Published Science

Whilst fruits and vegetables are an essential part of our dietary intake, the role of fiber in the prevention of colorectal diseases remains controversial. The main feature of a high-fiber diet is its poor digestibility. Soluble fiber like pectins, guar and ispaghula produce viscous solutions in the gastrointestinal tract delaying small bowel absorption and transit. Insoluble fiber, on the other hand, pass largely unaltered through the gut. The more fiber is ingested, the more stools will have to be passed. Fermentation in the intestines results in build up of large amounts of gases in the colon. This article reviews the physiology of ingestion of fiber and defecation. It also looks into the impact of dietary fiber on various colorectal diseases. A strong case cannot be made for a protective effect of dietary fiber against colorectal polyp or cancer. Neither has fiber been found to be useful in chronic constipation and irritable bowel syndrome. It is also not useful in the treatment of perianal conditions. The fiber deficit - diverticulosis theory should also be challenged. The authors urge clinicians to keep an open mind about fiber. One must be aware of the truths and myths about fiber before recommending it.

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F2α (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF2α were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P

Bariatric surgery may be complicated by enlargement of the liver, especially of the left lobe, caused by nonalcoholic fatty liver disease often present with morbid obesity.

Carbohydrate restriction as a strategy for control of obesity is based on two effects: a behavioral effect, spontaneous reduction in caloric intake and a metabolic effect, an apparent reduction in energy efficiency, greater weight loss per calorie consumed. Variable energy efficiency is established in many contexts (hormonal imbalance, weight regain and knock-out experiments in animal models), but in the area of the effect of macronutrient composition on weight loss, controversy remains. Resistance to the idea comes from a perception that variable weight loss on isocaloric diets would somehow violate the laws of thermodynamics, that is, only caloric intake is important ("a calorie is a calorie"). Previous explanations of how the phenomenon occurs, based on equilibrium thermodynamics, emphasized the inefficiencies introduced by substrate cycling and requirements for increased gluconeogenesis. Living systems, however, are maintained far from equilibrium, and metabolism is controlled by the regulation of the rates of enzymatic reactions. The principles of nonequilibrium thermodynamics which emphasize kinetic fluxes as well as thermodynamic forces should therefore also be considered. Here we review the principles of nonequilibrium thermodynamics and provide an approach to the problem of maintenance and change in body mass by recasting the problem of TAG accumulation and breakdown in the adipocyte in the language of nonequilibrium thermodynamics. We describe adipocyte physiology in terms of cycling between an efficient storage mode and a dissipative mode. Experimentally, this is measured in the rate of fatty acid flux and fatty acid oxidation. Hormonal levels controlled by changes in dietary carbohydrate regulate the relative contributions of the efficient and dissipative parts of the cycle. While no experiment exists that measures all relevant variables, the model is supported by evidence in the literature that 1) dietary carbohydrate, via its effect on hormone levels controls fatty acid flux and oxidation, 2) the rate of lipolysis is a primary target of insulin, postprandial, and 3) chronic carbohydrate-restricted diets reduce the levels of plasma TAG in response to a single meal. In summary, we propose that, in isocaloric diets of different macronutrient composition, there is variable flux of stored TAG controlled by the kinetic effects of insulin and other hormones. Because the fatty acid-TAG cycle never comes to equilibrium, net gain or loss is possible. The greater weight loss on carbohydrate restricted diets, popularly referred to as metabolic advantage can thus be understood in terms of the principles of nonequilibrium thermodynamics and is a consequence of the dynamic nature of bioenergetics where it is important to consider kinetic as well as thermodynamic variables.

