Published Science

Many antipsychotic drugs produce QT interval prolongation on the electrocardiogram (ECG). Blockade of the human cardiac K + channel known as human ether-a-go-go-related gene (HERG) often underlies such clinical findings. In fact, HERG channel inhibition is now commonly used as a screen to predict the ability of a drug to prolong QT interval. However, the exact relationship between HERG channel blockade, target receptor binding affinity and clinical QT prolongation is not known. Using patch-clamp electrophysiology, we examined a series of seven antipsychotic drugs for their ability to block HERG, and determined their IC50 values. We then compared these results to their binding affinities (Ki values) for the dopamine D2 receptor, the 5-HT2A receptor and, where available, to clinical QT prolongation data. We found that sertindole, pimozide and thioridazine displayed little (

OBJECTIVE: The purpose of this study was to determine whether energy expenditure estimated from physical activity and energy intake were equivalent to total daily energy expenditure in an elderly rural population. METHODS: Twenty-seven elderly male (n = 14) and female (n = 13) subjects (mean age, 74 y) were recruited from a rural Pennsylvania population. Over a 2-wk period, total daily energy expenditure was measured by doubly labeled water (TEE) and estimated from 7-d physical activity recall factors multiplied by weight (PA(WT)), estimated basal metabolic rate (PA(BMR)) and resting energy expenditure from indirect calorimetry (PA(REE)), and energy intake from 3-d self-reported diet records (EI). Analysis of variance was used to determine significant within-subject differences in physical activity, energy intake, and energy expenditure. RESULTS: PA(REE) (men: 13.69 +/- 3.23 MJ, women: 9.51 +/- 2.40 MJ) and PA(BMR) (men: 13.69 +/- 2.99 MJ, women: 10.15 +/- 2.21 MJ) were not significantly different from TEE (men: 12.43 +/- 1.63 MJ, women: 9.44 +/- 0.90 MJ). EI (men: 8.66 +/- 2.34 MJ, women: 7.12 +/- 0.93 MJ) was significantly less than TEE, and PA(WT) (men: 17.03 +/- 4.07 MJ, women: 12.86 +/- 3.41 MJ) was significantly greater than TEE. CONCLUSIONS: Whereas 7-d physical activity recall determined with an age- and gender-specific estimate of resting metabolic rate or measured using indirect calorimetry accurately estimated TEE for this group of rural elderly, self-reported diet records consistently underestimated and physical activity recall determined with weight alone consistently overestimated energy expenditure measured by doubly labeled water.

BACKGROUND: Although hypercholesterolemia is a well-defined risk factor for morbidity and mortality in coronary artery disease, the relationship between cholesterol and heart failure (HF) has rarely been investigated. METHODS: Cholesterol and lipoproteins were measured in 1,134 patients with advanced HF who presented to a single center for HF management and transplant evaluation. Patients were stratified into five groups based on quintiles of total cholesterol (TC) level, and differences in patient characteristics and survival were evaluated. RESULTS: Patients with low TC had significantly lower low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), sodium, albumin, left ventricular ejection fraction, and cardiac output. The TC quintiles were similar in terms of HF etiology, hypertension, diabetes, and lipid-lowering therapy at time of referral. TC, LDL, HDL, and TG each predicted survival (P

Consumption of n-6 polyunsaturated fatty acids greatly exceeds that of n-3 polyunsaturated fatty acids. The n-6 polyunsaturated fatty acid arachidonic gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of cytokines and the various balances within the immune system. Fish oil and oily fish are good sources of long chain n-3 polyunsaturated fatty acids. Consumption of these fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids act as arachidonic acid antagonists. Components of both natural and acquired immunity, including the production of key inflammatory cytokines, can be affected by n-3 polyunsaturated fatty acids. Although some of the effects of n-3 fatty acids may be brought about by modulation of the amount and types of eicosanoids made, it is possible that these fatty acids might elicit some of their effects by eicosanoid-independent mechanisms. Such n-3 fatty acid-induced effects may be of use as a therapy for acute and chronic inflammation, and for disorders which involve an inappropriately activated immune response.

Attention-deficit/hyperactivity disorder, a syndrome involving inattention, impulsivity, and hyperactivity, was originally thought to occur only in children. It is now a recognized condition throughout life in some individuals. For a valid diagnosis, the onset of symptoms should occur before age 7. Dysfunction of catecholamine neurotransmission is implied by the clinical improvement induced by stimulants. Positron emission tomography studies reveal reduced glucose metabolism in the basal ganglia and sometimes in the frontal cortex. Excessive cortical slowing is documented on the electroencephalogram. Twin studies show a familial, genetic influence. Data from multiple sources are necessary for a diagnosis, and rating scales are particularly useful for the adult syndrome. Older individuals typically manifest disorganization and impulsivity more than hyperactivity. Stimulant drugs are the principal forms of treatment for all ages, but bupropion is favored for patients with substance abuse history.

