Vitamin D supplementation in people with IBS has no effect on symptom severity and quality of life: results of a randomised controlled trial.

PURPOSE: Several small trials suggest a benefit of vitamin D supplementation in irritable bowel syndrome (IBS). The generalisability of these reports is limited by their design and scale. This study aimed to assess whether vitamin D supplementation improved IBS symptoms in a UK community setting. METHODS: This was a randomised, double-blind, placebo-controlled study. Participants were recruited from the community in winter months between December 2017 and March 2019. 135 participants received either vitamin D (3,000 IU p.d.) or placebo for 12 weeks. The primary outcome measure was change in IBS symptom severity; secondary outcomes included change in IBS-related quality of life. RESULTS: The participants were analysed on an intent-to-treat basis. 60% of participants were vitamin D deficient or insufficient at baseline. Although vitamin D levels increased in the intervention arm relative to placebo (45.1 ± 32.88 nmol/L vs 3.1 ± 26.15 nmol/L; p < 0.001). There was no difference in the change of IBS symptom severity between the active and placebo trial arms (- 62.5 ± 91.57 vs - 75.2 ± 84.35, p = 0.426) over time. Similarly there was no difference between trial arms in τhe change in quality of life (- 7.7 ± 25.36 vs - 11.31 ± 25.02, p = 0.427). CONCLUSIONS: There is no case for advocating use of vitamin D in the management of IBS symptoms. The prevalence of vitamin D insufficiency suggests routine screening and supplementation should be implemented in this population for general health reasons. This trial was retrospectively registered with ISRCTN (ISRCTN13277340) on 24th April 2018 after recruiting had been initiated.

Nutrition and Frailty: Opportunities for Prevention and Treatment.

Frailty is a syndrome of growing importance given the global ageing population. While frailty is a multifactorial process, poor nutritional status is considered a key contributor to its pathophysiology. As nutrition is a modifiable risk factor for frailty, strategies to prevent and treat frailty should consider dietary change. Observational evidence linking nutrition with frailty appears most robust for dietary quality: for example, dietary patterns such as the Mediterranean diet appear to be protective. In addition, research on specific foods, such as a higher consumption of fruit and vegetables and lower consumption of ultra-processed foods are consistent, with healthier profiles linked to lower frailty risk. Few dietary intervention studies have been conducted to date, although a growing number of trials that combine supplementation with exercise training suggest a multi-domain approach may be more effective. This review is based on an interdisciplinary workshop, held in November 2020, and synthesises current understanding of dietary influences on frailty, focusing on opportunities for prevention and treatment. Longer term prospective studies and well-designed trials are needed to determine the causal effects of nutrition on frailty risk and progression and how dietary change can be used to prevent and/or treat frailty in the future.

Short-Term Protein Supplementation Does Not Alter Energy Intake, Macronutrient Intake and Appetite in 50-75 Year Old Adults.

Ageing is associated with a reduction in muscle mass and strength, termed sarcopenia. Dietary protein is important for the maintenance of muscle mass through the promotion of muscle protein synthesis. However, protein is also reported to be a highly satiating nutrient. This raises concerns that protein intake for musculoskeletal health reasons in older adults may exacerbate age-related decreased appetite and may result in reduced energy and nutrient intake. This study aimed to investigate the effect of short-term protein supplementation and its timing (morning vs. evening), on energy and nutrient intake and appetite measures in middle-older age adults. Twenty-four 50-75 year olds were recruited to a randomised cross-over trial. In phase 1 (pre-supplementation) participants completed a food diary and reported hunger and appetite on three alternate days. During the second and third phases, participants consumed a 20 g whey protein gel (78 mL/368 kJ), for four days, either in the morning (after breakfast) or the evening (before bed), whilst completing the same assessments as phase 1. No differences in dietary intakes of energy, macronutrients and micronutrients were recorded when comparing the pre-supplementation phase to the protein supplementation phases, irrespective of timing (excluding the contribution of the protein supplement itself). Similarly, no differences were observed in self-reported feelings of hunger and appetite. In conclusion, a 20 g/day whey protein supplement given outside of meal-times did not alter habitual dietary intakes, hunger or appetite in this middle-older age adult population in the short-term. This approach may be a useful strategy to increasing habitual protein intake in the middle-older age population.

