INTRODUCTION: Epigenetics describes the phenomenon of heritable changes in gene regulation governed by non-Mendelian processes, primarily through biochemical modifications to chromatin that occur during cell differentiation and development. Abnormal levels of DNA and/or histone modifications are observed in patients with a wide variety of chronic diseases. Drugs that target the proteins controlling these chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents with single target pharmacologies that are susceptible to biochemical pathway degeneracy. AREAS COVERED: This article reviews research characterizing dysregulation of epigenetic processes in cancer, immuno-inflammatory, psychiatric, neurological, metabolic and virology disease areas, and summarizes recent developments in identifying small molecule modulators that are being used to inform target discovery and initiate drug discovery projects. EXPERT OPINION: There are numerous potential opportunities for epigenetic modulators in treating a wide range of chronic diseases; however, the field is complex, involving > 300 proteins, and much work is still required to provide tools to unravel the functions of individual proteins, particularly in vivo. This groundwork is essential to allow the drug discovery community to focus on those epigenetic proteins most likely to be suitable targets for safe, efficacious new therapies.

High-yielding cereals and other staples have produced adequate calories to ward off starvation for much of the world over several decades. However, deficiencies in certain amino acids, minerals, vitamins and fatty acids in staple crops, and animal diets derived from them, have aggravated the problem of malnutrition and the increasing incidence of certain chronic diseases in nominally well-nourished people (the so-called diseases of civilization). Enhanced global nutrition has great potential to reduce acute and chronic disease, the need for health care, the cost of health care, and to increase educational attainment, economic productivity and the quality of life. However, nutrition is currently not an important driver of most plant breeding efforts, and there are only a few well-known efforts to breed crops that are adapted to the needs of optimal human nutrition. Technological tools are available to greatly enhance the nutritional value of our staple crops. However, enhanced nutrition in major crops might only be achieved if nutritional traits are introduced in tandem with important agronomic yield drivers, such as resistance to emerging pests or diseases, to drought and salinity, to herbicides, parasitic plants, frost or heat. In this way we might circumvent a natural tendency for high yield and low production cost to effectively select against the best human nutrition. Here we discuss the need and means for agriculture, food processing, food transport, sociology, nutrition and medicine to be integrated into new approaches to food production with optimal human nutrition as a principle goal.

Many studies have suggested that autism may be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. One of the most important polymorphisms in this pathway is C677T of the methylenetetrahydrofolate reductase gene, because the T allele is associated with a decrease in enzymatic activity. We evaluated the association between C677T polymorphism and autism spectrum disorders through a case--control study. In addition, we analyzed the influence of this polymorphism on certain autistic behaviors like complex body movements, self-injury and averted gaze according to the Autism Diagnostic Interview-Revised. The analyses involved 151 children with idiopathic autism spectrum disorder and 100 healthy control children. The frequency of the T allele was 0.38 for the case group and 0.35 for the control group (P=0.77). The genotypic distribution did not show significant differences between cases and controls (P=0.72), nor association between the T allele and selected behaviors.

While undernutrition and anaemia have previously been linked to poor development of children, relatively little is known about the role of B-vitamins and fatty acids on cognition. The present study aims to explore the associations between indicators of body size, fatty acid and micronutrient status on cognitive performance in 598 Indian school children aged 6-10 years. Baseline data of a clinical study were used to assess these associations by analyses of variance adjusting for age, sex, school, maternal education and cognitive tester. The Kaufman Assessment Battery for Children II was used to measure four cognitive domains, including fluid reasoning, short-term memory, retrieval ability and cognitive speediness. Scores were combined into an overall measure, named mental processing index (MPI). Body size indicators and Hb concentrations were significantly positively related to cognitive domains and MPI, such that increases of 1 sd in height-for-age and weight-for-age z-scores would each translate into a 0.09 sd increase in MPI, P = 0.0006 and 0.002, respectively. A 10 g/l increase in Hb concentrations would translate into a 0.08 sd increase in MPI, P = 0.0008. Log-transformed vitamin B12 concentrations were significantly inversely associated with short-term memory, retrieval ability and MPI (beta (95 % CI)=- 0.124 (- 0.224,- 0.023), P = 0.02). Other indicators of Fe, iodine, folate and fatty acid status were not significantly related to cognition. Our findings for body size, fatty acids and micronutrients were in agreement with previous observational studies. The inverse association of vitamin B12 with mental development was unexpected and needed further study.