PURPOSE: To investigate the general characteristics of glucose metabolism distribution and the functional deficit in the brain of children with developmental language delay (DLD), we compared functional neuroradiological studies such as positron emission tomography (PET) of a patient group of DLD children and a control group of attention- deficit hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: Seventeen DLD children and 10 ADHD children under 10 years of age were recruited and divided into separate groups consisting of children less than 5 years of age or between 5 and 10 years of age. The PET findings of 4 DLD children and 6 control children whose ages ranged from 5 to 10 years were compared by Statistical Parametric Mapping (SPM) analysis. RESULTS: All of the DLD children revealed grossly normal findings in brain MRIs, however, 87.5% of them showed grossly abnormal findings in their PET studies. Abnormal findings were most frequent in the thalamus. The patient group showed significantly decreased glucose metabolism in both frontal, temporal and right parietal areas (p < 0.005) and significantly increased metabolism in both occipital areas (p

The receptor for advanced glycation end products (RAGE) is an important cell surface receptor being pursued as a therapeutic target because it has been implicated in complications arising from diabetes and chronic inflammatory conditions. RAGE is a single membrane spanning receptor containing a very small approximately 40 residue cytosolic domain and a large extracellular region composed of 3 Ig-like domains. In this study, high level bacterial expression systems and purification protocols were generated for the extracellular region of RAGE (sRAGE) and the five permutations of single and tandem domain constructs to enable biophysical and structural characterization of its tertiary and quaternary structure. The structure and stability of each of these six protein constructs was assayed by biochemical methods including limited proteolysis, dynamic light scattering, CD, and NMR. A homology model of sRAGE was constructed to aid in the interpretation of the experimental data. Our results show that the V and C1 domains are not independent domains, but rather form an integrated structural unit. In contrast, C2 is attached to VC1 by a flexible linker and is fully independent. The interaction with a known RAGE ligand, Ca2+-S100B, was mapped to VC1, with the major contribution from the V domain but clearly defined secondary effects from the C1 domain. The implications of these results are discussed with respect to models for RAGE signaling.

The interaction of reducing carbohydrates with proteins leads to a cascade of reactions that are known as glycation or Maillard reaction. We studied the impact of incubation of human serum albumin (HSA) with glucose, at various concentrations and incubation times, on the extent of HSA glycation and structural changes using circular dichroism (CD), fluorescence, and microviscometer techniques. The number of moles of glucose bound per mole of HSA (r), the number of reacted lysine and arginine residues, and the Amadori product formation during glycation were determined using 3-(dansylamino) phenyl boronic acid, fluorescamine, 9, 10 phenanthrenequinone, and p-nitroblue tetrazoliumchloride, respectively. The formation of advanced glycation end products (AGE) was detected using the autofluorescence characteristic of samples. We identified three stages of Maillard reaction for HSA upon incubation with the physiological level of glucose (0–630 mg/dl): the early, intermediate and late stages, which occurred after 7–14, 21, and >28 days of incubation, respectively. Structural information, Stokes radius, and 1-anilinonaphthalene-8-sulfonate (ANS) binding data indicated the formation of a molten globule-like state of HSA after 21 days of incubation with 35 mM (630 mg/dl) glucose. Thus, the extent of the Maillard reaction was influenced by the concentration of glucose and incubation time, such that longer exposure of HSA to glucose may have a more deleterious effect on its structure and especially on its half-life and turnover in the circulation. Our results suggest that in acute diabetes mellitus patients, HSA, after 21 days of glycation, passes through a molten globule-like state and may contribute to the pathogenesis of diabetes, and perhaps other diseases.

Post-reproductive longevity is a robust feature of human life and not only a recent phenomenon caused by improvements in sanitation, public health, and medical advances. We argue for an adaptive life span of 68-78 years for modern "Homo sapiens" based on our analysis of mortality profiles obtained from small-scale hunter-gatherer and horticultural populations from around the world. We compare patterns of survivorship across the life span, rates of senescence, modal ages at adult death, and causes of death. We attempt to reconcile our results with those derived from paleodemographic studies that characterize prehistoric human lives as "nasty, brutish, and short," and with observations of recent acculturation among contemporary subsistence populations. We integrate information on age-specific dependency and resource production to help explain the adaptive utility of longevity in humans from an evolutionary perspective. Copyright 2007 The Population Council, Inc..

