Surgery plays a key role in the management of both acute and, less frequently, chronic intestinal failure. Acute intestinal failure frequently requires surgical treatment when it arises as a consequence of intestinal fistulation or obstruction. In specialised clinical practice approximately 50% of acute intestinal failure is associated with intestinal fistulas and in approximately 50% of patients, this condition arises as part of the natural history or complicating treatment for Crohn's disease. A considerable proportion of such patients have abdominal infection and present complex nutritional and metabolic problems. The most important aspect of the surgical management of patients with acute intestinal failure associated with intra-abdominal infection is management of sepsis, since recovery is unlikely in the presence of active infection. Moreover, effective nutritional support and restoration of body composition is not possible if sepsis remains unresolved. Surgical strategies to deal with intra-abdominal infection may involve percutaneous drainage, laparotomy and resection of fistulating segments of intestine and, when infection is persistent and contamination extensive, laparostomy (a technique in which the abdomen is left open and allowed to heal by secondary intention). Surgical treatment should not only be timely and effective, but also aimed at preventing secondary damage to the small intestine, in order to minimise the risk of short bowel syndrome. In some cases a proximal defunctioning stoma may be required, with prolonged nutritional support, using either home total parenteral nutrition or feeding via the defunctioned distal gut (fistuloclysis), pending restoration of intestinal continuity. The role of surgical treatment for patients with short bowel syndrome is less clear. While surgery is frequently required for the management of complications of short bowel syndrome (including gallstones and possibly peptic ulcer disease), the role of intestinal lengthening and tapering procedures (to increase functional intestinal length), and artificial valves, reversed segments and colonic interposition (to reduce intestinal transit) remains controversial. For some patients with short bowel syndrome and, in particular, those with combined intestinal and hepatic failure, intestinal transplantation may become the treatment of choice as long-term results continue to improve.

The use of dietary phyto-oestrogens as a possible option for the prevention of osteoporosis has raised considerable interest because of the increased concern about the risks associated with the use of hormone-replacement therapy. However, the evidence in support of a bone-sparing effect in post-menopausal women is still not sufficiently convincing. Most studies have been performed on soyabean isoflavones (genistein and daidzein), either in the purified form or as a soyabean-based product or extract. In vitro studies using primary cell cultures or stabilised cell lines indicate that treatment with genistein may lead to a reduction in bone resorption, but effects on bone formation have also been shown. Investigations using animal models have provided convincing evidence of major improvements in bone mass or bone turnover following soyabean feeding. Cross-sectional observations in South-East Asian populations with moderately high intakes of soyabean isoflavones (50 mg/d) have shown that women in the high quartile of intake have higher bone mineral density (BMD) and reduced bone turnover, an effect that has not been shown in populations with low average intakes. Human trials have given an indication of a possible effect on lumbar spine BMD, although they have been either short term (<6 months) or methodologically weak. Unresolved issues are: the optimal dose compatible with safety; the individual differences in response that can be related to diet and genotypes; the duration of exposure. Furthermore, there needs to be an evaluation of the relative biological effects of phyto-oestrogens other than isoflavones (lignans, resorcylic acid lactones, flavanols, coumestans) that are also present in European diets.

Short-chain fatty acids (SCFA) affect local and remote motility of the gastrointestinal tract by mechanisms that are not completely understood. In the large intestine where they are produced, they inhibit peristaltic activity and may stimulate tonic activity. When present in the terminal ileum as a result of reflux of colon contents, they elicit propulsive contractions. These local motor effects could involve a neuro-hormonal sensory mechanism located in the mucosa of the terminal ileum and proximal colon. Finally, through a humoral pathway probably involving polypeptide YY release, ileal and colonic SCFA modify upper motility by inducing relaxation of the proximal stomach and lower oesophageal sphincter and reducing gastric emptying. One characteristic feature of the SCFA effects is the dose-dependency of the gastrointestinal motor responses. Indeed, the effects occur only below or above a threshold of SCFA concentration in lumen contents. One putative physiological role of the motor effects of SCFA might be to maintain the physico-chemical balance of the lumen environment in the terminal ileum and proximal colon. Another role might be to co-regulate motility of the upper intestine. The clinical relevance of these effects is unclear. However, some recent findings suggest that excessive SCFA concentrations might induce adverse effects on gastrointestinal and colonic motility and sensitivity in certain diseases such as inflammatory bowel disease and gastro-oesophageal reflux disease.

