bluuebunny/crossref_metadata_2025 huggingface dataset:
The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity
Authors: Kelly Karen R. , Brooks Latina M. , Solomon Thomas P. J. , Kashyap Sangeeta R. , O'Leary Valerie B. , Kirwan John P.
Published: April 2009

Aging and obesity are characterized by decreased β-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% V̇o2 max) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 ± 190, post: 1,269 ± 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 ± 1.5 yr), obese (34.4 ± 1.7 kg/m2) adults with impaired glucose tolerance. In addition to GIP, plasma PYY3–36, insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in V̇o2 max ( P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (−8.3 ± 1.1 vs. −2.8 ± 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO ( P = 0.02), as was the glucose-stimulated GIP response ( P < 0.05). Furthermore, after the intervention, changes in insulin (ΔI0–30/ΔG0–30) and GIP (Δ0–30) secretion were correlated ( r = 0.69, P = 0.05). The PYY3–36 (Δ0–30) response to glucose was increased after both interventions ( P < 0.05). We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY3–36 response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.
Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments
Authors: Zaobornyj Tamara , Valdez Laura B. , Iglesias Darío E. , Gasco Manuel , Gonzales Gustavo F. , Boveris Alberto
Published: April 2009

Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, Po2= 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by >75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly ( r2= 0.75, P ≤ 0.05). Chronic treatment for 28 days with sildenafil (50 mg·kg−1·day−1) decreased the response of mtNOS to high altitude by 25%. Conversely, NG-nitro-l-arginine methyl ester treatment (8.3 mg·kg−1·day−1) increased such response by 40%, whereas l-arginine treatment (106 mg·kg−1·day−1) had no effect. Nitric oxide (NO) production by mtNOS accounts for ∼49% of total cellular NO production in sea level rats and for ∼54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments.
Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study
Authors: Droogmans Steven , Roosens Bram , Cosyns Bernard , Degaillier Céline , Hernot Sophie , Weytjens Caroline , Garbar Christian , Caveliers Vicky , Pipeleers-Marichal Miriam , Franken Philippe R. , Lahoutte Tony , Schoors Danny , Van Camp Guy
Published: April 2009

Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)2Breceptor (5-HT2BR). Therefore, we sought to determine whether cyproheptadine, a 5-HT2BR antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups ( P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT2BR-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT2BR-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.
Two Distantly Spaced Basic Patches in the Flexible Domain of Huntingtin-Interacting Protein 1 (HIP1) Are Essential for the Binding of Clathrin Light Chain
Authors: Ybe Joel A. , Clegg Mary E. , Illingworth Melissa , Gonzalez Claire , Niu Qian
Published: April 2009

The interaction between HIP family proteins (HIP1 and HIP12/1R) and clathrin is fundamental to endocytosis. We used circular dichroism (CD) to study the stability of an HIP1 subfragment (aa468-530) that is splayed open. CD thermal melts show HIP1 468-530 is only stable at low temperatures, but this HIP1 fragment contains a structural unit that does not melt out even at 83C∘. We then created HIP1 mutants to probe our hypothesis that a short hydrophobic path in the opened region is the binding site for clathrin light chain. We found that the binding of hub/LCb was sensitive to mutating two distantly separated basic residues (K474 and K494). The basic patches marked by K474 and K494 are conserved in HIP12/1R. The lack of conservation insla2p (S. cerevisiae), HIP1 fromD. melanogaster, and HIP1 homolog ZK370.3 fromC. elegansimplies the binding of HIP1 and HIP1 homologs to clathrin light chain may be different in these organisms.
The Role of the PGC1α Gly482Ser Polymorphism in Weight Gain due to Intensive Diabetes Therapy
Authors: Deeb Samir S. , Brunzell John D.
Published: April 2009

The Diabetes Control and Complications Trial (DCCT) involved intensive diabetes therapy of subjects with type 1 diabetes mellitus (T1DM) for an average period of 6.5 years. A subset of these subjects gained excessive weight. We tested for association of polymorphisms in 8 candidate genes with the above trait. We found the Gly482Ser polymorphism in the peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC1α) to be significantly associated with weight gain in males (P = .0045) but not in females. The Ser allele was associated with greater weight gain than the Gly allele (P = .005). Subjects with a family history of type 2 diabetes mellitus (T2DM) were more common among those who gained excessive weight. We conclude that T2DM and the Gly482Ser polymorphism in PGC1α contribute to the effect of intensive diabetes therapy on weight gain in males with T1DM.
Networks-On-Chip Based on Dynamic Wormhole Packet Identity Mapping Management
Authors: Samman Faizal A. , Hollstein Thomas , Glesner Manfred
Published: April 2009

