Formulation and In Vitro-In Vivo Evaluation of Black Raspberry Extract-Loaded PLGA/PLA Injectable Millicylindrical Implants for Sustained Delivery of Chemopreventive Anthocyanins

Purpose The objective of this study was to formulate and evaluate freeze-dried black raspberry (FBR) ethanol extract (RE) loaded poly(DL-lactic-co-glycolic acid) (PLGA) and poly(DL-lactic acid) (PLA) injectable millicylindrical implants for sustained delivery of chemopreventive FBR anthocyanins (cyanidin-3-sambubioside (CS), cyanidin-3-glucoside (CG) and cyanidin-3-rutinoside (CR)). Methods Identification and quantitation of CS, CG, and CR in RE was performed by mass spectroscopy and HPLC. RE:triacetyl-β-cyclodextrin (TA-β-CD) inclusion complex (IC) was prepared by a kneading method and characterized by X-ray diffraction (XRD), nuclear magnetic resonance spectroscopy (NMR) and UV-visible spectroscopy. RE or RE:TA-β-CD IC-loaded PLGA or PLA implants were prepared by a solvent extrusion method. In vitro and in vivo controlled release studies were conducted in phosphate-buffered saline Tween-80 (pH 7.4, 37°C) and after subcutaneous administration in male Sprague-Dawley rats, respectively. Anthocyanins were quantified by HPLC at 520 nm. Results The content of CS, CG, and CR in RE was 0.2, 1.5, and 3.5 wt%, respectively. The chemical stability of anthocyanins in solution was determined to be pH-dependent, and their degradation rate increased with an increase in pH from 2.4 to 7.4. PLGA/PLA millicylindrical implants loaded with 5 or 10 wt% RE exhibited a high initial burst and short release duration of anthocyanins (35–52 and 80–100% CG + CR release after 1 and 14 days, respectively). The cause for rapid anthocyanins release was linked to higher polymer water uptake and porosity associated with the high osmolytic components of large non-anthocyanin fraction of RE. XRD, 1H NMR and UV-visible spectroscopy indicated that the non-anthocyanin fraction molecules of RE formed an IC with TA-β-CD, decreasing the hydrophilicity of RE. Formation of an IC with hydrophobic carrier, TA-β-CD, provided better in vitro/in vivo sustained release of FBR anthocyanins (16–24 and 97–99% CG + CR release, respectively, after 1 and 28 days from 20 wt% RE:TA-β-CD IC/PLA implants) over 1 month, owing to reduced polymer water uptake and porosity. Conclusion PLA injectable millicylindrical implants loaded with RE:TA-β-CD IC are optimal dosage forms for 1-month slow and continuous delivery of chemopreventive FBR anthocyanins.


Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries.

Black raspberries are a rich natural source of chemopreventive phytochemicals. Recent studies have shown that freeze-dried black raspberries inhibit the development of oral, esophageal, and colon cancer in rodents, and extracts of black raspberries inhibit benzo(a)pyrene-induced cell transformation of hamster embryo fibroblasts. However, the molecular mechanisms and the active components responsible for black raspberry chemoprevention are unclear. In this study, we found that 2 major chemopreventive components of black raspberries, ferulic acid and beta-sitosterol, and a fraction eluted with ethanol (RO-ET) during silica column chromatography of the organic extract of freeze-dried black raspberries inhibit the growth of premalignant and malignant but not normal human oral epithelial cell lines. Another fraction eluted with CH2Cl2/ethanol (DM:ET) and ellagic acid inhibited the growth of normal as well as premalignant and malignant human oral cell lines. We investigated the molecular mechanisms by which ferulic acid and beta-sitosterol and the RO-ET fraction selectively inhibited the growth of premalignant and malignant oral cells using flow cytometry and Western blotting of cell cycle regulatory proteins. There was no discernable change in the cell cycle distribution following treatment of cells with the RO-ET fraction. Premalignant and malignant cells redistributed to the G2/M phase of the cell cycle following incubation with ferulic acid. beta-sitosterol treated premalignant and malignant cells accumulated in the G0/G1 and G2/M phases, respectively. The RO-ET fraction reduced the levels of cyclin A and cell division cycle gene 2 (cdc2) in premalignant cells and cyclin B1, cyclin D1, and cdc2 in the malignant cell lines. This fraction also elevated the levels of p21waf1/cip1 in the malignant cell line. Ferulic acid treatment led to increased levels of cyclin B1 and cdc2 in both cell lines, and p21waf1/cip1 was induced in the malignant cell line. beta-sitosterol reduced the levels of cyclin B1 and cdc2 while increasing p21waf1/cip1 in both the premalignant and malignant cell lines. These results show for the first time that the growth inhibitory effects of black raspberries on premalignant and malignant human oral cells may reside in specific components that target aberrant signaling pathways regulating cell cycle progression.


Topical Application of a Bioadhesive Black Raspberry Gel Modulates Gene Expression and Reduces Cyclooxygenase 2 Protein in Human Premalignant Oral Lesions

Reduced expression of proapoptotic and terminal differentiation genes in conjunction with increased levels of the proinflammatory and angiogenesis-inducing enzymes, cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), correlate with malignant transformation of oral intraepithelial neoplasia (IEN). Accordingly, this study investigated the effects of a 10% (w/w) freeze-dried black raspberry gel on oral IEN histopathology, gene expression profiles, intraepithelial COX-2 and iNOS proteins, and microvascular densities. Our laboratories have shown that freeze-dried black raspberries possess antioxidant properties and also induce keratinocyte apoptosis and terminal differentiation. Oral IEN tissues were hemisected to provide samples for pretreatment diagnoses and establish baseline biochemical and molecular variables. Treatment of the remaining lesional tissue (0.5 g gel applied four times daily for 6 weeks) began 1 week after the initial biopsy. RNA was isolated from snap-frozen IEN lesions for microarray analyses, followed by quantitative reverse transcription-PCR validation. Additional epithelial gene-specific quantitative reverse transcription-PCR analyses facilitated the assessment of target tissue treatment effects. Surface epithelial COX-2 and iNOS protein levels and microvascular densities were determined by image analysis quantified immunohistochemistry. Topical berry gel application uniformly suppressed genes associated with RNA processing, growth factor recycling, and inhibition of apoptosis. Although the majority of participants showed posttreatment decreases in epithelial iNOS and COX-2 proteins, only COX-2 reductions were statistically significant. These data show that berry gel application modulated oral IEN gene expression profiles, ultimately reducing epithelial COX-2 protein. In a patient subset, berry gel application also reduced vascular densities in the superficial connective tissues and induced genes associated with keratinocyte terminal differentiation.


Dietary patterns and the risk of esophageal cancer.

BACKGROUND: The role of dietary habits on esophageal cancer risk has been rarely considered in terms of dietary patterns. PATIENTS AND METHODS: We analyzed data from an Italian case-control study, including 304 cases with squamous cell carcinoma of the esophagus and 743 hospital controls. Dietary habits were evaluated using a food frequency questionnaire. A posteriori dietary patterns were identified through principal component factor analysis performed on 28 selected nutrients. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from multiple logistic regression models applied on quartiles of factor scores, adjusting for potential confounding variables. RESULTS: We identified five major dietary patterns, named 'animal products and related components', 'vitamins and fiber', 'starch-rich', 'other polyunsaturated fatty acids and vitamin D', and 'other fats'. The 'animal products and related components' pattern was positively related to esophageal cancer (OR = 1.64, 95% CI:1.06-2.55, for the highest versus the lowest quartile of factor scores category). The 'vitamins and fiber' (OR = 0.50, 95% CI: 0.32-0.78) and the 'other polyunsaturated fatty acids and vitamin D' (OR = 0.48, 95% CI: 0.31-0.74) were inversely related to esophageal cancer. No significant association was observed for the other patterns. CONCLUSION: Our findings suggest that a diet rich in foods from animal origin and poor in foods containing vitamins and fiber increase esophageal cancer risk.


Dietary patterns and risk of oesophageal cancers: a population-based case-control study.

Epidemiological studies investigating the association between dietary intake and oesophageal cancer have mostly focused on nutrients and food groups instead of dietary patterns. We conducted a population-based case-control study, which included 365 oesophageal adenocarcinoma (OAC), 426 oesophagogastric junction adenocarcinoma (OGJAC) and 303 oesophageal squamous cell carcinoma (OSCC) cases, with frequency matched on age, sex and geographical location to 1580 controls. Data on demographic, lifestyle and dietary factors were collected using self-administered questionnaires. We used principal component analysis to derive three dietary patterns: 'meat and fat', 'pasta and pizza' and 'fruit and vegetable', and unconditional logistic regression models to estimate risks of OAC, OGJAC and OSCC associated with quartiles (Q) of dietary pattern scores. A high score on the meat-and-fat pattern was associated with increased risk of all three cancers: multivariable-adjusted OR 2·12 (95 % CI 1·30, 3·46) for OAC; 1·88 (95% CI 1·21, 2·94) for OGJAC; 2·84 (95% CI 1·67, 4·83) for OSCC (P-trend <0·01 for all three cancers). A high score on the pasta-and-pizza pattern was inversely associated with OSCC risk (OR 0·58, 95 % CI 0·36, 0·96, P for trend=0·009); and a high score on the fruit-and-vegetable pattern was associated with a borderline significant decreased risk of OGJAC (OR for Q4 v. Q1 0·66, 95% CI 0·42, 1·04, P=0·07) and significantly decreased risk of OSCC (OR 0·41, 95% CI 0·24, 0·70, P for trend=0·002). High-fat dairy foods appeared to play a dominant role in the association between the meat-and-fat pattern and risk of OAC and OGJAC. Further investigation in prospective studies is needed to confirm these findings.


Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells.

Drug resistance remains an on-going challenge in ovarian cancer chemotherapy. The objective of this study was to determine the effect on synergism in activity from the sequenced combinations of cisplatin (Cis) with curcumin (Cur) and epigallocatechin-3-gallate (EGCG) in the human ovarian cancer cell lines. The drugs were added in binary combinations: Cis combined with Cur, and Cis combined with EGCG to the human ovarian A2780 and A2780(cisR) cancer cell lines, using five different sequences of administration: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The combination index (CI) was used to assess the combined action of the drugs. CIs <1, =1 and >1 indicated synergism, additiveness and antagonism respectively. Cellular accumulation of platinum and platinum-DNA binding levels from Cis and its combination with the phytochemicals were determined using graphite furnace atomic absorption spectrometry. Addition of Cis 4 h before Cur and EGCG (0/4 h combination) produced the most synergistic outcomes in both the A2780 and A2780(cisR) cell lines. The cellular accumulations of platinum and platinum-DNA binding resulting from the 0/4 h combinations were greater as compared to the values using Cis alone, thus providing an explanation for the synergistic action. When sequenced combinations of Cis with Cur and with EGCG are applied to human ovarian A2780 and A2780(cisR) cancer cell lines, lower concentrations and shorter time gap between the two additions seem to produce a higher cytotoxic effect.


Combinatorial strategies employing nutraceuticals for cancer development.

Cancer is the second leading cause of death worldwide. Therefore, the fight against cancer is one of the most important areas of research in medicine, and one that possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. Cancer prevention by nutraceuticals present in fruits and vegetables has received considerable attention because of their low cost and wide safety margin. A substantial amount of evidence from human, animal, and cell culture studies has shown cancer chemopreventive effects from these natural products. However, single-agent intervention has failed to produce the expected outcome in clinical trials; therefore, combinations of nutraceuticals are gaining increasing popularity. Thus, combinations of nutraceuticals that mimic real-life situations and are competent in targeting multiple targets with very little or virtually no toxicity are needed. In this review, we summarize the results of those studies that report combinatorial cancer chemopreventive action of various nutraceuticals and their combinations with anticancer drugs. © 2011 New York Academy of Sciences.


Strawberry fields forever?

On the basis of copious preclinical data supporting the preventive efficacy of small fruits such as berries and grapes, Chen and colleagues conducted a randomized (noncomparative) phase II trial evaluating two doses of strawberry powder (60 g/d or 30 g/d for six months) to prevent esophageal cancer in China (reported in this issue of the journal, beginning on page 41); 60 g/d reduced the histologic grade of dysplastic lesions and reduced localized biomarkers, whereas 30 g/d was not effective. Fundamental questions remain such as the best formulation of strawberry powder, the active components associated with powder, and the actual mechanism of action, and standardized preparations will be required to permit the widespread use of strawberry powder with a predicable outcome. Clearly, however, this work is a good example of proof-of-principle and highlights the important role of diet, nutrition, and natural products in cancer prevention. ©2012 AACR.


Role of antioxidants in cancer therapy.

Oxidative stress is a key component in linking environmental toxicity to the multistage carcinogenic process. Reactive oxygen species (ROS) are generated in response to both endogenous and exogenous stimuli. To counterbalance ROS-mediated injury, an endogenous antioxidants defense system exists; however, when oxidation exceeds the control mechanisms, oxidative stress arises. Chronic and cumulative oxidative stress induces deleterious modifications to a variety of macromolecular components, such as DNA, lipids, and proteins. A primary mechanism of many chemotherapy drugs against cancer cells is the formation of ROS, or free radicals. Radiotherapy is based on the fact that ionizing radiation destroys tumor cells. Radiotherapy induces direct lesions in the DNA or biological molecules, which eventually affect DNA. Free radicals produced by oncology therapy are often a source of serious side effects as well. The objective of this review is to provide information about the effects of antioxidants during oncology treatments and to discuss the possible events and efficacy. Much debate has arisen about whether antioxidant supplementation alters the efficacy of cancer chemotherapy. There is still limited evidence in both quality and sample size, suggesting that certain antioxidant supplements may reduce adverse reactions and toxicities. Significant reductions in toxicity may alleviate dose-limiting toxicities so that more patients are able to complete prescribed chemotherapy regimens and thus, in turn, improve the potential for success in terms of tumor response and survival. Copyright © 2013 Elsevier Inc. All rights reserved.


Randomized phase II trial of lyophilized strawberries in patients with dysplastic precancerous lesions of the esophagus.

Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting. ©2011 AACR.


Esophageal cancer: epidemiology, pathogenesis and prevention.

Esophageal cancer is highly aggressive and is a common cancer both worldwide and in the US. In the past two decades, the incidence and mortality of esophageal cancer in the US have both increased, where as the incidence and mortality of other cancers have decreased. Although esophageal squamous cell carcinoma and esophageal adenocarcinoma differ in their histology and epidemiologic distribution, some of their risk factors (e.g. dietary deficiencies and tobacco) and underlying mechanisms of carcinogenesis are the same. Intensive research into risk factors combined with the ability to identify precursor lesions (e.g.squamous dysplasia in esophageal squamous cell carcinoma and Barrett's esophagus in esophageal adenocarcinoma) has paved the way for studies of chemoprevention for esophageal cancer, some of which have shown promising results.


Rectal laterally spreading tumors successfully treated in two steps by endoscopic submucosal dissection and endoscopic mucosal resection

Background Endoscopic submucosal dissection (ESD) is an advanced technique of therapeutic endoscopy alternative to endoscopic mucosal resection (EMR) for superficial gastrointestinal neoplasms >2 cm. ESD allows for the direct dissection of the submucosa and large lesions can be resected en bloc. ESD is not limited by resection size, increases histologically complete resection rates and may reduce the local recurrence. Nevertheless, the technique is time-consuming, technically demanding and associated with a high complication rate. To reduce the risk of complications, different devices and technical advances have been proposed with conflicting results and, still, ESD en bloc resections of huge lesions are associated with increased complications. Case Presentation We successfully used a combined ESD/EMR technique for huge rectal laterally spreading tumors (LSTs). ESD was used for circumferential resection of 2/3 of the lesion followed by piecemeal resection (2-3 pieces) of the central part of the tumour. In all three patients we obtained the complete dissection of the polyp and the complete histological evaluation in absence of complications and recurrence at 6 months' follow up. Conclusions In the treatment of rectal LSTs, the combined treatment - ESD/EMR resection may be considered a suitable therapeutic option, indicated in selected cases as an alternative to surgery, in which the two techniques are neither reliable nor safe separately. However, to confirm our results, larger trials with longer follow up are required together with improvement of the technique and of the technical devices.


Glycemic responses to sweetened dried and raw cranberries in humans with type 2 diabetes.

This study assessed the metabolic response to sweetened dried cranberries (SDC), raw cranberries (RC), and white bread (WB) in humans with type 2 diabetes. Development of palatable cranberry preparations associated with lower glycemic responses may be useful for improving fruit consumption and glycemic control among those with diabetes. In this trial, type 2 diabetics (n= 13) received WB (57 g, 160 cal, 1 g fiber), RC (55 g, 21 cal, 1 g fiber), SDC (40 g, 138 cal, 2.1 g fiber), and SDC containing less sugar (SDC-LS, 40 g, 113 cal, 1.8 g fiber + 10 g polydextrose). Plasma glucose (mmol/L) peaked significantly at 60 min for WB, and at 30 min for RC, SDC, and SDC-LS at 9.6 ± 0.4, 7.0 ± 0.4, 9.6 ± 0.5, and 8.7 ± 0.5, respectively, WB remained significantly elevated from the other treatments at 120 min. Plasma insulin (pmol/mL) peaked at 60 min for WB and SDC and at 30 min for RC and SDC-LS at 157 ± 15, 142 ± 27, 61 ± 8, and 97 ± 11, respectively. Plasma insulin for SDC-LS was significantly lower at 60 min than either WB or SDC. Insulin area under the curve (AUC) values for RC and SDC-LS were both significantly lower than WB or SDC. Phenolic content of SDC and SDC-LS was determined following extraction with 80% acetone prior to high-performance liquid chromatography (HPLC) and electronspray ionization-mass spectrometry (ESI-MS) and found to be rich in 5-caffeoylquinic cid, quercetin-3-galactoside, and quercetin-3-galactoside, and the proanthocyanidin dimer epicatechin. In conclusion, SDC-LS was associated with a favorable glycemic and insulinemic response in type 2 diabetics. Practical Application: This study compares phenolic content and glycemic responses among different cranberry products. The study seeks to expand the palatable and portable healthy food choices for persons with type 2 diabetes. The novel use of polydextrose as a bulking agent making possible a reduction in caloric content and potential glycemic response is also characterized in this study.


