Plasma metabolite profiles in children with current asthma.

BACKGROUND: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. OBJECTIVE: To identify differences in plasma metabolites between children with and without current asthma at mid-childhood. METHODS: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid-childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case-control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. RESULTS: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1-Methyl-2-pyridone-5-carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1-8.0)), a pyrimidine metabolite (5,6-dihydrothymine (OR = 0.4 (95% CI 0.2-0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1-0.9), taurocholate (OR = 2.0 (95% CI 1.2-3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p-cresol sulphate OR = 0.5 (95% CI 0.2-0.9)). The associations for N1-Methyl-2-pyridone-5-carboxamide and p-cresol sulphate replicated in the independent VDAART population (one-sided P values = .03-.04). CONCLUSIONS AND CLINICAL RELEVANCE: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome.

Genome-wide association study of leukotriene modifier response in asthma.

Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.

Biochar and peat amendments affect nitrogen retention, microbial capacity and nitrogen cycling microbial communities in a metal and polycyclic aromatic hydrocarbon contaminated urban soil.

Soil contaminants may restrict soil functions. A promising soil remediation method is amendment with biochar, which has the potential to both adsorb contaminants and improve soil health. However, effects of biochar amendment on soil-plant nitrogen (N) dynamics and N cycling microbial guilds in contaminated soils are still poorly understood. Here, a metal- and polycyclic aromatic hydrocarbon (PAH) contaminated soil was amended with either biochar (0, 3, 6 % w/w) and/or peat (0, 1.5, 3 % w/w) in a full-factorial design and sown with perennial ryegrass in an outdoor field trial. After three months, N and the stable isotopic ratio δ15N was measured in soil, roots and leaves, along with microbial responses. Aboveground grass biomass decreased by 30 % and leaf N content by 20 % with biochar, while peat alone had no effect. Peat in particular, but also biochar, stimulated the abundance of microorganisms (measured as 16S rRNA gene copy number) and basal respiration. Microbial substrate utilization (MicroResp™) was altered differentially, as peat increased respiration of all carbon sources, while for biochar, respiration of carboxylic acids increased, sugars decreased, and was unaffected for amino acids. Biochar increased the abundance of ammonia oxidizing archaea, while peat stimulated ammonia oxidizing bacteria, Nitrobacter-type nitrite oxidizers and comB-type complete ammonia oxidizers. Biochar and peat also increased nitrous oxide reducing communities (nosZI and nosZII), while peat alone or combined with biochar also increased abundance of nirK-type denitrifiers. However, biochar and peat lowered leaf δ15N by 2-4 ‰, indicating that processes causing gaseous N losses, like denitrification and ammonia volatilization, were reduced compared to the untreated contaminated soil, probably an effect of biotic N immobilization. Overall, this study shows that in addition to contaminant stabilization, amendment with biochar and peat can increase N retention while improving microbial capacity to perform important soil functions.

The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer.

BACKGROUND: Mutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC. PATIENTS: We analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n=197) and Colorectal Cancer in Umeå Study (CRUMS; n=414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression. RESULTS: Quadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P=0.003 and CRUMS; P=0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information. CONCLUSIONS: Our results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC.

Expression and immunolocalization of the plasma membrane monoamine transporter in the brain.

High affinity monoamine transporters efficiently terminate neurotransmission through synaptic reuptake of released neurotransmitter. We recently cloned and characterized a novel low-affinity, high capacity plasma membrane monoamine transporter (PMAT) that is strongly expressed in the human brain and efficiently transports 5-HT and dopamine (DA). In efforts to understand the physiological function of PMAT and its relevance in monoaminergic pathways, we cloned the PMAT homolog from the mouse brain, demonstrated its capability for transporting 5-HT and DA, and determined the regional and cellular localization of mouse plasma membrane monoamine transporter (mPMAT) in adult mouse brain by reverse-transcription polymerase chain reaction, non-radioactive in situ hybridization, and immunohistochemical methods. Our results showed that mPMAT mRNA and protein are broadly expressed in the mouse brain and are particularly abundant in forebrain cortex, olfactory tubercle, hippocampus, cerebellum and epithelial cells of the choroid plexus. Dual-immunofluorescence histochemistry with established phenotypic markers microtubule-associated protein (MAP2) and glial fibrillary acidic protein (GFAP) revealed that mPMAT is expressed in neuronal cells but not in astrocytes. mPMAT is co-expressed in many brain regions with the high affinity 5-HT transporter (SERT) and the dopamine transporter (DAT), but is also found in certain sites that receive monoamine innervation but lack significant expression of SERT or DAT. These findings suggest that mPMAT is a widely distributed, neuronally-expressed transporter, which may support the role of 5-HT and DA uptake under certain conditions.

Soil amendment affects Cd uptake by wheat - are we underestimating the risks from chloride inputs?

