query: liver disease

positive: Cross-analysis of dietary prescriptions and adherence in 356 hypercholesterolaemic patients. BACKGROUND: One of the major issues in controlling serum cholesterol through dietetic intervention appears to be the need to improve patient adherence. AIMS: To explore the many questions regarding barriers to, and motivators for, cholesterol-lowering diet adherence. METHODS: We surveyed French general practitioners' dietetic practices for patients with hypercholesterolaemia, and looked at their patients' attitudes towards such an approach. RESULTS: We analysed 234 doctors' personal questionnaires and 356 patient self-survey questionnaires. Patients' reasons for not complying with the prescribed diet included: 'already having satisfactory food habits' (34.7%), 'unwillingness to suffer nutritional deprivation' (33.3%), 'difficulties to conciliate a diet with family life' (27.8%) and 'taking cholesterol-lowering drugs' (22.2%). Despite a generally good understanding by patients of doctors' recommendations, some discrepancies were seen between their respective declarations. While doctors largely thought that patients needed more explanation on why and how a diet can lower cholesterol (and avoid taking drugs), only 39.4% of patients declared needing this kind of information. Other discrepancies were observed concerning barriers to, and motivators for, patient adherence. Moreover, some dietetic rules appeared to be more difficult to comply with than others, e.g. 82.6% patients remembered they should 'eat more fish' but only 51.3% actually did so. Finally, physicians, as well as patients, displayed a lack of confidence in lipid-lowering diet efficiency. CONCLUSION: Improving patient education, especially concerning their perception of risk, as well as increasing the involvement of dieticians, are motivators to explore in order to improve adherence. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

positive: Comparison of the cytotoxic and mutagenic potential of liquid smoke food flavourings, cigarette smoke condensate and wood smoke condensate. Although products of pyrolysis are often cytotoxic and mutagenic, the relationship between the type of material pyrolysed and the toxicity of the resulting pyrolysis products is poorly understood. The objective of this study was to evaluate and compare the cytotoxicity and mutagenicity of several types of common pyrolysis products. The cytotoxicity and mutagenicity of these products were assessed by using neutral red uptake and Ames mutagenicity assays, respectively. The biological activities of four liquid smoke food flavourings (LSF) were compared with two other pyrolysis-derived materials; cigarette smoke condensate (CSC) and a wood smoke condensate (WSC). Results indicated all of the mixtures exhibited a concentration-dependent cytotoxic response. The CSC and WSC were less cytotoxic than three of the LSFs, but more cytotoxic than one of the brands. The CSC was mutagenic in two Salmonella strains; however, none of the LSFs or WSC was mutagenic using TA98, and only three of the LSFs were positive with TA100. The six pyrolysis-derived materials evaluated in this study showed differing patterns and magnitudes of cytotoxicity and mutagenicity. These results indicate that the cytotoxicity and mutagenicity of complex mixtures derived from pyrolysis products are affected by the type of material pyrolysed and/or the method used to prepare the mixture. The cytotoxic potential of some commercial smoke flavourings is greater than cigarette smoke condensate and several of the food flavourings are mutagenic in one Salmonella strain.

positive: Mutagenicity testing in the Salmonella typhimurium assay of phenolic compounds and phenolic fractions obtained from smokehouse smoke condensates. Smokehouse smoke, which is used for flavouring meat products, was investigated for its mutagenic activity in the Salmonella typhimurium assay. We were chiefly concerned with the fractions free of polycyclic aromatic hydrocarbons but containing phenol compounds, which are responsible for the preservative and aromatizing properties of the smoke. The most abundantly occurring phenol compounds (phenol, cresols, 2,4-dimethylphenol, brenzcatechine, syringol, eugenol, vanilline and guaiacol) gave negative results when they were tested for mutagenicity at five concentrations up to 5000 micrograms/plate, with and without S-9 mix, using five strains of S. typhimurium. Even when phenol was further investigated in a variety of test conditions, no induction of his+ revertants was observed. When smokehouse smoke was condensed and fractionated the majority of the various phenolic fractions also gave negative results when tested at five concentrations using five strains of S. typhimurium. However there was a slight increase in the number of revertants in a few cases. The presence in the phenolic fractions of very small amounts of mutagenic impurities, the nature of which needs further investigation, cannot be excluded. These results support the further development of non-hazardous smoke-aroma preparations, based on the phenolic components of smokehouse smoke.

positive: Biological Clues to Potent DNA-Damaging Activities in Food and Flavoring Population differences in age-related diseases and cancer could stem from differences in diet. To characterize DNA strand-breaking activities in selected foods/beverages, flavorings, and some of their constituent chemicals, we used p53R cells, a cellular assay sensitive to such breaks. Substances testing positive included reference chemicals: quinacrine (peak response, 51X) and etoposide (33X); flavonoids: EGCG (19X), curcumin (12X), apigenin (9X), and quercetin (7X); beverages: chamomile (11X), green (21X), and black tea (26X) and coffee (3 to 29X); and liquid smoke (4 to 28X). Damage occurred at dietary concentrations: etoposide near 5 μg/ml produced responses similar to a 1:1000 dilution of liquid smoke, a 1:20 dilution of coffee, and a 1:5 dilution of tea. Pyrogallol-related chemicals and tannins are present in dietary sources and individually produced strong activity: pyrogallol (30X), 3-methoxycatechol (25X), gallic acid (21X), and 1,2,4-benzenetriol (21X). From structure-activity relationships, high activities depended on specific orientations of hydroxyls on the benzene ring. Responses accompanied cellular signals characteristic of DNA breaks such as H2AX phosphorylation. Breaks were also directly detected by comet assay. Cellular toxicological effects of foods and flavorings could guide epidemiologic and experimental studies of potential disease risks from DNA strand-breaking chemicals in diets.

positive: Polycyclic aromatic hydrocarbons in smoked food products and commercial liquid smoke flavourings. Smoked foods including turkey, pork, chicken, beef and fish products were screened for the presence of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons (PAHs). Eighteen commercial liquid smoke flavourings and seasonings were also analysed. Total PAH concentrations in smoked meat products ranged from 2.6 micrograms/kg in a cooked ham sample to 29.8 micrograms/kg in grilled pork chops, while those in fish products ranged from 9.3 micrograms/kg in smoked shrimp to 86.6 micrograms/kg in smoked salmon. Total concentrations of the carcinogenic PAHs (benzo[a]anthracene, benzo[b]fluoranthene, benzo[a]pyrene, dibenzo[a,h]anthracene, and indeno[1,2,3-c,d]pyrene) ranged from non-detectable in several meat products to 7.4 micrograms/kg in grilled pork chops, and from 0.2 micrograms/kg in trout to 16.0 micrograms/kg in salmon. In liquid smoke flavourings and seasonings, total PAH concentrations ranged from 6.3 to 43.7 micrograms/kg, with the carcinogenic PAHs ranging from 0.3 to 10.2 micrograms/kg.

positive: Commercial hickory-smoke flavouring is a human lymphoblast mutagen but does not induce lung adenomas in newborn mice. Commercial aqueous wood-smoke flavouring induced significant increases in the 6-thioguanine resistance mutation frequency of TK6 human lymphoblasts at 0.1 microliter flavouring/ml of cell suspension. This corresponds to 6 micrograms/ml of dissolved 'solids' as determined by fully drying the aqueous flavouring in a vacuum desiccator. In AHH-1 human lymphoblasts, which contain a cytochrome P-450 monooxygenase system, mutations were induced at 0.3 microliter/ml, corresponding to 18 microliters/ml of dissolved 'solids'. The flavouring did not induce 8-azaguanine resistant mutations in Salmonella typhimurium at concentrations up to 1.5 microliter/ml. At higher concentrations the flavouring was toxic to bacteria. The flavouring did not induce lung adenomas or other tumours in newborn mice when injected ip with total doses of up to 26 microliters over a 3-wk period. Toxicity to the kidney, colon and rectum was observed in some mice at 15 wk of age.

positive: Total and soluble oxalate content of some Indian spices. Spices, such as cinnamon, cloves, cardamom, garlic, ginger, cumin, coriander and turmeric are used all over the world as flavouring and colouring ingredients in Indian foods. Previous studies have shown that spices contain variable amounts of total oxalates but there are few reports of soluble oxalate contents. In this study, the total, soluble and insoluble oxalate contents of ten different spices commonly used in Indian cuisine were measured. Total oxalate content ranged from 194 (nutmeg) to 4,014 (green cardamom) mg/100 g DM, while the soluble oxalate contents ranged from 41 (nutmeg) to 3,977 (green cardamom) mg/100 g DM. Overall, the percentage of soluble oxalate content of the spices ranged from 4.7 to 99.1% of the total oxalate content which suggests that some spices present no risk to people liable to kidney stone formation, while other spices can supply significant amounts of soluble oxalates and therefore should be used in moderation.

positive: Curcumin as "Curecumin": from kitchen to clinic. Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

positive: The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. BACKGROUND: The extract of medicinal plants containing curcumin is traditionally believed to have a positive contraction effect on the human gall-bladder. AIMS: To compare the effect of 20 mg curcumin or placebo on the gall-bladder volume of healthy volunteers. METHODS: A randomized, double blind and crossover design study was carried out in 12 healthy volunteers (seven males and five females). Ultrasonography examination was carried out serially to measure the gall-bladder volume. The data obtained was analysed by paired Student's t-test. RESULTS: The fasting gall-bladder volumes of 15.74 +/- 4.29 mL on curcumin and 15.98 +/- 4.08 mL on placebo were similar (P > 0.20). The gall-bladder volume was reduced within the period after curcumin administration. The percentage of gall-bladder volume reduction at 0.5, 1.0, 1.5 and 2.0 h after 20 mg curcumin administration were 11.8 +/- 6.9, 16.8 +/- 7.4, 22.0 +/- 8.5 and 29. 3 +/- 8.3%, respectively, which was statistically significant compared to placebo. CONCLUSION: On the basis of the present findings, it appears that curcumin induces contraction of the human gall-bladder.

positive: Clinical utility of curcumin extract. Turmeric root has been used medicinally in China and India for thousands of years. The active components are thought to be the curcuminoids, primarily curcumin, which is commonly available worldwide as a standardized extract. This article reviews the pharmacology of curcuminoids, their use and efficacy, potential adverse effects, and dosage and standardization. Preclinical studies point to mechanisms of action that are predominantly anti-inflammatory and antineoplastic, while early human clinical trials suggest beneficial effects for dyspepsia, peptic ulcer, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, uveitis, orbital pseudotumor, and pancreatic cancer. Curcumin is well-tolerated; the most common side effects are nausea and diarrhea. Theoretical interactions exist due to purported effects on metabolic enzymes and transport proteins, but clinical reports do not support any meaningful interactions. Nonetheless, caution, especially with chemotherapy agents, is advised. Late-phase clinical trials are still needed to confirm most beneficial effects.

positive: The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. BACKGROUND: Gout, an inflammatory arthritis, reportedly afflicts more than 2 million men and women in the United States. Previous reports have suggested an association between gout and kidney stone disease; however, these studies did not adjust for such important potential confounders as obesity and the presence of hypertension. To our knowledge, no published study has examined the independent association between gout and kidney stone disease. METHODS: We used a national probability sample of the US population to determine the independent association between reported gout and history of kidney stone disease. RESULTS: Among men and women 20 years and older, 5.6% (10 million) reported the previous passage of a kidney stone and 2.7% (5.1 million) reported a diagnosis of gout by a physician. Moreover, 8.6% of individuals who reported the passage of a kidney stone on two or more occasions had a history of gout. Conversely, the prevalence of previous kidney stones in subjects with reported gout was 13.9%. In the age-adjusted model, gout was associated with an increased odds ratio (OR) for previous kidney stones (OR, 1.97; 95% confidence interval [CI], 1.37 to 2.83). After further adjustment for sex, race, body mass index, and presence of hypertension, the OR for previous kidney stones in individuals with gout decreased to 1.49 (95% CI, 1.04 to 2.14). CONCLUSION: Showing an independent association between kidney stone disease and gout strongly suggests that they share common underlying pathophysiological mechanisms. Identification of these mechanisms may lead to improved preventive strategies for both conditions. Copyright 2002 by the National Kidney Foundation, Inc.

positive: Plant-derived health: the effects of turmeric and curcuminoids. Plants contain numerous polyphenols, which have been shown to reduce inflammation and hereby to increase resistance to disease. Examples of such polyphenols are isothiocyanates in cabbage and broccoli, epigallocatechin in green tee, capsaicin in chili peppers, chalones, rutin and naringenin in apples, resveratrol in red wine and fresh peanuts and curcumin/curcuminoids in turmeric. Most diseases are maintained by a sustained discreet but obvious increased systemic inflammation. Many studies suggest that the effect of treatment can be improved by a combination of restriction in intake of proinflammatory molecules such as advanced glycation end products (AGE), advanced lipoperoxidation end products (ALE), and rich supply of antiinflammatory molecules such as plant polyphenols. To the polyphenols with a bulk of experimental documentation belong the curcuminoid family and especially its main ingredient, curcumin. This review summarizes the present knowledge about these turmericderived ingredients, which have proven to be strong antioxidants and inhibitors of cyclooxigenase-2 (COX-2), lipoxygenase (LOX) and nuclear factor kappa B (NF-kappaB) but also AGE. A plethora of clinical effects are reported in various experimental diseases, but clinical studies in humans are few. It is suggested that supply of polyphenols and particularly curcuminoids might be value as complement to pharmaceutical treatment, but also prebiotic treatment, in conditions proven to be rather therapy-resistant such as Crohn's, long-stayed patients in intensive care units, but also in conditions such as cancer, liver cirrhosis, chronic renal disease, chronic obstructive lung disease, diabetes and Alzheimer's disease.

positive: A pilot case-cohort study of liver and pancreatic cancers in poultry workers. PURPOSE: To test the hypothesis that exposure to poultry oncogenic viruses that widely occurs occupationally in poultry workers and in the general population, may be associated with increased risks of deaths from liver and pancreatic cancers, and to identify new risk factors. METHODS: A pilot case-cohort study of both cancers within a combined cohort of 30,411 highly exposed poultry workers and 16,408 control subjects was conducted, and risk assessed by logistic regression odds ratios (OR) and proportional hazards risk ratios. RESULTS: New occupational findings were recorded respectively for pancreatic/liver cancers, for slaughtering of poultry (OR = 8.9, 95% confidence interval [CI]: 2.7-29.3)/OR = 9.1, 95% CI: 1.9-42.9); catching of live chickens (OR = 3.6, 95% CI: 1.2-10.9)/OR = 1.0, 95% CI: 0.1-8.5); killing other types of animals for food (OR = 4.8, 95% CI: 1.5-16.6)/OR = 2.0, 95% CI: 0.2-18.2), and ever worked on a pig raising farm (OR = 3.0, 95% CI: 1.0-8.2) for pancreatic cancer only. New non-occupational findings for liver cancer were for receiving immunization with yellow fever vaccine (OR = 8.7, 95% CI: 1.0-76.3); and vaccination with typhoid vaccine (OR = 6.3, 95% CI: 1.1-37.4). The study also confirmed previously reported risk factors for both diseases. CONCLUSIONS: This study provides preliminary evidence that exposure to poultry oncogenic viruses may possibly be associated with the occurrence of liver and pancreatic cancers. Case-control studies nested within occupational cohorts of highly exposed subjects of sufficient statistical power may provide an efficient and valid method of investigating/confirming these findings. Copyright © 2011 Elsevier Inc. All rights reserved.

positive: Non-occupational malignant pleural mesothelioma due to asbestos and non-asbestos fibres. BACKGROUND AND AIM: The occurrence of malignant pleural mesothelioma (MPM) has been reported among population groups with no documented professional exposure to asbestos fibres living in different geographic areas. This paper reviews existing data related to non occupational MPM including its occurrence in the province of Catania (Sicily, Italy). METHODS: An electronic search of literature related to non occupational MPM was performed including the year 2005. RESULTS: Non occupational MPM in subjects living in areas contaminated by a variety of asbestos and non asbestos fibres has been well documented through a number of epidemiologic studies including cases series, case-control studies, and a cohort study. In addition, the observation of familial clustering of MPM, suggests that genetic factors may play a role in the pathogenesis of this malignancy. The epidemiological evidence also suggests that MPM may occur as a result of the interaction between environmental carcinogens, genetic factors, and virus infection. CONCLUSION: It is likely that genetic predisposition and non-occupational exposure to low doses of asbestos and asbestos-like fibres may concur to the development of malignant mesothelioma. However, additional epidemiological and laboratory studies are needed to further understand the relationship between environmental exposure and individual susceptibility to this malignancy.

positive: Third wave of asbestos-related disease from secondary use of asbestos. A case report from industry. An occupational health survey conducted in a workshop in which asbestos cement was used showed initial atmospheric asbestos levels ranging from 1.9 to 27.5 fibres per millilitre of air. Radiological changes suggestive of asbestos-related pleural disease were found in 2 workers (2.5%), while 3 (3.8%) had borderline features of asbestosis. The survey confirmed that uncontrolled and hazardous use of asbestos continues in industry despite public awareness of its dangers and the Asbestos Regulations of 1987.

positive: A new type of Hypersensitivity Pneumonitis: salami brusher's disease. We observed five consecutive cases of Hypersensitivity Pneumonitis in subjects working in a salami factory. The workers had to clean the white mould growing on salami surface using a manual wire brush. The five patients (four female) had a mean age of 39 +/- 15 years; two were smokers. Three patients had an acute clinical presentation with fever, dyspnoea, dry cough, oxygen desaturation, and presented at the emergency department with suspected diagnosis of community acquired pneumonia. The mean latency for developing respiratory symptoms was 11.6 days. Pulmonary function test demonstrated a reduction in diffusing capacity (DLCO) in all 5 patients (60 +/- 15% of predicted value). Skin prick test was positive for Penicillium spp in 3 cases and for Cladosporium and Aspergillus spp in 2 others. Specific IgG antibodies against Penicillium spp were positive in 3 subjects; 2 were positive for Aspergillus Fumigatus. The prevailing radiological pattern was a ground glass appearance in the three patients with acute clinical onset and a centrilobular one in patients with subacute onset. All patients were advised to avoid exposure to the antigens. Follow-up visits including pulmonary function testing, and DLCO measurement were conducted at one, three and six months. HRCT was performed at six month. Four subjects had a complete radiological and clinical resolution after changing work. Only one patient was treated with oral steroids for severe dyspnoea and progressive reduction of DLCO, gaining a complete radiological and clinical stability at six months.

positive: Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. BACKGROUND: Heavy alcohol consumption, viral hepatitis, and diabetes are risk factors for hepatocellular carcinoma (HCC). However, to the authors' knowledge, the information concerning their interaction effect in patients with risk of HCC is sparse. METHODS: A population-based, case-control study of HCC was conducted during 1984-2002. The study involved 295 HCC cases and 435 age-, gender-, and race-matched control subjects among Hispanic and non-Hispanic whites and blacks in Los Angeles County, California. Lifestyle risk factors were ascertained through in-person interviews. Infections with the hepatitis B and C (HCV) viruses were determined using their serologic markers. RESULTS: Fourteen HCC cases but no control subjects tested positive for the hepatitis B surface antigen. Seropositivity for antibodies to HCV was associated with an odds ratio (OR) of 125 (95% confidence interval [95% CI], 17-909) for HCC, whereas seropositivity for antibodies to the hepatitis B core antigen was related to an OR of 2.9 (95% CI, 1.7-5.0). Heavy alcohol consumption and cigarette smoking were found to be independently associated with a statistically significant two to threefold increase in risk of HCC after adjustment for hepatitis B and C serology. Subjects with a history of diabetes had an OR of 2.7 (95% CI, 1.6-4.3) for HCC compared with nondiabetic subjects. A synergistic interaction on HCC risk was observed between heavy alcohol consumption and diabetes (OR = 4.2; 95% CI, 2.6-5.8), heavy alcohol consumption and viral hepatitis (OR = 5.5; 95% CI, 3.9-7.0), or between diabetes and viral hepatitis (OR = 4.8; 95% CI, 2.7-6.9). CONCLUSIONS: Heavy alcohol consumption, diabetes, and viral hepatitis were found to exert independent and synergistic effects on risk of HCC in U.S. blacks and whites. Copyright 2004 American Cancer Society.

positive: Cigarette Smoking and Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Cohort Consortium Smoking is an established risk factor for pancreatic cancer; however, detailed examination of the association of smoking intensity, smoking duration, and cumulative smoking dose with pancreatic cancer is limited. The authors analyzed pooled data from the international Pancreatic Cancer Cohort Consortium nested case-control study (1,481 cases, 1,539 controls). Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Smoking intensity effects were examined with an excess odds ratio model that was linear in pack-years and exponential in cigarettes smoked per day and its square. When compared with never smokers, current smokers had a significantly elevated risk (odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.38, 2.26). Risk increased significantly with greater intensity (≥30 cigarettes/day: OR = 1.75, 95% CI: 1.27, 2.42), duration (≥50 years: OR = 2.13, 95% CI: 1.25, 3.62), and cumulative smoking dose (≥40 pack-years: OR = 1.78, 95% CI: 1.35, 2.34). Risk more than 15 years after smoking cessation was similar to that for never smokers. Estimates of excess odds ratio per pack-year declined with increasing intensity, suggesting greater risk for total exposure delivered at lower intensity for longer duration than for higher intensity for shorter duration. This finding and the decline in risk after smoking cessation suggest that smoking has a late-stage effect on pancreatic carcinogenesis.

positive: Occupational toxicology of asbestos-related malignancies. INTRODUCTION: Asbestos is banned in most Western countries but related malignancies are still of clinical concern because of their long latencies. This review identifies and addresses some controversial occupational and clinical aspects of asbestos-related malignancies. METHODS: Papers published in English from 1980 to 2009 were retrieved from PubMed. A total of 307 original articles were identified and 159 were included. ASSESSMENT OF EXPOSURE: The retrospective assessment of exposure is usually performed by using questionnaires and job exposure matrices and by careful collection of medical history. In this way crucial information about manufacturing processes and specific jobs can be obtained. In addition, fibers and asbestos bodies are counted in lung tissue, broncho-alveolar lavage, and sputum, but different techniques and interlaboratory variability hamper the interpretation of reported measurements. SCREENING FOR MALIGNANCIES: The effectiveness of low-dose chest CT screening in exposed workers is debatable. Several biomarkers have also been considered to screen individuals at risk for lung cancer and mesothelioma but reliable signatures are still missing. ATTRIBUTION OF LUNG CANCER: Exposures correlating with lung cancer are high and in the same range where asbestosis occurs. However, the unresolved question is whether the presence of fibrosis is a requirement for the attribution of lung cancer to asbestos. The etiology of lung cancer is difficult to define in cases of low-level asbestos exposure and concurrent smoking habits. MESOTHELIOMA: The diagnosis of malignant mesothelioma may also be difficult, because of procedures in sampling, fixation, and processing, and uses of immunohistochemical probes. CONCLUSIONS: Assessment of exposure is crucial and requires accurate medical and occupational histories. Quantitative analysis of asbestos body burden is better performed in digested lung tissues by counting asbestos bodies by light microscopy and/or uncoated fibers by transmission electron microscopy. The benefits of screenings for asbestos-related malignancies are equivocal. The attribution of lung cancer to asbestos exposure is difficult in a clinical setting because of the need to assess asbestos body burden and the fact that virtually all these patients are also tobacco smokers or former smokers. Given the premise that asbestosis is necessary to causally link lung cancer to asbestos, it follows that the assessment of both lung fibrosis and asbestos body burden is necessary.

positive: United States pharmacopeia safety evaluation of spirulina. The Dietary Supplements Information Expert Committee (DSI-EC) of the United States Pharmacopeial Convention (USP) reviews the safety of dietary supplements and dietary supplement ingredients for the purpose of determining whether they should be admitted as quality monographs into the United States Pharmacopeia and National Formulary (USP-NF). The United States Food and Drug Administration (FDA) has enforcement authority to pursue a misbranding action in those instances where a dietary supplement product indicates that it conforms to USP standards but fails to so conform. Recently DSI-EC undertook a safety evaluation of spirulina, a widely used dietary ingredient. DSI-EC reviewed information from human clinical trials, animal studies, and regulatory and pharmacopeial sources and analyzed 31 adverse event reports regarding spirulina to assess potential health concerns. At the conclusion of this review, DSI-EC assigned a Class A safety rating for Spirulina maxima and S. platensis, thereby permitting the admission of quality monographs for these dietary supplement ingredients in USP-NF. DSI-EC continually monitors reports concerning the safety of dietary supplements and dietary supplement ingredients for which USP dietary supplement monographs are developed. The DSI-EC may revisit the safety classification of spirulina as new information on this dietary ingredient becomes available.

positive: Effects of a natural extract of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extrac... AIM: The efficacy of optimal doses of highly bioavailable (-)-hydroxycitric acid (HCA-SX) alone and in combination with niacin-bound chromium (NBC) and a standardized Gymnema sylvestre extract (GSE) on weight loss in moderately obese subjects was evaluated by monitoring changes in body weight, body mass index (BMI), appetite, lipid profiles, serum leptin and excretion of urinary fat metabolites. HCA-SX has been shown to reduce appetite, inhibit fat synthesis and decrease body weight without stimulating the central nervous system. NBC has demonstrated its ability to maintain healthy insulin levels, while GSE has been shown to regulate weight loss and blood sugar levels. METHODS: A randomized, double-blind, placebo-controlled human study was conducted in Elluru, India for 8 weeks in 60 moderately obese subjects (ages 21-50, BMI >26 kg/m(2)). Subjects were randomly divided into three groups. Group A was administered HCA-SX 4667 mg, group B was administered a combination of HCA-SX 4667 mg, NBC 4 mg and GSE 400 mg, while group C was given placebo daily in three equally divided doses 30-60 min before meals. All subjects received a 2000 kcal diet/day and participated in supervised walking. RESULTS: At the end of 8 weeks, body weight and BMI decreased by 5-6% in both groups A and B. Food intake, total cholesterol, low-density lipoproteins, triglycerides and serum leptin levels were significantly reduced in both groups, while high-density lipoprotein levels and excretion of urinary fat metabolites increased in both groups. A marginal or non-significant effect was observed in all parameters in group C. CONCLUSION: The present study shows that optimal doses of HCA-SX and, to a greater degree, the combination of HCA-SX, NBC and GSE can serve as an effective and safe weight-loss formula that can facilitate a reduction in excess body weight and BMI, while promoting healthy blood lipid levels.

positive: Science of weight loss supplements: Compromised by conflicts of interest? Weight loss supplements often contain powerful pharmacoactive ingredients with the potential to cause harm. Trials used to determine product safety and effectiveness, meanwhile, tend to be small, of short duration, and frequently lack financial conflict of interest disclosures. These factors could conspire to place consumers at risk, especially when published research cited in advertising cloaks products with the suggestion that their safety and effectiveness have been proven by science. Examples of current and former weight loss products backed by potentially conflicted or low quality research include Metabolife-356, Hydroxycut, Xenadrine and LeptiCore. Published research, especially in the field of weight loss supplements, needs better conflict of interest disclosure, and regulators should consider how research findings are used in marketing claims.

positive: Acute hepatotoxicity after ingestion of Morinda citrifolia (Noni Berry) juice in a 14-year-old boy. We present a case of a 14-year-old previously healthy boy with acute hepatotoxicity after noni berry juice consumption. As the popularity of noni berry consumption continues to increase, heightened awareness of the relation between noni berry consumption and acute hepatotoxicity is important.

positive: Aloe-induced Toxic Hepatitis Aloe has been widely used in phytomedicine. Phytomedicine describes aloe as a herb which has anti-inflammatory, anti-proliferative, anti-aging effects. In recent years several cases of aloe-induced hepatotoxicity were reported. But its pharmacokinetics and toxicity are poorly described in the literature. Here we report three cases with aloe-induced toxic hepatitis. A 57-yr-old woman, a 62-yr-old woman and a 55-yr-old woman were admitted to the hospital for acute hepatitis. They had taken aloe preparation for months. Their clinical manifestation, laboratory findings and histologic findings met diagnostic criteria (RUCAM scale) of toxic hepatitis. Upon discontinuation of the oral aloe preparations, liver enzymes returned to normal level. Aloe should be considered as a causative agent in hepatotoxicity.

positive: An herbal supplement containing Ma Huang-Guarana for weight loss: a randomized, double-blind trial. OBJECTIVE: To examine in overweight humans the short-term safety and efficacy for weight loss of an herbal supplement containing Ma Huang, Guarana and other ingredients. DESIGN: An 8 week randomized, double-blind placebo controlled study of a herbal dietary supplement (72 mg/day ephedrine alkaloids and 240 mg/day caffeine). SUBJECTS: Overweight men and women (body mass index, > or =29 and < or =35 kg/m2). MEASUREMENTS: The primary outcome variable was body weight change. Secondary variables included anthropometric, metabolic and cardiovascular changes. RESULTS: Sixty-seven subjects were randomized to either placebo (n=32) or active Ma Huang/Guarana (n=35). Twenty-four subjects in each group completed the study. Active treatment produced significantly (P<0.006) greater loss of weight (X+/-s.d.,-4.0+/-3.4 kg) and fat (-2.1+/-3.0% fat) over the 8-week treatment period than did placebo (-0.8+/-2.4 kg and 0.2+/-2.3% fat). Active treatment also produced greater reductions in hip circumference and serum triglyceride levels. Eight of the 35 actively treated subjects (23%) and none of the 32 placebo-treated control subjects withdrew from the protocol because of potential treatment-related effects. Dry mouth, insomnia and headache were the adverse symptoms reported most frequently by the herbal vs placebo group at the final evaluation visit. CONCLUSIONS: This herbal mixture of Ma Huang and Guarana effectively promoted short-term weight and fat loss. Safety with long-term use requires further investigation.

positive: Science in Liquid Dietary Supplement Promotion: The Misleading Case of Mangosteen Juice Liquid dietary supplements represent a fast growing market segment, including botanically-based beverages containing mangosteen, acai, and noni. These products often resemble fruit juice in packaging and appearance, but may contain pharmacologically active ingredients. While little is known about the human health effects or safety of consuming such products, manufacturers make extensive use of low-quality published research to promote their products. This report analyzes the science-based marketing claims of two of the most widely consumed mangosteen liquid dietary supplements, and compares them to the findings of the research being cited. The reviewer found that analyzed marketing claims overstate the significance of findings, and fail to disclose severe methodological weaknesses of the research they cite. If this trend extends to other related products that are similarly widely consumed, it may pose a public health threat by misleading consumers into assuming that product safety and effectiveness are backed by rigorous scientific data.

