Anecdotal evidence links the initial phase of fasting or a low-carbohydrate diet with feelings of well-being and mild euphoria. These feelings have often been attributed to ketosis, the production of ketone bodies which can replace glucose as an energy source for the brain. One of these ketone bodies, beta-hydroxybutyrate (BHB), is an isomer of the notorious drug of abuse, GHB (gamma-hydroxybutyrate). GHB is also of interest in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. Here I hypothesize that, the mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABA(B) receptors. I outline several approaches that would test the hypothesis, including receptor binding studies in cultured cells, perception studies in trained rodents, and psychometric testing and functional magnetic resonance imaging in humans. These and other studies investigating whether BHB and GHB share common effects on brain chemistry and mood are timely and warranted, especially when considering their structural similarities and the popularity of ketogenic diets and GHB as a drug of abuse.

The cornerstone to treat metabolic syndrome and insulin resistance is dietary intervention. Both low-carbohydrate diet (LCD) and low-fat diet (LFD) have been reported to induce weight loss and improve these conditions. One of the factors associated with a subject's adherence to the diet is satiety. The aim of this study was to evaluate the effects of LCD and LFD on body weight, appetite hormones, and insulin resistance. Twenty guinea pigs were randomly assigned to LCD or LFD (60%:10%:30% or 20%:55%:25% of energy from fat/carbohydrate/protein, respectively) for 12 weeks. Weight and food intake were recorded every week. After this period, animals were killed and plasma was obtained to measure plasma glucose and insulin, appetite hormones, and ketone bodies. Guinea pigs fed LCD gained more weight than those fed LFD. The daily amount of food intake in grams was not different between groups, suggesting that food density and gastric distension played a role in satiety. There was no difference in leptin levels, which excludes the hypothesis of leptin resistance in the LCD group. However, plasma glucagon-like peptide-1 was 47.1% lower in animals fed LCD (P<.05). Plasma glucose, plasma insulin, and insulin sensitivity were not different between groups. However, the heavier animals that were fed LFD had impairment in insulin sensitivity, which was not observed in those fed LCD. These findings suggest that satiety was dependent on the amount of food ingested. The weight gain in animals fed LCD may be related to their greater caloric intake, lower levels of glucagon-like peptide-1, and higher protein consumption. The adoption of LCD promotes a unique metabolic state that prevents insulin resistance, even in guinea pigs that gained more weight. The association between weight gain and insulin resistance seems to be dependent on high carbohydrate intake.

CONTEXT:The ingestion of gluten is responsible for the symptoms of Celiac disease, but other environmental factors can also influence. Strains of the Bifidobacterium genus have been shown to afford protection against the inflammatory response and mucosal damage caused by gliadin peptides in vitro.

OBJECTIVES:This study was designed to compare the concentration of fecal bifidobacteria and pH of patients with celiac disease on gluten-free diet and control subjects in order to identify if the imbalance on fecal microbiota still remain during the treatment of celiac disease and identify the necessity of dietary supplementation with pre- or probiotics.

METHODS:It was analyzed the feces of 42 healthy subjects and 14 celiac patients. The bifidobacteria count in feces was done in selective medium BIM-25. Microscopic analysis of the colonies was performed by Gram stain. The identification of the genus Bifidobacterium was performed by determination of fructose-6-phosphate phosphoketolase. Fecal pH was measured using a pH meter.

RESULTS:The concentration of bifidobacteria per gram of feces was significantly higher in healthy subjects (controls) (1.5± 0.63 x108 CFU/g) when compared to celiac patients (2.5 ± 1.5 x107 CFU/g). The fecal pH was not different between celiac patients (7.19 ± 0.521) and controls (7.18 ± 0.522).

CONCLUSIONS:These results suggest that with lower levels of bifidobacteria, celiac patients have an imbalance in the intestinal microbiota, regardless of pH, even while on a gluten-free diet. This fact could favor the pathological process of the disorder.

A 36 year old woman presented with malabsorption and macroamylasemia. The macroamylase was characterized and shown to be a complex of pancreatic amylase and immunoglobulin A(IgA). The patient had the clinical and histologic features of adult celiac disease, and responded to a gluten-free diet. The macroamylase complex disappeared from the serum after gluten withdrawal, a hitherto unreported finding in the syndrome of malabsorption and hyperamylasemia.

Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient's body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOCtogether with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.

Maternal nutritional status during pregnancy is an important determinant of fetal growth. Although the effects of several nutrients and foods have been well examined, little is known about the relationship of overall maternal diet in pregnancy to fetal growth, particularly in non-Western populations. We prospectively examined the relationship of maternal dietary patterns in pregnancy to neonatal anthropometric measurements at birth and risk of small-for-gestational-age (SGA) birth among 803 Japanese women with live-born, singleton, term deliveries. Maternal diet in pregnancy was assessed using a validated, self-administered diet history questionnaire. Dietary patterns from thirty-three predefined food groups (g/4184 kJ) were extracted by cluster analysis. The following three dietary patterns were identified: the 'meat and eggs' (n 326), 'wheat products', with a relatively high intake of bread, confectioneries and soft drinks (n 303), and 'rice, fish and vegetables' (n 174) patterns. After adjustment for potential confounders, women in the 'wheat products' pattern had infants with the significantly lowest birth weight (P = 0·045) and head circumference (P = 0·036) among those in the three dietary patterns. Compared with women in the 'rice, fish and vegetables' pattern, women in the 'wheat products'pattern had higher odds of having a SGA infant for weight (multivariate OR 5·2, 95 % CI 1·1, 24·4), but this was not the case for birth length or head circumference. These results suggest that a diet high in bread, confectioneries, and soft drinks and low in fish and vegetables during pregnancymight be associated with a small birth weight and an increased risk of having a SGA infant.

Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCɛ translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCɛ-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis.

Antiseizure drugs (ASDs), also termed antiepileptic drugs, are the main form of symptomatic treatment for people with epilepsy, but not all patients become free of seizures. The ketogenic diet is one treatment option for drug-resistant patients. Both types of therapy exert their clinical effects through interactions with one or more of a diverse set of molecular targets in the brain. ASDs act by modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; by enhancement ofγ-aminobutyric acid (GABA)-mediated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA uptake transporter, or GABA transaminase; through interactions with elements of the synaptic release machinery, including synaptic vesicle 2A (SV2A) and α2δ; or by blockade of ionotropic glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures. Production in the brain of inhibitory mediators, suchas adenosine, or ion channel modulators, such as polyunsaturated fatty acids, may also play a role. Metabolic effects, including diversion from glycolysis, are a further postulated mechanism. For some ASDs and the ketogenic diet, effects on multiple targets may contribute to activity. Better understanding of the ketogenic diet will inform the development of improved drug therapies to treat refractory seizures.

This research evaluated five case studies of patients with psoriasis following a dietary regimen. There is no cure for psoriasis and the multiple treatments currently available only attempt to reduce the severity of symptoms. Treatments range from topical applications, systemic therapies, and phototherapy; while some are effective, many are associated with significant adverse effects. There is a need for effective, affordable therapies with fewer side effects that address the causes of the disorder. Evaluation consisted of a study group of five patients diagnosed with chronic plaque psoriasis (two men and three women, average age 52 years; range 40-68 years) attending a 10-day, live-in program during which a physician assessed psoriasis symptoms and bowel permeability. Subjects were then instructed on continuing the therapy protocol at home for six months. The dietary protocol, based on Edgar Cayce readings, included a diet of fresh fruits and vegetables, small amounts of protein from fish and fowl, fiber supplements, olive oil, and avoidance of red meat, processed foods, and refined carbohydrates. Saffron tea and slippery elm bark water were consumed daily. The five psoriasis cases, ranging from mild to severe at the study onset, improved on all measured outcomes over a six-month period when measured by the Psoriasis Area and Severity Index (PASI) (average pre- and post-test scores were 18.2 and 8.7, respectively), the Psoriasis Severity Scale (PSS) (average pre- and post-test scores were 14.6 and 5.4, respectively), and the lactulose/mannitol test of intestinal permeability (average pre- and post-test scores were 0.066 to 0.026, respectively). These results suggest a dietary regimen based on Edgar Cayce's readings may be an effective medical nutrition therapy for the complementary treatment of psoriasis; however, further research is warranted to confirm these results.

BACKGROUND:Comparative studies on dietary patterns and long-term mortality are sparse.