Micronutrient deficiencies are a major problem throughout the world and hundreds of millions of the world's population are affected by micronutrient deficiency disorders. In Europe the prevalence of clinical micronutrient deficiency disorders is less than that in the Third World. However, marginal deficiency of some of the micronutrients might be involved in the aetiology of many of the so-called lifestyle diseases, e.g. cancer, cardiovascular diseases, diabetes, osteoporosis. Supplementing domestic animals with micronutrients in excess of their needs could be one strategy to increase the intake and, thereby, status of micronutrients in the human population. This approach should, however, be considered carefully, in relation to both animal and human welfare. Many micronutrients that may accumulate in animal foods are toxic in high doses. It would also be unethical to expose animals to doses that might have deleterious effects on their health, and concentrations in animal products that might have adverse effects when consumed by man should be avoided. Furthermore, food quality should not be impaired by the supplement. On the other hand, to be relevant in relation to human nutrition, the given micronutrient should accumulate in animal tissue in concentrations that make an important contribution to total intake. Finally, the micronutrient should be incorporated in a way and in a form that is bioavailable to man, i.e. is well absorbed and utilized.

The British Artificial Nutrition Survey 2001 recorded 507 home parenteral nutrition (HPN) patients (Crohn's disease 31.5%, vascular disease 19.7%, cancer 6.9%). Parenteral nutrition was administered via tunnelled central line (92%) and supplied by a commercial homecare company in 89% of cases. The majority of HPN patients live at home (95.5%) with an independent life (74%), normal activity (59.2%) and 92% survive 1 year. However, there is good evidence that the geographical distribution of HPN patients is uneven (prevalence no patients to thirty-six patients per million of the population) suggesting inequity of access. Patients are increasingly concerned about the distances travelled to main centres and variable standards of more local support. Funding issues continue to cause difficulties as commissioning of health care transfers from Health Authorities to Primary Care Trusts. The two nationally-funded intestinal failure units provide HPN services to 220 HPN patients. HPN-related readmissions have displaced those awaiting admission for intestinal failure treatment, for which the waiting list mortality in one unit has risen to 14%. The government has now recognised HPN as a specialised service distinct from intestinal failure and that existing medium-sized HPN units should be encouraged to take on HPN patients from intestinal failure units and smaller units. In Scotland a Managed Clinical HPN Network supported by the Scottish administration now cares for seventy-two patients under common protocols. The challenge for the future is how to provide high-quality care to all who need it in the rest of the UK.

Can commonly-eaten food staple crops be developed that fortify their seeds with essential minerals and vitamins? Can farmers be induced to grow such varieties? If so, would this result in a marked improvement in human nutrition at a lower cost than existing nutrition interventions? An interdisciplinary international effort is underway to breed for mineral- and vitamin-dense varieties of rice, wheat, maize, beans and cassava for release to farmers in developing countries. The biofortification strategy seeks to take advantage of the consistent daily consumption of large amounts of food staples by all family members, including women and children as they are most at risk for micronutrient malnutrition. As a consequence of the predominance of food staples in the diets of the poor, this strategy implicitly targets low-income households. After the one-time investment is made to develop seeds that fortify themselves, recurrent costs are low and germplasm may be shared internationally. It is this multiplier aspect of plant breeding across time and distance that makes it so cost-effective. Once in place, the biofortified crop system is highly sustainable. Nutritionally-improved varieties will continue to be grown and consumed year after year, even if government attention and international funding for micronutrient issues fades. Biofortification provides a truly feasible means of reaching malnourished populations in relatively remote rural areas, delivering naturally-fortified foods to population groups with limited access to commercially-marketed fortified foods that are more readily available in urban areas. Biofortification and commercial fortification are, therefore, highly complementary. Breeding for higher trace mineral density in seeds will not incur a yield penalty. Mineral-packed seeds sell themselves to farmers because, as recent research has shown, these trace minerals are essential in helping plants resist disease and other environmental stresses. More seedlings survive and initial growth is more rapid. Ultimately, yields are higher, particularly in trace mineral-‘deficient’ soils in arid regions.