positive: Hepatotoxicity Due To Hydroxycut®: A Case Series Background Muscletech Hydroxycut® (Iovate Health Sciences Research, Oakville, Ontario) was a popular weight loss supplement that was recalled by the manufacturer in May 2009 based on reports of hepatotoxicity associated with this supplement. Objective To characterize the clinical presentation of Hydroxycut®-associated liver injury and to adjudicate these cases for causal association with Hydroxycut®. Design Case series. Setting Academic tertiary care hospitals and FDA databases. Measurements Assessment of causality and grading of severity of liver injury using methodology developed by the Drug-Induced Liver Injury Network (DILIN) study. Results Eight patients who developed liver injury after taking Hydroxycut treated at different medical centers were identified. All were hospitalized and 3 of 8 patients required liver transplantation. Nine other cases with adequate clinical information were obtained from the FDA MedWatch database including one fatal case of acute liver failure. Usual symptoms were jaundice, fatigue, nausea, vomiting and abdominal pain. Most patients exhibited a hepatocellular pattern of injury. Adjudication for causality revealed 8 cases as definite, 5 highly likely, 2 probable and 2 were considered as possible. Conclusions Hydroxycut® has been clearly implicated as a cause for severe liver injury that may lead to acute liver failure and death. Weight loss supplements represent a class of dietary supplements that should be regarded as capable of causing severe hepatic toxicity when the usual causes of identified liver injury cannot be otherwise elucidated.

positive: Cinnamon intake lowers fasting blood glucose: meta-analysis. Cinnamon, the dry bark and twig of Cinnamomum spp., is a rich botanical source of polyphenolics that has been used for centuries in Chinese medicine and has been shown to affect blood glucose and insulin signaling. Cinnamon's effects on blood glucose have been the subject of many clinical and animal studies; however, the issue of cinnamon intake's effect on fasting blood glucose (FBG) in people with type 2 diabetes and/or prediabetes still remains unclear. A meta-analysis of clinical studies of the effect of cinnamon intake on people with type 2 diabetes and/or prediabetes that included three new clinical trials along with five trials used in previous meta-analyses was done to assess cinnamon's effectiveness in lowering FBG. The eight clinical studies were identified using a literature search (Pub Med and Biosis through May 2010) of randomized, placebo-controlled trials reporting data on cinnamon and/or cinnamon extract and FBG. Comprehensive Meta-Analysis (Biostat Inc., Englewood, NJ, USA) was performed on the identified data for both cinnamon and cinnamon extract intake using a random-effects model that determined the standardized mean difference ([i.e., Change 1(control) - Change 2(cinnamon)] divided by the pooled SD of the post scores). Cinnamon intake, either as whole cinnamon or as cinnamon extract, results in a statistically significant lowering in FBG (-0.49±0.2 mmol/L; n=8, P=.025) and intake of cinnamon extract only also lowered FBG (-0.48 mmol/L±0.17; n=5, P=.008). Thus cinnamon extract and/or cinnamon improves FBG in people with type 2 diabetes or prediabetes.

positive: The impact of cereal grain consumption on the development and severity of non-alcoholic fatty liver disease. PURPOSE: There is evidence that dietary habits contribute to the presence and severity of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to explore any associations between consumption of grains and the development and severity of NAFLD. METHODS: Seventy-three consecutive NAFLD patients were enrolled. Additionally, 58 controls matched for age, sex and body mass index with 58 patients were also included. Consumption of grains was estimated through a semi-quantitative food frequency questionnaire. Medical history, anthropometric indices, body composition analysis, physical activity data, biochemical and inflammatory markers were available for all the participants. Liver stiffness measurement by transient elastography was performed in 58 and liver biopsy in 34 patients. RESULTS: In patients, consumption of whole grains was associated with lower abdominal fat level (β = -0.24, p = 0.02) and lower levels of insulin resistance index (β = -0.28, p = 0.009), while it also correlated inversely with interleukin-6 levels (ρ = -0.23, p = 0.05). Consumption of whole grains was associated with lower likelihood of having histological steatohepatitis (OR 0.97, 95% CI 0.94-1.000), after adjusting for sex and energy intake, but the association became weaker after further adjusting for abdominal fat or interleukin-6 levels. In the case-control analysis, consumption of refined grains was associated with higher odds of having NAFLD (OR 1.021, 95% CI 1.001-1.042), after adjusting for age, sex, energy intake, abdominal fat level, HOMA-IR, LDL, adiponectin and TNF-α. CONCLUSIONS: Although refined grain consumption increased the likelihood of having NAFLD, whole-grain consumption favorably affected clinical characteristics of patients with NAFLD and tended to be associated with less severe disease.

positive: Increasing Whole Grain Intake as Part of Prevention and Treatment of Nonalcoholic Fatty Liver Disease In conjunction with the rise in rates of obesity, there has been an increase in the rate of nonalcoholic fatty liver disease (NAFLD). While NAFLD at least partially originates from poor diet, there is a lack of nutritional recommendations for patients with suspected or confirmed diagnosis of NAFLD, beyond eating a healthy diet, increasing physical activity, and emphasising weight loss. The limited current literature suggests that there may be opportunities to provide more tailored dietary advice for people diagnosed with or at risk of NAFLD. Epidemiological studies consistently find associations between whole grain intake and a reduced risk of obesity and related diseases, yet no work has been done on the potential of whole grains to prevent and/or be a part of the treatment for fatty liver diseases. In this review, we examine the potential and the current evidence for whole grains having an impact on NAFLD. Due to their nutrient and phytochemical composition, switching from consuming mainly refined grains to whole grains should be considered as part of the nutritional guidelines for patients diagnosed with or at risk for fatty liver disease.

positive: Avena sativa (Oat), a potential neutraceutical and therapeutic agent: an overview. The aim of the present review article is to summarize the available information related to the availability, production, chemical composition, pharmacological activity, and traditional uses of Avena sativa to highlight its potential to contribute to human health. Oats are now cultivated worldwide and form an important dietary staple for the people in number of countries. Several varieties of oats are available. It is a rich source of protein, contains a number of important minerals, lipids, β-glucan, a mixed-linkage polysaccharide, which forms an important part of oat dietary fiber, and also contains various other phytoconstituents like avenanthramides, an indole alkaloid-gramine, flavonoids, flavonolignans, triterpenoid saponins, sterols, and tocols. Traditionally oats have been in use since long and are considered as stimulant, antispasmodic, antitumor, diuretic, and neurotonic. Oat possesses different pharmacological activities like antioxidant, anti-inflammatory, wound healing, immunomodulatory, antidiabetic, anticholesterolaemic, etc. A wide spectrum of biological activities indicates that oat is a potential therapeutic agent.

positive: Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ∼5% is believed to improve steatosis, whereas ∼10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.

positive: Whole grain intake in relation to body weight: from epidemiological evidence to clinical trials. This viewpoint aims to 1) review the available scientific literature on the relationship between whole grain consumption and body weight regulation; 2) evaluate the potential mechanisms whereby whole grain intake may help reduce overweight and 3) try to understand why epidemiological studies and clinical trials provide diverging results on this topic. All the prospective epidemiological studies demonstrate that a higher intake of whole grains is associated with lower BMI and body weight gain. However, these results do not clarify whether whole grain consumption is simply a marker of a healthier lifestyle or a factor favoring "per se" lower body weight. Habitual whole grain consumption seems to cause lower body weight by multiple mechanisms such as lower energy density of whole grain based products, lower glycemic index, fermentation of non digestible carbohydrates (satiety signals) and finally by modulating intestinal microflora. In contrast with epidemiological evidence, the results of few clinical trials do not confirm that a whole grain low-calorie diet is more effective in reducing body weight than a refined cereal diet, but their results may have been affected by small sample size or short duration of the intervention. Therefore, further intervention studies with adequate methodology are needed to clarify this question. For the time being, whole grain consumption can be recommended as one of the features of the diet that may help control body weight but also because is associated with a lower risk to develop type 2 diabetes, cardiovascular diseases and cancer. Copyright © 2011 Elsevier B.V. All rights reserved.

positive: Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine-kina... Current treatment modalities for epidermal growth factor (EGFR)-positive cancers have recently included the use of antibodies and small-molecule tyrosine-kinase inhibitors (TKI). A significant limiting step in the use of these agents is dermatological toxicity, frequently in the form of an acneiform eruption. Present management modalities for this toxicity are largely ineffective. Colloidal oatmeal lotion demonstrates multiple anti-inflammatory properties with known effects on arachidonic acid, cytosolic phospholipase A2 and tumour necrosis factor-alpha pathways, along with an excellent side-effect profile. Treatment with colloidal oatmeal was applied to 11 patients with a rash induced by cetuximab, erlotinib, panitumumab and sorafenib. Of the 10 assessable patients, 6 had complete response and 4 partial response, giving a response rate of 100% with no associated toxicities. Treatment with colloidal oatmeal lotion is efficient in controlling the rash associated with EGFR and multiple TKI, and allows continuation of the antineoplastic treatment.

positive: Bedside ultrasound in the diagnosis of nonalcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States. While the American Association for the Study of Liver Diseases guidelines define NAFLD as hepatic steatosis detected either on histology or imaging without a secondary cause of abnormal hepatic fat accumulation, no imaging modality is recommended as standard of care for screening or diagnosis. Bedside ultrasound has been evaluated as a non-invasive method of diagnosing NAFLD with the presence of characteristic sonographic findings. Prior studies suggest characteristic sonographic findings for NAFLD include bright hepatic echoes, increased hepatorenal echogenicity, vascular blurring of portal or hepatic vein and subcutaneous tissue thickness. These sonographic characteristics have not been shown to aid bedside clinicians easily identify potential cases of NAFLD. While sonographic findings such as attenuation of image, diffuse echogenicity, uniform heterogeneous liver, thick subcutaneous depth, and enlarged liver filling of the entire field could be identified by clinicians from bedside ultrasound. The accessibility, ease of use, and low-side effect profile of ultrasound make bedside ultrasound an appealing imaging modality in the detection of hepatic steatosis. When used with appropriate clinical risk factors and steatosis involves greater than 33% of the liver, ultrasound can reliably diagnose NAFLD. Despite the ability of ultrasound in detecting moderate hepatic steatosis, it cannot replace liver biopsy in staging the degree of fibrosis. The purpose of this review is to examine the diagnostic accuracy, utility, and limitations of ultrasound in the diagnosis of NAFLD and its potential use by clinicians in routine practices.

positive: The Role of Whole Grains in Body Weight Regulation Whole grain (WG)-rich diets are purported to have a variety of health benefits, including a favorable role in body weight regulation. Current dietary recommendations advocate substituting WG for refined grains (RG), because many of the beneficial bioactive components intrinsic to WG are lost during the refining process. Epidemiological studies consistently demonstrate that higher intakes of WG, but not RG, are associated with lower BMI and/or reduced risk of obesity. However, recent clinical trials have failed to support a role for WG in promoting weight loss or maintenance. Though the biochemical and structural characteristics of WG have been shown to modulate appetite, nutrient availability, and energy utilization, the capacity of WG foods to elicit these effects varies with the type and amount of grain consumed as well as the nature of its consumption. As such, WG foods differentially affect physiologic factors influencing body weight with the common practice of processing and reconstituting WG ingredients during food production likely mitigating the capacity for WG to benefit body weight regulation.

positive: Oat prevents obesity and abdominal fat distribution, and improves liver function in humans. Obesity is associated with a great diversity of diseases including non-alcoholic fatty liver disease. Our recent report suggested that oat, rich in beta-glucan, had a metabolic-regulating and liver-protecting effect in an animal model. In this study, we performed a clinical trial to further confirm the effect of oat. Subjects with BMI ≥27 and aged 18-65, were randomly divided into a control (n=18) and an oat-treated (n=16) group, taking a placebo or beta glucan-containing oat cereal, respectively, for 12 weeks. Our data showed that consumption of oat reduced body weight, BMI, body fat and the waist-to-hip ratio. Profiles of hepatic function, including AST, but especially ALT, were useful resources to help in the evaluation of the liver, since both showed decrements in patients with oat consumption. Nevertheless, anatomic changes were still not observed by ultrasonic image analysis. Ingestion of oat was well tolerated and there was no adverse effect during the trial. In conclusion, consumption of oat reduced obesity, abdominal fat, and improved lipid profiles and liver functions. Taken as a daily supplement, oat could act as an adjuvant therapy for metabolic disorders.

positive: Greater whole-grain intake is associated with lower risk of type 2 diabetes, cardiovascular disease, and weight gain. Whole-grain and high fiber intakes are routinely recommended for prevention of vascular diseases; however, there are no comprehensive and quantitative assessments of available data in humans. The aim of this study was to systematically examine longitudinal studies investigating whole-grain and fiber intake in relation to risk of type 2 diabetes (T2D), cardiovascular disease (CVD), weight gain, and metabolic risk factors. We identified 45 prospective cohort studies and 21 randomized-controlled trials (RCT) between 1966 and February 2012 by searching the Cumulative Index to Nursing and Allied Health Literature, Cochrane, Elsevier Medical Database, and PubMed. Study characteristics, whole-grain and dietary fiber intakes, and risk estimates were extracted using a standardized protocol. Using random effects models, we found that compared with never/rare consumers of whole grains, those consuming 48-80 g whole grain/d (3-5 serving/d) had an ~26% lower risk of T2D [RR = 0.74 (95% CI: 0.69, 0.80)], ~21% lower risk of CVD [RR = 0.79 (95% CI: 0.74, 0.85)], and consistently less weight gain during 8-13 y (1.27 vs 1.64 kg; P = 0.001). Among RCT, weighted mean differences in post-intervention circulating concentrations of fasting glucose and total and LDL-cholesterol comparing whole-grain intervention groups with controls indicated significantly lower concentrations after whole-grain interventions [differences in fasting glucose: -0.93 mmol/L (95% CI: -1.65, -0.21), total cholesterol: -0.83 mmol/L (-1.23, -0.42); and LDL-cholesterol: -0.82 mmol/L (-1.31, -0.33)]. [corrected] Findings from this meta-analysis provide evidence to support beneficial effects of whole-grain intake on vascular disease prevention. Potential mechanisms responsible for whole grains' effects on metabolic intermediates require further investigation in large intervention trials.

positive: The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome param... One of the proposed causes of obesity and metabolic syndrome is the excessive intake of products containing added sugars, in particular, fructose. Although the ability of excessive intake of fructose to induce metabolic syndrome is mounting, to date, no study has addressed whether a diet specifically lowering fructose but not total carbohydrates can reduce features of metabolic syndrome. A total of 131 patients were randomized to compare the short-term effects of 2 energy-restricted diets-a low-fructose diet vs a moderate natural fructose diet-on weight loss and metabolic syndrome parameters. Patients were randomized to receive 1500, 1800, or 2000 cal diets according to sex, age, and height. Because natural fructose might be differently absorbed compared with fructose from added sugars, we randomized obese subjects to either a low-fructose diet (<20 g/d) or a moderate-fructose diet with natural fruit supplements (50-70 g/d) and compared the effects of both diets on the primary outcome of weight loss in a 6-week follow-up period. Blood pressure, lipid profile, serum glucose, insulin resistance, uric acid, soluble intercellular adhesion molecule-1, and quality of life scores were included as secondary outcomes. One hundred two (78%) of the 131 participants were women, mean age was 38.8 ± 8.8 years, and the mean body mass index was 32.4 ± 4.5 kg/m(2). Each intervention diet was associated with significant weight loss compared with baseline. Weight loss was higher in the moderate natural fructose group (4.19 ± 0.30 kg) than the low-fructose group (2.83 ± 0.29 kg) (P = .0016). Compared with baseline, each intervention diet was associated with significant improvement in secondary outcomes. Reduction of energy and added fructose intake may represent an important therapeutic target to reduce the frequency of obesity and diabetes. For weight loss achievement, an energy-restricted moderate natural fructose diet was superior to a low-fructose diet. Copyright © 2011 Elsevier Inc. All rights reserved.

positive: Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells. The effect of polyphenols, phenolic acids and tannins (PPTs) from strawberry and apple on uptake and apical to basolateral transport of glucose was investigated using Caco-2 intestinal cell monolayers. Substantial inhibition on both uptake and transport was observed by extracts from both strawberry and apple. Using sodium-containing (glucose transporters SGLT1 and GLUT2 both active) and sodium-free (only GLUT2 active) conditions, we show that the inhibition of GLUT2 was greater than that of SGLT1. The extracts were analyzed and some of the constituent PPTs were also tested. Quercetin-3-O-rhamnoside (IC₅₀ =31 μM), phloridzin (IC₅₀=146 μM), and 5-caffeoylquinic acid (IC₅₀=2570 μM) contributed 26, 52 and 12%, respectively, to the inhibitory activity of the apple extract, whereas pelargonidin-3-O-glucoside (IC₅₀=802 μM) contributed 26% to the total inhibition by the strawberry extract. For the strawberry extract, the inhibition of transport was non-competitive based on kinetic analysis, whereas the inhibition of cellular uptake was a mixed-type inhibition, with changes in both V(max) and apparent K(m) . The results in this assay show that some PPTs inhibit glucose transport from the intestinal lumen into cells and also the GLUT2-facilitated exit on the basolateral side. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

positive: Postprandial glucose, insulin, and free fatty acid responses to sucrose consumed with blackcurrants and lingonberries in healthy women. BACKGROUND: Sucrose induces high postprandial glucose and insulin responses. In vitro studies suggest that berries may reduce the digestion and absorption of sucrose and thereby suppress postprandial glycemia, but the evidence in humans is limited. OBJECTIVE: We investigated the effects of sucrose ingested with blackcurrants (Ribes nigrum) and lingonberries (Vaccinium vitis-idaea) on postprandial glucose, insulin, and free fatty acid responses. DESIGN: Twenty healthy women participated in a randomized, controlled, crossover meal study. They consumed whole blackcurrants or lingonberries (150 g served as purées) or blackcurrant or lingonberry nectars (300 mL), each with 35 g added sucrose. Sucrose alone (35 g in 300 mL water) was used as a reference. Blood samples were collected at 0, 15, 30, 45, 60, 90, and 120 min. RESULTS: In comparison with sucrose alone, ingestion of sucrose with whole berries resulted in reduced glucose and insulin concentrations during the first 30 min and a slower decline during the second hour and a significantly improved glycemic profile. Berries prevented the sucrose-induced late postprandial hypoglycemic response and the compensatory free fatty acid rebound. Nearly similar effects were observed when sucrose was consumed with berry nectars. The improved responses were evident despite the higher content of available carbohydrate in the berry and nectar meals, because of the natural sugars present in berries. CONCLUSIONS: Blackcurrants and lingonberries, as either whole berries or nectars, optimize the postprandial metabolic responses to sucrose. The responses are consistent with delayed digestion of sucrose and consequent slower absorption of glucose.

positive: Sugar, Uric Acid, and the Etiology of Diabetes and Obesity The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.

positive: Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells. The effect of different classes of dietary polyphenols on intestinal glucose uptake was investigated using polarised Caco-2 intestinal cells. Glucose uptake into cells under sodium-dependent conditions was inhibited by flavonoid glycosides and non-glycosylated polyphenols whereas aglycones and phenolic acids were without effect. Under sodium-free conditions, aglycones and non-glycosylated polyphenols inhibited glucose uptake whereas glycosides and phenolic acids were ineffective. These data suggest that aglycones inhibit facilitated glucose uptake whereas glycosides inhibit the active transport of glucose. The non-glycosylated dietary polyphenols appear to exert their effects via steric hindrance, and (-)-epigallochatechingallate, (-)-epichatechingallate and (-)-epigallochatechin are effective against both transporters.

positive: Fructose: It’s “Alcohol Without the Buzz” What do the Atkins Diet and the traditional Japanese diet have in common? The Atkins Diet is low in carbohydrate and usually high in fat; the Japanese diet is high in carbohydrate and usually low in fat. Yet both work to promote weight loss. One commonality of both diets is that they both eliminate the monosaccharide fructose. Sucrose (table sugar) and its synthetic sister high fructose corn syrup consist of 2 molecules, glucose and fructose. Glucose is the molecule that when polymerized forms starch, which has a high glycemic index, generates an insulin response, and is not particularly sweet. Fructose is found in fruit, does not generate an insulin response, and is very sweet. Fructose consumption has increased worldwide, paralleling the obesity and chronic metabolic disease pandemic. Sugar (i.e., fructose-containing mixtures) has been vilified by nutritionists for ages as a source of “empty calories,” no different from any other empty calorie. However, fructose is unlike glucose. In the hypercaloric glycogen-replete state, intermediary metabolites from fructose metabolism overwhelm hepatic mitochondrial capacity, which promotes de novo lipogenesis and leads to hepatic insulin resistance, which drives chronic metabolic disease. Fructose also promotes reactive oxygen species formation, which leads to cellular dysfunction and aging, and promotes changes in the brain’s reward system, which drives excessive consumption. Thus, fructose can exert detrimental health effects beyond its calories and in ways that mimic those of ethanol, its metabolic cousin. Indeed, the only distinction is that because fructose is not metabolized in the central nervous system, it does not exert the acute neuronal depression experienced by those imbibing ethanol. These metabolic and hedonic analogies argue that fructose should be thought of as “alcohol without the buzz.”

positive: Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients. BACKGROUND & AIMS: Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology. METHODS: Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate-severe if ≥ 20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification). RESULTS: Mean daily intake of total, industrial and fruit fructose was 18.0±8.7g, 6.0±4.7g, and 11.9±7.2g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p=0.02) and hypercaloric diet (p<0.001). CHC patients with severe liver fibrosis (⩾F3) reported a significantly higher intake of total (20.8±10.2 vs. 17.2±8.1g/day; p=0.04) and industrial fructose (7.8±6.0 vs. 5.5±4.2; p=0.01), not fruit fructose (12.9±8.0 vs. 11.6±7.0; p=0.34). Multivariate logistic regression analysis showed that older age (OR 1.048, 95% CI 1.004-1.094, p=0.03), severe necroinflammatory activity (OR 3.325, 95% CI 1.347-8.209, p=0.009), moderate-severe steatosis (OR 2.421, 95% CI 1.017-6.415, p=0.04), and industrial fructose intake (OR 1.147, 95% CI 1.047-1.257, p=0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH. CONCLUSIONS: The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

positive: Berries reduce postprandial insulin responses to wheat and rye breads in healthy women. Starch in white wheat bread (WB) induces high postprandial glucose and insulin responses. For rye bread (RB), the glucose response is similar, whereas the insulin response is lower. In vitro studies suggest that polyphenol-rich berries may reduce digestion and absorption of starch and thereby suppress postprandial glycemia, but the evidence in humans is limited. We investigated the effects of berries consumed with WB or RB on postprandial glucose and insulin responses. Healthy females (n = 13-20) participated in 3 randomized, controlled, crossover, 2-h meal studies. They consumed WB or RB, both equal to 50 g available starch, with 150 g whole-berry purée or the same amount of bread without berries as reference. In study 1, WB was served with strawberries, bilberries, or lingonberries and in study 2 with raspberries, cloudberries, or chokeberries. In study 3, WB or RB was served with a mixture of berries consisting of equal amounts of strawberries, bilberries, cranberries, and blackcurrants. Strawberries, bilberries, lingonberries, and chokeberries consumed with WB and the berry mixture consumed with WB or RB significantly reduced the postprandial insulin response. Only strawberries (36%) and the berry mixture (with WB, 38%; with RB, 19%) significantly improved the glycemic profile of the breads. These results suggest than when WB is consumed with berries, less insulin is needed for maintenance of normal or slightly improved postprandial glucose metabolism. The lower insulin response to RB compared with WB can also be further reduced by berries.

positive: The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. The glycemic index was proposed in 1981 as an alternative system for classifying carbohydrate-containing food. Since then, several hundred scientific articles and numerous popular diet books have been published on the topic. However, the clinical significance of the glycemic index remains the subject of debate. The purpose of this review is to examine the physiological effects of the glycemic index and the relevance of these effects in preventing and treating obesity, diabetes, and cardiovascular disease.

positive: Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: health be damned! Pour on the sugar. Sugar-sweetened drinks have been associated with several health problems. In the point narrative as presented below, we provide our opinion and review of the data to date that we need to reconsider consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative following our contribution, Drs. Kahn and Sievenpiper provide a defense and suggest that dietary sugar is not the culprit. Data from the National Health and Nutrition Examination Survey and U.S. Department of Agriculture dietary surveys along with commercial Homescan data on household purchases were used to understand changes in sugar and fructose consumption. Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. About 75% of all foods and beverages contain added sugar in a large array of forms. Consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages (SSBs) is related to the risk of diabetes, the metabolic syndrome, and cardiovascular disease. Drinking two 16-ounce SSBs per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized controlled trials in children and adults lasting 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Recent studies suggest a gene-SSB potential relationship. Consumption of calorie-sweetened beverages has continued to increase and plays a role in the epidemic of obesity, the metabolic syndrome, and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain.

positive: Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. High intakes of dietary sugars in the setting of a worldwide pandemic of obesity and cardiovascular disease have heightened concerns about the adverse effects of excessive consumption of sugars. In 2001 to 2004, the usual intake of added sugars for Americans was 22.2 teaspoons per day (355 calories per day). Between 1970 and 2005, average annual availability of sugars/added sugars increased by 19%, which added 76 calories to Americans' average daily energy intake. Soft drinks and other sugar-sweetened beverages are the primary source of added sugars in Americans' diets. Excessive consumption of sugars has been linked with several metabolic abnormalities and adverse health conditions, as well as shortfalls of essential nutrients. Although trial data are limited, evidence from observational studies indicates that a higher intake of soft drinks is associated with greater energy intake, higher body weight, and lower intake of essential nutrients. National survey data also indicate that excessive consumption of added sugars is contributing to overconsumption of discretionary calories by Americans. On the basis of the 2005 US Dietary Guidelines, intake of added sugars greatly exceeds discretionary calorie allowances, regardless of energy needs. In view of these considerations, the American Heart Association recommends reductions in the intake of added sugars. A prudent upper limit of intake is half of the discretionary calorie allowance, which for most American women is no more than 100 calories per day and for most American men is no more than 150 calories per day from added sugars.

positive: Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: we have, but the pox on sugar is overwrought and ... In the preceding point narrative, Drs. Bray and Popkin provide their opinion and review data that suggest to them that we need to reconsider the consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative below, we argue that there is no clear or convincing evidence that any dietary or added sugar has a unique or detrimental impact relative to any other source of calories on the development of obesity or diabetes. Sugar is purely a highly palatable source of energy; because it has no other property that appears to contribute to our nutritional well-being, it is not an essential food for most of us. For those who wish to reduce energy consumption, ingesting less sugar is a good place to start. However, doing so does not automatically portend any clinical benefit.

positive: Energy and Fructose From Beverages Sweetened With Sugar or High-Fructose Corn Syrup Pose a Health Risk for Some People Sugar intake in the United States has increased by >40 fold since the American Revolution. The health concerns that have been raised about the amounts of sugar that are in the current diet, primarily as beverages, are the subject of this review. Just less than 50% of the added sugars (sugar and high-fructose corn syrup) are found in soft drinks and fruit drinks. The intake of soft drinks has increased 5-fold between 1950 and 2000. Most meta-analyses have shown that the risk of obesity, diabetes, cardiovascular disease, and metabolic syndrome are related to consumption of beverages sweetened with sugar or high-fructose corn syrup. Calorically sweetened beverage intake has also been related to the risk of nonalcoholic fatty liver disease, and, in men, gout. Calorically sweetened beverages contribute to obesity through their caloric load, and the intake of beverages does not produce a corresponding reduction in the intake of other food, suggesting that beverage calories are “add-on” calories. The increase in plasma triglyceride concentrations by sugar-sweetened beverages can be attributed to fructose rather than glucose in sugar. Several randomized trials of sugar-containing soft drinks versus low-calorie or calorie-free beverages show that either sugar, 50% of which is fructose, or fructose alone increases triglycerides, body weight, visceral adipose tissue, muscle fat, and liver fat. Fructose is metabolized primarily in the liver. When it is taken up by the liver, ATP decreases rapidly as the phosphate is transferred to fructose in a form that makes it easy to convert to lipid precursors. Fructose intake enhances lipogenesis and the production of uric acid. By worsening blood lipids, contributing to obesity, diabetes, fatty liver, and gout, fructose in the amounts currently consumed is hazardous to the health of some people.

positive: Erosive potentials of brewed teas. PURPOSE: To measure the pH, titratable acidity, fluoride concentration and erosive potential of brewed teas. METHODS: Bag teas were purchased to represent black, green, citrus, fruity, and floral tea flavors from Tulsi, Bigelow, HyVee, Tazo, and Yogi brands and brewed (1 bag/240 ml) in boiling water for 3 minutes. The pH, titratable acidity, and fluoride concentrations were measured. Following these measurements, a representative tea from each flavor was selected for investigation of erosion potential. Six extracted human molars were randomly assigned to each tea. Teeth were painted with fingernail polish to expose a 1 x 4 mm window and then soaked in tea for a total of 25 hours with teas refreshed every 5 hours. Teeth were then sectioned using a microtome and photographed using a polarized light microscope. Lesion depths (i.e., eroded surfaces) were measured using Image Pro Plus software. Differences in physiochemical properties and lesion depths between beverages were investigated using one-way ANOVA with post-hoc Tukey's HSD test. Relationships among lesion depths and physiochemical properties were evaluated using the Pearson correlation test. RESULTS: pH, titratable acidity and fluoride concentrations differed between tea flavors (P < 0.05) and between brands (P < 0.05). Lesion depths produced by the citrus tea (83.1 +/- 10.3 microm) were greater than those produced by the fruity tea (56.5 +/- 6.1 microm); both teas produced greater depths than black (30.1 +/- 7.4 microm), floral (25.0 +/- 3.2 microm) or green (22.3 +/- 6.3 microm) teas (P < 0.05). pH (r = -0.96; P = 0.009) was inversely and titratable acidity (r = 0.97; P = 0.006) was positively associated with lesion depths.

