query: accidents

positive: Growth Hormone Receptor Deficiency is Associated With a Major Reduction in Pro-aging Signaling, Cancer and Diabetes in Humans Life span extending mutations in growth signaling pathways protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies and combined this information with surveys to identify the cause and age of death for subjects who died before this period. The individuals with GHR deficiency (GHRD) exhibited only one non-lethal malignancy and no cases of diabetes, in contrast to 17% cancer and 5% diabetes prevalence in the controls. A possible explanation for the very low incidence of cancer may be revealed by in vitro studies: serum from GHRD subjects reduced DNA breaks but increased apoptosis in human mammary epithelial cells (HMECs) treated with hydrogen peroxide. We also observed reduced insulin concentrations (1.4 μU/ml vs. 4.4μU/ml in unaffected relatives) and a very low homoeostasis model assessment of insulin resistance (HOMA-IR) index (0.34 vs. 0.96 in unaffected relatives) in GHRD individuals, indicating increased insulin sensitivity, which could explain the absence of diabetes in these subjects. Incubation of HMECs with GHRD serum also resulted in reduced expression of RAS, PKA and TOR, and up-regulation of SOD2, changes that promote cellular protection and life span extension in model organisms. These results provide evidence for a role of evolutionarily conserved pathways in promoting aging and diseases in humans and identify a candidate drug target for healthy life span extension.

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


query: Finland

positive: Synergistic toxicity of the environmental neurotoxins methylmercury and β-N-methylamino-L-alanine. Determination of the environmental factors involved in neurodegenerative diseases has been elusive. Methylmercury and β-N-methylamino-L-alanine (BMAA) have both been implicated in this role. Exposure of primary cortical cultures to these compounds independently induced concentration-dependent neurotoxicity. Importantly, concentrations of BMAA (10-100 μM) that caused no toxicity alone potentiated methylmercury (3 μM) toxicity. In addition, concentrations of BMAA and methylmercury that had no effect by themselves on the main cellular antioxidant glutathione together decreased glutathione levels. Furthermore, the combined toxicity of methylmercury and BMAA was attenuated by the cell permeant form of glutathione, glutathione monoethyl ester. The results indicate a synergistic toxic effect of the environmental neurotoxins BMAA and methylmercury, and that the interaction is at the level of glutathione depletion.

positive: The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis). The non-protein amino acid beta-N-methylamino-L-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer’s disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin.

positive: From the Cover: Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure β-methylamino-L-alanine (BMAA), a neurotoxic nonprotein amino acid produced by most cyanobacteria, has been proposed to be the causative agent of devastating neurodegenerative diseases on the island of Guam in the Pacific Ocean. Because cyanobacteria are widespread globally, we hypothesized that BMAA might occur and bioaccumulate in other ecosystems. Here we demonstrate, based on a recently developed extraction and HPLC-MS/MS method and long-term monitoring of BMAA in cyanobacterial populations of a temperate aquatic ecosystem (Baltic Sea, 2007–2008), that BMAA is biosynthesized by cyanobacterial genera dominating the massive surface blooms of this water body. BMAA also was found at higher concentrations in organisms of higher trophic levels that directly or indirectly feed on cyanobacteria, such as zooplankton and various vertebrates (fish) and invertebrates (mussels, oysters). Pelagic and benthic fish species used for human consumption were included. The highest BMAA levels were detected in the muscle and brain of bottom-dwelling fishes. The discovery of regular biosynthesis of the neurotoxin BMAA in a large temperate aquatic ecosystem combined with its possible transfer and bioaccumulation within major food webs, some ending in human consumption, is alarming and requires attention.

positive: Linking β-methylamino-L-alanine exposure to sporadic amyotrophic lateral sclerosis in Annapolis, MD. Most amyotrophic lateral sclerosis (ALS) cases occur sporadically. Some environmental triggers have been implicated, including beta-methylamino-L-alanine (BMAA), a cyanobacteria produced neurotoxin. This study aimed to identify environmental risk factors common to three sporadic ALS patients who lived in Annapolis, Maryland, USA and developed the disease within a relatively short time and within close proximity to each other. A questionnaire was used to identify potential risk factors for ALS among the cohort of patients. One common factor among the ALS patients was the frequent consumption of blue crab. Samples of blue crab from the patients' local fish market were tested for BMAA using LC-MS/MS. BMAA was identified in these Chesapeake Bay blue crabs. We conclude that the presence of BMAA in the Chesapeake Bay food web and the lifetime consumption of blue crab contaminated with BMAA may be a common risk factor for sporadic ALS in all three patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

positive: Does α-Amino-β-methylaminopropionic Acid (BMAA) Play a Role in Neurodegeneration? The association of α-amino-β-methylaminopropionic acid (BMAA) with elevated incidence of amyotrophic lateral sclerosis/Parkinson’s disease complex (ALS/PDC) was first identified on the island of Guam. BMAA has been shown to be produced across the cyanobacterial order and its detection has been reported in a variety of aquatic and terrestrial environments worldwide, suggesting that it is ubiquitous. Various in vivo studies on rats, mice, chicks and monkeys have shown that it can cause neurodegenerative symptoms such as ataxia and convulsions. Zebrafish research has also shown disruption to neural development after BMAA exposure. In vitro studies on mice, rats and leeches have shown that BMAA acts predominantly on motor neurons. Observed increases in the generation of reactive oxygen species (ROS) and Ca2+ influx, coupled with disruption to mitochondrial activity and general neuronal death, indicate that the main mode of activity is via excitotoxic mechanisms. The current review pertaining to the neurotoxicity of BMAA clearly demonstrates its ability to adversely affect neural tissues, and implicates it as a potentially significant compound in the aetiology of neurodegenerative disease. When considering the potential adverse health effects upon exposure to this compound, further research to better understand the modes of toxicity of BMAA and the environmental exposure limits is essential.

positive: Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual.

positive: Dietary BMAA Exposure in an Amyotrophic Lateral Sclerosis Cluster from Southern France Background Dietary exposure to the cyanotoxin BMAA is suspected to be the cause of amyotrophic lateral sclerosis in the Western Pacific Islands. In Europe and North America, this toxin has been identified in the marine environment of amyotrophic lateral sclerosis clusters but, to date, only few dietary exposures have been described. Objectives We aimed at identifying cluster(s) of amyotrophic lateral sclerosis in the Hérault district, a coastal district from Southern France, and to search, in the identified area(s), for the existence of a potential dietary source of BMAA. Methods A spatio-temporal cluster analysis was performed in the district, considering all incident amyotrophic lateral sclerosis cases identified from 1994 to 2009 by our expert center. We investigated the cluster area with serial collections of oysters and mussels that were subsequently analyzed blind for BMAA concentrations. Results We found one significant amyotrophic lateral sclerosis cluster (p = 0.0024), surrounding the Thau lagoon, the most important area of shellfish production and consumption along the French Mediterranean coast. BMAA was identified in mussels (1.8 µg/g to 6.0 µg/g) and oysters (0.6 µg/g to 1.6 µg/g). The highest concentrations of BMAA were measured during summer when the highest picocyanobacteria abundances were recorded. Conclusions While it is not possible to ascertain a direct link between shellfish consumption and the existence of this ALS cluster, these results add new data to the potential association of BMAA with sporadic amyotrophic lateral sclerosis, one of the most severe neurodegenerative disorder.

