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 .)

Collective Motion of Cells Mediates Segregation and Pattern Formation in Co-Cultures

Pattern formation by segregation of cell types is an important process during embryonic development. We show that an experimentally yet unexplored mechanism based on collective motility of segregating cells enhances the effects of known pattern formation mechanisms such as differential adhesion, mechanochemical interactions or cell migration directed by morphogens. To study in vitro cell segregation we use time-lapse videomicroscopy and quantitative analysis of the main features of the motion of individual cells or groups. Our observations have been extensive, typically involving the investigation of the development of patterns containing up to 200,000 cells. By either comparing keratocyte types with different collective motility characteristics or increasing cells' directional persistence by the inhibition of Rac1 GTP-ase we demonstrate that enhanced collective cell motility results in faster cell segregation leading to the formation of more extensive patterns. The growth of the characteristic scale of patterns generally follows an algebraic scaling law with exponent values up to 0.74 in the presence of collective motion, compared to significantly smaller exponents in case of diffusive motion

Lymphocytes Accelerate Epithelial Tight Junction Assembly: Role of AMP-Activated Protein Kinase (AMPK)

The tight junctions (TJs), characteristically located at the apicolateral borders of adjacent epithelial cells, are required for the proper formation of epithelial cell polarity as well as for sustaining the mucosal barrier to the external environment. The observation that lymphocytes are recruited by epithelial cells to the sites of infection [1] suggests that they may play a role in the modulation of epithelial barrier function and thus contribute to host defense. To test the ability of lymphocytes to modulate tight junction assembly in epithelial cells, we set up a lymphocyte-epithelial cell co-culture system, in which Madin-Darby canine kidney (MDCK) cells, a well-established model cell line for studying epithelial TJ assembly [2], were co-cultured with mouse lymphocytes to mimic an infection state. In a typical calcium switch experiment, the TJ assembly in co-culture was found to be accelerated compared to that in MDCK cells alone. This accelaration was found to be mediated by AMP-activated protein kinase (AMPK). AMPK activation was independent of changes in cellular ATP levels but it was found to be activated by the pro-inflammatory cytokine TNF-α. Forced suppression of AMPK, either with a chemical inhibitor or by knockdown, abrogated the accelerating effect of lymphocytes on TJ formation. Similar results were also observed in a co-culture with lymphocytes and Calu-3 human airway epithelial cells, suggesting that the activation of AMPK may be a general mechanism underlying lymphocyte-accelerated TJ assembly in different epithelia. These results suggest that signals from lymphocytes, such as cytokines, facilitate TJ assembly in epithelial cells via the activation of AMPK

Clinician perceptions of factors influencing referrals to a smoking cessation program

<p>Abstract</p> <p>Background</p> <p>Referral of patients to smoking cessation telephone counseling (i.e., quitline) is an underutilized resource by primary care physicians. Previously, we conducted a randomized trial to determine the effectiveness of benchmarked feedback on clinician referrals to a quitline. Subsequently, we sought to understand the successful practices used by the high-referring clinicians, and the perceptions of the barriers of referring patients to a quitline among both high and non-referring clinicians in the trial.</p> <p>Methods</p> <p>We conducted a qualitative sub-study with subjects from the randomized trial, comparing high- and non-referring clinicians. Structured interviews were conducted and two investigators employed a thematic analysis of the transcribed data. Themes and included categories were organized into a thematic framework to represent the main response sets.</p> <p>Results</p> <p>As compared to non-referring clinicians, high-referring clinicians more often reported use of the quitline as a primary source of referral, an appreciation of the quitline as an additional resource, reduced barriers to use of the quitline referral process, and a greater personal motivation related to tobacco cessation. Time and competing demands were critical barriers to initiating smoking cessation treatment with patients for all clinicians. Clinicians reported that having one referral source, a referral coordinator, and reimbursement for tobacco counseling (as a billable code) would aid referral.</p> <p>Conclusion</p> <p>Further research is needed to test the effectiveness of new approaches in improving the connection of patients with smoking cessation resources.</p> <p>Trial Registration Number</p> <p>Clinicaltrials.gov NCT00529256</p

Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology

<p>Abstract</p> <p>Background</p> <p>Low-fat (LF) and high-fat (HF) weight loss diets improve brachial artery flow-mediated dilation (FMD) in obese individuals, although results are conflicting. Moreover, the role that adipose tissue plays in mediating these diet-related effects are unknown.</p> <p>Objective</p> <p>This study examined how modulations in FMD by HF and LF diets relate to changes in adipocyte parameters.</p> <p>Design</p> <p>Obese subjects (n = 17) were randomized to a HF diet (60% kcal as fat) or a LF diet (25% kcal as fat) for 6 weeks. Both groups were restricted by 25% of energy needs.</p> <p>Results</p> <p>Body weight decreased (<it>P <</it>0.05) in both groups (HF: -6.6 ± 0.5 kg, LF: -4.7 ± 0.6 kg). Fat mass and waist circumference were reduced (<it>P <</it>0.05) in the LF group only (-4.4 ± 0.3 kg; -3.6 ± 0.8 cm, respectively). FMD improved (<it>P <</it>0.05) in the LF group (7.4 ± 0.8% to 9.8 ± 0.8; 32% increase) and was impaired in the HF group (8.5 ± 0.6% to 6.9 ± 0.7; 19% reduction). Increases in plasma adiponectin (<it>P <</it>0.05, 16 ± 5%), and decreases in resistin (<it>P <</it>0.05, -26 ± 11%), were shown by the LF diet only. Greater decreases in leptin were observed with LF (-48 ± 9%) versus HF (-28 ± 12%) (<it>P <</it>0.05, diet × time). Increased FMD by the LF diet was associated with increased adiponectin, and decreased fat mass, waist circumference, leptin, and resistin.</p> <p>Conclusion</p> <p>Beneficial modulations in vascular health by LF diets may be mediated by improvements in adipocyte parameters.</p

