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SUMMARYPurpose: To pool data from four published case-control studies of sudden unexpected death in epilepsy (SUDEP) with live controls, to increase the power to determine risk factors. Methods: Case-control studies from the United States, Sweden, Scotland, and England were combined. SUDEP was defined as (1) a history of epilepsy (>1 epileptic seizure during a period of <5 years); (2) death occurring suddenly; (3) death unexpected (i.e., no life-threatening illness); and (4) death remained unexplained after all investigative efforts, including autopsy. Definite SUDEP required all criteria. Logistic regression analyses adjusted for study. Further analysis simultaneously adjusted for study, age at death, gender, and duration of epilepsy. Key Findings: Of the risk factors that could be analyzed across some or all studies, those that were statistically significant were increased frequency of generalized tonic-clonic seizures (GTCS), use of polytherapy, duration of epilepsy, young age at onset, gender, symptomatic etiology, and lamotrigine therapy. Results persisted when epilepsy onset was younger than 16 years and when it was 16 years or older. In univariate analysis, lamotrigine therapy was associated with significantly increased risk for SUDEP among individuals with idiopathic generalized epilepsy. Significance: This analysis refines the identification of people with epilepsy that are at particular risk of SUDEP. The emerging profile indicates that people with early onset refractory symptomatic epilepsy with frequent GTCS and antiepileptic drug (AED) polytherapy are at higher risk. The results suggest that reduction of the number of GTCS is a priority, of more importance than reducing the number of AEDs. The role of AEDs and other treatment should be analyzed further in future studies.

Background/Objectives Polyphenols are plant secondary metabolites with a large variability in their chemical structure and dietary occurrence that have been associated with some protective effects against several chronic diseases. To date, limited data exist on intake of polyphenols in populations. The current cross-sectional analysis aimed at estimating dietary intakes of all currently known individual polyphenols and total intake per class and subclass, and to identify their main food sources in the European Prospective Investigation into Cancer and Nutrition cohort. Methods Dietary data at baseline were collected using a standardized 24-h dietary recall software administered to 36,037 adult subjects. Dietary data were linked with Phenol-Explorer, a database with data on 502 individual polyphenols in 452 foods and data on polyphenol losses due to cooking and food processing. Results Mean total polyphenol intake was the highest in Aarhus-Denmark (1786 mg/day in men and 1626 mg/day in women) and the lowest in Greece (744 mg/day in men and 584 mg/day in women). When dividing the subjects into three regions, the highest intake of total polyphenols was observed in the UK healthconscious group, followed by non-Mediterranean (non-MED) and MED countries. The main polyphenol contributors were phenolic acids (52.5-56.9 %), except in men from MED countries and in the UK health-conscious group where they were flavonoids (49.1-61.7 %). Coffee, tea, and fruits were the most important food sources of total polyphenols. A total of 437 different individual polyphenols were consumed, including 94 consumed at a level [1 mg/day. The most abundant ones were the caffeoylquinic acids and the proanthocyanidin oligomers and polymers. Conclusion This study describes the large number of dietary individual polyphenols consumed and the high variability of their intakes between European populations, particularly between MED and non-MED countries.

Global gene expression was analyzed in Arabidopsis (Arabidopsis thaliana) by microarrays comprising 21,500 genes. Leaf segments derived from phosphorus (P)-starved and P-replenished plants were incubated with or without sucrose (Suc) to obtain tissues with contrasting combinations of P and carbohydrate levels. Transcript profiling revealed the influence of the two factors individually and the interactions between P-and sugar-dependent gene regulation. A large number of gene transcripts changed more than 2-fold: In response to P starvation, 171 genes were induced and 16 repressed, whereas Suc incubation resulted in 337 induced and 307 repressed genes. A number of new candidate genes involved in P acquisition were discovered. In addition, several putative transcription factors and signaling proteins of P sensing were disclosed. Several genes previously identified to be sugar responsive were also regulated by P starvation and known P-responsive genes were sugar inducible. Nearly 150 genes were synergistically or antagonistically regulated by the two factors. These genes exhibit more prominent or contrasting regulation in response to Suc and P in combination than expected from the effect of the two factors individually. The genes exhibiting interactions form three main clusters with different response patterns and functionality of genes. One cluster (cluster 1) most likely represents a regulatory program to support increased growth and development when both P and carbohydrates are ample. Another cluster (cluster 3) represents genes induced to alleviate P starvation and these are further induced by carbohydrate accumulation. Thus, interactions between P and Suc reveal two different signaling programs and novel interactions in gene regulation in response to environmental factors. cis-Regulatory elements were analyzed for each factor and for interaction clusters. PHR1 binding sites were more frequent in promoters of P-regulated genes as compared to the entire Arabidopsis genome, and E2F and PHR1 binding sites were more frequent in interaction clusters 1 and 3, respectively.