positive: Effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa in patients with mild to moderate hypertension: a controlled and ... In order to compare the antihypertensive effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa with captopril, a controlled and randomized clinical trial was done. Patients from 30 to 80 years old with diagnosed hypertension and without antihypertensive treatment for at least 1 month before were included. The experimental procedure consisted of the administration of an infusion prepared with 10 g of dry calyx from H. sabdariffa on 0.51 water (9.6 mg anthocyanins content), daily before breakfast, or captopril 25 mg twice a day, for 4 weeks. The outcome variables were tolerability, therapeutic effectiveness (diastolic reduction > or = 10 mm Hg) and, in the experimental group, urinary electrolytes modification. Ninety subjects were included, 15 withdrew from the study due to non-medical reasons; so, the analysis included 39 and 36 patients from the experimental and control group, respectively. The results showed that H. sabdariffa was able to decrease the systolic blood pressure (BP) from 139.05 to 123.73mm Hg (ANOVA p < 0.03) and the diastolic BP from 90.81 to 79.52mm Hg (ANOVA p < 0.06). At the end of the study, there were no significant differences between the BP detected in both treatment groups (ANOVA p > 0.25). The rates of therapeutic effectiveness were 0.7895 and 0.8438 with H. sabdariffa and captopril, respectively (chi2, p > 0.560), whilst the tolerability was 100% for both treatments. A natriuretic effect was observed with the experimental treatment. The obtained data confirm that the H. sabdariffa extract, standardized on 9.6mg of total anthocyanins, and captopril 50 mg/day, did not show significant differences relative to hypotensive effect, antihypertensive effectiveness, and tolerability.

positive: Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies The effectiveness of Hibiscus sabdariffa L. (HS) in the treatment of risk factors associated with cardiovascular disease is assessed in this review by taking a comprehensive approach to interpreting the randomized clinical trial (RCT) results in the context of the available ethnomedical, phytochemical, pharmacological, and safety and toxicity information. HS decoctions and infusions of calyxes, and on occasion leaves, are used in at least 10 countries worldwide in the treatment of hypertension and hyperlipidemia with no reported adverse events or side effects. HS extracts have a low degree of toxicity with a LD50 ranging from 2,000 to over 5,000 mg/kg/day. There is no evidence of hepatic or renal toxicity as the result of HS extract consumption, except for possible adverse hepatic effects at high doses. There is evidence that HS acts as a diuretic, however in most cases the extract did not significantly influence electrolyte levels. Animal studies have consistently shown that consumption of HS extract reduces blood pressure in a dose dependent manner. In RCTs, the daily consumption of a tea or extract produced from HS calyxes significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults with pre to moderate essential hypertension and type 2 diabetes. In addition, HS tea was as effective at lowering blood pressure as the commonly used blood pressure medication Captropril, but less effective than Lisinopril. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides were lowered in the majority of normolipidemic, hypolipidemic, and diabetic animal models, whereas high-density lipoprotein cholesterol (HDL-C) was generally not affected by the consumption of HS extract. Over half of the RCTs showed that daily consumption of HS tea or extracts had favorable influence on lipid profiles including reduced total cholesterol, LDL-C, triglycerides, as well as increased HDL-C. Anthocyanins found in abundance in HS calyxes are generally considered the phytochemicals responsible for the antihypertensive and hypocholesterolemic effects, however evidence has also been provided for the role of polyphenols and hibiscus acid. A number of potential mechanisms have been proposed to explain the hypotensive and anticholesterol effects, but the most common explanation is the antioxidant effects of the anthocyanins inhibition of LDL-C oxidation, which impedes atherosclerosis, an important cardiovascular risk factor. This comprehensive body of evidence suggests that extracts of HS are promising as a treatment of hypertension and hyperlipidemia, however more high quality animal and human studies informed by actual therapeutic practices are needed to provide recommendations for use that have the potential for widespread public health benefit.

positive: Dietary behavior and knowledge of dental erosion among Chinese adults Objectives To study the dietary behavior and knowledge about dental erosion and self-reported symptoms that can be related to dental erosion among Chinese adults in Hong Kong. Methods Chinese adults aged 25-45 years were randomly selected from a list of registered telephone numbers generated by computer. A telephone survey was administered to obtain information on demographic characteristics, dietary habits, dental visits, and knowledge of and presence of self-reported symptoms that can be related to dental erosion. Results A total of 520 participants were interviewed (response rate, 75%; sampling error, ± 4.4%) and their mean age was 37. Most respondents (79%) had ever had caries, and about two thirds (64%) attended dental check-ups at least once a year. Respondents had a mean of 5.4 meals per day and 36% had at least 6 meals per day. Fruit (89%) and lemon tea/water (41%) were the most commonly consumed acidic food and beverage. When asked if they ever noticed changes in their teeth, most respondents (92%) said they had experienced change that can be related to erosion. However, many (71%) had never heard about dental erosion and 53% mixed up dental erosion with dental caries. Conclusion Hong Kong Chinese adults have frequent intake of food and many have experienced symptoms that can be related to dental erosion. Their level of awareness of and knowledge about dental erosion is generally low, despite most of them have regular dental check-ups. Dental health education is essential to help the public understand dental erosion and its damaging effects.

positive: Periodontal conditions in vegetarians: a clinical study. BACKGROUND/OBJECTIVES: Investigations about possible correlations between vegetarian diet and periodontal conditions are rare and characterized by small case numbers. The aim of this clinical study was to investigate the influence of a vegetarian diet on periodontal parameters with an appropriate sample size. SUBJECTS/METHODS: A total of 200 patients, 100 vegetarians and 100 non-vegetarians, were included in the study. All patients were examined including a full mouth assessment of the periodontal and dental conditions. In addition, a questionnaire was handed out to ask for patients' oral hygiene habits and level of education. For statistical analysis the Mann-Whitney Test (χ(2) for analysis of the questionnaire) was applied (level of significance: P<0.05). RESULTS: Well known periodontal risk factors like age, gender and smoking habits were equally distributed within each group (71 females, 29 males, respectively and 10 smokers in each group; mean age: 41.45 years vegetarians versus 41.72 years non-vegetarians). Vegetarians had significantly lower probing pocket depths (P=0.039), bleeding on probing (P=0.001), periodontal screening index (P=0.012), a better hygiene index (P<0.001) and less mobile teeth (P=0.013). Dental examinations revealed significantly less missing teeth (P=0.018) but also more decayed (P=0.001) and eroded (P=0.026) teeth in vegetarians. Furthermore, vegetarians had a higher level of education (P<0.001), but visited dentists significantly less frequent. CONCLUSIONS: Vegetarians revealed better periodontal conditions (less inflammation signs, less periodontal damage and a better dental home care). However, it should be considered that vegetarians are not only avoiding meat in their nutrition but are also characterized by an overall healthier life style.

positive: Influence of drinking patterns of carbonated beverages on dental erosion. As a hard tissue dental disease, dental erosion has a multifactorial etiology. The majority of dental erosion that originates from extrinsic sources is the result of dietary intake, particularly acidic beverages. Several preventive means have been proposed to minimize the damage to the dentition, including a reduction in the consumption of causative beverages and the adoption of a specific method of drinking, utilizing a straw instead of a cup. This article presents two cases involving the clinical and radiographic features of erosion lesions associated with chronic and excessive intake of acidic carbonated beverages. These examples embody how drinking patterns influence the formation of erosion lesions in various anatomic locations within the dentition. The clinical and radiographic evidence presented in this report cautions against the use of nonspecific terms, such as "cup versus straw," and instead suggests implementing a more precise description of the suggested method. In view of the extensive damage inflicted by the chronic, excessive intake of carbonated beverages, preventive measures are considered to be the only effective course of management. This article offers illustrative examples of erosion lesions associated with long-term excessive intake of carbonated beverages. The influence of the drinking method--that is, a straw positioned into the labial vestibule versus a cup--on the anatomic location of the erosion lesions will be demonstrated through clinical and radiographic evidence.

positive: Roselle (Hibiscus sabdariffa L.) and soybean oil effects on quality characteristics of pork patties studied by response surface methodology. Response surface methodology was used to investigate the effect and interactions of processing variables such as roselle extract (0.1-1.3%), soybean oil (5-20%) on physicochemical, textural and sensory properties of cooked pork patties. It was found that reduction in thickness, pH, L* and b* values decreased; however, water-holding capacity, reduction in diameter and a* values increased, respectively, as the amount of roselle increased. Soybean oil addition increased water-holding capacity, reduction in thickness, b* values of the patties. The hardness depended on the roselle and soybean oil added, as its linear effect was negative at p<0.01. The preference of color, tenderness, juiciness, and overall quality depend on the addition of roselle and soybean oil. The maximum overall quality score (5.42) was observed when 12.5 g of soybean oil and 0.7 g of roselle extract was added. The results of this optimization study would be useful for meat industry that tends to increase the product yield for patties using the optimum levels of ingredients by RSM. Copyright © 2013 Elsevier Ltd. All rights reserved.

positive: The effects of sour tea (Hibiscus sabdariffa) on hypertension in patients with type II diabetes. To compare the antihypertensive effectiveness of sour tea (ST; Hibiscus sabdariffa) with black tea (BT) infusion in diabetic patients, this double-blind randomized controlled trial was carried out. Sixty diabetic patients with mild hypertension, without taking antihypertensive or antihyperlipidaemic medicines, were recruited in the study. The patients were randomly allocated to the ST and BT groups and instructed to drink ST and BT infusions two times a day for 1 month. Their blood pressure (BP) was measured on days 0, 15 and 30 of the study. The mean of systolic BP (SBP) in the ST group decreased from 134.4+/-11.8 mm Hg at the beginning of the study to 112.7+/-5.7 mm Hg after 1 month (P-value <0.001), whereas this measure changed from 118.6+/-14.9 to 127.3+/-8.7 mm Hg (P-value=0.002) in the BT group during the same period. The intervention had no statistically significant effect on the mean of diastolic BP (DBP) in either the ST or BT group. The mean pulse pressure (PP) of the patients in the ST group decreased from 52.2+/-12.2 to 34.5+/-9.3 mm Hg (P-value <0.001) during the study, whereas in the BT group, it increased from 41.9+/-11.7 to 47.3+/-9.6 mm Hg (P-value=0.01). In conclusion, consuming ST infusion had positive effects on BP in type II diabetic patients with mild hypertension. This study supports the results of similar studies in which antihypertensive effects have been shown for ST.

positive: A pulse-based diet is effective for reducing total and LDL-cholesterol in older adults. Our purpose was to determine the effects of a pulse-based diet in individuals 50 years or older for reducing CVD risk factors. A total of 108 participants were randomised to receive pulse-based foods (two servings daily of beans, chickpeas, peas or lentils; about 150 g/d dry weight) or their regular diet for 2 months, followed by a washout of 1 month and a cross-over to the other diet for 2 months. Anthropometric measures, body composition and biochemical markers (i.e. serum LDL-cholesterol (LDL-C), as the primary outcome, and other lipids, glucose, insulin and C-reactive protein) were assessed before and after each diet phase. A total of eighty-seven participants (thirty males and fifty-seven females; 59·7 (sd 6·3) years, body mass 76 (sd 16) kg) completed the study. Compared with the regular diet, the pulse-based diet decreased total cholesterol by 8·3 % (pulse, 4·57 (sd 0·93) to 4·11 (sd 0·91) mmol/l; regular, 4·47 (sd 0·94) to 4·39 (sd 0·97) mmol/l; P < 0·001) and LDL-C by 7·9 % (pulse, 2·93 (sd 0·84) to 2·55 (sd 0·75) mmol/l; regular, 2·96 (sd 0·86) to 2·81 (sd 0·83) mmol/l; P = 0·01). In a sub-analysis of individuals with high lipid levels at baseline (twenty individuals with high cholesterol), the pulse-based diet reduced cholesterol by 6 % compared with the regular diet (pulse, 5·62 (sd 0·78) to 5·26 (sd 0·68) mmol/l; regular, 5·60 (sd 0·91) to 5·57 (sd 0·85) mmol/l; P = 0·05). A pulse-based diet is effective for reducing total cholesterol and LDL-C in older adults and therefore reduces the risk of CVD.

positive: Nutritional quality and health benefits of chickpea (Cicer arietinum L.): a review. Chickpea (Cicer arietinum L.) is an important pulse crop grown and consumed all over the world, especially in the Afro-Asian countries. It is a good source of carbohydrates and protein, and protein quality is considered to be better than other pulses. Chickpea has significant amounts of all the essential amino acids except sulphur-containing amino acids, which can be complemented by adding cereals to the daily diet. Starch is the major storage carbohydrate followed by dietary fibre, oligosaccharides and simple sugars such as glucose and sucrose. Although lipids are present in low amounts, chickpea is rich in nutritionally important unsaturated fatty acids such as linoleic and oleic acids. β-Sitosterol, campesterol and stigmasterol are important sterols present in chickpea oil. Ca, Mg, P and, especially, K are also present in chickpea seeds. Chickpea is a good source of important vitamins such as riboflavin, niacin, thiamin, folate and the vitamin A precursor β-carotene. As with other pulses, chickpea seeds also contain anti-nutritional factors which can be reduced or eliminated by different cooking techniques. Chickpea has several potential health benefits, and, in combination with other pulses and cereals, it could have beneficial effects on some of the important human diseases such as CVD, type 2 diabetes, digestive diseases and some cancers. Overall, chickpea is an important pulse crop with a diverse array of potential nutritional and health benefits.

positive: Nutritional quality of legumes, and their role in cardiometabolic risk prevention: a review. Legumes (including alfalfa, clover, lupins, green beans and peas, peanuts, soybeans, dry beans, broad beans, dry peas, chickpeas, and lentils) represent an important component of the human diet in several areas of the world, especially in the developing countries, where they complement the lack of proteins from cereals, roots, and tubers. In some regions of the world, legume seeds are the only protein supply in the diet. The health benefits of legume consumption have received rising interest from researchers, and their consumption and production extends worldwide. Among European countries, higher legume consumption is observed around the Mediterranean, with per capita daily consumption between 8 and 23 g, while in Northern Europe, the daily consumption is less than 5 g per capita. The physiological effects of different legumes vary significantly. These differences may result from the polysaccharides composition, in particular, the quantity and variety of dietary fibers and starch, protein make-up, and variability in phytochemical content. The majority of legumes contain phytochemicals: bioactive compounds, including enzyme inhibitors, phytohemagglutinins (lectins), phytoestrogens, oligosaccharides, saponins, and phenolic compounds, which play metabolic roles in humans who frequently consume these foods. Dietary intake of phytochemicals may provide health benefits, protecting against numerous diseases or disorders, such as coronary heart disease, diabetes, high blood pressure and inflammation. The synergistic or antagonistic effects of these phytochemical mixtures from food legumes, their interaction with other components of the diet, and the mechanism of their action have remained a challenge with regard to understanding the role of phytochemicals in health and diseases. Their mitigating effects and the mechanism of their action need to be further addressed if we are to understand the role of phytochemicals in health and diseases. This review provides an overview of the nutritional quality of legumes and their potential contribution in cardiometabolic risk prevention.

positive: Exploratory study of the relationship between hypertension and diet diversity among Saba Islanders. The relationship between diet diversity and hypertension was examined in a cross-sectional exploratory study of 82 randomly selected adult residents of Saba Island, Netherlands Antilles, in the eastern Caribbean Basin. Blood pressure measurements, taken over 4 years, and the appropriate use of antihypertensive medications, were used to identify chronic hypertensives. A 24-hour dietary recall, semi-quantitative food frequency interviews, and ethnographic confirmation techniques were used to calculate diet diversity, a measure of the overall dietary pattern. Results suggest hypertension is associated with lack of an overall balance of food groups in the daily diet beyond any imbalance of a particular dietary cation such as sodium, potassium, or calcium. Bivariate analyses found a significant association between a poorly diversified diet and hypertension (odds ratio [OR] = 4.25, 95 percent confidence intervals [CI] = 1.47,12.30). Dietary intake of sodium, potassium, and calcium was also examined and found not to be associated with the presence of hypertension in bivariate analyses. Including these cations individually in logistic regression models, which also included diet diversity, did not diminish the diet diversity-hypertension association. Multiple logistic regression models in which other potential confounding variables were individually entered as a control variable (body fat, skin color, age, sex, perceived stress, alcohol intake, aerobic activity, and socioeconomic status) did not alter this result. Analysis of the presence or absence of individual food groups indicate a lack of legumes in the daily diet is also associated with the diagnosis of hypertension (OR = 4.71, 95 percent CI = [1.71,13.01]).

positive: Position statement. Part one: Immune function and exercise. An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies.

positive: Natural killer cell activity in peripheral blood of highly trained and untrained persons. Natural killer (NK) cell activity and concentration of CD16+ cells (NK cells) and CD20+ cells (monocytes) in peripheral blood were measured in highly trained racing cyclists and in age- and sex-matched untrained controls. Median NK cell activity was 38.1% (range 20.0%-57.1%) in trained vs 30.3% (range 19.7%-43.1%) in untrained (P = 0.008). Median %CD16+ cells was 17% (range 7%-33%) in trained vs 11% (3%-29%) in untrained (P = 0.007). Indomethacin in vitro enhanced the NK cell activity in both groups. There was, however, no significant difference between the NK cell activity in trained and untrained after exposure to indomethacin in vitro. Indomethacin-enhanced NK cell activity was 45.9% (range 24.4%-67.5%) in trained and 40.0% (range 23.9%-68.5%) in untrained (P = 0.138). Mean %CD14+ cells was 8.3% (range 2%-15%) in trained vs 3.8% (2%-8%) in untrained (P less than 0.0001). The increased NK cell function thus demonstrated in highly trained persons might result in better resistance against infectious disease.

positive: Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly? Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence - a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in 'inflammaging', a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

positive: Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. BACKGROUND & AIMS: The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications. METHODS: We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy. RESULTS: Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred. The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy. CONCLUSIONS: Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.

positive: Efficacy and safety of Chlorella supplementation in adults with chronic hepatitis C virus infection AIM: To evaluate the safety and efficacy of Chlorella in 18 patients chronically infected with hepatitis C virus (HCV) genotype 1. METHODS: Eighteen adults with chronic infection by HCV genotype 1 received daily oral supplementation of Chlorella for 12 wk. Changes in the RNA levels of HCV, as well as those of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated following this treatment period. Paired t tests were conducted to compare the means of the different variables at the beginning and end of the study. Side effects and quality of life aspects were also compared between weeks 0 and 12 of the study period. RESULTS: A majority 84.61% of the patients had a significant decrease in their ALT levels from week 0 to week 12. Evaluation of side effects showed that Chlorella was well tolerated. Quality of life assessment showed that 76.9 of the participants reported an improvement in their energy levels and 46.1% reported an improvement in their perception of general health. Although 69.23% also showed a decrease in their AST levels, this was not statistically significant. Most patients that exhibited an improvement in their ALT and AST levels also showed a tendency toward a decreased HCV viral load. The HCV RNA levels showed a decrease in 69.23% of the patients, which along with changes in AST/ALT ratios from week 0 to week 12, these results were not statistically significant. CONCLUSION: Chlorella supplementation was well tolerated in patients with chronic HCV and associated with a significant decrease in ALT liver enzyme levels.

positive: Physical activity and immune function in elderly women. The relationship between cardiorespiratory exercise, immune function, and upper respiratory tract infection (URTI) was studied in elderly women utilizing a randomized controlled experimental design with a follow-up of 12 wk. Thirty-two sedentary, elderly Caucasian women, 67-85 yr of age, who met specific selection criteria, were randomized to either a walking or calisthenic group; 30 completed the study. Twelve highly conditioned elderly women, 65-84 yr of age, who were active in endurance competitions, were recruited at baseline for cross-sectional comparisons. Intervention groups exercised 30-40 min, 5 d.wk-1, for 12 wk, with the walking group training at 60% heart rate reserve and the calisthenic group engaging in mild range-of-motion and flexibility movements that kept their heart rates close to resting levels. At baseline, the highly conditioned subjects exhibited superior NK (119 +/- 13 vs 77 +/- 8 lytic units, P < 0.01) and T (33.3 +/- 4.9 vs 21.4 +/- 2.1 cpm x 10(-3) using PHA, P < 0.05) cell function, despite no differences in circulating levels of lymphocyte subpopulations. Twelve weeks of moderate cardiorespiratory exercise improved the VO2max of the sedentary subjects 12.6%, but did not result in any improvement in NK cell activity or T cell function. Incidence of URTI was lowest in the highly conditioned group and highest in the calisthenic control group during the 12-wk study, with the walkers in an intermediate position (chi-square = 6.36, P = 0.042). In conclusion, the highly conditioned elderly women in this study had superior NK and T cell function when compared with their sedentary counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

positive: Salivary Secretory Immunoglobulin a secretion increases after 4-weeks ingestion of chlorella-derived multicomponent supplement in humans: a randomized cross over study Background Chlorella, a unicellular green alga that grows in fresh water, contains high levels of proteins, vitamins, minerals, and dietary fibers. Some studies have reported favorable immune function-related effects on biological secretions such as blood and breast milk in humans who have ingested a chlorella-derived multicomponent supplement. However, the effects of chlorella-derived supplement on mucosal immune functions remain unclear. The purpose of this study was to investigate whether chlorella ingestion increases the salivary secretory immunoglobulin A (SIgA) secretion in humans using a blind, randomized, crossover study design. Methods Fifteen men took 30 placebo and 30 chlorella tablets per day for 4 weeks separated by a 12-week washout period. Before and after each trial, saliva samples were collected from a sterile cotton ball that was chewed after overnight fasting. Salivary SIgA concentrations were measured using ELISA. Results Compliance rates for placebo and chlorella ingestions were 97.0 ± 1.0% and 95.3 ± 1.6%, respectively. No difference was observed in salivary SIgA concentrations before and after placebo ingestion (P = 0.38). However, salivary SIgA concentrations were significantly elevated after chlorella ingestion compared to baseline (P < 0.01). No trial × period interaction was identified for the saliva flow rates. Although the SIgA secretion rate was not affected by placebo ingestion (P = 0.36), it significantly increased after 4-week chlorella ingestion than before intake (P < 0.01). Conclusions These results suggest 4-week ingestion of a chlorella-derived multicomponent supplement increases salivary SIgA secretion and possibly improves mucosal immune function in humans.

positive: Beneficial immunostimulatory effect of short-term Chlorella supplementation: enhancement of Natural Killer cell activity and early inflammatory response (Randomized, double-blinded, placebo-controlled trial) Background In vitro and animal studies have demonstrated that Chlorella is a potent biological response modifier on immunity. However, there were no direct evidences for the effect of Chlorella supplementation on immune/inflammation response in healthy humans. Methods This study was designed for an 8-week randomized, double-blinded, placebo-controlled trial: 5g of Chlorella (n=23) or Placebo (n=28) as form of tablets. Mainly, cytotoxic activities of Natural killer (NK) cells and serum concentrations of interferon-γ, interleukin-1β and interleukin-12 were measured. Results After the 8-week, serum concentrations of interferon-γ (p<0.05) and interleukin-1β (p<0.001) significantly increased and that of interleukin-12 (p<0.1) tended to increase in the Chlorella group. The increments of these cytokines after the intervention were significantly bigger in the Chlorella group than those in the placebo group. In addition, NK cell activities (%) were significantly increased in Chlorella group, but not in Placebo group. The increments of NK cell activities (%) were also significantly bigger in the Chlorella group than the placebo group. Additionally, changed levels of NK cell activity were positively correlated with those of serum interleukin-1β (r=0.280, p=0.047) and interferon-γ (r=0.271, p<0.005). Signficantly positive correlations were also observed among the changed levels of serum cytokines; between interferon-γ and interleukin-1β (r=0.448, p<0.001), between interleukin-12 and interleukin-1β (r=0.416, p=0.003) and between interleukin-12 and interferon-γ (r=0.570, p<001). Conclusion These results may suggest a beneficial immunostimulatory effect of short-term Chlorella supplementation which enhances the NK cell activity and produces interferon-γ and interleukin-12 as well as interleukin-1β, the Th-1 cell-induced cytokines in healthy people.

positive: The effects of moderate exercise training on natural killer cells and acute upper respiratory tract infections. A randomly controlled 15-wk exercise training (ET) study (five 45-min sessions/wk, brisk walking at 60% heart rate reserve) with a group of 36 mildly obese, sedentary women was conducted to investigate the relationship between improvement in cardiorespiratory fitness, changes in natural killer (NK) cell number and activity, and acute upper respiratory tract infection (URI) symptomatology. The study was conducted using a 2 (exercise and nonexercise groups) x 3 (baseline, 6-, and 15-wk testing sessions) factorial design, with data analyzed using repeated measures ANOVA. No significant change in NK cell number occurred as a result of ET as measured by the CD16 and Leu-19 monoclonal antibodies. ET did have a significant effect on NK cell activity (E:T 50:1) especially during the initial 6-wk period [F(2.68) = 12.34, p less than 0.001]. Using data from daily logs kept by each subject, the exercise group was found to have significantly fewer URI symptom days/incident than the nonexercise group (3.6 +/- 0.7 vs 7.0 +/- 1.4 days, respectively, p = 0.049). Improvement in cardiorespiratory fitness was correlated significantly with a reduction in URI symptom days/incident (r = 0.37, p = 0.025) and a change in NK cell activity from baseline to six but not 15 wks (r = 0.35, p = 0.036). In summary, moderate ET is associated with elevated NK cell activity after six but not 15 weeks, and reduced URI symptomatology in comparison to a randomized, sedentary control group.

positive: Economic evaluation of direct-acting antiviral therapy in chronic hepatitis C. In 2011, the protease inhibitors boceprevir and telaprevir were approved in the United States and European Union for the treatment of hepatitis C infection. While remarkably effective, the newly approved therapies are also accompanied by additional side effects and considerable costs. Understanding the balance between costs and effectiveness is critical to making decisions about the optimal use of these new agents, especially for health care systems constrained by rising costs. Our goal for this review is to facilitate an understanding of the importance of cost-effectiveness analyses in guiding policy decisions about the use of newly approved drugs as well as future therapies for hepatitis C.

positive: Managing adverse effects and complications in completing treatment for hepatitis C virus infection. The addition of direct-acting antivirals (DAAs) to hepatitis C virus (HCV) treatment regimens has made treatment more effective and patient management more complex. Shepherding patients through a full course of HCV therapy requires motivation and involvement on the part of the patient and the physician. Indeed, physician inexperience and lack of confidence in guiding patients through the challenges of treatment appears to be a primary reason for early discontinuation of therapy. Among the many complications of HCV treatment that must be managed efficiently and effectively are depression and other psychiatric disorders; hematologic abnormalities including DAA- and ribavirin-associated anemia and peginterferon alfa-associated neutropenia and thrombocytopenia; rash and drug eruptions, including telaprevir-associated rash; and weight loss. Practical considerations in management of these common complications are offered. This article summarizes a presentation by Kenneth E. Sherman, MD, PhD, at the IAS-USA live continuing medical education course held in New York in June 2012.

positive: Bean and rice meals reduce postprandial glycemic response in adults with type 2 diabetes: a cross-over study Background Around the world, beans and rice are commonly consumed together as a meal. With type 2 diabetes increasing, the effect of this traditional diet pattern on glycemic response has not been studied fully. Methods We evaluated the glycemic response of bean and rice traditional meals compared to rice alone in adults with type 2 diabetes. Seventeen men and women with type 2 diabetes controlled by metformin (n = 14) or diet/exercise (n = 3) aged 35–70 years participated in the randomized 4 × 4 crossover trial. The white long grain rice control, pinto beans/rice, black beans/rice, red kidney beans/rice test meals, matched for 50 grams of available carbohydrate, were consumed at breakfast after a 12 hour fast. Capillary blood glucose concentrations at baseline and at 30 minute intervals up to 180 minutes postprandial were collected. MANOVA for repeated measures established glucose differences between treatments. Paired t tests identified differences between bean types and the rice control following a significant MANOVA. Results Postprandial net glucose values were significantly lower for the three bean/rice treatments in contrast to the rice control at 90, 120 and 150 minutes. Incremental area under the curve values were significantly lower for the pinto and black bean/rice meals compared to rice alone, but not for kidney beans. Conclusions Pinto, dark red kidney and black beans with rice attenuate the glycemic response compared to rice alone. Promotion of traditional foods may provide non-pharmaceutical management of type 2 diabetes and improve dietary adherence with cultural groups. Trial registration Clinical Trials number NCT01241253

positive: High intake of whole grains and beans pattern is inversely associated with insulin resistance in healthy Korean adult population. We investigated the association between dietary patterns and insulin resistance in the 3871 healthy Korean adults from the 2007 to 2008 Korea National Health and Nutrition Examination Survey. The whole grains and beans pattern was associated with lower prevalence of insulin resistance (OR for highest quintile=0.80, 95% CI=0.61-1.03, P for trend=0.013). Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

positive: Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis. The article gives an overview of phytic acid in food and of its significance for human nutrition. It summarises phytate sources in foods and discusses problems of phytic acid/phytate contents of food tables. Data on phytic acid intake are evaluated and daily phytic acid intake depending on food habits is assessed. Degradation of phytate during gastro-intestinal passage is summarised, the mechanism of phytate interacting with minerals and trace elements in the gastro-intestinal chyme described and the pathway of inositol phosphate hydrolysis in the gut presented. The present knowledge of phytate absorption is summarised and discussed. Effects of phytate on mineral and trace element bioavailability are reported and phytate degradation during processing and storage is described. Beneficial activities of dietary phytate such as its effects on calcification and kidney stone formation and on lowering blood glucose and lipids are reported. The antioxidative property of phytic acid and its potentional anticancerogenic activities are briefly surveyed. Development of the analysis of phytic acid and other inositol phosphates is described, problems of inositol phosphate determination and detection discussed and the need for standardisation of phytic acid analysis in foods argued.

positive: Antidiabetic drugs used in Europe prior to the discovery of insulin. Many therapeutic agents had been used for the treatment of diabetes mellitus before insulin was discovered and several hundred plants have shown some extent of antidiabetic activity. This study tries to explore which agents were most widely used in Europe in the pre-insulin era. According to the scientific literature and the proprietary drug industry around 1900, more than 100 agents were considered to have hypoglycemic activity. Most of them seem to have been used only occasionally while some others were recommended and marketed to a large extent. Among the medicinal plants, Syzygium cumini (syn. S. jambolanum, Eugenia jambolana), Vaccinum myrtillus and Phaseolus sp. were most common, and other frequently used agents were opium, opium alkaloids, other alkaloids like quinine or Belladonna alkaloids, salicylates, alkaline substances like sodium (bi)carbonate and even strong poisons like arsenic or uranium salts. Syzygium jambolanum seed powder seems to be one of the most intensively studied antidiabetic agents of plant origin.

positive: Beans and diabetes: Phaseolus vulgaris preparations as antihyperglycemic agents. Bean pods (Phaseolus vulgaris) are among the most widely used traditional remedies against diabetes mellitus. Historical knowledge is summarized and compared to recent study results. Reports dating from the first half of the 20(th) century as well as recent publications show contradictory results. It seems that Phaseolus preparations should not be considered the first choice in phytopharmaceutical treatment of diabetes or lead structure research. To be effective, fairly high doses of aqueous extracts need to be given. Because of their fiber content and an alpha-amylase inhibitory effect, beans might be more useful as food components in preventing or ameliorating type 2 diabetes.

