignancies. <=SEP=> The current practice of introducing phytochemicals to support the immune system or fight against diseases is based on centuries old traditions. Nutritional support is a recent advancement in the domain of diet-based therapies; green tea and its constituents are one of the important components of these strategies to prevent and cure various malignancies. The anti-carcinogenic and anti-mutagenic activities of green tea were highlighted some years ago suggesting that it could reduce the prevalence of cancer and even provide protection. The pharmacological actions of green tea are mainly attributed to polyphenols that includes epigallocatechin-3-gallate (EGCG), epicatechin, epicatechin-3-gallate, epigallocatechin. Green tea and its components effectively mitigate cellular damage arising due to oxidative stress. Green tea is supposed to enhance humoral and cell-mediated immunity, decreasing the risk of certain cancers, and may have certain advantage in treating inflammatory disorders. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest, by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing nuclear factor kappa-B activation. Besides, it regulates and promotes IL-23 dependent DNA repair and stimulates cytotoxic T cells activities in a tumor microenvironment. It also blocks carcinogenesis by modulating the signal transduction pathways involved in cell proliferation, transformation, inflammation and metastasis. The review is intended to highlight the chemistry of green tea, its antioxidant potential, its immunopotentiating properties and mode of action against various cancer cell lines that showed its potential as a chemopreventive agent against colon, skin, lung, prostate, and breast cancer.

Inhibitory effect of tea polyphenols on local tissue damage induced by snake venoms. <=SEP=> The methanolic extract of fresh tea leaves of Camellia sinensis L. (Theaceae) (CS) was assayed for its potential to inhibit enzymes with hydrolytic activity in Naja naja kaouthia Lesson (Elapidae) and Calloselasma rhodostoma Kuhl (Viperidae) venoms. These snake venom enzymes are responsible for the early effects of envenomation, such as local tissue damage and inflammation. The CS extract inhibited phospholipase A(2), proteases, hyaluronidase and L-amino acid oxidase in both venoms by in vitro neutralization and inhibited the hemorrhagic and the dermonecrotic activities of the venoms in vivo. It is suggested that the inhibitory potential of the CS extract against local tissue damage induced by snake venoms may be attributed to complexation and chelation between the venom proteins and the phenolic contents of the extract.

Tea Consumption and Risk of Type 2 Diabetes: A Meta-Analysis of Cohort Studies <=SEP=> ABSTRACT BACKGROUND Tea consumption has been extensively studied in relation to various diseases, several epidemiologic studies have been performed to investigate the association of tea consumption with type 2 diabetes; however, the results of these studies were not entirely consistent. OBJECTIVE To conduct a meta-analysis of studies that assessed the association of tea consumption and the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS We performed a systematic literature search through November 2008 in PUBMED, MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. The search was limited to English-language studies. Studies were excluded if they were type 1 diabetes, animal studies. Nine cohort studies were identified by two authors, and summary relative risks (RRs) were calculated using a random-effects model. RESULTS We identified nine cohort studies, including 324,141 participants and 11,400 incident cases of type 2 diabetes with follow-up ranging from 5 to 18 years. The summary adjusted RR did not show that tea consumption was associated with a reduced type 2 diabetes risk (RR, 0.96; 95% confidence interval (CI), 0.92–1.01). Evidence from the results of our stratified analyses revealed that tea consumption ≥4 cups per day (RR, 0.8; 95% CI, 0.7–0.93) might play a role in the prevention of type 2 diabetes. However, no statistically significant association was observed for sex and the follow-up durations stratified between tea consumption and type 2 diabetes. CONCLUSIONS This meta-analysis indicates that tea consumption ≥4 cups per day may lower the risk of type 2 diabetes.

Association between green tea consumption and tooth loss: cross-sectional results from the Ohsaki Cohort 2006 Study. <=SEP=> OBJECTIVE: To examine the association between green tea consumption and tooth loss. METHODS: We analyzed cross-sectional data from the Ohsaki Cohort 2006 Study. Usable self-administered questionnaires about green tea consumption and tooth loss were returned from 25,078 persons (12,019 men and 13,059 women) aged 40 to 64 years in Japan. Multivariate logistic regression analysis was used to calculate odds ratios (ORs) for tooth loss using 3 cut-off points of 10, 20, and 25 teeth relative to each category of green tea consumption. RESULTS: Consumption of > or = 1 cup/day of green tea was significantly associated with decreased odds for tooth loss, and the association appeared to fit a threshold model. In men, the multivariate-adjusted ORs for tooth loss with a cut-off point of <20 teeth associated with different frequencies of green tea consumption were 1.00 (reference) for <1 cup/day, 0.82 (95% CI, 0.74-0.91) for 1-2 cups/day, 0.82 (95% CI, 0.73-0.92) for 3-4 cups/day, and 0.77 (95% CI, 0.66-0.89) for > or = 5 cups/day. The corresponding data for women and the results for cut-off points of 10 and 25 teeth were essentially the same. CONCLUSIONS: The present findings indicate an association of green tea consumption with decreased odds for tooth loss. Copyright 2010 Elsevier Inc. All rights reserved.