Published Science

OBJECTIVE: To report a case of biopsy-documented nonalcoholic steatohepatitis (NASH), which improved appreciably through moderate exercise and weight loss in a young woman with polycystic ovary syndrome (PCOS) and insulin resistance. METHODS: We present a detailed case report, including laboratory and pathologic findings. In addition, we review the recent literature regarding the association of insulin resistance with NASH and PCOS. RESULTS: A 24-year-old woman was referred to the Duke Gastroenterology Clinic for evaluation of long-term high serum aminotransferase levels. She also reported a history of chronically irregular menses, infertility, and hirsutism and was diagnosed with PCOS. Subsequent glucose tolerance testing suggested the presence of insulin resistance. Liver biopsy findings were consistent with severe nonalcoholic steatohepatitis. Under the supervision of her physician and an exercise physiologist, the patient initiated a diet and exercise program that resulted in an 11.5% weight loss during approximately 8 months and yielded normalization of her aminotransferase levels. A repeat liver biopsy done 13 months after the initial biopsy revealed a substantial decrease in steatosis and a reduction in inflammation. CONCLUSION: Women with PCOS and insulin resistance have an increased risk of developing many of the consequences of the dysmetabolic syndrome, including type 2 diabetes, hypertension, and hyperlipidemia. This case report suggests that fatty liver and NASH may be other important diseases to identify in such women. It also demonstrates the improvement in this condition with moderate exercise and weight loss.

BACKGROUND: The relationship between serum triglycerides (TG) level and the risk of coronary heart disease (CHD) mortality remains controversial. AIMS: To evaluate whether TG level is a risk factor for CHD in elderly people from general population, and to look for interactions between TG and other risk factors. METHODS: 3257 subjects aged >or= 65 years followed up for 12 years from the CArdiovascular STudy in the ELderly. Blood tests and anthropometric measurements were performed. Continuous items were divided into quintiles and, for each quintile, adjusted hazard ratio (HR) with 95% confidence interval (CI) for CHD mortality was derived by genders from Cox analysis. RESULTS: In women, the HR of being in the fifth rather than in the first quintile of TG was 2.45 (CI 1.48-3.51). In turn, high-density-lipoprotein cholesterol (HDL-C) inversely predicted CHD mortality; the HR of being in the first rather than in the fifth quintiles of HDL-C was 1.52 (CI 1.24-2.36). The risk of CHD mortality further increased up to 3.81 (CI 1.62-5.43) when high TG and low HDL-C were combined. No predictive role for either TG or HDL-C was detected in men. CONCLUSIONS: TG and HDL-C were independent predictors of CHD mortality in elderly women. The combination high TG + low HDL-C quadrupled the risk of CHD mortality in this gender only.

PURPOSE: Tuberous sclerosis complex (TSC) is a condition that is frequently associated with intractable, early-onset epilepsy, and often is first seen as infantile spasms. If medications fail and no clear epileptogenic tuber is identified, nonpharmacologic therapies are often attempted. The use of the ketogenic diet specifically for children with TSC and epilepsy has not been previously described. METHODS: A chart review was performed of patients with TSC treated with the ketogenic diet over a 5-year period at Johns Hopkins Hospital and Massachusetts General Hospital. RESULTS: Twelve children, ages 8 months to 18 years, were identified. Eleven (92%) children had a >50% reduction in their seizures at 6 months on the diet, and 8 (67%) had a >90% response. Five children had at least a 5-month seizure-free response. Diet duration ranged from 2 months to 5 years (mean, 2 years). CONCLUSIONS: In this limited-duration case series of 12 patients, the ketogenic diet was a generally effective therapeutic modality for the intractable epilepsy occasionally seen in children with TSC.

Vegan diet in lactating women can induce vitamin B12 deficiency for their children with risk of an impaired neurological development. A 9.5-month-old girl presented with impaired growth and severe hypotonia. She had a macrocytic anemia secondary to vitamin B12 deficiency. MRI showed cerebral atrophy. She was exclusively breastfed. Her mother was also vitamin B12 deficient, secondary to a vegan diet. She had a macrocytic anemia when discharged from the maternity. Vegan diet is a totally inadequate regimen for pregnant and lactating women, especially for their children. Prevention is based on screening, information and vitamin supplementation.

