Sabine Westphal

Elevated plasma concentrations of homocysteine, a sulfur-containing amino acid, are a risk factor for coronary, cerebral and peripheral artery disease. Next to other factors, drugs used for the prevention or treatment of cardiovascular disease may modulate plasma homocysteine levels. Thus, a drug induced homocysteine increase may counteract the desired cardioprotective effect. The aim is to summarize the current knowledge on the effect of two important classes of drugs, lipid-lowering drugs and anti-hypertensive drugs, on homocysteine metabolism. Among the lipid-lowering drugs, especially the fibric acid derivatives, which are used for treatment of hypertriglyceridemia and low HDL-cholesterol, are associated with an increase of homocysteine by 20%-50%. This increase can be reduced, but not totally avoided by the addition of folic acid, vitamin B12 and B6 to fibrates. HMG-CoA reductase inhibitors (statins) do not influence homocysteine concentrations substantially. The effects of nic...

Ghrelin, a known orexigenic hormone, has been demonstrated to be produced and released by salivary glands. Obtaining saliva for metabolism studies would be preferable for patients since the procedure is non-invasive. The present study examined serum and salivary ghrelin levels in 41 morbidly obese subjects, 45 healthy controls, and 17 patients with metastatic carcinoma by using a commercial radioimmunoassay. When comparing serum and salivary levels under fasting conditions, ghrelin levels were significantly higher in saliva for morbidly obese and healthy subjects. A significant correlation between salivary and serum ghrelin could only be demonstrated for healthy subjects. Fasting serum ghrelin concentrations in morbidly obese patients were significantly lower compared with healthy controls and cancer patients, however the levels in whole saliva did not differ significantly between all groups. There was only a highly significant inverse correlation between BMI and serum ghrelin. Serum ghrelin correlated positively with age in morbidly obese. There was no significant difference in serum and saliva ghrelin concentrations between men and women. Following the standardized meal, no significant suppression of serum ghrelin levels in morbidly obese was observed, however salivary ghrelin concentrations were significantly decreased. The results of the present study support the hypothesis that there is an autonomous production of ghrelin in the salivary glands. Further research should focus on factors involved in the regulation of salivary ghrelin. Until the mechanism of regulation is fully understood, the testing of ghrelin levels in saliva is too limited to recommend a switch from serum testing.

Weight loss is associated with increased levels of adiponectin with a greater increase observed following Roux-en-Y gastric bypass (RYGB) compared to restrictive procedures. However, currently there are no data on changes in adiponectin following laparoscopic sleeve gastrectomy (LSG). Ghrelin was reported to be also produced by the salivary glands. There are also no data available regarding its changes following bariatric surgery. The present study examined weight loss, and salivary ghrelin and HMW adiponectin levels in 43 morbidly obese subjects undergoing three different types of bariatric surgery. We found that weight loss following LSG is superior to laparoscopic adjustable gastric banding (LAGB) and comparable to RYGB at 12 months after surgery. Although blood glucose decreased similarly following all three procedures, fasting insulin continuously declined only in LSG and RYGB patients. Changes in both fasting and postprandial salivary ghrelin greatly varied between all three procedures with no similarities to changes in serum ghrelin reported in the literature. HMW adiponectin significantly increased following LSG, and this increase was more marked than in LAGB patients and almost identical compared to RYGB. Weight loss following LSG is comparable to RYGB in the short term. Changes in HMW adiponectin are comparable following LSG and RYGB which may further contribute to the successful results after LSG. Furthermore, the results of the present study support the hypothesis that there is an autonomous production of ghrelin in salivary glands irrespective of nutritional status and weight loss.

Seven healthy, normal-weight subjects were fed breakfasts of 50 g protein, 50 g glucose, and 10, 30, or 50 g protein plus 50 g glucose in random sequence. Plasma glucose, insulin, C peptide, glucagon, nonesterified fatty acids, and alpha-amino nitrogen were then measured from samples obtained over 4 h. The postmeal net area of each response curve was calculated. Ingestion of 50 g protein alone did not change the serum glucose concentration. The various amounts of protein ingested with 50 g glucose also did not alter the serum glucose response compared with that observed with 50 g glucose alone. Ingestion of the various amounts of protein also did not result in a further increase in insulin concentration when ingested with glucose, except with the 50-g-protein dose. This increase was modest. Ingestion of glucose resulted in a decrease in alpha-amino nitrogen and glucagon concentrations whereas ingestion of protein increased them as expected. Additions of progressively larger amounts of protein to the glucose meal resulted in a progressive increase in the alpha-amino-nitrogen- and glucagon-area responses. The relationship was curvilinear for both the alpha-amino-nitrogen response and the glucagon response. The null point, that is, the protein dose ingested with 50 g glucose at which there would be no change in area response, was estimated to be 9 g protein for alpha-amino nitrogen and 5 g protein for glucagon.