Plants have evolved a number of adaptive strategies to cope with fluctuations in phosphorus (P) supply. The current knowledge of the transcriptional regulation of the P-starvation response in plants is limited. However, one MYB-related transcription factor, PHR1, is known to be involved in the P-starvation response. In this paper, we characterize a T-tagged phr1 knockout mutant and a series of transgenic plant lines which over-express PHR1 in wild type (WT) and phr1 mutant background. The knockout mutant has an altered phosphate (Pi) allocation between root and shoot; accumulates less anthocyanins, sugars and starch than P-starved WT; has a lower AGPase activity; and is impaired in induction of a subset of Pi starvation-induced genes. Expression of PHR1 in the phr1 mutant rescues the responsiveness to P-starvation and leads to WT levels of sugars and starch during Pi starvation conditions, confirming the involvement of PHR1 in adjusting carbon metabolism. Over-expression of PHR1 further resulted in a dramatic increase in the microRNA miR399d, and this resulted in changes in the transcript level for the target gene PHO2. Furthermore, over-expression of PHR1 in both WT and phr1 mutant results in strongly increased content of Pi irrespective of P regime. This shows that targeting a key regulatory element in the Pi starvation regulatory network represents a useful approach for molecular breeding of plants towards more efficient Pi uptake and assimilation.

SUMMARYPurpose: In an analysis of four case-control studies of sudden unexpected death in epilepsy (SUDEP), we found that yearly frequency of generalized tonic-clonic seizures (GTCS) and antiepileptic drug (AED) polytherapy were associated with an increased risk for SUDEP. The prior analysis, however, did not evaluate AEDs and GTCS frequency concurrently. Methods: We combined data from the three case-control studies with information on the frequency of GTCS and AED therapy, that is, carbamazepine, phenytoin, valproic acid, and other AED therapy. Number of AEDs was also considered. Lamotrigine and GTCS frequency were considered separately in two of the case-control studies. Logistic regression analysis was used to evaluate GTCS frequency, each of the AEDs, and number of AEDs. Adjusted analysis of the different AEDs accounted for study, age at death, gender, and GTCS frequency.Key Findings: In crude analysis, GTCS frequency, AED polytherapy, and number of AEDs were associated with an increased risk for SUDEP. Analysis of individual AEDs and of number of AEDs, adjusting for GTCS frequency, revealed no increased risk associated with AEDs as monotherapy, polytherapy, or total number. GTCS frequency remained strongly associated with an increased risk for SUDEP. Significance: Our findings-that none of the AEDs considered were associated with increased SUDEP risk as monotherapy or as polytherapy when GTCS frequency was taken into account-provide a consistent message that number of GTCS increases SUDEP risk and not AEDs. These results suggest that prevention of SUDEP must involve increased efforts to decrease GTCS frequency in order to avert the occurrence of this devastating epilepsy outcome. KEY WORDS: SUDEP, Epilepsy, Case-control study, Antiepileptic drugs, Generalized tonic-clonic seizures frequency.In a combined analysis of the four case-control studies of SUDEP with living epilepsy controls (Hesdorffer et al., 2011), we found that the risk for SUDEP was increased by number of generalized tonic-clonic seizures (GTCS) each year and by antiepileptic drug (AED) polytherapy; lamotrigine therapy was also associated with an increased risk for SUDEP. Our prior analysis did not simultaneously evaluate AEDs and GTCS frequency and thus we were unable to consider whether the increased risk for SUDEP was associated with GTCS frequency, AED polytherapy, or both, or with any specific AED. Here, we examine the association between SUDEP and each of the AEDs that were taken by a sufficient number of cases and controls to permit analysis while adjusting for GTCS frequency. MethodsWe combined the data from three of the four case-control studies of risk factors for SUDEP. These studies had information on GTCS frequency per year and AED therapy (Nilsson et al., 1999a;Walczak et al., 2001;Langan et al., 2005). SUDEP was defined as (1) a history of epilepsy (more than one epileptic seizure during a period of

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Background Earlier analyses within the EPIC study showed that dietary fibre intake was inversely associated with colorectal cancer risk, but results from some large cohort studies do not support this finding. We explored whether the association remained after longer follow-up with a near threefold increase in colorectal cancer cases, and if the association varied by gender and tumour location. Methodology/Principal Findings After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79–0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals. Conclusions/Significance Our results strengthen the evidence for the role of high dietary fibre intake in colorectal cancer prevention.