BACKGROUND: Advanced glycation end products (AGEs) play a critical role in the development of diabetic nephropathy. Reactive oxygen species (ROS) may play a critical role in AGEs induced growth factor expression. In this study, the effects of AGEs on transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF) and fibronectin (Fn) mRNA expression and oxidative stress in cultured NRK-49F cells were examined. METHODS: NRK-49F cells were incubated with medium containing different doses of AGEs (50, 100 or 200 microg/ml) for 24 hours, or with AGEs 100 microg/ml for different times (0, 12, 24 or 48 hours). Cells in the serum-free medium or medium containing 25 mmol/L glucose were controls. Cells were treated with 25 mmol/L glucose and 100 microg/ml AGEs for 24 hours to determine the effects between AGEs and glucose. We clarified the role of antioxidant by pretreating cells with N-acetylcysteine (10 mmol/L), ginkgo biloba extract (50 or 100 mg/L) for 24 hours and with 100 microg/ml AGEs for further 24 hours. Alamarblue dye assay was used to analyze cell growth; intracellular ROS generation was measured by flow cytometry; intracellular glutathione by fluorescence spectrophotometry; expressions of TGF-beta1, CTGF and Fn mRNA by semiquantitative RT-PCR. RESULTS: AGEs significantly increased the expressions of TGF-beta1, CTGF, Fn mRNA and intracellular ROS generation, and decreased the glutathion level in NRK-49F cells in dose- and time-dependent manners. High glucose and AGEs together significantly increased the expression of TGF-beta1, CTGF and Fn mRNA, compared with AGEs and high glucose separately. Preincubation with N-acetylcysteine or ginkgo biloba extract increased GSH level, suppressed AGEs-induced oxidative stress and TGF-beta1, CTGF and Fn mRNA overexpression. CONCLUSIONS: AGEs can significantly increase expression of TGF-beta1, CTGF, Fn mRNA in NRK-49F cells through enhancement of oxidative stress. The accumulation of AGEs may play a pivotal role in the pathogenesis of tubulointerstitial fibrosis in diabetic nephropathy. Suppression of AGEs induced TGF-beta1, CTGF and Fn mRNA overexpression in renal fibroblasts through inhibition of oxidative stress may be a mechanism underlying effect of ginkgo biloba extract in diabetic nephropathy. In addition, antioxidant therapy may help prevent AGEs accumulation and its induced damage.

Background Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. Methods In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. Results Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P = 0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. Conclusions The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558.)

IL-10 is an important immunosuppressive cytokine that can down-regulate expression of other cytokines and has been shown to down-regulate itself. We show, in this study, that treatment of human monocyte-derived macrophages with IL-10 induces IL-10 mRNA in a dose- and time-dependent manner with an optimum induction at 100 ng/ml and at 6 h, whereas IL-10-induced IL-10 protein can be detected at 18 h. In the same cells, IL-10 can partially suppress IL-10 mRNA induced by LPS, but only down to the level of IL-10-induced IL-10. An adenoviral luciferase reporter construct driven by the −195 IL-10 promoter, which contains a Stat motif, was readily induced by both IL-10 and LPS. Mutation of this Stat motif ablated IL-10 activation of this promoter, but not the LPS activation. Finally, we show that overexpression of a dominant-negative Stat3 protein will prevent IL-10 induction, but not LPS induction, of IL-10 mRNA. These data show that IL-10 induces IL-10 in monocyte-derived macrophages in an autocrine manner via activation of the transcription factor Stat3.

Roger Horowitz, Putting Meat on the American Table: Taste, Technology, Transformation (Baltimore, MD: The Johns Hopkins University Press, 2006, $19.00). Pp. 192. ISBN 0 8018 8240 0. - - Volume 41 Issue 1 - NATHAN ABRAMS

Abstract. Latinos have become the largest ethnic minority group in the U.S. and will become 25% of the population by 2050. The purpose of this critical review

Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean ± SD BMI 54.7 ± 12.6 kg/m2) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was ∼50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was ∼20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-α, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.