positive: Effect of non-oil-seed pulses on glycaemic control: a systematic review and meta-analysis of randomised controlled experimental trials in people wi... AIMS/HYPOTHESIS: Dietary non-oil-seed pulses (chickpeas, beans, peas, lentils, etc.) are a good source of slowly digestible carbohydrate, fibre and vegetable protein and a valuable means of lowering the glycaemic-index (GI) of the diet. To assess the evidence that dietary pulses may benefit glycaemic control, we conducted a systematic review and meta-analysis of randomised controlled experimental trials investigating the effect of pulses, alone or as part of low-GI or high-fibre diets, on markers of glycaemic control in people with and without diabetes. METHODS: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for relevant controlled trials of >or=7 days. Two independent reviewers (A. Esfahani and J. M. W. Wong) extracted information on study design, participants, treatments and outcomes. Data were pooled using the generic inverse variance method and expressed as standardised mean differences (SMD) with 95% CIs. Heterogeneity was assessed by chi (2) and quantified by I (2). Meta-regression models identified independent predictors of effects. RESULTS: A total of 41 trials (39 reports) were included. Pulses alone (11 trials) lowered fasting blood glucose (FBG) (-0.82, 95% CI -1.36 to -0.27) and insulin (-0.49, 95% CI -0.93 to -0.04). Pulses in low-GI diets (19 trials) lowered glycosylated blood proteins (GP), measured as HbA(1c) or fructosamine (-0.28, 95% CI -0.42 to -0.14). Finally, pulses in high-fibre diets (11 trials) lowered FBG (-0.32, 95% CI -0.49 to -0.15) and GP (-0.27, 95% CI -0.45 to -0.09). Inter-study heterogeneity was high and unexplained for most outcomes, with benefits modified or predicted by diabetes status, pulse type, dose, physical form, duration of follow-up, study quality, macronutrient profile of background diets, feeding control and design. CONCLUSIONS/INTERPRETATION: Pooled analyses demonstrated that pulses, alone or in low-GI or high-fibre diets, improve markers of longer term glycaemic control in humans, with the extent of the improvements subject to significant inter-study heterogeneity. There is a need for further large, well-designed trials.

positive: Antidiabetic potential of commonly consumed legumes: a review. Over the last few decades, lifestyle changes have resulted in a drastic increase in the incidence of diabetes all over the world, especially in the developing countries. Oral hypoglycemic agents and insulin form the mainstay in controlling diabetes, but they have prominent side effects and fail to significantly alter the course of diabetic complications. Appropriate diet and exercise programs that form a part of lifestyle modifications have proven to be greatly effective in the management of this disease. Dietary therapy is showing a bright future in the prevention and treatment of diabetes. Legumes, owing to their high nutritive value, are increasingly being used in dietetic formulations in the treatment and prevention of diabetes on account of their antidiabetic potential. Given this background, this paper reviews the glucose- and lipid-lowering action possessed by various commonly consumed legumes through several animal and human studies. It is concluded that the various legumes not only have varying degrees of antidiabetic potential but are also beneficial in decreasing the risk factors for cardiovascular and renal disease.

positive: Obesity-associated mechanisms of hepatocarcinogenesis. Obesity has been recognized as a key component of the metabolic syndrome, a cluster of risk factors associated with diabetes and cardiovascular morbidity. In addition, obesity has been linked to higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection or toxic injury and remains the third leading cause of cancer death in the world. However, HCC is increasingly diagnosed among individuals with obesity and related disorders. As these metabolic conditions have become globally prevalent, they coexist with well-established risk factors of HCC and create a unique challenge for the liver as a chronically diseased organ. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. These mechanisms synergize with those occurring in chronic liver disease resulting from other etiologies and accelerate the development of HCC before or after the onset of cirrhosis. Increasingly common interactions between oncogenic pathways linked to obesity and chronic liver disease may explain why HCC is one of the few malignancies with rising incidence in developed countries. Better understanding of this complex process will improve our strategies of cancer prevention, prediction, and surveillance. Published by Elsevier Inc.

positive: Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. Coffee, after water, is the most widely consumed beverage in the United States, and is the principal source of caffeine intake among adults. The biological effects of coffee may be substantial and are not limited to the actions of caffeine. Coffee is a complex beverage containing hundreds of biologically active compounds, and the health effects of chronic coffee intake are wide ranging. From a cardiovascular (CV) standpoint, coffee consumption may reduce the risk of type 2 diabetes mellitus and hypertension, as well as other conditions associated with CV risk such as obesity and depression; but it may adversely affect lipid profiles depending on how the beverage is prepared. Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks of a variety of adverse CV outcomes including coronary heart disease, congestive heart failure, arrhythmias, and stroke. Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks of mortality, both CV and all-cause. The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases. A daily intake of ∼2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes. However, most of the data on coffee's health effects are based on observational data, with very few randomized, controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness, and palpitations, as well as bone loss and possibly increased risk of fractures. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

positive: Effects of coffee consumption in chronic hepatitis C: a randomized controlled trial. BACKGROUND: Coffee is associated with a reduced risk of hepatocellular carcinoma in patients with chronic C hepatitis. This prospective trial was aimed at assessing the mechanisms underlying coffee-related protective effects. METHODS: Forty patients with chronic hepatitis C were randomized into two groups: the first consumed 4 cups of coffee/day for 30 days, while the second remained coffee "abstinent". At day 30, the groups were switched over for a second month. RESULTS: At baseline, aspartate aminotransferase and alanine aminotransferase were lower in patients drinking 3-5 (Group B) than 0-2 cups/day (Group A) (56 ± 6 vs 74 ± 11/60 ± 3 vs 73 ± 7 U/L p=0.05/p=0.04, respectively). HCV-RNA levels were significantly higher in Group B [(6.2 ± 1.5) × 10(5)vs (3.9 ± 1.0) × 10(5)UI/mL, p=0.05]. During coffee intake, 8-hydroxydeoxyguanosine and collagen levels were significantly lower than during abstinence (15 ± 3 vs 44 ± 16 8-hydroxydeoxyguanosine/10(5)deoxyguanosine, p=0.05 and 56 ± 9 vs 86 ± 21 ng/mL, p=0.04). Telomere length was significantly higher in patients during coffee intake (0.68 ± 0.06 vs 0.48 ± 0.04 Arbitrary Units, p=0.006). Telomere length and 8-hydroxydeoxyguanosine were inversely correlated. CONCLUSION: In chronic hepatitis C coffee consumption induces a reduction in oxidative damage, correlated with increased telomere length and apoptosis, with lower collagen synthesis, factors that probably mediate the protection exerted by coffee with respect to disease progression. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

positive: Hepatocellular carcinoma and other liver lesions. Patients with cirrhosis are at greatest risk for development of hepatocellular carcinoma (HCC) and should undergo semiannual surveillance using ultrasound, with or without alpha fetoprotein. Patients with positive surveillance testing should undergo contrast-enhanced MRI or 4-phase CT for diagnostic evaluation. There are therapeutic options for most patients with any tumor stage; however, treatment decisions must be individualized after accounting for degree of liver dysfunction and patient performance status. A multidisciplinary approach to care is recommended for optimal communication and treatment delivery. The aim of this review is to provide an up-to-date summary of the diagnosis and management of HCC. Copyright © 2014 Elsevier Inc. All rights reserved.

positive: Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis Background Epidemiologic studies have reported inconsistent results regarding coffee consumption and the risk of liver cancer. We performed a meta-analysis of published case–control and cohort studies to investigate the association between coffee consumption and liver cancer. Methods We searched Medline, EMBASE, ISI Web of Science and the Cochrane library for studies published up to May 2012. We performed a meta-analysis of nine case–control studies and seven cohort studies. Results The summary odds ratio (OR) for high vs no/almost never drinkers was 0.50 (95% confidence interval (CI): 0.42–0.59), with no significant heterogeneity across studies (Q = 16.71; P = 0.337; I2 = 10.2%). The ORs were 0.50 (95% CI: 0.40–0.63) for case–control studies and 0.48 (95% CI: 0.38–0.62) for cohort studies. The OR was 0.38 (95% CI: 0.25–0.56) in males and 0.60 (95% CI: 0.33–1.10) in females. The OR was 0.45 (95% CI: 0.36–0.56) in Asian studies and 0.57 (95% CI: 0.44–0.75) in European studies. The OR was 0.39 (95% CI: 0.28–0.54) with no adjustment for a history of liver disease and 0.54 (95% CI: 0.46–0.66) after adjustment for a history of liver disease. Conclusions The results of this meta-analysis suggested an inverse association between coffee consumption and liver cancer. Because of the small number of studies, further prospective studies are needed.

positive: Dose- and gender-dependent interactions between coffee consumption and serum GGT activity in alcohol consumers. AIMS: Coffee consumption has been recently linked with decreased blood gamma-glutamyltransferase (GGT) activities and protection from alcoholic liver disease. To explore the relationship and dose response, we assessed the impacts of coffee and alcohol intake on serum GGT activity in apparently healthy men and women with varying levels of coffee and alcohol consumption. METHODS: Data on coffee, alcohol consumption and serum GGT activities were collected from 18,899 individuals (8807 men and 10,092 women), mean age 48 years, range 25-74 years, who participated in a large national cross-sectional health survey. Body mass index, smoking index and age were used as covariates in all analyses. RESULTS: Among the study population, 89.8% reported varying levels of coffee consumption; 6.9% were abstainers from alcohol, 86.1% moderate drinkers, 3.7% heavy drinkers and 3.3% former drinkers. In men, the elevation of GGT induced by heavy drinking (>280 g/week) was found to be significantly reduced by coffee consumption exceeding 4 cups per day. A similar trend was also observed among women, which however, did not reach statistical significance. CONCLUSION: Coffee modulates the effect of ethanol on serum GGT activities in a dose- and gender-dependent manner. These observations should be implicated in studies on the possible hepatoprotective effects of coffee in alcohol consumers.

positive: The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers Background: Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. Methods: We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27 037 Finnish male smokers, aged 50–69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. Results: Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73–0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48–0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee. Conclusion: These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.

positive: Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. BACKGROUND & AIMS: Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). We performed a meta-analysis of epidemiological studies to provide updated information on how coffee drinking affects HCC risk. METHODS: We performed a PubMed/MEDLINE search of the original articles published in English from 1966 through September 2012, on case-control or cohort studies that associated coffee consumption with liver cancer or HCC. We calculated the summary relative risk (RR) for any, low, and high consumption of coffee vs no consumption. The cut-off point for low vs high consumption was set to 3 cups per day in 9 studies and 1 cup per day in 5 studies. RESULTS: The summary RR for any coffee consumption vs no consumption was 0.60 from 16 studies, comprising a total of 3153 HCC cases (95% confidence interval [CI], 0.50-0.71); the RRs were 0.56 from 8 case-control studies (95% CI, 0.42-0.75) and 0.64 from 8 cohort studies (95% CI, 0.52-0.78). Compared with no coffee consumption, the summary RR was 0.72 (95% CI, 0.61-0.84) for low consumption and 0.44 (95% CI, 0.39-0.50) for high consumption. The summary RR was 0.80 (95% CI, 0.77-0.84) for an increment of 1 cup of coffee per day. The inverse relationship between coffee and HCC risk was consistent regardless of the subjects' sex, alcohol drinking, or history of hepatitis or liver disease. CONCLUSIONS: From this meta-analysis, the risk of HCC is reduced by 40% for any coffee consumption vs no consumption. The inverse association might partly or largely exist because patients with liver and digestive diseases reduce their coffee intake. However, coffee has been shown to affect liver enzymes and development of cirrhosis, and therefore could protect against liver carcinogenesis. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

positive: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. BACKGROUND: The influence of excess body weight on the risk of death from cancer has not been fully characterized. METHODS: In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. RESULTS: The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin's lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. CONCLUSIONS: Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites. Copyright 2003 Massachusetts Medical Society

positive: The Tromsø Heart Study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Gamma-glutamyltransferase (GGT) was measured in 1579 men, aged 20-54 years, and 1654 women, aged 20-49 years, screened for coronary risk factors. The distribution was right-skewed with medians 15 and 10 U/l for men and women, respectively. Less than 3.8% of the men and 0.8% of the women had GGT greater than or equal to 50 U/l. The low level of GGT matched well with the low mortality of cirrhosis and the modest use of alcohol in Norway. Multiple regression analysis for each sex showed a strong positive association with body mass index, use of alcohol and, unexpectedly, a negative association with coffee consumption, whereas serum triglycerides and the time since the last meal showed a weaker positive association. In women, use of oral contraceptives was positively associated with GGT.

positive: How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Essential tremor (ET) is among the more prevalent neurological disorders, yet prevalence estimates have varied enormously, making it difficult to establish prevalence with precision. We: (1) reviewed the worldwide prevalence of ET in population-based epidemiological studies, (2) derived as precisely as possible an estimate of disease prevalence, and (3) examined trends and important differences across studies. We identified 28 population-based prevalence studies (19 countries). In a meta-analysis, pooled prevalence (all ages) = 0.9%, with statistically significant heterogeneity across studies (I(2) = 99%, P < 0.001). In additional descriptive analyses, crude prevalence (all ages) = 0.4%. Prevalence increased markedly with age, and especially with advanced age. In the meta-analysis, prevalence (age >or= 65 years) = 4.6%, and in additional descriptive analyses, median crude prevalence (age >or= 60-65) = 6.3%. In one study of those age >or= 95 years, crude prevalence = 21.7%. Several studies reported ethnic differences in prevalence, although more studies are needed. Greater than one-third of studies show a gender difference, with most demonstrating a higher prevalence among men. This possible gender preference is interesting given clinical, epidemiological, and pathological associations between ET and Parkinson's disease. Precise prevalence estimates such as those we provide are important because they form the numerical basis for planned public health initiatives, provide data on the background occurrence of disease for family studies, and offer clues about the existence of environmental or underlying biological factors of possible mechanistic importance. (c) 2010 Movement Disorder Society.

positive: Elevated levels of harman and norharman in cerebrospinal fluid of parkinsonian patients. Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, beta-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of beta-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n = 14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these beta-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.

positive: Blood Harmane (1-methyl-9h-pyrido[3,4-b]indole) Concentrations in Essential Tremor: Repeat Observation in Cases and Controls in New York Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors are likely to play important etiological roles. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. Previously, elevated blood harmane concentrations were demonstrated in ET cases compared to controls, but these observations were all been cross-sectional, assessing each subject at only one time point. Thus, no one has ever repeat-assayed blood harmane in the same subjects twice. Whether the observed case-control difference persists at a second time point, years later, is unknown. The current goal was to re-assess a sample of our ET cases and controls to determine whether blood harmane concentration remained elevated in ET at a second time point. Blood harmane concentrations were quantified by a well-established high performance liquid chromatography method in 63 ET cases and 70 controls. A mean of approximately 6 years elapsed between the initial and this subsequent blood harmane determination. The mean log blood harmane concentration was significantly higher in cases than controls (0.30 ± 0.61 g−10/ml vs. 0.08 ± 0.55 g−10/ml), and the median value in cases was double that of controls: 0.22 g−10/ml vs. 0.11 g−10/ml. The log blood harmane concentration was highest in cases with a family history of ET. Blood harmane concentration was elevated in ET cases compared to controls when re-assessed at a second time point several years later, indicating what seems to be a stable association between this environmental toxin and ET.

positive: Exploring the relationship between caffeine intake and essential tremor. BACKGROUND: It has been suggested that environmental factors may be associated with essential tremor (ET). This study was carried out to evaluate the association of caffeine intake with ET. METHOD: In a case control study, patients diagnosed with ET and healthy controls underwent a standardized questionnaire interview to evaluate the exposure to coffee and tea intake. A multivariate logistic regression analysis was carried out to evaluate the association of caffeine intake and other environmental factors with risk of ET. RESULTS: 179 subjects including 79 ET patients and 100 controls matched for age, gender and ethnicity were included in the analysis. Univariate analysis revealed that caffeine consumption in ET patients was higher than control group (median and 90th percentile range: 2300 (0, 9000) mg-years versus 1500 (0, 6090) mg-years, p=0.01). However, the multivariate logistic regression analysis demonstrated that caffeine was no longer a significant factor associated with ET (p=0.119). There was no significant correlation between amount of caffeine intake and disease duration (Spearman's r=0.194; p=0.202) or total tremor score (Spearman's r=0.045; p=0.771) in ET patients. CONCLUSION: Caffeine consumption was not associated with risk of ET in our study population. Further studies are needed to investigate the significance of gene-environmental interaction in ET.

positive: Quantification of the neurotoxic beta-carboline harmane in barbecued/grilled meat samples and correlation with level of doneness. Harmane, one of the heterocyclic amines (HCAs), is a potent neurotoxin linked to human diseases. Dietary exposure, especially in cooked meats, is the major source of exogenous exposure for humans. However, knowledge of harmane concentrations in cooked meat samples is limited. Our goals were to (1) quantify the concentration of harmane in different types of cooked meat samples, (2) compare its concentration to that of other more well-understood HCAs, and (3) examine the relationship between harmane concentration and level of doneness. Thirty barbecued/grilled meat samples (8 beef steak, 12 hamburger, 10 chicken) were analyzed for harmane and four other HCAs (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine [PhIP], amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [DiMeIQx], and 2-amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine [IFP]). Mean (+/- SD) harmane concentration was 5.63 (+/- 6.63) ng/g; harmane concentration was highest in chicken (8.48 +/- 9.86 ng/g) and lowest in beef steak (3.80 +/- 3.6 ng/g). Harmane concentration was higher than that of the other HCAs and significantly correlated with PhIP concentration. Harmane concentration was associated with meat doneness in samples of cooked beef steak and hamburger, although the correlation between meat doneness and concentration was greater for PhIP than for harmane. Evidence indicates that harmane was detectable in nanograms per gram quantities in cooked meat (especially chicken) and, moreover, was more abundant than other HCAs. There was some correlation between meat doneness and harmane concentration, although this correlation was less robust than that observed for PhIP. Data such as these may be used to improve estimation of human dietary exposure to this neurotoxin.

positive: Relative exposure to beta-carbolines norharman and harman from foods and tobacco smoke. Norharman and harman are two heterocyclic beta-carboline (9H-pyrido[3,4-b]indole) alkaloids with biological and potential toxicological activity that appear in foodstuffs and environmental sources. To assess the occurrence and distribution of these compounds and to estimate the exposure levels based on the detected amounts, numerous samples of foodstuffs and cigarette smoke were analysed by solid-phase extraction and high-performance liquid chromatography-fluorescence. The levels found of beta-carbolines were highly variable. Low processed foodstuffs (i.e. milk, yoghurt, uncooked meats and fish) did not contain norharman and harman above the detection limit. Others, however, contained relatively high concentrations (at the tens of ng g(-1) or microg l(-1) level) depending on the processing conditions as, for example, 'well-done' cooked meat and fish. The highest amounts of norharman and harman were found in brewed coffee (29-207 microg l(-1)), sauces (soy sauce and Tabasco, among others; 4-252 microg l(-1)), 'well done' cooked meat and fish (57-160 ng g(-1)), toasted bread (42-160 ng g(-1)), and fermented alcoholic beverages (n.d.-41 mug l(-1)). beta-Carbolines also occurred in a high amount in the mainstream of cigarette smoke (207-2780 ng/cigarette), which is an important contributor to daily exposure to these compounds. Based on these results, it is concluded that the daily exposure to beta-carbolines in humans might be from tens to hundreds of micrograms, with cigarette smoke, coffee, certain seasonings, cooked foods and alcoholic beverages, in this order, being the major contributors. Many other foodstuffs might also contribute with minor amounts of norharman and harman. Foods and tobacco smoke might be potential contributors to the reported endogenous presence of beta-carbolines in humans.

positive: Dietary Epidemiology of Essential Tremor: Meat Consumption and Meat Cooking Practices Background/Aim Harmane [1-methyl-9H-pyrido(3,4-b)indole] is a tremor-producing neurotoxin. Blood harmane concentrations are elevated in essential tremor (ET) patients for unclear reasons. Potential mechanisms include increased dietary harmane intake (especially through well-cooked meat) or genetic-metabolic factors. We tested the hypothesis that meat consumption and level of meat doneness are higher in ET cases than in controls. Methods Detailed data were collected using the Lawrence Livermore National Laboratory Meat Questionnaire. Results Total current meat consumption was greater in men with than without ET (135.3 ± 71.1 vs. 110.6 ± 80.4 g/day, p = 0.03) but not in women with versus without ET (80.6 ± 50.0 vs. 79.3 ± 51.0 g/day, p = 0.76). In an adjusted logistic regression analysis in males, higher total current meat consumption was associated with ET (OR = 1.006, p = 0.04, i.e., with 10 additional g/day of meat, odds of ET increased by 6%). Male cases had higher odds of being in the highest than lowest quartile of total current meat consumption (adjusted OR = 21.36, p = 0.001). Meat doneness level was similar in cases and controls. Conclusion This study provides evidence of a dietary difference between male ET cases and male controls. The etiological ramifications of these results warrant additional investigation. Copyright © 2008 S. Karger AG, Basel

positive: β-Carboline Alkaloids and Essential Tremor: Exploring the Environmental Determinants of One of the Most Prevalent Neurological Diseases Essential tremor (ET) is among the most prevalent neurological diseases, yet its etiology is not well understood. Susceptibility genotypes undoubtedly underlie many ET cases, although no genes have been identified thus far. Environmental factors are also likely to contribute to the etiology of ET. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent, tremor-producing β-carboline alkaloid, and emerging literature has provided initial links between this neurotoxin and ET. In this report, we review this literature. Two studies, both in New York, have demonstrated higher blood harmane levels in ET cases than controls and, in one study, especially high levels in familial ET cases. Replication studies of populations outside of New York and studies of brain harmane levels in ET have yet to be undertaken. A small number of studies have explored several of the biological correlates of exposure to harmane in ET patients. Studies of the mechanisms of this putative elevation of harmane in ET have explored the role of increased dietary consumption, finding weak evidence of increased exogenous intake in male ET cases, and other studies have found initial evidence that the elevated harmane in ET might be due to a hereditarily reduced capacity to metabolize harmane to harmine (7-methoxy-1-methyl-9H-pyrido[3,4-β]-indole). Studies of harmane and its possible association with ET have been intriguing. Additional studies are needed to establish more definitively whether these toxic exposures are associated with ET and are of etiological importance.

positive: Quantification of the co-mutagenic beta-carbolines, norharman and harman, in cigarette smoke condensates and cooked foods. Co-mutagenic beta-carbolines, such as norharman and harman, were quantified in mainstream and sidestream smoke condensates of six Japanese brands of cigarettes, and also in 13 kinds of cooked foods, using a combination of blue cotton treatment and HPLC. Norharman and harman were detected in all the cigarette smoke condensate samples. Their levels in the mainstream smoke case were 900-4240 ng per cigarette for norharman, and 360-2240 ng for harman, and in sidestream smoke, 4130-8990 ng for norharman and 2100-3000 ng for harman. These beta-carbolines were also found to be present in all the cooked food samples, at levels of 2.39-795 ng for norharman and 0.62-377 ng for harman per gram of cooked food. The observed concentrations are much higher than those found for mutagenic and carcinogenic heterocyclic amines (HCAs), suggesting that humans are exposed to norharman and harman in daily life to a larger extent than to HCAs.

positive: MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans and other primates. It is less specific and much less potent in mice and has only slight effects in rats. Differences in rates and sites of metabolism of MPTP to its active, toxic, highly polar metabolite, MPP+ (1-methyl-4-phenylpyridine), appear to influence species specificity. In rats, type B monoamine oxidase (MAO-B), which mediates the conversion of MPTP to MPP+, may act as an enzymatic barrier at brain microvessels, whereas in primates the enzyme, present mainly in astrocytes, appears important for bioactivation of MPTP into the toxic metabolite. MPP+ is a substrate for catecholamine uptake sites and is concentrated in these neurons. The molecular mechanism of MPP+ toxicity has not been established definitively, but conversion to a free radical or uptake by mitochondria and inhibition of mitochondrial respiratory enzymes, leading to calcium release and cell death have been suggested. The discovery of toxin which causes an animal model of Parkinson's disease has stimulated new research on environmental factors that might contribute to this progressive degenerative disorder and provides a means for assessing new approaches to therapy.

positive: Cancer and Blood Concentrations of the Co-mutagen Harmane in Essential Tremor Background Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a co-mutagen. Objective To compare the prevalence of cancer in ET cases vs. controls, and determine whether blood harmane concentrations are elevated among ET cases with cancer. Methods Case-control design. Results 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01 – 2.30, p = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, p = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (p = 0.02) and in participants with vs. without cancer (p = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (p = 0.009). Discussion These links between cancer and ET and between high blood harmane and cancer in ET deserve further study.

positive: Blood harmane is correlated with cerebellar metabolism in essential tremor: a pilot study. BACKGROUND: On proton magnetic resonance spectroscopic imaging ((1)H MRSI), there is a decrease in cerebellar N-acetylaspartate/total creatine (NAA/tCr) in essential tremor (ET), signifying cerebellar neuronal dysfunction or degeneration. Harmane, which is present in the human diet, is a potent tremor-producing neurotoxin. Blood harmane concentrations seem to be elevated in ET. OBJECTIVES: To assess in patients with ET whether blood harmane concentration is correlated with cerebellar NAA/tCR, a neuroimaging measure of neuronal dysfunction or degeneration. METHODS: Twelve patients with ET underwent (1)H MRSI. The major neuroanatomic structure of interest was the cerebellar cortex. Secondary regions were the central cerebellar white matter, cerebellar vermis, thalamus, and basal ganglia. Blood concentrations of harmane and another neurotoxin, lead, were also assessed. RESULTS: Mean +/- SD cerebellar NAA/tCR was 1.52 +/- 0.41. In a linear regression model that adjusted for age and gender, log blood harmane concentration was a predictor of cerebellar NAA/tCR (beta = -0.41, p = 0.009); every 1 g(-10)/mL unit increase in log blood harmane concentration was associated with a 0.41 unit decrease in cerebellar NAA/tCR. The association between blood harmane concentration and brain NAA/tCR only occurred in the cerebellar cortex; it was not observed in secondary brain regions of interest. Furthermore, the association was specific to harmane and not another neurotoxin, lead. CONCLUSION: This study provides additional support for the emerging link between harmane, a neurotoxin, and ET. Further studies are warranted to address whether cerebellar harmane concentrations are associated with cerebellar pathology in postmortem studies of the ET brain.

positive: Exposure to beta-carbolines norharman and harman. The aromatic beta-carbolines norharman and harman have been implicated in a number of human diseases including Parkinson's disease, tremor, addiction and cancer. It has been shown that these compounds are normal body constituents formed endogenously but external sources have been identified. Here, we summarise literature data on levels of norharman and harman in fried meat and fish, meat extracts, alcoholic drinks, and coffee brews. Other sources include edible and medicinal plants but tobacco smoke has been identified as a major source. Exposure levels from these different dietary sources are estimated to a maximum of 4 microg norharman per kg body weight (bw) per day and 1 microg harman per kg bw per day. Exposure via tobacco smoke depends on smoking habits and type of cigarettes but can be estimated to 1.1 microg/kg bw for norharman and 0.6 microg/kg bw for harman per package of cigarettes smoked. Studies on toxicokinetics indicate that inhalative exposure leads to a rapid increase in plasma levels and high bioavailability of norharman and harman. Oral bioavailability is lower but there are indications that sublingual absorption may increase dietary uptake of beta-carbolines. Endogenous formation can be estimated to be 50-100 ng/kg bw per day for norharman and about 20 ng/kg bw per day for harman but these rates may increase with high intake of precursors. Biomarker studies on plasma levels of beta-carbolines reported on elevated levels of norharman, harman or both in diseased patients, alcoholics and following tobacco smoking or consumption of beta-carboline-containing food. Cigarette smoking has been identified as major influence but dietary exposure may contribute to exposure.

positive: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.

positive: Blood Harmane, Blood Lead, and Severity of Hand Tremor: Evidence of Additive Effects Background Tremor is a widespread phenomenon in human populations. Environmental factors are likely to play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent tremor-producing β-carboline alkaloid. Lead is another tremor-producing neurotoxicant. The effects of harmane and lead with respect to tremor have been studied in isolation. Objectives We tested the hypothesis that tremor would be particularly severe among individuals who had high blood concentrations of both of these toxicants. Methods Blood concentrations of harmane and lead were each quantified in 257 individuals (106 essential tremor cases and 151 controls) enrolled in an environmental epidemiological study. Total tremor score (range = 0 – 36) was a clinical measure of tremor severity. Results The total tremor score ranged from 0 – 36, indicating that a full spectrum of tremor severities was captured in our sample. Blood harmane concentration correlated with total tremor score (p = 0.007), as did blood lead concentration (p = 0.045). The total tremor score was lowest in participants with both low blood harmane and lead concentrations (8.4 ± 8.2), intermediate in participants with high concentrations of either toxicant (10.5 ± 9.8), and highest in participants with high concentrations of both toxicants (13.7 ± 10.4)(p = 0.01). Conclusions Blood harmane and lead concentrations separately correlated with total tremor scores. Participants with high blood concentrations of both toxicants had the highest tremor scores, suggesting an additive effect of these toxicants on tremor severity. Given the very high population prevalence of tremor disorders, identifying environmental determinants is important for primary disease prevention.

positive: Specific stimulation of Graves' disease thyrocytes by the natural anti-Gal antibody from normal and autologous serum. Anti-Gal is a natural Ab abundantly produced in humans. It interacts specifically with the carbohydrate epitope Gal alpha 1-3Gal beta 1-4GlcNAc-R (termed the alpha-galactosyl epitope). This epitope is expressed in large amounts on thyrocytes of nonprimate mammals, but not of humans. We have previously found that binding of anti-Gal to alpha-galactosyl epitopes on porcine thyrocytes results in stimulatory effects similar to those exerted by thyroid-stimulating hormone (thyrotropin). In the present study, we tested the hypothesis that anti-Gal may contribute to Graves' disease (GD) pathogenesis by stimulation of the thyrocytes of patients with this autoimmune disorder. Anti-Gal binding and stimulatory effects were assessed in primary thyrocyte cultures. Anti-Gal specifically bound to GD thyrocytes and induced an increase in cAMP synthesis, 125I uptake, and DNA synthesis in these cells. Furthermore, the stimulatory effects of autologous sera on GD thyrocytes were greatly reduced after specific depletion of anti-Gal from these sera. No binding and no stimulatory effects of anti-Gal were observed, however, with normal human thyrocytes and with thyrocytes from thyrotoxic patients who lack thyroid-stimulating Igs or thyrotropin binding inhibiting Igs. These in vitro stimulatory effects of anti-Gal on GD thyrocytes suggest that this natural Ab may contribute to the in vivo continuous stimulation of thyrocytes in GD patients. The possibility that anti-Gal may stimulate GD thyrocytes via interaction with aberrantly expressed alpha-galactosyl epitopes on the thyroid-stimulating hormone receptor is discussed.