This paper presents a network-on-chip (NoC)
with flexible infrastructure based on dynamic wormhole packet
identity management. The NoCs are developed based on a VHDL
approach and support the design flexibility. The on-chip router
uses a wormhole packet switching method with a synchronous
parallel pipeline technique. Routing algorithms and dynamic
wormhole local packet identity (ID-tag) mapping management are
proposed to support a wire sharing methodology and an ID slot
division multiplexing technique. At each communication link, flits
belonging to the same message have the same local ID-tag, and the
ID-tag is updated before the packet enters the next communication
link by using an ID-tag mapping management unit. Therefore, flits
from different messages can be interleaved, identified, and routed
according to their allocated ID slots. Our NoC guarantees in order
and lossless message delivery.
Modification of the cytoprotective protein C pathway during Dengue virus infection of human endothelial vascular cells
Authors: Cabello-Gutiérrez Carlos , Manjarrez-Zavala Maria Eugenia , Huerta-Zepeda Alejandra , Cime-Castillo Jorge , Monroy-Martínez Verónica , Biruete-Correa Benjamín , Ruiz-Ordaz Blanca
Published: April 2009

Dengue fever (DF) is the most prevalent arthropod-borne viral disease of humans. No safe vaccine is available, there is no experimental animal model and no specific treatment (antiviral) for Dengue virus (DV) infection exists. The pathogenic mechanisms of the severe forms of the disease, such as Dengue shock syndrome (DSS) and Dengue haemorrhagic fever (DHF), in which endothelial damage is the pathognomonic sign, are not fully understood. Clinical observations have revealed significant abnormalities in the coagulation and inflammation systems, with increased levels of soluble thrombomodulin (sTM) in the plasma of patients with DHF/DSS (grade III or IV). Blood sTM was proposed as an early predictor of DSS during the febrile stage. However, the role of the DV in endothelial injury during DSS is unclear. Here, we present novel insights into the participation of DV in the downregulation of the thrombomodulin-thrombin-protein C complex formation at the endothelial surface, with a reduction in activated protein C (APC). APC is the most important vasoprotective protein because it downregulates thrombin generation (by the inactivation of procoagulant factors Va and VIIIa) and has anti-inflammatory, antiapoptotic, and barrier protection properties. These biological functions of APC are associated with the endothelial protein C receptor (EPCR) and pro-tease-activated receptor 1 (PAR-1) signalling pathways, which link the coagulation-inflammation responses. We found alterations in the antithrombotic and cytoprotective protein C pathways during DV infection of human endothelial vascular cells, which may explain the vasculopathy observed during DHF/DSS. Clarification of the basic principles that underlie these processes has important implications for the design of new therapeutic strategies for DHF/DSS.
Comparative study of accuracy and clinical agreement of the CoaguChek XS portable device versus standard laboratory practice in unexperienced patients
Authors: Fernández Elizabeth Gómez , Rodríguez Rosa Mariño , López Carmen Vázquez , Núñez Julia Barreal , Torreiro Eduardo
Published: April 2009