ContextPopular diets, particularly those low in carbohydrates, have challenged current recommendations advising a low-fat, high-carbohydrate diet for weight loss. Potential benefits and risks have not been tested adequately.ObjectiveTo compare 4 weight-loss diets representing a spectrum of low to high carbohydrate intake for effects on weight loss and related metabolic variables.Design, Setting, and ParticipantsTwelve-month randomized trial conducted in the United States from February 2003 to October 2005 among 311 free-living, overweight/obese (body mass index, 27-40) nondiabetic, premenopausal women.InterventionParticipants were randomly assigned to follow the Atkins (n = 77), Zone (n = 79), LEARN (n = 79), or Ornish (n = 76) diets and received weekly instruction for 2 months, then an additional 10-month follow-up.Main Outcome MeasuresWeight loss at 12 months was the primary outcome. Secondary outcomes included lipid profile (low-density lipoprotein, high-density lipoprotein, and non–high-density lipoprotein cholesterol, and triglyceride levels), percentage of body fat, waist-hip ratio, fasting insulin and glucose levels, and blood pressure. Outcomes were assessed at months 0, 2, 6, and 12. The Tukey studentized range test was used to adjust for multiple testing.ResultsWeight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12-month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, −4.7 kg (95% confidence interval [CI], −6.3 to −3.1 kg), Zone, −1.6 kg (95% CI, −2.8 to −0.4 kg), LEARN, −2.6 kg (−3.8 to −1.3 kg), and Ornish, −2.2 kg (−3.6 to −0.8 kg). Weight loss was not statistically different among the Zone, LEARN, and Ornish groups. At 12 months, secondary outcomes for the Atkins group were comparable with or more favorable than the other diet groups.ConclusionsIn this study, premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight and experienced more favorable overall metabolic effects at 12 months than women assigned to follow the Zone, Ornish, or LEARN diets. While questions remain about long-term effects and mechanisms, a low-carbohydrate, high-protein, high-fat diet may be considered a feasible alternative recommendation for weight loss.Trial Registrationclinicaltrials.gov Identifier: NCT00079573

Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones β-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of β-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 μM glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+/NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress.

CONTEXT: Antioxidant supplements are used for prevention of several diseases. OBJECTIVE: To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. DATA SOURCES AND TRIAL SELECTION: We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials. DATA EXTRACTION: We included 68 randomized trials with 232 606 participants (385 publications). DATA SYNTHESIS: When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.04[corrected]-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality. CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.

BACKGROUND: Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG). METHODS: Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet. RESULTS: KetoCal administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal diet reduced plasma glucose levels while elevating plasma ketone body (beta-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, beta-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy. CONCLUSION: The results indicate that KetoCal has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.

The Archaeology of Disease shows how the latest scientific and archaeological techniques can be used to identify the common illnesses and injuries from which humans suffered in antiquity. Charlotte Roberts and Keith Manchester offer a vivid picture of ancient disease and trauma by combining the results of scientific research with information gathered from documents, other areas of archaeology, art, and ethnography. The book contains information on congenital, infectious, dental, joint, endocrine, and metabolic diseases. The authors provide a clinical context for specific ailments and accidents and consider the relevance of ancient demography, basic bone biology, funerary practices, and prehistoric medicine. This fully revised third edition has been updated to and encompasses rapidly developing research methods of in this fascinating field.

A recent prospective study showed that higher consumption of red meat and total protein was associated with increased risk for inflammatory polyarthritis. We therefore prospectively examined the relationship between diet (in particular, protein, iron, and corresponding food sources) and incident rheumatoid arthritis (RA) among 82,063 women in the Nurses' Health Study. From 1980 to 2002, 546 incident cases of RA were confirmed by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria for RA. Diet was assessed at baseline in 1980 and five additional times during follow up. We conducted Cox proportional hazards analyses to calculate the rate ratio of RA associated with intakes of protein (total, animal, and vegetable) and iron (total, dietary, from supplements, and heme iron) and their primary food sources, adjusting for age, smoking, body mass index, and reproductive factors. The multivariate models revealed no association between RA and any measure of protein or iron intake. In comparisons of highest with lowest quintiles of intake, the rate ratio for total protein was 1.17 (95% confidence interval 0.89–1.54; P for trend = 0.11) and for total iron it was 1.04 (95% confidence interval 0.77–1.41; P for trend = 0.82). Red meat, poultry, and fish were also not associated with RA risk. We were unable to confirm that there is an association between protein or meat and risk for RA in this large female cohort. Iron was also not associated with RA in this cohort.