Many parts of the world are investigating the efficacy of recycling nutrient resources to agriculture from different industry and domestic sectors as part of a more circular economy. The complex nature of recycled products as soil amendments coupled to the large diversity of soil types and their inherent properties make it difficult to optimize the benefits and minimize the risks from potentially toxic elements often present in recycled materials. Here we investigated how wheat grain cadmium (Cd) concentration was affected by soil amendments, namely human urine and biogas digestate compared to traditional farm manures and mineral fertilizers. We show that Cl(-) inadvertently added to soils with e.g. urine or biogas digestate strongly increased crop Cd concentrations, largely by mobilizing inherent soil Cd. This resulted in wheat grain Cd levels that could result in exceeding recommended WHO limits for dietary intake. This was evident even in soils with low inherent Cd content and when Cd inputs were low. The future of a circular economy that helps to underpin global food security needs to ensure that the effects of applying complex materials to different types of agricultural land are fully understood and do not jeopardize food safety.

The "90 degrees bent" two-stage venous cannula.

A 90 degree bent two-stage venous cannula for cardiopulmonary bypass is presented and discussed. Its main advantages, compared to similar straight ones, are that it is out of the way of the surgeon, by being placed under the right sternum and also that the venous return seems uninfluenced by displacement of the heart when operating on the posterior side of the heart. No major drawbacks for the cannula have been noticed so far.

The de-airing clamp in cardiac surgery.

De-airing of the heart in open heart surgery is a necessary routine. Most of the air is evacuated from the heart before the aortic cross clamp is removed, but the de-airing may be continued even after declamping. One way to continue de-airing is to partially clamp the ascending aorta, proximally to the aortic cannula, in order to create a pocket for trapping residual air coming from the left ventricle. This paper describes a clamp specially designed and developed for this purpose. It has been used in our center since 1990 and our experience is reported. The clamp has been used on 250 patients and in 50% ultrasonography has been used to examine the heart being free from air bubbles within 20 min from releasing the aortic cross clamp.

Health of women: associations among life events, social support, and personality for selected patient groups.

This study examined the effects of life events, social support, personality traits, and siblings' birth-order on the health of women. 199 middle-class participants were included. 95 women, randomly assigned from four different patient groups, were compared with a control group of 96 randomly selected women without any special health problems. They completed a questionnaire which included questions regarding family background, health, different life events, social support, and signs of disease and a projective test, the Sivik Psychosomatism Test. Analysis indicated that report of negative life events was associated with more physical symptoms than positive life events and that the patient groups reported more negative life events and less social support than the control group.

The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

A randomized controlled trial evaluating the effect of a support and education programme for spouses of people affected by stroke.

OBJECTIVE: To determine whether a nurse-led support and education programme for spouses of patients affected by stroke improved the psychological health of the spouses. DESIGN: A longitudinal, open, randomized controlled trial. SAMPLE: One hundred spouses of stroke patients were randomly assigned to either an intervention or a control group. SETTING: The study was conducted in a hospital setting. INTERVENTION: The intervention consisted of six group meetings during six months, with a follow-up after further six months. Comparison between the intervention and the control groups was made at baseline, after six and 12 months using analysis with repeated measures. MAIN MEASURES: The Comprehensive Psychopathological Rating Scale--Self-Affective for psychological health. RESULTS: No significant difference was found between the intervention and control groups concerning overall psychological health. However, a subanalysis revealed that those who participated more frequently in the group meetings (five or six times) had significantly stronger psychological health (P<0.05). Knowledge about stroke increased over time in both groups, but participants in the intervention group learned more (P=0.041). CONCLUSION: Encouraging participation in the group meetings of a support programme might have a positive effect on psychological health.

Insulin(GIK) improves myocardial metabolism in patients during blood cardioplegia.

The aim of this study was to test the hypothesis that abnormalities of myocardial substrate metabolism during blood cardioplegic aortic cross-clamping and early reperfusion are attenuated further by insulin(GIK) than by alpha-ketoglutarate enrichment of blood cardioplegia alone. Twenty-eight males (47 to 78 years) undergoing coronary artery bypass grafting (CABG) participated in a prospective, controlled, randomized study. All patients had alpha-ketoglutarate-enriched blood cardioplegia. Insulin(GIK) was infused in 13 patients during aortic cross-clamping. Insulin(GIK) prevented lactate release during cardioplegia (1.5+/-15 vs -44+/-14 micromol/min, p = 0.04), and a significant extraction of lactate was induced shortly after declamping the aorta (15+/-3 vs 2+/-1%, p = 0.001). Free fatty acid uptake was reduced after cardioplegic cross-clamping (5.7+/-1.6 vs 16.0+/-3.8 micromol/min, p = 0.02). More positive/less negative levels of alanine, aspartate, glutamine, glycine, ornithine, taurine and tyrosine were found in all the insulin-treated patients. We conclude that insulin(GIK) attenuates abnormalities of myocardial substrate metabolism during blood cardioplegic aortic cross-clamping and early reperfusion further than is obtained with alpha-ketoglutarate enrichment of blood cardioplegia alone.