Short-chain fatty acids (SCFA), particularly butyrate, were shown to regulate cell proliferation in vitro and in vivo. Indeed, butyrate is the major fuel for colonic epithelial cells, and it can influence cell proliferation through the release of growth factors or gastrointestinal peptides such as gastrin, or through modulation of mucosal blood flow. Lastly, SCFA can act directly on genes regulating cell proliferation, and butyrate is the main SCFA to display such an effect. Butyrate inhibits histone deacetylase, which will allow histone hyperacetylation. Such hyperacetylation leads to transcription of several genes, including p21/Cipl. Moreover, it will allow cyclin D3 hyper-expression by inhibiting its degradation. The induction of the cyclin-dependent kinase inhibitory protein p21/Cipl accounts for cell arrest in the Gl phase of the cell cycle. However, in the absence of p21 other mechanisms are initiated, leading to inhibition of cell proliferation.

These famous words by Mencken in the early 20th century about the meaning of life and death, may also apply to the struggle of the healthy skeleton against the deleterious effects of retained acid!’ ( Kraut & Coburn, 1994). The health-related benefit of a high consumption of fruit and vegetables and the influence of this food group on a variety of diseases has been gaining increasing prominence in the literature over a number of years. Of considerable interest to the osteoporosis field is the role that bone plays in acid–base balance. Natural, pathological and experimental states of acid loading and acidosis have been associated with hypercalciuria and negative Ca balance, and more recently the detrimental effects of ‘acid’ from the diet on bone mineral have been demonstrated. Suprisingly, consideration of the skeleton as a source of ‘buffer’ contributing to both the preservation of the body's pH and defence of the system against acid–base disorders has been ongoing for over three decades. However, it is only more recently that the possibility of a positive link between a high consumption of fruit and vegetables and indices of bone health has been more fully explored. A number of population-based studies published in the last decade have demonstrated a beneficial effect of fruit and vegetable and K intake on axial and peripheral bone mass and bone metabolism in men and women across the age-ranges. Further support for a positive link between fruit and vegetable intake and bone health can be found in the results of the Dietary Approaches to Stopping Hypertension (DASH) and DASH-Sodium intervention trials. There is now an urgent requirement for the implementation of: (1) fruit and vegetable and alkali administration–bone health intervention trials, including fracture risk as an end point; (2) reanalysis of existing dietary–bone mass and metabolism datasets to look specifically at the impact of dietary ‘acidity’ on the skeleton.

Despite the reported high survival with total parenteral nutrition (TPN) therapy for patients with intestinal failure, a considerable number of patients do not escape the potential risks of TPN-associated complications, including hepatic failure, vanishing of central venous access and line sepsis. Thus, intestinal, liver-intestinal and multivisceral transplantation have recently emerged to rescue those who can no longer be maintained on TPN. Before this development, and for nearly three decades, small-bowel transplantation was plagued with uncontrolled rejection, graft v. host disease and fatal infection. These barriers stemmed from the large gut lymphoid mass and heavy microbial load contained in the intestinal lumen. The recent improvement in survival after the clinical introduction of tacrolimus with achievement of full enteric nutritional autonomy qualified the procedure by the US Health Care Financing Administration as the standard of care for patients with intestinal and TPN failure. The decision was supported by a decade of clinical experience with cumulative improvement in patient and graft survival. In addition, the introduction of new effective immunoprophylactic agents and novel therapeutic approaches has contributed to a further increase in the therapeutic advantages of the procedure. The present review article outlines the current clinical practice of intestinal transplantation and defines new management strategies with the aim of raising the level of the procedure to be a better alternative therapy for TPN-dependent patients.

Epidemiological evidence suggests that a high intake of resistant starch and NSP protects against colo-rectal cancer. The mechanisms underlying this protection are thought to be mediated by the short-chain fatty acid butyrate, which is present in the colonic lumen in millimolar concentrations as a result of bacterial fermentation of carbohydrates that have resisted digestion in the small intestine. In vitro studies have shown that butyrate displays a host of chemo-preventative properties including increased apoptosis, reduced proliferation, down regulation of angiogenesis, enhanced immunosurveillance and anti-inflammatory effects in colo-rectal cancer cell lines. However, the molecular mechanisms underlying the apparent chemo-preventative actions of butyrate are largely unknown. The evidence supporting the role of butyrate as an anti-cancer agent is reviewed, with particular emphasis on those studies that have attempted to elucidate the mechanism of action of butyrate. Our understanding of the mechanistic action of butyrate and its role in cancer prevention is likely to advance considerably in this post-genomic era with the application of genomic and proteomic technologies. Studies are described that have used gene array and proteomic techniques to investigate the response of colo-rectal cancer cells to butyrate. These pioneering studies illustrate the potential of these technologies to help characterise the molecular responses of the cancer cell to butyrate, and to define the role of butyrate (and other nutrients) in the prevention of colo-rectal cancer.