positive: A cluster of amyotrophic lateral sclerosis in New Hampshire: a possible role for toxic cyanobacteria blooms. Cyanobacteria produce many neurotoxins including beta-methylamino-L-alanine (BMAA) that has been liked to amyotrophic lateral sclerosis (ALS) and neurodegenerative disease. A number of ALS cases have been diagnosed among residents of Enfield, NH, a town encompassing a lake with a history of cyanobacteria algal blooms. To investigate an association between toxic cyanobacterial blooms in New Hampshire and development of ALS, we reviewed records from our institution and other community databases to obtain demographic information on patients diagnosed with ALS within New England. We identified nine ALS patients who lived near Lake Mascoma in Enfield, NH, an incidence of sporadic ALS that is 10 to 25 times the expected incidence of 2/100,000/year. We suggest that the high incidence of ALS in this potential cluster could be directly related to chronic exposure to cyanobacterial neurotoxins such as BMAA. Possible routes of toxin exposure include inhalation of aerosolized toxins, consuming fish, or ingestion of lake water. Further investigation, including analysis of brain tissue for cyanobacterial toxins, will be helpful to test for an association between BMAA and ALS.

positive: Amyotrophic lateral sclerosis. A case-control study following detection of a cluster in a small Wisconsin community. From 1975 to 1983, six cases of amyotrophic lateral sclerosis (ALS) were diagnosed in long-term residents of Two Rivers, Wis; the probability that this occurred due to chance was less than .05. To investigate potential risk factors for ALS, we conducted a case-control study using two control subjects matched to each case patient for age, gender, and duration of residence in Two Rivers. Physical trauma, the frequent consumption of freshly caught Lake Michigan fish, and a family history of cancer were reported more often by case patients than control subjects. These findings support previous studies proposing a role for trauma in ALS pathogenesis and suggest that the causative role of diet should be further explored. Continued surveillance for and epidemiologic investigation of ALS clusters with subsequent retrospective analysis may provide clues concerning the cause of ALS.

positive: Cyanobacterial Neurotoxin β-N-Methylamino-L-alanine (BMAA) in Shark Fins Sharks are among the most threatened groups of marine species. Populations are declining globally to support the growing demand for shark fin soup. Sharks are known to bioaccumulate toxins that may pose health risks to consumers of shark products. The feeding habits of sharks are varied, including fish, mammals, crustaceans and plankton. The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) has been detected in species of free-living marine cyanobacteria and may bioaccumulate in the marine food web. In this study, we sampled fin clips from seven different species of sharks in South Florida to survey the occurrence of BMAA using HPLC-FD and Triple Quadrupole LC/MS/MS methods. BMAA was detected in the fins of all species examined with concentrations ranging from 144 to 1836 ng/mg wet weight. Since BMAA has been linked to neurodegenerative diseases, these results may have important relevance to human health. We suggest that consumption of shark fins may increase the risk for human exposure to the cyanobacterial neurotoxin BMAA.

positive: Cyanobacterial Blooms and the Occurrence of the neurotoxin beta-N-methylamino-L-alanine (BMAA) in South Florida Aquatic Food Webs Recent studies demonstrate that most cyanobacteria produce the neurotoxin beta-N-methylamino-L-alanine (BMAA) and that it can biomagnify in at least one terrestrial food chain. BMAA has been implicated as a significant environmental risk in the development of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS). We examined several blooms of cyanobacteria in South Florida, and the BMAA content of resident animals, including species used as human food. A wide range of BMAA concentrations were found, ranging from below assay detection limits to approximately 7000 μg/g, a concentration associated with a potential long-term human health hazard.

positive: Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death. Previous evidence for spatial clustering of amyotrophic lateral sclerosis is inconclusive. Studies that have identified apparent clusters have often been based on a small number of cases, which means the results may have occurred by chance processes. Also, most studies have used the geographic location at the time of death as the basis for cluster detection, rather than exploring clusters at other points in the life cycle. In this study, the authors examine 1,000 cases of amyotrophic lateral sclerosis distributed throughout Finland who died between June 1985 and December 1995. Using a spatial-scan statistic, the authors examine whether there are significant clusters of the disease at both time of birth and time of death. Two significant, neighboring clusters were identified in southeast and south-central Finland at the time of death. A single significant cluster was identified in southeast Finland at the time of birth, closely matching one of the clusters identified at the time of death. These results are based on a large sample of cases, and they provide convincing evidence of spatial clustering of this condition. The results demonstrate also that, if the cluster analysis is conducted at different stages of the cases' life cycle, different conclusions about where potential risk factors may exist might result.

positive: The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine promotes invasive behaviour of breast cancer cells. The cooked meat derived genotoxic carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces cancer of the colon, prostate and mammary gland when fed to rats. Epidemiology studies link these tumours to a Western diet and exposure to heterocyclic amines such as PhIP. We have shown that PhIP is also potently estrogenic and have proposed that this hormonal activity contributes to its target site carcinogenicity. We now postulate that the estrogenic properties of PhIP influence metastatic potential. We have used an in vitro assay for cell invasion based upon digestion and migration through a reconstituted basement membrane model. Zymography and immunoblotting were used to confirm PhIP-mediated changes associated with induction of the invasive phenotype. Treatment of the mammary cancer cell lines MCF-7 and T47D with PhIP induces cells to digest and migrate through a reconstituted basement membrane. The response was dose dependent, observed at sub-nanomolar concentrations of PhIP and was inhibited by the antiestrogen ICI 182,780. The PhIP-induced invasive phenotype was associated with expression of cathepsin D, cyclooxygenase-2 and matrix metalloproteinase activity. These findings emphasise the range and potency of the biological activities associated with this cooked meat product and mechanistically support the tissue-specific carcinogenicity of the chemical. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

positive: Meat, fat and risk of breast cancer: a case-control study from Uruguay. To examine whether meat intake modifies breast-cancer risk, a case-control study was conducted in Uruguay. Dietary patterns were assessed in detail (for cases, before diagnosis or symptoms occurred) using a food frequency questionnaire involving 64 food items, which allowed total energy intake to be calculated. Nutrient residuals were calculated through regression analysis. After adjustment for potential confounders (which included family history of breast cancer, menopausal status, body-mass index, total energy and total alcohol intake), an increased risk associated with consumption of total meat intake, red meat intake, total fat and saturated fat intake was observed. The strongest effect was observed for red meat intake (OR 4.2, 95% CL 2.3-7.7) for consumption in the upper quartile, after controlling for protein and fat intake. This suggests an independent effect for meat. Since experimental studies have shown a strong effect of heterocyclic amines in rat mammary carcinogenesis, further studies should be performed in human epidemiology, perhaps using biomarkers of heterocyclic amine exposure.

positive: Intake of fried meat and risk of cancer: a follow-up study in Finland. It has been suggested that mutagens in fried meat may be involved in the cancer process. Therefore the relationships between intake of fried meat and subsequent risk of cancers at different sites were studied among 9,990 Finnish men and women, 15-99 years of age and initially free of cancer. The baseline study was carried out in 1966-1972, and cases of cancer were identified through data linkage with the Finnish Cancer Registry. During a 24-year follow-up, 853 cancer cases were diagnosed. The intake of fried meat was estimated from a dietary history interview covering the total diet of the participants during the previous year. There was a positive association between fried meat intake and the risk of female-hormone-related cancers, i.e., cancer of the breast, endometrium and ovary combined. The relative risk of these cancers combined between persons in the highest and lowest tertiles of daily intake of fried meat adjusted for age, personal characteristics and intake of other main food groups was 1.77 (95% confidence interval = 1.11-2.84). Pancreatic and nervous system cancers also presented non-significant suggestive associations. No associations were observed with respect to other single cancer sites studied or to all sites of cancer combined. Further epidemiological efforts are needed to ascertain the potential link between fried-food mutagens and cancer risk.

