Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

Exendin-4 Improves Blood Glucose Control in Both Young and Aging Normal Non-Diabetic Mice, Possible Contribution of Beta Cell Independent Effects

Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages.We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment.Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice.Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion

Desmoglein 2 mutant mice develop cardiac fibrosis and dilation

Desmosomes are cell–cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2

Global Assessment of Functioning (GAF): properties and frontier of current knowledge

ABSTRACT: BACKGROUND: Global Assessment of Functioning (GAF) is well known internationally and widely used for scoring the severity of illness in psychiatry. Problems with GAF show a need for its further development (for example validity and reliability problems). The aim of the present study was to identify gaps in current knowledge about properties of GAF that are of interest for further development. Properties of GAF are defined as characteristic traits or attributes that serve to define GAF (or may have a role to define a future updated GAF). METHODS: A thorough literature search was conducted. RESULTS: A number of gaps in knowledge about the properties of GAF were identified: for example, the current GAF has a continuous scale, but is a continuous or categorical scale better? Scoring is not performed by setting a mark directly on a visual scale, but could this improve scoring? Would new anchor points, including key words and examples, improve GAF (anchor points for symptoms, functioning, positive mental health, prognosis, improvement of generic properties, exclusion criteria for scoring in 10-point intervals, and anchor points at the endpoints of the scale)? Is a change in the number of anchor points and their distribution over the total scale important? Could better instructions for scoring within 10-point intervals improve scoring? Internationally, both single and dual scales for GAF are used, but what is the advantage of having separate symptom and functioning scales? Symptom (GAF-S) and functioning (GAF-F) scales should score different dimensions and still be correlated, but what is the best combination of definitions for GAF-S and GAF-F? For GAF with more than two scales there is limited empirical testing, but what is gained or lost by using more than two scales? CONCLUSIONS: In the history of GAF, its basic properties have undergone limited changes. Problems with GAF may, in part, be due to lack of a research programme testing the effects of different changes in basic properties. Given the widespread use, research-based development of GAF has not been especially strong. Further research could improve GAF

Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload

Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure-volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 ± 0.4 μm, SHAM 18.2 ± 0.3 μm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m(2), SHAM 18.6 ± 1.4 kN/m(2)), Ca(2+) sensitivity (BA 5.56 ± 0.02, SHAM 5.50 ± 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K (tr); BA 14.9 ± 1.1 s(-1), SHAM 25.2 ± 1.5 s(-1)). At the extracellular matrix level, fibrosis (BA 10.8 ± 0.9%, SHAM 5.3 ± 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (τ; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 μm, 13.9 ± 1.8%, DB 20.6 ± 0.4 μm, 13.8 ± 0.8%, respectively), myofilament Ca(2+)sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm(2), DB 5.1 ± 0.4 score/mm(2), SHAM 2.1 ± 0.3 score/mm(2)), and apoptosis, while decreasing K (tr) (DM 13.5 ± 1.9 s(-1), DB 15.2 ± 1.4 s(-1)), Akt phosphorylation and MMP-9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end-diastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolic-pressure-volume relation: DM 0.59 ± 0.18, DB 0.83 ± 0.17, SHAM 0.41 ± 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 ± 0.21 g/kg, SHAM 3.80 ± 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals

Developing high-capacity hydrogen storage materials via quantum simulations

Hydrogen is considered by some to be a promising non-CO2-emitting energy carrier for the future. However, to realize a hydrogen economy, there are several technological barriers to overcome. Currently, safe and efficient storage of hydrogen is a bottleneck in the practical usage of hydrogen for fuels. In this article, we present a review on the first-principles computational approach in designing hydrogen storage materials with an emphasis on molecular hydrogen storage in nanostructured materials. Given the limitation of pristine nanostructures for room-temperature hydrogen storage, the strategy of decorating the backbone structure of the nanostructure with transition metal atoms in order to enhance the hydrogen adsorption energy is addressed, and the interplay between the Coulomb interactions and the so-called Kubas interaction (nondissociative weak chemisorption via electron donation and back-donation channels) has been studied. The influence of electron spin on the hydrogen binding energy, problems of metal clustering and oxidation, and the structural instability that may arise during hydrogen sorption are also discussed. We address the limitations and challenges in the development of high-capacity hydrogen storage materials and provide perspectives for how computational materials design can help cope with those problems.X111111sciescopu

PSEUDOPOTENTIAL STUDY OF THE STRUCTURAL-PROPERTIES OF BULK LI

The phase stability of the hcp, fcc, and bcc structures of Li is studied using the pseudopotential density-functional total-energy calculation scheme. The order of the crystal energy at zero pressure is E(hcp) < E(fcc) < E(bcc). The two closed-packed structures (fcc and hcp) are fairly stable compared to the bcc structure for all volumes considered, i.e., there is no pressure-induced bcc transition from either hcp or fcc. The energy difference between hcp and fcc is very small and a hcp-to-fcc transition occurs at a pressure of about 15 kbar. Unlike a previous pseudopotential calculation, which predicted a fcc-to-bcc transition, but no hcp-to-fcc transition, the present result on the transitions is in good agreement with existing all-electron calculations.open119sciescopu