How aware are people of food-related decisions they make and how the environment influences these decisions? Study 1 shows that 139 people underestimated the number of food-related decisions they made—by an average of more than 221 decisions. Study 2 examined 192 people who overserved and overate 31% more food as a result of having been given an exaggerated environmental cue (such as a large bowl). Of those studied, 21% denied having eaten more, 75% attributed it to other reasons (such as hunger), and only 4% attributed it to the cue. These studies underscore two key points: First, we are aware of only a fraction of the food decisions we make. Second, we are either unaware of how our environment influences these decisions or we are unwilling to acknowledge it.

In the ongoing discussion about brain evolution in vertebrates, the main interest has shifted from theories focusing on energy balance to theories proposing social or ecological benefits of enhanced intellect. With the availability of a wealth of new data on basal metabolic rate (BMR) and brain size and with the aid of reliable techniques of comparative analysis, we are able to show that in fact energetics is an issue in the maintenance of a relatively large brain, and that brain size is positively correlated with the BMR in mammals, controlling for body size effects. We conclude that attempts to explain brain size variation in different taxa must consider the ability to sustain the energy costs alongside cognitive benefits.

The calorie was not a unit of heat in the original metric system. Some histories state that a defined Calorie (modern kcal) originated with Favre and Silbermann in 1852 or Mayer in 1848. However, Nicholas Clément introduced Calories in lectures on heat engines that were given in Paris between 1819 and 1824. The Calorie was already defined in Bescherelle's 1845 Dictionnaire National. In 1863, the word entered the English language through translation of Ganot's popular French physics text, which defined a Calorie as the heat needed to raise the temperature of 1 kg of water from 0 to 1°C. Berthelot distinguished between g- and kg-calories by 1879, and Raymond used the kcal in a discussion of human energy needs in an 1894 medical physiology text. The capitalized Calorie as used to indicate 1 kcal on U.S. food labels derives from Atwater's 1887 article on food energy in Century magazine and Farmers' Bulletin 23 in 1894. Formal recognition began in 1896 when the g-calorie was defined as a secondary unit of energy in the cm-g-s measurement system. The thermal calorie was not fully defined until the 20th century, by which time the nutritional Calorie was embedded in U.S. popular culture and nutritional policy.

This paper examines Neanderthal survival skills in Britain. Its starting point is that there are major tensions between the three main sources of relevant information – archaeological, palaeoanthropological and palaeoenvironmental data and their subsequent interpretation – that make our understanding of Neanderthal survival much more precarious than is generally supposed. The paper is speculative, and proffers questions not answers. It challenges us to look past the often mute material record, and to equip Neanderthals with a number of logically prerequisite but generally archaeologically invisible survival tools and practices, beyond the well-trodden paths of mobility, hunting and planning.

The Active Low-Carber Forums (ALCF) is an on-line support group started in 2000 which currently has more than 86,000 members. Data collected from posts to the forum and from an on-line survey were used to determine the behavior and attitudes of people on low carbohydrate diets. Members were asked to complete a voluntary 27-item questionnaire over the internet. Our major findings are as follows: survey respondents, like the membership at large, were mostly women and mostly significantly overweight, a significant number intending to and, in many cases, succeeding at losing more than 100 lbs. The great majority of members of ALCF identify themselves as following the Atkins diet or some variation of it. Although individual posts on the forum and in the narrative part of our survey are critical of professional help, we found that more than half of respondents saw a physician before or during dieting and, of those who did, about half received support from the physician. Another 28 % found the physician initially neutral but supportive after positive results were produced. Using the same criteria as the National Weight Registry (without follow-up) – 30 lbs or more lost and maintained for more than one year – it was found that more than 1400 people had successfully used low carb methods. In terms of food consumed, the perception of more than half of respondents were that they ate less than before the diet and whereas high protein, high fat sources replaced carbohydrate to some extent, the major change indicated by survey-takers is a large increase in green vegetables and a large decrease in fruit intake. Government or health agencies were not sources of information for dieters in this group and a collection of narrative comments indicates a high level of satisfaction, indeed enthusiasm for low carbohydrate dieting., The results provide both a tabulation of the perceived behavior of a significant number of dieters using low carbohydrate strategies as well as a collection of narratives that provide a human perspective on what it is like to be on such a diet. An important conclusion for the family physician is that it becomes possible to identify a diet that is used by many people where the primary principle is replacement of starch and sugar-containing foods with non-starchy vegetables, with little addition of fat or protein. Used by many people who identify themselves as being on the Atkins diet, such a strategy provides the advantages of carbohydrate-restricted diets but is less iconoclastic than the popular perception and therefore more acceptable to traditional nutritionists. It is reasonable for family practitioners to turn this observation into a recommendation for patients for weight control and other health problems.

