The nutritional biochemistry of trivalent Cr has been a poorly understood field of study; investigations of the biochemistry of the other essential transition metals have not proven as problematic. Despite over four decades of endeavour, only recently has a picture of the role of Cr potentially started to be defined. The biologically-relevant form is the trivalent ion. Cr3+ appears to be required for proper carbohydrate and lipid metabolism in mammals, although fortunately Cr deficiency is difficult to achieve. Conditions that increase circulating glucose and insulin concentrations increase urinary Cr output. Cr is probably excreted in the form of the oligopeptide chromodulin. Chromodulin may be the key to understanding the role of Cr at a molecular level, as the molecule has been found to bind to activated insulin receptor, stimulating its kinase activity. A mechanism for the action of chromodulin has recently been proposed; this mechanism can serve as a potential framework for further studies to test the role of Cr in metabolism. An examination of the nutritional supplement chromium picolinate illustrates some of the difficulties associated with these biochemical studies.

The World Health Organization's (1990) definition of palliative care describes an holistic approach to care for patients with advanced progressive illness. Issues relating to nutrition, lack of appetite and the subsequent weight loss the individuals may experience present a challenge to all concerned with providing both formal and informal care to this patient group. The philosophy of palliative care requires a multidisciplinary approach to the constellation of issues and problems related to food that are faced by both patients and carers in receipt of palliative care. The literature in this area is mainly related to those patients with a cancer diagnosis. The developing role of palliative care in patients with non-malignant disease provides further challenges for health care professionals. The present paper aims to reflect an entire philosophical approach to care through an examination of one area of practice.

A world epidemic of diet-related chronic disease is currently being faced. In the UK incidence of obesity alone has tripled in the last 20 years and this trend is predicted to continue. Consensus exists for the urgent need for a change in diet and other lifestyle factors and for the direction and targets for this change. The evidence for how this change can be achieved is less certain. It has been established that disease processes begin in childhood. Recent evidence indicates that dietary habits too are established in childhood but that these habits are amenable to change. While establishing a healthy lifestyle in childhood is paramount, interventions have the potential to promote positive change throughout the life course. Success in reversing current trends in diet-related disease will depend on commitment from legislators, health professionals, industry and individuals, and this collaboration must seek to address not only the food choices of the individual but also the environment that influences such choices. Recent public health policy development in England, if fully supported and implemented, is a positive move towards this goal. Evidence for effective strategies to promote dietary change at the individual level is emerging and three reviews of this evidence are discussed. In addition, three recent dietary intervention studies, in three different settings and with different methods and aims, are presented to illustrate methods of effecting dietary change. Further work is required on what factors influence the eating behaviour and physical activity of individuals. There is a need for further theory-based research on which to develop more effective strategies to enable individuals to adopt healthier lifestyles.

Muscle glycogen is an important fuel for contracting skeletal muscle during prolonged strenuous exercise, and glycogen depletion has been implicated in muscle fatigue. It is also apparent that glycogen availability can exert important effects on a range of metabolic and cellular processes. These processes include carbohydrate, fat and protein metabolism during exercise, post-exercise glycogen resynthesis, excitation–contraction coupling, insulin action and gene transcription. For example, low muscle glycogen is associated with reduced muscle glycogenolysis, increased glucose and NEFA uptake and protein degradation, accelerated glycogen resynthesis, impaired excitation–contraction coupling, enhanced insulin action and potentiation of the exercise-induced increases in transcription of metabolic genes. Future studies should identify the mechanisms underlying, and the functional importance of, the association between glycogen availability and these processes.

Exercise training improves glucose homeostasis through enhanced insulin sensitivity in skeletal muscle. Muscle contraction through physical exercise is a physiological stimulus that elicits multiple biochemical and biophysical responses and therefore requires an appropriate control network. Mitogen-activated protein kinase (MAPK) signalling pathways constitute a network of phosphorylation cascades that link cellular stress to changes in transcriptional activity. MAPK cascades are divided into four major subfamilies, including extracellular signal-regulated kinases 1 and 2, p38 MAPK, c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 5. The present review will present the current understanding of parallel MAPK signalling in human skeletal muscle in response to exercise and muscle contraction, with an emphasis on identifying potential signalling mechanisms responsible for changes in gene expression.

During this workshop, held as part of a joint Nutrition Society and Food Standards Agency (Agency) meeting on Micronutrient interactions and public health, several precepts for a successful funding application to the Agency were discussed. These precepts, many of which can be used as guiding principles for project proposals to other funding bodies, are summarised as follows: remember that the Agency only supports research that will help them formulate or change human food policy; read the research requirements document thoroughly and plan your project to answer the call; remember that the Agency issues contracts, not grants; your project will be just one project within a focused and coordinated programme; collaborative work is encouraged, but this type of approach is not a licence to double or treble your costs; write a one-page executive summary and attach it to the front of the form; the statistical basis for your experimental design and proposed statistical analysis of your results are important criteria in the evaluation of your proposal; your plans for dissemination and exploitation are very important; match your project duration against your research plan; abide by the Agency plan for quality assurance for the management of research; make full use of the programme adviser and the Agency policy contact and the ‘feedback’ stage to refine your scientific ideas in line with Agency policy.