A randomized placebo-controlled trial to investigate the effect of lactolycopene on semen quality in healthy males.

PURPOSE: Poor sperm quality is a major contributor to infertility in heterosexual couples, but at present there are few empirical therapies. Several studies have examined the role of dietary factors and data from randomized controlled trials suggest that oral antioxidant therapy can improve some sperm parameters. Health benefits of lycopene supplementation have been proposed for a variety of health conditions and here we examine whether it can help improve sperm quality. This study aimed to investigate the effect of 14 mg daily lactolycopene for 12 weeks on semen quality in healthy men. METHODS: Sixty healthy male participants were recruited and randomized to this double-blind, placebo-controlled parallel study and received either 14 mg/d lactolycopene or a placebo for 12 weeks. The primary endpoint was a change in motile sperm concentration. Secondary endpoints were all other aspects of sperm quality, including the level of sperm DNA damage. RESULTS: Fifty-six men completed the intervention and the level of plasma lycopene was significantly increased in the men randomized to receive lycopene supplementation. There was no significant change in the primary endpoint (motile sperm concentration) post-intervention (p = 0.058). However, the proportion of fast progressive sperm (p = 0.006) and sperm with normal morphology (p < 0.001) did improve significantly in response to lactolycopene intervention. CONCLUSIONS: Supplementation with 14 mg/d lactolycopene improves sperm motility and morphology in young healthy men. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ISRCTN33248724 http://www.isrctn.com/ISRCTN33248724.

Rate of change of circulating 25-hydroxyvitamin D following sublingual and capsular vitamin D preparations.

BACKGROUND: Vitamin D is critical for skeletal health, and is increasingly associated with other pathologies encompassing gastrointestinal, immunological and psychological effects. A significant proportion of the population exhibits suboptimal levels of vitamin D, particularly in Northern latitudes in winter. Supplementation is advocated, but few data are available on achievable or typical rates of change. There has been considerable interest in the potential use of sublingual sprays for delivery of nutrient supplements, but data on efficacy remain sparse. METHODS: A randomised, placebo-controlled, three-arm parallel design study was conducted in healthy volunteers (n = 75) to compare the rate of change of vitamin D status in response to vitamin D3 (3000 IU/day) supplementation in capsule and sublingual spray preparations over a 6-week period between January and April 2017. Blood 25(OH)D concentrations were measured after day 0, 3, 7, 14, 21 and 42 days of supplementation with 3000 IU per diem. RESULTS: Baseline measurements show 25(OH)D deficiency (<30 nmol/l), insufficiency (31-46 nmol/l) and sufficiency (> 50 mmol/l) in 14.9, 44.6 and 40.5% of the participants, respectively. There was a significant elevation in blood concentrations of 25(OH)D in both of the treatment arms (capsule p = 0.003, spray p = 0.001) compared with control. The capsule and spray were equally efficacious. The rate of change ranged from 0.69 to 3.93 (capsule) and 0.64 to 3.34 (spray) nmol/L day with average change in blood 25(OH)D levels of 2 nmol/l/day. Rates followed a simple normal distribution in the study population (ks = 0.94 and 0.82 for capsule and spray, respectively). The data suggest that rates of change are higher in individuals with lower levels of 25(OH)D. CONCLUSIONS: A sublingual vitamin D spray is an effective mode of delivery for supplementation in a healthy population. The data provide reference values and ranges for the rate of change of 25(OH)D for nutrikinetic analyses.

