The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

A fixed carbohydrate: protein ratio <= 1.8 on an energy basis consumed in the context of an energy-restricted diet and reduction of body weight: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006.

Following an application from Marks and Spencer PLC, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of the United Kingdom, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to a CHO:P ratio &lt;= 1.8 on an energy basis in the context of an energy-restricted diet and body weight. The Panel considers that the food/constituent that is the subject of the health claim is sufficiently characterised. The Panel also considers that reduction of body weight in the context of an energy-restricted diet is a beneficial physiological effect. The target population proposed by the applicant is 'adults between the ages of 18 and 70 years with excess body weight'. No conclusions could be drawn from two unpublished studies investigating the effect of ready-to-eat meals with a CHO: P ratio &lt;= 1.8 on body weight. The remaining 14 human intervention studies investigated the effect of diets targeting a CHO: P ratio &lt;= 1.8 as compared to diets targeting a CHO: P ratio &gt;= 3.0 on overweight and obese adults in the context of energy restriction. Four out of seven studies lasting &lt; 12 weeks reported an effect of a CHO: P ratio &lt;= 1.8 on body weight in overweight/obese subjects, whereas no significant effect was observed in six out of the seven studies lasting 12 weeks or more. The Panel considers that these studies do not provide evidence for a sustained effect of the food/constituent on body weight. The Panel concludes that a cause and effect relationship has not been established between the consumption of a fixed CHO: P ratio &lt;= 1.8 on an energy basis consumed in the context of an energy-restricted diet and reduction of body weight. (C) 2017 European Food Safety Authority

Estrus cyclicity of spinogenesis: underlying mechanisms

Hippocampal spine density varies with the estrus cycle. The cyclic change in estradiol levels in serum was hypothesized to underlie this phenomenon, since treatment of ovariectomized animals with estradiol induced an increase in spine density in hippocampal dendrites of rats, as compared to ovariectomized controls. In contrast, application of estradiol to hippocampal slice cultures did not promote spinogenesis. In addressing this discrepancy, we found that hippocampal neurons themselves are capable of synthesizing estradiol de novo. Estradiol synthesis can be suppressed by aromatase inhibitors and by knock-down of Steroid Acute Regulatory Protein (StAR) and enhanced by substrates of steroidogenesis. Expression of estrogen receptors (ERs) and synaptic proteins, synaptogenesis, and long-term potentiation (LTP) correlated positively with aromatase activity in hippocampal cultures without any difference between genders. All effects due to inhibition of aromatase activity were rescued by application of estradiol to the cultures. Most importantly, gonadotropin-releasing hormone (GnRH) increased estradiol synthesis dose-dependently via an aromatase-mediated mechanism and consistently increased spine synapse density and spinophilin expression. As a consequence, our data suggest that cyclic fluctuations in spine synapse density result from pulsative release of GnRH from the hypothalamus and its effect on hippocampal estradiol synthesis, rather than from varying levels of serum estradiol. This hypothesis is further supported by higher GnRH receptor (GnRH-R) density in the hippocampus than in the cortex and hypothalamus and the specificity of estrus cyclicity of spinogenesis in the hippocampus, as compared to the cortex

Imputation strategies for missing binary outcomes in cluster randomized trials

<p>Abstract</p> <p>Background</p> <p>Attrition, which leads to missing data, is a common problem in cluster randomized trials (CRTs), where groups of patients rather than individuals are randomized. Standard multiple imputation (MI) strategies may not be appropriate to impute missing data from CRTs since they assume independent data. In this paper, under the assumption of missing completely at random and covariate dependent missing, we compared six MI strategies which account for the intra-cluster correlation for missing binary outcomes in CRTs with the standard imputation strategies and complete case analysis approach using a simulation study.</p> <p>Method</p> <p>We considered three within-cluster and three across-cluster MI strategies for missing binary outcomes in CRTs. The three within-cluster MI strategies are logistic regression method, propensity score method, and Markov chain Monte Carlo (MCMC) method, which apply standard MI strategies within each cluster. The three across-cluster MI strategies are propensity score method, random-effects (RE) logistic regression approach, and logistic regression with cluster as a fixed effect. Based on the community hypertension assessment trial (CHAT) which has complete data, we designed a simulation study to investigate the performance of above MI strategies.</p> <p>Results</p> <p>The estimated treatment effect and its 95% confidence interval (CI) from generalized estimating equations (GEE) model based on the CHAT complete dataset are 1.14 (0.76 1.70). When 30% of binary outcome are missing completely at random, a simulation study shows that the estimated treatment effects and the corresponding 95% CIs from GEE model are 1.15 (0.76 1.75) if complete case analysis is used, 1.12 (0.72 1.73) if within-cluster MCMC method is used, 1.21 (0.80 1.81) if across-cluster RE logistic regression is used, and 1.16 (0.82 1.64) if standard logistic regression which does not account for clustering is used.</p> <p>Conclusion</p> <p>When the percentage of missing data is low or intra-cluster correlation coefficient is small, different approaches for handling missing binary outcome data generate quite similar results. When the percentage of missing data is large, standard MI strategies, which do not take into account the intra-cluster correlation, underestimate the variance of the treatment effect. Within-cluster and across-cluster MI strategies (except for random-effects logistic regression MI strategy), which take the intra-cluster correlation into account, seem to be more appropriate to handle the missing outcome from CRTs. Under the same imputation strategy and percentage of missingness, the estimates of the treatment effect from GEE and RE logistic regression models are similar.</p