The few studies that have examined body composition after a carbohydrate-restricted diet have reported enhanced fat loss and preservation of lean body mass in obese individuals. The role of hormones in mediating this response is unclear. We examined the effects of a 6-week carbohydrate-restricted diet on total and regional body composition and the relationships with fasting hormone concentrations. Twelve healthy normal-weight men switched from their habitual diet (48% carbohydrate) to a carbohydrate-restricted diet (8% carbohydrate) for 6 weeks and 8 men served as controls, consuming their normal diet. Subjects were encouraged to consume adequate dietary energy to maintain body mass during the intervention. Total and regional body composition and fasting blood samples were assessed at weeks 0, 3, and 6 of the experimental period. Fat mass was significantly (P

To determine the effect of a 6-month very low carbohydrate diet program on body weight and other metabolic parameters.Fifty-one overweight or obese healthy volunteers who wanted to lose weight were placed on a very low carbohydrate diet (<25 g/d), with no limit on caloric intake. They also received nutritional supplementation and recommendations about exercise, and attended group meetings at a research clinic. The outcomes were body weight, body mass index, percentage of body fat (estimated by skinfold thickness), serum chemistry and lipid values, 24-hour urine measurements, and subjective adverse effects.Forty-one (80%) of the 51 subjects attended visits through 6 months. In these subjects, the mean (+/- SD) body weight decreased 10.3% +/- 5.9% (P <0.001) from baseline to 6 months (body weight reduction of 9.0 +/- 5.3 kg and body mass index reduction of 3.2 +/- 1.9 kg/m(2)). The mean percentage of body weight that was fat decreased 2.9% +/- 3.2% from baseline to 6 months (P <0.001). The mean serum bicarbonate level decreased 2 +/- 2.4 mmol/L (P <0.001) and blood urea nitrogen level increased 2 +/- 4 mg/dL (P <0.001). Serum total cholesterol level decreased 11 +/- 26 mg/dL (P = 0.006), low-density lipoprotein cholesterol level decreased 10 +/- 25 mg/dL (P = 0.01), triglyceride level decreased 56 +/- 45 mg/dL (P <0.001), high-density lipoprotein (HDL) cholesterol level increased 10 +/- 8 mg/dL (P <0.001), and the cholesterol/HDL cholesterol ratio decreased 0.9 +/- 0.6 units (P

We have examined the independent effect of vitamin B(12) deficiency on hematological indices in older Chinese vegetarian women using a cross-sectional study design: 119 women older than 55 years who had been vegetarian for more than 3 years were studied. Fasting blood samples were taken for complete blood count, serum iron, total serum iron binding capacity, serum iron saturation, serum vitamin B(12), serum folate, serum methylmalonic acid levels (MMA), and renal function test. Subjects with iron deficiency (iron saturation 150 mmol/L were excluded. The prevalence of definite vitamin B(12) deficiency (vitamin B(12) level or= 0.4 micromol/L) was 42%. Another 32.8% had possible vitamin B(12) deficiency (either criterion). The prevalence of iron deficiency was 10%. After exclusions, 96 subjects were further analyzed. Vitamin B(12) deficiency defined by serum vitamin B(12) and MMA was associated with a decrease in hemoglobin concentrations by up to 0.9 g/dL, but it was not associated with an increase in mean corpuscular volume (MCV). Serum MMA but not vitamin B(12) levels correlated inversely with hemoglobin and platelet counts and positively with MCV, after adjustment of confounding factors. However, the percentage of subjects with anemia did not increase significantly until serum MMA became >1.0 micromol/L. In conclusion, vitamin B(12) deficiency was associated with a significant decrease in hemoglobin concentration. However, anemia associated with vitamin B(12) deficiency was seldom macrocytic. We recommend that older vegetarians should be given vitamin B(12) supplements routinely.

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was initially identified as the major receptor for oxidized LDL (OxLDL) in endothelial cells. Its inducible expression in macrophages and smooth muscle cell was also observed. LOX-1 is a Type II membrane protein with a typical C-type lectin structure at the extracellular C-terminus. It can be cleaved by an unknown protease at the extracellular juxtamembrane region to release the soluble form of LOX-1. The extracellular domains of LOX-1 are post-translationally modified by N-linked glycosylation. Mutagenesis studies revealed that the lectin domain of LOX-1 is the functional domain that recognizes the LOX-1 ligand. The C-terminal end residues and several conserved positively charged residues spanning the lectin domain are essential for OxLDL binding. LOX-1 activation by OxLDL causes endothelial changes that are characterized by activation of nuclear factor-kappaB through an increased reactive oxygen species, subsequent induction of adhesion molecules, and endothelial apoptosis. In vitro, expression of LOX-1 is induced by many inflammatory cytokines, oxidative stress, hemodynamic stimuli, and OxLDL. In vivo, the expression is enhanced in pro-atherogenic settings including, hypertension, hyperlipidemia, and diabetes, and, indeed, is accumulated in the atherosclerotic and glomerulosclerotic lesions. LOX-1 binds multiple classes of ligands that are implicated in the pathogenesis of atherosclerosis. Besides OxLDL, LOX-1 can recognize apoptotic/aged cells, activated platelets, and bacteria, implying versatile physiological functions. Taken together, all these findings support the possible contribution of LOX-1 to the pathogenesis of vascular disorders, particularly atherosclerosis. Development of antagonists for LOX-1 might be a good therapeutic approach to vascular diseases.