The impact of AGEs on human MSCs was studied. AGEs inhibited the proliferation of MSCs, induced apoptosis, and prevented cognate differentiation into adipose tissue, cartilage, and bone, suggesting a deleterious effect of AGEs in the pathogenesis of musculoskeletal disorders in aged and diabetic patients. INTRODUCTION: Advanced glycation end-products (AGEs) are accumulated on long-lived proteins of various tissues in advanced age and diabetes mellitus and have been implicated in chronic complication, including musculoskeletal disorders. Human mesenchymal stem cells (MSCs) potentially differentiate into mature musculoskeletal tissues during tissue repair, but the pathogenetic role of AGEs on MSCs is unclear. MATERIALS AND METHODS: AGEs were prepared by incubating BSA with glucose, glyceraldehydes, or glycolaldehyde (designated as AGE-1, AGE-2, or AGE-3, respectively). Proliferation, apoptosis, and reactive oxygen species (ROS) generation were assayed in AGE-treated cells. The expression of the receptor for AGE (RAGE) was examined by immunohistochemistry and Western blotting. Involvement of RAGE-mediated signaling was examined using a neutralizing antiserum against RAGE. Differentiation into adipose tissue, cartilage, and bone were morphologically and biochemically monitored with specific markers for each. RESULTS: AGE-2 and AGE-3, but not control nonglycated BSA and AGE-1, reduced the viable cell number and 5-bromo-2'deoxyuridine (BrdU) incorporation with increased intracellular ROS generation and the percentage of apoptotic cells. MSCs expressed RAGE and its induction was stimulated by AGE-2 and AGE-3. These AGEs inhibited adipogenic differentiation (assayed by oil red O staining, lipoprotein lipase production, and intracellular triglyceride content) and chondrogenic differentiation (assayed by safranin O staining and type II collagen production). On osteogenic differentiation, AGE-2 and AGE-3 increased alkaline phosphatase activity and intracellular calcium content; however, von Kossa staining revealed the loss of mineralization and mature bone nodule formation. The antiserum against RAGE partially prevented AGE-induced cellular events. CONCLUSION: AGE-2 and AGE-3 may lead to the in vivo loss of MSC mass and the delay of tissue repair by inhibiting the maturation of MSC-derived cells. The AGE-RAGE interaction may be involved in the deleterious effect of AGEs on MSCs.

BACKGROUND: Inflammation is considered a key mechanism leading to type 2 diabetes, but dietary exposures that lead to inflammation and diabetes are largely unknown. OBJECTIVE: Our objective was to investigate the relation between a dietary pattern associated with biomarkers of inflammation and the incidence of type 2 diabetes. DESIGN: We conducted a nested case-control study of 656 cases of type 2 diabetes and 694 controls among women in the Nurses' Health Study and 2 prospective cohort studies of 35 340 women in the Nurses' Health Study and 89 311 women in the Nurses' Health Study II who were followed for incident diabetes. RESULTS: Through the use of reduced rank regression, we identified a dietary pattern that was strongly related to inflammatory markers in the nested case-control study. This pattern, which was high in sugar-sweetened soft drinks, refined grains, diet soft drinks, and processed meat but low in wine, coffee, cruciferous vegetables, and yellow vegetables, was associated with an increased risk of diabetes (multivariate-adjusted odds ratio comparing extreme quintiles: 3.09; 95% CI: 1.99, 4.79). We identified 1517 incident cases of confirmed type 2 diabetes in the Nurses' Health Study (458 991 person-years) and 724 incident cases in the Nurses' Health Study II (701 155 person-years). After adjustment for body mass index and other potential lifestyle confounders, the relative risks comparing extreme quintiles of the pattern were 2.56 (95% CI: 2.10, 3.12; P for trend < 0.001) in the Nurses' Health Study and 2.93 (95% CI: 2.18, 3.92; P for trend

Metabolomics has been widely adopted in pharmacology and toxicology but is relatively new in human nutrition. The ultimate goal, to understand the effects of exogenous compounds on human metabolic regulation, is similar in all 3 fields. However, the application of metabolomics to nutritional research will be met with unique challenges. Little is known of the extent to which changes in the nutrient content of the human diet elicit changes in metabolic profiles. Moreover, the metabolomic signal from nutrients absorbed from the diet must compete with the myriad of nonnutrient signals that are absorbed, metabolized, and secreted in both urine and saliva. The large-bowel microflora also produces significant metabolic signals that can contribute to and alter the metabolome of biofluids in human nutrition. Notwithstanding these possible confounding effects, every reason exists to be optimistic about the potential of metabolomics for the assessment of various biofluids in nutrition research. This potential lies both in metabolic profiling through the use of pattern-recognition statistics on assigned and unassigned metabolite signals and in the collection of comprehensive data sets of identified metabolites; both objectives have the potential to distinguish between different dietary treatments, which would not have been targeted with conventional techniques. The latter objective sets out a well-recognized challenge to modern biology: the development of libraries of small molecules to aid in metabolite identification. The purpose of the present review was to highlight some early challenges that need to be addressed if metabolomics is to realize its great potential in human nutrition. Copyright © 2005 American Society for Clinical Nutrition

This study assessed the nutrient adequacy of a very low-fat vegan diet. Thirty-nine men (mean age=65 years) with early stage prostate cancer who chose the "watchful waiting" approach to disease management, were instructed by a registered dietitian and a chef on following a very low-fat (10%) vegan diet with the addition of a fortified soy protein powdered beverage. Three-day food diaries, excluding vitamin and mineral supplements, were analyzed and nutrient values were compared against Dietary Reference Intakes (DRI). Mean dietary intake met the recommended DRIs. On the basis of the Adequate Intake standard, a less than adequate intake was observed for vitamin D. This demonstrates that a very low-fat vegan diet with comprehensive nutrition education emphasizing nutrient-fortified plant foods is nutritionally adequate, with the exception of vitamin D. Vitamin D supplementation, especially for those with limited sun exposure, can help assure nutritional adequacy.

