Twenty selected patients with recurrent aphthous stomatitis in whom celiac disease had been specifically excluded were placed on a gluten-free diet. Five patients (25%) showed a favorable response to gluten withdrawal and a positive gluten challenge. Jejunal morphology was normal in all patients indicating gluten sensitivity without enteropathy. Gluten withdrawal provides a further method of treating some patients with recurrent aphthous stomatitis.

BACKGROUND:Tumors are largely unable to metabolize ketone bodies for energy due to various deficiencies in one or both of the key mitochondrial enzymes, which may provide a rationale for therapeutic strategies that inhibit tumor growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat.

MATERIALS AND METHODS:Thirty-six male BALB/C nude mice were injected subcutaneously with tumor cells of the colon cancer cell line HCT116. The animals were then randomly split into three feeding groups and fed either a ketogenic diet rich in omega-3 fatty acids and MCT (MKD group; n=12) or lard only (LKD group; n=12) or a standard diet (SD group; n=12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The three diets were compared for tumor growth and survival time (interval between tumor cell injection and attainment of target tumor volume).

RESULTS:The tumor growth in the MKD and LKD groups was significantly delayed compared to that in the SD group.

CONCLUSIONS:Application of an unrestricted ketogenic diet delayed tumor growth in a mouse xenograft model. Further studies are needed to address the mechanism of this diet intervention and the impact on other tumor-relevant parameters such as invasion and metastasis.

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy.

CASE REPORT:In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86× 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely.

CONCLUSIONS:The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.

Background:Plant-based diets, often referred to as vegetarian diets, are associated with health benefits. However, the association with mortality is less clear.

Objective:We investigated associations between plant-based diet indexes and all-cause and cardiovascular disease mortality in a nationally representative sample of US adults.

Methods:Analyses were based on 11,879 participants (20-80 y of age) from NHANES III (1988-1994) linked to data on all-cause and cardiovascular disease mortality through 2011. We constructed an overall plant-based diet index (PDI), which assigns positive scores for plant foods and negative scores for animal foods, on the basis of a food-frequency questionnaire administered at baseline. We also constructed a healthful PDI (hPDI), in which only healthy plant foods received positive scores, and a less-healthful (unhealthy) PDI (uPDI), in which only less-healthful plant foods received positive scores. Cox proportional hazards models were used to estimate the association between plant-based diet consumption in 1988-1994 and subsequent mortality. We tested for effect modification by sex.

Results:In the overall sample, PDI and uPDI were not associated with all-cause or cardiovascular disease mortality after controlling for demographic characteristics, socioeconomic factors, and health behaviors. However, among those with an hPDI score above the median, a 10-unit increase in hPDI was associated with a 5% lower risk in all-cause mortality in the overall study population (HR: 0.95; 95% CI: 0.91, 0.98) and among women (HR: 0.94; 95% CI: 0.88, 0.99), but not among men (HR: 0.95; 95% CI: 0.90, 1.01). There was no effect modification by sex (P-interaction>0.10).

Conclusions:A nonlinear association between hPDI and all-cause mortality was observed. Healthy plant-based diet scores above the median were associated with a lower risk of all-cause mortality in US adults. Future research exploring the impact of quality of plant-based diets on long-term health outcomes is necessary.

BACKGROUND & AIMS:Mediterranean diet (MeDi) is considered as a key component for healthy aging, including prevention of age-related disability, while its association with frailty, independent of disability has never been assessed. Our objective was to investigate the relation between MeDi adherence and frailty incidence among persons aged≥75 years participating at the prospective population-based French Three-City Study.

METHODS:The study sample consisted of 560 initially non-frail participants of the Three-City-Bordeaux center, seen at the 2009-2010 follow-up, and re-examined two years later. Adherence to MeDi was computed from a food frequency questionnaire (scored as 0-9). Frailty was defined as having at least three out of the following five slightly modified Fried frailty criteria: involuntary weight loss, exhaustion, slowness, weakness and low physical activity. Logistic regression models adjusted for sociodemographic and clinical covariates, including cognitive performance and depressive symptomatology, were used to assess the association between MeDi score and subsequent frailty risk.