BACKGROUND: Although multiple micronutrient interventions have been shown to benefit children's intellectual development, a thorough evaluation of the totality of evidence is currently lacking to direct public health policy. Objective: This study aimed to systematically review the present literature and to quantify the effect of multiple micronutrients on cognitive performance in schoolchildren. Methods: The Institute for Scientific Information Web of Knowledge and local medical databases were searched for trials published from 1970 to 2008. Randomized controlled trials that investigated the effect of >/=3 micronutrients compared with placebo on cognition in healthy children aged 0-18 y were included following protocol. Data were extracted by 2 independent researchers. The cognitive tests used in the trials were grouped into several cognitive domains (eg, fluid and crystallized intelligence), and pooled effect size estimates were calculated per domain. Heterogeneity was explored through sensitivity and meta-regression techniques. RESULTS: Three trials were retrieved in children aged <5 y, and 17 trials were retrieved in children aged 5-16 y. For the older children, pooled random-effect estimates for intervention were 0.14 SD (95% CI:-0.02, 0.29; P = 0.083) for fluid intelligence and -0.03 SD (95% CI:-0.21, 0.15; P = 0.74) for crystallized intelligence, both of which were based on 12 trials. Four trials yielded an overall effect of 0.30 SD (95% CI: 0.01, 0.58; P = 0.044) for academic performance. For other cognitive domains, no significant effects were found. CONCLUSIONS: Multiple micronutrient supplementation may be associated with a marginal increase in fluid intelligence and academic performance in healthy schoolchildren but not with crystallized intelligence. More research is required, however, before public health recommendations can be given.

There is accumulating evidence for oxidative stress mechanisms as common pathophysiological pathways in diverse psychiatric disorders, which offers novel treatment targets in oxidation biology systems. Of these the glutathione system has the most favourable theoretical foundation, given its dominance as the most generic of cellular antioxidants. Clinically, this hypothesis has been supported by several recently published studies that have reported on the efficacy of N-acetylcysteine, a glutathione precursor, in the treatment of various psychiatric disorders. This article outlines the multidimensional evidence that currently exists for oxidative stress mechanisms in psychiatric disorders and specifically discusses glutathione as a promising novel therapeutic target.

The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X(2)=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X(2)=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X(2)=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X(2)=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.

Members of the SNF1-related protein kinase-1 (SnRK1) subfamily of protein kinases are higher plant homologues of mammalian AMP-activated and yeast SNF1 protein kinases. Based on analogies with the mammalian system, we surmised that the SnRK1 kinases would be regulated by phosphorylation on a threonine [equivalent to Thr175 in Arabidopsis thaliana SnRK1 (AKIN10)] within the 'T loop' between the conserved DFG and APE motifs. We have raised an antibody against a phosphopeptide based on this sequence, and used it to show that inactivation of two spinach SnRK1 kinases by protein phosphatases, and reactivation by a mammalian upstream protein kinase, is associated with changes in the phosphorylation state of this threonine. We also show that dephosphorylation of this threonine by protein phosphatases, and consequent inactivation, is inhibited by low concentrations of 5'-AMP, via binding to the substrate (i.e. the kinase). This is the first report showing that the plant SnRK1 kinases are regulated by AMP in a manner similar to their mammalian counterparts. The possible physiological significance of these findings is discussed.

We resolved from spinach (Spinacia oleracea) leaf extracts four Ca2+-independent protein kinase activities that phosphorylate the AMARAASAAALARRR (AMARA) and HMRSAMSGLHLVKRR (SAMS) peptides, originally designed as specific substrates for mammalian AMP-activated protein kinase and its yeast homolog, SNF1. The two major activities, HRK-A and HRK-C (3-hydroxy-3-methylglutaryl-coenzyme A reductase kinase A and C) were extensively purified and shown to be members of the plant SnRK1 (SNF1-related protein kinase 1) family using the following criteria:(a) They contain 58-kD polypeptides that cross-react with an antibody against a peptide sequence characteristic of the SnRK1 family;(b) they have similar native molecular masses and specificity for peptide substrates to mammalian AMP-activated protein kinase and the cauliflower homolog;(c) they are inactivated by homogeneous protein phosphatases and can be reactivated using the mammalian upstream kinase; and (d) they phosphorylate 3-hydroxy-3-methylglutaryl-coenzyme A reductase from Arabidopsis at the inactivating site, serine (Ser)-577. We propose that HRK-A and HRK-C represent either distinct SnRK1 isoforms or the same catalytic subunit complexed with different regulatory subunits. Both kinases also rapidly phosphorylate nitrate reductase purified from spinach, which is associated with inactivation of the enzyme that is observed only in the presence of 14-3-3 protein, a characteristic of phosphorylation at Ser-543. Both kinases also inactivate spinach sucrose phosphate synthase via phosphorylation at Ser-158. The SNF1-related kinases therefore potentially regulate several major biosynthetic pathways in plants: isoprenoid synthesis, sucrose synthesis, and nitrogen assimilation for the synthesis of amino acids and nucleotides.

Since the government introduced the loan scheme for university students in 1990, it has become abundantly apparent that students are falling increasingly into debt. This paper describes the results of two studies undertaken by Manchester undergraduate dental students into the level and consequences of debt on dental students.

We have studied the effects of choice of local anaesthetic and temperature of extradural injectate on speed of onset of sensory block for elective extradural Caesarean section in a double-blind trial in 120 women allocated randomly to one of four groups to receive either plain 0.5% bupivacaine or 2% lignocaine with 1:200,000 adrenaline at either room temperature or 38 degrees C. The onset time of lignocaine with adrenaline was shorter than that of bupivacaine regardless of temperature (P < 0.01). Warmed lignocaine produced the most rapid block overall (P < 0.025). The incidence of hypotension, ephedrine requirement, shivering, quality of analgesia and additional analgesic requirements were similar for all groups.