Objective—To evaluate scopolamine as a potential antidepressant agent. Design—Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Setting—The National Institute of Mental Health. Patients—Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial. Interventions—Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 μg/kg). Individuals were randomized to a placebo/ scopolamine or scopolamine/ placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart. Main Outcome Measures—Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine. Results—The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/ placebo group also showed reductions in depression and anxiety rating scale scores (P

The purpose of this study was to compare the effects of black and green tea consumption on human metabolism. Seventeen healthy male volunteers consumed black tea, green tea, or caffeine in a randomized crossover study. Twenty-four-hour urine and blood plasma samples were analyzed by NMR-based metabonomics, that is, high-resolution 1H NMR metabolic profiling combined with multivariate statistics. Green and black tea consumption resulted in similar increases in urinary excretion of hippuric acid and 1,3-dihydroxyphenyl-2-O-sulfate, both of which are end products of tea flavonoid degradation by colonic bacteria. Several unidentified aromatic metabolites were detected in urine specifically after green tea intake. Interestingly, green and black tea intake also had a different impact on endogenous metabolites in urine and plasma. Green tea intake caused a stronger increase in urinary excretion of several citric acid cycle intermediates, which suggests an effect of green tea flavanols on human oxidative energy metabolism and/or biosynthetic pathways.

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.

BACKGROUND: Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD. THE HYPOTHESIS: We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing). TESTING THE HYPOTHESIS: Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca2+), as well as astrocyte function (alpha1, alpha2 and beta-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin). IMPLICATIONS OF THE HYPOTHESIS: The hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype - namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well.

Reducing the incidence of coronary heart disease with diet is possible. The main dietary strategies include adequate omega-3 fatty acids intake, reduction of saturated and trans-fats, and consumption of a diet high in fruits, vegetables, nuts, and whole grains and low in refined grains. Each of these strategies may be associated with lower generation of inflammation. This review examines the epidemiologic and clinical evidence concerning diet and inflammation. Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The whole diet approach seems particularly promising to reduce the inflammation associated with the metabolic syndrome. The choice of healthy sources of carbohydrate, fat, and protein, associated with regular physical activity and avoidance of smoking, is critical to fighting the war against chronic disease. Western dietary patterns warm up inflammation, while prudent dietary patterns cool it down.

