Some biochemical functions of vitamin C make it an essential component of parenteral nutrition (PN) and an important therapeutic supplement in other acute conditions. Ascorbic acid is a strong aqueous antioxidant and is a cofactor for several enzymes. The average body pool of vitamin C is 1.5 g, of which 3%-4% (40-60 mg) is used daily. Steady state is maintained with 60 mg/d in nonsmokers and 140 mg/d in smokers. Shocked surgical, trauma, and septic patients have a drastic reduction of circulating plasma ascorbate concentrations. These low concentrations require 3-g doses/d to restore normal plasma ascorbate concentrations, questioning the recommended PN dose of 100 mg/d. Determination of intravenous requirements is usually based on plasma concentrations, which are altered during the inflammatory response. There is no clear indicator of deficiency: serum or plasma ascorbate concentrations <0.3 mg/dL (20 micromol/L) indicates inadequate vitamin C status. On the basis of available pharmacokinetic data the 100 mg/d dose for patients receiving home PN and 200 mg/d for stable adult patients receiving PN are adequate, but requirements have been shown to be higher in perioperative, trauma, burn, and critically ill patients, paralleling oxidative stress. One recommendation cannot fit all categories of patients. Large vitamin C supplements may be considered in severe critical illness, major trauma, and burns because of increased requirements resulting from oxidative stress and wound healing. Future research should distinguish therapeutic use of high-dose ascorbic acid antioxidant therapy from nutritional PN requirements.

Zinc is an essential trace element for human nutrition that is an integral part of many enzyme systems, including DNA polymerase complex. Zinc deficiency has been associated with stunting of growth and sexual immaturity. In children, deficiency causes a fatal condition called acrodermatitis enteropathica. The same syndrome has been observed in patients on total parenteral nutrition (TPN) who do not receive zinc. In TPN the requirements have been estimated by balance studies to be 3 mg/d in patients without gastrointestinal losses and a mean of 12 mg/d in patients with diarrhea and fistula losses.

Selenium (Se) is an essential nutrient for human beings, with serious consequences resulting from clinical deficiency. It therefore should be provided intravenously to all patients who require parenteral nutrition (PN). Moreover, because the effects of suboptimal status are variable and unclear, this supplementation should be provided from the beginning of the course of PN. In most patients receiving PN at home or after surgery, 60-100 mcg/day will meet their requirements. Patients who commence PN already depleted in selenium may require more. Critically ill patients or those with severe burns may have higher requirements. There is good evidence that up to 400 mcg/day is beneficial in burn patients, but the evidence is inconclusive regarding the benefit of high-dose selenium in severe sepsis. Where increased Se provision is used, or in long-term PN, selenium status should be monitored by measurement of plasma Se together with a measure of systemic inflammatory response syndrome, such as C-reactive protein. There are many research issues, including which biochemical measurements best reflect tissue function, especially immune function in seriously ill patients, the clinical consequences of suboptimal biochemical Se status, whether high-dose Se improves outcome in critically ill patients, and whether extra Se always should be given with extra intakes of other antioxidants.

Boron may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and silicon may be beneficial for bone maintenance and wound healing. Fluoride is not an essential element but amounts provided by contamination may be beneficial for bone strength. Fluoride toxicity may be a concern in parenteral nutrition. Further studies are warranted to determine whether there are optimal amounts of boron and silicon that should be delivered to typical and special population patients receiving parenteral nutrition. In addition, further studies are needed to determine whether providing the dietary guideline of adequate intake amounts of fluoride parenterally would prevent or treat parenteral nutrition osteopenia.