High calorie and fat consumption and the production of free radicals are two major mechanistic pathways between diet and disease. In this study we evaluated the effect of a plant-based diet poor in animal fat and rich in (n-3) fatty acids on fatty acids of serum phospholipids and on the production of reactive oxygen metabolites (ROMs). One hundred and four healthy female postmenopausal volunteers were recruited and randomized to a dietary intervention or a control group. Dietary intervention included a program of food education and biweekly common meals for 18 weeks. When the intervention and control groups were compared, it was seen that dietary intervention resulted in a significant reduction of saturated fatty acids (-1.5%) and a significant increase in (n-3) fatty acids (+20.6%), in particular docosahexaenoic acid (+24.8%). We observed that arachidonic acid decreased (-7.7%), while (n-6) fatty acids did not, and the (n-3)/(n-6) polyunsaturated ratio increased significantly (+24.1%). As expected, ROMs decreased significantly in the intervention group (-6%). The results indicated that a plant-based diet can improve the serum fatty acid profile and decrease ROMs production. These results suggest that a plant-based diet may reduce the body's exposure to oxidative stress.

OBJECTIVE: To assess the short- and long-term cardiovascular effects of once-daily treatment with a mixed amphetamine salts extended-release formulation (MAS XR; Adderall XR(R)) in children age 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD). STUDY DESIGN: Short-term cardiovascular effects were assessed during a 4-week, double-blind, randomized, placebo-controlled, forced-dose-titration study of once-daily 10, 20, and 30 mg MAS XR (n = 580). Long-term cardiovascular effects were assessed in 568 subjects during a 2-year, open-label extension study of MAS XR (10 to 30 mg/day). Resting sitting blood pressure and pulse were measured at baseline and weekly during the short-term study, then monthly during long-term treatment. RESULTS: Changes in blood pressure, pulse, and QT interval corrected by Bazett's formula (QTcB) in children receiving MAS XR were not statistically significantly different than those changes seen in children receiving placebo during short-term treatment. Mean increases in blood pressure after 2 years of MAS XR treatment (systolic, 3.5 mm Hg; diastolic, 2.6 mm Hg) and pulse (3.4 bpm) were clinically insignificant, and there was no apparent dose-response relationship. CONCLUSIONS: Cardiovascular effects of short- and long-term MAS XR were minimal during short- and long-term MAS XR treatment at doses of

OBJECTIVE: To investigate whether low-carbohydrate diets are efficient for reduction of body weight and through which mechanism. DESIGN: A couple of studies using low-carbohydrate diets in the treatment of obesity are reviewed. Mechanisms for explaining the reduced appetite are described in relation to knowledge on regulation of appetite for fat and carbohydrate. RESULTS: Studies with low-carbohydrate diets demonstrate a rapid weight loss, being more pronounced after 3 and 6 months compared to low-fat diets. After 12 months there is no difference between the low-carbohydrate and the conventional low-fat diet on weight loss. Both diets lead to improvements in risk factors for coronary heart disease, the low-carbohydrate diet leading to a greater decrease in serum triglycerides and increase in HDL cholesterol compared to the low-fat diet. Blood pressure, insulin sensitivity and LDL cholesterol were improved to a similar degree by the two diets. The mechanism for the rapid weight loss with the low-carbohydrate diet is a suppressed appetite, first through the high-protein content of the diet, second through the ketogenic nature of the diet with satiety signals for fat being active and third through the absence of hunger-promoting carbohydrate components like sucrose and/or fructose. CONCLUSION: A rapid initial weight loss occurs with a low-carbohydrate diet due to a suppressed appetite. There is as yet no indication of an increased metabolic rate and an increased thermogenesis by the low-carbohydrate diet. The safety and efficacy of low-carbohydrate diets have to await further studies.

Sirtuins are NAD(+)-dependent protein deacetylases that are involved in transcriptional regulation, metabolism, apoptosis, differentiation and ageing. These unique enzymes are inhibited by nicotinamide, which is a form of vitamin B3. Recent studies have uncovered the molecular basis for nicotinamide inhibition, and provided the framework to understand the physiological processes mediated by sirtuins and to develop strategies to modulate their cellular activity.

CONCLUSIONS: The RFS and DDS-R performed as well or better than the HEI for predicting serum concentration of nutrients and biomarkers of disease risk.

This study examined the interaction of 2 diets (high protein, reduced carbohydrates vs. low protein, high carbohydrates) with exercise on body composition and blood lipids in women (n = 48, approximately 46 y old, BMI = 33 kg/m(2)) during weight loss. The study was a 4-mo weight loss trial using a 2 x 2 block design (Diet x Exercise). Diets were equal in total energy (7.1 MJ/d) and lipids ( approximately 30% energy intake) but differed in protein content and the ratio of carbohydrate:protein at 1.6 g/(kg . d) and 3.5 (CHO group), respectively. Exercise comparisons were lifestyle activity (control) vs. a supervised exercise program (EX: 5 d/wk walking and 2 d/wk resistance training). Subjects in the PRO and PRO + EX groups lost more total weight and fat mass and tended to lose less lean mass (P = 0.10) than the CHO and CHO + EX groups. Exercise increased loss of body fat and preserved lean mass. The combined effects of diet and exercise were additive for improving body composition. Serum lipid profiles improved in all groups, but changes varied among diet treatments. Subjects in the CHO groups had larger reductions in total cholesterol and LDL cholesterol, whereas subjects in the PRO groups had greater reductions in triacylglycerol and maintained higher concentrations of HDL cholesterol. This study demonstrated that a diet with higher protein and reduced carbohydrates combined with exercise additively improved body composition during weight loss, whereas the effects on blood lipids differed between diet treatments.