Weight loss is associated with increased levels of adiponectin with a greater increase observed following Roux-en-Y gastric bypass (RYGB) compared to restrictive procedures. However, currently there are no data on changes in adiponectin following laparoscopic sleeve gastrectomy (LSG). Ghrelin was reported to be also produced by the salivary glands. There are also no data available regarding its changes following bariatric surgery. The present study examined weight loss, and salivary ghrelin and HMW adiponectin levels in 43 morbidly obese subjects undergoing three different types of bariatric surgery. We found that weight loss following LSG is superior to laparoscopic adjustable gastric banding (LAGB) and comparable to RYGB at 12 months after surgery. Although blood glucose decreased similarly following all three procedures, fasting insulin continuously declined only in LSG and RYGB patients. Changes in both fasting and postprandial salivary ghrelin greatly varied between all three procedures with no similarities to changes in serum ghrelin reported in the literature. HMW adiponectin significantly increased following LSG, and this increase was more marked than in LAGB patients and almost identical compared to RYGB. Weight loss following LSG is comparable to RYGB in the short term. Changes in HMW adiponectin are comparable following LSG and RYGB which may further contribute to the successful results after LSG. Furthermore, the results of the present study support the hypothesis that there is an autonomous production of ghrelin in salivary glands irrespective of nutritional status and weight loss.

Ghrelin, a known orexigenic hormone, has been demonstrated to be produced and released by salivary glands. Obtaining saliva for metabolism studies would be preferable for patients since the procedure is non-invasive. The present study examined serum and salivary ghrelin levels in 41 morbidly obese subjects, 45 healthy controls, and 17 patients with metastatic carcinoma by using a commercial radioimmunoassay. When comparing serum and salivary levels under fasting conditions, ghrelin levels were significantly higher in saliva for morbidly obese and healthy subjects. A significant correlation between salivary and serum ghrelin could only be demonstrated for healthy subjects. Fasting serum ghrelin concentrations in morbidly obese patients were significantly lower compared with healthy controls and cancer patients, however the levels in whole saliva did not differ significantly between all groups. There was only a highly significant inverse correlation between BMI and serum ghrelin. Serum ghrelin correlated positively with age in morbidly obese. There was no significant difference in serum and saliva ghrelin concentrations between men and women. Following the standardized meal, no significant suppression of serum ghrelin levels in morbidly obese was observed, however salivary ghrelin concentrations were significantly decreased. The results of the present study support the hypothesis that there is an autonomous production of ghrelin in the salivary glands. Further research should focus on factors involved in the regulation of salivary ghrelin. Until the mechanism of regulation is fully understood, the testing of ghrelin levels in saliva is too limited to recommend a switch from serum testing.

Vitamin deficiencies are common in patients with end-stage renal disease (ESRD) owing to dietary restrictions, drug-nutrient interactions, changes in metabolism, and vitamin losses during dialysis. The present study investigated the levels of serum and red blood cell (RBC) folate, plasma pyridoxal-5'-phosphate (PLP), serum cobalamin, blood thiamine, blood riboflavin, and plasma homocysteine (tHcy) before and after haemodialysis treatment. Vitamin and tHcy blood concentrations were measured in 30 patients with ESRD before and after dialysis session either with low-flux (n = 15) or high-flux (n = 15) dialysers. After the dialysis procedure, significantly lower concentrations of serum folate (37%), plasma PLP (35%), blood thiamine (6%) and blood riboflavin (7%) were observed. No significant changes were found for serum cobalamin or for RBC folate. There were no differences in the washout of water-soluble vitamins between treatments with low-flux and high-flux membranes. Furthermore, a 41% lower concentration in tHcy was observed. The percentage decrease in tHcy was significantly greater in the patients treated with high-flux dialysers (48% vs 37%; P < 0.01). The percentage change during dialysis was significantly inversely related to the molecular weight of the vitamins measured (r =-0.867, P < 0.01). This study showed significantly lower blood or serum levels of various water-soluble vitamins after dialysis, independently of the dialyser membrane. The monitoring of the vitamin status is essential in patients treated with high-flux dialysers as well as in patients treated with low-flux dialysers.