Vitamin D status in irritable bowel syndrome and the impact of supplementation on symptoms: what do we know and what do we need to know?

BACKGROUND: Low vitamin D status is associated with risk of colorectal cancer and has been implicated in inflammatory bowel disease. Irritable bowel syndrome (IBS) is a chronic, relapsing, functional bowel disorder. A nascent literature suggests a role for vitamin D in IBS, but this has not been collated or critiqued. To date, seven studies have been published: four observational studies and three randomised controlled trials (RCTs). All observational studies reported that a substantial proportion of the IBS population was vitamin D deficient. Two intervention studies reported improvement in IBS symptom severity scores and quality of life (QoL) with vitamin D supplementation. There are limited data around the role of vitamin D in IBS. CONCLUSIONS: The available evidence suggests that low vitamin D status is common among the IBS population and merits assessment and rectification for general health reasons alone. An inverse correlation between serum vitamin D and IBS symptom severity is suggested and vitamin D interventions may benefit symptoms. However, the available RCTs do not provide strong, generalisable evidence; larger and adequately powered interventions are needed to establish a case for therapeutic application of vitamin D in IBS.

Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release.

Exercise is an effective intervention for the prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals that contribute to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance, and performance. The transcriptional regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers, an effect reversed in insulin resistance and diabetes. We found that nitrate induces PGC1α expression and a switch toward type I and IIa fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1α-dependent myokine FNDC5/irisin and ß-aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1α-mediated γ-aminobutyric acid (GABA) secretion from muscle. Circulating GABA concentrations were increased in exercising mice and nitrate-treated rats and humans; thus, GABA may function as an exercise/PGC1α-mediated myokine-like small molecule. Moreover, nitrate increased circulating growth hormone levels in humans and rodents. Nitrate induces physiological responses that mimic exercise training and may underlie the beneficial effects of this metabolite on exercise and cardiometabolic health.

Dietary nitrate does not affect physical activity or outcomes in healthy older adults in a randomized, cross-over trial.

Although dietary nitrate (NO3-) ingestion appears to enhance exercise capacity and performance in young individuals, inconclusive findings have been reported in older people. Therefore, we conducted a double-blind, crossover randomized clinical trial using beetroot juice in older healthy participants, who were classified as normal weight and overweight. We tested whether consumption of beetroot juice (a rich source of NO3-) for 1 week would increase nitric oxide bioavailability via the nonenzymatic pathway and enhance (1) exercise capacity during an incremental exercise test, (2) physical capability, and (3) free-living physical activity. Twenty nonsmoking, healthy participants between 60 and 75 years of age and with a body mass index of 20.0 to 29.9 kg/m2 were included. Presupplementation and postsupplementation resting, submaximal, maximal, and recovery gas exchanges were measured. Physical capability was measured by hand-grip strength, time-up-and-go, repeated chair rising test, and 10-m walking speed. Free-living physical activity was assessed by triaxal accelerometry. Changes in urinary and plasmaNO3-concentrations were measured by gas chromatography-mass spectrometry. Nineteen participants (male-to-female ratio, 9:10) completed the study.Beetroot juice increased significantly both plasma and urinary NO3-concentrations (P<.001) when compared with placebo. Beetroot juice did not influence resting or submaximal and maximal oxygen consumption during the incremental exercise test. In addition, measures of physical capability and physical activity levels measured in free-living conditions were not modified by beetroot juice ingestion. The positive effects of beetroot juice ingestion on exercise performance seen in young individuals were not replicated in healthy, older adults. Whether aging represents a modifier of the effects of dietary NO3-on muscular performance is not known, and mechanistic studies and larger trials are needed to test this hypothesis.

Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial.