BACKGROUND: Plasma concentrations of long-chain n-3 polyunsaturated fatty acids are lower in vegetarians and in vegans than in omnivores. No data are available on whether these concentrations differ between long- and short-term vegetarians and vegans. OBJECTIVES: We compared plasma fatty acid composition in meat-eaters, vegetarians, and vegans and examined whether the proportions of eicosapentaenoic acid (20:5n-3; EPA), docosapentaenoic acid (22:5n-3; DPA), and docosahexaenoic acid (22:6n-3; DHA) were related to the subjects' duration of adherence to their diets or to the proportions of plasma linoleic acid (18:2n-6; LA) and alpha-linolenic acid (18:3n-3; ALA). DESIGN: The present cross-sectional study included 196 meat-eating, 231 vegetarian, and 232 vegan men in the United Kingdom. Information on anthropometry, diet, and smoking habits was obtained through a questionnaire. Total fatty acid composition in plasma was measured. RESULTS: The proportions of plasma EPA and DHA were lower in the vegetarians and in the vegans than in the meat-eaters, whereas only small differences were seen for DPA. Plasma EPA, DPA, and DHA proportions were not significantly associated with the duration of time since the subjects became vegetarian or vegan, which ranged from 20 y. In the vegetarians and the vegans, plasma DHA was inversely correlated with plasma LA. CONCLUSIONS: The proportions of plasma long-chain n-3 fatty acids were not significantly affected by the duration of adherence to a vegetarian or vegan diet. This finding suggests that when animal foods are wholly excluded from the diet, the endogenous production of EPA and DHA results in low but stable plasma concentrations of these fatty acids.

BACKGROUND: Plasma concentrations of long-chain n-3 polyunsaturated fatty acids are lower in vegetarians and in vegans than in omnivores. No data are available on whether these concentrations differ between long- and short-term vegetarians and vegans. OBJECTIVES: We compared plasma fatty acid composition in meat-eaters, vegetarians, and vegans and examined whether the proportions of eicosapentaenoic acid (20:5n-3; EPA), docosapentaenoic acid (22:5n-3; DPA), and docosahexaenoic acid (22:6n-3; DHA) were related to the subjects' duration of adherence to their diets or to the proportions of plasma linoleic acid (18:2n-6; LA) and alpha-linolenic acid (18:3n-3; ALA). DESIGN: The present cross-sectional study included 196 meat-eating, 231 vegetarian, and 232 vegan men in the United Kingdom. Information on anthropometry, diet, and smoking habits was obtained through a questionnaire. Total fatty acid composition in plasma was measured. RESULTS: The proportions of plasma EPA and DHA were lower in the vegetarians and in the vegans than in the meat-eaters, whereas only small differences were seen for DPA. Plasma EPA, DPA, and DHA proportions were not significantly associated with the duration of time since the subjects became vegetarian or vegan, which ranged from 20 y. In the vegetarians and the vegans, plasma DHA was inversely correlated with plasma LA. CONCLUSIONS: The proportions of plasma long-chain n-3 fatty acids were not significantly affected by the duration of adherence to a vegetarian or vegan diet. This finding suggests that when animal foods are wholly excluded from the diet, the endogenous production of EPA and DHA results in low but stable plasma concentrations of these fatty acids.

The emergence of a new variant of Creutzfeldt-Jacob disease during the bovine spongiform encephalopathy epidemic has focused attention on the use of tissues from the central nervous system (CNS) in food. For efficient consumer protection, European legislation prohibits several bovine tissues, encompassing mainly the central nervous system, from the food chain. A quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was designed to identify bovine spongiform encephalopathy risk material in meat and meat products. This was based on an mRNA assay that used bovine, ovine, and caprine glial fibrillary acidic protein (GFAP) encoding gene sequences as a marker. The real-time RT-PCR assay allowed the detection of bovine, ovine, or caprine CNS tissues in meat and meat products. Bovine brain at a concentration of 0.01% yielded a positive PCR reaction. The real-time RT-PCR assay included a housekeeping gene as an endogenous control. The detection was not affected by heat treatment of the meat products. The quantitative real-time RT-PCR detection of GFAP mRNA appeared to be useful as a routine diagnostic test for the detection of illegal use of CNS tissues in meat and meat products. The stability of the specific region of GFAP mRNA also allows the detection of CNS tissues after meat processing steps. The use of organ- and species-specific subunits of mRNA might be a promising approach for the detection of other banned tissues.

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (

Clinical history and inappropriate insulin secretion during hypoglycemic episodes permit the diagnosis of hyperinsulinism. We report 2 cases of factitious hyperinsulinism leading to partial pancreatectomy. Case 1 was an 8-year-old girl who presented with severe hypoglycemia and elevated insulin and C-peptide levels. Catheterization of pancreatic veins was performed to localize the excess insulin secretion. Insulinoma was suspected, and partial pancreatectomy was performed. Ten days after surgery, severe hypoglycemia recurred with severely elevated plasma insulin levels (x100) but very low C-peptide plasma levels, suggesting factitious hyperinsulinemia. Hypoglycemic episodes before surgery were provoked by oral sulfonamides; postoperative episodes were caused by parenteral insulin. Falsified prescriptions for sulfonamides and insulin by the mother, a nurse, were found. Case 2 was a 6-month-old girl who presented with seizures and hypoglycemia but had a symptom-free interval of many months afterward. At 2 years of age, repeated hypoglycemic seizures and elevated insulin plasma levels suggested congenital hyperinsulinism. C-peptide plasma level, measured once, was normal, but blood sampling was performed 15 minutes after a hypoglycemic episode. Partial pancreatectomy was performed. Two weeks after surgery, hypoglycemic seizures recurred, and the patient was admitted for pancreatic vein catheterization. This investigation was performed during hypoglycemia and revealed high insulin levels and undetectable C-peptide levels, suggesting factitious hypoglycemia. Insulin/C-peptide ratio analysis is crucial to assess factitious hypoglycemia, although sulfonamide-induced hypoglycemia is not thereby detected. One percent (2 of 250) of all cases of hyperinsulinemic hypoglycemia in our unit have been identified as Munchausen syndrome by proxy. Atypical disease history should raise the question of factitious hypoglycemia.