RESULTS:Over the 2-year follow-up, 79 participants (14%) became frail. Older adults with the highest MeDi adherence (score 6-9) had a significantly 68% frailty risk reduction (95% CI: 28-86%, p = 0.006) compared to those in the lowest MeDi category (score 0-3). Regarding the frailty criterion separately, the highest MeDi adherence was associated with a significantly reduced risk of incident slowness (OR = 0.45; 95% CI: 0.20-0.99, p = 0.04), poor muscle strength (OR = 0.44; 95% CI:0.20-0.98, p = 0.04) and low physical activity (OR = 0.39; 95% CI: 0.18-0.82, p = 0.01), compared to the lowest MeDi adherence.

CONCLUSION:In addition to its well-documented beneficial effects on health, adherence to MeDi might contribute to prevent the onset of frailty, even at late stages of life.

The objective of this study was to compare the effect of a high fat, low carbohydrate enteral feed with a standard isocaloric, isonitrogenous enteral feed on PaCO2 and ventilation time in patients with acute respiratory failure requiring artificial ventilation. 20 clinically stable patients requiring enteral feeding were randomized to either feed in a double-blind fashion. Initial ventilator standard settings were adjusted according to clinical state. Measurements including minute volume and arterial blood gases were made twice daily. Weaning was carried out according to set criteria. During the feeding period, PaCO2 just prior to weaning fell by 16% in the high fat group but increased by 4% in the standard feed group (p = 0.003). The high fat group spent a mean of 62 h less time on the ventilator (p = 0.006). A high fat, low carbohydrate enteral feed appears to be beneficial in patients undergoing artificial ventilation.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. Epidemiologic data suggest that malnutrition is a common feature in amyotrophic lateral sclerosis and being overweight or obese confers a survival advantage in this patient population. In amyotrophic lateral sclerosis mouse models, a high-fat diet has been shown to lead to weight gain and prolonged survival. However, little research has been conducted to test whether nutritional interventions might ameliorate the disease course in humans. Here we review the currently available evidence supporting the potential role of dietary interventions as a therapeutic tool for amyotrophic lateral sclerosis. Ultimately, determining whether a high-fat or ketogenic diet could be beneficial in amyotrophic lateral sclerosis will require large randomized, placebo-controlled clinical trials.

Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-kappaB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans-resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-kappaB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 micromol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-kappaB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-kappaB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IkappaB-alpha and IkappaB-beta by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47(phox) subunit. NF-kappaB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by>60% at 10(-6) mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-kappaB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage.

The high-fat ketogenic diet (KD) is a remarkably effective treatment for medically intractable epilepsy and has been part of the clinical armamentarium for nearly a century. However, the mechanisms underlying the KD's actions have remained elusive. Over the past decade, there has been phenomenal international growth of clinical centers offering metabolism-based therapies for epilepsy, and rapidly expanding research into the cellular and biochemical effects induced by the KD. At present, there are many hypotheses regarding KD action, and while each is uniquely compelling, it is becoming more apparent that the KD likely works through multiple mechanisms that target fundamental biochemical pathways linked to cellular substrates (e.g., ion channels) and mediators responsible for neuronal hyperexcitability. This is not altogether surprising given the complexity of the epileptic brain, and the many different pathophysiologic mechanisms that underlie seizure genesis and epileptogenicity. The scientific literature involving the KD strongly supports the notion that epilepsy may indeed in part represent a"metabolic disease", and that this concept could serve as a novel framework for the development of more effective anti-seizure drugs.

Aim:A very-low-calorie diet (VLCD) can reverse the underlying defects of type 2 diabetes mellitus (DM) in obese subjects. We determined the efficacy, safety, and durability of VLCD in Thai patients with DM and obesity.