positive: Detection of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in the milk of healthy women. An increased risk of breast cancer has been observed in women who consume "very well-done" meats. Heterocyclic amines are mutagenic and carcinogenic pyrolysis products formed during high temperature cooking of meats. In the present study, human milk samples were analyzed for PhIP, one of the most abundant dietary heterocyclic amine. A protocol was developed with a mixed-mode cation exchange sorbent for the extraction of heterocyclic amines from milk. Milk samples were acquired from healthy Canadian women. With LC/MS analysis and the method of isotope dilution for quantification, levels of PhIP were determined in human milk samples. PhIP was detected in 9 of the 11 milk samples, at levels as high as 59 pg/mL (ppt). No PhIP was detected in the milk of the vegetarian donor. Detection of PhIP in milk indicates that ductal mammary epithelial cells are directly exposed to this carcinogen, suggesting that heterocyclic amines are possible human mammary carcinogens.

positive: Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue. It was the aim of this study to examine the association of the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in the breast tissue of women undergoing reduction mammoplasty. Dietary intake of meat and HCA were assessed via questionnaire in 44 women undergoing reduction mammoplasty. DNA adduct analysis in breast tissue was performed by (32)P-postlabelling analysis. Spearman rank correlation coefficients (r) were calculated to examine the association of meat consumption and dietary HCA intake with tissue DNA adduct levels. A median DNA adduct level of 18.45 (interquartile range 12.81-25.65) per 10(9) nucleotides in breast tissue was observed; median HCA intake was 40.43 ng/day (interquartile range 19.55-102.33 ng/day). Total HCA intake (r = 0.33, P = 0.03), consumption of fried meat (r = 0.39, P = 0.01), beef (r = 0.32, P = 0.03) and processed meat (r = 0.51, P = 0.0004) were statistically significantly correlated with the level of DNA adducts in breast tissue. The detected DNA adducts could not be confirmed to be specific HCA-derived DNA adducts by comparison with external standards, using the (32)P-postlabelling assay. We observed strong correlations of dietary HCA intake and consumption of fried and processed meat with DNA adduct levels in breast tissue of 44 women. Since the detected DNA adducts were not necessarily specific only for HCA, it is possible that HCA intake is a surrogate of other genotoxic substances, such as polycyclic aromatic hydrocarbons, in meat prepared at high temperatures.

positive: The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine is a potent oestrogen: a mechanistic basis for its tissue-speci... The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces tumours of the breast, colon and prostate in rats. Here we show that in addition to its well-established genotoxicity, which can be detected at concentrations >10(-6) M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10(-10)-10(-6) M) mediated transcription through oestrogen receptor (ER) alpha, but not ER-beta, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally, we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt(-) locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from its oestrogenic activity. To determine whether the oestrogenicity of PhIP could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and, again, this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP ( approximately 10(-9)-10(-11)M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events provide a mechanism for the tissue-specific tumorigenicity of this compound.

positive: Cooked meat and risk of breast cancer--lifetime versus recent dietary intake. BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) are carcinogens formed in or on the surface of well-done meat, cooked at high temperature. METHODS: We estimated breast cancer risk in relation to intake of cooked meat in a population-based, case-control study (1508 cases and 1556 controls) conducted in Long Island, NY from 1996 to 1997. Lifetime intakes of grilled or barbecued and smoked meats were derived from the interviewer-administered questionnaire data. Dietary intakes of PAH and HCA were derived from the self-administered modified Block food frequency questionnaire of intake 1 year before reference date. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Modest increased risk was observed among postmenopausal, but not premenopausal, women consuming the most grilled or barbecued and smoked meats over the life course (OR = 1.47; CI = 1.12-1.92 for highest vs. lowest tertile of intake). Postmenopausal women with low fruit and vegetable intake, but high lifetime intake of grilled or barbecued and smoked meats, had a higher OR of 1.74 (CI = 1.20-2.50). No associations were observed with the food frequency questionnaire-derived intake measures of PAHs and HCAs, with the possible exception of benzo(alpha)pyrene from meat among postmenopausal women whose tumors were positive for both estrogen receptors and progesterone receptors (OR = 1.47; CI = 0.99-2.19). CONCLUSIONS: These results support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cancer.

positive: Formation of a mutagenic heterocyclic aromatic amine from creatinine in urine of meat eaters and vegetarians. Liquid chromatography electrospray ionization mass spectrometry (MS) with a triple quadrupole MS was used to identify known and novel heterocyclic aromatic amines (HAAs) in human urine. The identities of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were confirmed by their product ion spectra. The constant neutral loss scan mode was employed to probe for other analytes in urine that display the transition [M+H]+-->[M+H-CH3*]+*, which is common to HAAs containing an N-methylimidazo moiety, and led to the detection of a previously unreported isomer of 8-MeIQx [Holland, R., et al. (2004) Chem. Res. Toxicol. 17, 1121-1136]. We now report the identification of another novel HAA, 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]), an isomer of the powerful animal carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The amounts of IQ[4,5-b] measured in the urine of human volunteers who consumed grilled beef ranged from 15 to 135% of the ingested dose, while the amounts of 8-MeIQx and PhIP excreted in urine were on average <2% of the ingested dose. Base treatment of urine at 70 degrees C increased the concentrations of 8-MeIQx and PhIP by as much as 6-fold, indicating the presence of phase II conjugates; however, the amount of IQ[4,5-b] increased by more than 100-fold. IQ[4,5-b] was also detected in the urine of vegetarians following base hydrolysis. The formation of IQ[4,5-b], but not IQ, 8-MeIQx, or PhIP, also occurred in urine incubated at 37 degrees C. Creatinine and 2-aminobenzaldehyde are likely precursors of IQ[4,5-b]. The detection of IQ[4,5-b] in the urine of both meat eaters and vegetarians suggests that this HAA may be present in nonmeat staples or that IQ[4,5-b] formation may occur endogenously within the urinary bladder or other biological fluids.

positive: Diet and disease symptoms in rheumatic diseases--results of a questionnaire based survey. Experiences with food intake, diet manipulations and fast were registered in rheumatic patients. The study was a questionnaire-based survey in which 742 patients participated. It comprised 290 patients with rheumatoid arthritis, 51 patients with juvenile rheumatoid arthritis, 87 patients with ankylosing spondylitis, 51 patients with psoriatic arthropathy, 65 patients with primary fibromyalgia and 34 patients with osteoarthritis. One third of the patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthropathy reported aggravation of disease symptoms after intake of certain foods while 43% of the patients with juvenile rheumatoid arthritis and 42% of the patients with primary fibromyalgia stated the same. Twenty-six percent of the patients with juvenile rheumatoid arthritis and 23% of the patients with rheumatoid arthritis, ankylosing spondylitis and primary fibromyalgia had previously tried certain diets in the attempt to alleviate disease symptoms, whereas 13% of the patients with psoriatic arthropathy and 10% with osteoarthritis had tried diet therapy. Less pain and stiffness were reported by 46% of the patients and 36% reported reduced joint swelling. Similar beneficial effects of diet were also reported in other rheumatic disease groups. Fifteen percent of the patients with rheumatoid arthritis and ankylosing spondylitis had been through a fasting period. Less pain and stiffness were reported by 2/3 of the patients in both groups and half of the patients in both groups reported a reduced number of swollen joints.

positive: Vegan diet alleviates fibromyalgia symptoms. The effect of a strict, low-salt, uncooked vegan diet rich in lactobacteria on symptoms in 18 fibromyalgia patients during and after a 3-month intervention period in an open, non-randomized controlled study was evaluated. As control 15 patients continued their omnivorous diet. The groups did not differ significantly from each other in the beginning of the study in any other parameters except in pain and urine sodium. The results revealed significant improvements in Visual analogue scale of pain (VAS) (p=0.005), joint stiffness (p=0.001), quality of sleep (p=0.0001), Health assessment questionnaire (HAQ) (p=0.031), General health questionnaire (GHQ) (p=0.021), and a rheumatologist's own questionnaire (p=0.038). The majority of patients were overweight to some extent at the beginning of the study and shifting to a vegan food caused a significant reduction in body mass index (BMI) (p=0.0001). Total serum cholesterol showed a statistically significant lowering (p=0.003). Urine sodium dropped to 1/3 of the beginning values (p=0.0001) indicating good diet compliance. It can be concluded that vegan diet had beneficial effects on fibromyalgia symptoms at least in the short run.