While traditional nutrition research has dealt with providing nutrients to nourish populations, it nowadays focuses on improving health of individuals through diet. Modern nutritional research is aiming at health promotion and disease prevention and on performance improvement. As a consequence of these ambitious objectives, the disciplines "nutrigenetics" and "nutrigenomics" have evolved. Nutrigenetics asks the question how individual genetic disposition, manifesting as single nucleotide polymorphisms, copy-number polymorphisms and epigenetic phenomena, affects susceptibility to diet. Nutrigenomics addresses the inverse relationship, that is how diet influences gene transcription, protein expression and metabolism. A major methodological challenge and first pre-requisite of nutrigenomics is integrating genomics (gene analysis), transcriptomics (gene expression analysis), proteomics (protein expression analysis) and metabonomics (metabolite profiling) to define a "healthy" phenotype. The long-term deliverable of nutrigenomics is personalised nutrition for maintenance of individual health and prevention of disease. Transcriptomics serves to put proteomic and metabolomic markers into a larger biological perspective and is suitable for a first "round of discovery" in regulatory networks. Metabonomics is a diagnostic tool for metabolic classification of individuals. The great asset of this platform is the quantitative, non-invasive analysis of easily accessible human body fluids like urine, blood and saliva. This feature also holds true to some extent for proteomics, with the constraint that proteomics is more complex in terms of absolute number, chemical properties and dynamic range of compounds present. Apart from addressing the most complex "-ome", proteomics represents the only platform that delivers not only markers for disposition and efficacy but also targets of intervention. The Omics disciplines applied in the context of nutrition and health have the potential to deliver biomarkers for health and comfort, reveal early indicators for disease disposition, assist in differentiating dietary responders from non-responders, and, last but not least, discover bioactive, beneficial food components. This paper reviews the state-of-the-art of the three Omics platforms, discusses their implication in nutrigenomics and elaborates on applications in nutrition and health such as digestive health, allergy, diabetes and obesity, nutritional intervention and nutrient bioavailability. Proteomic developments, applications and potential in the field of nutrition have been specifically addressed in another review issued by our group.

Obese patients with gastroesophageal reflux disease (GERD) may experience resolution of symptoms utilizing a very low-carbohydrate diet. The mechanism of this improvement is unknown. This studied aimed to prospectively assess changes in distal esophageal acid exposure and GERD symptoms among obese adults initiating a very low-carbohydrate diet. We studied obese individuals with GERD initiating a diet containing less than 20 g/day of carbohydrates. Symptom severity was assessed using the GERD Symptom Assessment Scale—Distress Subscale (GSAS-ds). Participants underwent 24-hr esophageal pH probe testing and initiated the diet upon its completion. Within 6 days, a second pH probe test was performed. Outcomes included changes in the Johnson-DeMeester score, percentage total time with a pH<4 in the distal esophagus, and GSAS-ds scores. Eight participants were enrolled. Mean Johnson-DeMeester score decreased from 34.7 to 14.0 (P=0.023). Percentage time with pH

Objective: To examine the influence of initial interest, pre-clerkship experiences, clerkship experiences, and enrichment activities on choosing a career in psychiatry. Method: Residents in psychiatry at the authors’ medical school completed a survey that examined each of these factors in relation to career choice. Results: Thirty participants ranked initial interest as the most influential factor. Thirteen residents with low initial interest ranked clerkship experiences and negative experiences in other specialties as more influential than the 17 residents with high initial interest. Twelve residents who had attended the authors’ medical school rated enrichment activities, particularly psychiatry electives, as more influential than the remaining 18 from other medical schools did. Conclusions: Although limited by small sample size and potential recall biases, this study suggests that positive clerkship experiences and participation in psychiatry electives may be modifiable programmatic factors that could enhance recruitment to psychiatry.

ABSTRACT. Background: A very-low-energy diet (VLED) can result in substantial, rapid weight loss and is increasingly prescribed before obesity surgery to minim

Negative environmental consequences of fossil fuels and concerns about petroleum supplies have spurred the search for renewable transportation biofuels. To be a viable alternative, a biofuel should provide a net energy gain, have environmental benefits, be economically competitive, and be producible in large quantities without reducing food supplies. We use these criteria to evaluate, through life-cycle accounting, ethanol from corn grain and biodiesel from soybeans. Ethanol yields 25% more energy than the energy invested in its production, whereas biodiesel yields 93% more. Compared with ethanol, biodiesel releases just 1.0%, 8.3%, and 13% of the agricultural nitrogen, phosphorus, and pesticide pollutants, respectively, per net energy gain. Relative to the fossil fuels they displace, greenhouse gas emissions are reduced 12% by the production and combustion of ethanol and 41% by biodiesel. Biodiesel also releases less air pollutants per net energy gain than ethanol. These advantages of biodiesel over ethanol come from lower agricultural inputs and more efficient conversion of feedstocks to fuel. Neither biofuel can replace much petroleum without impacting food supplies. Even dedicating all U.S. corn and soybean production to biofuels would meet only 12% of gasoline demand and 6% of diesel demand. Until recent increases in petroleum prices, high production costs made biofuels unprofitable without subsidies. Biodiesel provides sufficient environmental advantages to merit subsidy. Transportation biofuels such as synfuel hydrocarbons or cellulosic ethanol, if produced from low-input biomass grown on agriculturally marginal land or from waste biomass, could provide much greater supplies and environmental benefits than food-based biofuels.