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH β2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene–environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

Data from the European Society for Parenteral and Enteral Nutrition Home Artificial Nutrition Survey suggest that the use of home parenteral nutrition (HPN) in patients with cancer as the primary diagnosis varies markedly between different countries in Europe, being highest in The Netherlands and low in the UK. This finding is difficult to explain on the basis of cancer incidence. The main indication for HPN remains malignant gastrointestinal tract obstruction, which occurs most frequently in gynaecological and colon cancers. The use of HPN should be planned in the light of the proposed cancer treatment and should be discussed beforehand with the patient. Before HPN is considered, a patient should typically require intravenous fluids to maintain hydration, be capable of self care, be able to control the treatment, have an expected survival of ≥3 months and have no other available route of feeding. The effect of HPN on quality of life remains controversial, but nutrition is only one of the factors that influence the quality of life in cancer patients. The differing rates of HPN in Europe are probably related to cultural attitudes to incurable cancer as much as to meeting the nutritional needs of the patient.

Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcohol-induced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis.

Pregnancy is a period of rapid growth and cell differentiation for both the mother and fetus. Consequently, it is a period when both are vulnerable to changes in dietary supply, especially of those nutrients that are marginal under normal circumstances. In developed countries this vulnerability applies mainly to micronutrients. Even now, Fe deficiency is a common disorder, especially in pregnancy. Similarly, Cu intake in the UK population is rarely above adequate levels, which is a matter of some concern, both in terms of public health and possible clinical consequences. In early studies it was shown that lambs born to mothers on Cu-deficient pastures develop ‘swayback,’ with neurological and muscular symptoms that cannot be reversed by postnatal supplementation. More recently, rat studies have shown that responses such as the ‘startle’ response are lost in offspring of Cu-deficient mothers. Data have shown that prenatal Fe deficiency results in increased postnatal blood pressure, even though the offspring have normal dietary Fe levels from birth. These observations emphasise the importance of Fe and Cu in growth and development. In the present review the importance of these metals and the consequences, both short term and long term, of deficiency will be discussed and some possible mechanisms whereby these effects may be generated will be considered.

The medical care of patients with sepsis or severe inflammatory response syndromes has seen tremendous technological advancements in recent years; yet, several clinical studies with anti-cytokine therapies targetted to this population have met with disappointing results. Four primary factors have been identified that represent potential pitfalls involving the use of biological response modifiers in critically-ill patients. First, the physiological response in the stressed patient is complex. Redundancy within this system may not allow a single intervention to produce a clinical response. Second, the critically-ill patient population is heterogenous and important factors including the age of the patient, associated co-morbidities, the nature of the original injury and the presence or absence of an ongoing injury can modulate the effectiveness of a specific therapy. Third, the timing of the therapeutic intervention can be difficult to standardize among patients and can often produce differing results. A greater understanding of the physiological response to injury has shown that there are both proinflammatory and anti-inflammatory processes ongoing simultaneously. Determining the optimal time to intervene within this framework can be problematic. Fourth, the presence of genetic polymorphisms within the general population has identified subsets of individuals who may have different physiological responses to similar stresses. The relative proportions of patients with these polymorphisms within clinical trials may affect outcome and data analysis. Thus, a better understanding of these issues will result in improvement of the experimental design of clinical trials involving anti-cytokine therapies and critically-ill patients. Avoidance of these pitfalls will enhance the quality and utility of outcomes research in this subset of patients.

Glycogen synthase (GS) catalyses the rate-limiting step of UDP-glucose incorporation into glycogen. Exercise is a potent regulator of GS activity, leading to activation of GS immediately after exercise promoting glycogen repletion by mechanisms independent of insulin. The incorporation of UDP-glucose is energy demanding, and during intense exercise GS is deactivated, diminishing energy utilization but also increasing the potential for glycogen breakdown. An apparent activation of GS is observed during moderate exercise, which could be considered as a potential waste of energy, although the cellular capacity for glycogen breakdown is considerably higher than that for glycogen synthesis. The understanding of this complex regulation of GS activity in response to exercise is just at its beginning. In the present review potential mechanisms by which exercise regulates GS activity are described, factors that may promote GS activation and factors that may deactivate GS are discussed, pointing to the view that GS activity during exercise is the result of the relative strength of these opposing factors.