AIMS: Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes. METHODS: Cord (fetal) and maternal blood were obtained at delivery from control subjects (n = 33) and women with gestational diabetes (n = 40) and analysed for plasma triglycerides and cholinephosphoglycerides, and erythrocyte choline- and ethanolaminephosphoglycerides fatty acids. RESULTS: Babies of gestational diabetic mothers had reduced docosahexaenoic acid in the plasma (5.9 +/- 1.4 vs. 7.1 +/- 2.0, P < 0.01) and erythrocyte (4.0 +/- 2.2 vs. 5.4 +/- 2.9, P < 0.05) cholinephosphoglycerides. Moreover, the total omega-6 and omega-3 fatty acids of the erythrocyte cholinephosphoglycerides were significantly lower (P

Meat increases absorption of non-haem iron in single-meal studies. The aim of the present study was to investigate, over a 5 d period, the potential increasing effect of consumption of pork meat in a whole diet on the fractional absorption of non-haem iron and the total absorption of iron, when compared to a vegetarian diet. A randomised cross-over design with 3 x 5 d whole-diet periods with diets containing Danish-produced meat, Polish-produced meat or a vegetarian diet was conducted. Nineteen healthy female subjects completed the study. All main meals in the meat diets contained 60 g of pork meat and all diets had high phytic acid content (1250 mumol/d). All main meals were extrinsically labelled with the radioactive isotope (59)Fe and absorption of iron was measured in a whole body counter. The non-haem iron absorption from the Danish meat diet was significantly higher compared to the vegetarian diet (P=0.031). The mean fractional absorption of non-haem iron was 7.9 (se1.1), 6.8 (se 1.0) and 5.3 (se 0.6) % for the Danish and Polish meat diets and vegetarian diet, respectively. Total absorption of iron was higher for both meat diets compared to the vegetarian diet (Danish meat diet: P=0.006, Polish meat diet: P=0.003). The absorption ratios of the present study were well in accordance with absorption ratios estimated using algorithms on iron bioavailability. Neither the meat diets nor the vegetarian diets fulfilled the estimated daily requirements of absorbed iron in spite of a meat intake of 180 g/d in the meat diets.

The crucial role of lipids in cell, tissue and organ physiology is demonstrated by a large number of genetic studies and by many human diseases that involve the disruption of lipid metabolic enzymes and pathways. Examples of such diseases include cancer, diabetes, as well as neurodegenerative and infectious diseases. So far, the explosion of information in the fields of genomics and proteomics has not been matched by a corresponding advancement of knowledge in the field of lipids, which is largely due to the complexity of lipids and the lack of powerful tools for their analysis. Novel analytical approaches--in particular, liquid chromatography and mass spectrometry--for systems-level analysis of lipids and their interacting partners (lipidomics) now make this field a promising area of biomedical research, with a variety of applications in drug and biomarker development.

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2–3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4–5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class – may among the antidepressants – favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.

Vegetarian diets have been suggested to be beneficial for bone health due to increased consumption of plant foods, including soya, or reduced consumption of meat. However, meat may also be beneficial for bone health. The evidence relating diet to bone health is based largely on studies of women, often in those at high risk of osteoporosis. Few studies have investigated dietary inter-relationships in men as well as women from general populations. We examined broadband ultrasound attenuation (BUA) of the calcaneum, using a CUBA clinical instrument, in 6,369 men and 5,379 postmenopausal women. The population was divided into four groups according to vegetarian status and frequency of soya consumption, which was defined by response to a food frequency questionnaire that estimates frequency of consumption of food types over the year prior to completion. Regular soya consumers were defined as those who ate soya products with a frequency of between once a day and once a week. Calcaneum BUA in vegetarian men was significantly lower than omnivores by approximately 6% (5 dB/MHz) and was 15% (13.6 dB/MHz) lower in those who were also regular soya consumers. This difference remained after adjustment for age, height, weight, smoking habit, physical activity, selected foods and nutrients and exclusion of those with a prior history of osteoporosis, fractures or cancer. Calcaneum BUA in omnivorous men with regular soya consumption was not lower than the remaining population. In women, there were no significant differences by usual dietary pattern. This surprising finding indicates that regular soya intake is not associated with better bone indices in vegetarian men. The difference in BUA was not explained by the known common covariates; however, it is possible that other aspects of lifestyle associated with these eating behaviors might explain this observation. Plausible mechanisms exist for our findings; soya contains phytoestrogens, likened to naturally occurring estrogens, and meat has been shown to influence levels of IGF-1 and sex hormone binding globulin, which may be related to bone health. Our findings emphasize the need for further research and investigation into dietary inter-relationships and bone health and the effects of vegetarian status, including consumption of soya-based foods, in men as well as women.