positive: Antioxidants in vegan diet and rheumatic disorders. Plants are rich natural sources of antioxidants in addition to other nutrients. Interventions and cross sectional studies on subjects consuming uncooked vegan diet called living food (LF) have been carried out. We have clarified the efficacy of LF in rheumatoid diseases as an example of a health problem where inflammation is one of the main concerns. LF is an uncooked vegan diet and consists of berries, fruits, vegetables and roots, nuts, germinated seeds and sprouts, i.e. rich sources of carotenoids, vitamins C and E. The subjects eating LF showed highly increased levels of beta and alfa carotenes, lycopen and lutein in their sera. Also the increases of vitamin C and vitamin E (adjusted to cholesterol) were statistically significant. As the berry intake was 3-fold compared to controls the intake of polyphenolic compounds like quercetin, myricetin and kaempherol was much higher than in the omnivorous controls. The LF diet is rich in fibre, substrate of lignan production, and the urinary excretion of polyphenols like enterodiol and enterolactone as well as secoisolaricirecinol were much increased in subjects eating LF. The shift of fibromyalgic subjects to LF resulted in a decrease of their joint stiffness and pain as well as an improvement of their self-experienced health. The rheumatoid arthritis patients eating the LF diet also reported similar positive responses and the objective measures supported this finding. The improvement of rheumatoid arthritis was significantly correlated with the day-to-day fluctuation of subjective symptoms. In conclusion the rheumatoid patients subjectively benefited from the vegan diet rich in antioxidants, lactobacilli and fibre, and this was also seen in objective measures.

positive: Fibromyalgia and nutrition, what do we know? Many people suffer from fibromyalgia (FM) without an effective treatment. They do not have a good quality of life and cannot maintain normal daily activity. Among the different hypotheses for its ethiopathophysiology, oxidative stress is one of the possibilities. Non-scientific information addressed to patients regarding the benefits of nutrition is widely available, and they are used to trying non-evidenced strategies. The aim of this paper is to find out what we know right now from scientific studies regarding fibromyalgia disease and nutritional status, diets and food supplements. A systematic search has been performed on Medline with a wide range of terms about these nutritional issues. The search has been made during 2009, for articles published between 1998 and 2008. TARGET POPULATION: people suffering from FM. Vegetarian diets could have some beneficial effects probably due to the increase in antioxidant intake. There is a high prevalence of obesity and overweight in patients, and weight control seems to be an effective tool to improve the symptoms. Some nutritional deficiencies have been described, it is not clear whether they are directly related to this disease or not. About the usefulness of some food supplements we found very little data, and it seems that more studies are needed to prove which ones could be of help. Dietary advice is necessary to these patients to improve their diets and maintain normal weight. It would be interesting to investigate more in the field of nutrition and FM to reveal any possible relationships.

positive: Reduced plasma fibrinogen, serum peroxides, lipids, and apolipoproteins after a 3-week vegetarian diet. The influence of a 3-week vegetarian diet and fasting on serum concentration of peroxides, lipids, apolipoproteins, and plasma fibrinogen was studied in ten middle-aged fibromyalgia/fibrositis patients (eight women, two men). Mean serum peroxide concentration (estimated as thiobarbituric acid reacting substances) was reduced from 3.60 +/- 0.14 to 2.82 +/- 0.15 umol/l (p = 0.01) and plasma fibrinogen from 3.33 +/- 0.25 to 2.74 +/- 0.15 g/l (p = 0.02). Serum total cholesterol fell from 6.61 +/- 0.50 to 4.83 +/- 0.35 mmol/l (p < 0.0001), apolipoprotein B from 1.77 +/- 0.14 to 1.31 +/- 0.11 g/l (p < 0.0001), and apolipoprotein A from 1.41 +/- 0.09 to 1.23 +/- 0.05 g/l (p = 0.03). High density lipoprotein cholesterol concentration also decreased somewhat (from 1.26 +/- 0.09 to 1.07 +/- 0.04 mmol/l, p = 0.03) An atherogenic index, reflecting the balance between low and high density lipoproteins, was reduced by 31% (from 5.74 +/- 0.79 to 3.97 +/- 0.60, p = 0.02). The results suggest that vegetarian diet/fasting may have a beneficial influence on the concentration of serum peroxides and plasma fibrinogen concentration, and on the serum level of several lipoprotein-related coronary risk factors.

negative: Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. BACKGROUND: Several cross-sectional studies have focused on the low blood folate levels of depressive patients. Nevertheless, no prospective studies have been published on the association between dietary folate and depression. METHODS: We studied the association between dietary folate and cobalamin and receiving a discharge diagnosis of depression in a prospective follow-up setting. Our cohort was recruited between 1984 and 1989 and followed until the end of 2000, and it consisted of 2,313 men aged between 42 and 60 years from eastern Finland. RESULTS: The mean intake of folate in the whole cohort was 256 microg/day (SD=76). Those below the median of energy-adjusted folate intake had higher risk of getting discharge diagnosis of depression (RR 3.04, 95% CI: 1.58, 5.86) during the follow-up period than those who had a folate intake above the median. This excess risk remained significant after adjustment for current socioeconomic status, the baseline HPL depression score, the energy-adjusted daily intake of fibre and vitamin C, and the total fat intake. CONCLUSIONS: A low dietary intake of folate may be a risk factor for severe depression. This also indicates that nutrition may have a role in the prevention of depression.

negative: Hypothesis: is antibiotic use associated with breast cancer? The hypothesis that antibiotic use may increase cancer risk was first proposed several decades ago and some research suggests an increased risk of breast cancer among women with conditions likely to require long-term antibiotic use (e.g., acne, recurrent urinary-tract infections, UTI). However, this hypothesis has not been verified and the possible biological mechanisms are not entirely clear. A recent cohort study in Finland reported an increased risk of breast-cancer associated with antibiotic use for UTI. The effect of antibiotics on the ability of intestinal microflora to metabolise phytochemicals from edible plants into compounds that may protect against cancer was proposed as a potential mechanism. We extend this hypothesis by proposing that antibiotic use may be associated with breast-cancer risk through effects on immune and inflammatory factors, such as cytokines, T lymphocytes, prostaglandins, and matrix metalloproteinases, as well as disruption of phytochemical and oestrogen metabolism by intestinal microflora. We suggest that some mechanisms may increase breast-cancer risk, while others may decrease risk, depending on the antibiotic classification.

negative: 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.