Nandrolone and other 19-norsteroid potent anabolic steroids have been prohibited in sports for 30 years. The detection of the main urinary metabolite--19-norandrosterone--in amounts greater than 2 ng/ml constitutes an adverse analytical finding. The presence in nutritional sport supplements of steroids not listed on the label has undoubtedly resulted in positive tests, but inadvertent consumption of meat containing residues of hormonal treatment should not realistically cause apprehension. Although highly improbable, athletes should prudently avoid meals composed of pig offal in the hours preceding the test since the consumption of edible parts of a non-castrated pig, containing 19-nortestosterone, has been shown to results in the excretion of 19-norandrosterone in the following hours. Norsteroid metabolites are formed during pregnancy and excreted as minor metabolites of norethisterone, and minute amounts have been identified in some male and female samples when using more sensitive techniques of detection. Whereas exercise does not seem to be a significant factor in 19-norandrosterone excretion, some rare urine samples were found to be a suitable medium for in situ 19-demethylation of urinary metabolites.

Updating recommendations last made by the National Research Council in the mid-1980s, this report provides nutrient recommendations based on physical activity and stage in life, major factors that influence nutrient needs. It looks at how nutrients are metabolized in the bodies of dogs and cats, indications of nutrient deficiency, and diseases related to poor nutrition. The report provides a valuable resource for industry professionals formulating diets, scientists setting research agendas, government officials developing regulations for pet food labeling, and as a university textbook for dog and cat nutrition. It can also guide pet owners feeding decisions for their pets with information on specific nutrient needs, characteristics of different types of pet foods, and factors to consider when feeding cats and dogs.

Association of SLE and alfalfa was first reported in a volunteer who developed lupus-like autoimmunity while ingesting alfalfa seed for a hypercholesterolemia study. This was corroborated with studies in monkeys fed with alfalfa sprout that developed SLE. Re-challenge with l-canavanine relapsed the disease. Arginine homologue l-canavanine, present in alfalfa, was suspected as a cause. l-canavanine can be charged by arginyl tRNA synthetase to replace l-arginine during protein synthesis. Aberrant canavanyl proteins have disrupted structure and functions. Induction or exacerbation of SLE by alfalfa tablets reported in a few cases remains controversial. Epidemiological studies on the relationship between alfalfa and SLE are sparse. In mice, NZB/W F1, NZB, and DBA/2 mice fed with l-canavanine show exacerbation/triggering of the SLE, however, BALB/c studies were negative. l-canavanine incorporation may be more efficient in the presence of inflammation or other conditions that can cause arginine deficiency. The l-canavanine induced apoptotic cells can be phagocytosed and a source of autoantigens processed by endosomal proteases. Endogenous canavanyl proteins are ubiquitinated and processed via proteasome. Incorporation of l-canavanine into proteasome or endosome can also cause disruption of antigen processing. Alfalfa/l-canavanine-induced lupus will be an interesting model of autoimmunity induced by the modification of self-proteins at the translational level.

Because of its effect on insulin, carbohydrate restriction is one of the obvious dietary choices for weight reduction and diabetes. Such interventions generally lead to higher levels of dietary fat than official recommendations and have long been criticized because of potential effects on cardiovascular risk although many literature reports have shown that they are actually protective even in the absence of weight loss. A recent report of Krauss et al. (AJCN, 2006) separates the effects of weight loss and carbohydrate restriction. They clearly confirm that carbohydrate restriction leads to an improvement in atherogenic lipid states in the absence of weight loss or in the presence of higher saturated fat. In distinction, low fat diets seem to require weight loss for effective improvement in atherogenic dyslipidemia.