There is ample evidence that iron is an essential trace element, but assessment of iron status and decisions on the amounts needed and the means of delivery in patients on parenteral nutrition (PN) have been unclear. Although iron requirements may diminish during acute illness, the frequent concurrence of blood loss and iron deficiency argue strongly for maintenance of levels of delivery in line with basal requirements. Maintenance of iron delivery has not been thought likely to present risk, but new data are questioning this. The needs of menstruating, pregnant, and lactating women are greater than those of adult men. The evidence favors an intravenous dose of around 1 mg of elemental iron per day in adult men and postmenopausal women. Doses of 1.5 mg/d [DOSAGE ERROR CORRECTED] in menstruating women and 2.0 mg/d [DOSAGE ERROR CORRECTED] for those in the later stages of pregnancy or lactating can be supported. A calibrated response is required in the growing child. Continued monitoring of iron status is recommended. Iron is an essential component for most PN regimens. The quantity of iron to be included should take account of predicted requirements.

Iodine deficiency has multiple adverse effects on growth and development because of inadequate thyroid hormone production. Four methods are generally recommended for assessment of iodine nutrition: urinary iodine concentration, thyroid size, and blood concentrations of thyroid-stimulating hormone and thyroglobulin. Iodine intakes < or = 1 mg/d are well tolerated by most adults, because the thyroid is able to adjust to a wide range of intakes. A daily dose of 1 microg iodine/kg body weight is recommended for infants and children receiving parenteral nutrition (PN), but this is far below their requirement. Daily iodine requirements in adults receiving enteral nutrition or PN are estimated to be 70-150 microg, but most PN formulations do not contain iodine. Despite this, deficiency is unlikely because absorption from iodine-containing skin disinfectants and other adventitious sources can provide sufficient iodine. However, if chlorhexidine replaces iodine-containing disinfectants for catheter care, iodine deficiency may occur during long-term PN, and periodic testing of thyroid functions may be prudent. Infants may be particularly vulnerable because of their small thyroidal iodine store, but available data do not yet support routine supplementation of preterm infants with iodine. Adults may be less vulnerable because thyroidal iodine stores may be able to support thyroid hormone production for several months. More studies to clarify this issue would be valuable.

Micronutrient requirements are not fully understood. Parenteral nutrition (PN) usually contains the trace element (TE) manganese (Mn) from fixed-concentration TE supplements. Multiple TE formulations may not be optimal in pediatric and home PN. Moreover, most PN products contain Mn as a ubiquitous contaminant. Excessive Mn can lead to Parkinson-like symptoms resulting from hypermanganesemia. A survey of 40 Australasian hospitals that contributed data on 108 patients to the annual home PN register and a systematic review of the literature were conducted to establish the scope of the potential problem of Mn toxicity in PN patients. Exposure to Mn doses 5-6 times current daily requirements, together with the TE contamination that is reported in PN products, can lead to neurotoxicity. Whole-blood levels are more accurate for monitoring and correlate well with signal intensity of magnetic resonance imaging. Current TE formulations restrict prescribing options. The regulatory mechanisms of Mn homeostasis are bypassed via the parenteral route so elimination via the hepatobiliary system is impaired, resulting in tissue or brain accumulation. Published dosage recommendations may be excessive and official guidelines require revision. Variability in clinical practices necessitates that individual TE additives are more widely available and multiple TE products reformulated. More frequent monitoring for any brain accumulation is recommended. The scarcity of PN-associated Mn deficiency, plus the growing evidence for Mn toxicity, leads to the conclusion that it is unnecessary for Mn to be prescribed routinely for pediatric or long-term PN patients.

Although guidelines for routine parenteral supplements of chromium (Cr) were published, there remain major concerns about the infusion of excess Cr. In addition, little information is available on appropriate dosage for intravenous usage. Cr functions as a regulator of insulin action. In humans, the 3 reported cases of Cr deficiency developed peripheral neuropathy, weight loss, and hyperglycemia. Supplementation of Cr to the parenteral nutrition (PN) solution corrected these abnormalities. For parenteral Cr, concerns arise from the high levels found in sera (up to 40-fold higher) and tissues (10- to 100-fold higher) and their effects on kidneys: In 15 children receiving long-term PN, the glomerular filtration rate was lower than that of non-PN controls and was inversely correlated with Cr indices. Furthermore, in a randomized blinded prospective protocol involving 75 newborns, the group receiving the recommended dose of Cr showed higher levels of creatinine that were positively correlated with Cr intake. Of note, Cr contaminants in PN solutions can increase the amount delivered by 10%-100%. A possible method for estimating adequate Cr to be provided IV is to calculate the amount physiologically absorbed in healthy people. This amount is 10 to 100 times less than the daily recommended parenteral Cr in adults. The accumulated scientific data presented here point to a serious need to lower the recommended amount of parenteral Cr.