OBJECTIVE:The objective was to examine the relations between 10-y mortality and adherence to the World Health Organization dietary guidelines [Healthy Diet Indicator (HDI)], a Mediterranean-like diet, and a carbohydrate-restricted (CR) diet in elderly Swedish men.

DESIGN:Dietary habits were determined by 7-d dietary records in a population-based longitudinal study of 924 Swedish men (age: 71± 1 y). The HDI score (-1 to 8 points), the Mediterranean Diet Score (MDS; 0-8 points), and the CR score (2-20 points) were calculated for each participant. Nonadequate reporters of energy intake were identified (n = 413). Mortality was registered during a median follow-up of 10.2 y. Cox proportional hazards regression, with multivariable adjustments, was used to determine the effects of adherence to each dietary pattern.

RESULTS:Two hundred fifteen and 88 subjects died of all-cause and cardiovascular disease, respectively. In all individuals, risk relations to mortality for each SD increment in the scores were observed for only MDS, with an adjusted hazard ratio (HR) of 0.83 (95% CI: 0.70, 0.99). Among adequate dietary reporters (n = 511), adjusted HRs for each SD increment in scores were enhanced for MDS (ie, 0.71; 95% CI: 0.55, 0.92) for all-cause mortality and 0.63 (95% CI: 0.42, 0.96) for cardiovascular mortality. Corresponding HRs for CR diet score were 1.19 (95% CI: 0.97, 1.45) for all-cause mortality and 1.44 (95% CI: 1.03, 2.02) for cardiovascular mortality.

CONCLUSION:Adherence to a Mediterranean-like dietary pattern reduced mortality, whereas adherence to a CR dietary pattern appeared to increase mortality in elderly Swedish men, especially when only adequate dietary reporters were considered.

OBJECTIVES:To our knowledge, no study has addressed the relationship between adherence to a Mediterranean diet style and severity of heart failure. The aim of this retrospective study was to evaluate the relationship between adherence to the Mediterranean diet assessed using the calculation of Mediterranean diet score and congestive heart failure (CHF), its severity, and pathogenesis.

METHODS:We analyzed charts and collected data of all consecutive patients with a diagnosis of CHF at admission to our Internal Medicine Ward from 2008 to 2014.

RESULTS:We analyzed 209 patients with CHF and 200 controls. Patients with CHF showed a significantly lower mean MeDi score than controls. At receiver operating characteristic curve analysis, we found a good sensitivity and specificity of mean MeDi score to predict CHF. We also observed a significant positive correlation between MeDi score and ischemic pathogenesis of CHF, a positive relationship between New York Heart Association (NYHA) class and ischemic heart disease, and a significant negative relationship between NYHA class and MeDi score.

CONCLUSION:The beneficial effects of adherence to the Mediterranean diet suggest a possible answer to the question of the biochemical bases of our data, which should be seen as the direct consequence of the anti-inflammatory, antioxidant, and anti-remodeling effects linked to the diet.

OBJECTIVE:To examine in a 3-year brain imaging study the effects of higher vs lower adherence to a Mediterranean-style diet (MeDi) on Alzheimer disease (AD) biomarker changes (brainβ-amyloid load viaC-Pittsburgh compound B [PiB] PET and neurodegeneration viaF-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife.

METHODS:Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi-) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally.

RESULTS:MeDi groups were comparable for clinical and neuropsychological measures. At baseline, compared to the MeDi+ group, the MeDi- group showed reduced FDG-PET glucose metabolism (CMRglc) and higher PiB-PET deposition in AD-affected regions (<0.001). Longitudinally, the MeDi--group showed CMRglc declines and PiB increases in these regions, which were greater than those in the MeDi+ group (<0.001). No effects were observed on MRI. Higher MeDi adherence was estimated to provide 1.5 to 3.5 years of protection against AD.

CONCLUSION:Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD.

OBJECTIVE: To ascertain whether simple dietary advice to increase the consumption of Mediterranean foods, given in a clinical setting, leads to reduced mortality after a myocardial infarction. DESIGN: Data were used from the GISSI-Prevenzione clinical trial, analysed as a cohort study with adjustment for treatment allocation.