As, for ethical reasons, it is difficult to investigate by an experiment the effect of acute intoxication on leptin levels in alcoholics, we tested the hypothesis of lowered levels as an effect of acute ethanol intake in healthy volunteers. The subjects comprised (1) 17 healthy male participants, recruited via newspaper advertisements [age 29+/-3.75 years, body mass index (BMI) 24.3+/-3.5, leptin at baseline 3.3+/-3.1 ng/ml]; (2) for comparison, leptin levels of 16 male alcoholic patients at day 1 of withdrawal were used. They were characterized as follows: (mean, median, standard deviation and range) age in years (41.1, 40.5, 10.2, 24, 57), BMI (23.3, 21.7, 5.4, 16.6, 37.5), 1,032 g of ethanol (median) consumed within the last 7 days, leptin levels 2.3 mg/ml. A placebo-controlled double-blind trial was performed. Leptin levels of blood samples were taken at baseline (t(1)), before ethanol intake (t(2)), when blood alcohol had reached its maximum (t(3)) and the morning after (t(4)). The oral dose of ethanol administered was 0.6 g/kg ethanol. (1) VOLUNTEERS: (a) the ethanol and placebo group exhibited leptin levels corresponding closely with levels measured at baseline (t(1)) (rs=0.85, p<0.0001) and follow-up (t(4)) (rs=0.768, p<0.0001). (b) Leptin levels for the placebo and the alcohol-consuming (verum) group did not differ significantly at baseline, after ethanol intake or on the morning after [Mann-Whitney U-test (p=0.669, p=1.0 and p=0.887, respectively)]. (2) Leptin levels in relation to BMI did not significantly differ at any measurement time in either group. (3) Leptin levels/BMI of the healthy volunteers at t(1) and t(4) were not significantly different from those of 16 alcoholics. The data do not support the hypothesis of a significant effect of acute moderate alcohol intake on leptin levels in healthy volunteers.

Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-β) appear to be state markers, whereas IL-12, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia.

Persisting chylomicron remnant concentrations have been linked to premature atherosclerosis. The analysis of persisting chylomicron remnant concentrations by an oral triglyceride tolerance test, however, is time-consuming for the study subjects and requires large resources in the laboratory. Therefore, only small numbers of subjects have been studied in the past.We describe major improvements of the testing procedure in regard of composition of the fatty meal, of patient testing, and measurement of postprandial remnants. Shifting the time of the (ready-to-use) fatty drink from the morning hours to bedtime was well accepted by the study subjects and allowed the analysis of blood samples drawn at the morning with minimal impact on the participants’ time and with minimal interferences by confounding factors (e.g. smoking, additional food intake, physical activity). Chylomicron remnants were measured by fluorometry of the supernatant after ultracentrifugation. This procedure was sensitive, was specific for chylomicron remnants, and was easy to perform. The biological validity of the improved procedure was evaluated by studying type III hyperlipoproteinemia patients and normolipemic apolipoprotein (Apo) E2 homozygotes.In conclusion, this improved test permits the rapid testing for persisting chylomicron remnants in the clinical routine and in large epidemiological studies.

Previous studies of lymphocyte distribution in schizophrenia have yielded inconsistent results, as summarized in the present study. Based on our own original data, potential confounds that might explain these variations are analyzed and discussed. Blood samples from 26 patients with acute paranoid schizophrenia were investigated in comparison with 32 matched healthy controls by flow cytometry (CD3, CD4, CD8, CD19, and CD56 phenotyping). A subgroup of drug-free patients was followed up after 6 weeks of treatment. Cotinine levels and the free cortisol index (FCI) were provided in order to control for medication, smoking, and stress. Cotinine levels correlated with natural killer (NK) cell counts (CD3⁻/CD56(+): r = -0.383, P = 0.003) while the FCI was related to B cell numbers (CD19(+): r = 0.390, P = 0.003). Considering these covariates, a lower level of T helper cells (P = 0.010), a reduced CD4/CD8 ratio (P = 0.029), and elevated B cells (P = 0.008) were found during acute psychosis. After 6 weeks of medication, an inverse pattern was observed in initially drug-free patients: total T cell (P = 0.005), T helper (P = 0.003), and T suppressor/cytotoxic cells (P = 0.005) increased, while B cell counts declined (P = 0.049). In conclusion, acute paranoid schizophrenia may be accompanied by a reduced T cell defense and a shift towards B cell immunity, which normalizes in response to treatment. In addition to disease stage or subtype and medication, cigarette smoking and stress are important co-factors.