Cranberries and cranberry products: powerful in vitro, ex vivo, and in vivo sources of antioxidants.

Cranberry products and especially cranberry juice (CJ) have been consumed for health reasons primarily due to their effect on urinary tract infections. We investigated the quantity of both free and total (after hydrolysis) phenolic antioxidants in cranberry products using the Folin assay. The order of amount of total polyphenols in cranberry foods on a fresh weight basis was as follows: dried > frozen > sauce > jellied sauce. On a serving size basis for all cranberry products, the order was as follows: frozen > 100% juice > dried > 27% juice > sauce > jellied sauce. High fructose corn syrup (HFCS) is a major source of sugar consumption in the U.S. and contains both glucose and fructose, potential mediators of oxidative stress. We investigated the effect of the consumption of HFCS and ascorbate with CJ antioxidants or without CJ (control) given to 10 normal individuals after an overnight fast. Plasma antioxidant capacity, glucose, triglycerides, and ascorbate were measured 6 times over 7 h after the consumption of a single 240 mL serving of the two different beverages. The control HFCS caused a slight decrease in plasma antioxidant capacity at all time points and thus an oxidative stress in spite of the presence of ascorbate. CJ produced an increase in plasma antioxidant capacity that was significantly greater than control HFCS at all time points. Postprandial triglycerides, due to fructose in the beverages, were mainly responsible for the oxidative stress and were significantly correlated with the oxidative stress as measured by the antioxidant capacity. Cranberries are an excellent source of high quality antioxidants and should be examined in human supplementation studies.


Comparison of health-relevant flavonoids in commonly consumed cranberry products.

The human health benefits from consumption of cranberry products have been associated with the fruits' unique flavonoid composition, including a complex profile of anthocyanins and proanthocyanidins. However, when processed by techniques such as pressing, canning, concentrating, or drying, a number of these natural components may be compromised or inactivated due to physical separation, thermal degradation, or oxidation. Fresh cranberries were compared to freeze-dried berries and individual fruit tissues (skin and peeled fruit). Products examined included cranberry juices (commercial and prepared from concentrate), cranberry sauces (commercial and homemade), and sweetened-dried cranberries (commercial). Freeze-drying resulted in no detectable losses of anthocyanins or proanthocyanidins from cranberry fruits. Anthocyanins were localized in the skin. Proanthocyanins were higher in the skin than in the flesh, with the exception of procyanidin A-2 dimer which was concentrated in the flesh. Anthocyanins were significantly higher in not-from-concentrate juice than in reconstituted juice from concentrate (8.3 mg and 4.2 mg/100 mL, respectively). Similarly, proanthocyanidins were markedly higher in not-from-concentrate juice compared to juice from concentrate (23.0 mg and 8.9 mg/100 mL, respectively). Homemade sauce contained far higher anthocyanins and proanthocyanidins (15.9 and 87.9 mg/100 g, respectively) than canned sauces processed with whole berries (9.6 and 54.4 mg/100 g, respectively) or jelled-type (1.1 and 16 mg/100 g, respectively). Sweetened-dried cranberries were quite low in anthocyanins (7.9 mg/100 g), but they still retained considerable proanthocyanidins (64.2 mg/100 g). Commercially processed products contained significantly lower levels of polyphenols as compared to fresh and home-processed preparations. Anthocyanins were more sensitive to degradation than proanthocyanidins. PRACTICAL APPLICATION: As cranberry juices and other products are increasingly consumed for their recognized health benefits (including prophylaxis against urinary tract infection), it is relevant to consider how various degrees of commercial and home processing can alter innate levels of the biologically active flavonoids (especially anthocyanins and proanthocyanidins) characteristic to the intact fruits. © 2012 Institute of Food Technologists®


Habitual intake of flavonoid subclasses and incident hypertension in adults

Background: Dietary flavonoids have beneficial effects on blood pressure in intervention settings, but there is limited information on habitual intake and risk of hypertension in population-based studies. Objective: We examined the association between habitual flavonoid intake and incident hypertension in a prospective study in men and women. Design: A total of 87,242 women from the Nurses' Health Study (NHS) II, 46,672 women from the NHS I, and 23,043 men from the Health Professionals Follow-Up Study (HPFS) participated in the study. Total flavonoid and subclass intakes were calculated from semiquantitative food-frequency questionnaires collected every 4 y by using an updated and extended US Department of Agriculture database. Results: During 14 y of follow-up, 29,018 cases of hypertension in women and 5629 cases of hypertension in men were reported. In pooled multivariate-adjusted analyses, participants in the highest quintile of anthocyanin intake (predominantly from blueberries and strawberries) had an 8% reduction in risk of hypertension [relative risk (RR): 0.92; 95% CI: 0.86, 0.98; P < 0.03] compared with that for participants in the lowest quintile of anthocyanin intake; the risk reduction was 12% (RR: 0.88; 95% CI: 0.84, 0.93; P < 0.001) in participants ≤60 y of age and 0.96 (0.91, 1.02) in participants >60 y of age (P for age interaction = 0.02). Although intakes of other subclasses were not associated with hypertension, pooled analyses for individual compounds suggested a 5% (95% CI: 0.91, 0.99; P = 0.005) reduction in risk for the highest compared with the lowest quintiles of intake of the flavone apigenin. In participants ≤60 y of age, a 6% (95% CI: 0.88, 0.97; P = 0.002) reduction in risk was observed for the flavan-3-ol catechin when the highest and the lowest quintiles were compared. Conclusions: Anthocyanins and some flavone and flavan-3-ol compounds may contribute to the prevention of hypertension. These vasodilatory properties may result from specific structural similarities (including the B-ring hydroxylation and methyoxylation pattern).


Anthocyanin composition of wild bananas in Thailand.

Anthocyanins were isolated from male bracts of 10 wild species of bananas (Musa spp. and Ensete spp.) distributed in Thailand. Six major anthocyanin pigments were identified by high performance liquid chromatography (HPLC), mass spectrometry (MS), and tandem mass spectrometry (MS/MS). They are delphinidin-3-rutinoside (m/z 611.2), cyanidin-3-rutinoside (m/z 595.8), petunidin-3-rutinoside (m/z 624.9), pelargonidin-3-rutinoside (m/z 579.4), peonidin-3-rutinoside (m/z 608.7), and malvidin-3-rutinoside (m/z 638.8). On the basis of the types of pigment present, the wild bananas can be divided into 5 groups. The first group comprises M. itinerans, Musa sp. one, Musa sp. two, and M. acuminata accessions, which contain almost or all anthocyanin pigments except for pelargonidin-3-rutinoside, including both nonmethylated and methylated anthocyanins. The second group, M. acuminata subsp. truncata, contains only malvidin-3-rutinoside while the third group, M. coccinea, contains cyanidin-3-rutinoside and pelargonidin-3-rutinoside. The forth group, M. acuminata yellow bract and E. glaucum do not appear to contain any anthocyanin pigment. The fifth group consists of M. balbisiana, M. velutina, M. laterita, and E. superbum which contain only nonmethylated anthocyanin, delphinidin-3-rutinoside, and cyanidin-3-rutinoside. Total anthocyanin content in the analyzed bracts ranged from 0-119.70 mg/100 g bract fresh weight. The differences in the type of anthocyanin and variation in the amounts present indicate that wild bananas show biochemical diversity, which may be useful for identifying specific groups of bananas or for clarifying the evolution of flavonoid metabolism in each banana group.


Antioxidant and antiproliferative activities of common fruits.

Consumption of fruits and vegetables has been associated with reduced risk of chronic diseases such as cardiovascular disease and cancer. Phytochemicals, especially phenolics, in fruits and vegetables are suggested to be the major bioactive compounds for the health benefits. However, the phenolic contents and their antioxidant activities in fruits and vegetables were underestimated in the literature, because bound phenolics were not included. This study was designed to investigate the profiles of total phenolics, including both soluble free and bound forms in common fruits, by applying solvent extraction, base digestion, and solid-phase extraction methods. Cranberry had the highest total phenolic content, followed by apple, red grape, strawberry, pineapple, banana, peach, lemon, orange, pear, and grapefruit. Total antioxidant activity was measured using the TOSC assay. Cranberry had the highest total antioxidant activity (177.0 +/- 4.3 micromol of vitamin C equiv/g of fruit), followed by apple, red grape, strawberry, peach, lemon, pear, banana, orange, grapefruit, and pineapple. Antiproliferation activities were also studied in vitro using HepG(2) human liver-cancer cells, and cranberry showed the highest inhibitory effect with an EC(50) of 14.5 +/- 0.5 mg/mL, followed by lemon, apple, strawberry, red grape, banana, grapefruit, and peach. A bioactivity index (BI) for dietary cancer prevention is proposed to provide a new alternative biomarker for future epidemiological studies in dietary cancer prevention and health promotion.


Total cranberry extract versus its phytochemical constituents: antiproliferative and synergistic effects against human tumor cell lines.