The aim was to assess how urinary creatinine is affected by age, gender, body size and meat intake, and to determine to what extent such factors might affect the creatinine adjustment of urinary cadmium. The study was based on three Swedish studies: (1) 67 non-smoking women aged 20-50 years (24-h urine samples); (2) 289 men and 434 women aged 16-81 years (spot urine samples); and (3) 98 men and 105 women aged 19-72 years (spot urine samples). The effects of age, body surface area (as an indicator of muscle mass), and meat intake on urinary creatinine and cadmium were analysed using multiple regression analyses. Gender- and age-related variations in urinary creatinine and cadmium adjusted for creatinine or specific gravity were compared by ANOVA or ANCOVA. In the multiple regression analyses, body surface area, gender, age and meat intake were the major determinants of urinary creatinine. Urinary cadmium adjusted for creatinine and specific gravity were also dependent on body size, gender and age. Urinary cadmium adjusted for creatinine was 15-92% higher in women or older individuals than in men or younger individuals. Women or older individuals had -3 to 79% higher urinary cadmium adjusted for specific gravity than men or younger individuals had, and such a difference between gender or age group was less obvious in specific gravity adjustment than in creatinine adjustment. Thus, urinary cadmium adjusted for creatinine is more affected by age, gender, body size and meat intake than is specific gravity adjustment. When comparing individuals or populations with large differences in muscle mass or meat intake, such effects can be especially important. In such studies, specific gravity adjustment seems to be more appropriate.

BACKGROUND: Limited evidence suggests that a higher ratio of protein to carbohydrate during weight loss has metabolic advantages. OBJECTIVE: The objective was to evaluate the effects of a diet with a high ratio of protein to carbohydrate during weight loss on body composition, cardiovascular disease risk, nutritional status, and markers of bone turnover and renal function in overweight women. DESIGN: The subjects were randomly assigned to 1 of 2 isocaloric 5600-kJ dietary interventions for 12 wk according to a parallel design: a high-protein (HP) or a high-carbohydrate (HC) diet. RESULTS: One hundred women with a mean (+/-SD) body mass index (in kg/m(2)) of 32 +/- 6 and age of 49 +/- 9 y completed the study. Weight loss was 7.3 +/- 0.3 kg with both diets. Subjects with high serum triacylglycerol (>1.5 mmol/L) lost more fat mass with the HP than with the HC diet (x +/- SEM: 6.4 +/- 0.7 and 3.4 +/- 0.7 kg, respectively; P = 0.035) and had a greater decrease in triacylglycerol concentrations with the HP (-0.59 +/- 0.19 mmol/L) than with the HC (-0.03 +/- 0.04 mmol/L) diet (P = 0.023 for diet x triacylglycerol interaction). Triacylglycerol concentrations decreased more with the HP (0.30 +/- 0.10 mmol/L) than with the HC (0.10 +/- 0.06 mmol/L) diet (P = 0.007). Fasting LDL-cholesterol, HDL-cholesterol, glucose, insulin, free fatty acid, and C-reactive protein concentrations decreased with weight loss. Serum vitamin B-12 increased 9% with the HP diet and decreased 13% with the HC diet (P < 0.0001 between diets). Folate and vitamin B-6 increased with both diets; homocysteine did not change significantly. Bone turnover markers increased 8-12% and calcium excretion decreased by 0.8 mmol/d (P

Background: Essential tremor is one of the most common neurological diseases. Its links with Parkinson disease (PD) are often debated. There have been few published postmortem studies. Objective: To study our first case of essential tremor through the recently established Essential Tremor Centralized Brain Repository. Design: Report of a case of a patient with a diagnosis of severe essential tremor for 46 years who exhibited no signs of parkinsonism. Results: On postmortem examination, gross brain sections showed no abnormalities. Results of microscopic examination of hematoxylin-eosin-stained sections revealed that the locus coeruleus contained multiple Lewy bodies (LBs), although none were found in the substantia nigra, dorsal vagal nuclei, thalamus, substantia innominata, inferior olivary nucleus, or cerebellum. Immunochemical staining using antibodies directed against α-synuclein confirmed the presence of many LBs in the locus ceruleus and showed rare LBs in the substantia innominata and dorsal vagal nuclei. There were no LBs in the substantia nigra. Conclusions: Our patient had a very focal presence of LBs in the locus ceruleus, an anatomically restricted form of LB disease. This study provides support for the link between essential tremor and LB disease and raises the question as to what proportion of patients with essential tremor might have unusual forms of LB disease. ©2005 American Medical Association. All rights reserved.

To validate our hypothesis that reduction in dietary fat may result in changes in androgen metabolism, 39 middle-aged, white, healthy men (50-60 yr of age) were studied while they were consuming their usual high-fat, low-fiber diet and after 8 wk modulation to an isocaloric low-fat, high-fiber diet. Mean body weight decreased by 1 kg, whereas total caloric intake, energy expenditure, and activity index were not changed. After diet modulation, mean serum testosterone (T) concentration fell (P