Copper is an essential nutrient for humans. Copper is a component of numerous enzymes that affect a wide variety of metabolic processes. Copper deficiency can result in anemia, neutropenia, skeletal abnormalities, and other clinical manifestations. There is no well-established laboratory measurement of body copper status. Copper supplementation is essential in parenteral nutrition to prevent an adverse effect of deficiency. Balance studies indicate that copper requirements in total parenteral nutrition amount to 0.3 mg/day in the adult. For children and infants, the estimated requirement is 20 microg/kg body wt/day. These amounts may have to be decreased in patients with cholestasis.

Choline is a quaternary amine endogenously synthesized from the amino acid methionine or absorbed via the portal circulation. It is ubiquitous in the diet, although it has a greater presence in organ meats. Choline is an essential component of all cell membranes, and has been considered a required dietary nutrient since 1998 by the US Institute of Medicine's Food and Nutrition Board. Choline is necessary for DNA repair, mediated by its role as a methyl donor. It also serves as the precursor for the neurotransmitter acetylcholine. Evidence has accumulated that hepatic steatosis, which occurs during parenteral nutrition therapy, develops as a result of choline deficiency because endogenous production of choline from parenterally infused methionine is deficient. In addition, memory deficits and skeletal muscle abnormalities have been described, and choline deficiency appears to activate cellular apoptosis. Provision of intravenous choline ameliorates hepatic steatosis associated with parenteral nutrition infusion.

Vitamin K (as phylloquinone and menaquinones) is an essential cofactor for the conversion of peptide-bound glutamate to gamma-carboxy glutamic acid (Gla) residues in a number of specialized Gla-containing proteins. The only unequivocal deficiency outcome is a bleeding syndrome caused by an inability to synthesize active coagulation factors II, VII, IX, and X, although there is growing evidence for roles for vitamin K in bone and vascular health. An adult daily intake of about 100 microg of phylloquinone is recommended for the maintenance of hemostasis. Traditional coagulation tests for assessing vitamin K status are nonspecific and insensitive. Better tests include measurements of circulating vitamin K and inactive proteins such as undercarboxylated forms of factor II and osteocalcin to assess tissue and functional status, respectively. Common risk factors for vitamin K deficiency in the hospitalized patient include inadequate dietary intakes, malabsorption syndromes (especially owing to cholestatic liver disease), antibiotic therapy, and renal insufficiency. Pregnant women and their newborns present a special risk category because of poor placental transport and low concentrations of vitamin K in breast milk. Since 2000, the Food and Drug Administration has mandated that adult parenteral preparations should provide a supplemental amount of 150 microg phylloquinone per day in addition to that present naturally, in variable amounts, in the lipid emulsion. Although this supplemental daily amount is probably beneficial in preventing vitamin K deficiency, it may be excessive for patients taking vitamin K antagonists, such as warfarin, and jeopardize their anticoagulant control. Natural forms of vitamin K have no proven toxicity.