BACKGROUND: The general increase in reactive oxygen species generated from glucose-derived advanced glycation endproducts (AGEs) is among the key mechanisms implicated in tissue injury due to diabetes. AGE-rich foods could exacerbate diabetic injury, at least by raising the endogenous AGE. MATERIALS AND METHODS: Herein, we tested whether, prior to ingestion, diet-derived AGEs contain species with cell activating (TNFalpha), chemical (cross-linking) or cell oxidative properties, similar to native AGEs. Glutathione (GSH) and GSH peroxidase (GPx) were assessed after exposure of human umbilical vein endothelial cell (HUVECs) to affinity-purified food-AGE extracts, each exposed to 250 degrees C, for 10 min, along with synthetic AGEs. RESULTS: Animal product-derived AGE, like synthetic methylglyoxal-bovine serum albumin (MG-BSA), AGE-BSA, and AGE-low density lipoprotein (AGE-LDL), induced a dose- and time-dependent depletion of GSH (()60-75%, p, 0.01) and an increase in GPx activity (()500-600%, p < 0.01), consistent with marked TNFalpha and cross-link formation (p < 0.05); this contrasted with the low bioreactivity of starch/vegetable AGE-extracts, which was similar to that of control BSA and CML- BSA and BSA (p:NS). Anti-AGE-R1,2,3 and -RAGE IgG each inhibited cell-associated (125) I-dAGE by approximately 30-55%; GSH/GPx were effectively blocked by N-acetyl-cysteine (NAC, 800 uM, p < 0.01) and aminoguanidine-HCl (AG, 100 uM, p

ADHD/ADD, once thought to occur only in children, is now recognized as continuing into adulthood in many people. In order to be labeled as such, signs and symptoms must start before age 7 and are primarily characterized by inattention, distractibility, and impulsiveness. Although the exact mechanism is unknown, a number of associated neurochemical and structural abnormalities have been observed. This disorder can negatively affect the educational, social, and occupational lives of those who suffer from its symptoms. It interferes with the ability to establish and maintain close relationships. Pharmacotherapy remains the primary mode of treatment. Stimulants such as dextroamphetamine and methylphenidate are the main drugs utilized; they are available in immediate and longer duration versions. Bupropion is another important medicinal option, and there are a variety of other miscellaneous medications to consider, including modafinil, venlafaxine, tricyclic antidepressants, and guanfacine. Psychotherapy is shown to help control impulsiveness, form more satisfactory relationships, rear children more effectively, and improve organizational and problem-solving skills.

Endothelial lipase (EL) is a new member of the triglyceride lipase gene family previously reported to have phospholipase activity. Using radiolabeled lipid substrates, we characterized the lipolytic activity of this enzyme in comparison to lipoprotein lipase (LPL) and hepatic lipase (HL) using conditioned medium from cells infected with recombinant adenoviruses encoding each of the enzymes. In the absence of serum, EL had clearly detectable triglyceride lipase activity. Both the triglyceride lipase and phospholipase activities of EL were inhibited in a dose-dependent fashion by the addition of serum. The ratio of triglyceride lipase to phospholipase activity of EL was 0.65, compared with ratios of 24.1 for HL and 139.9 for LPL, placing EL at the opposite end of the lipolytic spectrum from LPL. Neither lipase activity of EL was influenced by the addition of apolipoprotein C-II (apoC-II), indicating that EL, like HL, does not require apoC-II for activation. Like LPL but not HL, both lipase activities of EL were inhibited by 1 M NaCl. The relative ability of EL, versus HL and LPL, to hydrolyze lipids in isolated lipoprotein fractions was also examined using generation of FFAs as an end point. As expected, based on the relative triglyceride lipase activities of the three enzymes, the triglyceride-rich lipoproteins, chylomicrons, VLDL, and IDL, were efficiently hydrolyzed by LPL and HL. EL hydrolyzed HDL more efficiently than the other lipoprotein fractions, and LDL was a poor substrate for all of the enzymes.

We compared the effects of high-fat and high-carbohydrate dietary conditions on metabolism and short- and ultra-endurance cycling performance. Seven cyclists (VO(2)max 72 +/- 7 mL x kg(-1) x min(-1)) underwent a 2-week adaptation to each of the following 3 diets: 14-day high carbohydrate with 70 +/- 9 percent energy (%E) carbohydrate, 16 +/- 5%E fat, and 14 +/- 2%E protein; 14-day high fat with 66 +/- 10%E fat, 20 +/- 3%E protein, and 15 +/- 4%E carbohydrate; and 11.5-day high-fat diet followed by 2.5-day carbohydrate-loading. The conditions included a pre-exercise meal of the same composition as the preceding diet. Each diet condition was preceded by a 2-week standardizing normal diet. The exercise test lasted approximately 5 hours and comprised a 15-minute trial, an incremental test to measure the peak fat-oxidation rate, and a 100-km trial. Sports bars and a 5% carbohydrate solution were ingested during the tests. The diets had no statistically significant effect on 15-minute performance, although the high-fat condition tended to reduce distance covered by -2.4% (95% confidence interval: -5.4% to +0.6%, P =.11) relative to the fat with carbo-loading condition. In the 100-km time trial, the high-fat and the fat with carbohydrate-loading conditions attenuated the decline in power output observed in the high-carbohydrate condition (P =.03 to.07), although the corresponding improvement in performance time of 3% to 4% (-2% to 10%) was not statistically significant (P =.16 to.22). Power output during the final 5 km of the time trial in the fat with carbo-loading condition was 1.3-fold (1.0 to 1.6, P =.04) greater than in the high-carbohydrate condition. Overall, for every 10%E increase in dietary fat, 100-km mean power increased by 2% (-0.0% to 4%, P =.06). Relative to the high-carbohydrate condition, the high-fat conditions resulted in the following metabolic changes consistent with greater lipolysis and fuel availability: lower plasma insulin concentration before exercise (P <.0001), and during exercise a 10% to 20% higher plasma-glucose concentration (P <.01), higher plasma glycerol (P <.05), and a 2.5-fold to 2.9-fold increase in the peak fat-oxidation rate (P