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

negative: Role of maca (Lepidium meyenii) consumption on serum interleukin-6 levels and health status in populations living in the Peruvian central Andes over 4000 m of altitude Lepidium meyenii (Maca) is a plant that grows at over 4000 meters above sea level in the central Peruvian Andes. The hypocotyls of this plant are traditionally consumed for their nutritional and medicinal properties. The aim of this study was to determine the health status based on a health related quality of life (HRQL) questionnaire (SF-20) and serum levels of interleukin 6 (IL-6) in subjects that are maca consumers. For this, a cross-sectional study was designed to be performed in 50 subjects from Junin (4100 m): 27 subjects were maca consumers and 23 were non-consumers. The SF-20 survey is used to obtain a summary measure of health status. The stand up from a chair and sit down (SUCSD) test (to assess lower-extremity function), hemoglobin measurement, blood pressure, sexual hormone levels, serum IL-6 levels and the score of chronic mountain sickness (CMS) were evaluated. Testosterone/estradiol ratio (P≪0.05), IL-6 (P<0.05) and CMS score were lower, whereas the health status score was higher, in maca consumers when compared to non-consumers (P<0.01). A greater proportion of maca consumers successfully completed the SUCSD test compared to non-consumers (P<0.01), showing a significant association with lower values of serum IL-6 (P<0.05). In conclusion, consumption of maca was associated with low serum IL-6 levels and in turn with better health status scores in the SF-20 survey and low chronic mountain sickness scores.

negative: Persistent organic pollutants and diabetes: a review of the epidemiological evidence. The prevalence of diabetes and obesity has increased rapidly over the last few decades in both developed and developing countries. While it is intuitively appealing to suggest that lifestyle risk factors such as decreased physical activity and adoption of poor diets can explain much of the increase, the evidence to support this is poor. Given this, there has been an impetus to look more widely than traditional lifestyle and biomedical risk factors, especially those risk factors, which arise from the environment. Since the industrial revolution, there has been an introduction of many chemicals into our environment, which have now become environmental pollutants. There has been growing interest in one key class of environmental pollutants known as persistent organic pollutants (POPs) and their potential role in the development of diabetes. This review will summarise and appraise the current epidemiological evidence relating POPs to diabetes and highlight gaps and flaws in this evidence. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

negative: Respiratory tract illnesses during the first year of life: effect of dog and cat contacts. OBJECTIVES: To investigate the effect of dog and cat contacts on the frequency of respiratory symptoms and infections during the first year of life. METHODS: In this birth cohort study, 397 children were followed up from pregnancy onward, and the frequency of respiratory symptoms and infections together with information about dog and cat contacts during the first year of life were reported by using weekly diaries and a questionnaire at the age of 1 year. All the children were born in eastern or middle Finland between September 2002 and May 2005. RESULTS: In multivariate analysis, children having dogs at home were healthier (ie, had fewer respiratory tract symptoms or infections) than children with no dog contacts (adjusted odds ratio, [aOR]: 1.31; 95% confidence interval [CI]: 1.13-1.52). Furthermore, children having dog contacts at home had less frequent otitis (aOR: 0.56; 95% CI: 0.38-0.81) and tended to need fewer courses of antibiotics (aOR: 0.71; 95% CI: 0.52-0.96) than children without such contacts. In univariate analysis, both the weekly amount of contact with dogs and cats and the average yearly amount of contact were associated with decreased respiratory infectious disease morbidity. CONCLUSIONS: These results suggest that dog contacts may have a protective effect on respiratory tract infections during the first year of life. Our findings support the theory that during the first year of life, animal contacts are important, possibly leading to better resistance to infectious respiratory illnesses during childhood.

negative: Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study. AIMS/HYPOTHESIS: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption. RESULTS: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants. CONCLUSIONS/INTERPRETATION: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

negative: Empirical evaluation of very large treatment effects of medical interventions. CONTEXT: Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms. OBJECTIVE: To evaluate the frequency and features of very large effects in medicine. DATA SOURCES: Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7). STUDY SELECTION: We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ≥5). We also sampled randomly 250 topics from each group for further in-depth evaluation. DATA EXTRACTION: We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses. RESULTS: Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns). CONCLUSIONS: Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

negative: A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). High dietary intakes of calcium and dairy products have been hypothesized to enhance prostate cancer risk, but available prospective data regarding these associations are inconsistent. We examined dietary intakes of calcium and dairy products in relation to risk of prostate cancer in the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a cohort of 29,133 male smokers aged 50-69 years at study entry. Dietary intake was assessed at baseline using a validated 276-item food use questionnaire. Cox proportional hazards regression was used to adjust for known or suspected risk factors for prostate cancer. During 17 years of follow-up, we ascertained 1,267 incident cases of prostate cancer. High versus low intake of dietary calcium was associated with a marked increase in prostate cancer risk. The multivariate relative risk (RR) of prostate cancer for > or =2,000 mg/day compared to <1,000 mg/day of calcium intake was 1.63 (95% confidence interval (CI), 1.27-2.10; p trend < 0.0001). Total dairy intake was also positively associated with risk of prostate cancer. The multivariate RR of prostate cancer comparing extreme quintiles of intake was 1.26 (95% CI, 1.04-1.51; p trend = 0.03). However, no association with total dairy intake remained after we adjusted for calcium (p trend = 0.17). Findings were similar by stage and grade of prostate cancer. The results from this large prospective study suggest that intake of calcium or some related component contained in dairy foods is associated with increased prostate cancer risk.

negative: Ceylon cinnamon does not affect postprandial plasma glucose or insulin in subjects with impaired glucose tolerance. Previous studies on healthy subjects have shown that the intake of 6 g Cinnamomum cassia reduces postprandial glucose and that the intake of 3 g C. cassia reduces insulin response, without affecting postprandial glucose concentrations. Coumarin, which may damage the liver, is present in C. cassia, but not in Cinnamomum zeylanicum. The aim of the present study was to study the effect of C. zeylanicum on postprandial concentrations of plasma glucose, insulin, glycaemic index (GI) and insulinaemic index (GII) in subjects with impaired glucose tolerance (IGT). A total of ten subjects with IGT were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with placebo or C. zeylanicum capsules. Finger-prick capillary blood samples were taken for glucose measurements and venous blood for insulin measurements, before and at 15, 30, 45, 60, 90, 120, 150 and 180 min after the start of the OGTT. The ingestion of 6 g C. zeylanicum had no significant effect on glucose level, insulin response, GI or GII. Ingestion of C. zeylanicum does not affect postprandial plasma glucose or insulin levels in human subjects. The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects with poor glycaemic control would then be lost.

negative: A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. BACKGROUND: Recently, two centers have independently developed a risk score for predicting postoperative nausea and vomiting (PONV). This study investigated (1) whether risk scores are valid across centers and (2) whether risk scores based on logistic regression coefficients can be simplified without loss of discriminating power. METHODS: Adult patients from two centers (Oulu, Finland: n = 520, and Wuerzburg, Germany: n = 2202) received inhalational anesthesia (without antiemetic prophylaxis) for various types of surgery. PONV was defined as nausea or vomiting within 24 h of surgery. Risk scores to estimate the probability of PONV were obtained by fitting logistic regression models. Simplified risk scores were constructed based on the number of risk factors that were found significant in the logistic regression analyses. Original and simplified scores were cross-validated. A combined data set was created to estimate a potential center effect and to construct a final risk score. The discriminating power of each score was assessed using the area under the receiver operating characteristic curves. RESULTS: Risk scores derived from one center were able to predict PONV from the other center (area under the curve = 0.65-0.75). Simplification did not essentially weaken the discriminating power (area under the curve = 0.63-0.73). No center effect could be detected in a combined data set (odds ratio = 1.06, 95% confidence interval = 0.71-1.59). The final score consisted of four predictors: female gender, history of motion sickness (MS) or PONV, nonsmoking, and the use of postoperative opioids. If none, one, two, three, or four of these risk factors were present, the incidences of PONV were 10%, 21%, 39%, 61% and 79%. CONCLUSIONS: The risk scores derived from one center proved valid in the other and could be simplified without significant loss of discriminating power. Therefore, it appears that this risk score has broad applicability in predicting PONV in adult patients undergoing inhalational anesthesia for various types of surgery. For patients with at least two out of these four identified predictors a prophylactic antiemetic strategy should be considered.