BACKGROUND: Observational studies suggest that a plant-based diet is inversely related to body mass index (BMI), overweight, and obesity. OBJECTIVE: Our objective was to examine the BMI (kg/m(2)) and risk of overweight and obesity of self-defined semivegetarian, lactovegetarian, and vegan women. DESIGN: Data analyzed in this cross-sectional study were from 55459 healthy women participating in the Swedish Mammography Cohort. Women were asked whether they considered themselves to be omnivores (n = 54257), semivegetarians (n = 960), lactovegetarians (n = 159), or vegans (n = 83), and this question was the main exposure variable in this study. In secondary analyses, we reclassified women as lactovegetarians on the basis of food intakes reported on the food-frequency questionnaire. RESULTS: The prevalence of overweight or obesity (BMI >/= 25) was 40% among omnivores, 29% among both semivegetarians and vegans, and 25% among lactovegetarians. In multivariate, adjusted logistic regression analyses, self-identified vegans had a significantly lower risk of overweight or obesity [odds ratio (OR) = 0.35; 95% CI: 0.18, 0.69] than did omnivores, as did lactovegetarians (OR = 0.54; 95% CI: 0.35, 0.85) and semivegetarians (OR = 0.52; 95% CI: 0.43, 0.62). Risk of overweight or obesity remained significantly lower among lactovegetarians classified on the basis of the food-frequency questionnaire (OR = 0.48; 95% CI: 0.30, 0.78). CONCLUSIONS: Even if vegetarians consume some animal products, our results suggest that self-identified semivegetarian, lactovegetarian, and vegan women have a lower risk of overweight and obesity than do omnivorous women. The advice to consume more plant foods and less animal products may help individuals control their weight.

The Mediterranean diet is rich in vegetables, cereals, fruit, fish, milk, wine and olive oil and has salutary biological functions. Epidemiological studies have shown a lower incidence of atherosclerosis, cardiovascular diseases and certain kinds of cancer in the Mediterranean area. Olive oil is the main source of fat, and the Mediterranean diet's healthy effects can in particular be attributed not only to the high relationship between unsaturated and saturated fatty acids in olive oil but also to the antioxidant property of its phenolic compounds. The main phenolic compounds, hydroxytyrosol and oleuropein, which give extra-virgin olive oil its bitter, pungent taste, have powerful antioxidant activity both in vivo and in vitro. The present review focuses on recent works analysing the relationship between the structure of olive oil polyphenolic compounds and their antioxidant activity. These compounds' possible beneficial effects are due to their antioxidant activity, which is related to the development of atherosclerosis and cancer, and to anti-inflammatory and antimicrobial activity.

Holstein steer calves (n = 32; 156 +/- 33.2 kg average BW) were used to evaluate the duration of restraint and isolation stress (RIS) on endocrine and blood metabolite status and the incidence of dark-cutting LM. Calves were blocked by BW and assigned randomly within blocks to one of four stressor treatments: unstressed controls (NS) or a single bout of RIS for 2, 4, or 6 h. Venous blood was collected via indwelling jugular catheters at 40, 20, and 0 min before stressor application and at 20-min intervals during RIS. Unstressed calves remained in their home stanchions and, except for blood sampling, were subjected to minimal handling and stress. Serum cortisol and plasma lactate concentrations were increased (P < 0.01) during the first 20 min after RIS application, and remained elevated throughout the 6 h of RIS. Plasma concentrations of glucose and insulin were greater (P 0.80) affect plasma NEFA concentrations. Calves were slaughtered within 20 min of completion of RIS, and muscle samples were excised from right-side LM at 0, 0.75, 1.5, 3, 6, 12, 24, and 48 h after exsanguination for quantifying LM pH, and glycogen and lactate concentrations. The pH of the LM from calves subjected to 6 h of RIS exceeded 6.0, and was greater (P < 0.05) at 24 and 48 h postmortem than the pH of NS calves or calves subjected to 2 or 4 h RIS. Muscle glycogen concentrations did not differ (P = 0.16; 25.58, 10.41, 13.80, and 14.41 micromol/g of wet tissue weight for NS and 2-, 4-, and 6-h RIS, respectively), and LM lactate concentrations tended to be lower (P = 0.08) in calves subjected to 6 h of RIS. At 48 h after exsanguination, the LM from calves subjected to 6 h of RIS had more (P < 0.05) bound and less (P < 0.05) free moisture than did the LM from NS calves or calves subjected to 2 or 4 h of RIS. Additionally, the LM from RIS calves was darker (lower L* values; P < 0.05) than the LM of NS calves. Visual color scores for the LM were greatest (P < 0.05) for calves subjected to 6 h of RIS and least (P

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

Contrary to empirical reports of inhibitory dysfunction in ADHD, parental reports suggest that when playing computer games, the inhibitory abilities of children with ADHD are unimpaired. This small-scale preliminary investigation into this phenomenon looks at inhibition of an ongoing response and activity exhibited by children with ADHD between 6 and 14 years old on two commercially available games, on the Conners's Continuous Performance Test II (CPT II), and on a more game-like version of the same task that incorporates characteristics commonly found in commercially available computer games. The performance of participants with ADHD on commercially available games is equivalent to that of typically developing participants and is significantly better on the more game-like version of the CPT II.