A little-noticed clinical report indicates that a low-fat, whole-food vegan diet, coupled with daily walking exercise, leads to rapid remission of neuropathic pain in the majority of type 2 diabetics expressing this complication. Concurrent marked improvements in glycemic control presumably contribute to this benefit, but are unlikely to be solely responsible. Consideration should be given to the possibility that improved blood rheology - decreased blood viscosity and increased blood filterability - plays a prominent role in mediating this effect. There is considerable evidence that neural hypoxia, secondary to impaired endoneurial microcirculatory perfusion, is a crucial etiologic factor in diabetic neuropathy; the unfavorable impact of diabetes on hemorheology would be expected to exacerbate endoneurial ischemia. Conversely, measures which improve blood fluidity would likely have a beneficial impact on diabetic neuropathy. There is indeed evidence that vegan diets, as well as exercise training, tend to decrease the viscosity of both whole blood and plasma; reductions in hematocrit and in fibrinogen may contribute to this effect. The fact that vegan diets decrease the white cell count is suggestive of an improvement in blood filterability as well; filterability improves with exercise training owing to an increase in erythrocyte deformability. Whether these measures influence the activation of leukocytes in diabetics - an important determinant of blood filterability - remains to be determined. There are various reasons for suspecting that a vegan diet can reduce risk for other major complications of diabetes - retinopathy, nephropathy, and macrovascular disease - independent of its tendency to improve glycemic control in type 2 patients. The vegan diet/exercise strategy represents a safe, 'low-tech' approach to managing diabetes that deserves far greater attention from medical researchers and practitioners.

Hypertriglyceridemia is made up of a complex array of dyslipidemias. Difficulties in establishing the independent predictive value of elevated triglycerides in coronary artery disease arise because the triglyceride-rich lipoprotein particles that accumulate are diverse, with differential atherogenic potential, and because hypertriglyceridemia states are typically associated with low high-density lipoprotein cholesterol. When high-density lipoprotein cholesterol is considered in multivariate analysis of the role of hypertriglyceridemia in coronary artery disease, the importance of elevated triglycerides pales, emerging as a statistical second fiddle. However, recent data have affirmed the primary role of triglycerides in the genesis of atherosclerosis. This process involves the overabundance of triglyceride-rich lipoprotein particles, which, paradoxically, can be enriched with cholesterol through the action of cholesterol ester transfer protein. These particles appear to be especially atherogenic. Also, low-density lipoproteins become smaller and denser-small, dense phenotype or pattern B-in hypertriglyceridemia states. This profile is associated with a threefold increase in coronary artery disease risk and is not evident on routine lipid testing. Aggressive management of hypertriglyceridemia requires more detailed lipid analyses to identify patients at risk. In treating hypertriglyceridemia, a risk factor beyond low-density lipoprotein would allow a broader definition of patients at risk for coronary artery disease so that more people would benefit from lipid-lowering initiatives.

CONCLUSION: The present study did not provide evidence of any changes in kidney integrity and function in subjects exposed to very low levels of inorganic Hg resulting in urinary Hg lower than 35 micrograms/g creatinine. Nor did we obtain evidence of Hg-induced autoimmunity towards kidney components. The potential modifying role of GST polymorphisms could not be clarified in the absence of effects associated with exposure to the risk factor, i.e., to inorganic Hg. Preliminary data suggesting nephrotoxic effects of organic Hg from a diet rich in large fish resulting in increased levels of both blood and urinary Hg--which however did not exceed 20 micrograms/g creatinine--deserves further investigation.

We hypothesized that food texture modifications might alter anticipatory reflexes, feeding behavior, and the postabsorptive consequences of ingestion. Two sets of complete meals with different textures but the same macronutrient composition were prepared. The first set was either a soup containing chunks of food (mixture) or the same soup blended until smooth (purée). The second set was either a rusk (R), a sandwich loaf (SL), or a liquid rusk meal (LR). We measured hunger and fullness feelings after ingestion of each food in a calibrated lunch, the ingestion rate, the duration between lunch and a spontaneous dinner request, the energy value, and the macronutrient composition of the ad libitum dinner. We also studied plasma modifications and respiratory gas exchanges from lunch to dinner. Feelings of hunger and fullness were not affected by texture modifications. The purée soup was consumed faster than the mixture (P < 0.05), and insulin, triacylglycerol, and energy expenditure were greater with the purée (P < 0.05). LR was less palatable than the other rusk lunch versions (P < 0.001), and R was ingested more slowly (P < 0.05). The lowest increase in plasma glucose occurred with SL, and the highest energy expenditure was seen with LR (P