BACKGROUND: Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer, as well as with depression. No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome (IBS). A single case report has suggested a benefit in IBS of vitamin D supplementation. We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms. We undertook a pilot trial to provide data to support a power calculation and to justify a full trial. METHODS: This was a randomised, double blinded, three-arm parallel design trial of vitamin D, placebo or a combination of vitamin D and probiotics. Participants were further stratified according to whether they were vitamin D replete or insufficient. Vitamin D status was determined by blood test at baseline and exit; IBS symptoms were assessed by validated questionnaire; dietary intakes were assessed by food frequency questionnaire. RESULTS: A significant proportion of the IBS population were vitamin D deficient, such that the replete stratum could not be adequately recruited. There was a significant association in the baseline data between circulating vitamin D level and quality of life ("How much has IBS affected your life?"). Supplementation significantly improved vitamin D level versus placebo. IBS symptoms were not significantly improved in this pilot, although a power calculation was enabled from the intervention data. CONCLUSIONS: The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation. The impact of IBS on quality of life may be reduced by vitamin D level. Future trials should have a sample size of over 97. TRIAL REGISTRATION NUMBER: ICTRN 6116003917.

Folate, colorectal cancer and the involvement of DNA methylation.

Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a high-dose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.

Improvement in nutritional status reduces the clinical impact of infections in older adults.

OBJECTIVES: To determine the effect of a dietary intervention and micronutrient supplementation on self-reported infections in older adults. DESIGN: A randomized, placebo-controlled intervention trial. SETTING: Community living older people in South Yorkshire, United Kingdom. PARTICIPANTS: Two-hundred seventeen older adults aged 65 to 85. INTERVENTION: Participants were randomized to a dietary intervention, a daily micronutrient supplement, or placebo for 3 months, with a 3-month follow-up. MEASUREMENTS: Self-reported measures of infection were reported over the 6-month study period. Secondary outcome measures were nutritional status, dietary intake, quality of life, and depression. RESULTS: Self-reported measures of infection over the 6-month duration of the study were significantly different between the treatment groups. The number of weeks in which illness affected life and the number of general practitioner and hospital visits were significantly lower in the food and micronutrient groups than in the placebo group. The number of weeks in which symptoms of an infection were described was significantly lower in the food group than the placebo and micronutrient groups. Significant improvements in biomarkers of micronutrient status were achieved in the food and micronutrient groups and showed significantly greater change than observed in the placebo group. Significant improvement in dietary intakes was observed in the food group only. CONCLUSION: Improving dietary intake and micronutrient status reduces the clinical impact of self-reported infections in older adults.

Correcting a marginal riboflavin deficiency improves hematologic status in young women in the United Kingdom (RIBOFEM).

BACKGROUND: Moderate riboflavin deficiency is prevalent in certain population groups in affluent countries, but the functional significance of this deficiency is not clear. Studies have indicated a role for riboflavin in the absorption and use of iron. OBJECTIVE: We investigated the effect of riboflavin supplementation on hematologic status in a group of moderately riboflavin-deficient women aged 19-25 y in the United Kingdom. DESIGN: One hundred twenty-three women with biochemical evidence of riboflavin deficiency [erythrocyte glutathione reductase activation coefficient (EGRAC) >1.40] were randomly assigned to receive 2 or 4 mg riboflavin or a placebo for 8 wk. Measurements of hematologic status were made pre- and postsupplementation, and dietary intakes were also assessed; iron absorption was measured in a subgroup of women. RESULTS: One hundred nineteen women completed the intervention. The use of a riboflavin supplement for 8 wk elicited a significant improvement in riboflavin status with a dose response (P < 0.0001). For women who received supplemental riboflavin, an increase in hemoglobin status correlated with improved riboflavin status (P < 0.02). Women in the lowest tertile of riboflavin status at baseline (EGRAC >1.65) showed a significantly greater increase in hemoglobin status in response to the supplement than did women in the first and second tertiles (P < 0.01). Dietary iron intake and iron absorption did not change during the study. CONCLUSIONS: Moderately poor riboflavin status can affect iron status: the lower the riboflavin status, the greater the hematologic benefits of improving status. The results also suggest that consideration should be given to raising the currently accepted EGRAC threshold for deficiency. This trial was registered at controlled-trials.com as ISRCTN35811298.