BACKGROUND AND AIM: In individuals with biopsy-proven non-alcoholic steatohepatitis (NASH), short-term weight loss has been shown to improve biochemical abnormalities; however, its effect on liver histology is largely unknown. The aim of the article is to determine if dietary intervention is effective in improving histological features of steatohepatitis in patients with biopsy-proven NASH. METHODS: Twenty-three patients (11M/12F) with BMI >25 kg/m(2) and biopsy-proven NASH received standardized nutritional counseling aimed at reducing insulin resistance (IR) and weight. Blood tests were checked at baseline and every 1-4 months, and liver biopsy was repeated at month 12. IR was assessed by the homeostasis model assessment (HOMA). Liver biopsies were scored according to modified Brunt criteria for NASH. "Histologic response" was defined as a reduction in total NASH score of >/=2 points with at least one point being in the non-steatosis component. RESULTS: Sixteen patients (8M/8F) completed 12 months of dietary intervention, and 15 underwent repeat liver biopsies. At month 12, mean weight decreased from 98.3 to 95.4 kg. Mean waist circumference, visceral fat, fasting glucose, IR, triglycerides, AST, ALT, and histologic score were all reduced but the difference was not significant. Nine patients had a histologic response, six had stable scores, and none had a worsened score. Compared to patients with unchanged histologic scores, patients with improved scores had significantly greater reduction in weight, waist circumference, AST, ALT, steatosis grade, and total NASH score. CONCLUSION: Among patients who successfully completed 1 yr of intense dietary intervention, nine of 15 patients with NASH displayed histologic improvement. This pilot study suggests that dietary intervention can be effective in improving histology in patients with biopsy-proven NASH.

INTRODUCTION: Persistent sexual arousal syndrome is an uncommon sexual complaint. Patients with this disorder can be distressed by the escalation of tension in the pelvic region and the prevailing necessity to diminish the pressure by self-stimulation. Patients frequently suffer from guilt or shame and often do not seek medical care. There are many potential causes of this disorder; however, a definitive etiology has yet to be elucidated. CASE: The patient is a 44-year-old female who presented to her gynecologist for evaluation of dysmenorrhea and menometrorrhagia. During the review of systems, the patient reported 5-6 months of increased pelvic tension, not associated with an increase in desire that required her to self-stimulate to orgasm approximately 15 times daily. Upon further inquiry, the patient disclosed that her dietary regimen included soy intake in excess of 4 pounds per day that began approximately 1 month prior to the onset of symptoms. RESULTS: Treatment consisted of supportive counseling and dietary modification. At the 3-month follow-up visit, the patient's menstrual difficulties and sexual complaints resolved. CONCLUSIONS: Although no known cause or cure of persistent sexual arousal syndrome has been identified to date, the success of reducing dietary of phytoestrogens in this patient may provide insight into the etiology of the disorder and suggest potential treatments.

Dietary fatty acids have a profound impact on atherosclerosis, but mechanisms are not fully understood. We studied the effects of a saturated fat diet supplemented with fish oil, trans10,cis12 conjugated linoleic acid (CLA), or elaidic acid on lipid and glucose metabolism and liver protein levels of APOE*3 Leiden transgenic mice, a model for lipid metabolism and atherosclerosis. Fish oil lowered plasma and liver cholesterol and triglycerides, plasma free fatty acids, and glucose but increased plasma insulin. CLA lowered plasma cholesterol but increased plasma and liver triglycerides, plasma beta-hydroxybutyrate, and insulin. Elaidic acid lowered plasma and liver cholesterol. Proteomics identified significant regulation of 65 cytosolic and 8-membrane proteins. Many of these proteins were related to lipid and glucose metabolism, and to oxidative stress. Principal component analysis revealed that fish oil had a major impact on cytosolic proteins, and elaidic acid on membrane proteins. Correlation analysis between physiological and protein data revealed novel clusters of correlated variables, among which a metabolic syndrome cluster. The combination of proteomics and physiology gave new insights in mechanisms by which these dietary fatty acids regulate lipid metabolism and related pathways, for example, by altering protein levels of long-chain acyl-CoA thioester hydrolase and adipophilin in the liver.

BACKGROUND: The ketogenic diet is a low-carbohydrate, adequate-protein, and high-fat diet with a long history of use for the treatment of intractable seizures in children. This dietary therapy has been enjoying increasing popularity in recent years, despite the availability of increasing numbers of new antiepileptic drugs and surgical treatments. REVIEW SUMMARY: The authors review the history of the ketogenic diet, the traditional protocol in initiating it, possible mechanisms of its action, evidence for efficacy, and side effects. In addition, they highlight some of the areas of active research in this field as well as future directions and unanswered questions. CONCLUSION: The ketogenic diet is an efficacious and relatively safe treatment of intractable seizures. Despite its long history, however, much remains unknown about the diet, including its mechanisms of action, the optimal protocol, and the full range of its applicability. Investigations of the diet are providing new insight into the mechanisms behind seizures and epilepsy itself, as well as possible new therapies.

Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.

The use of 24-hour urinary sucrose and fructose as potential biomarkers for sugars consumption was investigated in two studies of 21 healthy participants living in a volunteer suite where dietary intake was known and all specimens collected. The dose-response was assessed in 12 males using a randomized crossover design of three diets containing constant levels of 63, 143, and 264 g of sugars for 10 days each. Both sugars and sucrose intake were significantly correlated with the sum of sucrose and fructose concentration in urine (0.888; P < 0.001). To assess effects with volunteers consuming their habitual varying diets, seven males and six females were fed their usual diet (assessed beforehand from four consecutive self-completed 7-day food diaries) for 30 days under controlled conditions in the volunteer suite. The mean (+/-SD) calculated total sugars intake was 202 +/- 69 g/d, 41% from sucrose. Mean (+/-SD) urinary sucrose and fructose were 36.6 +/- 16.6 and 61.8 +/- 61.3 mg/d, respectively. The sum of sucrose and fructose in urine was significantly correlated with sugars (0.841; P