The process by which dietary carbohydrate is transformed into fat in the human body is termed de novo lipogenesis. New methods for the measurement of this process in humans are available and have been used to investigate the role of the carbohydrate form (fed as a liquid or solid), the level of processing of carbohydrate in foods, and the role of lipogenesis in the control of liver triacylglycerol secretion. The present paper will discuss how research results are affected by both the physical state of the carbohydrate in the diet and by the metabolic state of individual research subjects. Of interest is the relationship between the glycemic index of a food (or indicators of a food's glycemic index) and that food's ability to stimulate lipogenesis in humans. Given the increasing prevalence of obesity worldwide, future scientific emphasis will expand methods to quantitate the lipogenic potential of specific foods and dietary patterns and investigate how the metabolic state of insulin resistance affects lipogenesis and/or contributes to obesity.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic aromatic amine formed in meat products during cooking. The genotoxity of PhIP requires an initial cytochrome P450-mediated N-oxidation followed by N-O-esterification catalyzed generally by N-acetyltransferases and sulfotransferases. This study examined the urinary excretion of N(2)-(beta-1-glucos-iduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-the major human urinary N-oxidation metabolite of PhIP-and determined its relationship to individual activity levels of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). The subjects (33 males and 33 females) in the dietary study were phenotyped for their CYP1A2 and NAT2 activity prior to consumption of meat-based diet, and urine collections were obtained 0-12 and 12-24 h after ingestion of the meal. Acidic hydrolysis of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine and its d(3)-analog to form their respective deaminated products 2-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (2-OH-PhIP) was used in the assay. The products after derivatization were analyzed by capillary gas chromatography-negative ion chemical ionization mass spectrometry with selective ion monitoring. The amount of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine measured as the acid hydrolysis product 2-OH-PhIP in the 0-12 h urine was 20.2 +/- 8.0% (mean +/- SD) of the ingested dose; the median was 18.8% and the range varied from 5.4 to 39.6% within the group. In a subset (n = 18) of samples from individual urine collected from the 12-24 h period, an average value of 4.4 +/- 2.5% (+/- SD) of the dose was recovered. The excretion of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the 0-12 h urine was significantly related to the quantity of PhIP ingested for all subjects (r = 0.52, P

With reduced intake of meat and increased intake of phytate-containing legumes and whole grains, movement toward plant-based diets reduces dietary iron and zinc absorption. Although vegetarians have lower iron stores, adverse health effects of lower iron and zinc absorption have not been demonstrated with varied, plant-based diets consumed in developed countries. Improved assessment methods and monitoring are needed to detect and prevent possible iron and zinc deficiency with plant-based diets.

Epidemiological studies suggest that foods rich in flavonoids might reduce the risk of cardiovascular disease and cancer. The objective of the present study was to investigate the effect of green tea extract (GTE) used as a food antioxidant on markers of oxidative status after dietary depletion of flavonoids and catechins. The study was designed as a 2 x 3 weeks blinded human cross-over intervention study (eight smokers, eight non-smokers) with GTE corresponding to a daily intake of 18.6 mg catechins/d. The GTE was incorporated into meat patties and consumed with a strictly controlled diet otherwise low in flavonoids. GTE intervention increased plasma antioxidant capacity from 1.35 to 1.56 (P

Epidemiological studies suggest that foods rich in flavonoids might reduce the risk of cardiovascular disease and cancer. The objective of the present study was to investigate the effect of green tea extract (GTE) used as a food antioxidant on markers of oxidative status after dietary depletion of flavonoids and catechins. The study was designed as a 2×3 weeks blinded human cross-over intervention study (eight smokers, eight non-smokers) with GTE corresponding to a daily intake of 18·6 mg catechins/d. The GTE was incorporated into meat patties and consumed with a strictly controlled diet otherwise low in flavonoids. GTE intervention increased plasma antioxidant capacity from 1·35 to 1·56 (P

The acute phase reactions, associated with injury, inflammation, or sepsis, markedly affect the concentration and composition of plasma lipids and lipoproteins. Hepatic production of triglycerides and very low density lipoprotein formation are increased, but do not necessarily result in high plasma triglyceride levels. In contrast, all conditions lower plasma cholesterol by decreasing its content in both low-density and high-density lipoproteins. In addition, substantial changes in protein and lipid composition of lipoproteins are observed that may redefine the function of these particles, but also increase their atherogenic and inflammatory properties.

Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.

The purpose of this study was to determine time of onset of ketosis and efficacy when the classic ketogenic diet is initiated at full calories without a prior fast in children with epilepsy. A retrospective hospital and neurology clinic chart review was done of all 14 children commenced on the classic ketogenic diet at full calories without a prior fast between January 1, 1997, and May 31, 2001, to determine time to ketosis, time to good ketosis (urine ketones > or =80 mg/dL), and success of the ketogenic diet. Median age at diet initiation was 63 months (25th-75th percentile 47-149 months). There were 7 girls and 7 boys. Four had symptomatic generalized epilepsy, whereas the remainder had partial seizures +/- secondary generalization. Twelve of 14 children suffered seizures on a daily basis prior to the ketogenic diet. Six were commenced on the diet as outpatients, whereas 8 were admitted to hospital. No patients were fasted. All admitted patients were started on a 1:1 ketogenic ratio at full calories for the first 24 hours and advanced to a 3:1 or 4:1 ratio over 3 to 4 days, while outpatients were started on a 1:1 or 2:1 ratio and similarly advanced. Thirteen of 14 patients were successfully started on the diet, with 1 developing vomiting and food refusal during the initial hospitalization but after ketosis was established. One child was lost to follow-up after initial hospital discharge. Information regarding time to ketosis was determined for all inpatients. Mean time to onset of ketosis was 33 hours (range 17 to 48) and to good ketosis, 58 hours (range 40 to 84). Five of 12 children (42%) experienced success with the ketogenic diet, and all of these had their antiepileptic medications either withdrawn (n = 3) or decreased (n = 2). The ketogenic diet can be effectively initiated without a fast in children with epilepsy. Time to ketosis and diet efficacy are similar to protocols that use a fast.