Cranberries (Vaccinium macrocarpon Ait.) are an excellent dietary source of phytochemicals that include flavonol glycosides, anthocyanins, proanthocyanidins (condensed tannins), and organic and phenolic acids. Using C-18 and Sephadex Lipophilic LH-20 column chromatography, HPLC, and tandem LC-ES/MS, the total cranberry extract (TCE) has been analyzed, quantified, and separated into fractions enriched in sugars, organic acids, total polyphenols, proanthocyanidins, and anthocyanins (39.4, 30.0, 10.6, 5.5, and 1.2% composition, respectively). Using a luminescent ATP cell viability assay, the antiproliferative effects of TCE (200 microg/mL) versus all fractions were evaluated against human oral (KB, CAL27), colon (HT-29, HCT116, SW480, SW620), and prostate (RWPE-1, RWPE-2, 22Rv1) cancer cell lines. The total polyphenol fraction was the most active fraction against all cell lines with 96.1 and 95% inhibition of KB and CAL27 oral cancer cells, respectively. For the colon cancer cells, the antiproliferative activity of this fraction was greater against HCT116 (92.1%) than against HT-29 (61.1%), SW480 (60%), and SW620 (63%). TCE and all fractions showed >/=50% antiproliferative activity against prostate cancer cells with total polyphenols being the most active fraction (RWPE-1, 95%; RWPE-2, 95%; 22Rv1, 99.6%). Cranberry sugars (78.8 microg/mL) did not inhibit the proliferation of any cancer cell lines. The enhanced antiproliferative activity of total polyphenols compared to TCE and its individual phytochemicals suggests synergistic or additive antiproliferative interactions of the anthocyanins, proanthocyanidins, and flavonol glycosides within the cranberry extract.


Anthocyanins are bioavailable in humans following an acute dose of cranberry juice.

Research suggests that anthocyanins from berry fruit may affect a variety of physiological responses, including endothelial function, but little information is available regarding the pharmacokinetics of these flavonoids in humans. To determine the pharmacokinetics of cranberry anthocyanins, a study was undertaken in 15 participants (age: 62 +/- 8 y) with coronary artery disease. Blood and urine samples were collected between baseline (0 h) and 4 h after consumption of 480 mL cranberry juice (54% juice; 835 mg total polyphenols; 94.47 mg anthocyanins). Marked inter-individual differences in plasma anthocyanin pharmacokinetics were observed with maximum anthocyanin concentrations detected between 1 and 3 h. Cranberry anthocyanins were bioavailable but with notable differences in the maximum concentration and area under the curve(0-4h) between individual participants. The pattern of anthocyanin glucosides observed in plasma and urine generally reflected the relative concentration determined in the juice. Plasma concentrations of the individual anthocyanins ranged between 0.56 and 4.64 nmol/L. Total recovery of urinary anthocyanin was 0.79 +/- 0.90% of the dose delivered. These data are in agreement with the pharmacokinetics of anthocyanins from other foods suggesting that cranberry anthocyanins are poorly absorbed and rapidly removed from plasma. Observed concentrations of plasma anthocyanins appear insufficient to alter radical load or redox potential but may be adequate to affect signal transduction and/or gene expression.


American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell...

Prostate cancer is one of the most common cancers in the world, and its prevalence is expected to increase appreciably in the coming decades. As such, more research is necessary to understand the etiology, progression and possible preventative measures to delay or to stop the development of this disease. Recently, there has been interest in examining the effects of whole extracts from commonly harvested crops on the behaviour and progression of cancer. Here, we describe the effects of whole cranberry extract (WCE) on the behaviour of DU145 human prostate cancer cells in vitro. Following treatment of DU145 human prostate cancer cells with 10, 25 and 50 μg ml⁻¹ of WCE, respectively for 6 h, WCE significantly decreased the cellular viability of DU145 cells. WCE also decreased the proportion of cells in the G2-M phase of the cell cycle and increased the proportion of cells in the G1 phase of the cell cycle following treatment of cells with 25 and 50 μg ml⁻¹ treatment of WCE for 6 h. These alterations in cell cycle were associated with changes in cell cycle regulatory proteins and other cell cycle associated proteins. WCE decreased the expression of CDK4, cyclin A, cyclin B1, cyclin D1 and cyclin E, and increased the expression of p27. Changes in p16(INK4a) and pRBp107 protein expression levels also were evident, however, the changes noted in p16(INK4a) and pRBp107 protein expression levels were not statistically significant. These findings demonstrate that phytochemical extracts from the American cranberry (Vaccinium macrocarpon) can affect the behaviour of human prostate cancer cells in vitro and further support the potential health benefits associated with cranberries.


Cranberries: ripe for more cancer research?

Berries have been recognized as a functional food with potential to protect against a variety of health conditions, including some cancers. Cranberry (Vaccinium macrocarpon) production and consumption have grown in recent years, warranting further evaluation of potential health benefits. Extracts and isolated constituents from cranberry fruit inhibit growth and proliferation of tumor cells in vitro, and recent data from animal studies lend further support to cranberry's reputation as a cancer fighter. Several likely mechanisms of action for cranberry against prostate and other cancers have been identified, including induction of apoptosis and inhibition of events linked to cellular invasion and migration. This article attempts to put into perspective what is known about cranberry's potential chemopreventive properties, what is yet to be determined, and some factors to consider as research moves forward. Copyright © 2011 Society of Chemical Industry.


Placebos in clinical practice: comparing attitudes, beliefs, and patterns of use between academic psychiatrists and nonpsychiatrists.

Controversial and ethically tenuous, the use of placebos is central to medicine but even more pivotal to psychosocial therapies. Scholars, researchers, and practitioners largely disagree about the conceptualization of placebos. While different professionals often confound the meanings of placebo effects with placebo responses, physicians continue to prescribe placebos as part of clinical practice. Our study aims to review attitudes and beliefs concerning placebos outside of clinical research. Herein we compare patterns of placebo use reported by academic psychiatrists with those reported by physicians from different specialties across Canadian medical schools. Using a web-based tool, we circulated an online survey to all 17 Canadian medical schools, with a special emphasis on psychiatry departments therein and in university-affiliated teaching hospitals. A variation on earlier efforts, our 5-minute, 21-question survey was anonymous. Among the 606 respondents who completed our online survey, 257 were psychiatrists. Our analysis revealed that psychiatrists prescribed significantly more subtherapeutic doses of medication than physicians in other specialties, although about 20% of both psychiatrists and nonpsychiatrists prescribed placebos regularly as part of routine clinical practice. However, compared with 6% of nonpsychiatrists, only 2% of psychiatrists deemed placebos of no clinical benefit. In addition, more than 60% of psychiatrists either agreed or strongly agreed that placebos had therapeutic effects relative to fewer than 45% of other practitioners. Findings from this pan-Canadian survey suggest that, compared with other physicians, psychiatrists seem to better value the influence placebos wield on the mind and body and maintain more favourable beliefs and attitudes toward placebo phenomena.


Bach flower remedies: a systematic review of randomised clinical trials.

Bach flower remedies continue to be popular and its proponents make a range of medicinal claims for them. The aim of this systematic review was to critically evaluate the evidence for these claims. Five electronic databases were searched without restrictions on time or language. All randomised clinical trials of flower remedies were included. Seven such studies were located. All but one were placebo-controlled. All placebo-controlled trials failed to demonstrate efficacy. It is concluded that the most reliable clinical trials do not show any differences between flower remedies and placebos.


Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.


Questionnaire survey on use of placebo

Objectives To gauge the frequency and circumstances of use of placebo in clinical practice and the attitudes towards its use among those who administer it. Design Retrospective questionnaire. Setting Two large hospitals and various community clinics in the Jerusalem area. Participants 31 physicians working in hospital inpatient and outpatient departments, 31 head nurses working in hospital inpatient departments, and 27 family physicians working in community clinics. Main outcome measures Self report of frequency and circumstances of, and attitudes towards, use of placebo. Results Among the 89 respondents, 53 (60%) used placebos (95% confidence interval 49% to 70%). Among users, 33 (62%) prescribed a placebo as often as once a month or more; 36 (68%) told patients they were receiving actual medication; 15 (28%) considered that placebos were a diagnostic tool; and 48/51 (94%) reported that they found placebos generally or occasionally effective. Conclusion Most practitioners questioned in this study continue to use placebos. Used wisely, placebos might have a legitimate place in therapeutics. Wider recognition of the practice and debate about its implications are imperative.


What's in placebos: who knows? Analysis of randomized, controlled trials.

BACKGROUND: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting. PURPOSE: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials. DATA SOURCES: 4 English-language general and internal medicine journals with high impact factors. STUDY SELECTION: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009. DATA EXTRACTION: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus. DATA SYNTHESIS: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002). LIMITATION: Journals with high impact factors may not be representative. CONCLUSION: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.


A survey of placebo use in a general hospital.

Two hundred thirty registered nurses and seventy physicians participated in a retrospective study scrutinizing placebo effects, prescribing patterns, and staff attitudes in a university-based general hospital setting. Despite copious experimental literature devoted to placebo effects over the past thirty years, the medical and surgical use of placebos seems to disregard experimental data. Although 80% of the staff had used placebos in the hospital, their knowledge of placebo effects was in many respects deficient. Within the hospital, 89% of placebo use was directed toward the amelioration of "pain"; the authors believe that emphasis should be placed on the education of staff to perceive emotional, social, and physiological concomitants of pain rather than resorting to a purely physicalistic approach. A need to acknowledge staff conflicts over the ethical use of placebos should be a significant part of this educational approach.


Can deceiving patients be morally acceptable?