Methods:Twenty Thai patients with DM and obesity were enrolled. After a 2-week trial, VLCD (600 kcal/day) was continued for 8 weeks, followed by a 4-week transition period. Data on diabetes remission (fasting plasma glucose level<126 mg/dl and HbA<6.5% without the use of glucose-lowering medications), glycemic control, metabolic parameters, and quality of life (QOL) were collected along with indices of insulin resistance (IR) and beta cell function. Glycemic control 12 months after discontinuation of VLCD was also examined.

Results:Among 19 patients (age 48 ± 2 years, BMI 27.7 kg/m) who completed the study, rapid improvement in glycemic control was observed in the first 2 weeks of VLCD. At both 8 and 12 weeks, diabetes remission was achieved in 79%. Significant weight loss was accompanied by a significant reduction in IR and an increase in beta cell function, starting at 4 weeks of VLCD. QOL also significantly increased. At 12 months after VLCD, however, DM remission was achieved in approximately 30%.

Conclusion:Very-low-calorie diet was effective and safe in inducing short-term diabetes remission in Thai subjects by ameliorating beta cell function and IR. Optimal long-term glycemic control was potentially durable as one-third of subjects remained without diabetes medication 12 months after VLCD.

The dietary pattern can influence the immune system directly, but may also modulate it indirectly by regulating the gut microbiota. Here, we investigated the effect of a 3-months lacto-ovo-vegetarian diet on the diversity of gut microbiota and the immune system in healthy omnivorous volunteers, using high-throughput sequencing technologies. The short-term vegetarian diet did not have any major effect on the diversity of the immune system and the overall composition of the metagenome. The prevalence of bacterial genera/species with known beneficial effects on the intestine, including butyrate-producers and probiotic species and the balance of autoimmune-related variable genes/families were, however, altered in the short-term vegetarians. A number of bacterial species that are associated with the expression level of IgA, a key immunoglobulin class that protects the gastrointestinal mucosal system, were also identified. Furthermore, a lower diversity of T-cell repertoire and expression level of IgE, as well as a reduced abundance of inflammation-related genes in the gut microbiota were potentially associated with a control group with long-term vegetarians. Thus, the composition and duration of the diet may have an impact on the balance of pro-/anti-inflammatory factors in the gut microbiota and immune system.

BACKGROUND:Based on promising preclinical data, ketogenic diets (KDs) have been proposed as supplementary measures for cancer patients undergoing standard-of-care therapy. However, data is still scarce on the tolerability and effects of KDs on cancer patients undergoing radiotherapy (RT). Here we present six cases of patients who underwent RT and concurrently consumed a self-administered KD in our clinic within a busy community hospital setting.

METHODS:All patients were followed prospectively with measurements of blood parameters, quality of life and body weight and composition using bioelectrical impedance analysis.

RESULTS:No adverse diet-related side effects occurred. Two patients had no elevated ketone body levels in serum despite self-reporting compliance to the diet. There was consensus that the KD was satiating and weight loss occurred in all patients, although this was only significant in two patients. Our data indicate that weight loss was mainly due to fat mass loss with concurrent preservation of muscle mass. Overall quality of life remained fairly stable, and all subjects reported feeling good on the diet. Tumor regression occurred as expected in five patients with early stage disease; however one subject with metastatic small cell lung cancer experienced slight progression during three cycles of combined chemotherapy + KD and progressed rapidly after ending the KD.

CONCLUSIONS:Our data lend support to the hypothesis that KDs administered as supportive measures during standard therapy are safe and might be helpful in preservation of muscle mass. Further studies with control groups are needed to confirm these findings and address questions regarding any putative anti-tumor effects. Based on the experience with these six cases we implemented further steps to improve issues with KD compliance and initiated a clinical study that is described in a companion paper.