OBJECTIVE: To assess the diversity of vegetarians' dietary practices and how they change over time, and to explore perceptions of meat and dairy products among vegetarians, former vegetarians, and nonvegetarians. DESIGN: Cross-sectional survey; qualitative interviews with a subsample. SUBJECTS/SETTING: Ninety self-defined current vegetarian, 35 former vegetarian and 68 nonvegetarian women in Vancouver, British Columbia. A subsample of 15 subjects completed qualitative interviews. STATISTICAL ANALYSIS PERFORMED: Group comparisons using 1-way analysis of variance with post-hoc testing for continuous variables, chi2 for categorical variables. RESULTS: Of 90 current vegetarians, 51 and 14 reported occasional use of fish or chicken respectively. Fifty-six vegetarians, including 4 of 6 vegans, reported that their diets had become more restrictive over time, and 48 planned additional changes, most frequently a reduction in dairy product use. Reasons cited by former vegetarians for resuming omnivorous diets included: not feeling healthy, concern about their nutritional status, a change in living situation, or missing the taste of meat. Perceptions of meat and dairy products differed significantly by dietary pattern: nonvegetarians and former vegetarians were more likely than current vegetarians to agree with statements inferring positive attributes (eg, nutrient content). In contrast, more current and former vegetarians than nonvegetarians agreed with statements inferring negative attributes (eg, presence of contaminants). APPLICATIONS/CONCLUSIONS: Dietitians who counsel women need to be aware of the heterogeneity of dietary practices and beliefs regarding use of animal products to provide advice appropriate to each individual. At a broader level, addressing women's food safety and animal welfare concerns will likely require collaboration among food industry and government, health, and consumer agencies.

Adult-type hypolactasia, also known as lactase non-persistence (lactose intolerance), is a common autosomal recessive condition resulting from the physiological decline in activity of the lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning. LPH hydrolyzes lactose into glucose and galactose. Sequence analyses of the coding and promoter regions of LCT, the gene encoding LPH, has revealed no DNA variations correlating with lactase non-persistence. An associated haplotype spanning LCT, as well as a distinct difference in the transcript levels of 'non-persistence' and 'persistence' alleles in heterozygotes, suggest that a cis-acting element contributes to the lactase non-persistence phenotype. Using linkage disequilibrium (LD) and haplotype analysis of nine extended Finnish families, we restricted the locus to a 47-kb interval on 2q21. Sequence analysis of the complete region and subsequent association analyses revealed that a DNA variant, C/T-13910, roughly 14 kb upstream from the LCT locus, completely associates with biochemically verified lactase non-persistence in Finnish families and a sample set of 236 individuals from four different populations. A second variant, G/A-22018, 8 kb telomeric to C/T-13910, is also associated with the trait in 229 of 236 cases. Prevalence of the C/T-13910 variant in 1,047 DNA samples is consistent with the reported prevalence of adult-type hypolactasia in four different populations. That the variant (C/T-13910) occurs in distantly related populations indicates that it is very old.

OBJECTIVE: To compare the mortality of British vegetarians and non-vegetarians. DESIGN: Analysis of original data from two prospective studies each including a large proportion of vegetarians--the Oxford Vegetarian Study and the Health Food Shoppers Study. Standardised mortality ratios (SMRs) compared with the population of England and Wales were calculated from deaths before age 90 for vegetarians and non-vegetarians in each study. Death rate ratios (DRRs) for vegetarians compared with non-vegetarians within each study were calculated for each of 14 major causes of death. SETTING: UK. SUBJECTS: Twenty-one thousand men and women aged 16-89 years at recruitment, including more than 8,000 vegetarians. RESULTS: SMRs for all causes of death were significantly below the reference level of 100 in both studies: 52 (95% confidence interval (CI) 49-56) based on 1,131 deaths in the Oxford Vegetarian Study and 59 (57-61) based on 2,346 deaths in the Health Food Shoppers Study. For all causes of death, the DRR for vegetarians compared with non-vegetarians was close to one in both studies: 1.01 (95% CI 0.89-1.14) in the Oxford Vegetarian Study, 1.03 (0.95-1.13) in the Health Food Shoppers Study. CONCLUSIONS: British vegetarians have low mortality compared with the general population. Their death rates are similar to those of comparable non-vegetarians, suggesting that much of this benefit may be attributed to non-dietary lifestyle factors such as a low prevalence of smoking and a generally high socio-economic status, or to aspects of the diet other than the avoidance of meat and fish.