Screening interventions for Barrett's esophagus (BE) are appealing, but there is little supporting evidence. We reviewed health economics studies about BE endoscopic screening followed by, as required, endoscopic surveillance ("screening and surveillance" hereafter) to help inform the design and conduct of future research. Health economics studies about BE screening and surveillance were identified using electronic database searches and personal contact with authors of identified studies. No studies examined general population screening. Five US studies published between 2003 and 2007 examined the cost effectiveness of screening and surveillance (against no intervention) in patients with chronic gastroesophageal reflux disease (GERD). There was no randomized trial evidence to inform model construction. Assumptions about prevalence and transition probabilities between BE histologic subtypes and about surveillance and treatment protocols varied substantially between studies. Parameters such as potential BE diagnosis-related reduction in quality of life or increase in health care use, diagnostic accuracy, and infrastructural costs (for quality assurance) were considered either "optimistically" or not at all. Only 2 studies considered endoscopic treatments. No study considered the recently introduced radiofrequency ablation technique, or the potential for biomarker-based risk stratification of surveillance interval or duration. Current health economics evidence is likely to have provided optimistic cost-effectiveness estimates and is not sufficient to support introduction of endoscopic BE screening programs among GERD patients. The evidence does not adequately incorporate novel (endoscopic) treatments and the potential for (clinical, endoscopic, or biomarker-based) risk stratification of surveillance. Future research should aim to encompass both these factors.

The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies.

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the gastrointestinal tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the gastrointestinal tract, have important functions in the control of gastrointestinal motility and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances will be the focus of this review.

Celiac disease has become one of the best-understood HLA-linked disorders. Although it shares many immunologic features with inflammatory bowel disease, celiac disease is uniquely characterized by (1) a defined trigger (gluten proteins from wheat and related cereals), (2) the necessary presence of HLA-DQ2 or HLA-DQ8, and (3) the generation of circulating autoantibodies to the enzyme tissue transglutaminase (TG2). TG2 deamidates certain gluten peptides, increasing their affinity to HLA-DQ2 or HLA-DQ8. This generates a more vigorous CD4(+) T-helper 1 T-cell activation, which can result in intestinal mucosal inflammation, malabsorption, and numerous secondary symptoms and autoimmune diseases. Moreover, gluten elicits innate immune responses that act in concert with the adaptive immunity. Exclusion of gluten from the diet reverses many disease manifestations but is usually not or less efficient in patients with refractory celiac disease or associated autoimmune diseases. Based on the advanced understanding of the pathogenesis of celiac disease, targeted nondietary therapies have been devised, and some of these are already in phase 1 or 2 clinical trials. Examples are modified flours that have been depleted of immunogenic gluten epitopes, degradation of immunodominant gliadin peptides that resist intestinal proteases by exogenous endopeptidases, decrease of intestinal permeability by blockage of the epithelial ZOT receptor, inhibition of intestinal TG2 activity by transglutaminase inhibitors, inhibition of gluten peptide presentation by HLA-DQ2 antagonists, modulation or inhibition of proinflammatory cytokines, and induction of oral tolerance to gluten. These and other experimental therapies will be discussed critically.

Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant hepatitis B virus (HBV) mutants frequently arise, leading to treatment failure and progression to liver disease. There has been much research into the mechanisms of resistance to NA and selection of these mutants. Five NA have been approved by the US Food and Drug Administration for treatment of CHB; it is unlikely that any more NA will be developed in the near future, so it is important to better understand mechanisms of cross-resistance (when a mutation that mediates resistance to one NA also confers resistance to another) and design more effective therapeutic strategies for these 5 agents. The genes that encode the polymerase and envelope proteins of HBV overlap, so resistance mutations in polymerase usually affect the hepatitis B surface antigen; these alterations affect infectivity, vaccine efficacy, pathogenesis of liver disease, and transmission throughout the population. Associations between HBV genotype and resistance phenotype have allowed cross-resistance profiles to be determined for many commonly detected mutants, so genotyping assays can be used to adapt therapy. Patients that experience virologic breakthrough or partial response to their primary therapy can often be successfully treated with a second NA, if this drug is given at early stages of these events. However, best strategies for preventing NA resistance include first-line use of the most potent antivirals with a high barrier to resistance. It is important to continue basic research into HBV replication and pathogenic mechanisms to identify new therapeutic targets, develop novel antiviral agents, design combination therapies that prevent drug resistance, and decrease the incidence of complications of CHB.

There is debate about how best to measure patient-reported outcomes (PROs) in irritable bowel syndrome (IBS). We pooled data to measure the psychometric properties of IBS end points, including binary responses (eg, "adequate relief") and 50% improvement in symptom severity.