The objective of the study was to compare the accuracy and clinical agreement of the CoaguChek XS versus the standard laboratory practice. Forty-one patients on long-term anticoagulation with acenocumarol without previous experience in self-monitoring participated to obtain 218 pairs of data. Several methods for comparative statistics were applied to assess the possible disagreements between techniques as well as a range of previously published criteria of clinical agreement and the very recently described error-grid for INR comparison that we partially modify. The mean age was 52.1 and the indications for oral anticoagulation were prosthetic valves (36.59%), atrial fibrillation (34.15%), venous thromboembolic disease (21.95%) and others (7.31%) with a target range of 2–3 INR units (63.4%) or 2.5–3.5 (36.6%). Analyzing the whole series of data, the Pearsons ρ correlation coefficient for precision between methods was 0.95 and the Cb bias correction factor for accuracy 0.99 with a minimal bias of 0.1 INR units between methods applying the Bland-Altman plot. The linear regression procedure described by Passing and Bablok showed a minimal deviation from the best-fit line and a slope of 0.90. The mean of the absolute relative differences was 7% which is in the “very good” range of agreement. No results were found in the clinically “dangerous” D zone of the error-grids with 99% of data in the clinically irrelevant and low relevant areas A and B. In this study self-management with the CoaguChek XS was clinically safe and reliable.
Influence of platelet count on the expression of platelet collagen receptor glycoprotein VI (GPVI) in patients with acute coronary syndrome
Authors: Bigalke Boris , Stellos Konstantinos , Stakos Dimitrios , Joos Thomas , Pötz Oliver , Geisler Tobias , Bischofs Christian , Kremmer Elisabeth , Krämer Björn , Seizer Peter , May Andreas , Lindemann Stephan , Gawaz Meinrad
Published: April 2009

Platelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) ± standard deviation): 1st vs. 4th: 20.44 ± 6.1 vs. 18.62 ± 3.7; p=0.012; 2ndvs.3rd:21.2±8.5vs.18.76±3.7;P=0.03; 2ndvs.4th: 21.2±8.5vs.18.62±3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1st vs. 4th: 11.2 ± 6.8 vs. 12.3 ± 9; p=0.057; 2nd vs. 3rd: 16.3 ± 16 vs.12.7 ± 5.3; p=0.138; 2nd vs. 4th: 16.3 ± 16 vs.11 ± 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1stvs.4th: 1.6 ± 0.6 vs. 1.2 ± 0.4; p=0.046; 1st vs. 3rd: 1.6 ± 0.6 vs. 1.1 ± 0.5; p=0.038; 2nd vs. 3rd: 1.9 ± 0.8 vs. 1.1 ± 0.5; p=0.04; 2nd vs. 4th: 1.9 ± 0.8 vs. 1.2 ± 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.
Influence of molecular weight of chemically sulfated citrus pectin fractions on their antithrombotic and bleeding effects
Authors: Cipriani Thales , Gracher Ana Helena , de Souza Lauro , Fonseca Roberto , Belmiro Celso , Gorin Philip , Sassaki Guilherme , Iacomini Marcello
Published: April 2009

Evaluated were the anticoagulant and antithrombotic activities, and bleeding effect of two chemically sulfated polysaccharides, obtained from citric pectin, with different average molar masses. Both low-molecular-weight (Pec-LWS, 3,600 g/mol) and high-molecular-weight sulfated pectins (Pec-HWS, 12,000 g/mol) had essentially the same structure, consisting of a (1→4)-linked α-D-GalpA chain with almost all its HO-2 and HO-3 groups substituted by sulfate. Both polysaccharides had anticoagulant activity in vitro, although Pec-HWS was a more potent anti-thrombotic agent in vivo, giving rise to total inhibition of venous thrombosis at a dose of 3.5 mg/kg body weight. Surprisingly, in contrast with heparin, Pec-HWS and Pec-LWS are able to directly inhibit α-thrombin and factor Xa by a mechanism independent of antithrombin (AT) and/or heparin co-factor II (HCII). Moreover, Pec-HWS provided a lower risk of bleeding than heparin at a dose of 100% effectiveness against venous thrombosis, indicating it to be a promising antithrombotic agent.
Argatroban and bivalirudin compared to unfractionated heparin in preventing thrombus formation on mechanical heart valves
Authors: Linde Torsten , Michel Thomas , Hamilton Kathrin , Steinseifer Ulrich , Friedrich Ivar , Schubert Sebastian , Hauroeder Baerbel , Raaz Uwe , Buerke Michael , Werdan Karl , Schlitt Axel , Maegdefessel Lars
Published: April 2009