negative: Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia. Polycystic ovary syndrome (PCOS), defined as the combination of oligoanovulation and hyperandrogenism, affects more than 5% of women of reproductive age. Insulin resistance and hyperinsulinemia appear to play an important role in its pathogenesis. Here, we will present a characterization of a PCOS cohort from North Rhine-Westphalia in Germany. Clinical features, family history as well as endocrine and metabolic parameters were prospectively recorded from 200 successive patients. All patients were evaluated for insulin resistance and beta-cell-function by oral glucose tolerance test. Patient data were compared with those of 98 age-matched control women. PCOS patients showed significantly higher BMI, body fat mass and androgen levels as well as impaired glucose and insulin metabolism. A positive family history of PCOS and diabetes was more frequent in PCOS patients. Insulin resistance (71%) was the most common metabolic abnormality in PCOS patients followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for the metabolic syndrome. C-reactive protein and other cardiovascular risk factors were frequently elevated even in young PCOS patients. While the clinical characteristics and endocrine parameters of this German PCOS cohort were heterogeneous, they were comparable to those from other Caucasian populations.

negative: Internal exposure to pollutants and sexual maturation in Flemish adolescents. Flanders is densely populated with much industry and intensive farming. Sexual maturation of adolescents (aged 14-15 years) was studied in relation to internal exposure to pollutants. Serum levels of pollutants and sex hormones were measured in 1679 participants selected as a random sample of the adolescents residing in the study areas. Data on sexual development were obtained from the medical school examination files. Self-assessment questionnaires provided information on health, use of medication and lifestyle factors. In boys, serum levels of hexachlorobenzene (HCB), p,p'-DDE and polychlorinated biphenyls (sum of marker PCB138, 153 and 180) were significantly and positively associated with pubertal staging (pubic hair and genital development). Higher levels of serum HCB and blood lead were associated with, respectively, a lower and a higher risk of gynecomastia. In girls, significant and negative associations were detected between blood lead and pubic hair development; higher exposure to PCBs was significantly associated with a delay in timing of menarche. Environmental exposures to pollutants at levels actually present in the Flemish population are associated with measurable effects on pubertal development. However, further understanding of toxic mode of action and sensitive windows of exposure is needed to explain the current findings.

negative: Changing prevalence of coronary heart disease risk factors and cardiovascular diseases in men of a rural area of Crete from 1960 to 1991. This study compares the prevalence of coronary heart disease (CHD), risk factors (RF), and cardiovascular diseases (CVD) among Cretan men from a rural area examined in 1960 and 1991. The study population consisted of 148 men in 1960 and 42 men in 1991 of the same age group (fifty-five to fifty-nine years old) and from the same rural area. All men had a complete examination of the cardiovascular system and a resting electrocardiogram (ECG). Systolic BP (SBP) > or = 140 mmHg was found in 42.6% of the subjects in 1960 and in 45.2% in 1991 (NS). Diastolic BP > or = 95 mmHG was found in 14.9% of the subjects in 1960 as opposed to 33.3% in 1991 (P < 0.02). Total serum cholesterol (TSCH) > or = 260 mg/dL approximately 6.7 mmol/L) was found in 12.8% of the subjects in 1960 and in 28.6% in 1991 (P < 0.01). Heavy smokers ( > or = 20 cigarettes/daily) were 27.0% in 1960 as compared with 35.7% in 1991 (:NS); 5.4% of the subjects in 1960 had light physical activity (PA) as compared with 14.3% in 1991 (P < 0.01); 74.7% of the subjects were farmers in 1960 as compared with 43.6% in 1991 (P < 0.1). The prevalence of CHD was 0.7% in 1960 as compared with 9.5% in 1991 (P < 0.001). Hypertensive heart disease was found in 3.4% of the subjects in 1960 and 4.8% in 1991 (NS). The prevalence of all major CVD was much higher in 1991 (19.1%) as compared with 1960 (8.8%) (P < 0.01). In conclusion, the prevalence of CHD RF and CVD was much higher in 1991 than in 1960 for Cretan men of the same age group. This higher prevalence seems to be related to dietary and life-style changes that have taken place in Crete during the last thirty years.

negative: Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study Objective To investigate the relative importance of the individual components of the Mediterranean diet in generating the inverse association of increased adherence to this diet and overall mortality. Design Prospective cohort study. Setting Greek segment of the European Prospective Investigation into Cancer and nutrition (EPIC). Participants 23 349 men and women, not previously diagnosed with cancer, coronary heart disease, or diabetes, with documented survival status until June 2008 and complete information on nutritional variables and important covariates at enrolment. Main outcome measure All cause mortality. Results After a mean follow-up of 8.5 years, 652 deaths from any cause had occurred among 12 694 participants with Mediterranean diet scores 0-4 and 423 among 10 655 participants with scores of 5 or more. Controlling for potential confounders, higher adherence to a Mediterranean diet was associated with a statistically significant reduction in total mortality (adjusted mortality ratio per two unit increase in score 0.864, 95% confidence interval 0.802 to 0.932). The contributions of the individual components of the Mediterranean diet to this association were moderate ethanol consumption 23.5%, low consumption of meat and meat products 16.6%, high vegetable consumption 16.2%, high fruit and nut consumption 11.2%, high monounsaturated to saturated lipid ratio 10.6%, and high legume consumption 9.7%. The contributions of high cereal consumption and low dairy consumption were minimal, whereas high fish and seafood consumption was associated with a non-significant increase in mortality ratio. Conclusion The dominant components of the Mediterranean diet score as a predictor of lower mortality are moderate consumption of ethanol, low consumption of meat and meat products, and high consumption of vegetables, fruits and nuts, olive oil, and legumes. Minimal contributions were found for cereals and dairy products, possibly because they are heterogeneous categories of foods with differential health effects, and for fish and seafood, the intake of which is low in this population.

negative: Swimming with death: Naegleria fowleri infections in recreational waters. Naegleria fowleri is a free-living amoeba commonly found in warm freshwater environments such as hot springs, lakes, natural mineral water, and resort spas frequented by tourists. N. fowleri is the etiologic agent of primary amoebic meningoencephalitis (PAM), an acute fatal disease of the central nervous system that results in death in approximately seven days. Previously thought to be a rare condition, the number of reported PAM cases is increasing each year. PAM is difficult to diagnose because the clinical signs of the disease are similar to bacterial meningitis. Thus, the key to diagnosis is physician awareness and clinical suspicion. With the intent of creating awareness among travel medicine practitioners and the tourism industry, this review focuses on the presenting features of N. fowleri and PAM and offers insight into the prevention and treatment of the disease. Copyright © 2010 Elsevier Ltd. All rights reserved.

negative: Dioxins, dibenzofurans, dioxin-like PCBs, and DDE in U.S. fast food, 1995. Food, especially dairy products, meat, and fish, is the primary source of environmental exposure to dioxins in the general population. Little data exists on dioxin levels in the popular and widely consumed "fast foods". Data presented in a previously published pilot study was limited to measuring only the levels of dioxins and dibenzofurans in three types of U.S. fast food. This study adds to the previous paper by presenting data, in addition to dioxins and dibenzofurans, on the closely related dioxin-like polychlorinated biphenyls (PCBs), and the persistent metabolite of DDT, 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (DDE), in four types of popular U.S. fast food. These include McDonald's Big Mac Hamburger, Pizza Hut's Personal Pan Pizza Supreme, Kentucky Fried Chicken (KFC) three piece original recipe mixed dark and white meat luncheon package, and Häagen-Daz chocolate-chocolate chip ice cream. Dioxin plus dibenzofuran dioxin toxic equivalents (TEQ) ranged from 0.03 to 0.28 TEQ pg/g wet or whole weight for the Big Mac, from 0.03 to 0.29 for the Pizza, from 0.01 to 0.31 for the KFC, and from 0.03 to 0.49 TEQ pg/g for the ice cream. Daily TEQ consumption per kilogram body weight (kg/BW), assuming an average 65 kg adult and a 20 kg child, from one serving of each of these fast food ranged between 0.046 and 1.556 pg/kg in adults whereas in children the values were between 0.15 and 5.05 pg/kg. Total measured PCDD/Fs in the Big Mac, Personal Pan Pizza, KFC, and the Häagen-Daz ice cream varied from 0.58 to 9.31 pg/g. Measured DDE levels in the fast foods ranged from 180 to 3170 pg/g. Total mono-ortho PCB levels ranged up to 500 pg/g or 1.28 TEQ pg/g for the KFC and for di-ortho PCBs up to 740 pg/g or 0.014 TEQ pg/g for the pizza sample. Total PCB values in the four samples ranged up to 1170 pg/g or 1.29 TEQ pg/g for the chicken sample.