Daniel K Sokol argues that on rare occasions benignly deceiving patients can be morally acceptable, and he has devised a decision checklist to help doctors facing such a dilemma


Placebos and general practice: attitudes to, and the use of, the placebo effect.

The present study surveyed Dunedin general practitioners to determine whether they would deliberately use placebo treatments, under what conditions they would do so, their basic understanding of the placebo effect, and their perception of their use of placebos relative to that of their colleagues. Results indicated that almost all GPS surveyed would deliberately use a placebo treatment under some circumstances. However, there was a clear and statistically significant tendency to understate their use relative to that of their colleagues. It was also clear that a significant number of those surveyed felt placebo treatments to be more appropriate for "imaginary illnesses". Results are discussed in comparison with overseas studies and in regard to their implications for medical training.


A duty to deceive: placebos in clinical practice.

Among medical researchers and clinicians the dominant view is that it is unethical to deceive patients by prescribing a placebo. This opinion is formalized in a recent policy issued by the American Medical Association (AMA [Chicago, IL]). Although placebos can be shown to be always safe, often effective, and sometimes necessary, doctors are now effectively prohibited from using them in clinical practice. I argue that the deceptive administration of placebos is not subject to the same moral objections that face other forms of deception in clinical practice and medical research. Although deception is normally objectionable on the grounds that it limits autonomy and breaches trust, these grounds do not apply to placebos when they are prescribed within appropriate ethical limits. Patients have reason to prefer that doctors can prescribe placebos in ethically responsible ways. Hence, the AMA has an obligation to endorse and to promote the responsible use of deceptive placebos in clinical practice.


A systematic review of systematic reviews of homeopathy

Homeopathy remains one of the most controversial subjects in therapeutics. This article is an attempt to clarify its effectiveness based on recent systematic reviews. Electronic databases were searched for systematic reviews/meta-analysis on the subject. Seventeen articles fulfilled the inclusion/exclusion criteria. Six of them related to re-analyses of one landmark meta-analysis. Collectively they implied that the overall positive result of this meta-analysis is not supported by a critical analysis of the data. Eleven independent systematic reviews were located. Collectively they failed to provide strong evidence in favour of homeopathy. In particular, there was no condition which responds convincingly better to homeopathic treatment than to placebo or other control interventions. Similarly, there was no homeopathic remedy that was demonstrated to yield clinical effects that are convincingly different from placebo. It is concluded that the best clinical evidence for homeopathy available to date does not warrant positive recommendations for its use in clinical practice.


Prescribing “placebo treatments”: results of national survey of US internists and rheumatologists

Objective To describe the attitudes and behaviours regarding placebo treatments, defined as a treatment whose benefits derive from positive patient expectations and not from the physiological mechanism of the treatment itself. Design Cross sectional mailed survey. Setting Physicians’ clinical practices. Participants 1200 practising internists and rheumatologists in the United States. Main outcome measures Investigators measured physicians’ self reported behaviours and attitudes concerning the use of placebo treatments, including measures of whether they would use or had recommended a “placebo treatment,” their ethical judgments about the practice, what they recommended as placebo treatments, and how they typically communicate with patients about the practice. Results 679 physicians (57%) responded to the survey. About half of the surveyed internists and rheumatologists reported prescribing placebo treatments on a regular basis (46-58%, depending on how the question was phrased). Most physicians (399, 62%) believed the practice to be ethically permissible. Few reported using saline (18, 3%) or sugar pills (12, 2%) as placebo treatments, while large proportions reported using over the counter analgesics (267, 41%) and vitamins (243, 38%) as placebo treatments within the past year. A small but notable proportion of physicians reported using antibiotics (86, 13%) and sedatives (86, 13%) as placebo treatments during the same period. Furthermore, physicians who use placebo treatments most commonly describe them to patients as a potentially beneficial medicine or treatment not typically used for their condition (241, 68%); only rarely do they explicitly describe them as placebos (18, 5%). Conclusions Prescribing placebo treatments seems to be common and is viewed as ethically permissible among the surveyed US internists and rheumatologists. Vitamins and over the counter analgesics are the most commonly used treatments. Physicians might not be fully transparent with their patients about the use of placebos and might have mixed motivations for recommending such treatments.


The use of placebo interventions in medical practice--a national questionnaire survey of Danish clinicians.

The authors sent a questionnaire to 772 randomly selected Danish clinicians and asked them about their use of placebo interventions. Sixty-five percent responded. Among the general practitioners, 86% (95% confidence interval 81-91) reported to have used placebo interventions at least once, and 48% (41-55) to have used placebo interventions more than ten times, within the last year. Hospital-based doctors and private specialists reported to have used placebo interventions less frequently (p < .001). The most important reason for the use of placebo interventions was to avoid a confrontation with the patient. Typical placebos were antibiotics for viral infections. Approximately 30% (28-36) of the clinicians believed in an effect of placebo interventions on objective outcomes, and 46% (42-50) found clinical placebo interventions generally ethically acceptable.


General practice consultations: is there any point in being positive?

A group of 200 patients who presented in general practice with symptoms but no abnormal physical signs and in whom no definite diagnosis was made were randomly selected for one of four consultations: a consultation conducted in a "positive manner," with and without treatment, and a consultation conducted in a "non-positive manner," called a negative consultation, with and without treatment. Two weeks after consultation there was a significant difference in patient satisfaction between the positive and negative groups but not between the treated and untreated groups. Similarly, 64% of those receiving a positive consultation got better, compared with 39% of those who received a negative consultation (p = 0.001) and 53% of those treated got better compared with 50% of those not treated (p = 0.5).


Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk

Context Multiple studies have linked alcohol consumption to breast cancer risk, but the risk of lower levels of consumption has not been well quantified. In addition, the role of drinking patterns (i.e. frequency of drinking and “binge” drinking) and consumption at different times of adult life are not well understood. Objective To evaluate the association of breast cancer with alcohol consumption during adult life, including quantity, frequency, and age at consumption. Design, Setting, and Participants Prospective observational study of 105,986 women enrolled in the Nurses’ Health Study followed from 1980 until 2008 with early adult and eight updated alcohol assessments during this time. Main Outcome Measures Relative risks of developing invasive breast cancer. Results 7690 cases developed during 2.4 million person-years of follow-up. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels as low as 5.0-9.9 gm/day, equivalent to 3-6 drinks/week (RR 1.15 (95% CI 1.06-1.24) 332 cases/100,000 person-years). After controlling for cumulative alcohol intake, binge drinking, but not frequency of drinking, was associated with breast cancer risk. Alcohol intake both earlier and later in adult life was independently associated with risk. Conclusion Low levels of alcohol consumption were associated with a small increase in breast cancer risk, with the most consistent measure being cumulative alcohol intake throughout adult life. Alcohol intake both earlier and later in adult life was independently associated with risk.


A single sip of a strong alcoholic beverage causes exposure to carcinogenic concentrations of acetaldehyde in the oral cavity.

The aim of this study was to explore oral exposure to carcinogenic (group 1) acetaldehyde after single sips of strong alcoholic beverages containing no or high concentrations of acetaldehyde. Eight volunteers tasted 5 ml of ethanol diluted to 40 vol.% with no acetaldehyde and 40 vol.% calvados containing 2400 μM acetaldehyde. Salivary acetaldehyde and ethanol concentrations were measured by gas chromatography. The protocol was repeated after ingestion of ethanol (0.5 g/kg body weight). Salivary acetaldehyde concentration was significantly higher after sipping calvados than after sipping ethanol at 30s both with (215 vs. 128 μmol/l, p<0.05) and without (258 vs. 89 μmol/l, p<0.05) alcohol ingestion. From 2 min onwards there were no significant differences in the decreasing salivary acetaldehyde concentration, which remained above the level of carcinogenicity still at 10 min. The systemic alcohol distribution from blood to saliva had no additional effect on salivary acetaldehyde after sipping of the alcoholic beverages. Carcinogenic concentrations of acetaldehyde are produced from ethanol in the oral cavity instantly after a small sip of strong alcoholic beverage, and the exposure continues for at least 10 min. Acetaldehyde present in the beverage has a short-term effect on total acetaldehyde exposure. Copyright © 2011 Elsevier Ltd. All rights reserved.


Salivary acetaldehyde increase due to alcohol-containing mouthwash use: a risk factor for oral cancer.

Increasing evidence suggests that acetaldehyde, the first and genotoxic metabolite of ethanol, mediates the carcinogenicity of alcoholic beverages. Ethanol is also contained in a number of ready-to-use mouthwashes typically between 5 and 27% vol. An increased risk of oral cancer has been discussed for users of such mouthwashes; however, epidemiological evidence had remained inconclusive. This study is the first to investigate acetaldehyde levels in saliva after use of alcohol-containing mouthwashes. Ready-to-use mouthwashes and mouthrinses (n = 13) were rinsed in the mouth by healthy, nonsmoking volunteers (n = 4) as intended by the manufacturers (20 ml for 30 sec). Saliva was collected at 0.5, 2, 5 and 10 min after mouthwash use and analyzed using headspace gas chromatography. The acetaldehyde content in the saliva was 41 +/- 15 microM, range 9-85 microM (0.5 min), 52 +/- 14 microM, range 11-105 microM (2 min), 32 +/- 7 microM, range 9-67 microM (5 min) and 15 +/- 7 microM, range 0-37 microM (10 min). The contents were significantly above endogenous levels and corresponding to concentrations normally found after alcoholic beverage consumption. A twice-daily use of alcohol-containing mouthwashes leads to a systemic acetaldehyde exposure of 0.26 microg/kg bodyweight/day on average, which corresponds to a lifetime cancer risk of 3E-6. The margin of exposure was calculated to be 217,604, which would be seen as a low public health concern. However, the local acetaldehyde contents in the saliva are reaching concentrations associated with DNA adduct formation and sister chromatid exchange in vitro, so that concerns for local carcinogenic effects in the oral cavity remain.