Prevention of valve thrombosis in patients after prosthetic mechanical heart valve replacement and heparin-induced thrombocytopenia (HIT) is still an open issue. The aim of the present in-vitro study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves. Blood (230 ml) from healthy young male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion. Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anticoagulated blood samples. To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment. Mean thrombus weight in group 1 (UFH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p-value <0.001). Electron microscopy showed increased rates of thrombus formation in groups 2 and 3. Argatroban and bivalirudin were as effective as UFH in preventing thrombus formation on valve prostheses in our in-vitro investigation when they were administered continuously. We hypothesise that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa.
Reduced levels of putative endothelial progenitor and CXCR4+ cells in coronary artery disease: Kinetics following percutaneous coronary intervention and association with clinical characteristics
Authors: Egan Colin Gerard , Caporali Francesca , Huqi Alda , Zito Maria Cristina , Focardi Marta , Mondillo Sergio , Pierli Carlo , Marzilli Mario , Sorrentino Vincenzo
Published: April 2009

Levels of circulating endothelial progenitor cells (EPCs) and CXCR4-positive cells are decreased in patients with coronary artery disease (CAD); however, their ability to change in response to acute vascular injury remains to be elucidated. Progenitor and CXCR4-positive cells were analysed by flow cytometry from the peripheral blood of 23 healthy controls and 23 patients with CAD, of which 13 patients underwent angiogram and 10 patients received percutaneous coronary intervention (PCI) with stent implantation. Baseline levels of progenitor and CXCR4-positive cells were substantially reduced in CAD patients compared to controls, although they were still capable of increasing in response to vascular injury. Levels of progenitor and CXCR4-positive cells were increased to a greater extent in the PCI group compared to angiogram patients. At presentation, levels of putative endothelial progenitor and CXCR4-positive cells were found to be negatively correlated with disease severity. A one-year follow-up revealed that out of the cell populations examined, only levels of CXCR4-positive cells were positively correlated with angina frequency in the PCI group, but not in patients receiving angiogram. Baseline levels of progenitor cells are differentially increased depending upon the severity of vascular injury incurred, regardless of a significant deficit in baseline levels in CAD patients. Levels of putative EPCs and CXCR4-positive cells were negatively correlated with disease severity at presentation, however, only CXCR4-positive cells were associated with patient condition in a one-year follow-up.
Association of genetic variants with myocardial infarction in Japanese individuals with chronic kidney disease
Authors: Fujimaki Tetsuo , Kato Kimihiko , Yoshida Tetsuro , Oguri Mitsutoshi , Watanabe Sachiro , Metoki Norifumi , Yoshida Hidemi , Satoh Kei , Aoyagi Yukitoshi , Nishigaki Yutaka , Tanaka Masashi , Nozawa Yoshinori , Kimura Genjiro , Yamada Yoshiji
Published: April 2009

Chronic kidney disease (CKD) is a serious clinical condition that is associated with a high incidence of cardiovascular disease and end-stage renal disease. Although CKD has been recognised as a risk factor for myocardial infarction (MI), genetic factors for predisposition to MI in individuals with CKD have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to MI in Japanese individuals with CKD. The study subjects comprised 1,339 Japanese individuals with CKD, including 496 subjects with MI and 843 controls. The genotypes for 248 polymorphisms of 181 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. An initial screen of allele frequencies by the chi-square test revealed that the 11496G→A (Arg353Gln) polymorphism of F7 (rs6046) was significantly (false discovery rate <0.05) associated with the prevalence of MI in individuals with CKD. Subsequent multivariable logistic regression analysis with adjustment for covariates and a stepwise forward selection procedure also revealed that this polymorphism was significantly (p <0.005) associated with MI, with the variant A (Gln) allele protecting against this condition. Determination of genotype for the 11496G→A (Arg353Gln) polymorphism of F7 may prove informative for assessment of the genetic risk for MI in individuals with CKD.
The comparative immunogenicity of human and porcine factor VIII in haemophilia A mice
Authors: Healey John F. , Parker Ernest T. , Barrow Rachel T. , Langley Travis J. , Church William R. , Lollar Pete
Published: April 2009