negative: Iodine toxicity from soy milk and seaweed ingestion is associated with serious thyroid dysfunction. We report a series of cases of thyroid dysfunction in adults associated with ingestion of a brand of soy milk manufactured with kombu (seaweed), and a case of hypothyroidism in a neonate whose mother had been drinking this milk. We also report two cases of neonatal hypothyroidism linked to maternal ingestion of seaweed made into soup. These products were found to contain high levels of iodine. Despite increasing awareness of iodine deficiency, the potential for iodine toxicity, particularly from sources such as seaweed, is less well recognised.

negative: High intakes of protein and processed meat associate with increased incidence of type 2 diabetes. Diets high in protein have shown positive effects on short-term weight reduction and glycaemic control. However, the understanding of how dietary macronutrient composition relates to long-term risk of type 2 diabetes is limited. The aim of the present study was to examine intakes of macronutrients, fibre and protein sources in relation to incident type 2 diabetes. In total, 27 140 individuals, aged 45-74 years, from the population-based Malmö Diet and Cancer cohort, were included. Dietary data were collected with a modified diet history method, including registration of cooked meals. During 12 years of follow-up, 1709 incident type 2 diabetes cases were identified. High protein intake was associated with increased risk of type 2 diabetes (hazard ratio (HR) 1.27 for highest compared with lowest quintile; 95 % CI 1.08, 1.49; P for trend = 0.01). When protein consumption increased by 5 % of energy at the expense of carbohydrates (HR 1.20; 95 % CI 1.09, 1.33) or fat (HR 1.21; 95 % CI 1.09, 1.33), increased diabetes risk was observed. Intakes in the highest quintiles of processed meat (HR 1.16; 95 % CI 1.00, 1.36; P for trend = 0.01) and eggs (HR 1.21; 95 % CI 1.04, 1.41; P for trend = 0.02) were associated with increased risk. Intake of fibre-rich bread and cereals was inversely associated with type 2 diabetes (HR 0.84; 95 % CI 0.73, 0.98; P for trend = 0.004). In conclusion, results from the present large population-based prospective study indicate that high protein intake is associated with increased risk of type 2 diabetes. Replacing protein with carbohydrates may be favourable, especially if fibre-rich breads and cereals are chosen as carbohydrate sources.

negative: Meat and fish consumption and cancer in Canada. In this study, we examined the association between meat and fish intake and the risk of various cancers. Mailed questionnaires were completed by 19,732 incident, histologically confirmed cases of cancer of the stomach, colon, rectum, pancreas, lung, breast, ovary, prostate, testis, kidney, bladder, brain, non-Hodgkin's lymphomas (NHL), and leukemia and 5,039 population controls between 1994 and 1997 in 8 Canadian provinces. Measurement included information on socioeconomic status, lifestyle habits, and diet. A 69-item food frequency questionnaire provided data on eating habits 2 yr before data collection. Odds ratios and 95% confidence intervals were derived through unconditional logistic regression. Total meat and processed meat were directly related to the risk of stomach, colon, rectum, pancreas, lung, breast (mainly postmenopausal), prostate, testis, kidney, bladder, and leukemia. Red meat was significantly associated with colon, lung (mainly in men), and bladder cancer. No relation was observed for cancer of the ovary, brain, and NHL. No consistent excess risk emerged for fish and poultry, which were inversely related to the risk of a number of cancer sites. These findings add further evidence that meat, specifically red and processed meat, plays an unfavorable role in the risk of several cancers. Fish and poultry appear to be favorable diet indicators.

negative: The Ethiopian Field Epidemiology and Laboratory Training Program: strengthening public health systems and building human resource capacity. The Ethiopian Field Epidemiology and Laboratory Training Program (EFELTP) is a comprehensive two-year competency-based training and service program designed to build sustainable public health expertise and capacity. Established in 2009, the program is a partnership between the Ethiopian Federal Ministry of Health, the Ethiopian Health and Nutrition Research Institute, Addis Ababa University School of Public Health, the Ethiopian Public Health Association and the US Centers of Disease Control and Prevention. Residents of the program spend about 25% of their time undergoing didactic training and the 75% in the field working at program field bases established with the MOH and Regional Health Bureaus investigating disease outbreaks, improving disease surveillance, responding to public health emergencies, using health data to make recommendations and undertaking other field Epidemiology related activities on setting health policy. Residents from the first 2 cohorts of the program have conducted more than 42 outbreaks investigations, 27analyses of surveillance data, evaluations of 11 surveillance systems, had28oral and poster presentation abstracts accepted at 10 scientific conferences and submitted 8 manuscripts of which 2are already published. The EFELTP has provided valuable opportunities to improve epidemiology and laboratory capacity building in Ethiopia. While the program is relatively young, positive and significant impacts are assisting the country better detect and respond to epidemics and address diseases of major public health significance.

negative: Intake of whole-grain products and risk of prostate cancer among men in the Danish Diet, Cancer and Health cohort study. OBJECTIVE: High intake of whole-grain products may protect against prostate cancer, but overall evidence is limited and inconclusive. The aim of the present study was to investigate the relationship between the intake of whole-grain products and risk of prostate cancer in a large prospective cohort. METHODS: A total of 26,691 men aged 50-64 years participated in the Diet, Cancer and Health cohort study and provided information about diet and potential prostate cancer risk factors. During a median follow-up of 12.4 years, we identified 1,081 prostate cancer cases. Associations between whole-grain product intake and prostate cancer incidence were analyzed using Cox's regression model. RESULTS: Overall, there was no association between total intake of whole-grain products and prostate cancer risk (adjusted incidence rate ratio per 50 g day(-1): 1.00 (95% confidence interval: 0.96, 1.05)) as well as between intake of the specific whole-grain products: whole-grain rye bread, whole-grain bread, and oatmeal, and risk of prostate cancer. No risk estimates did differ according to either stage or grade of disease. CONCLUSIONS: Results from this prospective study suggest that higher intakes of total or specific whole-grain products are not associated with risk of prostate cancer in a population of Danish middle-aged men.

negative: Fish consumption, insulin sensitivity and beta-cell function in the Insulin Resistance Atherosclerosis Study (IRAS) Background and aims Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population. Methods and results We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as <2 vs. ≥2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Higher fish consumption was independently associated with lower SI-adjusted AIR (β=−0.13 [−0.25, −0.016], p=0.03, comparing ≥ 2 vs. <2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted β=0.073 [−0.014, 0.16] for intact proinsulin/C-peptide ratio, β=0.031 [−0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted β=2.27 [0.68, 3.86], p=0.005). We found no association between fish consumption and SI (multivariable-adjusted β= −0.015 [−0.083, 0.053]) or fasting insulin (multivariable-adjusted β=0.016 [−0.066, 0.10]). Conclusions Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction.