Molecular mechanisms of alcohol-mediated carcinogenesis.

Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.


Epidemiology and pathophysiology of alcohol and breast cancer: Update 2012.

AIMS: To update epidemiological data on alcohol and breast cancer, with special emphasis on light alcohol consumption, and to review mechanisms of alcohol mediated mammary carcinogenesis. METHODS: For epidemiological data, in November 2011 we performed a literature search in various bibliographic databases, and we conducted a meta-analysis of data on light alcohol drinking. Relevant mechanistic studies were also reviewed to November 2011. RESULTS: A significant increase of the order of 4% in the risk of breast cancer is already present at intakes of up to one alcoholic drink/day. Heavy alcohol consumption, defined as three or more drinks/day, is associated with an increased risk by 40-50%. This translates into up to 5% of breast cancers attributable to alcohol in northern Europe and North America for a total of approximately 50,000 alcohol-attributable cases of breast cancer worldwide. Up to 1-2% of breast cancers in Europe and North America are attributable to light drinking alone, given its larger prevalence in most female populations when compared with heavy drinking. Alcohol increases estrogen levels, and estrogens may exert its carcinogenic effect on breast tissue either via the ER or directly. Other mechanisms may include acetaldehyde, oxidative stress, epigenetic changes due to a disturbed methyl transfer and decreased retinoic acid concentrations associated with an altered cell cycle. CONCLUSIONS: Women should not exceed one drink/day, and women at elevated risk for breast cancer should avoid alcohol or consume alcohol occasionally only.


Light alcohol drinking and cancer: a meta-analysis.

BACKGROUND: There is convincing evidence that alcohol consumption increases the risk of cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx. Most of the data derive from studies that focused on the effect of moderate/high alcohol intakes, while little is known about light alcohol drinking (up to 1 drink/day). PATIENTS AND METHODS: We evaluated the association between light drinking and cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx, through a meta-analytic approach. We searched epidemiological studies using PubMed, ISI Web of Science and EMBASE, published before December 2010. RESULTS: We included 222 articles comprising ∼92 000 light drinkers and 60 000 non-drinkers with cancer. Light drinking was associated with the risk of oropharyngeal cancer [relative risk, RR = 1.17; 95% confidence interval (CI) 1.06-1.29], esophageal squamous cell carcinoma (SCC) (RR = 1.30; 95% CI 1.09-1.56) and female breast cancer (RR = 1.05; 95% CI 1.02-1.08). We estimated that ∼5000 deaths from oropharyngeal cancer, 24 000 from esophageal SCC and 5000 from breast cancer were attributable to light drinking in 2004 worldwide. No association was found for colorectum, liver and larynx tumors. CONCLUSIONS: Light drinking increases the risk of cancer of oral cavity and pharynx, esophagus and female breast.


The positive and negative health effects of alcohol- and the public health implications.

In this paper, the negative and the positive effects of alcohol on health are reviewed. It is first of all established facts that a high alcohol intake implies an increased risk of a large number of health outcomes, such as dementia, breast cancer, colorectal cancer, cirrhosis, upper digestive tract cancer and alcohol dependency. Second, it is justified that alcohol has beneficial effects for some individuals, especially with regard to prevention of thrombosis of the heart. The public health relevance of these results is considered. The sensible drinking limits, used in both the UK and Denmark, of a maximum of 21 drinks per week for men and 14 drinks per week for women seem valid. A broader public health message of the beneficial effects of alcohol does not seem to be of interest in Western societies, where only a very small fraction of the population are non drinkers and may have very good reasons therefore.


Energy density, nutrient adequacy, and cost per serving can provide insight into food choices in the lower Mississippi Delta.

OBJECTIVE: To compare differences across food groups for food cost, energy, and nutrient profiles of 100 items from a cross-sectional survey of 225 stores in 18 counties across the Lower Mississippi Delta of Arkansas, Louisiana, and Mississippi. METHODS: Energy, nutrient, and cost profiles for food items were calculated by using Naturally Nutrient Rich methodology and converting price per 100 g edible portion to price per serving. Foods were grouped into 6 food groups. Mean differences were compared with ANOVA. RESULTS: Significant differences existed by food group for each measure. Energy density was highest for fats/oils/sweets, whereas nutrient density was highest for vegetables. Price per serving was lowest for fats/oils/sweets and highest for meats. CONCLUSIONS AND IMPLICATIONS: Educational messages focusing on a complete diet should consider the role of food costs and provide specific recommendations for increasing nutrient-dense foods by replacing a portion of the meat serving at meals with culturally acceptable lower-cost nutrient-dense foods. Copyright Â© 2012 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.


The cost of US foods as related to their nutritive value

Background: Comparisons of the cost of different foods relative to their energy and nutritive value were conducted in the 1800s by the US Department of Agriculture (USDA). Objective: The objective was to reestablish the relations between food cost, energy, and nutrients by using contemporary nutrient composition and food prices data from the USDA. Design: The USDA Food and Nutrient Database for Dietary Studies 1.0 (FNDDS 1.0) and the Center for Nutrition Policy and Promotion food prices database were used for analysis. For 1387 foods, key variables were as follows: energy density (kcal/g), serving size (g), unit price ($/100 g), serving price ($/serving), and energy cost ($/kcal). A regression model tested associations between nutrients and unit price ($/100 g). Comparisons between food groups were tested by using one-factor analyses of variance. Relations between energy density and price within food groups were tested by using Spearman's correlations. Results: Grains and fats food groups supplied the lowest-cost dietary energy. The energy cost for vegetables was higher than that for any other food group except for fruit. Serving sizes increased with water content and varied inversely with energy density of foods. The highest prices per serving were for meats, poultry, and fish, and the lowest prices per serving were for the fats category. Although carbohydrates, sugar, and fat were associated with lower price per 100 g, protein, fiber, vitamins, and minerals were associated with higher price per 100 g, after adjustment for energy. Conclusions: Grains and sugars food groups were cheaper than vegetables and fruit per calorie and were cheaper than fruit per serving. These price differentials may help to explain why low-cost, energy-dense foods that are nutrient poor are associated with lower education and incomes.


What is the cell hydration status of healthy children in the USA? Preliminary data on urine osmolality and water intake.

OBJECTIVE: Hyperosmotic stress on cells limits many aspects of cell function, metabolism and health. International data suggest that schoolchildren may be at risk of hyperosmotic stress on cells because of suboptimal water intake. The present study explored the cell hydration status of two samples of children in the USA. DESIGN: Cross-sectional study describing the urine osmolality (an index of hyperosmotic cell shrinkage) and water intake of convenience samples from Los Angeles (LA) and New York City (NYC). SETTING: Each participant collected a urine sample at an outpatient clinic on the way to school on a weekday morning in spring 2009. Each was instructed to wake, eat, drink and do as usual before school, and complete a dietary record form describing the type and amounts of all foods and beverages consumed after waking, before giving the sample. SUBJECTS: The children (9-11 years) in LA (n 337) and NYC (n 211) considered themselves healthy enough to go to school on the day they gave the urine sample. RESULTS: Elevated urine osmolality (>800 mmol/kg) was observed in 63 % and 66 % of participants in LA and NYC, respectively. In multivariable-adjusted logistic regression models, elevated urine osmolality was associated with not reporting intake of drinking water in the morning (LA: OR = 2·1, 95 % CI 1·2, 3·5; NYC: OR = 1·8, 95 % CI 1·0, 3·5). Although over 90 % of both samples had breakfast before giving the urine sample, 75 % did not drink water. CONCLUSIONS: Research is warranted to confirm these results and pursue their potential health implications.


Hydration and cognitive performance.

A clinical link exists between severe dehydration and cognitive performance. Using rapid and severe water loss induced either by intense exercise and/or heat stress, initial studies suggested there were alterations in short-term memory and cognitive function related to vision, but more recent studies have not all confirmed these data. Some studies argue that water loss is not responsible for the observations made, and studies compensating water losses have failed to prevent the symptoms. Studies in children have suggested that drinking extra water helps cognitive performance, but these data rely on a small number of children. In older adults (mean age around 60) the data are not strong enough to support a relationship between mild dehydration and cognitive function. Data on frail elderly and demented people are lacking. Methodological heterogeneity in these studies are such that the relationship between mild dehydration and cognitive performance cannot be supported.


Mild dehydration impairs cognitive performance and mood of men.