There is compelling evidence to suggest that both the development of bone to peak bone mass at maturity and subsequent loss depend on the interaction between genetic, hormonal, environmental and nutritional factors. The major part (≤80%) of the age-specific variation in bone turnover and bone density is genetically determined. However, the notion of genetic determinant is of little value unless the specific genes that are involved can be identified. Most work in this area of osteoporosis research has focused on the candidate gene approach, which has identified several candidate genes for osteoporosis, including genes encoding the vitamin D receptor (VDR), oestrogen receptors (α and β), apolipoprotein E, collagen type I α 1 and methylenetetrahydrofolate reductase, amongst many others. However, in general, findings from numerous studies of the association between such genes and various bone variables have been inconsistent. In addition to possible gene—gene interactions it is likely that there are interactions between these genes and certain environmental factors, especially nutrition, that may mediate expression of bone-related phenotypes. While these potential interactions add a level of complexity to our understanding of these apparent genetic effects on bone, identification of a role for genetic factors without knowledge of their interaction with nutrients can do little to advance prevention and treatment of osteoporosis. This information is especially important because, unlike genotype, diet and nutrition can be modified. The aim of the present review is to critically evaluate current knowledge relating to candidate genes for osteoporosis, with particular emphasis on their interaction with nutrients and dietary factors in determining bone health.

For many nutrients, a systematic determination of the effects of high intakes over extended periods of time has not been conducted. Governments and scientific bodies have just begun to establish the methodology for, and to conduct, nutrient risk assessments for setting ‘tolerable upper levels of intake’ (UL) for nutrients. Nutrient risk assessment provides the framework for using available information to evaluate the safety of nutrients when added to foods or when consumed as supplements, in order to minimize the risks from over-consumption. When intakes are inadequate, food fortification may be the appropriate choice for some nutrients, while in other situations, when requirements are markedly higher for some population subgroups than for the general population, supplements may be the most appropriate intervention. The present paper will present some examples of how to use the UL along with food consumption data to assess the appropriateness of food fortification v. supplementation strategies and to assess their impact on nutrient intakes of the population. The important steps to be followed when evaluating which approach is best are: (a) establishing need, i.e. assessing the gap between current and desired intakes; (b) assessing safety, i.e. consider the margin of safety between requirement and UL as well as the severity and reversibility of the adverse effect that was used to establish the UL; (c) estimating exposure through statistical modelling, in which population-based estimates of intakes before and after the intervention are compared; (d) monitoring the impact of the intervention to ensure that the desired benefits are achieved and that excessive intakes are minimized. This approach can optimize the public health benefits of food fortification or supplement use while minimizing the risks due to excessive intakes.

Manufacturing of healthy whole-grain foods demands knowledge of process-induced changes in macro-, micro- and non-nutrients. The high content of dietary fibre is a challenge in relation to good product texture and sensory quality. The stability and bioavailability of bioactive compounds have a marked influence on the health effects of cereal foods. It was confirmed that sterols, folates, tocopherols and tocotrienols, alkylresorcinols, lignans, phenolic acids and total phenolics are concentrated in the bran layers of the rye grain, and are only present at low levels in the flour endosperm. The levels of folate and easily-extractable phenolic compounds increase in germination and sourdough baking, but there are negligible changes in the levels of sterols, lignans and alk(en)ylresorcinols. The levels of tocopherols and tocotrienols are reduced during the sourdough fermentation. In conclusion, many of the bioactive compounds in whole-grain rye are stable during food processing, and their levels can even be increased with suitable processing.