Inhibitory antibodies to factor VIII (FVIII inhibitors) are the most significant complication in the management of haemophilia A. The immunogenicity of FVIII may be driven in part by structural determinants within the FVIII molecule itself. Regions of nonidentity between human and porcine FVIII possibly could drive differential immune responses. The goal of this study was to compare the overall antibody response and levels of antibodies to the individual FVIII domains in naïve haemophilia A mice immunised with human or porcine FVIII. Haemophilia A mice were immunised with human or porcine FVIII using a protocol that mimics human clinical use. Inhibitor and total anti-FVIII antibody titers were measured and the domain-specificity of antibodies from 1,759 anti-FVIII hybridomas was determined. The overall immunogenicity of human and porcine FVIII was similar but significant differences in domain recognition were discovered. Anti-A2 and anti-C2 antibodies constituted the majority of inhibitors in both the human and porcine FVIII groups, similar to inhibitors that develop in humans.The proportions of anti-A2 or anti-C2 antibodies were not significantly different between the two groups. However, the specific inhibitory activity of anti-A2 antibodies was higher in the human FVIII group. Additionally, proportion of anti-C1 antibodies was significantly higher in the human FVIII group. In contrast, anti-A3 antibodies were more common in the porcine FVIII group.The differential immune response to human and porcine FVIII suggests that it may be possible to reduce the immunogenicity of FVIII by mutagenesis of the A2, A3 and C1 domains.
Prescription of fondaparinux in hospitalised patients
Authors: Labreche Matthew , Niles Matthew , Fanikos John , Goldhaber Samuel , Baroletti Steven
Published: April 2009

Fondaparinux is an antithrombotic agent with unique properties that may offer benefit to patients beyond the current approved indications. To explore the off-label use versus approved use of fondaparinux, we initiated a single-center registry of fondaparinux use. During the 25-month study period, 219 patients were prescribed fondaparinux: 157 (71.7%) for prophylaxis and 62 (28.3%) patients for the treatment of thrombosis. When fondaparinux was used for prophylaxis in our registry, 94% of patients had documentation of heparin-induced thrombocytopenia (HIT). Fondaparinux warrants further evaluation in patients with HIT or suspected HIT. In the meantime, its off-label use may exceed its use for FDA-approved indications.
Bridging of oral anticoagulation with low-molecular-weight heparin: Experience in 373 patients with renal insufficiency undergoing invasive procedures
Authors: Hammerstingl Christoph , Omran Heyder ,   for the Bonn Registry of Alternative Anticoagulation to Prevent Vascular Events
Published: April 2009

If surgery or another intervention is planned, current guidelines recommend bridging oral anticoagulation (OAC) with heparins in patients at elevated thromboembolic (TE) risk. While patients with renal impairment have a higher risk of bleeding and dosing of heparins is more difficult, there are no specific recommendations for bridging the latter patients. Hence, we aimed to investigate the efficacy and tolerability of using reduced low-molecular-weight heparin (enoxaparin) dosages for bridging of OAC. Three hundred twenty-two hospitalised and 51 ambulatory adult patients at moderate to high TE risk were enrolled. Patients with renal insufficiency (n=274 with creatinine clearance [CrCl] 30–50 ml/min and n=99 with CrCl 20–29 ml/min) received after discontinuation of OAC therapy enoxaparin 1mg/ kg once daily. Surgery was performed at international normalised ratio (INR) <1.5. Mean time between the last enoxaparin dose and procedure was 26.8 ± 2.7 hours. Within 30 days of individual follow-up, no case of TE was observed (0 %; 95 % confidence interval [CI] 0– 0.9). A total of 30 bleeding events (8.0 %; CI 5.5–11.3) occurred (3 major [0.8 %; CI 0.2–2.3] and 27 minor [7.2 %; CI 4.8–10.4]). Bleeding events occurred in 6.5% (CI 3.9–10.2) of patients with CrCl 30–50 ml/min and in 12.1% (CI 6.4–20.2) of patients with CrCl 20–29 ml/min (p between groups =0.08). Logistic regression analysis identified the CHADS2 score as the only independent haemorrhagic risk factor (p= 0.03). No heparin-induced thrombocytopenia (HIT-II) was reported. Bridging therapy could be performed in 51 (13.7%) ambulatory patients. In renally impaired patients undergoing bridging of OAC, the use of a priori reduced dosage of enoxaparin was not compromised by any TE events. It appeared well tolerated as the rate of major bleeds was low.
Evaluation of the Glycometabolic Effects of Ranolazine in Patients With and Without Diabetes Mellitus in the MERLIN-TIMI 36 Randomized Controlled Trial
Authors: Morrow David A. , Scirica Benjamin M. , Chaitman Bernard R. , McGuire Darren K. , Murphy Sabina A. , Karwatowska-Prokopczuk Ewa , McCabe Carolyn H. , Braunwald Eugene
Published: April 2009

Background—

Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A
1c
(HbA
1c
). We designed a prospective evaluation of the effect of ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial.