positive: Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose. BACKGROUND: Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-α-1,3-galactose (αGal)-specific IgE. METHODS: Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux(®) (cetuximab). IgE antibodies to αGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP(®). The αGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross-reactivity between αGal and pork kidney was studied with the ImmunoCAP(®) inhibition assay. RESULTS: Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux(®). All patients tested positive for IgE to αGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to αGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of αGal determinants. CONCLUSIONS: Pork or beef kidney anaphylaxis is related to αGal IgE. Its peculiar severity could be due to an elevated content of αGal epitopes in kidney. © 2012 John Wiley & Sons A/S.

positive: Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits Summary Anti-Gal is the most abundant natural antibody in humans, constituting ∼ 1% of immunoglobulins. Anti-Gal is naturally produced also in apes and Old World monkeys. The ligand of anti-Gal is a carbohydrate antigen called the ‘α-gal epitope’ with the structure Galα1-3Galβ1-4GlcNAc-R. The α-gal epitope is present as a major carbohydrate antigen in non-primate mammals, prosimians and New World monkeys. Anti-Gal can contributes to several immunological pathogeneses. Anti-Gal IgE produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting α-gal epitopes. Aberrant expression of the α-gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in Graves' disease. α-Gal epitopes produced by Trypanosoma cruzi interact with anti-Gal and induce ‘autoimmune like’ inflammatory reactions in Chagas' disease. Anti-Gal IgM and IgG further mediate rejection of xenografts expressing α-gal epitopes. Because of its abundance, anti-Gal may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting α-gal epitopes by targeting them for effective uptake by antigen-presenting cells. Tumour lesions are converted into vaccines against autologous tumour-associated antigens by intra-tumoral injection of α-gal glycolipids, which insert into tumour cell membranes. Anti-Gal binding to α-gal epitopes on tumour cells targets them for uptake by antigen-presenting cells. Accelerated wound healing is achieved by application of α-gal nanoparticles, which bind anti-Gal, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves.

positive: A unique natural human IgG antibody with anti-alpha-galactosyl specificity A new natural anti-alpha-galactosyl IgG antibody (anti-Gal) was found to be present in high titer in the serum of every normal individual studied. The antibody was isolated by affinity chromatography on a melibiose-Sepharose column. The reactivity of the antibody was assessed by its interaction with alpha-galactosyl residues on rabbit erythrocytes (RabRBC). The specificity was determined by inhibition experiments with various carbohydrates. The anti-Gal interacts with alpha-galactosyl residues, possibly on glycolipids of human RBC (HuRBC), after removal of membrane proteins by treatment with pronase. In addition, the anti-Gal bind specifically to normal and pathologically senescent HuRBC, suggesting a physiological role for this natural antibody in the aging of RBC. The ubiquitous presence of anti-Gal in high titers throughout life implies a constant antigenic stimulation. In addition to the theoretical interest in the antibody, the study of the anti-Gal reactivity seems to bear immunodiagnostic significance. Decrease in the antibody titer was found to reflect humoral immunodeficiency disorders.

positive: Delayed Anaphylaxis to Red Meat in Patients with IgE Specific for Galactose alpha-1,3-Galactose (alpha-gal) Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3–6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.

positive: The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose Background In 2009, we reported a novel form of delayed anaphylaxis to red meat, which is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives To investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur. Methods Serum assays were carried out using biotinylated proteins and extracts bound to a streptavidin ImmunoCAP. Results Prospective studies on IgE antibodies in three subjects following tick bites showed an increase in IgE to alpha-gal of twenty-fold or greater. Other evidence included i) a strong correlation between histories of tick bites and IgE to alpha-gal (χ2=26.8, p<0.001), ii) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and iii) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, p<0.001). Conclusion The results presented here provide evidence that tick bites are a cause, or possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.

positive: Evidence for a human-specific mechanism for diet and antibody-mediated inflammation in carcinoma progression Patients with cancer have circulating heterophile antibodies that agglutinate animal red cells via recognition of the mammalian cell surface sialic acid N-glycolylneuraminic acid (Neu5Gc), which was long considered an oncofetal antigen in humans. However, humans are genetically deficient in Neu5Gc production and instead metabolically accumulate Neu5Gc from dietary sources, particularly red meats and milk products. Moreover, mice with a human-like defect showed no alternate pathway for Neu5Gc synthesis and even normal humans express anti-Neu5Gc antibodies. We show here that human tumors accumulate Neu5Gc that is covalently attached to multiple classes of glycans. The paradox of human tumor Neu5Gc accumulation in the face of circulating anti-Neu5Gc antibodies was hypothesized to be due to facilitation of tumor progression by the resulting low-grade chronic inflammation. Indeed, murine tumors expressing human-like levels of Neu5Gc show accelerated growth in syngeneic mice with a human-like Neu5Gc deficiency, coincident with the induction of anti-Neu5Gc antibodies and increased infiltration of inflammatory cells. Transfer of polyclonal monospecific syngeneic mouse anti-Neu5Gc serum also enhanced growth of transplanted syngeneic tumors bearing human-like levels of Neu5Gc, with tumors showing evidence for antibody deposition, enhanced angiogenesis and chronic inflammation. These effects were suppressed by a cyclooxygenase-2 inhibitor, a drug type known to reduce human carcinoma risk. Finally, affinity-purified human anti-Neu5Gc antibodies also accelerate growth of Neu5Gc-containing tumors in Neu5Gc-deficient mice. Taken together, the data suggest that the human propensity to develop diet-related carcinomas is contributed to by local chronic inflammation, resulting from interaction of metabolically-accumulated dietary Neu5Gc with circulating anti-Neu5Gc antibodies.

positive: An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study. BACKGROUND: Between November, 2006, and May, 2008, a subacute neurological syndrome affected workers from two swine abattoirs in Minnesota and Indiana who had occupational exposure to aerosolised porcine brain. We aimed to describe the pathogenic and immunological characteristics of this illness. METHODS: All patients from two abattoirs who presented or were referred to the Mayo Clinic (Rochester, MN, USA) with neurological symptoms were included. We recorded details of exposure to aerosolised brain tissue and did comprehensive neurological, laboratory, neuroimaging, electrophysiological, pathological, and autoimmune serological assessments. Healthy controls were recruited from the community and from workers at the plant in Minnesota. FINDINGS: 24 patients were identified (21 from Minnesota, three from Indiana). The shortest duration from first exposure to symptom onset was 4 weeks. No infectious agent that could trigger disease was identified. All patients developed polyradiculoneuropathy, which was usually sensory predominant and painful. Two patients had initial CNS manifestations: transverse myelitis and meningoencephalitis. Nerve conduction studies localised abnormalities to the most proximal and distal nerve segments. Quantitative sensory and autonomic testing revealed involvement of large and small sensory fibres and sweat fibres. MRI showed prominent abnormalities of roots and ganglia. Nerve biopsies identified mild demyelination, axonal degeneration, and perivascular inflammation. Protein concentrations were high in the CSF of 18 (86%) of 21 patients. Sera from all patients and 29 (34%) of 85 unaffected workplace controls (but none of 178 community controls) had a distinctive neural-reactive IgG; 75% of patients' sera contained an IgG specific to myelin basic protein. Seropositivity correlated directly with exposure risk in patients and controls. 17 patients required immunomodulatory therapies, six improved spontaneously, and one was lost to follow-up after exposure stopped. INTERPRETATION: The neurological disorder described is autoimmune in origin and is related to occupational exposure to multiple aerosolised porcine brain tissue antigens. The pattern of nerve involvement suggests vulnerability of nerve roots and terminals where the blood-nerve barrier is most permeable. FUNDING: Mayo Clinic Foundation; Minnesota Department of Health; Centers for Disease Control and Prevention. Copyright 2010 Elsevier Ltd. All rights reserved.

positive: Anti-Gal titers in healthy adults and inflammatory bowel disease patients. INTRODUCTION: ALPHA-GAL is a glycoconjugate present on cell membranes of mammals and bacteria but not humans who display anti-Gal antibodies (AB) in high titers provoked by the commensal gut flora. In the present study, we sought to determine the longitudinal course of alpha-Gal specific AB titers of all isotypes over 8 weeks among healthy adult subjects. Furthermore, we hypothesized that inflammatory bowel disease (IBD) patients display increased anti-Gal titers. MATERIALS AND METHODS: We drew serum from healthy probands (n=20) weekly for 8 weeks and obtained plasma samples of from patients suffering from Crohn's disease (n=20) and ulcerative colitis (n=20). We measured anti-Gal ABs of all isotypes and total immunoglobulin (Ig) content using an enzyme-linked immunosorbent assay technique. For statistical evaluation of the longitudinal titers, we calculated confidence intervals for the slopes of a random intercept model, comparing variances between and within the probands. For group comparisons, we performed paired student t-tests and Pearson correlations. RESULTS: Alpha-Gal specific IgG, IgM, IgD, and IgA titers remained unvaried within a narrow range upon longitudinal observation. Most probands did not display alpha-Gal specific IgE ABs. Crohn's disease patients showed highly increased alpha-Gal-specific IgA titers compared with control subjects (P<.01). CONCLUSION: Apart from IgE, alpha-Gal-specific ABs of all isotypes remained constant over longer time periods in healthy subjects. Thus, significant titer changes actually represent increased antigen exposure and a specific anti-alpha-Gal response. Crohn's disease patients display increased anti-Gal IgA titers compared with healthy controls, which reflects a chronically impaired mucosal gut barrier in this patient cohort. Copyright © 2011 Elsevier Inc. All rights reserved.

positive: STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Lyme-like illness (also known as southern tick-associated rash illness [STARI] or Masters disease) is vectored by the Lone Star tick (Amblyomma americanum). Lyme-like illness lesions, which are similar to the erythema migrans rash of Lyme disease, tend to have lymphocytic dermal infiltrates. With the exception of Borrelia lonestari, the possible causative agent or agents of Lyme-like illness have not been cultured. More research is needed to fully understand this newly recognized zoonosis. Clinicians are encouraged to increase their knowledge and awareness of this Lyme disease mimic.

positive: Southern Tick-Associated Rash Illness (STARI) in the North: STARI following a tick bite in Long Island, New York. The most common clinical manifestation of Lyme disease is the characteristic rash, erythema migrans (EM). In the 1980s EM-like eruptions were reported in Missouri and other southeastern states. The EM-like eruptions, which were of unknown etiology, often followed the bite of the Lone Star tick (Amblyomma americanum) and the rash is called STARI (southern tick-associated rash illness). Although the Lone Star tick is found in the Lyme disease-endemic areas of New England and Mid-Atlantic regions of the United States, STARI has been reported only once from the Northeast and Mid-Atlantic regions. We report a child from Connecticut who visited Long Island, New York, and developed a rash that was thought to be EM. Because the patient failed to respond to antibiotics used to treat Lyme disease, an investigation ensued, and the diagnosis of STARI was established.

positive: Distribution of Gal alpha 1----3Gal beta 1----4GlcNAc residues on secreted mammalian glycoproteins (thyroglobulin, fibrinogen, and immunoglobulin G... The study of the expression of Gal alpha 1----3Gal beta 1----4GlcNAc residues on mammalian glycoconjugates is of particular interest since as many as 1% of circulating IgG antibodies in man (the natural anti-Gal antibody) interact specifically with this carbohydrate residue. In recent studies, we have found that Gal alpha 1----3Gal beta 1----4GlcNAc residues are abundant on red cells and nucleated cells of nonprimate mammals, prosimians, and New World monkeys, but their expression is diminished in Old World monkeys, apes, and humans. In the present work, we have analyzed the expression of these residues on secreted mammalian glycoproteins. For this purpose, we have developed a radioimmunoassay (RIA) which enables the quantification of Gal alpha 1----3Gal beta 1----4GlcNAc residues on the secreted glycoproteins. Purified biotinylated anti-Gal was used as the antibody in the RIA, and bovine thyroglobulin enriched for Gal alpha 1----3Gal beta 1----4GlcNAc residues served as a solid-phase antigen. In this study, it is reported for the first time that the evolutionary pattern of Gal alpha 1----3Gal beta 1----4GlcNAc residue distribution in in vivo secreted glycoproteins is similar to that observed in membranes of cell lines and of red cells. Thyroglobulin, fibrinogen, or IgG molecules from nonprimate mammals and from New World monkeys express varying amounts of Gal alpha 1----3Gal beta 1----4GlcNAc residues ranging between 0.01 and 11 residues per molecule, whereas no such residues are present on any of these glycoproteins of human or Old World monkey origin.(ABSTRACT TRUNCATED AT 250 WORDS)

positive: A pattern of anti-carbohydrate antibody responses present in patients with advanced atherosclerosis. We have previously shown that an antibody pool present in normal human serum binds cytokine receptors in vitro and may therefore interfere with assays that capture cytokines using their receptors. Here we show that this antibody pool is the same as the natural antibody termed anti-gal, that binds to the alpha-galactosyl carbohydrate epitope (alpha-gal) and which is the predominant obstacle to xenotransplantation. We report that there are high levels of IgD anti alpha-gal in most volunteers, in addition to the IgG2, IgA and IgM immunoglobulin isotypes against alpha-gal previously described. To determine if anti-gal may interfere with assays that depend on capture of cytokine with its receptor, we measured levels of several anti-carbohydrate antibodies in a cohort of patients with advanced atherosclerosis that had previously been used to measure levels of active TGF-beta using such an assay. For many isotype / carbohydrate combinations, there is a large and significant difference between the levels of anti-carbohydrate antibodies in patients with atherosclerosis and controls, after adjustment for age, sex and blood group. These results are similar to the previous data obtained for active TGF-beta, and therefore we cannot discount the possibility that anti-gal contributed to the previous data. Following further adjustment for several risk factors associated with cardiovascular disease, several anti-carbohydrate antibodies were still significantly different between patients and controls. Therefore, anti-carbohydrate antibodies may represent a new class of risk factors that may be associated with presence of advanced atherosclerosis, although larger studies will be required to confirm this hypothesis.

positive: Natural human anti-Gal alpha(1,3)Gal antibodies react with human mucin peptides. We have recently demonstrated that both antibodies to Gal alpha(1,3)Gal, and the Gal alpha(1,3)Gal binding lectin (IB4), bind a synthetic peptide (DAHWESWL), there being a similar recognition of carbohydrate and peptide structures. We now report that the anti-Gal alpha(1,3)Gal antibodies and IB4 lectin also react with peptides encoded by mucin genes (MUC 1, 3, 4)-sequences known to be rich in serine, threonine and proline. This activity was demonstrated (1) by the ability of mucin derived peptides to block the reaction of anti-Gal alpha(1,3)Gal antibodies and IB4 lectin with a Gal alpha(1,3)Gal+ pig endothelial cell line; the reactions were specific and did not occur with a random peptide containing the same sequences or with other mucin peptides; (2) by the fact that anti-mucin1 antibodies could react with the Gal alpha(1,3)Gal expressed after transfection of COS cells (Gal alpha(1,3)Gal-,Muc1-) with cDNA encoding the pig alpha, 3galactosyltransferase; and (3) that the IB4 lectin and anti-Gal alpha(1,3)Gal antibodies could react with mucin 1 found on the surface of human breast cancer cells. Thus natural occurring anti-Gal alpha(1,3)Gal antibodies found in all human serum can react with self (Muc1) peptides expressed in large amounts on the surface of tumour cells but not on normal cells. The findings are of interest and serve to explain the previously reported findings that human cells can, at times, express Gal alpha(1,3)Gal; such expression is an artefact, the reaction is due to the phenomenon described herein, i.e. that anti-Gal alpha(1,3)Gal antibodies react with mucin peptides.

positive: An association between tick bite reactions and red meat allergy in humans. Twenty-five patients living in a tick-endemic region of Sydney, New South Wales developed red meat allergy after experiencing large local reactions to tick bites. This represents a potentially novel cross-reaction between an arthropod and a food protein. (MJA 2009; 190: 510-511).

positive: A possible role for the alpha 1-->3 galactosyl epitope and the natural anti-gal antibody in oncogenesis. Glycoconjugates and their antibodies are vital components of host-tumor interaction. This review concentrates on the oncological implications of research concerning the alpha gal triad; the alpha 1-->3 galactosyl epitope (alpha Gal), the enzyme responsible for its construction, alpha 1,3 galactosyl transferase (alpha 1-3GT), and its associated antibody: anti-gal. Alpha gal epitopes, previously assumed to be absent from human tissue, have been demonstrated on several human cancer cell lines, senescent red blood cells, and Graves' disease thyrocytes. Alpha-gal presence on neoplastic lines is correlated with increased metastatic formation in animal models. The mechanisms of human response to these neoantigens are complex, as natural anti-gal antibodies exist in high titers in normal sera, thus predicting immunological recognition of cells expressing alpha gal epitopes. Hypotheses vary regarding the pathogenic contributions of metastasis-associated phenomena such as de novo expression of alpha gal and its unmasking by desialylation. The means by which alpha gal is sporadically expressed in human tissue remain unknown, as the galactosyl transferase which produces this epitope in constitutively expressive animals has undergone significant mutation at the genomic level in humans. Pathological re-expression is presumed to require permissive changes at a cellular level. Detailing these alterations is a prerequisite to the comprehension of the metastatic phenotype. In this context, the possibility of therapeutic strategies affecting alpha gal expression are also discussed.

positive: Naturally developing memory T cell xenoreactivity to swine antigens in human peripheral blood lymphocytes. Naturally developing xenospecific Abs are well-documented barriers to xenograft transplantation in humans, but whether analogous xenoreactive T cell immunity develops is not known. We used an enzyme-linked immunospot assay to determine the frequency and cytokine profiles of xenoreactive PBLs from a panel of human volunteers. Because naive T cells produce only IL-2 in short term culture, IFN-gamma production by this approach is a measure of a memory immune response. Stimulation of human PBLs or purified T lymphocytes with stimulator cells from inbred swine revealed a high frequency of IFN-gamma producers with 5-fold fewer IL-2 producers. In contrast, lymphocytes obtained from neonatal umbilical cord blood contained swine-specific IL-2 producers but few IFN-gamma producers, which is what one would expect to find with a naive phenotype. Moreover, PBLs from adults with a history of abstention from pork consumption responded to swine cells with a significantly lower frequency of IFN-gamma producers than PBLs from adults with unrestricted diets did, suggesting that pork consumption may result in priming of swine-specific T cell immunity. Our findings provide the first evidence for naturally occurring xenospecific T cell immunity in humans. The detected strength of this memory response suggests that it will present a formidable barrier to transplantation of swine organs.

positive: Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. BACKGROUND: Microparticles (MPs) with procoagulant activity are present in human atherosclerosis, but no detailed information is available on their composition. METHODS AND RESULTS: To obtain insights into the role of MPs in atherogenesis, MP proteins were identified by tandem mass spectrometry, metabolite profiles were determined by high-resolution nuclear magnetic resonance spectroscopy, and antibody reactivity was assessed against combinatorial antigen libraries. Plaque MPs expressed surface antigens consistent with their leukocyte origin, including major histocompatibility complex classes I and II, and induced a dose-dependent stimulatory effect on T-cell proliferation. Notably, taurine, the most abundant free organic acid in human neutrophils, which scavenges myeloperoxidase-catalyzed free radicals, was highly enriched in plaque MPs. Moreover, fluorescent labeling of proteins on the MP surface suggested immunoglobulins to be trapped inside, which was confirmed by flow cytometry analysis on permeabilized and nonpermeabilized plaque MPs. Colabeling for CD14 and IgG established that more than 90% of the IgG containing MPs were CD14(+), indicating a macrophage origin. Screening against an antigen library revealed that the immunologic profiles of antibodies in MPs were similar to those found in plaques but differed profoundly from antibodies in plasma and unexpectedly, showed strong reactions with oligosaccharide antigens, in particular blood group antigen A. CONCLUSIONS: This study provides the first evidence that immunoglobulins are present within MPs derived from plaque macrophages, that the portfolio of plaque antibodies is different from circulating antibodies in plasma, and that anticarbohydrate antibodies are retained in human atherosclerotic lesions.

positive: Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose Background Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. Objective We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. Methods Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. Results Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal. Conclusion We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.

positive: Medical nutrition therapy for hypercholesterolemia positively affects patient satisfaction and quality of life outcomes. Following a heart-healthy diet to lower cholesterol levels is often assumed to be difficult, to be burdensome, and to have a negative impact on quality of life (QOL). The purpose of this study was to evaluate the impact of medical nutrition therapy (MNT) versus usual care (UC) for hypercholesterolemia on patient satisfaction and QOL. Ninety ambulatory care patients (60 men and 30 women), age 28 to 66, were randomly assigned to receive either MNT from dietitians using a National Cholesterol Education Program-based protocol or UC from their physicians. Patients who received MNT reported no difference in QOL related to the taste or enjoyment of food compared with UC patients. However, the MNT group reported initial improvements in QOL related to the convenience and cost of following a low-fat diet when compared with the UC group. The MNT group also reported significant and lasting improvements in perceived QOL related to self-care compared with the UC group. MNT patients were more satisfied with the interaction at visits, knowledge and ability to manage their cholesterol, eating habits, appearance, time spent exercising, and life in general. Moreover, MNT patients did not report any negative impact related to following a low-fat diet in regard to feeling restricted by diet; interference with lifestyle activities; or difficulty planning, purchasing, or preparing meals or eating away from home. Contrary to popular belief there is no apparent reduction but rather an improvement in some measures of QOL and patient satisfaction with MNT for hypercholesterolemia.

positive: A global survey of physicians' perceptions on cholesterol management: the From The Heart study. AIMS: Guidelines for cardiovascular disease (CVD) prevention cite high levels of low-density lipoprotein cholesterol (LDL-C) as a major risk factor and recommend LDL-C goals for various risk groups. Lifestyle changes are advised as first-line treatment for patients with high cholesterol, and statins are recommended in high-risk patients. The From The Heart study investigated current practice for the diagnosis and treatment of high cholesterol, and attitudes towards management of the condition. METHODS: Physicians were randomly selected from 10 countries, and completed a confidential, semi-structured questionnaire. RESULTS: Of 2790 physicians agreeing to participate, 750 (27%) responded. Physicians rated CVD as the leading cause of death, although physicians (80%) perceived that cancer was the most feared illness among patients. Physicians (71%) believed smoking to be the greatest CVD risk factor, while only 50% thought high cholesterol was the greatest risk. Most physicians (81%) used guidelines to set cholesterol goals, primarily their national guidelines (34%) or the National Cholesterol Education Program Adult Treatment Panel III guidelines (24%). Although only 47% of patients reached and maintained their cholesterol goals, 61% of physicians believed that a sufficient number of patients achieved goals, and 53% did not feel frustrated that they could not always effectively treat patients with CVD. CONCLUSION: Results indicate discrepancies between guideline recommendations and clinical practice. Although physicians appreciate the risk of CVD, the importance of achieving healthy cholesterol levels for CVD prevention does not seem to be widely endorsed. There is a need for improved communication regarding the importance of cholesterol lowering and investigation of initiatives to improve goal achievement among physicians.

positive: Diet, lifestyle, and the etiology of coronary artery disease: the Cornell China study. Investigators collected and analyzed mortality data for >50 diseases, including 7 different cancers, from 65 counties and 130 villages in rural mainland China. Blood, urine, food samples, and detailed dietary data were collected from 50 adults in each village and analyzed for a variety of nutritional, viral, hormonal, and toxic chemical factors. In rural China, fat intake was less than half that in the United States, and fiber intake was 3 times higher. Animal protein intake was very low, only about 10% of the US intake. Mean serum total cholesterol was 127 mg/dL in rural China versus 203 mg/dL for adults aged 20-74 years in the United States. Coronary artery disease mortality was 16.7-fold greater for US men and 5.6-fold greater for US women than for their Chinese counterparts. The combined coronary artery disease mortality rates for both genders in rural China were inversely associated with the frequency of intake of green vegetables and plasma erythrocyte monounsaturated fatty acids, but positively associated with a combined index of salt intake plus urinary sodium and plasma apolipoprotein B. These apolipoproteins, in turn, are positively associated with animal protein intake and the frequency of meat intake and inversely associated with plant protein, legume, and light-colored vegetable intake. Rates of other diseases were also correlated with dietary factors. There was no evidence of a threshold beyond which further benefits did not accrue with increasing proportions of plant-based foods in the diet.

positive: Improvements in hostility and depression in relation to dietary change and cholesterol lowering. The Family Heart Study. OBJECTIVE: To describe changes in negative emotions among participants of a cholesterol-lowering study. DESIGN: Cohort study. Quantitative evaluation of changes in negative emotions in relation to diet and plasma cholesterol levels before and after a 5-year dietary intervention program aimed at reducing plasma cholesterol levels. SETTING: Community-dwelling families of the Family Heart Study, Portland, Oregon. PARTICIPANTS: One hundred forty-nine men and 156 women from 233 families (mean age, 37.7 years). MEASUREMENTS: Changes in negative emotions including depression and aggressive hostility as measured by the Hopkins Symptom Checklist (SCL-90). RESULTS: Improvement in overall emotional state was noted for the entire sample. Those who consumed a low-fat, high complex-carbohydrate diet at the end of the study showed significantly greater improvements in depression (P = 0.044; difference in improvement, 2.9 points) and aggressive hostility (P = 0.035; difference in improvement, 3.3 points) as well as a reduction in their plasma cholesterol levels (P = 0.024; difference in improvement, 2.7%) compared with those who ate a high-fat "American diet." CONCLUSIONS: Participation in a cholesterol-lowering program may not be associated with a worsening in emotional state. To the contrary, improvements in diet appear to be associated with reductions in depression and aggressive hostility as well as with lowered plasma cholesterol levels.

positive: Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function. We tested the effects of feeding a diet very high in fiber from fruit and vegetables. The levels fed were those, which had originally inspired the dietary fiber hypothesis related to colon cancer and heart disease prevention and also may have been eaten early in human evolution. Ten healthy volunteers each took 3 metabolic diets of 2 weeks duration. The diets were: high-vegetable, fruit, and nut (very-high-fiber, 55 g/1,000 kcal); starch-based containing cereals and legumes (early agricultural diet); or low-fat (contemporary therapeutic diet). All diets were intended to be weight-maintaining (mean intake, 2,577 kcal/d). Compared with the starch-based and low-fat diets, the high-fiber vegetable diet resulted in the largest reduction in low-density lipoprotein (LDL) cholesterol (33% +/- 4%, P <.001) and the greatest fecal bile acid output (1.13 +/- 0.30 g/d, P =.002), fecal bulk (906 +/- 130 g/d, P <.001), and fecal short-chain fatty acid outputs (78 +/- 13 mmol/d, P <.001). Nevertheless, due to the increase in fecal bulk, the actual concentrations of fecal bile acids were lowest on the vegetable diet (1.2 mg/g wet weight, P =.002). Maximum lipid reductions occurred within 1 week. Urinary mevalonic acid excretion increased (P =.036) on the high-vegetable diet reflecting large fecal steroid losses. We conclude that very high-vegetable fiber intakes reduce risk factors for cardiovascular disease and possibly colon cancer. Vegetable and fruit fibers therefore warrant further detailed investigation. Copyright 2001 by W.B. Saunders Company

positive: The new pathophysiology of coronary artery disease. Our understanding of coronary artery disease risk and the atherosclerotic process has changed greatly in recent years. For example, it is now known that angiographically apparent coronary artery plaque is not the major cause of myocardial infarction (MI). Rather, it is unstable, soft plaque that cannot be seen angiographically that is prone to rupture and result in infarction. Also important are changes in vascular reactivity resulting from diet. Cholesterol levels by themselves reveal little about a patient's coronary artery disease risk. Most infarctions occur in patients who have normal total cholesterol levels. At-risk patients can be identified using the ratio of total-to-high-density lipoprotein (HDL) cholesterol levels. The ratio of triglyceride to HDL cholesterol levels is also important. Simple steps to assess patients' risk in practice are outlined. Primary prevention trials demonstrate that coronary artery disease risk can be lowered dramatically with diet and drug therapy.

positive: The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes. Azo dyes are widely used in textile, printing, cosmetic, drug and food-processing industries. They are also used extensively in laboratories as either biological stains or pH indicators. The extent of such use is related to the degree of industrialization. Since intestinal cancer is more common in highly industrialized countries, a possible connection may exist between the increase in the number of cancer cases and the use of azo dyes. Azo dyes can be reduced to aromatic amines by the intestinal microflora. The mutagenicity of a number of azo dyes is reviewed in this paper. They include Trypan Blue, Ponceau 3R, Pinceau 2R, Methyl Red, Methyl Yellow, Methyl Orange, Lithol Red, Orange I, Orange II, 4-Phenylazo-Naphthylamine, Sudan I, Sudan IV, Acid Alizarin Violet N, Fast Garnet GBC, Allura Red, Ponceau SX, Sunset Yellow, Tartrazine, Citrus Red No. 2, Orange B, Yellow AB, Carmoisine, Mercury Orange, Ponceau S, Versatint Blue, Phenylazophenol, Evan's Blue and their degraded aromatic amines. The significance of azo reduction in the mutagenesis and carcinogenesis of azo dyes is discussed.

positive: Teratological evaluation of FD&C Red no. 2 -a collaborative government-industry study. II. FDA's study. Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No. 2, and ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrial Bio-Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD&C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River strain at IBT showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.

positive: Toxicology of food dyes. BACKGROUND: Food dyes, synthesized originally from coal tar and now petroleum, have long been controversial because of safety concerns. Many dyes have been banned because of their adverse effects on laboratory animals or inadequate testing. CONCLUSIONS: This review finds that all of the nine currently US-approved dyes raise health concerns of varying degrees. Red 3 causes cancer in animals, and there is evidence that several other dyes also are carcinogenic. Three dyes (Red 40, Yellow 5, and Yellow 6) have been found to be contaminated with benzidine or other carcinogens. At least four dyes (Blue 1, Red 40, Yellow 5, and Yellow 6) cause hypersensitivity reactions. Numerous microbiological and rodent studies of Yellow 5 were positive for genotoxicity. Toxicity tests on two dyes (Citrus Red 2 and Orange B) also suggest safety concerns, but Citrus Red 2 is used at low levels and only on some Florida oranges and Orange B has not been used for several years. The inadequacy of much of the testing and the evidence for carcinogenicity, genotoxicity, and hypersensitivity, coupled with the fact that dyes do not improve the safety or nutritional quality of foods, indicates that all of the currently used dyes should be removed from the food supply and replaced, if at all, by safer colorings. It is recommended that regulatory authorities require better and independent toxicity testing, exercise greater caution regarding continued approval of these dyes, and in the future approve only well-tested, safe dyes.

