Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels.

Calibrated integrated backscatter and myocardial fibrosis in patients undergoing cardiac surgery.

Objective - The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis is based on study of patients with dilated or hypertrophic cardiomyopathy and extensive (mean 15–34%) fibrosis. Its association with lesser degrees of fibrosis is unknown. We examined the relationship between cIB and myocardial fibrosis in patients with coronary artery disease.

Methods - Myocardial histology was examined in left ventricular epicardial biopsies from 40 patients (29 men and 11 women) undergoing coronary artery bypass graft surgery, who had preoperative echocardiography with cIB measurement.

Results - Total fibrosis (picrosirius red staining) varied from 0.7% to 4%, and in contrast to previous reports, cIB showed weak inverse associations with total fibrosis (r=−0.32, p=0.047) and interstitial fibrosis (r=−0.34, p=0.03). However, cIB was not significantly associated with other histological parameters, including immunostaining for collagens I and III, the advanced glycation end product (AGE) Nε-(carboxymethyl)lysine (CML) and the receptor for AGEs (RAGE). When biomarkers were examined, cIB was weakly associated with log plasma levels of amino-terminal pro-B-type natriuretic peptide (r=0.34, p=0.03), creatinine (r=0.33, p=0.04) and glomerular filtration rate (r=−0.33, p=0.04), and was more strongly associated with log plasma levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) (r=0.44, p=0.01) and soluble RAGE (r=0.53, p=0.002).

Conclusions - Higher cIB was not a marker of increased myocardial fibrosis in patients with coronary artery disease, but was associated with higher plasma levels of sVEGFR-1 and soluble RAGE. The role of cIB as a non-invasive index of fibrosis in clinical studies of patients without extensive fibrosis is, therefore, questionable.

Persistent endothelial activation and inflammation after Plasmodium falciparum Infection in Malawian children

Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits. These vascular changes may represent a previously unrecognized contributor to ongoing malaria-associated morbidity and mortality.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

Experimentally elevated plasma testosterone levels do not influence singing behaviour of male blue tits (Parus caeruleus) during the early breeding season

Sexual selection theory suggests that females might prefer males on the basis of testosterone (T)-dependent secondary sexual traits such as song. Correlational studies have linked high plasma T-levels to high diurnal song output. This has been confirmed in experiments where T-levels were kept high at times when natural T-levels have decreased. However, surprisingly little is known about the relation between T-levels during the early breeding season and song. In many passerine birds males sing at a high rate at dawn early in the breeding season, referred to as the dawn chorus. In blue tits (Parus caeruleus), the dawn chorus coincides with the fertile period of the female, whereas diurnal song occurs throughout the breeding season. Previous studies on blue tits showed that characteristics of the dawn chorus correlate with male reproductive success. We experimentally elevated plasma T-levels in male blue tits during the pre-fertile and fertile period. Our aim was to test whether increased plasma T-levels affect dawn song characteristics and increase the amount of diurnal song. Although T-implants successfully raised circulating T-levels, we did not find any difference between T- and control males in temporal performance measures of dawn song or in diurnal song output. Our results suggest that either there is no direct causal link between song output or quality and individual T-levels, or experimental manipulations of T-levels using implants do not permit detection of such effects during the early breeding season. Although we cannot exclude that individual T-levels are causally linked to other (e.g. structural) song parameters, our results cast doubt on T-dependence as the mechanisms that enforces honesty on song as a sexually selected trait.

Chronic treatment with a stable obestatin analogue significantly alters plasma triglyceride levels but fails to influence food intake, fluid intake, body weight, or body composition in rats.