The ongoing hypermetabolic response in patients with prolonged critical illness leads to the loss of lean tissue mass. Since the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, hormonal intervention has been thought to be beneficial. However, most interventions have been shown to be ineffective and their indiscriminate use even causes harm. Before considering endocrine intervention in these frail patients, a detailed understanding of the neuroendocrinology of the stress response is warranted. It is now clear that the acute phase and the later phase of critical illness behave differently from an endocrinological point of view. The acute stress reponse consists primarily of an actively-secreting pituitary in the presence of low circulating peripheral anabolic hormones, suggesting resistance of the peripheral tissues to the effects of anterior pituitary hormones. However, when the disease process becomes prolonged, there is a uniformly-reduced pulsatile secretion of anterior pituitary hormones with proportionally reduced concentrations of peripheral anabolic hormones. The origin of this suppressed pituitary secretion is located in the hypothalamus, as hypothalamic secretagogues can reactivate the anterior pituitary and restore pulsatile secretion. The reactivated pituitary secretion is accompanied by an increase in peripheral target hormones, indicating at least partial sensitivity of these tissues to anterior pituitary hormones in this chronic phase of illness. Thus, endocrine intervention with a combination of hypothalamic secretagogues that more completely reactivate the anterior pituitary could be a more physiological and effective strategy for inducing anabolism in patients with prolonged critical illness.

The deleterious health effects of high alcohol consumption are numerous and well recognized; however, the effect of moderate alcohol consumption on overall health continues to be a debated issue. Among the more prevalent diseases in Westernized countries, epidemiological research suggests that alcohol in moderation substantially reduces the risk of CHD, while it modestly increases the risk for certain cancers, such as breast and colon cancer. Despite the overwhelming data supporting the beneficial effect of moderate alcohol consumption on the cardiovascular system, some researchers are not convinced. Sceptics argue that the reduction in risk is attributed to a favourable lifestyle factor associated with moderate alcohol consumption, or that it may be attributed to constituents of alcoholic beverages other than ethanol, such as the antioxidants in the grapes. In order to promote overall health for the general public, it is necessary to elucidate these issues. One approach is to study population differences in alcohol metabolic efficiency, which is likely to contribute to an individual's susceptibility to alcohol-associated diseases. Among the population there is substantial variability in the efficiency to metabolize alcohol. Genetic variation among the alcohol-metabolizing genes is known to produce isoenzymes with distinct kinetic properties. Studying genetic differences that potentially influence disease susceptibility among populations may provide insight into the mechanism(s) for the relationship between risk factor and disease, such as alcohol and CHD.

The intimate relationship between Fe and Cu in human nutrition has been recognised for many years. The best-characterised link is provided by caeruloplasmin, a multiCu-binding protein that acts as a serum ferrioxidase and is essential for the mobilisation of Fe from storage tissues. Decreased Cu status has been shown to reduce holo-caeruloplasmin production and impair ferrioxidase activity, leading, in a number of cases, to decreased tissue Fe release and the generation of anaemia that is responsive to dietary supplementation with Cu but not Fe. Dietary Fe absorption also requires the presence of a multiCu ferrioxidase. Hephaestin, a caeruloplasmin homologue, works in concert with the IREG1 transporter to permit Fe efflux from enterocytes for loading onto transferrin. The essential role of hephaestin in this process has been recognised from studies in the sex-linked anaemic (sla) mouse, in which Fe efflux is markedly impaired as a result of a mutation in the hephaestin gene that results in a truncated and non-functional version of the protein. There is emerging evidence that a number of other components of the intestinal Fe transport pathway are also Cu sensitive. Divalent metal transporter 1 (DMT1), the Fe transporter located at the apical membrane of enterocytes, is also a physiologically-relevant Cu transporter, suggesting that these two metals may compete with each other for uptake into the duodenal enterocytes. Furthermore, expression of both DMT1 and the basolateral Fe-efflux transporter IREG1 can be regulated by Cu, suggesting that the Fe–Cu relationship may be more complex than first thought.

The first putative fatty acid transporter identified was plasma membrane fatty acid-binding protein (FABPpm). Later it was demonstrated that this protein is identical to the mitochondrial isoform of the enzyme aspartate aminotransferase. In recent years data from several cell types have emerged, indicating that FABPpm plays a role in the transport of long-chain saturated and unsaturated fatty acids. In the limited number of studies in human skeletal muscle it has been demonstrated that dietary composition and exercise training can influence the content of FABPpm. Ingestion of a fat-rich diet induces an increase in FABPpm protein content in human skeletal muscle in contrast to the decrease seen during consumption of a carbohydrate-rich diet. A similar effect of a fat-rich diet is also observed for cytosolic fatty acid-binding protein and fatty acid translocase/CD36 protein expression. Exercise training up regulates FABPpm protein content in skeletal muscle, but only in male subjects; no significant differences were observed in muscle FABPpm content in a cross-sectional study of female volunteers of varying training status, even though muscle FABPpm content did not depend on gender in the untrained state. A higher utilization of plasma long-chain fatty acids during exercise in males compared with females could explain the gender-dependent influence of exercise training on FABPpm. The mechanisms involved in the regulation of the function and expression of FABPpm protein remain to be clarified.