UK food standards agency workshop report: diet and immune function.

The UK Food Standards Agency convened a workshop on 13 May 2009 to discuss recently completed research on diet and immune function. The objective of the workshop was to review this research and to establish priorities for future research. Several of the trials presented at the workshop showed some effect of nutritional interventions (e.g. vitamin D, Zn, Se) on immune parameters. One trial found that increased fruit and vegetable intake may improve the antibody response to pneumococcal vaccination in older people. The workshop highlighted the need to further clarify the potential public health relevance of observed nutrition-related changes in immune function, e.g. susceptibility to infections and infectious morbidity.

Inter-individual variation in DNA damage and base excision repair in young, healthy non-smokers: effects of dietary supplementation and genotype.

Diets rich in fruits and vegetables are associated with lower risk of cancer which may be conferred in part by the antioxidant properties of these foods. However, antioxidant supplementation or increased consumption of antioxidant-rich foods has been reported to have inconsistent effects on DNA damage. The present work (the DART study) investigated the extent of inter-individual variation in DNA damage, the capacity for base excision repair (BER) and the responses of both variables to supplementation with an antioxidant supplement for 6 weeks. There was a wide inter-individual variation in endogenous lymphocyte DNA strand breaks (8-fold variation), in damage after a challenge with H2O2 (16-fold variation) and in DNA repair (41-fold variation) measured using the comet assay. When stratified into tertiles according to the pre-supplementation level of endogenous DNA damage, there was a statistically significant decrease in DNA damage after supplementation in the tertile with the highest pre-supplementation level of damage. There was no effect of supplementation on BER. Endogenous DNA damage level before supplementation was significantly different (P = 0.037) between the three genotypes for the Val16Ala single nucleotide polymorphism in manganese superoxide dismutase (rs4880) with individuals homozygous/wild type showing less damage than those carrying the alanine variant.

Study Protocol: randomised controlled trial to investigate the functional significance of marginal riboflavin status in young women in the UK (RIBOFEM).

BACKGROUND: The functional significance of moderate riboflavin deficiency as it is currently assessed is not well understood. Animal and human studies have suggested a role for riboflavin in the absorption and mobilisation of iron and as such may be important in maintaining haematological status. Recent National Diet and Nutrition Surveys in the United Kingdom have shown that young women in particular are at risk of moderate riboflavin deficiency and low iron status. METHODS/DESIGN: A randomised placebo controlled intervention trial was conducted to investigate the effect of riboflavin supplementation on various measures of haematological status in a group of moderately riboflavin deficient young women aged 19 to 25 years. Women who were low milk consumers were initially screened for riboflavin status as assessed by the erythrocyte glutathione reductase activation coefficient assay (EGRAC). One hundred and twenty three women with EGRAC values >1.40 were randomised to receive 2 mg, 4 mg riboflavin or placebo for 8 weeks. In addition 36 of these women were randomly allocated to an iron bioavailability study to investigate the effect of the intervention on the absorption or utilisation of iron using an established red cell incorporation technique. DISCUSSION: One hundred and nineteen women completed the intervention study, of whom 36 completed the bioavailability arm. Compliance was 96 +/- 6% (mean +/- SD). The most effective recruitment strategy for this gender and age group was e-communication (e-mail and website). The results of this study will clarify the functional significance of the current biochemical deficiency threshold for riboflavin status and will inform a re-evaluation of this biochemical threshold. TRIAL REGISTRATION: Current Controlled Trials Registration No. ISRCTN35811298.

Inter-individual variation in nucleotide excision repair in young adults: effects of age, adiposity, micronutrient supplementation and genotype.