positive: Genotoxic and mutagenic effects of erythrosine B, a xanthene food dye, on HepG2 cells. Erythrosine (ErB) is a xanthene and an US Food and Drug Administration approved dye used in foods, drugs and cosmetics. Although its utilization is permitted, ErB is described as inhibitor of enzymes and protein-protein interactions and is toxic to pituitary and spermatogenesis processes. However, the genotoxicity and mutagenicity of ErB is inconclusive in the literature. This study aimed to analyze the genotoxicity of this dye using the alkaline comet assay and is the first investigation to evaluate ErB mutagenicity using the cytokinesis block micronucleus cytome (CBMN-Cyt) assay in HepG2 cells. These cells were chosen because they produce phase I and phase II enzymes that can mimic in vivo metabolism. The cells were treated with seven concentrations (0.1-70.0 μg mL(-1)) of ErB, and the results showed genotoxicity at the two highest concentrations and mutagenicity at six concentrations. Furthermore, as micronuclei result from clastogenic and aneugenic processes, while comet assay is often considered more sensitive and detects DNA single strain breaks, we suggest that an aneugenic is responsible for the observed damage. Although ErB is approved for use in the food, cosmetic and pharmaceutical industries, it must be used carefully because it damages the DNA structure. Copyright © 2012 Elsevier Ltd. All rights reserved.

positive: p53: guardian of the genome and policeman of the oncogenes. The process of malignant transformation universally entails genetic damage and oncogenic signaling, two stresses that are signaled to p53 through different genetic pathways. Based on this, it is possible to distinguish two jobs for p53: "guardian of the genome" that consists in sensing and reacting to DNA damage through the ATM/ATR and Chk1/Chk2 kinases, and "policeman of the oncogenes" that, correspondingly, consists in responding to oncogenic signaling through the p53-stabilizing protein ARF. Contrary to expectation, recent genetic evidence in mice indicates that the response of p53 to DNA damage has little or no impact on cancer protection. In contrast, ARF-dependent activation of p53 is critical for p53-mediated tumor suppression. Here, we discuss the mechanistic implications of these observations and their relevance for cancer therapy.

positive: Curcumin, a component of turmeric: from farm to pharmacy. Curcumin, an active polyphenol of the golden spice turmeric, is a highly pleiotropic molecule with the potential to modulate the biological activity of a number of signaling molecules. Traditionally, this polyphenol has been used in Asian countries to treat such human ailments as acne, psoriasis, dermatitis, and rash. Recent studies have indicated that curcumin can target newly identified signaling pathways including those associated with microRNA, cancer stem cells, and autophagy. Extensive research from preclinical and clinical studies has delineated the molecular basis for the pharmaceutical uses of this polyphenol against cancer, pulmonary diseases, neurological diseases, liver diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, and numerous other chronic diseases. Multiple studies have indicated the safety and efficacy of curcumin in numerous animals including rodents, monkeys, horses, rabbits, and cats and have provided a solid basis for evaluating its safety and efficacy in humans. To date, more than 65 human clinical trials of curcumin, which included more than 1000 patients, have been completed, and as many as 35 clinical trials are underway. Curcumin is now used as a supplement in several countries including the United States, India, Japan, Korea, Thailand, China, Turkey, South Africa, Nepal, and Pakistan. In this review, we provide evidence for the pharmaceutical uses of curcumin for various diseases. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

positive: Effect of different curcumin dosages on human gall bladder. Our previous study demonstrated that curcumin, an active compound of Curcuma xanthorrhiza and C. domestica, produces a positive cholekinetic effect. A 20 mg amount of curcumin is capable of contracting the gall bladder by up to 29% within an observation time of 2 h. The aim of the current study was to define the dosage of curcumin capable of producing a 50% contraction of the gall bladder, and to determine if there is a linear relationship between doubling the curcumin dosage and the doubling of gall bladder contraction. A randomised, single-blind, three-phase, crossover-designed examination was carried out on 12 healthy volunteers. Ultrasonography was carried out serially to measure the gall bladder volume. The data obtained was analysed by analysis of variance (ANOVA). The fasting volumes of gall bladders were similar (P > 0.50), with 17.28 +/- 5.47 mL for 20 mg curcumin, 18.34 +/- 3.75 mL for 40 mg and 18.24 +/- 3.72 mL for 80 mg. The percentage decrease in gall bladder volume 2 h after administration of 20, 40 and 80 mg was 34.10 +/- 10.16, 51.15 +/- 8.08 and 72.25 +/- 8.22, respectively, which was significantly different (P < 0.01). On the basis of the present findings, it appears that the dosage of cucumin capable of producing a 50% contraction of the bladder was 40 mg. This study did not show any linear relationship between doubling curcumin dosage and the doubling of gall bladder contraction.

positive: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. BACKGROUND & AIMS: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). METHODS: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. RESULTS: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. CONCLUSIONS: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

positive: Multitargeting by turmeric, the golden spice: From kitchen to clinic. Although much has been published about curcumin, which is obtained from turmeric, comparatively little is known about turmeric itself. Turmeric, a golden spice obtained from the rhizome of the plant Curcuma longa, has been used to give color and taste to food preparations since ancient times. Traditionally, this spice has been used in Ayurveda and folk medicine for the treatment of such ailments as gynecological problems, gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of turmeric against such disorders. Various chemical constituents have been isolated from this spice, including polyphenols, sesquiterpenes, diterpenes, triterpenoids, sterols, and alkaloids. Curcumin, which constitutes 2-5% of turmeric, is perhaps the most-studied component. Although some of the activities of turmeric can be mimicked by curcumin, other activities are curcumin-independent. Cell-based studies have demonstrated the potential of turmeric as an antimicrobial, insecticidal, larvicidal, antimutagenic, radioprotector, and anticancer agent. Numerous animal studies have shown the potential of this spice against proinflammatory diseases, cancer, neurodegenerative diseases, depression, diabetes, obesity, and atherosclerosis. At the molecular level, this spice has been shown to modulate numerous cell-signaling pathways. In clinical trials, turmeric has shown efficacy against numerous human ailments including lupus nephritis, cancer, diabetes, irritable bowel syndrome, acne, and fibrosis. Thus, a spice originally common in the kitchen is now exhibiting activities in the clinic. In this review, we discuss the chemical constituents of turmeric, its biological activities, its molecular targets, and its potential in the clinic. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

positive: Curcumin: the story so far. Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.

positive: Mitochondrial and nuclear DNA damage induced by curcumin in human hepatoma G2 cells. Curcumin is extensively used as a spice and pigment and has anticarcinogenic effects that could be linked to its antioxidant properties. However, some studies suggest that this natural compound possesses both pro- and antioxidative effects. In this study, we found that curcumin induced DNA damage to both the mitochondrial and nuclear genomes in human hepatoma G2 cells. Using quantitative polymerase chain reaction and immunocytochemistry staining of 8-hydroxydeoxyguanosine, we demonstrated that curcumin induced dose-dependent damage in both the mitochondrial and nuclear genomes and that the mitochondrial damage was more extensive. Nuclear DNA fragments were also evident in comet assays. The mechanism underlies the elevated level of reactive oxygen species and lipid peroxidation generated by curcumin. The lack of DNA damage at low doses suggested that low levels of curcumin does not induce DNA damage and may play an antioxidant role in carcinogenesis. But at high doses, we found that curcumin imposed oxidative stress and damaged DNA. These data reinforce the hypothesis that curcumin plays a conflicting dual role in carcinogenesis. Also, the extensive mitochondrial DNA damage might be an initial event triggering curcumin-induced cell death.

positive: Therapeutic potential of turmeric in Alzheimer's disease: curcumin or curcuminoids? Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease. Copyright © 2013 John Wiley & Sons, Ltd.

positive: Farming, growing up on a farm, and haematological cancer mortality. OBJECTIVES: Occupation as a farmer has been associated with increased risks of haematological cancers in adults. This study aimed to examine whether farm exposures in childhood contribute to these risks, by using parental occupation in farming as a proxy for growing up on a farm. METHODS: New Zealand death records (1998-2003) of persons aged 35-85 were extracted (n=114 289). For 82.3% usual occupation and the occupation of at least one of the parents could be coded (n=94 054). Unconditional logistic regression analyses included 3119 haematological cancer deaths (cases) and 90 935 deaths from other causes (controls). ORs for farming and growing up on a farm were adjusted for each other, year of birth, age at death, socio-economic status, Māori ethnicity, immigration status and sex. RESULTS: Growing up on a livestock farm was positively associated with haematological cancer (OR 1.22, 95% CI 1.05 to 1.41), particularly for poultry farms (OR 2.99, 95% CI 1.44 to 6.21), while growing up on a crop farm was not (OR 0.81, 95% CI 0.64 to 1.03). Crop farming in adulthood was associated with an increased haematological cancer risk (OR 1.49, 95% CI 1.13 to 1.96), while livestock farming was not (OR 0.80, 95% CI 0.63 to 1.00), except for beef cattle farming (OR 2.99, 95% CI 1.28 to 7.00). These results did not change appreciably when different control groups with different causes of death were used. CONCLUSIONS: These results could suggest a role for early life biological exposures in the development of haematological cancers.

positive: Mortality in workers employed in pig abattoirs and processing plants. OBJECTIVE: workers in slaughterhouses and processing plants that handle pigs, and pork butchers/meatcutters have been little studied for health risks associated with employment, in spite of the fact that they are potentially exposed to oncogenic and non-oncogenic transmissible agents and chemical carcinogens at work. We report here on an update of mortality in 510 workers employed in abattoirs and processing plants that almost exclusively handled pigs and pork products. METHODS: standardized mortality ratios (SMRs) were estimated for the cohort as a whole, and in subgroups defined by race and sex, using the corresponding US general population mortality rates for comparison. Study subjects were followed up from January 1950 to December 2006, during which time 45% of them died. RESULTS: mortality was significantly increased overall in the cohort. A statistically significant excess of deaths was observed for colon and lung cancers in the entire cohort, SMR=2.7 (95% CI, 1.2-5.1), SMR=1.8 (95% CI, 1.1-2.7), respectively. Significant SMRs in the cohort as a whole were also observed for senile and pre-senile psychotic conditions (SMR=5.1, 95% CI, 1.4-13.1), and pneumonia (SMR=2.6, 95% CI, 1.3-4.8). An observed excess of subarachnoid hemorrhage was seen mainly in whites (SMR=10.1, 95% CI, 1.2-36.3). There was a suggestion of an excess of deaths from ischemic heart disease also, but the elevated SMR was confined to men and was not statistically significant. CONCLUSION: this study confirms the excess occurrence of lung and colon cancers, and stroke previously reported in this occupational group. New findings are the excess of risk for senile and pre-senile psychotic conditions and pneumonia, which together with the excess of colon cancer appear specific for pig/pork workers, as they were not evident in much larger studies of workers in abattoirs and processing plants handling cattle and sheep. However, caution should be exercised in interpreting these findings, since some of them could have occurred by chance, resulting from our examination of a large number of causes of death in multiple study subgroups. For the moment, the significance of these findings remains unknown until they are confirmed in larger studies of adequate statistical power. Studies that will take into account possible occupational and non-occupational confounding factors are needed. Copyright © 2011. Published by Elsevier Inc.

positive: The Restriction of Zoonotic PERV Transmission by Human APOBEC3G The human APOBEC3G protein is an innate anti-viral factor that can dominantly inhibit the replication of some endogenous and exogenous retroviruses. The prospects of purposefully harnessing such an anti-viral defense are under investigation. Here, long-term co-culture experiments were used to show that porcine endogenous retrovirus (PERV) transmission from pig to human cells is reduced to nearly undetectable levels by expressing human APOBEC3G in virus-producing pig kidney cells. Inhibition occurred by a deamination-independent mechanism, likely after particle production but before the virus could immortalize by integration into human genomic DNA. PERV inhibition did not require the DNA cytosine deaminase activity of APOBEC3G and, correspondingly, APOBEC3G-attributable hypermutations were not detected. In contrast, over-expression of the sole endogenous APOBEC3 protein of pigs failed to interfere significantly with PERV transmission. Together, these data constitute the first proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. These studies suggest that human APOBEC3G-transgenic pigs will provide safer, PERV-less xenotransplantation resources and that analogous cross-species APOBEC3-dependent restriction strategies may be useful for thwarting other endogenous as well as exogenous retrovirus infections.

positive: Cancer mortality in workers employed in cattle, pigs, and sheep slaughtering and processing plants. OBJECTIVES: We studied mortality in two separate cohorts of workers in abattoirs (N=4996) and meat processing plants (N=3642) belonging to a meatcutters' union, because they were exposed to viruses that cause cancer in food animals, and also to chemical carcinogens at work. METHODS: Standardized mortality ratios (SMRs) and proportional mortality ratios (PMRs) were estimated for each cohort as a whole and in subgroups defined by race and sex, using the US general population mortality rates for comparison. Study subjects were followed up from January 1950 to December 2006, during which time over 60% of them died. RESULTS: An excess of deaths from cancers of the base of the tongue, esophagus, lung, skin, bone and bladder, lymphoid leukemia, and benign tumors of the thyroid and other endocrine glands, and possibly Hodgkin's disease, was observed in abattoir and meat processing workers. Significantly lower SMRs were recorded for cancer of the thymus, mediastinum, pleura, etc., breast cancer, and non-Hodgkin's lymphoma. CONCLUSION: This study confirms the excess occurrence of cancer in workers in abattoirs and meat processing plants, butchers, and meatcutters, previously reported in this cohort and other similar cohorts worldwide. Large nested case-control studies are now needed to examine which specific occupational and non-occupational exposures are responsible for the excess. There is now sufficient evidence for steps to be taken to protect workers from carcinogenic exposures at the workplace. There are also serious implications for the general population which may also be exposed to some of these viruses. Copyright © 2011 Elsevier Ltd. All rights reserved.

positive: Occupation and risk of lymphoma: a multicentre prospective cohort study (EPIC). OBJECTIVES: Evidence suggests that certain occupations and related exposures may increase the risk of malignant lymphoma. Farming, printing and paper industry, wood processing, meat handling and processing, welding, shoe and leather manufacturing and teaching profession are among the categories that have been implicated in previous studies. The relationship between occupation and malignant lymphoma has been investigated in a large European prospective study. METHODS: We investigated occupational risks for lymphomas in the European Prospective Investigation into Cancer and Nutrition (EPIC). The mean follow-up time for 348,555 subjects was 9 years (SD: 2 years). The analysis was based on 866 and 48 newly diagnosed cases of non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). These were identified in the EPIC subcohorts with occupational data. Data on 52 occupations were collected through standardised questionnaires. Cox proportional hazard models were used to explore the association between occupation and risk of malignant lymphoma. RESULTS: The following occupations were positively associated with malignant NHL after adjustment for study centre, age, sex, socioeconomic status (SES), smoking and alcohol: butchers (HR=1.53, 95% CI 1.05 to 2.48, including multiple myeloma/plasmacytoma; HR=1.30, 95% CI 1.00 to 2.66, excluding multiple myeloma/plasmacytoma) and car repair workers (HR=1.50, 95% CI 1.01 to 2.00, including multiple myeloma/plasmacytoma; HR=1.51, 95% CI 1.01 to 2.31, excluding multiple myeloma/plasmacytoma). HL was associated with gasoline station occupation (HR=4.59, 95% CI 1.08 to 19.6). CONCLUSION: The findings in this current study of a higher risk of NHL among car repair workers and butchers and a higher risk of HL among gasoline station workers suggest a possible role from occupationally related exposures, such as solvents and zoonotic viruses, as risk factors for malignant lymphoma.

positive: Auto-immune polyradiculoneuropathy and a novel IgG biomarker in workers exposed to aerosolized porcine brain. Twenty-four patients, all of whom were exposed to aerosolized porcine brain tissue through work-place environment (abattoir), developed a syndrome of immune-mediated polyradiculoneuropathy; three also had central nervous system manifestations (transverse myelitis, meningoencephalitis, and aseptic meningitis). Patients had characteristic electrophysiological findings of very distal and proximal conduction slowing (prolonged distal and F-wave latencies, regions where the blood-nerve barrier is the most permeable) and all patients' serum contained a novel IgG immunofluorescence pattern. Nerve pathology, when available, showed mild changes of segmental demyelination, axonal degeneration, and inflammatory changes. Patients had meaningful improvement of symptoms and electrophysiologic findings with immune therapy and with removal of exposure to aerosolized brain tissue. We postulate that this outbreak is an auto-immune polyradiculoneuropathy triggered by occupational exposure to multiple aerosolized porcine neural tissue antigens that result in neural damage where the blood-nerve barrier is the least robust. © 2011 Peripheral Nerve Society.

positive: Epidemiologic Investigation of Immune-Mediated Polyradiculoneuropathy among Abattoir Workers Exposed to Porcine Brain Background In October 2007, a cluster of patients experiencing a novel polyradiculoneuropathy was identified at a pork abattoir (Plant A). Patients worked in the primary carcass processing area (warm room); the majority processed severed heads (head-table). An investigation was initiated to determine risk factors for illness. Methods and Results Symptoms of the reported patients were unlike previously described occupational associated illnesses. A case-control study was conducted at Plant A. A case was defined as evidence of symptoms of peripheral neuropathy and compatible electrodiagnostic testing in a pork abattoir worker. Two control groups were used - randomly selected non-ill warm-room workers (n = 49), and all non-ill head-table workers (n = 56). Consenting cases and controls were interviewed and blood and throat swabs were collected. The 26 largest U.S. pork abattoirs were surveyed to identify additional cases. Fifteen cases were identified at Plant A; illness onsets occurred during May 2004–November 2007. Median age was 32 years (range, 21–55 years). Cases were more likely than warm-room controls to have ever worked at the head-table (adjusted odds ratio [AOR], 6.6; 95% confidence interval [CI], 1.6–26.7), removed brains or removed muscle from the backs of heads (AOR, 10.3; 95% CI, 1.5–68.5), and worked within 0–10 feet of the brain removal operation (AOR, 9.9; 95% CI, 1.2–80.0). Associations remained when comparing head-table cases and head-table controls. Workers removed brains by using compressed air that liquefied brain and generated aerosolized droplets, exposing themselves and nearby workers. Eight additional cases were identified in the only two other abattoirs using this technique. The three abattoirs that used this technique have stopped brain removal, and no new cases have been reported after 24 months of follow up. Cases compared to controls had higher median interferon-gamma (IFNγ) levels (21.7 pg/ml; vs 14.8 pg/ml, P<0.001). Discussion This novel polyradiculoneuropathy was associated with removing porcine brains with compressed air. An autoimmune mechanism is supported by higher levels of IFNγ in cases than in controls consistent with other immune mediated illnesses occurring in association with neural tissue exposure. Abattoirs should not use compressed air to remove brains and should avoid procedures that aerosolize CNS tissue. This outbreak highlights the potential for respiratory or mucosal exposure to cause an immune-mediated illness in an occupational setting.

positive: Industrial hygiene assessment of reticuloendotheliosis viruses exposure in the poultry industry. OBJECTIVES: Reticuloendotheliosis viruses (REV) are a group of retroviruses like avian leukosis/sarcoma viruses (ALSV) that naturally infect and cause cancers in chickens. We recently found that ALSV antibody levels were associated with job tasks in the poultry industry. The objectives of this study are to examine whether a similar association can be found with REV antibody levels and to examine the correlation between REV and ALSV antibody levels. METHODS: Relative risk was estimated comparing REV antibody levels of 45 poultry workers with those of 44 controls. The expected mean antibody level was predicted for the association with employment by a generalized linear model. Correlation coefficient was measured between ALSV and REV antibody levels. RESULTS: REV antibody levels were significantly higher in poultry workers than in control subjects and were associated with gender and employment conditions, especially employment duration. The relative risk was significantly higher for some job categories. A significant correlation was observed between REV and ALSV antibody levels, which was strong among poultry workers, but weak among the control subjects. CONCLUSION: Antibody levels can be validly used to identify certain job tasks associated with high risk of exposure to REV in the workplace, and the practical implication is recommendations for protection at these job tasks. Importantly, in situations where there is exposure to multiple pathogens in the workplace, the analysis of antibody levels of one pathogen may sufficiently represent exposure to the other correlated pathogens. This suggested exposure assessment may hold true for pathogens with a similar route of transmission.

positive: Occupational exposure assessment using antibody levels: exposure to avian leukosis/sarcoma viruses in the poultry industry. Avian leukosis/sarcoma viruses (ALSV) infect and cause cancers in chickens. Poultry workers are exposed to ALSV and other infectious agents in the workplace. This study examines if industrial hygiene assessment of antibody levels in poultry workers can identify risky job tasks at the higher exposure risk to an infectious agent, i.e., ALSV. We compared ALSV antibody levels in poultry workers and control subjects. Occupational and demographical factors were examined for an association with the exposure risk in poultry workers. We found that the antibody levels were significantly higher in poultry workers than in control subjects. Job category and age together were significantly associated with the antibody levels in workers. Certain job tasks were identified with significantly higher antibody levels as compared to others, implying that recommendations should be made to protect workers at these jobs. The findings of this study indicate that the measurement of antibody levels in workers can be useful for industrial hygiene assessment of exposure to infectious agents.

positive: 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.

positive: 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.

positive: 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.

positive: 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.

positive: 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).

positive: 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®

positive: 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.

positive: 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.

positive: 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.

positive: The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. The contribution of obesity to cardiovascular risk has not been adequately appreciated because of a failure to recognize the involvement of upper-body predominance of body weight with hypertension, diabetes, and hypertriglyceridemia even in the absence of significant overall obesity. This article examines the evidence that upper-body obesity, as usually induced by caloric excess in the presence of androgens, mediates these problems by way of hyperinsulinemia. Because of these interrelationships, there is a need to identify and prevent upper-body obesity or, failing that, to provide therapies that will control the associated problems without aggravating hyperinsulinemia.

positive: Epidemiology of the metabolic syndrome in the USA. The metabolic syndrome is a common complex entity that has emerged as a worldwide epidemic and major public health care concern with a prevalence of approximately 25% in the United States. There have been a number of different definitions of the metabolic syndrome but all center around the metabolic abnormalities of central obesity, hypertension, decreased high-density lipoproteins and elevated triglycerides with insulin resistance as the uniting physiologic factor. The importance of the metabolic syndrome is not just related to its high prevalence rate but also because it predicts the development of diabetes and cardiovascular disease. Nonalcoholic fatty liver disease is now recognized to be the hepatic component of the metabolic syndrome, which along with its individual components - particularly diabetes and elevated triglycerides, are the major risk factors for the development of nonalcoholic steatohepatitis (NASH); the most severe form of nonalcoholic fatty liver disease. NASH may progress to cirrhosis, hepatocellular carcinoma, and liver failure. It is currently the third most common cause for liver transplantation and is projected to be the leading cause for liver transplantation in 2020. Weight loss (via diet or bariatric surgery) and vitamin E have recently been demonstrated to be effective treatments of NASH. Although these and other agents may prove to be effective treatments for NASH, the most effective therapeutic strategy would be early screening and intervention to prevent the development of insulin resistance and oxidative stress at a societal level. © 2011 The Author. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

positive: Vegetarian Dietary Patterns Are Associated With a Lower Risk of Metabolic Syndrome OBJECTIVE The study objective was to compare dietary patterns in their relationship with metabolic risk factors (MRFs) and the metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS Cross-sectional analysis of 773 subjects (mean age 60 years) from the Adventist Health Study 2 was performed. Dietary pattern was derived from a food frequency questionnaire and classified as vegetarian (35%), semi-vegetarian (16%), and nonvegetarian (49%). ANCOVA was used to determine associations between dietary pattern and MRFs (HDL, triglycerides, glucose, blood pressure, and waist circumference) while controlling for relevant cofactors. Logistic regression was used in calculating odds ratios (ORs) for MetS. RESULTS A vegetarian dietary pattern was associated with significantly lower means for all MRFs except HDL (P for trend < 0.001 for those factors) and a lower risk of having MetS (OR 0.44, 95% CI 0.30–0.64, P < 0.001) when compared with a nonvegetarian dietary pattern. CONCLUSIONS A vegetarian dietary pattern is associated with a more favorable profile of MRFs and a lower risk of MetS. The relationship persists after adjusting for lifestyle and demographic factors.

positive: The flip side of immune surveillance: immune dependency. The growths of many and perhaps all tumors may be stimulated rather than inhibited by a quantitatively low level of immunity. The reason tumors have antigens may be that tumors do not develop in vivo in the absence of at least a minimal immune reaction; in this sense, cancer may be considered an autoimmune disease. This review, based largely on the work of our own laboratory, outlines the data showing that the titration of anti-tumor immunity exhibits the phenomenon of hormesis, i.e. the dose-response curve is non-linear such that low levels of immunity are generally stimulatory but larger quantities of the same immune reactants may inhibit tumor growth. Evidence is also reviewed that suggests that the immune response may vary qualitatively and quantitatively during progression, such that there seems to be, during oncogenesis, a very low level of immune reaction that aids initial tumor growth, followed by a larger reaction that may cause remission of early neoplasms, followed, if the neoplasm survives, by a relative immunologic tolerance to the tumor that may be dependent, at least in part, on suppressor cells. This knowledge may help to explain some clinical observations concerning the relationships among tumor types and the organ distribution of metastases.

positive: Immunological enhancement of breast cancer. Breast cancer is a complex disease. Its aetiology is multifactorial, its period of development can span decades, and its clinical course is highly variable. Evaluation of the role of the immune response in either the development or control of breast cancer is also complex. Nevertheless, there is substantial information that in this disease, the immune response is not a host defence reaction and may even serve to facilitate cancer development. This evidence comes from a variety of sources including clinical-pathological investigations in women that show a correlation between the intensity of lymphocytic infiltration into the tumour mass with poor prognosis, studies in breast cancer patients that demonstrate a similar correlation between delayed hypersensitivity reactivity or in vitro assays of immune reactivity to tumour cell membranes or non-specific antigens and poor prognosis, and analyses of cancer incidence in chronically immunosuppressed, kidney transplant recipients who develop an unexpectedly low incidence of breast cancer. The overall conclusions from these human studies are corroborated by observations in mouse mammary tumour models that also demonstrate immune enhancement of breast cell proliferation in vitro and of breast cancer development in vivo. Potential mechanisms for these effects include production, by inflammatory cell infiltrates, of direct or indirect modulators of breast cell growth, e.g. cytokines, peptide or steroid hormones, enzymes involved in steroid metabolism, as well as of antibodies to growth factors or their receptors. These immune facilitatory mechanisms must be overcome if immune-based therapies are to be applied successfully in breast cancer.

positive: Recrudescent Kaposi's sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome. The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.

positive: Melanomas in renal transplant recipients. BACKGROUND: It is well documented that renal transplant recipients are at increased risk of developing skin cancers, in particular squamous cell carcinomas. Less extensively reviewed in the literature is the increased incidence of malignant melanoma. We have reviewed 10 patients in the Oxford renal transplant population who developed 12 melanomas following transplantation. OBJECTIVES: To determine the incidence and characteristics of melanoma in renal transplant recipients. METHODS: We reviewed the case notes and pathology of all patients who developed melanoma within the Oxford Renal Transplant Unit. The clinical details were recorded including date of transplant, immunosuppressive therapy, interval between transplant and melanoma, site of occurrence, history of sun exposure, type of clinician diagnosing the melanoma, history of other skin malignancies and outcome. From the histopathology we documented various prognostic factors. RESULTS: Ten patients developed 12 melanomas (one patient had three melanomas) from a population of 1874 transplanted patients. The total number of transplant years was 11 942.2. The incidence of melanoma in our population was 12 per 11 942.2 transplant years, which is approximately 8 times greater than the standardized rate for this region. We found that the mean interval between transplant and melanoma was approximately 11 years (median 8.5). A dermatologist was the diagnosing clinician in at least 67% of cases. Melanomas occurred on the trunk in the majority of cases (58%), followed by the upper limb (25%). All patients apart from one are alive with no recurrence of their melanoma. One patient died as a result of metastatic melanoma. The mean follow-up period following melanoma was 3.7 years. In all patients apart from the patient who died, the melanomas were < 1 mm Breslow thickness. That patient's melanoma was 4.5 mm thick. There was no precursor naevus in eight of the 12 melanomas. In two there was a precursor dysplastic naevus. In the cases in vertical growth phase the tumour-infiltrating lymphocyte response was absent in four cases and nonbrisk in one patient. CONCLUSIONS: In the Oxford transplant population studied melanomas occurred at approximately 8 times the rate in the general population. This is the highest rate reported in the literature. The patients had a better outcome than reported previously. This may be due to detection at a relatively early stage. Renal transplant recipients attend dedicated dermatology clinics in Oxford, which may have contributed to the early diagnosis and good outcome.

positive: Dietary sources and antioxidant effects of ergothioneine. Ergothioneine is a native membrane-impermeable thiol compound that is specifically accumulated in cells via the organic cation transporter OCTN1. In humans, OCTN1 and ergothioneine have been implicated in the etiopathogenesis of autoimmune disorders. However, available evidence about dietary sources and the functional role of ergothioneine in human physiology is scarce. Here, we analyzed the ergothioneine content in common foods using liquid chromatography tandem-mass spectrometry. Additionally, we assessed the protective potency of ergothioneine against various oxidative stressors in OCTN1-expressing cells in comparison with the main intracellular thiol antioxidant glutathione by evaluating cell viability with the MTT reduction assay. Only some food contained ergothioneine with highest concentrations detected in specialty mushrooms, kidney, liver, black and red beans, and oat bran. Ergothioneine exhibited cell protection only against copper(II)-induced toxicity but was far less potent than glutathione, indicting that ergothioneine is not involved in the intracellular antioxidant thiol defense system.

positive: Hand washing frequencies and procedures used in retail food services. Transmission of viruses, bacteria, and parasites to food by way of improperly washed hands is a major contributing factor in the spread of foodborne illnesses. Field observers have assessed compliance with hand washing regulations, yet few studies have included consideration of frequency and methods used by sectors of the food service industry or have included benchmarks for hand washing. Five 3-h observation periods of employee (n = 80) hand washing behaviors during menu production, service, and cleaning were conducted in 16 food service operations for a total of 240 h of direct observation. Four operations from each of four sectors of the retail food service industry participated in the study: assisted living for the elderly, childcare, restaurants, and schools. A validated observation form, based on 2005 Food Code guidelines, was used by two trained researchers. Researchers noted when hands should have been washed, when hands were washed, and how hands were washed. Overall compliance with Food Code recommendations for frequency during production, service, and cleaning phases ranged from 5% in restaurants to 33% in assisted living facilities. Procedural compliance rates also were low. Proposed benchmarks for the number of times hand washing should occur by each employee for each sector of food service during each phase of operation are seven times per hour for assisted living, nine times per hour for childcare, 29 times per hour for restaurants, and 11 times per hour for schools. These benchmarks are high, especially for restaurant employees. Implementation would mean lost productivity and potential for dermatitis; thus, active managerial control over work assignments is needed. These benchmarks can be used for training and to guide employee hand washing behaviors.