Optimal nutrition depends on the multiple complex functions performed by the gastrointestinal tract, which range from basic functions such as storage, conduit and mechanical processing to more finely regulated capabilities such as vectorial transport, immune defence and cell signalling. Surgical strategies to supply lacking gastrointestinal tract tissues have relied on either replacement by proxy (surgical substitution) or the introduction of prostheses. Tissue engineering seeks to replace missing tissues with engineered tissues that more accurately reproduce the native physiological and anatomical milieu. It is now possible to engineer several areas of the gastrointestinal tract with high fidelity, and to employ tissue-engineered bowel in replacement in animal models. These replacement models have reflected excellent anatomical and physiological recapitulation of native bowel by the tissue-engineered constructs in vivo.

Uncoupling proteins (UCP) 1 and 2 are members of the subfamily of inner mitochondrial membrane carriers. UCP1 is specific to brown adipose tissue (BAT), where it is responsible for the rapid production of heat at birth. In fetal sheep UCP1 is first detectable at approximately 900d of gestation; its abundance increases with gestational age and peaks at the time of birth. The mRNA and protein for both the long and short form of the prolactin (PRL) receptor (PRLR) are also highly abundant in BAT. Enhanced PRLR abundance in late gestation is associated with an increase in the abundance of UCP1. This relationship between PRLR and UCP is not only present in BAT. Similar findings are now reported in the pregnant ovine uterus, where PRLR abundance reaches a maximum just before that of UCP2. However, the role of PRLR in BAT remains undetermined. Rat studies have shown that PRL administration throughout pregnancy results in offspring with increased UCP1 at birth. Studies in newborn lambs have shown that administration of PRL (20mg/d) causes an acute response, increasing colonic temperature in the first hour by 1°. This increased colonic temperature is maintained for the first 240h of life, in conjunction with enhanced lipolysis. After 70d of treatment there is no difference in the abundance of UCP1 but an increase in UCP1 activity; this effect may be mediated by an increase in lipolysis. Taken together these findings suggest that PRL could be an important endocrine factor during pregnancy and early postnatal life.

Regular consumption of whole grain foods has been associated with a reduction in the incidence of cardiovascular disease and diabetes, reductions in cancer mortality at certain sites and an overall reduction in premature death. Although benefits are observed at relatively low levels of intake (between two and three servings per d), the consumption of whole grain foods in some Western countries is less than one serving per d. The main sources of whole grain are wholemeal and rye breads and whole grain breakfast cereals. Typical consumers of whole-grain foods tend to be older, from a high socio-economic group, are less likely to smoke and are more likely to exercise than non-consumers. Some of these attributes may contribute to the observed health benefits. However whole grain foods are an important source of a range of nutrients as part of a healthy eating plan. There is considerable scope for strategies to promote increased consumption of whole grain foods to reduce the risk of a variety of chronic diseases

Neonatal sepsis is an important cause of morbidity and mortality as a result of multiple organ system failure, particularly in neonates requiring total parenteral nutrition. Suitable therapies and support are needed both to prevent sepsis and to prevent multiple organ failure. After bacterial infection, pro-inflammatory cytokines trigger the antimicrobial activity of macrophages and neutrophils, resulting in production of reactive species such as H2O2, NO, superoxide and peroxynitrite. However, excess production can lead to host tissue damage. Incubation of either hepatocytes or heart mitochondria from neonatal rats with these reactive species, or with cytokines, leads to impairment of mitochondrial oxidative function, and in an animal model of neonatal sepsis similar results to the in vitro findings have been demonstrated. Recent in vivo studies, using indirect calorimetry of suckling rat pups, show that during endotoxaemia there is a profound hypometabolism, associated with hypothermia. Having determined that cellular oxidative function may be impaired during sepsis, it is of great importance to try to identify therapeutic measures. Much interest has been shown in glutamine, which may become essential during sepsis. It has been shown that hepatic glutamine is rapidly depleted during endotoxaemia. When hepatocytes from endotoxaemic rats were incubated with glutamine, there was a restoration of mitochondrial structure and metabolism. In vivo, intraperitoneal injection of glutamine into endotoxic suckling rats partially reversed hypometabolism, markedly reduced the incidence of hypothermia and improved clinical status. These results suggest that glutamine has a beneficial effect during sepsis in neonates.