Nucleotide excision repair (NER) is responsible for repairing bulky helix-distorting DNA lesions and is essential for the maintenance of genomic integrity. Severe hereditary impairment of NER leads to cancers such as those in xeroderma pigmentosum, and more moderate reductions in NER capacity have been associated with an increased cancer risk. Diet is a proven modifier of cancer risk but few studies have investigated the potential relationships between diet and NER. In the present study, the plasmid-based host cell reactivation assay was used to measure the NER capacity in peripheral blood mononuclear cells from fifty-seven volunteers aged 18-30 years before and after 6 weeks of supplementation with micronutrients (selenium and vitamins A, C and E). As a control, nine individuals remained unsupplemented over the same period. Volunteers were genotyped for the following polymorphisms in NER genes: ERCC5 Asp1104His (rs17655); XPC Lys939Gln (rs2228001); ERCC2 Lys751Gnl (rs13181); XPC PAT (an 83 bp poly A/T insertion-deletion polymorphism in the XPC gene). NER capacity varied 11-fold between individuals and was inversely associated with age and endogenous DNA strand breaks. For the first time, we observed an inverse association between adiposity and NER. No single polymorphism was associated with the NER capacity, although significant gene-gene interactions were observed between XPC Lys939Gln and ERCC5 Asp1104His and XPC Lys939Gln and ERCC2 Lys751Gnl. While there was no detectable effect of micronutrient supplementation on NER capacity, there was evidence that the effect of fruit intake on the NER capacity may be modulated by the ERCC2 Lys751Gnl single nucleotide polymorphism.

Gender-specific modulation of tumorigenesis by folic acid supply in the Apc mouse during early neonatal life.

Epidemiological studies suggest an inverse association between folic acid intake and colorectal cancer risk. Conversely, conventional treatment of existing tumours includes the use of folate antagonists. This suggests that the level of exposure to folate and its timing in relation to stage of tumorigenesis may be critical in determining outcomes. We hypothesised that folic acid depletion in utero and during early neonatal life may affect tumorigenesis in offspring. To investigate this hypothesis, female C57Bl6/J mice were randomised to a folic acid adequate (2 mg folic acid/kg diet) or folic acid depleted diet (0.4 mg folic acid/kg) from mating with Apc+/Min sires and throughout pregnancy and lactation. At weaning the Apc+/Min offspring were randomised to a folic acid adequate (2 mg folic acid/kg diet) or depleted (0.26 mg folic acid/kg diet) diet, creating four in utero/post-weaning dietary regimens. At 10 weeks post-weaning, mice were killed and the intestinal tumour number and size were recorded. Folic acid depletion during pregnancy and post-weaning reduced erythrocyte folate concentrations in offspring significantly. Folic acid depletion during pregnancy and lactation did not affect tumour multiplicity or size. However, female mice fed normal folic acid diets post-weaning had more, and larger, tumours when compared with depleted females and both depleted and adequate folic acid fed males. These data suggest that folate depletion post-weaning was protective against neoplasia in female Apc+/Min mice and highlights the need for further investigation of the optimal timing and dose of folic acid supplementation with regard to colorectal cancer risk.

Of two lives one? Jean-Charles-Marguerite-Guillaume Grimaud and the question of holism in vitalist medicine.

Montpellier vitalists upheld a medical perspective akin to modern "holism" in positing the functional unity of creatures imbued with life. While early vitalists focused on the human organism, Jean-Charles-Marguerite-Guillaume Grimaud investigated digestion, growth, and other physiological processes that human beings shared with simpler organisms. Eschewing modern investigative methods, Grimaud promoted a medically-grounded "metaphysics." His influential doctrine of the "two lives" broke with Montpellier holism, classifying some vital phenomena as "higher" and others as "lower" and attributing the "nobility" of the human species to the predominance of the former. In place of Montpellier teaching that attributed health to the holistic equilibration of vital activities, Grimaud embraced spiritualist dualisms of soul and body, Creator and created. Celebrating the divinely-ordained "wisdom" evident in involuntary physiological processes, he argued that such life functions were incomprehensible to human investigators. While Grimaud's work encouraged inquiry into the division between the central and "vegetative" nervous systems that became paradigmatic in nineteenth-century neuroscience, it also opened Montpellier vitalism to charges of conservatism and obscurantism that are still lodged against it to the present day.

Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 Study).

Epidemiologic data suggest that increasing folate intake may protect against colorectal cancer. Riboflavin may interact with folate to modulate the effect. A double-blind randomized placebo-controlled intervention study (the FAB2 Study) was carried out in healthy controls and patients with colorectal polyps (adenomatous and hyperplastic) to examine effects of folic acid and riboflavin supplements on biomarkers of nutrient status and on putative biomarkers of colorectal cancer risk (DNA methylation and DNA damage; to be reported elsewhere). Ninety-eight healthy controls and 106 patients with colorectal polyps were stratified for the thermolabile variant of methylene tetrahydrofolate reductase, MTHFR C677T, and were randomized to receive 400 microg of folic acid, 1,200 microg of folic acid, or 400 microg of folic acid plus 5 mg of riboflavin or placebo for 6 to 8 weeks. Blood samples and colon biopsy samples were collected for the measurement of biomarkers of folate and riboflavin status. Supplementation with folic acid elicited a significant increase in mucosal 5-methyl tetrahydrofolate, and a marked increase in RBC and plasma, with a dose-response. Measures of riboflavin status improved in response to riboflavin supplementation. Riboflavin supplement enhanced the response to low-dose folate in people carrying at least one T allele and having polyps. The magnitude of the response in mucosal folate was positively related to the increase in plasma 5-methyl tetrahydrofolate but was not different between the healthy group and polyp patients. Colorectal mucosal folate concentration responds to folic acid supplementation to an extent comparable to that seen in plasma, but with a suggestion of an upper limit.

A double-blind, placebo-controlled, glutamine-supplementation trial in growth-faltering Gambian infants.

BACKGROUND: Growth faltering during infancy is a characteristic of life in developing countries. Previous studies have shown that small-intestine mucosal enteropathy, accompanied by endotoxemia and a persistent systemic inflammatory response, accounts for up to 64% of the growth faltering in Gambian infants. OBJECTIVE: The objective was to test whether glutamine, with its putative trophic effects on enterocytes, immune cells, and intestinal integrity, can accelerate the repair of the intestine, lower immunostimulation, and reduce growth faltering. DESIGN: Ninety-three infants aged 4-10 mo from the West Kiang region of The Gambia were studied in a double-blind, double-placebo, controlled trial. Glutamine (0.25 mg/kg body wt) or a placebo that contained an isonitrogenous, isoenergetic mix of nonessential amino acids was orally administered twice daily throughout the 5-mo rainy season. Anthropometric measurements were made monthly during the supplementation period and for 6 mo after supplementation. Intestinal permeability was measured monthly (by determining the ratio of lactulose to mannitol), and finger-prick blood samples were collected for the analysis of plasma proteins on 3 occasions. RESULTS: Gambian infants showed a seasonal deterioration in growth and persistently elevated acute phase protein concentrations and intestinal permeability. Oral supplementation with glutamine did not improve growth (x +/- SE: weight gain, 60 +/- 19 and 69 +/- 20 g/mo; length gain, 1.01 +/- 0.05 and 0.95 +/- 0.03 cm/mo) or intestinal permeability [lactulose:mannitol ratio: 0.29 (95% CI: 0.23, 0.35) and 0.26 (95% CI: 0.21, 0.32)] in the glutamine and placebo groups, respectively. It also had no effect on infant morbidity or on plasma concentrations of immunoglobulins or acute phase proteins. CONCLUSION: Glutamine supplementation failed to improve growth or intestinal status in malnourished Gambian infants.