positive: From Barnyard to Food Table: the Omnipresence of Hepatitis E virus and Risk for Zoonotic Infection and Food Safety Hepatitis E virus (HEV) is an important but extremely understudied pathogen. The mechanisms of HEV replication and pathogenesis are poorly understood, and a vaccine against HEV is not yet available. HEV is classified in the family Hepeviridae consisting of at least four recognized major genotypes. Genotypes 1 and 2 HEV are restricted to humans and associated with epidemics in developing countries, whereas genotypes 3 and 4 HEV are zoonotic and responsible for sporadic cases worldwide. The identification and characterization of a number of animal strains of HEV from pigs, chickens, rabbits, rats, mongoose, deer, and possibly cattle and sheep have significantly broadened the host range and diversity of HEV. The demonstrated ability of cross-species infection by some animal strains of HEV raises public health concerns for zoonotic HEV infection. Pigs are a recognized reservoir for HEV, and pig handlers are at increased risk of zoonotic HEV infection. Sporadic cases of hepatitis E have been definitively linked to the consumption of raw or undercooked animal meats such as pig livers, sausages, and deer meats. In addition, since large amounts of viruses excreted in feces, animal manure land application and runoffs can contaminate irrigation and drinking water with concomitant contamination of produce or shellfish. HEV RNA of swine origin has been detected in swine manure, sewage water and oysters, and consumption of contaminated shellfish has also been implicated in sporadic cases of hepatitis E. Therefore, the animal strains of HEV pose not only a zoonotic risk but also food and environmental safety concerns.

positive: Occupational transmission of hepatitis C virus resulting from use of the same supermarket meat slicer. Tracing risk factors for acquiring hepatitis C virus (HCV) in an HCV-infected patient, the only identified risk was working at the same butcher's counter of a supermarket as another HCV-infected patient, using a common ham cutting machine, with frequent bleeding hand injuries. A phylogenetic analysis showed a high percentage of nucleotide homology between the two patients' strains. © 2010 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.

positive: Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia. The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by cancer patients, who may however be at risk for hypercalcemia. We note that many of our patients who have developed symptomatic hypercalcemia were taking vitamin D, calcium, or shark cartilage supplements. We report eight cases of hypercalcemia in cancer patients seen at the Cleveland Clinic Foundation in whom these nutritional supplements may have contributed to the prevalence or severity of hypercalcemia.

positive: Health food store recommendations for breast cancer patients. CONTEXT: Despite cancer patients' widespread and growing use of complementary and alternative medicine, minimal attention has been paid to the role of health food stores in the "supply side" of this phenomenon. OBJECTIVE: To gain a better understanding of health food store personnel's recommendations for breast cancer patient care. DESIGN: Researcher posing as the daughter of a breast cancer patient and surveying health food store personnel on their product recommendations for cancer care. SETTING: Oahu, Hawaii, summer 1998. PARTICIPANTS: All health food stores (N = 40) offering products for cancer patients. MAIN OUTCOME MEASURES: Recommended products and services, proposed mechanism of action, and costs. RESULTS: Store personnel readily provided information and product recommendations, with shark cartilage being the most frequent. Suggested mechanisms of action drew on traditional healing, scientific, and pseudoscientific rationales. Costs for recommended dosages varied multifold across stores and brands. CONCLUSIONS: Retailers supplying supplements can play an important role in the network of "authorities" for patients with breast and other cancers, as they readily provide advice and recommend products. The reasons why patients seek health food store remedies are useful in developing approaches to patient education. Physicians and other providers are in a key position to assist cancer patients in making informed choices when considering health store products.

positive: Cinnamon and health. Cinnamon has been used as a spice and as traditional herbal medicine for centuries. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumor, cardiovascular, cholesterol-lowering, and immunomodulatory effects. In vitro studies have demonstrated that cinnamon may act as an insulin mimetic, to potentiate insulin activity or to stimulate cellular glucose metabolism. Furthermore, animal studies have demonstrated strong hypoglycemic properties. However, there are only very few well-controlled clinical studies, a fact that limits the conclusions that can be made about the potential health benefits of cinnamon for free-living humans. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area, but further research is needed before definitive recommendations can be made.

positive: Cinnamon intake lowers fasting blood glucose: meta-analysis. Cinnamon, the dry bark and twig of Cinnamomum spp., is a rich botanical source of polyphenolics that has been used for centuries in Chinese medicine and has been shown to affect blood glucose and insulin signaling. Cinnamon's effects on blood glucose have been the subject of many clinical and animal studies; however, the issue of cinnamon intake's effect on fasting blood glucose (FBG) in people with type 2 diabetes and/or prediabetes still remains unclear. A meta-analysis of clinical studies of the effect of cinnamon intake on people with type 2 diabetes and/or prediabetes that included three new clinical trials along with five trials used in previous meta-analyses was done to assess cinnamon's effectiveness in lowering FBG. The eight clinical studies were identified using a literature search (Pub Med and Biosis through May 2010) of randomized, placebo-controlled trials reporting data on cinnamon and/or cinnamon extract and FBG. Comprehensive Meta-Analysis (Biostat Inc., Englewood, NJ, USA) was performed on the identified data for both cinnamon and cinnamon extract intake using a random-effects model that determined the standardized mean difference ([i.e., Change 1(control) - Change 2(cinnamon)] divided by the pooled SD of the post scores). Cinnamon intake, either as whole cinnamon or as cinnamon extract, results in a statistically significant lowering in FBG (-0.49±0.2 mmol/L; n=8, P=.025) and intake of cinnamon extract only also lowered FBG (-0.48 mmol/L±0.17; n=5, P=.008). Thus cinnamon extract and/or cinnamon improves FBG in people with type 2 diabetes or prediabetes.

positive: Glycated haemoglobin and blood pressure-lowering effect of cinnamon in multi-ethnic Type 2 diabetic patients in the UK: a randomized, placebo-contr... AIMS: To determine the blood glucose lowering effect of cinnamon on HbA1c, blood pressure and lipid profiles in people with type 2 diabetes. METHODS: 58 type 2 diabetic patients (25 males and 33 females), aged 54.9 ± 9.8, treated only with hypoglycemic agents and with an HbA1c more than 7% were randomly assigned to receive either 2g of cinnamon or placebo daily for 12 weeks. RESULTS: After intervention, the mean HbA1c was significantly decreased (P<0.005) in the cinnamon group (8.22% to 7.86%) compared with placebo group (8.55% to 8.68%). Mean systolic and diastolic blood pressures (SBP and DBP) were also significantly reduced (P<0.001) after 12 weeks in the cinnamon group (SBP: 132.6 to 129.2 mmHg and DBP: 85.2 to 80.2 mmHg) compared with the placebo group (SBP: 134.5 to 134.9 mmHg and DBP: 86.8 to 86.1 mmHg). A significant reduction in fasting plasma glucose (FPG), waist circumference and body mass index (BMI) was observed at week 12 compared to baseline in the cinnamon group, however, the changes were not significant when compared to placebo group. There were no significant differences in serum lipid profiles of total cholesterol, triglycerides, HDL and LDL cholesterols neither between nor within the groups. CONCLUSIONS: Intake of 2g of cinnamon for 12 weeks significantly reduces the HbA1c, SBP and DBP among poorly controlled type 2 diabetes patients. Cinnamon supplementation could be considered as an additional dietary supplement option to regulate blood glucose and blood pressure levels along with conventional medications to treat type 2 diabetes mellitus. © 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.

positive: Toxicology and risk assessment of coumarin: focus on human data. Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. For the carcinogenic effect, a genotoxic mechanism was considered possible, but was discounted by the European Food Safety Authority in 2004 based on new evidence. This allowed the derivation of a tolerable daily intake (TDI) for the first time, and a value of 0.1 mg/kg body weight was arrived at based on animal hepatotoxicity data. However, clinical data on hepatotoxicity from patients treated with coumarin as medicinal drug is also available. This data revealed a subgroup of the human population being more susceptible for the hepatotoxic effect than the animal species investigated. The cause of the high susceptibility is currently unknown; possible mechanisms are discussed. Using the human data, a TDI of 0.1 mg/kg body weight was derived, confirming that of the European Food Safety Authority. Nutritional exposure may be considerably, and is mainly due to use of cassia cinnamon, which is a popular spice especially, used for cookies and sweet dishes. To estimate exposure to coumarin during the Christmas season in Germany, a telephone survey was performed with more than 1000 randomly selected persons. Heavy consumers of cassia cinnamon may reach a daily coumarin intake corresponding to the TDI.

positive: Antitumour effects of Phyllanthus emblica L.: induction of cancer cell apoptosis and inhibition of in vivo tumour promotion and in vitro invasion o... Phyllanthus emblica Linn. (PE) is a medicinal fruit used in many Asian traditional medicine systems for the treatment of various diseases including cancer. The present study tested the potential anticancer effects of aqueous extract of PE in four ways: (1) against cancer cell lines, (2) in vitro apoptosis, (3) mouse skin tumourigenesis and (4) in vitro invasiveness. The PE extract at 50-100 microg/mL significantly inhibited cell growth of six human cancer cell lines, A549 (lung), HepG2 (liver), HeLa (cervical), MDA-MB-231 (breast), SK-OV3 (ovarian) and SW620 (colorectal). However, the extract was not toxic against MRC5 (normal lung fibroblast). Apoptosis in HeLa cells was also observed as PE extract caused DNA fragmentation and increased activity of caspase-3/7 and caspase-8, but not caspase-9, and up-regulation of the Fas protein indicating a death receptor-mediated mechanism of apoptosis. Treatment of PE extract on mouse skin resulted in over 50% reduction of tumour numbers and volumes in animals treated with DMBA/TPA. Lastly, 25 and 50 microg/mL of PE extract inhibited invasiveness of MDA-MB-231 cells in the in vitro Matrigel invasion assay. These results suggest P. emblica exhibits anticancer activity against selected cancer cells, and warrants further study as a possible chemopreventive and antiinvasive agent. Copyright 2010 John Wiley & Sons, Ltd.

positive: Amla (Emblica officinalis Gaertn), a wonder berry in the treatment and prevention of cancer. Emblica officinalis Gaertn. or Phyllanthus emblica Linn, commonly known as Indian gooseberry or amla, is arguably the most important medicinal plant in the Indian traditional system of medicine, the Ayurveda. Various parts of the plant are used to treat a range of diseases, but the most important is the fruit. The fruit is used either alone or in combination with other plants to treat many ailments such as common cold and fever; as a diuretic, laxative, liver tonic, refrigerant, stomachic, restorative, alterative, antipyretic, anti-inflammatory, hair tonic; to prevent peptic ulcer and dyspepsia, and as a digestive. Preclinical studies have shown that amla possesses antipyretic, analgesic, antitussive, antiatherogenic, adaptogenic, cardioprotective, gastroprotective, antianemia, antihypercholesterolemia, wound healing, antidiarrheal, antiatherosclerotic, hepatoprotective, nephroprotective, and neuroprotective properties. In addition, experimental studies have shown that amla and some of its phytochemicals such as gallic acid, ellagic acid, pyrogallol, some norsesquiterpenoids, corilagin, geraniin, elaeocarpusin, and prodelphinidins B1 and B2 also possess antineoplastic effects. Amla is also reported to possess radiomodulatory, chemomodulatory, chemopreventive effects, free radical scavenging, antioxidant, anti-inflammatory, antimutagenic and immunomodulatory activities, properties that are efficacious in the treatment and prevention of cancer. This review for the first time summarizes the results related to these properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a cancer preventive and therapeutic drug in humans.

positive: Effectiveness of alcohol-based hand rubs for removal of Clostridium difficile spores from hands. BACKGROUND: Alcohol-based hand rubs (ABHRs) are an effective means of decreasing the transmission of bacterial pathogens. Alcohol is not effective against Clostridium difficile spores. We examined the retention of C. difficile spores on the hands of volunteers after ABHR use and the subsequent transfer of these spores through physical contact. METHODS: Nontoxigenic C. difficile spores were spread on the bare palms of 10 volunteers. Use of 3 ABHRs and chlorhexidine soap-and-water washing were compared with plain water rubbing alone for removal of C. difficile spores. Palmar cultures were performed before and after hand decontamination by means of a plate stamping method. Transferability of C. difficile after application of ABHR was tested by having each volunteer shake hands with an uninoculated volunteer. RESULTS: Plain water rubbing reduced palmar culture counts by a mean (+/- standard deviation [SD]) of 1.57 +/- 0.11 log10 colony-forming units (CFU) per cm2, and this value was set as the zero point for the other products. Compared with water washing, chlorhexidine soap washing reduced spore counts by a mean (+/- SD) of 0.89 +/- 0.34 log10 CFU per cm2; among the ABHRs, Isagel accounted for a reduction of 0.11 +/- 0.20 log10 CFU per cm2 (P = .005), Endure for a reduction of 0.37 +/- 0.42 log10 CFU per cm2 (P = .010), and Purell for a reduction of 0.14 +/- 0.33 log10 CFU per cm2 (P = .005). There were no statistically significant differences between the reductions achieved by the ABHRs; only Endure had a reduction statistically different from that for water control rubbing (P = .040). After ABHR use, handshaking transferred a mean of 30% of the residual C. difficile spores to the hands of recipients. CONCLUSIONS: Hand washing with soap and water is significantly more effective at removing C. difficile spores from the hands of volunteers than are ABHRs. Residual spores are readily transferred by a handshake after use of ABHR.

positive: Much meat, much malady: changing perceptions of the epidemiology of hepatitis E. Hepatitis E, which is caused by hepatitis E virus (HEV), may now be considered a zoonosis as well as an anthroponosis. Pigs, boars and deer have been identified as reservoirs, and their flesh and entrails--as meat and offal--as vehicles of HEV transmission. Shellfish also act as vehicles. Dietary, gastronomic and culinary preferences influence how extensively HEV conveyed by these vehicles can be inactivated before their ingestion by the host. Another route of infection is paved by HEV that is enterically shed by humans and by live animals into the environment. Although anthroponotic transmission of HEV is primarily environmental, zoonotic transmission may proceed along both foodborne and environmental routes.

positive: Detection and characterization of infectious Hepatitis E virus from commercial pig livers sold in local grocery stores in the USA. Hepatitis E virus (HEV) is a zoonotic pathogen of which pigs are reservoirs. To determine the presence of HEV RNA in commercial pig livers sold in local grocery stores in the USA, 127 packages of commercial pig liver were purchased and tested by a universal RT-PCR assay capable of detecting all four known HEV genotypes. Among the 127 livers tested, 14 were positive for HEV RNA. Sequence and phylogenetic analyses revealed that the 14 isolates all belonged to genotype 3. An animal study was subsequently conducted in pigs to determine whether the PCR-positive pig livers still contained infectious virus. The results showed that pigs inoculated with two of the three PCR-positive pig-liver homogenates became infected, as evidenced by the detection of faecal virus shedding, viraemia and seroconversion. The data demonstrated that commercial pig livers sold in grocery stores are contaminated by HEV and that the contaminating virus remains infectious, thus raising a public-health concern for food-borne HEV infection.

positive: National mortality rates from chronic liver disease and consumption of alcohol and pig meat. A correlation between national pig-meat consumption and mortality rates from chronic liver disease (CLD) across developed countries was reported in 1985. One possible mechanism explaining this may be hepatitis E infection spread via pig meat. We aimed to re-examine the original association in more recent international data. Regression models were used to estimate associations between national pig-meat consumption and CLD mortality, adjusting for confounders. Data on CLD mortality, alcohol consumption, hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence for 18 developed countries (1990-2000) were obtained from WHO databases. Data on national pig-meat and beef consumption were obtained from the UN database. Univariate regression showed that alcohol and pig-meat consumption were associated with mortality from CLD, but beef consumption, HBV and HCV seroprevalence were not. A 1 litre per capita increase in alcohol consumption was associated with an increase in mortality from CLD in excess of 1.6 deaths/100,000 population. A 10 kg higher national annual average per capita consumption of pork meat was associated with an increase in mortality from CLD of between 4 and 5 deaths/100,000 population. Multivariate regression showed that alcohol, pig-meat consumption and HBV seroprevalence were independently associated with mortality from CLD, but HCV seroprevalence was not. Pig-meat consumption remained independently associated with mortality from CLD in developed countries in the 1990-2000 period. Further work is needed to establish the mechanism.

positive: Hepatitis E virus load in swine organs and tissues at slaughterhouse determined by real-time RT-PCR. Although uncommon in North America, Hepatitis E virus (HEV) has been identified in some industrialized countries in patients without a history of travel to HEV-endemic countries. Its presence is ubiquitous worldwide in swine populations. Zoonotic transmission of swine HEV to non human primates has been achieved experimentally and transmission of HEV after ingestion of contaminated raw or undercooked meat is well documented. In Canada, so far, no HEV outbreak has been documented but HEV genotype 3 strains have been identified in sera and faecal samples of swine origin. The objective of the present study was to determine the viral load of HEV in liver, loin, bladder, hepatic lymph node, bile, tonsil, plasma and faeces samples of 43 pigs at slaughter. Feline calicivirus (FCV) was used as sample process control to validate the RNA extraction process, as a confirmation of the absence of sample inhibitors and as an amplification control. Using FCV/HEV multiplex TaqMan RT-qPCR system, HEV RNA was detected in 14 out of the 43 animals tested. HEV was detected in lymph nodes (11/43), bladder (10/43), liver (9/43), bile (8/43), faeces (6/43), tonsils (3/43), plasma (1/43) samples from infected animals. No HEV-positive loin samples were observed. Viral loads of 10(3) to 10(7) copies/g were estimated in positive liver and bile samples. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.

positive: Thermal stability of hepatitis E virus. The thermal stability of virulent hepatitis E virus (HEV) and hepatitis A virus (HAV) was compared. Fecal suspensions of virus were heated to temperatures between 45 degrees C and 70 degrees C, and residual infectivity was determined in a cell culture system that was permissive for both viruses. Although HEV was less stable than was HAV, some HEV would most likely survive the internal temperatures of rare-cooked meat.

positive: Sporadic acute or fulminant hepatitis E in Hokkaido, Japan, may be food-borne, as suggested by the presence of hepatitis E virus in pig liver as food. Among ten patients who contracted sporadic acute or fulminant hepatitis E between 2001 and 2002 in Hokkaido, Japan, nine (90 %) had a history of consuming grilled or undercooked pig liver 2-8 weeks before the disease onset. We tested packages of raw pig liver sold in grocery stores as food in Hokkaido for the presence of hepatitis E virus (HEV) RNA by RT-PCR. Pig liver specimens from seven (1.9 %) of 363 packages had detectable HEV RNA. Partial sequence analyses revealed that the seven swine HEV isolates belonged to genotype III or IV. One swine HEV isolate (swJL145) from a packaged pig liver had 100 % identity with the HE-JA18 isolate recovered from an 86-year-old patient in Hokkaido. Two swine HEV isolates (swJL234 and swJL325) had 98.5-100 % identity with the HE-JA4 isolate obtained from a 44-year-old patient in Hokkaido. These results indicate that inadequately cooked pig liver may transmit HEV to humans.

positive: First detection of anatoxin-a in human and animal dietary supplements containing cyanobacteria. Anatoxin-a is a potent neurotoxin produced by several species of cyanobacteria. This alkaloid may cause fatal intoxication to exposed organisms and this has raised concerns over the increasing popularity of food supplements containing cyanobacteria. These are being marketed with alleged health properties for animal and human consumption. These supplements most commonly contain the genera Spirulina (Arthrospira) and Aphanizomenon and their consumption represent a potential route for anatoxin-a exposure in cases where adequate quality control is not undertaken. In this work, several dietary supplements containing cyanobacteria from different commercial suppliers were evaluated for the presence of anatoxin-a by high performance liquid chromatography with fluorescence detection. Additionally, the presence of the previously derivatized anatoxin-a was confirmed by using Gas chromatography-mass spectrometry. A total of 39 samples were analysed in the study. Results showed that three of the samples (7.7%) contained anatoxin-a, at concentrations ranging from 2.50 to 33 microg g(-1). Quality control of cyanobacterial food supplements is required to avoid potential health effects in humans and animals.

positive: Safety considerations and potential interactions of vitamins: should vitamins be considered drugs? OBJECTIVE: To examine adverse effects, adverse events, and potential interactions of vitamins in light of their current prevalence of use, and to discuss whether vitamins should be considered over-the-counter drugs or natural health products/dietary supplements. DATA SOURCES: We performed a MEDLINE/PubMed search, explored 4 online databases (Medline Plus, Drug Digest, Natural Medicine Comprehensive Database, and the database of the University of Maryland), and examined reference lists of included studies published from 1966 through October 2009. STUDY SELECTION AND DATA EXTRACTION: The studies were reviewed, with an emphasis on randomized controlled clinical trials. We included articles with the most clinically important information with regard to adverse events and interactions. DATA SYNTHESIS: Vitamins are used by over one third of the North American population. Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs. While some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin B(12), vitamin K) have minor and reversible adverse effects, others, such as fat-soluble vitamins (A, E, D), can cause serious adverse events. Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events. CONCLUSIONS: Our recommendation is that vitamins A, E, D, folic acid, and niacin should be categorized as over-the-counter medications. Labeling of vitamins, especially those intended for children and other vulnerable groups, should include information on possible toxicities, dosing, recommended upper intake limits, and concurrent use with other products. Vitamin A should be excluded from multivitamin supplements and food fortificants.

positive: Hypervitaminosis A inducing intra-hepatic cholestasis--a rare case report. The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one Herbalife shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease. Copyright 2009 Elsevier Inc. All rights reserved.

positive: Species identification and vitamin A level in lutjanid fish implicated in vitamin A poisoning. One outbreak of food poisoning associated with ingestion of the liver of a large lutjanid fish was investigated in this study. The symptoms in three patients primarily included headache, nausea, vomiting, fever, vertigo, and visual disorientation and later included peeling of the skin. The species of fish implicated in this incident was Etelis carbunculus (family Lutjanidae) as determined by direct sequence analysis and PCR plus restriction fragment length polymorphism analysis for detection of the cytochrome b gene. Subsequently, several specimens of E. carbunculus of different body weights were collected, and the level of vitamin A in the muscle and liver was determined by high-performance liquid chromatography. The average level of vitamin A in E. carbunculus muscle was 12 +/- 2 IU/g and that in the liver was 9,844 +/- 7,812 IU/g. Regression models indicate that E. carbunculus with higher body weight and liver weight will have higher levels of vitamin A levels in the liver.

positive: Potential liver damage associated with over-the-counter vitamin supplements. The growing popularity and availability of over-the-counter (OTC) health products, including vitamins, raises serious concern about vitamin toxicity. We report a case of cirrhosis in a patient with habitual daily ingestion of an OTC dietary supplement that contained 13,000 microg vitamin A and was associated with marked clinical improvement after discontinuation. This case highlights the potential for liver damage that may be associated with long-term intake of OTC vitamin supplements, and indicates the need for medical supervision of such products.

positive: Bean consumption is associated with greater nutrient intake, reduced systolic blood pressure, lower body weight, and a smaller waist circumference ... BACKGROUND: Epidemiological studies have shown positive findings associated with legume consumption and measures of cardiovascular disease and obesity. However, few observational trials have examined beans as a separate food variable when determining associations with health parameters. OBJECTIVE: To determine the association of consuming beans on nutrient intakes and physiological parameters using the National Health and Examination Survey (NHANES) 1999-2002. METHODS: Using data from NHANES 1999-2002, a secondary analysis was completed with a reliable 24-hour dietary recall where three groups of bean consumers were identified (N = 1,475). We determined mean nutrient intakes and physiological values between bean consumers and non-consumers. Least square means, standard errors and ANOVA were calculated using appropriate sample weights following adjustment for age, gender, ethnicity and energy. RESULTS: Relative to non-consumers, bean consumers had higher intakes of dietary fiber, potassium, magnesium, iron, and copper (p's < 0.05). Those consuming beans had a lower body weight (p = 0.008) and a smaller waist size (p = 0.043) relative to non-consumers. Additionally, consumers of beans had a 23% reduced risk of increased waist size (p = 0.018) and a 22% reduced risk of being obese (p = 0.026). Also, baked bean consumption was associated with a lower systolic blood pressure. CONCLUSIONS: Bean consumers had better overall nutrient intake levels, better body weights and waist circumferences, and lower systolic blood pressure in comparison to non-consumers. These data support the benefits of bean consumption on improving nutrient intake and health parameters.

positive: Determination of bisphenol a and bisphenol B residues in canned peeled tomatoes by reversed-phase liquid chromatography. Bisphenol A (BPA) and bisphenol B (BPB) concentrations were determined in peeled canned tomatoes of different brands bought in Italian supermarkets. Tomato samples analyzed were packaged in cans coated with either epoxyphenolic lacquer or low BADGE enamel. A solid phase extraction (SPE) was performed on C-18 Strata E cartridge followed by a step on Florisil cartridge. Detection and quantitation were performed by a reversed phase high-performance liquid chromatography (RP-HPLC) method with both UV and fluorescence detection (FD). On the total of 42 tested tomato samples, BPA was detected in 22 samples (52.4%), while BPB was detected in 9 samples (21.4%). BPA and BPB were simultaneously present in 8 of the analyzed samples. The levels of BPA found in this study are much lower than the European Union migration limits of 3 mg/kg food and reasonably unable to produce a daily intake exceeding the limit of 0.05 mg/kg body weight, established by European Food Safety Authority.

positive: Detection of the hepatotoxic microcystins in 36 kinds of cyanobacteria Spirulina food products in China. Gel filtration chromatography, ultra-filtration, and solid-phase extraction silica gel clean-up were evaluated for their ability to remove microcystins selectively from extracts of cyanobacteria Spirulina samples after using the reversed-phase octadecylsilyl ODS cartridge for subsequent analysis by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The reversed-phase ODS cartridge/silica gel combination were effective and the optimal wash and elution conditions were: H(2)O (wash), 20% methanol in water (wash), and 90% methanol in water (elution) for the reversed-phase ODS cartridge, followed by 80% methanol in water elution in the silica gel cartridge. The presence of microcystins in 36 kinds of cyanobacteria Spirulina health food samples obtained from various retail outlets in China were detected by LC-MS/MS, and 34 samples (94%) contained microcystins ranging from 2 to 163 ng g(-1) (mean = 14 +/- 27 ng g(-1)), which were significantly lower than microcystins present in blue green alga products previously reported. MC-RR - which contains two molecules of arginine (R) - (in 94.4% samples) was the predominant microcystin, followed by MC-LR - where L is leucine - (30.6%) and MC-YR - where Y is tyrose - (27.8%). The possible potential health risks from chronic exposure to microcystins from contaminated cyanobacteria Spirulina health food should not be ignored, even if the toxin concentrations were low. The method presented herein is proposed to detect microcystins present in commercial cyanobacteria Spirulina samples.

positive: Pinto bean consumption reduces biomarkers for heart disease risk. OBJECTIVE: To determine effects of daily intake of 1/2 cup pinto beans, black-eyed peas or carrots (placebo) on risk factors for coronary heart disease (CHD) and diabetes mellitus (DM) in free-living, mildly insulin resistant adults over an 8 week period. METHODS: Randomized, crossover 3x3 block design. Sixteen participants (7 men, 9 women) received each treatment for eight-weeks with two-week washouts. Fasting blood samples collected at beginning and end of periods were analyzed for total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol, triacylglycerols, high-sensitivity C-reactive protein, insulin, glucose, and hemoglobin A1c. RESULTS: A significant treatment-by-time effect impacted serum TC (p = 0.026) and LDL (p = 0.033) after eight weeks. Paired t-tests indicated that pinto beans were responsible for this effect (p = 0.003; p = 0.008). Mean change of serum TC for pinto bean, black-eyed pea and placebo were -19 +/- 5, 2.5 +/- 6, and 1 +/- 5 mg/dL, respectively (p = 0.011). Mean change of serum LDL-C for pinto bean, black-eyed pea and placebo were -14 +/- 4, 4 +/- 5, and 1 +/- 4 mg/dL, in that order (p = 0.013). Pinto beans differed significantly from placebo (p = 0.021). No significant differences were seen with other blood concentrations across the 3 treatment periods. CONCLUSIONS: Pinto bean intake should be encouraged to lower serum TC and LDL-C, thereby reducing risk for CHD.

positive: Phytochemicals of black bean seed coats: isolation, structure elucidation, and their antiproliferative and antioxidative activities. Bioactivity-guided fractionation of black bean (Phaseolus vulgaris) seed coats was used to determine the chemical identity of bioactive constituents, which showed potent antiproliferative and antioxidative activities. Twenty-four compounds including 12 triterpenoids, 7 flavonoids, and 5 other phytochemicals were isolated using gradient solvent fractionation, silica gel and ODS columns, and semipreparative and preparative HPLC. Their chemical structures were identified using MS, NMR, and X-ray diffraction analysis. Antiproliferative activities of isolated compounds against Caco-2 human colon cancer cells, HepG2 human liver cancer cells, and MCF-7 human breast cancer cells were evaluated. Among the compounds isolated, compounds 1, 2, 6, 7, 8, 13, 14, 15, 16, 19, and 20 showed potent inhibitory activities against the proliferation of HepG2 cells, with EC50 values of 238.8 +/- 19.2, 120.6 +/- 7.3, 94.4 +/- 3.4, 98.9 +/- 3.3, 32.1 +/- 6.3, 306.4 +/- 131.3, 156.9 +/- 11.8, 410.3 +/- 17.4, 435.9 +/- 47.7, 202.3 +/- 42.9, and 779.3 +/- 37.4 microM, respectively. Compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 14, 15, 19, and 20 showed potent antiproliferative activities against Caco-2 cell growth, with EC50 values of 179.9 +/- 16.9, 128.8 +/- 11.6, 197.8 +/- 4.2, 105.9 +/- 4.7, 13.9 +/- 2.8, 35.1 +/- 2.9, 31.2 +/- 0.5, 71.1 +/- 11.9, 40.8 +/- 4.1, 55.7 +/- 8.1, 299.8 +/- 17.3, 533.3 +/- 126.0, 291.2 +/- 1.0, and 717.2 +/- 104.8 microM, respectively. Compounds 5, 7, 8, 9, 11, 19, 20 showed potent antiproliferative activities against MCF-7 cell growth in a dose-dependent manner, with EC50 values of 129.4 +/- 9.0, 79.5 +/- 1.0, 140.1 +/- 31.8, 119.0 +/- 7.2, 84.6 +/- 1.7, 186.6 +/- 21.1, and 1308 +/- 69.9 microM, respectively. Six flavonoids (compounds 14-19) showed potent antioxidant activity. These results showed the phytochemical extracts of black bean seed coats have potent antioxidant and antiproliferative activities.