Methods and Results—

We compared HbA
1c
(percentage) and the time to onset of a ≥1% increase in HbA
1c
among 4918 patients with acute coronary syndrome randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA
1c
at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, −0.30 versus −0.04;
P
<0.001). In patients with diabetes mellitus treated with ranolazine, HbA
1c
declined from 7.5 to 6.9 (change from baseline, −0.64;
P
<0.001). Diabetic patients were more likely to achieve an HbA
1c
<7% at 4 months with ranolazine compared with placebo (59% versus 49%;
P
<0.001) and were less likely to have a ≥1% increase in HbA
1c
(14.2% versus 20.6% at 1 year; hazard ratio, 0.63; 95% confidence interval, 0.51 to 0.77;
P
<0.001). Moreover, ranolazine reduced recurrent ischemia in diabetic patients (hazard ratio, 0.75; 95% confidence interval, 0.61 to 0.93;
P
=0.008). Notably, in patients without diabetes mellitus at baseline, the incidence of new fasting glucose >110 mg/dL or HbA
1c
≥6% was reduced by ranolazine (31.8% versus 41.2%; hazard ratio, 0.68; 95% confidence interval, 0.53 to 0.88;
P
=0.003). Reported hypoglycemia did not increase with ranolazine (
P
=NS).

Conclusions—

Ranolazine significantly improved HbA
1c
and recurrent ischemia in patients with diabetes mellitus and reduced the incidence of increased HbA
1c
in those without evidence of previous hyperglycemia. The mechanism of this effect is under investigation.
Pioglitazone Improves Cardiac Function and Alters Myocardial Substrate Metabolism Without Affecting Cardiac Triglyceride Accumulation and High-Energy Phosphate Metabolism in Patients With Well-Controlled Type 2 Diabetes Mellitus
Authors: van der Meer Rutger W. , Rijzewijk Luuk J. , de Jong Hugo W.A.M. , Lamb Hildo J. , Lubberink Mark , Romijn Johannes A. , Bax Jeroen J. , de Roos Albert , Kamp Otto , Paulus Walter J. , Heine Robert J. , Lammertsma Adriaan A. , Smit Johannes W.A. , Diamant Michaela
Published: April 2009

Background—

Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients.

Methods and Results—

Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [
18
F]-2-fluoro-2-deoxy-
d
-glucose and [
11
C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate (
P
=0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (
P
<0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone (
P
=0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content (
P
<0.001).

Conclusions—

In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.
Lifestyle Interventions Reduce Coronary Heart Disease Risk
Authors: Maruthur Nisa M. , Wang Nae-Yuh , Appel Lawrence J.
Published: April 2009

Background—

Although trials of lifestyle interventions generally focus on cardiovascular disease risk factors rather than hard clinical outcomes, 10-year coronary heart disease (CHD) risk can be estimated from the Framingham risk equations. Our objectives were to study the effect of 2 multicomponent lifestyle interventions on estimated CHD risk relative to advice alone and to evaluate whether differences can be observed in the effects of the lifestyle interventions among subgroups defined by baseline variables.

Methods and Results—

A total of 810 healthy adults with untreated prehypertension or stage I hypertension were randomized to 1 of 3 intervention groups: An “advice-only” group, an “established” group that used established lifestyle recommendations for blood pressure control (sodium reduction, weight loss, and increased physical activity), or an “established-plus-DASH” group that combined established lifestyle recommendations with the DASH (Dietary Approaches to Stop Hypertension) diet. The primary outcome was 10-year CHD risk, estimated from follow-up data collected at 6 months. A secondary outcome was 10-year CHD risk at 18 months. Of the 810 participants, 62% were women and 34% were black. Mean age was 50 years, mean systolic/diastolic blood pressure was 135/85 mm Hg, and median baseline Framingham risk was 1.9%. The relative risk ratio comparing 6-month to baseline Framingham risk was 0.86 (95% confidence interval 0.81 to 0.91,
P
<0.001) in the established group and 0.88 (95% confidence interval 0.83 to 0.94,
P
<0.001) in the established-plus-DASH group relative to advice alone. Results were virtually identical in sensitivity analyses, in each major subgroup, and at 18 months.