Use of psychotropic drugs before pregnancy and the risk for induced abortion: population-based register-data from Finland 1996-2006

<p>Abstract</p> <p>Background</p> <p>Some, though not all studies have reported an increased risk for mental health problems after an induced abortion. Problems with design and data have compromised these studies and the generalisation of their results.</p> <p>Methods</p> <p>The Finnish Medication and Pregnancy database (N = 622 671 births and 114 518 induced abortions for other than fetal reasons) in 1996-2006 was utilised to study the use of psychotropic drugs in the three months before a pregnancy ending in a birth or an induced abortion.</p> <p>Results</p> <p>In total 2.1% of women with a birth and 5.1% of women with an induced abortion had used a psychotropic medicine 0-3 months before pregnancy. Psychotropic drug users terminated their pregnancies (30.9%) more often than other pregnant women (15.5%). Adjustment for background characteristics explained one third of this elevated risk, but the risk remained significantly increased among users of psychotropic medicine (OR 1.94, 95% confidence intervals 1.87-2.02). A similar risk was found for first pregnancies (30.1% vs. 18.9%; adjusted OR 1.53, 95% confidence intervals 1.42-1.65). The rate for terminating pregnancy was the highest for women using hypnotics and sedatives (35.6% for all pregnancies and 29.1% for first pregnancies), followed by antipsychotics (33.9% and 36.0%) and antidepressants (32.0% and 32.1%).</p> <p>Conclusions</p> <p>The observed increased risk for induced abortion among women with psychotropic medication highlighs the importance to acknowledge the mental health needs of women seeking an induced abortion. Further studies are needed to establish the impact of pre-existing differences in mental health on mental health outcomes of induced abortions compared to outcomes of pregnancies ending in a birth.</p

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

OBJECTIVE: To identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model, for each cohort. The two cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified two replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10-17 , OR [95%CI] = 1.51 [1.37-1.66]) and rs4519530 (p = 6.98 x 10-17 , OR = 1.47 [1.34-1.61]) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10-8 , OR = 1.36 [1.22-1.52]) and rs11153082 (p = 1.85 x 10-8 , OR = 1.30 [1.19-1.42]) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide-significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to e.g. treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache

Female leadership in French voluntary associations

Drawing on a recent national survey, this paper focuses on the female representation on executive committees in French voluntary associations. To begin with, we observe that this representation is very unequal according to the different officer positions. It is especially low among presidents. Then we study the relationship between the associations' attributes and the likelihood of women being appointed as executive committee members. We notice that the probabilities that women hold president, treasurer and secretary positions are highly correlated to each other. We find that the proportion of female officers is higher in organizations whose activities pertain to social service, health and humanitarian sectors. It is lower in the oldest associations and it decreases as their geographical area of activity increases and as their budget becomes larger. The probability that associations have female presidents is higher in associations with few volunteers

Role of Caveolae in Cardiac Protection

Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality. The molecular signaling pathways involved in cardiac protection from myocardial ischemia/reperfusion injury are complex. An emerging idea in signal transduction suggests the existence of spatially organized complexes of signaling molecules in lipid-rich microdomains of the plasma membrane known as caveolae. Caveolins—proteins abundant in caveolae—provide a scaffold to organize, traffic, and regulate signaling molecules. Numerous signaling molecules involved in cardiac protection are known to exist within caveolae or interact directly with caveolins. Over the last 4 years, our laboratories have explored the hypothesis that caveolae are vitally important to cardiac protection from myocardial ischemia/reperfusion injury. We have provided evidence that (1) caveolae and the caveolin isoforms 1 and 3 are essential for cardiac protection from myocardial ischemia/reperfusion injury, (2) stimuli that produce preconditioning of cardiac myocytes, including brief periods of ischemia/reperfusion and exposure to volatile anesthetics, alter the number of membrane caveolae, and (3) cardiac myocyte-specific overexpression of caveolin-3 can produce innate cardiac protection from myocardial ischemia/reperfusion injury. The work demonstrates that caveolae and caveolins are critical elements of signaling pathways involved in cardiac protection and suggests that caveolins are unique targets for therapy in patients at risk of myocardial ischemia

Identification and characterization of a rich population of CD34mesenchymal stem/stromal cells in human parotid, sublingual and submandibular glands

Mesenchymal stem/stromal cells (MSCs) play crucial roles in maintaining tissue homeostasis during physiological turnovers and injuries. Very little is known about the phenotype, distribution and molecular nature of MSCs in freshly isolated human salivary glands (SGs) as most reports have focused on the analysis of cultured MSCs. Our results demonstrate that the cell adhesion molecule CD34 was widely expressed by the MSCs of human major SGs, namely parotid (PAG), sublingual (SLG) and submandibular (SMG) glands. Further, gene expression analysis of CD34+ cells derived from fetal SMGs showed significant upregulation of genes involved in cellular adhesion, proliferation, branching, extracellular matrix remodeling and organ development. Moreover, CD34+ SMG cells exhibited elevated expression of genes encoding extracellular matrix, basement membrane proteins, and members of ERK, FGF and PDGF signaling pathways, which play key roles in glandular development, branching and homeostasis. In vitro CD34+ cell derived SG-MSCs revealed multilineage differentiation potential. Intraglandular transplantation of cultured MSCs in immunodeficient mice led to their engraftment in the injected and uninjected contralateral and ipsilateral glands. Engrafted cells could be localized to the stroma surrounding acini and ducts. In summary, our data show that CD34+ derived SG-MSCs could be a promising cell source for adoptive cell-based SG therapies, and bioengineering of artificial SGs