The present study assessed the effects of mild dehydration on cognitive performance and mood of young males. A total of twenty-six men (age 20·0 (sd 0·3) years) participated in three randomised, single-blind, repeated-measures trials: exercise-induced dehydration plus a diuretic (DD; 40 mg furosemide); exercise-induced dehydration plus placebo containing no diuretic (DN); exercise while maintaining euhydration plus placebo (EU; control condition). Each trial included three 40 min treadmill walks at 5·6 km/h, 5 % grade in a 27·7°C environment. A comprehensive computerised six-task cognitive test battery, the profile of mood states questionnaire and the symptom questionnaire (headache, concentration and task difficulty) were administered during each trial. Paired t tests compared the DD and DN trials resulting in >1 % body mass loss (mean 1·59 (sd 0·42) %) with the volunteer's EU trial (0·01 (sd 0·03) %). Dehydration degraded specific aspects of cognitive performance: errors increased on visual vigilance (P = 0·048) and visual working memory response latency slowed (P = 0·021). Fatigue and tension/anxiety increased due to dehydration at rest (P = 0·040 and 0·029) and fatigue during exercise (P = 0·026). Plasma osmolality increased due to dehydration (P < 0·001) but resting gastrointestinal temperature was not altered (P = 0·238). In conclusion, mild dehydration without hyperthermia in men induced adverse changes in vigilance and working memory, and increased tension/anxiety and fatigue.


Should children drink more water?: the effects of drinking water on cognition in children.

While dehydration has well-documented negative effects on adult cognition, there is little research on hydration and cognitive performance in children. We investigated whether having a drink of water improved children's performance on cognitive tasks. Fifty-eight children aged 7-9 years old were randomly allocated to a group that received additional water or a group that did not. Results showed that children who drank additional water rated themselves as significantly less thirsty than the comparison group (p=0.002), and they performed better on visual attention tasks (letter cancellation, p=0.02; spot the difference memory tasks, ps=0.019 and 0.014).


Effects of drinking supplementary water at school on cognitive performance in children.

We investigated the beneficial effects of drinking supplementary water during the school day on the cognitive performance and transitory subjective states, such as fatigue or vigor, in 168 children aged between 9 and 11years who were living in a hot climate (South Italy, Sardinia). The classes were randomly divided into an intervention group, which received water supplementation, and a control group. Dehydration was determined by urine sampling and was defined as urine osmolality greater than 800mOsm/kg H(2)O (Katz, Massry, Agomn, & Toor, 1965). The change in the scores from the morning to the afternoon of hydration levels, cognitive performance and transitory subjective states were correlated. In line with a previous observational study that evaluated the hydration status of school children living in a country with a hot climate (Bar-David, Urkin, & Kozminsky, 2005), our results showed that a remarkable proportion of children were in a state of mild, voluntary dehydration at the beginning of the school day (84%). We found a significant negative correlation between dehydration and the auditory number span, which indicates a beneficial effect of drinking supplementary water at school on short-term memory. Moreover, there was a positive correlation between dehydration and performance in the verbal analogy task. The results are discussed in the light of the complexity of the neurobiological mechanisms involved in the relationship between hydration status and cognition. Copyright © 2012 Elsevier Ltd. All rights reserved.


Does having a drink help you think? 6-7-Year-old children show improvements in cognitive performance from baseline to test after having a drink of ...

Little research has examined the effect of water consumption on cognition in children. We examined whether drinking water improves performance from baseline to test in twenty-three 6-7-year-old children. There were significant interactions between time of test and water group (water/no water), with improvements in the water group on thirst and happiness ratings, visual attention and visual search, but not visual memory or visuomotor performance. These results indicate that even under conditions of mild dehydration, not as a result of exercise, intentional water deprivation or heat exposure, children's cognitive performance can be improved by having a drink of water.


Vegetarian vs nonvegetarian diets, dietary restraint, and subclinical ovulatory disturbances: prospective 6-mo study.

Ovulatory function was prospectively assessed over 6 mo in 23 vegetarians and 22 nonvegetarians with clinically normal menstrual cycles. Subjects were 20-40 y of age, of stable weight (body mass index, in kg/m2, of 18-25), on current diets for > or = 2 y, and not using oral contraceptives. Quantitative analysis of basal body temperature records classified cycles as normally ovulatory, short luteal phase (< 10 d), or anovulatory. Subjects completed the Three-Factor Eating Questionnaire (subjects completed the Three-Factor Eating Questionnaire (subscales for restraint, hunger, and disinhibition) and kept three 3-d food records. Vegetarians had lower BMIs (21.1 +/- 2.3 vs 22.7 +/- 1.9, P < 0.05), percentage body fat (24.0 +/- 5.5% vs 27.4 +/- 5.1%, P < 0.05), and restraint scores (6.4 +/- 4.4 vs 9.5 +/- 3.7, P < 0.05). Mean cycle lengths were similar, but vegetarians had longer luteal phase lengths (11.2 +/- 2.6 vs 9.1 +/- 3.8 d, P < 0.05). Cycle types also differed (chi 2 = 9.64, P < 0.01): vegetarians had fewer anovulatory cycles (4.6% vs 15.1% of cycles). Compared with those with restraint scores below the median, highly restrained women had fewer ovulatory cycles (3.6 +/- 2.3 vs 5.0 +/- 1.4, P < 0.05) and shorter mean luteal phase lengths (7.4 +/- 4.1 vs 10.7 +/- 3.1 d, P < 0.05). We conclude that ovulatory disturbances and restrained eating are less common among vegetarians, and that restraint influences ovulatory function.


Vegetarianism and menstrual cycle disturbances: is there an association?

The question of whether menstrual disturbances are more common in vegetarian than in nonvegetarian women is complex. Disturbances of the cycle may be clinical (ie, amenorrhea or oligomenorrhea) or subclinical (i.e., normal-length cycles with anovulation or a short or defective luteal phase). Detection of the latter requires that the menstrual cycle be monitored, but may help prevent recruitment bias in studies comparing vegetarians with nonvegetarians because vegetarians with menstrual disturbances may be more likely to volunteer for a study on menstrual disturbances and vegetarianism. Three general mechanisms that could contribute to menstrual disturbances that may differ between vegetarians and nonvegetarians include energy imbalances associated with body-weight disturbances or exercise, psychosocial and cognitive factors, and dietary components. Evidence for each of these mechanisms is reviewed and studies comparing menstrual function between vegetarians and nonvegetarians are described in this article. Although results from several cross-sectional studies suggest that clinical menstrual disturbances may be more common in vegetarians, a prospective study that controlled for many potential confounders found that subclinical disturbances were less common in weight-stable, healthy vegetarian women. Because the sample studied may not be representative of all vegetarian women, however, these results cannot be generalized. Population studies are needed to draw definitive conclusions.


Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.


Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prosta...

In this study, a panel of normal human prostate cells (HPCs) and tumor cells derived from metastases were studied by (1)H NMR spectroscopy to determine whether the malignant transformation of HPCs results in the elevation of choline compounds. Although an elevated choline signal has been observed previously in clinical studies, the contribution of the different Cho compounds to this elevation, as well as their quantification, has not been established until now. Here we have shown that HPCs derived from metastases exhibit significantly higher phosphocholine as well as glycerophosphocholine levels compared with normal prostate epithelial and stromal cells. Thus the elevation of the choline peak observed clinically in prostate cancer is attributable to an alteration of phospholipid metabolism and not simply to increased cell density, doubling time, or other nonspecific effects. Androgen deprivation of the androgen receptor-positive cell lines resulted in a significant increase of choline compounds after chronic androgen deprivation of the LNCaP cell line and in a decrease of choline compounds after a more acute androgen deprivation of the LAPC-4 cell line. These data strongly support the use of proton magnetic resonance spectroscopic imaging to detect the presence of prostate cancer for diagnosis, to detect response subsequent to androgen ablation therapy, and to detect recurrence.


Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate specific antigen-era: incidence and survival

Red and processed meat may increase risk of advanced prostate cancer. Data on post-diagnostic diet and prostate cancer are sparse, but post-diagnostic intake of poultry with skin and eggs may increase risk of disease progression. Therefore, we prospectively examined total, unprocessed, and processed red meat, poultry, and eggs in relation to risk of lethal prostate cancer (e.g. men without cancer at baseline who developed distant organ metastases or died from prostate cancer during follow-up) among 27, 607 men followed from 1994–2008. We also performed a case-only survival analysis to examine post-diagnostic consumption of these foods and risk of lethal prostate cancer among the 3,127 men initially diagnosed with non-metastatic prostate cancer during follow-up. In the incidence analysis, we observed 199 events during 306,715 person-years. Men who consumed 2.5 or more eggs per week had an 81% increased risk of lethal prostate cancer compared to men who consumed less than 0.5 eggs per week (HR: 1.81; 95% confidence interval (CI): 1.13, 2.89; p-trend: 0.01). In the case-only survival analysis, we observed 123 events during 19,354 person-years. There were suggestive, but not statistically significant, positive associations between post-diagnostic poultry (HR ≥3.5 vs. <1.5 servings per week: 1.69; 95%CI: 0.96, 2.99; p-trend: 0.07) and post-diagnostic processed red meat (HR ≥3 vs. <0.5 servings per week: 1.45; 95%CI: 0.73, 2.87; p-trend: 0.08) and risk of progression of localized prostate cancer to lethal disease. In conclusion, consumption of eggs may increase risk of developing a lethal-form of prostate cancer among healthy men.