Major depression increases cardiovascular risk despite lower cholesterol levels. Little is known about effects of antidepressants on metabolic risk factors. We studied lipoprotein composition, insulin sensitivity (quantitative insulin sensitivity check index), and saliva cortisol in 78 depressed patients before and after 35 days of amitriptyline or paroxetin treatment. Data were analyzed by principal component factor analyses and analysis of variance (ANOVA). At baseline, quantitative insulin sensitivity check index was inversely correlated with cortisol (r = -0.46; P = 0.005) in normal weight patients, with body mass index in overweight patients (r = -0.50; P < 0.001). In overweight patients, hypercortisolemia correlated inversely with total and low density lipoprotein cholesterol (eg, cortisol at 4:00 PM and low density lipoprotein cholesterol: r = -0.49, P = 0.002). After treatment, quantitative insulin sensitivity check index was unchanged. Triglycerides increased in responders to amitriptyline only (P < 0.05). Parameters of cholesterol metabolism improved slightly without differences between treatment groups (eg, high density lipoprotein: pre 43.5 +/- 12.0; post 47.6 +/- 13.0 mg/dL; P = 0.01; low density lipoprotein triglycerides, a measure of low density lipoprotein atherogenicity: pre 458 +/- 120; post 415 +/- 130 mg/g; P < 0,01). The inverse correlation of cortisol and cholesterol, at least in the obese subgroup, proposes a mechanism for the known association of depression with low cholesterol. As determinants of plasma lipids in major depression, we identified body mass index, insulin sensitivity, and cortisol. Although uncontrolled, our data suggest that treatment of depression exerts a mainly beneficial effect on lipid regulation.

A simplified feed system for the Na used in the Na-SiFâ reactor has been developed. Solid Na is added directly to the reaction zone, thus avoiding the handling of liquid Na. The reduction of sodium fluosilicate with sodium metal has been proven to be an alternative path for the production of high purity silicon. Batches containing about 1 kg of silicon have been produced with a purity similar to the products obtained with the SiFâ-Na reaction. During the leaching process to recover silicon from the products of the SiFâ-Na reaction, hydrogen is evolved. Kinetic studies indicate that the hydrogen evolution may be a diffusion-limited process. Mechanism studies are continuing; at present, it appears that small amounts of sodium are incorporated in the silicon, although the type of inclusion is uncertain. During leaching, the resulting local regions of high alkalinity could promote the oxidation of silicon. Studies of silicon separation by the melting of the reaction product have been continued. Analyses have been made of the purification of the processes of melting and solidification. Reaction products from both the SiF-Na reaction and the Na-SiF-Na reaction have been successfully separated by melting to yield silicon in bulk form.

A process was developed for the economic production of high purity Si from inexpensive reactants, based on the Na reduction of SiF4 gas. The products of reaction (NaF, Si) are separated by either aqueous leaching or by direct melting of the NaF-Si product mixture. Impurities known to degrade solar cell performance are all present at sufficiently low concentrations so that melt solidification (e.g., Czochralski) will provide a silicon material suitable for solar cells.

Elevated blood levels of S100B in neuropsychiatric disorders have so far been mainly attributed to glial pathologies. However, increases or dysfunction of adipose tissue may be alternatively responsible. Our study assessed S100B serum levels in 60 adult subjects without a prior history of neuropsychiatric disorders. S100B concentrations were closely correlated with the body mass index (BMI, range 18-45 kg/m(2)) as well as levels of leptin and adipocyte-type fatty acid-binding protein (A-FABP/FABP4) that are well-known adipose-related factors. Effect sizes as measured by Cohen's d indicated medium (0.8 > d > 0.5) to strong effects (d > 0.9) of BMI on S100B blood levels. In conclusion, physiological S100B levels in humans appear to closely reflect adipose tissue mass, which should therefore be considered as an important confounding factor in clinical studies examining the role of S100B.

The appetite-stimulating hormone ghrelin is a fundamental regulator of human energy metabolism. A series of studies support the notion that long-term appetite and weight regulation may be already programmed in early life and it could be demonstrated that the intrauterine environment affects the ghrelin system of the offspring. Animal studies have also shown that intrauterine programming of orexigenic systems persists even until adolescence/adulthood. We hypothesized that plasma ghrelin concentrations in adulthood may be associated with the intrauterine exposure to cigarette smoke. We examined this hypothesis in a sample of 19-year-olds followed up since birth in the framework of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study of the long-term outcome of early risk factors. As a main finding, we found that ghrelin plasma concentrations in young adults who had been exposed to cigarette smoke in utero were significantly higher than in those without prena...