Efficacy and safety of two fixed-dose combinations of S-amlodipine and telmisartan (CKD-828) versus S-amlodipine monotherapy in patients with hypertension inadequately controlled using S-amlodipine monotherapy: an 8-week, multicenter, randomized, double-blind, Phase III clinical study

Sang-Hyun Ihm,1 Hui-Kyung Jeon,1 Tae-Joon Cha,2 Taek-Jong Hong,3 Sang-Hyun Kim,4 Nae-Hee Lee,5 Jung Han Yoon,6 Namsik Yoon,7 Kyung-Kuk Hwang,8 Sang-Ho Jo,9 Ho-Joong&nbsp;Youn1 1Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 2Division of&nbsp;Cardiology, Department of Internal Medicine, Kosin University College of Medicine, 3Division of Cardiology, Department of Internal Medicine, Pusan National University Hospital, Busan, 4Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, 5Department of Cardiology, Soonchunhyang University Hospital, Bucheon, 6Division of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, 7Department of Cardiology, Chonnam National University Hospital, Gwangju, 8Department of Internal Medicine, Chungbuk National University, College of Medicine, Cheongju, 9Division of Cardiology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea Purpose: To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy.Patients and methods: Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] &ge;90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings.Results: After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were -9.67&plusmn;6.50/-12.89&plusmn;11.78, -10.72&plusmn;6.19/-13.79&plusmn;9.41, and -4.93&plusmn;7.26/-4.55&plusmn;11.27 mmHg in the CKD-828 2.5/40 mg (P&lt;0.0001/P&lt;0.0001), CKD-828 2.5/80 mg (P&lt;0.0001/P&lt;0.0001), and S-amlodipine 2.5 mg (P&lt;0.0001/P=0.0027) groups, respectively, which were all significant BP reductions. At Week 8, the CKD-828 2.5/40 mg (sitDBP/SBP:&nbsp;P=0.0002/P&lt;0.0001) and CKD-828 2.5/80 mg (sitDBP/SBP:&nbsp;P=0.0001/P&lt;0.0001) showed superior BP-lowering effects to S-amlodipine 2.5 mg (P&lt;0.001). At Week 4, all groups showed significant antihypertensive effects but both CKD-828 combinations (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) exhibited superior BP-lowering effects to that of S-amlodipine 2.5 mg (sitDBP/SBP:&nbsp;P=0.0028/P=0.0001 and&nbsp;P&lt;0.0001/P=0.0012, respectively). The adverse event incidence was significantly lower in the CKD-828 2.5/40 mg (9.52%,&nbsp;P=0.0086) than in the S-amlodipine 2.5 mg group (27.87%) and increasing the telmisartan dose induced no unexpected adverse events, suggesting the safety of CKD-828.Conclusion: CKD-828 is an effective and safe option for patients with inadequate responses to S-amlodipine monotherapy. Keywords: blood pressure, antihypertensive, calcium channel blocker, angiotensin receptor blocker, efficacy, safet

The clinical usefulness of central hemodynamics to evaluate diastolic dysfunction in subjects without hypertension

GeeHee Kim,1 Ji-Hoon Kim,1 Keon-Woong Moon,1 Ki-Dong Yoo,1 Sang-Hyun Ihm,2 Ho-Joong Youn,2 Chul-Min Kim11Division of Cardiology, Department of Internal Medicine, St Vincent&#39;s Hospital, Catholic University of Korea, Suwon, 2Division of Cardiology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul, South KoreaObjective: Diastolic dysfunction is associated with increased arterial stiffness in patients with hypertension. However, the role of arterial stiffness in diastolic dysfunction in subjects without hypertension has not been fully established.Materials and methods: A total of 287 subjects (male:female ratio 121:166, mean age 53.0&plusmn;14.4 years) without hypertension or any heart disease who simultaneously received transthoracic echocardiography and noninvasively semiautomated radial artery applanation tonometry (with an Omron HEM-9000AI) in the Department of Internal Medicine, St Vincent&rsquo;s Hospital, from July 2011 to September 2012, were enrolled in this study.Results: A total of 147 subjects (male:female ratio 59:88, mean age 61.7&plusmn;9.9 years), representing 51.2% of the 287 subjects, had diastolic dysfunction (defined as abnormal relaxation pattern of mitral inflow). There were significant differences in systolic blood pressure (BP), pulse pressure, late systolic peak pressure (SBP2), and radial augmentation index (RaAIx) between normal diastolic function and diastolic dysfunction. &Delta;BP was defined as systolic BP minus SBP2, because of the difference in systolic BP between the two groups. &Delta;BP (odds ratio [OR] 1.059, 95% confidence interval [CI] 1.005&ndash;1.115; P=0.032) and RaAIx (odds ratio 1.027, 95% CI 1.009&ndash;1.044, P=0.003) were associated with diastolic dysfunction. A receiver operating-characteristic curve showed that &Delta;BP (area under the curve 0.875, 95% CI 0.832&ndash;0.911) and RaAIx (area under the curve 0.878, 95% CI 0.835&ndash;0.914) were associated with diastolic dysfunction.Conclusion: We found that &Delta;BP and increased RaAIx were associated with diastolic dysfunction in subjects without hypertension after adjustment for age and sex. Therefore, it is suggested that noninvasive estimation of central BP may be useful to reflect diastolic dysfunction in subjects with normal peripheral BP.Keywords: central blood pressure, augmentation index, diastolic dysfunctio