Fish odour syndrome

Fish odour syndrome (trimethylaminuria) is a metabolic syndrome caused by abnormal excretion of trimethylamine in the breath, urine, sweat, saliva and vaginal secretions. Trimethylamine is derived from the intestinal bacterial degradation of foods rich in choline and carnitine and is normally oxidised by the liver to odourless trimethylamine N-oxide which is then excreted in the urine. Impaired oxidation of trimethylamine is thought to be the cause of the fish odour syndrome and is responsible for the smell of rotting fish. Certain foods rich in choline exacerbate the condition and the patients have a variety of psychological problems. Recognition of the condition is important as dietary adjustments reduce the excretion of trimethylamine and may reduce the odour. Occasionally, a short course of metronidazole, neomycin and lactulose may suppress production of trimethylamine by reducing the activity of gut microflora. Keywords: fish odour syndrome; trimethylaminuria


Choline and betaine intake and the risk of colorectal cancer in men

Dietary choline and betaine have been hypothesized to decrease the risk of cancer because of their role as methyl donors in the one-carbon metabolism. However, it remains unknown whether dietary intake of choline and betaine is associated with colorectal cancer risk. We prospectively examined the associations between dietary choline and betaine intake and risk of colorectal cancer in men in the Health Professionals Follow-up Study. We followed 47,302 men and identified a total of 987 incident colorectal cancer cases from 1986 to 2004. We assessed dietary and supplemental choline and betaine intake every four years using a validated semi-quantitative food frequency questionnaire. The Cox proportional hazards model was used to estimate multivariate relative risks (RRs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided. We did not find any statistically significant associations between choline intake or betaine intake and risk of colorectal cancer. Comparing the top quintile with bottom quintile, multivariate RRs (95% CI) were 0.97 (0.79-1.20; Ptrend = 0.87) for choline intake and 0.94 (0.77-1.16; Ptrend = 0.79) for betaine intake. Similarly, we observed no associations between colorectal cancer risk and choline from free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, or sphingomyelin. Our data do not support that choline and betaine intake is inversely associated with colorectal cancer risk.


One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites.

PURPOSE: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before. MATERIALS AND METHODS: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression. RESULTS: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk. CONCLUSION: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation.


Choline- and betaine-defined diets for use in clinical research and for the management of trimethylaminuria.

This article describes the development of a series of choline- and betaine-controlled diets that were served to research subjects as part of an ongoing study of diet requirements in humans. These diets were developed based on the analysis of choline and betaine in individual foods. The calculated diets were compared with analyses of all foods combined into a single sample for each day. The laboratory analyses of choline and betaine in the whole-diet aliquots matched the estimated amounts in the diets that were calculated from the analyses of individual foods. These diets were adjusted for several levels of choline and betaine and were well accepted by research subjects who consumed them for a time period of up to 2 months. This article describes applications of this diet for use in clinical research on methyl-group requirements in humans and for use in clinical practice for counseling the client who requires a choline-controlled diet.


11C-choline vs. 18F-FDG PET/CT in assessing bone involvement in patients with multiple myeloma

Background Multiple Myeloma (MM) is a B cell neoplasm causing lytic or osteopenic bone abnormalities. Whole body skeletal survey (WBSS), Magnetic resonance (MR) and 18F-FDG PET/CT are imaging techniques routinely used for the evaluation of bone involvement in MM patients. Aim As MM bone lesions may present low 18F-FDG uptake; the aim of this study was to assess the possible added value and limitations of 11C-Choline to that of 18F-FDG PET/CT in patients affected with MM. Methods Ten patients affected with MM underwent a standard 11C-Choline PET/CT and an 18F-FDG PET/CT within one week. The results of the two scans were compared in terms of number, sites and SUVmax of lesions. Results Four patients (40%) had a negative concordant 11C-Choline and 18F-FDG PET/CT scans. Two patients (20%) had a positive 11C-Choline and 18F-FDG PET/CT scans that identified the same number and sites of bone lesions. The remaining four patients (40%) had a positive 11C-Choline and 18F-FDG PET/CT scan, but the two exams identified different number of lesions. Choline showed a mean SUVmax of 5 while FDG showed a mean SUVmax of 3.8 (P = 0.042). Overall, 11C-Choline PET/CT scans detected 37 bone lesions and 18F-FDG PET/CT scans detected 22 bone lesions but the difference was not significant (P = 0.8). Conclusion According to these preliminary data, 11C-Choline PET/CT appears to be more sensitive than 18F-FDG PET/CT for the detection of bony myelomatous lesions. If these data are confirmed in larger series of patients, 11C-Choline may be considered a more appropriate functional imaging in association with MRI for MM bone staging.


Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk.


Choline intake and risk of lethal prostate cancer: incidence and survival

Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer.


Intakes of meat, fish, poultry, and eggs and risk of prostate cancer progression

Background: Processed meat and fish have been shown to be associated with the risk of advanced prostate cancer, but few studies have examined diet after prostate cancer diagnosis and risk of its progression. Objective: We examined the association between postdiagnostic consumption of processed and unprocessed red meat, fish, poultry, and eggs and the risk of prostate cancer recurrence or progression. Design: We conducted a prospective study in 1294 men with prostate cancer, without recurrence or progression as of 2004–2005, who were participating in the Cancer of the Prostate Strategic Urologic Research Endeavor and who were followed for an average of 2 y. Results: We observed 127 events (prostate cancer death or metastases, elevated prostate-specific antigen concentration, or secondary treatment) during 2610 person-years. Intakes of processed and unprocessed red meat, fish, total poultry, and skinless poultry were not associated with prostate cancer recurrence or progression. Greater consumption of eggs and poultry with skin was associated with 2-fold increases in risk in a comparison of extreme quantiles: eggs [hazard ratio (HR): 2.02; 95% CI: 1.10, 3.72; P for trend = 0.05] and poultry with skin (HR: 2.26; 95% CI: 1.36, 3.76; P for trend = 0.003). An interaction was observed between prognostic risk at diagnosis and poultry. Men with high prognostic risk and a high poultry intake had a 4-fold increased risk of recurrence or progression compared with men with low/intermediate prognostic risk and a low poultry intake (P for interaction = 0.003). Conclusions: Our results suggest that the postdiagnostic consumption of processed or unprocessed red meat, fish, or skinless poultry is not associated with prostate cancer recurrence or progression, whereas consumption of eggs and poultry with skin may increase the risk.


Recommendations for the prevention of chronic disease: the application for breast disease.

Experimental and epidemiological evidence suggest that a diet with dietary fat as low as 20% of kcal may be necessary to reduce the risk of breast cancer. Two groups of women, postmenopausal women treated for breast cancer and premenopausal women with cystic breast disease accompanied by cyclical mastaligia, participated in an intervention program to determine the feasibility of such a low-fat diet. After 3 mo of intervention both groups were consuming a low-fat diet; in the premenopausal groups serum estrogen levels decreased in response to the fat reduction. Other nutrition-education programs in research institutions, restaurants, and schools are attempting to influence the public's knowledge and behavior regarding the importance of dietary fat reduction.


Serum prolactin and oestradiol levels in women with cyclical mastalgia.

Basal serum prolactin and serum oestradiol-17-beta concentrations were measured four times during one menstrual cycle in 20 women with severe cyclical mastalgia and normal to slightly fibroadenotic breasts. A group of 10 normal women who had never experienced mastalgia served as controls. Basal serum prolactin was significantly elevated in patients compared to normals, although within the normal range. Serum oestradiol concentrations did not differ in the two groups and were also within the normal range. A significant positive correlation between oestradiol and prolactin was found in patients and normals, but with larger prolactin levels in patients. The results point towards a prolactin secretory hypersensitivity for oestradiol in patients with cyclical mastalgia. Prolactin is considered a central factor in the eliciting of cyclical mastalgia.


Global study of women's experiences of premenstrual symptoms and their effects on daily life.

OBJECTIVES: To determine cross-cultural and other effects on women's experiences of premenstrual symptoms and their impact on activities of daily life (ADL). STUDY DESIGN: Cross-sectional survey. Sample A total of 7226 women aged 15-49 recruited by random sampling with approximately 400 each from France, Germany, Hungary, Italy, Spain, UK, Brazil, Mexico, Hong Kong, Pakistan and Thailand. Approximately 1000 women in Japan and Korea and 500 Australian women were found using Internet panels. MAIN OUTCOME MEASURES: Questionnaire of 23 premenstrual symptoms, sociodemographic and lifestyle variables, ADL and women's knowledge of premenstrual terms. RESULTS: The most prevalent symptoms were abdominal bloating, cramps or abdominal pain, irritability, mastalgia and joint/muscle/back pains. Severity of symptoms was directly proportional to duration (number of affected cycles) (R = 0.78). A linear model found that symptom prevalence (duration × severity) was associated with age (linear and quadratic effects), parity, current smoking and country. Premenstrual physical and mental symptom domains had similar negative effects on ADL. Impact on ADL was affected by education and exercise participation. Women's knowledge of the terms premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) varied by symptom intensity, age, education and country. CONCLUSIONS: Four of the five most prevalent premenstrual symptoms were physical. There was a great deal of similarities of women's experiences of these symptoms across countries and regions. Women's knowledge of PMS terms is highly dependent on the country in which they live.