negative: The association of diet with respiratory symptoms and asthma in schoolchildren in Taipei, Taiwan. This study aimed to evaluate the association of diet with respiratory symptoms and asthma in schoolchildren in Taipei, Taiwan. An in-class interview survey elicited experiences of asthma and respiratory symptoms and consumption frequencies of the major food categories in 2290 fifth graders. Respiratory symptoms surveyed included persistent cough, chest tightness, wheezing with cold, wheezing without cold, dyspnea-associated wheezing, and exercise-induced cough or wheezing. Results showed that the consumption of sweetened beverages had the strongest association with respiratory symptoms and was positively associated with six of the seven respiratory symptoms (all p < 0.05). The adjusted odds ratios (aOR) ranged from 1.05 (95% confidence interval (CI = 1.01-1.09) for exercise-induced cough to 1.09 (95% CI = 1.03-1.16) for wheezing without cold. Egg consumption was associated with 5 of the 7 respiratory symptoms. Consumptions of seafood, soy products, and fruits were each negatively associated with one of the seven respiratory symptoms (all p < 0.05). Consumption of seafood was negatively associated with physician-diagnosed asthma and consumptions of sweetened beverages and eggs were positively associated with suspected asthma (p < 0.05). In conclusion, the study suggests that diet is associated with the respiratory symptoms in schoolchildren in Taipei. Consumptions of sweetened beverages and eggs are associated with increased risk of respiratory symptoms and asthma whereas consumptions of soy products and fruits are associated with reduced risk of respiratory symptoms.

negative: Extending healthy ageing: nutrient sensitive pathway and centenarian population Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.

negative: Hair mercury levels of women of reproductive age in Ontario, Canada: implications to fetal safety and fish consumption. OBJECTIVE: To study hair mercury concentrations among women of reproductive age in relation to fish intake in Ontario, Canada. STUDY DESIGN: Three groups were studied: 22 women who had called the Motherisk Program for information on the reproductive safety of consuming fish during pregnancy, a group of Japanese residing in Toronto (n=23) consuming much larger amounts of fish, and a group of Canadian women of reproductive age (n=20) not seeking advice, were studied. Mercury concentrations in hair samples were measured using inductively coupled plasma mass spectrometry. Seafood consumption habits were recorded for each participant. Based on the types of fish consumed and consumption frequencies, the estimated monthly intake of mercury was calculated. Hair mercury concentrations were correlated to both the number of monthly seafood servings and the estimated ingested mercury dose. RESULTS: There were significant correlations between fish servings and hair mercury (Spearman r=0.73, P<.0001) and between amounts of consumed mercury and hair mercury concentrations (Spearman r=0.81, P<.0001). Nearly two thirds of the Motherisk callers, all of the Japanese women, and 15% of the Canadian women of reproductive age had hair mercury above 0.3 microg/g, which was shown recently to be the lowest observable adverse effect level in a large systematic review of all perinatal studies. CONCLUSIONS: Because of very wide variability, general recommendations for a safe number of fish servings may not be sufficient to protect the fetus. Analysis of hair mercury may be warranted before pregnancy in selected groups of women consuming more than 12 ounces of fish per week, as dietary modification can decrease body burden and ensure fetal safety. Copyright (c) 2010. Published by Mosby, Inc.

negative: Salmonella enterica serotype Enteritidis: increasing incidence of domestically acquired infections. BACKGROUND: Salmonella enterica causes an estimated 1 million cases of domestically acquired foodborne illness in humans annually in the United States; Enteritidis (SE) is the most common serotype. Public health authorities, regulatory agencies, food producers, and food processors need accurate information about rates and changes in SE infection to implement and evaluate evidence-based control policies and practices. METHODS: We analyzed the incidence of human SE infection during 1996-2009 in the Foodborne Diseases Active Surveillance Network (FoodNet), an active, population-based surveillance system for laboratory-confirmed infections. We compared FoodNet incidence with passively collected data from complementary surveillance systems and with rates of SE isolation from processed chickens and egg products; shell eggs are not routinely tested. We also compared molecular subtyping patterns of SE isolated from humans and chickens. RESULTS: Since the period 1996-1999, the incidence of human SE infection in FoodNet has increased by 44%. This change is mirrored in passive national surveillance data. The greatest relative increases were in young children, older adults, and FoodNet sites in the southern United States. The proportion of patients with SE infection who reported recent international travel has decreased in recent years, whereas the proportion of chickens from which SE was isolated has increased. Similar molecular subtypes of SE are commonly isolated from humans and chickens. CONCLUSIONS: Most SE infections in the United States are acquired from domestic sources, and the problem is growing. Chicken and eggs are likely major sources of SE. Continued close attention to surveillance data is needed to monitor the impact of recent regulatory control measures.

negative: Consumption of a boiled Greek type of coffee is associated with improved endothelial function: the Ikaria study. OBJECTIVE: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. METHODS: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as 'low' (< 200 ml/day), 'moderate' (200-450 ml/day), or 'high' (> 450 ml/day). RESULTS: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a 'low', 48% a 'moderate' and 13% a 'high' daily coffee consumption. There was a linear increase in FMD according to coffee consumption ('low': 4.33 ± 2.51% vs 'moderate': 5.39 ± 3.09% vs 'high': 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages (p = 0.035). CONCLUSIONS: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

negative: Adherence to Mediterranean diet and sexual function in women with type 2 diabetes. INTRODUCTION: There are no reported studies assessing the relation between diet and sexual function in women with diabetes. AIM: In the present study, we explored the relation between consumption of a Mediterranean-type diet and sexual function in a population of type 2 diabetic women. METHODS: Patients with type 2 diabetes were enrolled if they had a diagnosis of type 2 diabetes for at least six months but less than 10 years, age 35-70 years, body mass index (BMI) of 24 or higher, HbA1c of 6.5% or higher, treatment with diet or oral drugs. All diabetic patients were invited to complete a food-frequency questionnaire and self-report measures of sexual function. A total of 595 (90.2%) of the 659 women completed both questionnaires and were analyzed in the present study. MAIN OUTCOME MEASURES: Adherence to a Mediterranean diet was assessed by a 9-point scale that incorporated the salient characteristics of this diet (range of scores, 0-9, with higher scores indicating greater adherence). The Female Sexual Function Index (FSFI) was used for assessing the key dimensions of female sexual function. RESULTS: Diabetic women with the highest scores (6-9) had lower BMI, waist circumference, and waist-to-hip ratio, a lower prevalence of depression, obesity and metabolic syndrome, a higher level of physical activity, and better glucose and lipid profiles than the diabetic women who scored <3 points on the scale. The proportion of sexually active women showed a significant increase across tertiles of adherence to Mediterranean diet (from 54.2% to 65.1%, P = 0.01). Based on the FSFI cutoff score for female sexual dysfunction (FSD) of 23, women with the highest score of adherence had a lower prevalence of sexual dysfunction as compared with women of lower tertiles (47.6%, 53.9%, and 57.8%, higher, middle, and lower tertile, respectively, P = 0.01). These associations remained significant after adjustment for many potential confounders. CONCLUSIONS: In women with type 2 diabetes, greater adherence to Mediterranean diet is associated with a lower prevalence of FSD.

negative: Animal food intake and cooking methods in relation to endometrial cancer risk in Shanghai We evaluated animal food intake and cooking methods in relation to endometrial cancer risk in a population-based case–control study in Shanghai, China. A validated food frequency questionnaire was used to collect the usual dietary habits of 1204 cases and 1212 controls aged 30–69 years between 1997 and 2003. Statistical analyses were based on an unconditional logistic regression model adjusting for potential confounders. High intake of meat and fish was associated with an increased risk of endometrial cancer, with adjusted odds ratios for the highest vs the lowest quartile groups being 1.7 (95% confidence interval: 1.3–2.2) and 2.4 (1.8–3.1), respectively. The elevated risk was observed for all types of meat and fish intake. Intake of eggs and milk was not related to risk. Cooking methods and doneness levels for meat and fish were not associated with risk, nor did they modify the association with meat and fish consumption. Our study suggests that animal food consumption may play an important role in the aetiology of endometrial cancer, but cooking methods have minimal influence on risk among Chinese women.

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.