Vitamin C is an essential micronutrient. Absence from the diet will result in the deficiency disease scurvy, typically characterised by weakening of collagenous structures. High intakes of vitamin C have been associated with decreased incidence or severity of a number of diseases, including cancer and cardiovascular disease. These beneficial effects may be attributed to its antioxidant properties, although the exact mechanisms of action remain elusive. It is also unclear what intake levels are required for optimal health benefits. The task of defining optimal intakes is hindered by the lack of a reliable functional marker of tissue vitamin C status in man. Many different pathways have been investigated, but none of them have measurable outcome variables relating directly to scorbutic changes. The bone-collagen formation pathway has the potential to provide a functional index of tissue vitamin C adequacy. Vitamin C acts as a cofactor for the enzyme lysyl hydroxylase, which is required for the hydroxylation of lysine residues in procollagen chains. Pyridinoline is a mature collagen cross-link formed from three hydroxylysine residues, deoxypyridinoline is formed from two hydroxylysine and one lysine residue. Guinea-pig studies have shown an alteration in the pyridinium cross-link ratios in response to graded vitamin C intakes ‘Tsuchiya & Bates, 1998’. In order to investigate whether these changes can be seen in a human population group, a study was carried out in rural Gambia, where there is a marked seasonal variation in dietary vitamin C. The present review discusses the rationale behind the study and presents some preliminary results.

Prospective cohort and case-control studies suggest an association between low folate intake and increased risk of colo-rectal adenoma and cancer. Some, but not all, animal studies indicate that folate supplementation protects against the development of colo-rectal neoplasms, although supraphysiological folate doses have been shown to enhance tumour growth. Folate is a methyl donor for nucleotide synthesis and biological methylation reactions, including DNA methylation. A low dietary folate intake may increase the risk of colo-rectal neoplasia by inducing genomic DNA hypomethylation, which can affect the expression of proto-oncogenes and tumour suppressor genes associated with the development of cancer. Common polymorphisms in genes involved in the methylation pathway, such as methylenetetrahydrofolate reductase and methionine synthase, have been shown to influence risk of colo-rectal neoplasia, with interactions dependent on folate status and/or alcohol intake, which is known to antagonise methyl group availability. There is some evidence to show that DNA from normal-appearing colo-rectal mucosa in individuals with colo-rectal cancer is hypomethylated. In a case-control study DNA methylation in normal-appearing colo-rectal mucosa has been shown to be lower in individuals with colo-rectal cancer (P=0.08) and colo-rectal adenoma (P=0.009) than in controls free of colo-rectal abnormalities. Human intervention trials to date suggest that supraphysiological doses of folate can reverse DNA hypomethylation in colo-rectal mucosa of individuals with colo-rectal neoplasia. In a double-blind randomised placebo-controlled study folate supplementation at physiological doses has been shown to increase DNA methylation in leucocytes (P=0.05) and colonic mucosa (P=0.09). Further studies are required to confirm these findings in larger populations and to define abnormal ranges of DNA methylation.

Epidemiological studies find that whole-grain intake is protective against cancer, cardiovascular disease, diabetes and obesity. Potential mechanisms for this protection are diverse since whole grains are rich in nutrients and phytochemicals. First, whole grains are concentrated sources of dietary fibre, resistant starch and oligosaccharides, carbohydrates that escape digestion in the small intestine and are fermented in the gut, producing short-chain fatty acids (SCFA). SCFA lower colonic pH, serve as an energy source for the colonocytes and may alter blood lipids. These improvements in the gut environment may provide immune protection beyond the gut. Second, whole grains are rich in antioxidants, including trace minerals and phenolic compounds, and these compounds have been linked to disease prevention. Additionally, whole grains mediate insulin and glucose responses. Although lower glycaemic load and glycaemic index have been linked to diabetes and obesity, risk of cancers such as colon and breast cancer have also been linked to high intake of readily-available carbohydrate. Finally, whole grains contain many other compounds that may protect against chronic disease. These compunds include phytate, phyto-oestrogens such as lignan, plant stanols and sterols, and vitamins and minerals. As a consequence of the traditional models of conducting nutrition studies on isolated nutrients, few studies exist on the biological effects of increased whole-grain intake. The few whole-grain feeding studies that are available show improvements in biomarkers with whole-grain consumption, such as weight loss, blood lipid improvement and antioxidant protection.