In view of the developments in health care relating to the increased prevalence and incidence of chronic diseases and the continuing increase in health-care expenditure, more attention should be paid to health maintenance and disease prevention. Any strategy that can influence health maintenance is of interest, especially lifestyle factors such as nutrition, exercise or stress control. Alcohol has an important place in the daily life of many healthy as well as sick individuals. Alcohol has three major characteristics; it is a nutrient (energy source), a psycho-active drug and a toxin. Each consumer has the choice of which of the characteristics of alcohol he/she wants to utilise. Thus, alcohol represents one of the most important self-implemented disease modifiers in our modern society. The major determinants of the health effects of alcohol are the absolute amount consumed, the consumption frequency, associated lifestyle factors (e.g. smoking, nutrient intake, substrate composition, physical activity pattern) and last, but not least, the genetic background. There are few known disease conditions that have not already been associated positively or negatively with alcohol consumption. The list of diseases includes atherosclerosis, dementia, diabetes, obesity and conditions relating to Zn metabolism. Obesity represents the most important disease modifier in the world and the prevalence rates are increasing rapidly. Evidence suggests that alcohol represents a risk factor for overweight and obesity as a result of specific effects on energy metabolism and substrate metabolism. The potential role of alcohol as an important modulator for the postprandial lipidaemia and its role in the pathogenesis of modern diseases will be discussed.

Lower levels of dietary folate are associated with the development of epithelial cell tumours in man, particularly colo-rectal cancer. In the majority of epidemiological studies blood folate or reported folate intake have been shown to be inversely related to colo-rectal cancer risk. Folate, via its pivotal role in C1 metabolism, is crucial both for DNA synthesis and repair, and for DNA methylation. This function is compromised when vitamin B12 is low. Vitamin B12 deficiency has been shown to increase biomarkers of DNA damage in man but there is no evidence directly linkinglow vitamin B12 with cancer. Disturbingly, folate and vitamin B12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How folate and/or vitamin B12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instabilityin the DNA molecule via a futile cycle of uracil misincorporation and removal. The relative importance of these two pathways may become clear by determining both DNA stability and cytosine methylation in individuals with different polymorphic variants of key folate-metabolising enzymes. 5,10-Methylenetetrahydrofolate reductase converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and thereby controls whether folate is employed for DNA synthesis or DNA methylation. Colo-rectal cancer risk is decreased in subjects homozygous for a common variant (C677T) of the gene coding for this enzyme, suggesting that DNA synthesis and repair may be ‘enhanced’ in these individuals. Evidence from animal and human studies is presented here in support of folate acting to maintain genomic stability through both these mechanisms.

There is ongoing debate about the respective roles of enteral and parenteral nutrition. The present short review suggests that these two feeding modalities are not mutually exclusive and that optimal nutritional support may necessitate the concomitant administration of enteral together with parenteral nutrition.

Fatty acid (FA) translocase (FAT)/CD36 is a key protein involved in regulating the uptake of FA across the plasma membrane in heart and skeletal muscle. A null mutation of FAT/CD36 reduces FA uptake rates and metabolism, while its overexpression increases FA uptake rates and metabolism. FA uptake into the myocyte may be regulated (a) by altering the expression of FAT/CD36, thereby increasing the plasmalemmal content of this protein (i.e. streptozotocin-induced diabetes, chronic muscle stimulation), or (b) by relocating this protein to the plasma membrane, without altering its expression (i.e. obese Zucker rats). By repressing FAT/CD36 expression, and thereby lowering the plasmalemmal FAT/CD36 (i.e. leptin-treated animals), the rate of FA transport is reduced. Within minutes of beginning muscle contraction or being exposed to insulin FA transport is increased. This increase is a result of the contraction- and insulin-induced translocation of FAT/CD36 from an intracellular depot to the cell surface. Neither PPARα nor PPARγ activation alter FAT/CD36 expression in muscle, despite the fact that PPARα activation increases FAT/CD36 by 80% in liver. A novel observation is that FAT/CD36 also appears to be involved in mitochondrial FA oxidation, as this protein is located on the mitochondrial membrane and seems to be required to participate in moving FA across the mitochondrial membrane. Clearly, FAT/CD36 has an important role in FA homeostasis in skeletal muscle and the heart.