SETTING: A total of 172 centres in Italy. SUBJECTS: A total of 11323 men and women with myocardial infarction. All subjects received advice to increase their consumption of fish, fruit, raw and cooked vegetables and olive oil.

MEASUREMENTS: The intakes of the five foods were assessed at baseline, 6, 18 and 42 months. Associations of food intakes, a combined dietary score, and the risk of death over 6.5 y were estimated adjusting for several non-dietary variables, using pooled logistic regression.

RESULTS: Subjects generally improved their diet according to the advice given. All foods were associated with a significant reduction in risk of death. Compared with people in the worst dietary score quarter, the odds ratio for those in the best score quarter was 0.51 (95% CI 0.44-0.59). A good diet had a protective effect in sub-groups defined by age, sex, smoking, randomized treatment and concomitant drug therapy.

CONCLUSIONS: Myocardial infarction patients can respond positively to simple dietary advice, and this can be expected to lead to a substantial reduction in the risk of early death. Regardless of any drug treatment prescribed, clinicians should routinely advise patients with myocardial infarction to increase their frequency of consumption of Mediterranean foods.

Metalloproteinases (MMPs) are zinc-dependent endopeptidases responsible for the hydrolysis of various component of extracellular matrix such as gelatin and collagen. MMPs, namely MMP-2 and MMP-9 correlate with cardiovascular events in patients. We sought to determine whether supplementation with polyphenol-rich Cynara cardunculus (wild artichoke, traditional component of the Mediterranean diet) modulates MMP-9 expression and activity in cell cultures. A fully characterized C. cardunculus extract was able to inhibit, in a dose-dependent manner, the gelatinolytic activity of secreted MMP-9 and both secretion and human MMP-9 promoter-driven transcription. Analysis by HPLC of the Cynara extract identified polyphenols such as luteolin, apigenin, and caffeic acid, among others. However, testing a mix of the individual components suggested that the inhibitory effects of C. cardunculus are due to minor constituent fraction(s) as a whole. In promoting the health benefits of the Mediterranean diet, the role of wild plants as important meal components deserves further reappraisal.

OBJECTIVE:Few data are available on the Italian elderly population with regard to adherence to the Mediterranean diet (MD) and cognitive impairment. Our aim was to investigate adherence to the MD and its association with cognitive function in an Italian urban sample.

METHODS:A cross-sectional study of 279 participants aged≥ 65 years (80 men, 199 women) was carried out at a nutritional center. Adherence to the MD was evaluated using a 14-item questionnaire. Cognitive function was assessed with the Mini-Mental State Examination (MMSE).

RESULTS:The clinical and nutritional assessments performed revealed 30.1% to have a dietary pattern in accordance with the MD; 13.6% had suspected or mild cognitive impairment (MMSE score≤ 23). The MD pattern was associated with a lower risk of cognitive impairment (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.15-0.99; p = 0.045), as was the consumption of wine (OR = 0.37; 95% CI, 0.16-0.84; p = 0.018) and nuts (OR = 0.30; 95% CI, 0.13-0.69, p = 0.005). No association was found with other food groups.

CONCLUSION:A closer adherence to the MD was associated with a better cognitive status. Further cohort studies and randomized controlled trials are warranted.

BACKGROUND:Adherence to the Mediterranean diet (MD) is associated with a reduced risk of several cancers. However, studies conducted in Mediterranean regions are scanty.

METHODS:To investigate the relation between MD and colorectal cancer risk in Italy, we pooled data from three case-control studies, including a total of 3745 colorectal cancer cases and 6804 hospital controls. Adherence to the MD was assessed using an a priori Mediterranean Diet Score (MDS), based on nine components.

RESULTS:Compared with the lowest adherence to the MD (0-2 MDS), the odds ratio (OR) was 0.52 (95% confidence interval (CI) 0.43-0.62) for the highest adherence (7-9 MDS), with a significant inverse trend in risk (P<0.0001). The OR for a 1-point increment in the MDS was 0.89 (95% CI 0.86-0.91). The inverse association was consistent across studies, cancer anatomical subsites and strata of selected covariates.

CONCLUSIONS:This Italian study confirms a favourable role of MD on colorectal cancer risk.British Journal of Cancer advance online publication, 18 August 2016; doi:10.1038/bjc.2016.245 www.bjcancer.com.