Safety of betaine as a novel food pursuant to Regulation (EC) No 258/97

Following a request from the European Commission, the EFSA Panelon Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on betaine as a novel food (NF) pursuant to Regulation (EC) No 258/97. The information provided on the composition, the specifications, the batch-to-batch variability, stability and production process of the NF is sufficient and does not raise concerns about the safety of the NF. The NF is proposed to be used in foods intended to meet additional requirements for intense muscular effort with a maximum intake of 2.5 g/day of betaine for sports people above 10 years of age. Based on the lowest BMDL05, which was derived from a chronic toxicity study in rats in which a dose-related increase in platelet counts was observed, and the anticipated daily intake of the NF in the target population, the Margins of Exposure are 3.6 and 5, which are generally regarded as not sufficient. However, the total exposure to betaine from the diet (about 830 mg/day) is not known to be associated with adverse effects. Moreover, no adverse effects on platelet counts were noted in human intervention studies with exposure levels of 4 g/day of betaine for up to 6 months. A significant increase in total and low-density lipoprotein (LDL)-cholesterol concentrations was noted at intakes of 4 g/day of betaine in overweight subjects with metabolic syndrome but not in healthy subjects, nor at intakes of 3 g/day. Thus, considering 4 g/day of betaine as a reference point and applying an uncertainty factor of 10 to account for interindividual variability, an amount of 400 mg/day of betaine in addition to the background exposure is considered as safe. The Panelconsiders that the NF is safe to be used at maximum intake of 400 mg/day in the target population

Statement on the safety of taxifolin-rich extract from Dahurian Larch (Larix gmelinii)

Following a request from the European Commission, the EFSA Panelon Dietetic Products, Nutrition and Allergies (NDA) was asked to carry out a supplementary safety assessment for taxifolin by considering also those population groups which were originally excluded at the request of the applicant (i.e. infants, young children and children up to 9 years) for the food categories set out in the application, and by taking into the extension of use of taxifolin from yogurt to a wider range of dairy products. In 2016, the EFSA NDA Paneladopted the Scientific Opinion on the safety of taxifolin-rich extract from Dahurian Larch (Larix gmelinii) as a novel food ingredient in non-alcoholic beverages, yogurts, chocolate confectionery and food supplements pursuant to Regulation (EC) No 258/97. In order to address the present mandate, an intake assessment was carried out by taking into account all population groups (including now also children below 9years of age) and by considering the food intended categories for which the applicant provided maximum use levels of taxifolin. Intakes were estimated for all age groups of the general population. The highest 95 th percentile intakes per kg bw per day among all population groups are 0.94 and 1.54 mg, respectively, derived for toddlers. Noting that the no-observed-adverse effect level (NOAEL) of the subchronic study was 1,500 mg/kg body weight (bw), the resulting margin of exposure (MOE) would be almost 1,000. For adults weighing 70 kg, the MOE to the combined intake from fortified foods and food supplements would be about 772. For adolescents, taking into account a default mean body weight of 61 kg, the MOE to the combined intake (including 100 mg from food supplements) would be about 627. The Panelconsiders that these MOEs are sufficient. The Panelconcludes that the NF food, taxifolin-rich extract from Dahurian Larch, is safe under the proposed conditions of use

Safety of Ecklonia cava phlorotannins as a novel food pursuant to Regulation (EC) No 258/97

Following a request from the European Commission, the EFSA Panelon Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the safety of Ecklonia cava phlorotannins (marketed as SeaPolynol) as a novel food submitted pursuant to Regulation (EC) No258/97. The novel food is a phlorotannin-rich alcohol extract of Ecklonia cava, which is an edible marine brown alga species. The information provided on the composition, the specifications, the production process and the batch-to-batch variability of the novel food is sufficient and does not raise safety concerns. The intention is to market the novel food as a food supplement for healthy individuals over the age of 12years. A subchronic repeated dose oral toxicity study in rodents tested the novel food at daily doses of 0, 375, 750 and 1,500mg/kg body weight (bw). The Panelconsiders the mid-dose as the no-observed-adverse-effect-level (NOAEL) of the study. Taking into account this NOAEL of 750mg/kg bw per day and by applying an uncertainty factor of 200, the Panelconsiders an intake level of 3.75mg/kg bw per day as safe. The Panelconcludes that the novel food, Ecklonia cava phlorotannins, is safe for the use in food supplements at a maximum daily intake level of 163mg/day for adolescents from 12 to 14years of age, 230mg/day for adolescents above 14years of age and 263mg/day for adults. (C) 2017 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority

Safety of dried aerial parts of Hoodia parviflora as a novel food pursuant to Regulation (EC) No258/97

Following a request from the European Commission, the EFSA Panelon Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on the dried aerial parts of Hoodiaparviflora as a novel food (NF) submitted pursuant to Regulation (EC) No258/97. The information provided on the composition, the specifications, the production process, the batch-to-batch variability and the stability of the NF is sufficient and does not raise safety concerns. The applicant intends to use the NF in a number of energy-reduced/sugar-free/no-added-sugar foods in quantities of up to 15mg per serving. The applicant also proposes to provide the NF as a food supplement. The target population proposed by the applicant is adults. The highest intake estimates were found in the group of elderly (65years) individuals, with a high intake of 1.0mg/kg body weight (bw) per day. One 90-day toxicity study in rodents was provided from which a benchmark dose lower confidence limit (BMDL05) of 53.5mg/kg bw per day was derived for effects of the NF on bodyweight. The Panelconcludes that the addition of the NF to foods as a food ingredient at the uses and use levels as proposed by the applicant would exceed intake levels considered safe in humans. The Panelconsiders that the NF is safe to be used as a food supplement at a maximum dose of 9.4mg/day. The target population is adults. (C) 2017 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority

Statement on the safety of synthetic L-ergothioneine as a novel food - supplementary dietary exposure and safety assessment for infants and young children, pregnant and breastfeeding women

Following a request from the European Commission, the EFSA Panelon Dietetic Products, Nutrition and Allergies (NDA) was asked to provide a supplementary dietary exposure and safety assessment of synthetic l-ergothioneine for those groups of the population which had been excluded by the applicant in the original application, i.e. infants and young children (i.e. toddlers), pregnant and breastfeeding women. Thus, intake estimates were calculated for these population groups and the following maximum anticipated daily intakes of l-ergothioneine from the NF, in addition to the background diet, were calculated: 2.82 mg/kg body weight (bw) per day for infants, 3.39 mg/kg bw per day for toddlers and 1.31 mg/kg bw per day for adults including pregnant and breastfeeding women. The Panelconsiders that based on the overall toxicological data the no-observed-adverse-effect level (NOAEL) of 800 mg/kg bw per day as established in the original assessment also pertains to pregnant and breastfeeding women as well as to young children (i.e. toddlers) and infants. The corresponding margins of exposure (i.e. the ratio between the NOAEL and the maximum anticipated daily intakes) are 284 for infants, 236 for young children and 610 for pregnant and breastfeeding women. These margins of exposure are considered sufficient. The Panelconcludes that the novel food, synthetic l-ergothioneine, is safe under the proposed uses and use levels for infants, young children (i.e. toddlers) and pregnant and breastfeeding women

The influence of a pre-exercise sports drink (PRX) on factors related to maximal aerobic performance

<p>Abstract</p> <p>Background</p> <p>Pre-exercise sports drinks (PRX) are commonly used as ergogenic aids in athletic competitions requiring aerobic power. However, in most cases, claims regarding their effectiveness have not been substantiated. In addition, the ingredients in PRX products must be deemed acceptable by the athletic governing bodies that regulate their use in training and competition. The purpose of this study was to examine the effects of a modified PRX formulation (known as EM·PACT™) from earlier investigations on factors related to maximal aerobic performance during a graded exercise test. The modification consisted of removing creatine to meet the compliance standards set forth by various athletic organizations that regulate the use of nutritional supplements.</p> <p>Methods</p> <p>Twenty-nine male and female college students varying in levels of aerobic fitness participated in a randomized crossover administration of PRX (containing 14 g/serving of fructose, medium-chain triglycerides, and amino acids mixed with 8 oz. of water) and placebo (PL) 30 minutes prior to performing a treadmill test with approximately one week separation between the trials. VO₂max, maximal heart rate (HR), time to exhaustion (Time), and percentage estimated non-protein fat substrate utilization (FA) during two <it>a priori </it>submaximal stages of a graded exercise testing were evaluated.</p> <p>Results</p> <p>The VO₂max mean value of the PRX trial was significantly greater than the PL trial (P < 0.01). The mean value for Time was also observed to be greater for the PRX trial compared to PL (P < 0.05). Additionally, percentage of FA during submaximal stages of the exercise test was greater for PRX trial in comparison to PL (P < 0.01).</p> <p>Conclusions</p> <p>The modified PRX formulation utilized in this investigation supports the findings of the previous investigation and its efficacy for enhancing indices of aerobic performance (specifically VO₂max, Time, & FA) during graded exercise testing.</p