Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients

Background A role of nociceptin and its receptor (NOP) in pain and immune function has been suggested. The hypothesis was that mRNA expression of NOP and the nociceptin precursor pre-pronociceptin (pN/OFQ) in peripheral blood cells differs in end-stage cancer patients suffering from chronic pain and septic intensive care unit (ICU) patients compared with healthy controls. Methods Blood samples were drawn from end-stage cancer patients and septic ICU patients. Additionally, postoperative patients representing individuals with surgical stress and healthy controls were enrolled as comparative groups. NOP and pN/OFQ mRNA expression, quantified by real-time polymerase chain reaction (RT-PCR), was compared between study groups, and associated to opioid medication, pain intensities, and the inflammatory markers procalcitonin (PCT) and interleukin-6. Results NOP expression was significantly higher in cancer patients [normalized ratio, median (inter-quartile range): 10.2 (7.4/17.8)], postoperative patients [8.0 (5.3/10.2)], and ICU patients [6.6 (4.2/9.5)] compared with healthy controls [4.4 (2.7/7.0); P<0.001]. Expression of pN/OFQ was lower in cancer patients [3.8 (1.9/5.9)] and ICU patients [1.9 (1.0/2.7)] but not in postoperative patients compared with healthy controls [7.2 (6.1/9.4); P<0.001]. Increased plasma PCT was associated with decreased pN/OFQ in all patient groups. In cancer patients, no association was seen with pain scores, opioid medication or duration of analgesia, and NOP or pN/OFQ mRNA. Conclusions NOP and pN/OFQ expression in peripheral blood cells was modulated in end-stage cancer and septic patients compared with healthy controls, whereas changes in postoperative patients were minor. The involvement of the NOP-pN/OFQ system in inflammation, impaired immune function, and pain has to be further elucidate

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Is the blue tit falling into an ecological trap in Argentine ant invaded forests?

Because insectivorous birds must evaluate resources for reproduction before settling into a breed- ing habitat, they can fall into an ecological trap if informative cues about habitat suitability become dissociated from their actual yield. Given their potential to affect ecological networks, invasive ant species are potential candidates for triggering such ecological traps. We combined observational and experimental approaches to examine whether the variation in food supply for nestlings resulting from the invasion of the Argentine ant, Linepithema humile, had any influence on the breeding ecology of the blue tit, Cyanistes caeruleus, an insectivorous foliage-gleaner. We inves- tigated the effects of the ant invasion on breeding performance (nesting success, clutch size, brood size and breeding success) and offspring quality (body size and condition, developmental stability and plumage colour) in replicated Mediterranean forest areas over a period of 3 years. There was no evidence that the reduction in caterpillar availability resulting from the invasion had a concurrent negative effect on the blue tit’s ability to successfully rear nestlings in optimal conditions, at least as measured here. Although the raw figures suggest an increased level of nutritional stress in blue tits breeding in invaded forests, the data analyses showed no significant alterations in terms of productiv- ity or offspring fitness. The reproductive performance of the blue tit has been shown to be remarkably resilient to the Argentine ant-mediated food shortage, either because the prey reduction following the invasion did not reach a critical threshold or because of compensa- tory activity by the progenitors. We cannot conclusively reject an ecological trap triggered by the ant invasion on blue tits, since neither fledgling recruitment nor the prospective survival of parents were assessed. Even though we could not confirm short-term consequences of the Argentine ant invasion on blue tit reproductive fitness, the long-term bottom-up effects of the invasion remain unknown and should not be ruled outPeer reviewe

Reference standardization and triglyceride interference of a new homogeneous HDL-cholesterol assay compared with a former chemical precipitation assay

A homogeneous HDL-c assay (HDL-H), which uses polyethylene glycol-modified enzymes and sulfated alpha-cyclodextrin, was assessed for precision, accuracy, and cholesterol and triglyceride interference. In addition, its analytical performance was compared with that of a phosphotungstic acid (PTA)/MgCl2 precipitation method (HDL-P). Within-run CVs were < or = 1.87%; total CVs were < or = 3.08%. Accuracy was evaluated in fresh normotriglyceridemic sera using the Designated Comparison Method (HDL-H = 1.037 Designated Comparison Method + 4 mg/L; n = 63) and in moderately hypertriglyceridemic sera by using the Reference Method (HDL-H = 1.068 Reference Method - 17 mg/L; n = 41). Mean biases were 4.5% and 2.2%, respectively. In hypertriglyceridemic sera (n = 85), HDL-H concentrations were increasingly positively biased with increasing triglyceride concentrations. The method comparison between HDL-H and HDL-P yielded the following equation: HDL-H = 1.037 HDL-P + 15 mg/L; n = 478. We conclude that HDL-H amply meets the 1998 NCEP recommendations for total error; its precision is superior compared with that of HDL-P, and its average bias remains below +/-5% as long as triglyceride concentrations are < or = 10 g/L and in case of moderate hypercholesterolemia

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases

Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial.

BACKGROUND: Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. CONCLUSIONS: LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM

Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

Synthesis of new DPP-4 inhibitors based on a novel tricyclic scaffold

A novel molecular scaffold has been synthesized and its synthesis and incorporation into new analogues of biologically active molecules will be discussed. A comparison of the inhibitory activity of these compounds to the known type-2 diabetes compound (sitagliptin) against dipeptidyl peptidase-4 (DPP-4) will be shown

‘I think I'm more free with them'—Conflict, Negotiation and Change in Intergenerational Relations in African Families Living in Britain

While the family is increasingly being recognised as pivotal to migration, there remain too few studies examining how migration impacts on intergenerational relationships. Although traditional intergenerational gaps are intensified by migration, arguably there has been an over-emphasis on the divisions between ‘traditional’ parents and ‘modern’ children at the expense of examining the ways in which both generations adapt. As Foner and Dreby [2011. “Relations Between the Generations in Immigrant Families.” Annual Review of Sociology 37: 545–564] stress, the reality of post-migration intergenerational relations is inevitably more complex, requiring the examination of both conflict and cooperation. This article contributes to this growing literature by discussing British data from comparative projects on intergenerational relations in African families (in Britain, France and South Africa). It argues that particular understandings can be gained from examining the adaptation of parents and parenting strategies post-migration and how the reconfiguration of family relations can contribute to settlement. By focusing on how both parent and child generations engage in conflict and negotiation to redefine their relationships and expectations, it offers insight into how families navigate and integrate the values of two cultures. In doing so, it argues that the reconfiguration of gender roles as a result of migration offers families the space to renegotiate their relationships and make choices about what they transmit to the next generation