Obestatin (OB(1-23) is a 23 amino acid peptide encoded on the preproghrelin gene, originally reported to have metabolic actions related to food intake, gastric emptying and body weight. The biological instability of OB(1-23) has recently been highlighted by studies demonstrating its rapid enzymatic cleavage in a number of biological matrices. We assessed the stability of both OB(1-23) and an N-terminally PEGylated analogue (PEG-OB(1-23)) before conducting chronic in vivo studies. Peptides were incubated in rat liver homogenate and degradation monitored by LC-MS. PEG-OB(1-23) was approximately 3-times more stable than OB(1-23). Following a 14 day infusion of Sprague Dawley rats with 50 mol/kg/day of OB(1-23) or a N-terminally PEGylated analogue (PEG-OB(1-23)), we found no changes in food/fluid intake, body weight and plasma glucose or cholesterol between groups. Furthermore, morphometric liver, muscle and white adipose tissue (WAT) weights and tissue triglyceride concentrations remained unaltered between groups. However, with stabilised PEG-OB(1-23) we observed a 40% reduction in plasma triglycerides. These findings indicate that PEG-OB(1-23) is an OB(1-23) analogue with significantly enhanced stability and suggest that obestatin could play a role in modulating physiological lipid metabolism, although it does not appear to be involved in regulation of food/fluid intake, body weight or fat deposition.

Plasma cortisol levels and illness appraisal in deficit syndrome schizophrenia

Research investigating the association between negative symptoms and plasma cortisol levels in individuals with schizophrenia has produced inconsistent findings. This study investigated whether deficit syndrome schizophrenia (characterized by high levels of primary negative symptoms) is associated with comparatively high morning plasma cortisol levels, more negative appraisals about illness and higher levels of depression. Participants were 85 individuals diagnosed with schizophrenia and 85 individuals with no history of contact with psychiatric services matched for age and gender. All participants provided fasting 9.00 a.m. plasma cortisol samples. There were no significant differences between the schizophrenia and control participants in plasma cortisol levels. The Proximal Deficit Syndrome method was used to identify individuals with deficit syndrome schizophrenia. Contrary to what had been hypothesized, participants with deficit syndrome schizophrenia had significantly lower plasma cortisol levels than both non-deficit syndrome participants and control participants. Participants with the deficit syndrome reported significantly less negative appraisals about illness (assessed by PBIQ) and lower levels of depression (assessed by BDI-II). Differences in cortisol levels continued to trend toward significance when levels of depression were controlled for. The patterns of illness-related appraisals and plasma cortisol levels raise the possibility that the deficit syndrome could be a form of adaptation syndrome.

Plasma Clusterin Levels and the rs11136000 Genotype in Individuals with Mild Cognitive Impairment and Alzheimer's Disease

Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD.

Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay.

Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 +/- 61.3 and 193.6 +/- 58.2 vs. 178.6 +/- 52.3 mu g/ml, respectively; p

Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.

Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC–MS metabolomics

Introduction: Obestatin is a controversial gastrointestinal peptide purported to have metabolic actions.

Objectives: This study investigated whether treatment with a stable obestatin analogue (PEG-OB(Cys10, Cys13)) changed plasma metabolite levels firstly in lean and subsequently in diet-induced obesity (DIO) C57BL6/J mice.

Methods: Untargeted LC-HRMS metabolomics experiments were carried out in ESI + mode with plasma extracts from both groups of animals. Data were normalised, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified.

Results: In lean mice, 39 metabolites were significantly changed by obestatin treatment and the majority of these were increased, including various C16 and C18 moieties of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and monoacylglycerol, along with vitamin A, vitamin D3, tyrosine, acetylcarnitine and 2α-(hydroxymethyl)-5α-androstane-3β,17β-diol. Decreased concentrations of glycolithocholic acid, 3-dehydroteasterone and various phospholipids were observed. In DIO mice, 25 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater in DIO mice than in lean mice, and in contrast, the majority of metabolite changes were decreases. Four metabolites affected in both groups included glycolithocholic acid, and three different long-chain (C18) phospholipid molecules (phosphatidylethanolamine, platelet activating factor (PAF), and monoacylglycerol). Metabolites exclusively affected in DIO mice included various phosphatidylcholines, lysophosphatidylcholines and fatty acyls, as well as creatine and oxidised glutathione.

Conclusion: This investigation demonstrates that obestatin treatment affects phospholipid turnover and influences lipid homeostasis, whilst providing convincing evidence that obestatin may be acting to ameliorate diet-induced impairments in lipid metabolism, and it may influence steroid, bile acid, PAF and glutathione metabolism.