positive: Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products. BACKGROUND/AIMS: Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife products. METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.

positive: Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. BACKGROUND/AIMS: Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. METHODS: In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. RESULTS: Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. CONCLUSIONS: An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.

positive: Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg? A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month. Copyright 2006 S. Karger AG, Basel.

positive: Reduction of faecal coliform, coliform and heterotrophic plate count bacteria in the household kitchen and bathroom by disinfection with hypochlori... Fourteen sites evenly divided between the household kitchen and bathroom were monitored on a weekly basis for numbers of faecal coliforms, total coliforms and heterotrophic plate count bacteria. The first 10 weeks comprised the control period, hypochlorite cleaning products were introduced into the household during the second 10 weeks, and a strict cleaning regimen using hypochlorite products was implemented during the last 10 weeks. The kitchen was more heavily contaminated than the bathroom, with the toilet seat being the least contaminated site. The highest concentrations of all three classes of bacteria were found on sites that were moist environments and/or were frequently touched; these included the sponge/dishcloth, the kitchen sink drain area, the bath sink drain area, and the kitchen faucet handle(s). The implementation of a cleaning regimen with common household hypochlorite products resulted in the significant reduction of all three classes of bacteria at these four sites and other household sites.

positive: Microbiological quality of sushi from sushi bars and retailers. Sushi is a traditional Japanese food, mostly consisting of rice and raw fish. Fish is considered a healthy food, but as with other animal products, consumption of raw muscle incurs potential health risks such as ingestion of pathogenic bacteria or parasites. In this study, 250 sushi samples were analyzed for their microbiological status and the prevalence of pathogenic bacteria. A comparison was made between frozen sushi from supermarkets and fresh sushi from sushi bars. Aerobic mesophilic bacteria counts differed for sushi from these two sources, with means of 2.7 log CFU/g for frozen sushi and 6.3 log CFU/g for fresh sushi. The prevalence of Escherichia coli and Staphylococcus aureus was higher in the fresh samples. Salmonella was found in four (1.6%) of the sushi samples, and Listeria monocytogenes was found in three (1.2%) of the samples. These results indicate that the microbiological quality of industrially processed sushi is higher than that of freshly prepared sushi. The quality of freshly prepared sushi strongly depends on the skills and habits of the preparation cooks, which may vary.

negative: Hibiscus sabdariffa extract inhibits obesity and fat accumulation, and improves liver steatosis in humans. Obesity is associated with a great diversity of diseases including non-alcoholic fatty liver disease. Our previous report suggested that Hibiscus sabdariffa extracts (HSE) had a metabolic-regulating and liver-protecting potential. In this study, we performed a clinical trial to further confirm the effect of HSE. Subjects with a BMI ≧ 27 and aged 18-65, were randomly divided into control (n = 17) and HSE-treated (n = 19) groups, respectively, for 12 weeks. Our data showed that consumption of HSE reduced body weight, BMI, body fat and the waist-to-hip ratio. Serum free fatty acid (FFA) was lowered by HSE. Anatomic changes revealed that HSE improved the illness of liver steatosis. Ingestion of HSE was well tolerated and there was no adverse effect during the trial. No alteration was found for serum α-amylase and lipase. The clinical effect should mainly be attributed to the polyphenols of HSE, since composition analysis showed that branched chain-amino acids, which is associated with obesity, is not obviously high. In conclusion, consumption of HSE reduced obesity, abdominal fat, serum FFA and improved liver steatosis. HSE could act as an adjuvant for preventing obesity and non-alcoholic fatty liver.

negative: Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Plasma free fatty acid (FFA) levels are elevated in obesity. FFA, by causing insulin resistance in muscle, liver, and endothelial cells, contributes to the development of type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). The mechanism through which FFA induces insulin resistance involves intramyocellular and intrahepatocellular accumulation of triglycerides and diacylglycerol, activation of several serine/threonine kinases, reduction in tyrosine phosphorylation of the insulin receptor substrate (IRS)-1/2, and impairment of the IRS/phosphatidylinositol 3-kinase pathway of insulin signaling. FFA also produces low-grade inflammation in skeletal muscle and liver through activation of nuclear factor-kappaB, resulting in release of several proinflammatory and proatherogenic cytokines. Thus, elevated FFA levels (due to obesity or to high-fat feeding) cause insulin resistance in skeletal muscle and liver, which contributes to the development of T2DM, and produce low-grade inflammation, which contributes to the development of atherosclerotic vascular diseases and NAFLD.

negative: Cod liver oil intake and incidence of asthma in Norwegian adults--the HUNT study. BACKGROUND: Cod liver oil is an important source of vitamin D, but also contains other fat-soluble components such as vitamin A. Before 1999, the cod liver oil formula in Norway contained a high concentration of vitamin A (1000 µg per 5 ml). High vitamin A status is associated with increased risks of several chronic diseases. OBJECTIVE: To investigate the association between cod liver oil intake and asthma development. METHODS: In the Nord-Trøndelag Health Study, a total of 25 616 Norwegian adults aged 19-55 years were followed up from 1995-1997 to 2006-2008. Current analysis based on 17 528 subjects who were free of asthma and had complete information on cod liver oil intake at baseline. Cod liver oil intake was defined as daily intake ≥ 1 month during the year prior to baseline. Incident asthma was reported as new-onset asthma during the 11-year follow-up. RESULTS: Of the 17 528 subjects, 18% (n=3076) consumed cod liver oil daily for ≥ 1 month over the past year. Cod liver oil intake was significantly associated with incident asthma with an OR of 1.62 (95% CI 1.32 to 1.98) after adjustment for age, sex, daily smoking, physical activity, education, socio-economic status, family history of asthma, and body mass index (BMI). The positive association was consistent across age (< 40/≥ 40 years), sex (men/women), family history of asthma (yes/no) and BMI subgroups (< 25/≥ 25 kg/m(2)). CONCLUSIONS: Intake of cod liver oil with high vitamin A content was significantly associated with increased incidence of adult-onset asthma.

negative: Molecular Mechanisms and the Role of Saturated Fatty Acids in the Progression of Non-Alcoholic Fatty Liver Disease The steady rise in Western obesity rates has been closely linked to significant increases in a multitude of accompanying health problems including Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD severity ranges from simple steatosis to acute steatohepatitis, but the molecular mechanisms controlling progression of this disease are poorly understood. Recent literature suggests that elevated free fatty acids (FFAs), especially saturated FFAs, may play an important role in lipotoxic mechanisms, both in experimental models and in NAFLD patients. This review highlights important cellular pathways involved in hepatic lipotoxicity and how the degree of intrahepatic lipid saturation controls cell fate in response to an elevated FFA load. Relevant cellular processes that have been causally linked to lipid-induced apoptosis, known as lipoapoptosis, include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, and Jun N-terminal kinase (JNK) signaling. In contrast, increased triglyceride synthesis has been shown to have a protective effect against lipotoxicity, despite being one of the hallmark traits of NAFLD. Developing a more nuanced understanding of the molecular mechanisms underlying NAFLD progression will lead to more targeted and effective therapeutics for this increasingly prevalent disease, which to date has no proven pharmacologic treatment to prevent or reverse its course.

negative: Do Organohalogen Contaminants Contribute to Histopathology in Liver from East Greenland Polar Bears (Ursus maritimus)? In East Greenland polar bears (Ursus maritimus), anthropogenic organohalogen compounds (OHCs) (e.g., polychlorinated biphenyls, dichlorodiphenyltrichloroethane, and polybrominated diphenyl ethers) contributed to renal lesions and are believed to reduce bone mineral density. Because OHCs are also hepatotoxic, we investigated liver histology of 32 subadult, 24 adult female, and 23 adult male East Greenland polar bears sampled during 1999–2002. Light microscopic changes consisted of nuclear displacement from the normal central cytoplasmic location in parenchymal cells, mononuclear cell infiltrations (mainly portally and as lipid granulomas), mild bile duct proliferation accompanied by fibrosis, and fat accumulation in hepatocytes and pluripotent Ito cells. Lipid accumulation in Ito cells and bile duct hyperplasia accompanied by portal fibrosis were correlated to age, whereas no changes were associated with either sex or season (summer vs. winter). For adult females, hepatocytic intracellular fat increased significantly with concentrations of the sum of hexachlorocyclohexanes, as was the case for lipid granulomas and hexachlorobenzene in adult males. Based on these relationships and the nature of the chronic inflammation, we suggest that these findings were caused by aging and long-term exposure to OHCs. Therefore, these changes may be used as biomarkers for OHC exposure in wildlife and humans. To our knowledge, this is the first time liver histology has been evaluated in relation to OHC concentrations in a mammalian wildlife species, and the information is important to future polar bear conservation strategies and health assessments of humans relying on OHC-contaminated food resources.

negative: Cigarette Smoke Toxins Deposited on Surfaces: Implications for Human Health Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered – Thirdhand smoke (THS) – the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS.

negative: From the Cover: The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake Numerous clinical trials using folic acid for prevention of cardiovascular disease, stroke, cognitive decline, and neural tube defects have been completed or are underway. Yet, all functions of folate are performed by tetrahydrofolate and its one-carbon derivatives. Folic acid is a synthetic oxidized form not significantly found in fresh natural foods; to be used it must be converted to tetrahydrofolate by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans. Here we show, using a sensitive assay we developed, that the reduction of folic acid by DHFR per gram of human liver (n = 6) obtained from organ donors or directly from surgery is, on average, less than 2% of that in rat liver at physiological pH. Moreover, in contrast to rats, there was almost a 5-fold variation of DHFR activity among the human samples. This limited ability to activate the synthetic vitamer raises issues about clinical trials using high levels of folic acid. The extremely low rate of conversion of folic acid suggests that the benefit of its use in high doses will be limited by saturation of DHFR, especially in individuals possessing lower than average activity. These results are also consistent with the reports of unmetabolized folic acid in plasma and urine.

negative: Pathological aspects of lipid peroxidation. Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.

negative: Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.

negative: Lipotoxicity: Effects of Dietary Saturated and Transfatty Acids The ingestion of excessive amounts of saturated fatty acids (SFAs) and transfatty acids (TFAs) is considered to be a risk factor for cardiovascular diseases, insulin resistance, dyslipidemia, and obesity. The focus of this paper was to elucidate the influence of dietary SFA and TFA intake on the promotion of lipotoxicity to the liver and cardiovascular, endothelial, and gut microbiota systems, as well as on insulin resistance and endoplasmic reticulum stress. The saturated and transfatty acids favor a proinflammatory state leading to insulin resistance. These fatty acids can be involved in several inflammatory pathways, contributing to disease progression in chronic inflammation, autoimmunity, allergy, cancer, atherosclerosis, hypertension, and heart hypertrophy as well as other metabolic and degenerative diseases. As a consequence, lipotoxicity may occur in several target organs by direct effects, represented by inflammation pathways, and through indirect effects, including an important alteration in the gut microbiota associated with endotoxemia. Interactions between these pathways may perpetuate a feedback process that exacerbates an inflammatory state. The importance of lifestyle modification, including an improved diet, is recommended as a strategy for treatment of these diseases.

negative: Correlation of lead, cadmium and mercury levels in tissue and liver samples with age in cattle. The aim of this study was to determine the accumulation of selected heavy metals (Pb, Cd, Hg, As) in meat and liver of cattle. The animals were divided into four age-groups which allowed the analysis of statistical-mathematical correlations between the age of the animals and contamination of meat. The research material for determination of heavy metal levels was taken from the longissimus back muscle (m. longissimus dorsi) and samples from the tail lobe of the liver. Analysis showed that contamination by Cd and Pb is clearly dependent on the age of the animal.

negative: Fatal fulminant hepatitis associated with Ganoderma lucidum (Lingzhi) mushroom powder. Hepatotoxic effect related to Ganoderma lucidum (Lingzhi) mushroom powder was first described in a patient from Hong Kong in 2004. In 2005, the authors experienced a case of fatal fulminant hepatitis associated with such a preparation. Both patients had taken other therapeutic agents and traditionally boiled Lingzhi without any toxic effect. After switching to taking Lingzhi in powder form for 1-2 months, the hepatotoxic episode occurred in both patients. The toxic role of Lingzhi powder needs close monitoring in the future, especially in combination with other drugs.

negative: Dioxins (PCDD/Fs) and PCBs in offal: occurrence and dietary exposure. Offals are widely consumed in different cuisines, but information on the occurrence of dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in these foods is sparse. In the first structured investigation of its kind, this study reports levels of these contaminants in commonly consumed offals (n=173) such as lamb, ox, deer and pig's liver, kidneys, tongue and heart, and offal products such as pâté, haggis, tripe and black pudding. The results support literature observations on the preferential accumulation of contaminants in liver tissue, as the highest concentrations of PCDD/Fs were observed in liver, relative to the other organs (e.g. 8.4 ng WHO-TEQ kg(-1) lamb liver compared to 1.1 ng WHO-TEQ kg(-1) lamb kidney and 1.27 ng WHO-TEQ kg(-1) lamb heart). Offal products generally showed lower contaminant levels which may be a result of processing or dilution. For most samples, the main contribution to WHO-TEQ arose from PCDD/Fs rather than PCBs. Just under half of the lamb liver samples showed PCDD/F concentrations that exceeded the EU maximum limit of 6 ng kg(-1) fat weight (although deer liver which is not subject to the regulation, generally showed higher levels). Dietary exposure estimates indicate that the weekly consumption of up to two 100g portions of lamb, ox, calf or pig liver or one portion of deer liver would not breach the tolerable daily intake (TDI) level even when the rest of the diet was included. However, the consumption of more than one portion of deer liver per week may lead to the TDI being exceeded. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

negative: A survey of feeding N-nitrosodimethylamine (NDMA) to domestic animals over an 18 year period. Sodium nitrite and formalin have been used as preservatives in the fish meal industry in Norway since 1953. In 1957, fur farms suffered losses of mink due to a new, malignant liver disease. Experimental feeding of herring meal to cows and sheep resulted in the death of some of the animals. Further studies showed that amines (TMAO) normally present in fish, can react with sodium nitrite used as preservative, or nitrogen oxides from the combustion of fuel oils used during processing, to produce the toxic agent, NDMA. Mink and fox may consume considerable amounts of fish meal in their diets. If the fish meal contains sufficient NDMA, the incidence of liver failure or tumours can be quite high. Long-term exposure to as little as 0.1 mg NDMA/kg b.w./day in the diet of mink, cows and sheep can produce fibro-occlusive changes in the hepatic vessels. These lesions can later cause capillary ectasies-like changes in cows, which are similar in appearance to hemangiomas seen in mink. The mink liver hemangiomas develop into hemangiosarcomas. We currently consider capillary ectasies-like changes in cows exposed to NDMA to represent pre-cancerous lesions.

negative: The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease. It is a pleasure and an honor to contribute a paper to a special issue of the Journal of the American College of Nutrition honoring Stanley Wallach and Pearl Small. In this brief review I advance the hypothesis that copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.

negative: Saturated free fatty acid sodium palmitate-induced lipoapoptosis by targeting glycogen synthase kinase-3β activation in human liver cells. BACKGROUND: Elevated serum saturated fatty acid levels and hepatocyte lipoapoptosis are features of nonalcoholic fatty liver disease (NAFLD). AIM: The purpose of this study was to investigate saturated fatty acid induction of lipoapoptosis in human liver cells and the underlying mechanisms. METHODS: Human liver L02 and HepG2 cells were treated with sodium palmitate, a saturated fatty acid, for up to 48 h with or without lithium chloride, a glycogen synthase kinase-3β (GSK-3β) inhibitor, or GSK-3β shRNA transfection. Transmission electron microscopy was used to detect morphological changes, flow cytometry was used to detect apoptosis, a colorimetric assay was used to detect caspase-3 activity, and western blot analysis was used to detect protein expression. RESULTS: The data showed that sodium palmitate was able to induce lipoapoptosis in L02 and HepG2 cells. Western blot analysis showed that sodium palmitate activated GSK-3β protein, which was indicated by dephosphorylation of GSK-3β at Ser-9. However, inhibition of GSK-3β activity with lithium chloride treatment or knockdown of GSK-3β expression with shRNA suppressed sodium palmitate-induced lipoapoptosis in L02 and HepG2 cells. On a molecular level, inhibition of GSK-3β expression or activity suppressed sodium palmitate-induced c-Jun-N-terminal kinase (JNK) phosphorylation and Bax upregulation, whereas GSK-3β inhibition did not affect endoplasmic reticulum stress-induced activation of unfolded protein response. CONCLUSIONS: The present data demonstrated that saturated fatty acid sodium palmitate-induced lipoapoptosis in human liver L02 and HepG2 cells was regulated by GSK-3β activation, which led to JNK activation and Bax upregulation. This finding indicates that GSK-3β inhibition may be a potential therapeutic target to control NAFLD.

negative: Bridging the gap in life expectancy of the aborigines in Taiwan. BACKGROUND: Similar to the general population in Taiwan, the health of aborigines has steadily improved over the last 30 years, but the gap remains wide, especially in males, despite an infusion of substantial medical resources. The objectives of this study are to quantify the contribution of major causes of death to the gap in life expectancy and to propose initiatives to bridge the health gap between aborigines and the general population. METHODS: This study included residents (slightly over 200000) from 30 'aboriginal townships' in Taiwan. The gap in life expectancy between aborigines and the general population was analysed by decomposing these gaps according to major causes of deaths. This analysis quantifies the contribution of different causes of deaths to the gap in life expectancy between the two populations. RESULTS: The overall mortality of aborigines in these townships was approximately 70% higher than the respective male and female general populations over the past 30 years. Mortality from infectious disease, cirrhosis of the liver, accidents, and suicide are substantially higher than the general population. The gap in life expectancy at birth in males was 8.5 years during 1971-1973, increasing to 13.5 years by 1998-2000, however, the gap in females remained relatively stable (8.0 years and 8.4 years, respectively). Of the 13.5-year difference in life expectancy in males, the differential mortality from diseases of the digestive system (mainly due to cirrhosis of the liver), accidents (from both motor vehicle and non-motor vehicle accidents), and infectious and parasitic disease contributed half (50%) of the gap in life expectancy. In females, the above primarily preventable causes of deaths accounted for 41% of the life expectancy gap. CONCLUSIONS: Based on the findings of this study, we suggest that future focus should be in the area of primary prevention in order to reduce the incidence of infectious and parasitic diseases, liver cirrhosis, and accidents.

negative: Toxicological and mutagenic analysis of Artemisia dracunculus (tarragon) extract. Mutagenicity and liver toxicity of the herb tarragon (Artemisia dracunculus) were evaluated using single cell gel (comet) electrophoresis. Ten microlitres aliquots of peripheral venous human blood were incubated with tarragon extract, saline, or the mutagen sodium dichromate. Cell suspensions dispersed in low-melting agarose were electrophoresed in ethidium bromide. The resulting DNA migration trails were obtained using fluorescent microscopy at 400× magnification, and graded according to the mutagenicity index (MI) for each cell incubation condition. The in vivo liver toxicity of Artemisia dracunculus was assessed in the blood of mice treated orally with the extract of the herb, using alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as liver function indicators. Liver morphology was assessed using hematoxylin and eosin (HE) staining of liver tissue. The present study demonstrated a direct correlation between tarragon extract dosage and three major outcome variables: MI; serum liver enzyme activity; and liver histopathology. These outcomes are possibly due to the presence in tarragon of methylchavicol and other genotoxic compounds. These findings provide a preliminary guide for risk assessment of tarragon in diet and in possible therapeutic applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

negative: Cholesterol gallstone disease. With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.

negative: When can we cure Crohn's? Crohn's disease is a life-long idiopathic inflammatory disease which affects the entire gastrointestinal tract and occasionally extra-intestinal organs. CD is thought to result from complex interactions between environmental factors, the gut microbes, and the genetic background and the immune system of the host. In the last decades research on these pathogenetic components, and especially on mucosal immunity, has led to the development of biologic agents and therapeutic strategies that have improved dramatically the treatment of CD but we are still far away from curing the disease. If there is a treatment for CD that will probably evolve through methodical steps towards integrating research on all the components involved in the pathogenesis of CD. This holistic and global approach may aid at unravelling the mysteries of CD and developing novel agents and therapeutic strategies which by targeting multiple pathogenetic pathways and at different stages of disease may lead hopefully to cure. Copyright © 2014 Elsevier Ltd. All rights reserved.

negative: Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer. OBJECTIVE: High concentrations of plasma deoxycholic acid (DCA) are found in human breast cyst fluid and it has been hypothesised that this may be related to risk of breast cancer. The aim of this pilot study was to ascertain whether plasma bile acid concentrations were greater in women with breast cancer. DESIGN: A case-control study comparing postmenopausal women with breast cancer with healthy controls was conducted. SUBJECTS: Twenty Caucasian postmenopausal breast cancer patients were recruited at the time of diagnosis together with 20 healthy controls matched for age and body mass index. Exclusion criteria included any treatment for breast cancer, use of hormone replacement therapy in the last 12 months, diabetes mellitus, a history of liver or gall bladder disease or abnormal liver function. MEASUREMENTS: Fasting plasma bile acid concentrations were determined by gas-liquid chromatography/mass spectrometry. RESULTS: The mean plasma DCA concentration was 52% higher (P=0.012) in patients with breast cancer compared with controls. CONCLUSION: These results support the hypothesis that DCA may be involved in the aetiology of breast cancer.

negative: The case of the purple colon. Purple discoloration of the large bowel at autopsy was related to beetroot ingestion and post-mortem changes.

negative: Systemic regulation of intestinal iron absorption. The intestinal absorption of the essential trace element iron and its mobilization from storage sites in the body are controlled by systemic signals that reflect tissue iron requirements. Recent advances have indicated that the liver-derived peptide hepcidin plays a central role in this process by repressing iron release from intestinal enterocytes, macrophages and other body cells. When iron requirements are increased, hepcidin levels decline and more iron enters the plasma. It has been proposed that the level of circulating diferric transferrin, which reflects tissue iron levels, acts as a signal to alter hepcidin expression. In the liver, the proteins HFE, transferrin receptor 2 and hemojuvelin may be involved in mediating this signal as disruption of each of these molecules decreases hepcidin expression. Patients carrying mutations in these molecules or in hepcidin itself develop systemic iron loading (or hemochromatosis) due to their inability to down regulate iron absorption. Hepcidin is also responsible for the decreased plasma iron or hypoferremia that accompanies inflammation and various chronic diseases as its expression is stimulated by pro-inflammatory cytokines such as interleukin 6. The mechanisms underlying the regulation of hepcidin expression and how it acts on cells to control iron release are key areas of ongoing research. IUBMB Life, 57: 499-503, 2005.

negative: Crohn's disease: a review of treatment options and current research. Crohn's disease is an autoimmune disorder that affects nearly 1.4 million Americans. The etiology of Crohn's disease is not completely understood, however, research has suggested a genetic link. There is currently no known cure for Crohn's disease and, as a result, most government-funded research is being conducted to increase the quality of life of afflicted patients (i.e. reducing chronic inflammation and alleviating growth impairment in pediatric patients). A number of treatment options are available including an alpha-4 integrin inhibitor and several TNF-alpha inhibitors. Furthermore, research is being conducted on several alternative treatment options to help understand exactly which cellular mechanisms (i.e. inducing apoptosis in leukocytes) are required for clinical efficacy. This review seeks to chronicle the current available treatment options for patients affected by Crohn's disease to aid in understanding potential cellular mechanistic requirements for an efficacious drug, and shed light on potential options for future treatment. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

negative: Diverticular disease of the colon. The first of the Western diseases shown to be due to a deficiency of dietary fibre. Diverticular disease of the colon is a new disease that appeared at the beginning of this century. It is now the commonest disease of the colon in the Western world, being found in 1 in 3 people of over 60 years of age. The pathogenesis of the disease involves excessive segmentation, but this does not explain its aetiology. The historical appearance of the disease on the clinical scene and its geographical distribution suggest that it is due to the removal of fibre from carbohydrates. The author treated 70 patients with symptomatic diverticular disease with a high-fibre diet. The results of this and the effects of bran are discussed.

negative: Updating a 12-year experience with arrest and reversal therapy for coronary heart disease (an overdue requiem for palliative cardiology). Coronary artery disease is essentially nonexistent in cultures whose nutrition assures cholesterol levels <150 mg/dl. Patients with advanced coronary artery disease may abolish disease progression through a plant-based diet and cholesterol-lowering medication to achieve and maintain a total cholesterol <150 mg/dl.

negative: Dietary clues to the pathogenesis of Crohn's disease. Crohn's disease is a complex inherited disorder of unknown pathogenesis with environmental, genetic and microbial factors involved in the development of the disease. A remarkable feature of this disease in childhood is the effective response to exclusive enteral nutrition (EEN) therapy and the need for complete exclusion of normal diet required for success (principle of exclusivity). EEN or dietary interventions might act through removal of dietary components, which affect microbial composition, decrease a proinflammatory response and promote restitution of the epithelial barrier, likewise allowing termination of this vicious disease-forming cycle before a critical threshold is reached. Multiple traditional and nontraditional dietary components may affect the microbiome, mucous layer, intestinal permeability, or adherence and translocation of pathobionts. We review the epidemiological data, as well as data from animal models and cell lines, and propose a model for pathogenesis we have termed the 'bacterial penetration cycle', whereby dietary components such as animal fat, high sugar intake and gliadin, and consumption of emulsifiers, maltodextrin as well as low-fiber diets may be able to cause a localized acquired bacterial clearance defect, leading to bacterial adhesion and penetration, and subsequently inflammation in the gut. © 2014 S. Karger AG, Basel.

negative: Milk-induced pulmonary disease in infants (Heiner syndrome). Heiner syndrome (HS) is a food hypersensitivity pulmonary disease that affects primarily infants, and is mostly caused by cow's milk (CM). Only a few reports have been published, which may be due to its misdiagnosis. We review here a series of eight cases. When first diagnosed they were 4-29 months of age. They were fed CM from birth and their chronic respiratory symptoms began at age 1-9 months. The symptoms were in the form of cough in seven, wheezing in three, hemoptysis in two, nasal congestion in three, dyspnea in one, recurrent otitis media (OM) in three, recurrent fever in four, anorexia, vomiting, colic or diarrhea in five, hematochezia in one, and failure to thrive (FTT) in two. All had radiologic evidence of pulmonary infiltrates. High titers of precipitating antibodies to CM proteins were demonstrated in six of six and milk-specific immunoglobulin E (IgE) was positive in one of two. Pulmonary hemosiderosis (PH) was confirmed in one patient who showed iron-laden macrophages (ILM) in the bronchoalveolar lavage (BAL), gastric washing, and open lung biopsy. Additional findings, in a descending frequency, were eosinophilia, anemia, and elevated level of total IgM, IgE or IgA. Milk elimination resulted in remarkable improvement in symptoms within days and clearing of the pulmonary infiltrate within weeks. Parents consented to milk challenge in only three cases, all of whom developed recurrence of symptoms. After 2 yr of milk avoidance in one patient, milk challenge was tolerated for 2 months, and then the patient developed symptoms, serum milk precipitins, pulmonary infiltrate, and ILM. The HS should be suspected in young children with chronic pulmonary disease of obscure cause. The diagnosis is supported with a positive milk precipitin test and improvement on a trial of milk elimination. Severe cases may be complicated with PH, which should be suspected in the presence of anemia or hemoptysis and be confirmed with the demonstration of ILM.

negative: Varicose Veins, Deep Vein Thrombosis, and Haemorrhoids: Epidemiology and Suggested Aetiology Current concepts on the aetiology of varicose veins, deep vein thrombosis, and haemorrhoids have been examined and, in the light of epidemiological evidence, found wanting.It is suggested that the fundamental cause of these disorders is faecal arrest which is the result of a low-residue diet.

negative: Bowel obsession syndrome in a patient with ulcerative colitis. Gastroenterologists are often faced with the diagnostic problem of differentiating acute symptoms of ulcerative colitis from functional intestinal disorders. Bowel obsession syndrome (BOS) is an OCD-like, functional syndrome characterized by fear of fecal incontinence and compulsive behaviors of evacuation-checking. Only sparse case studies on treatment of BOS with antidepressants have been published. This is the first study on successful psychotherapy of a male patient with ulcerative colitis overlapping functional bowel symptoms and marked symptoms of BOS. Clinical recognition of BOS may help clinicians in differential diagnosis, prevent unnecessary investigations, and give patients the most appropriate treatment.

negative: Mortality from malignant diseases-update of the Baltimore union poultry cohort. We previously studied mortality up to 1989 in 2,639 members of a local union who had ever worked in poultry slaughtering and processing plants, because they were exposed to oncogenic viruses present in poultry. In this report, cancer mortality was updated to the year 2003 for 2,580 of the 2,639 subjects who worked exclusively in poultry plants. Mortality in poultry workers was compared with that in the US general population through the estimation of proportional mortality and standardized mortality ratios separately for each race/sex group and for the whole cohort. Compared to the US general population, an excess of cancers of the buccal and nasal cavities and pharynx (base of the tongue, palate and other unspecified mouth, tonsil and oropharynx, nasal cavity/middle ear/accessory sinus), esophagus, recto-sigmoid/rectum/anus, liver and intrabiliary system, myelofibrosis, lymphoid leukemia and multiple myeloma was observed in particular subgroups or in the entire poultry cohort. We hypothesize that oncogenic viruses present in poultry, and exposure to fumes, are candidates for an etiologic role to explain the excess occurrence of at least some of these cancers in the poultry workers. Larger studies which can control for confounding factors are urgently needed to determine the significance of these findings.

negative: "Bowel obsession syndrome" in a patient with chronic constipation. OBJECTIVE: The bowel obsession syndrome (BOS) is a psychosomatic disorder which often remains at the intersection of somatic and psychological domains without being adequately diagnosed and treated. CASE REPORT: A 32-year-old man with chronic constipation presented with restricted diet, compulsions on evacuation, social isolation and depressed mood, thus satisfying the diagnosis of BOS. Cognitive behavioral therapy led to complete remission of symptoms, and results were maintained after 1 year of follow-up. CONCLUSION: Although BOS is not frequently diagnosed, it is probably more prevalent than thought. Clinicians should be aware of its existence in order to assess, diagnose and properly treat it. Copyright © 2013 Elsevier Inc. All rights reserved.