To examine prospectively whether early parental child-rearing behavior is a predictor of cardiometabolic outcome in young adulthood when other potential risk factors are controlled. Metabolic factors associated with increased risk for cardiovascular disease have been found to vary, depending on lifestyle as well as genetic predisposition. Moreover, there is evidence suggesting that environmental conditions, such as stress in pre- and postnatal life, may have a sustained impact on an individual's metabolic risk profile. Participants were drawn from a prospective, epidemiological, cohort study followed up from birth into young adulthood. Parent interviews and behavioral observations at the age of 3 months were conducted to assess child-rearing practices and mother-infant interaction in the home setting and in the laboratory. In 279 participants, anthropometric characteristics, low-density lipoprotein and high-density lipoprotein cholesterol, apolipoproteins, and triglycerides were...

Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolis...

Elevated blood levels of S100B in schizophrenia have so far been mainly attributed to glial pathology, as S100B is produced by astro- and oligodendroglial cells and is thought to act as a neurotrophic factor with effects on synaptogenesis, dopaminergic and glutamatergic neutrotransmission. However, adipocytes are another important source of S100B since the concentration of S100B in adipose tissue is as high as in nervous tissue. Insulin is downregulating S100B in adipocytes, astrocyte cultures and rat brain. As reviewed in this paper, our recent studies suggest that overweight, visceral obesity, and peripheral/cerebral insulin resistance may be pivotal for at least part of the elevated S100B serum levels in schizophrenia. In the context of this recently identified framework of metabolic disturbances accompanying S100B elevation in schizophrenia, it rather has to be attributed to systemic alterations in glucose metabolism than to be considered a surrogate marker for astrocyte-specifi...

Visfatin is a recently described protein that is thought to regulate the process of adipocyte differentiation. Findings suggest that visfatin may be actively involved in the control of weight regulatory networks. However, to what extent and which role it plays in eating disorders is still poorly understood, as mixed results have been reported. The aim of the current study was to investigate serum visfatin concentrations on a cross sectional sample between acute anorexia nervosa patients (n=44), weight recovered patients (n=13) and healthy controls (n=46) and a longitudinal sample of acute patients (n=57) during weight recovery at three different time-points. Results did not show significant differences in visfatin between the three groups; however, acute patients showed a higher visfatin/BMI-SDS ratio than controls and recovered patients. Longitudinal results revealed an increase of visfatin levels during therapy. Our results suggest that high ratios of visfatin/BMI-SDS could be a s...

The present study in the South American rodent Octodon degus shows for the first time that the postnatal development of hypothalamic-pituitary-adrenal axis function in this semi-precocial species differs from that of altricial rodents, i.e. rats or mice, in several aspects. Our experiments revealed a particular pattern of hypothalamic-pituitary-adrenal axis activity during the first 3 weeks of life characterized by (i) a period of low plasma glucocorticoid concentrations, during which (ii) brief stress exposure (1 h parental separation) is able to elevate glucocorticoids significantly. In addition, (iii) repeated stress exposure (1 h parental separation daily) during the first 3 weeks of life resulted in females, but not in males, in an attenuated separation-induced increase of glucocorticoids, and a higher behavioural activity in both sexes at postnatal day 21. These data indicate that parental separation early in life acts as a 'strong' stressor in this species, which on the long run can alter endocrine stress response at the time of weaning in a sex-specific manner. These findings support the role of the hypothalamic-pituitary-adrenal axis as one of the key factors mediating the effects of early life stress on the neuronal network and behaviour in O. degus.

Elevated blood levels of S100B in neuropsychiatric disorders have so far been mainly attributed to glial pathologies. However, increases or dysfunction of adipose tissue may be alternatively responsible. Our study assessed S100B serum levels in 60 adult subjects without a prior history of neuropsychiatric disorders. S100B concentrations were closely correlated with the body mass index (BMI, range 18-45 kg/m(2)) as well as levels of leptin and adipocyte-type fatty acid-binding protein (A-FABP/FABP4) that are well-known adipose-related factors. Effect sizes as measured by Cohen's d indicated medium (0.8 > d > 0.5) to strong effects (d > 0.9) of BMI on S100B blood levels. In conclusion, physiological S100B levels in humans appear to closely reflect adipose tissue mass, which should therefore be considered as an important confounding factor in clinical studies examining the role of S100B.