This study evaluates the relation of a Mediterranean dietary pattern and its individual components with the cardiovascular risk factors profile, plasma glucose and body mass index (BMI) in people with type 2 diabetes. We studied 2568 participants at 57 diabetes clinics. Diet was assessed with the EPIC (European Prospective Investigation into Cancer and Nutrition) questionnaire, adherence to the Mediterranean diet was evaluated with the relative Mediterranean diet score (rMED). A high compared to a low score was associated with a better quality of diet and a greater adherence to the nutritional recommendations for diabetes. However, even in the group achieving a high score, only a small proportion of participants met the recommendations for fiber and saturated fat (respectively 17% and 30%). Nonetheless, a high score was associated with lower values of plasma lipids, blood pressure, glycated hemoglobin, and BMI. The relationship of the single food items components of the rMED score with the achievement of treatment targets for plasma lipids, blood pressure, glucose, and BMI were also explored. The study findings support the Mediterranean dietary model as a suitable model for type 2 diabetes and the concept that the beneficial health effects of the Mediterranean diet lie primarily in its synergy among various nutrients and foods rather than on any individual component.

BACKGROUND AND AIMS:The Mediterranean diet (MD) affects the risk of myocardial infarction and long-term prognosis after a coronary event. Limited data are available regarding the influence of MD on short-term prognosis. We assessed the impact of the MD adherence on in-hospital and short-term outcome in patients with first ST-elevation Myocardial Infarction (STEMI).

METHODS AND RESULTS:As many as 533 European patients with STEMI and no previous history of coronary artery disease were included in this analysis. Previous dietary habits of each patient were collected with a food frequency questionnaire from which we calculated the FAMI Mediterranean Diet Score (FAMI MD Score), according to the MD adherence. A blood sample was drawn to each patient within 6 h of symptoms onset. Levels of high-sensitivity C-Reactive Protein (hsCRP), Interleukin-6 (IL-6) were measured. Clinical outcome at 180 days and myocardial reperfusion were assessed. Patients with higher FAMI MD Score had lower levels of hsCRP; there were no differences between IL-6 level among FAMI MD Score quintiles. There were no associations between adherence to MD and 180-day adverse events. Lower FAMI MD Score was associated with a higher risk of ineffective myocardial reperfusion after thrombolysis or percutaneous coronary intervention. Similar results were observed for daily consumption of ≥4 portions of fruit and vegetable.

CONCLUSIONS:A positive effect of the Mediterranean diet, and fruit and vegetable intake was observed on hsCRP and the occurrence of effective myocardial reperfusion. These findings confirm the favorable impact of Mediterranean diet adherence not only in primary but also in secondary prevention.

DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346-CPT1B/CHKB-CPT1B and cg17071192-GNAS/GNASAS, being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genesrelated to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes.

BACKGROUND: The aim of this study was to examine the impact of elemental diet on mucosal inflammation in Crohn's disease (CD), mainly by cytokine measurements.

METHODS: Twenty-eight consecutive patients with active CD were treated with an elemental diet (Elental) for 4 weeks. The mucosal biopsies were obtained from the terminal ileum and large bowel before and after treatment. As a control group, mucosal biopsies were obtained from 20 patients without inflammation. Mucosal cytokine concentrations were measured by enzyme-linked immunosorbent assay.

RESULTS: After treatment, clinical remission was achieved in 20 patients (71%). Endoscopic healing and improvement rates were 44% and 76% in the terminal ileum and 39% and 78% in the large bowel, respectively. Histologic healing and improvement rates were 19% and 54% in the terminal ileum and 20% and 55% in the large bowel, respectively. Before treatment, the mucosal concentrations of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, and tumor necrosis factor-alpha in the ileum and large bowel were significantly higher than in controls. These cytokine concentrations decreased to the levels of control after treatment. IL-1ra/IL-1beta ratio in the ileum and large bowel was significantly lower than in controls before treatment. The ratio increased to the level of controls after treatment. The endoscopic and histologic healing of the mucosal inflammation was associated with a decline of the mucosal cytokines and an increase of the IL-1ra/IL-1beta ratio.

CONCLUSIONS: The elemental diet (Elental) reduced mucosal cytokine production and corrected an imbalance between proinflammatory and anti-inflammatory cytokines in CD.