OBJECTIVE: The overall aim of this study was to examine a variety of belief and demographic factors that are associated with the perception that meat is intrinsically unhealthy. DESIGN: State-wide survey (written questionnaire) that included questions on meat and nutrition beliefs, perceived barriers and benefits of vegetarian diets, personal values, number of vegetarian friends and family members, and use and trust of health/nutrition/food information sources. SETTING: South Australia. SUBJECTS: Six hundred and one randomly selected South Australians and 106 non-randomly selected vegetarians and semi-vegetarians. RESULTS: For all respondents considered as a group, the most important predictors of the belief that meat is intrinsically unhealthy were the perceived benefits of vegetarian diets (all positive predictors). These included: (1) the perceived links between vegetarianism, peace and increased contentment; (2) animal welfare and environmental benefits; and (3) health benefits. There were differences between different dietary groups however. For non-vegetarians, social concerns about vegetarianism (positive) were most important, followed by health and non-health benefits (positive) of vegetarianism. Red meat appreciation was the strongest (positive) predictor for vegetarians, with health benefits of vegetarianism (positive) and education (negative predictor) also important. CONCLUSIONS: The implications of the findings for health and other issues are discussed. Judgements about the healthiness of meat are likely to be related to moral and environmental beliefs and, for non-vegetarians, to social concerns about vegetarianism, in addition to health beliefs. These need to be considered if any attempts are made to influence meat consumption.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder, which is very common among the school aged population. Its core symptoms are inattention, hyperactivity, and impulsivity. Currently, three principal subtypes of ADHD are recognized: ADHD predominantly inattentive type, ADHD predominantly hyperactive/impulsive type or ADHD combined type. Affected individuals have increased comorbidity risks, often followed by cognitive, emotional and/or social impairments as adults. Stimulants drugs such methylphenidate (Ritalin) or D amphetamine (Dexedrine) represent the first line drugs for the treatment of ADHD. DEVELOPMENT: The clinical features of ADHD were first described by Dr. George Frederick Still for Lancet in 1902, and in spite of the investigations carried out since then, the precise cause is still not clear. The purpose of this review is to describe recent advances of the neurobiological basis of ADHD. CONCLUSIONS: Recent neuroimaging studies in humans indicate a dysfunctions of the frontal striatal circuits in patients with ADHD, which can be improved by pharmacological treatment. Both pre and clinical studies implicate a dysregulation of the dopaminergic and noradrenergic systems, which are known to regulate the functions of these circuits. More recent evidence indicate that some features of ADHD could be linked to alterations in the posterior inferior vermis. These studies also stress the importance of taking into consideration factors such as age, gender and duration of pharmacological treatment when interpreting the results.

The present randomised, crossover study sought to determine the effect of meals rich in safflower oil and olive oil (60 g) which had been heated for 8 h at 210 degrees C and the corresponding unheated oils on copper ion oxidation of dilute serum from 16 healthy men. Four hours after the meals rich in the heated oils, there were significant decreases of similar magnitude (-12%) in the lag time in conjugated diene formation during diluted serum oxidation. In the 12 subjects who consumed meals containing unheated oils, the lag time also decreased (-11%) significantly after the meal rich in unheated safflower oil (US) and did not change significantly after the unheated olive oil (UO) meal and these changes were different between the meals at a marginal level of significance (P=0.05). Our data suggest that susceptibility to oxidation of lipoproteins in low antioxidant environments similar to dilute serum may be increased in the postprandial period following meals rich in heat-modified vegetable oils and unheated oils rich in polyunsaturated fatty acids but not following meals rich in native olive oil. These findings may be relevant to the choice of fat to replace saturated fats in lipid-lowering diets and to low risk of coronary heart disease in communities which have a high consumption of olive oil.

CLINICAL CHARACTERISTICS MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, occurring after normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome. Pigmentary retinopathy and lipomatosis are occasionally observed. DIAGNOSIS/TESTING The clinical diagnosis of MERRF is based on the following four "canonic" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. The mitochondrial DNA (mtDNA) gene MT-TK encoding tRNALys is the gene most commonly associated with MERRF. The most common pathogenic variant, present in more than 80% of affected individuals with typical findings, is an A-to-G transition at nucleotide 8344 (m.8344A\textgreaterG). Pathogenic variants in MT-TF, MT-TL1, MT-TI, and MT-TP have also been described in a subset of individuals with MERRF. Pathogenic variants are usually present in all tissues and are conveniently detected in mtDNA from blood leukocytes. However, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having few symptoms consistent with MERRF or in asymptomatic maternal relatives of an affected individual, the pathogenic variant may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa, saliva, hair follicles, or (most reliably) skeletal muscle. MANAGEMENT Treatment of manifestations: Conventional antiepileptic drugs for seizures; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms. Levetiracetam, clonazepam, zonisamide, and valproic acid (VPA) have been used to treat myoclonic epilepsy; however, VPA may cause secondary carnitine deficiency and should be avoided or used with L-carnitine supplementation. Prevention of primary manifestations: Coenzyme Q10 (50-100 mg 3x/day) and L-carnitine (1000 mg 3x/day) are often used in hopes of improving mitochondrial function. Surveillance: Routine evaluations every 6-12 months initially; annual neurologic, ophthalmologic, cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (fasting blood sugar and TSH) evaluations. Pregnancy management: During pregnancy, affected or at-risk women should be monitored for diabetes mellitus and respiratory insufficiency, which may require therapeutic interventions. GENETIC COUNSELING MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk for having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. A male with a mtDNA pathogenic variant cannot transmit the pathogenic variant to any of his offspring. A female with the pathogenic variant (whether affected or unaffected) transmits the pathogenic variant to all of her offspring. Prenatal diagnosis for MERRF is possible if an mtDNA pathogenic variant has been detected in the mother. However, because the mutational load in the mother's tissues and in the fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth secondary to random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.

Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms 'transcriptome' and proteome', the set of metabolites synthesized by a biological system constitute its 'metabolome'. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.

Prenatal choline supplementation can protect rats against cognitive deficits induced by status epilepticus induced by the cholinergic agent pilocarpine [J. Neurosci. 20 (2000) 1]. In the present day, we have extended this novel finding by investigating the effects of pre- and postnatal choline supplementation in memory deficits associated with status epilepticus induced with kainic acid (KA). In the first experiment pregnant rats received a normal, choline-supplemented, or choline deficient diet starting on the 11th day of gestation and continuing until postnatal (P) 7. At P42, rats were given a convulsant dosage of KA. Two weeks following the KA-induced status epilepticus rats underwent testing of visual-spatial memory using the Morris water maze test. Rats receiving supplemental choline performed better in the water maze than the deficient and control groups. Moreover, the activity of hippocampal choline acetyltransferase was 18% lower in the choline deficient animals as compared with the other two groups. In the second experiment we administered KA to P35 rats that had been given a normal diet. Following the status epilepticus the rats were given a choline-supplemented or control diet for 4 weeks and then tested in the water maze. Rats receiving choline supplementation performed far better than rats receiving a regular diet. This study demonstrates that choline supplementation prior to or following KA-induced status epilepticus can protect rats from memory deficits induced by status epilepticus.

Advanced glycation end products (AGEs) may play an important adverse role in process of atherosclerosis, diabetes, aging and chronic renal failure. Levels of N(epsilon)-carboxymethyllysine and fluorescent AGE values were estimated in two nutritional population groups--alternative group (vegetarians--plant food, milk products, eggs) and traditional group (omnivorous subjects). Vegetarians have a significantly higher carboxymethyllysine content in plasma and fluorescent AGE values. Intake of proteins, lysine and monosaccharides as well as culinary treatment, consumption of food AGEs (mainly from technologically processed products) and the routes of Maillard reaction in organism are the substantial sources of plasma AGEs. Vegetarians consume less proteins and saccharides. Lysine intake is significantly reduced (low content in plant proteins). Subjects on alternative nutrition do not use high temperature for culinary treatment and consume low amount of technologically processed food. Fructation induced AGE fluorescence is greater as compared with that induced by glucose. It is due to higher participation of a more reactive acyclic form of fructose. Intake of vegetables and fruit with predominance of fructose is significantly higher in vegetarians. Comparison of nutrition and plasma AGEs in vegetarian and omnivorous groups shows that the higher intake of fructose in alternative nutrition of healthy subjects may cause an increase of AGE levels.

(1) Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. (2) The neuropathological hallmarks of AD, i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but may occur independently. (3) In brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. The decreased metabolic rate appears not to be induced by the presence of pretangles, NFT or NPs. (4) Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of AD, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in AD patients also supports the view that AD has a metabolic basis. (5) Moreover, several observations in postmortem brain indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as 'use it or lose it'. (6) It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in AD. A number of pharmacological and non-pharmacological studies support the concept that activation of the brain has beneficial effects and may, to a certain degree, restore several aspects of cognition and other central functions. For instance, the circadian system may be restimulated in AD patients by exposing them to more light or transcutaneous nerve stimulation. A procedure has been developed to culture human postmortem brain tissue that allows testing of the efficacy of putative stimulatory compounds such as neurotrophins.

We suggest that the evolution of the large human brain could not have occurred on the savannahs of Africa. It depended on avoiding the trap of universal loss of brain capacity amongst all land species as they evolved larger bodies. The nutrition at the water's front would have given evolving humans the edge over other hominid species. They would have had access to a rich, plentiful and easily harvested food resource, rich in DHA, trace elements and anti-oxidants, for little energy expenditure. This does not deny the possibility that the men hunted for meat. However, a reliable and consistent nutrient dense food resource, rich in DHA would have been especially important for women during pregnancy and lactation and of course the children during the period of fetal and neonatal brain development and reproductive maturation.

Because of its critical importance in atherogenesis, low-density lipoprotein (LDL) cholesterol is the focus of current guidelines for the determination of the risk of cardiovascular disease.1 However, atherothrombosis often occurs in the absence of hyperlipidemia, and recent consensus panels assembled by the National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention have concluded that population-based data on other risk factors are urgently needed.2,3 Among the biologic markers considered by those panels, there was particular interest in C-reactive protein, a marker of inflammation that has been shown in several prospective, nested case–control studies to be . . .

Eating right has been an obsession for longer than we think. Renaissance Europe had its own flourishing tradition of dietary advice. Then, as now, an industry of experts churned out diet books for an eager and concerned public. Providing a cornucopia of i.