Conclusions—

The observed reductions of 12% to 14% in estimated CHD risk are substantial and, if achieved, should have important public health benefits.
A Novel Role for Tumor Necrosis Factor–Like Weak Inducer of Apoptosis (TWEAK) in the Development of Cardiac Dysfunction and Failure
Authors: Jain Mohit , Jakubowski Aniela , Cui Lei , Shi Jianru , Su Lihe , Bauer Michael , Guan Jian , Lim Chee Chew , Naito Yoshiro , Thompson Jeffrey S. , Sam Flora , Ambrose Christine , Parr Michael , Crowell Thomas , Lincecum John M. , Wang Monica Z. , Hsu Yen-Ming , Zheng Timothy S. , Michaelson Jennifer S. , Liao Ronglih , Burkly Linda C.
Published: April 2009

Background—

Tumor necrosis factor–like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, is a multifunctional cytokine known to regulate cellular functions in contexts of injury and disease through its receptor, fibroblast growth factor–inducible molecule 14 (Fn14). Although many of the processes and downstream signals regulated by the TWEAK/Fn14 pathway have been implicated in the development of cardiac dysfunction, the role of TWEAK in the cardiovascular system is completely unknown.

Methods and Results—

Herein, we demonstrate that mouse and human cardiomyocytes express the TWEAK receptor Fn14. Furthermore, we determine that elevated circulating levels of TWEAK, induced via transgenic or adenoviral-mediated gene expression in mice, result in dilated cardiomyopathy with subsequent severe cardiac dysfunction. This phenotype was mediated exclusively by the Fn14 receptor, independent of tumor necrosis factor-α, and was associated with cardiomyocyte elongation and cardiac fibrosis but not cardiomyocyte apoptosis. Moreover, we find that circulating TWEAK levels were differentially upregulated in patients with idiopathic dilated cardiomyopathy compared with other forms of heart disease and normal control subjects.

Conclusions—

Our data suggest that TWEAK/Fn14 may be important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy.
High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus
Authors: Drew Brian G. , Duffy Stephen J. , Formosa Melissa F. , Natoli Alaina K. , Henstridge Darren C. , Penfold Sally A. , Thomas Walter G. , Mukhamedova Nigora , de Courten Barbora , Forbes Josephine M. , Yap Felicia Y. , Kaye David M. , van Hall Gerrit , Febbraio Mark A. , Kemp Bruce E. , Sviridov Dmitri , Steinberg Gregory R. , Kingwell Bronwyn A.
Published: April 2009

Background—

Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle.

Methods and Results—

Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL=−2.6±0.4; placebo=−2.1±0.3mmol/L;
P
=0.018). rHDL increased plasma insulin (at 4 hours rHDL=3.4±10.0; placebo= −19.2±7.4 pmol/L;
P
=0.034) and also the homeostasis model assessment β-cell function index (at 4 hours rHDL=18.9±5.9; placebo=8.6±4.4%;
P
=0.025). Acetyl-CoA carboxylase β phosphorylation in skeletal muscle biopsies was increased by 1.7±0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177±12% and 144±18%, respectively;
P
<0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n=5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway.

Conclusions—

rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.
Swimming Prevents Vulnerable Atherosclerotic Plaque Development in Hypertensive 2-Kidney, 1-Clip Mice by Modulating Angiotensin II Type 1 Receptor Expression Independently From Hemodynamic Changes
Authors: Pellegrin Maxime , Alonso Florian , Aubert Jean-François , Bouzourene Karima , Braunersreuther Vincent , Mach François , Haefliger Jacques-Antoine , Hayoz Daniel , Berthelot Alain , Nussberger Jürg , Laurant Pascal , Mazzolai Lucia
Published: April 2009

Exercise is known to reduce cardiovascular risk. However, its role on atherosclerotic plaque stabilization is unknown. Apolipoprotein E
−/−
mice with vulnerable (2-kidney, 1-clip: angiotensin [Ang] II–dependent hypertension model) or stable atherosclerotic plaques (1-kidney, 1-clip: Ang II–independent hypertension model and normotensive shams) were used for experiments. Mice swam regularly for 5 weeks and were compared with sedentary controls. Exercised 2-kidney, 1-clip mice developed significantly more stable plaques (thinner fibrous cap, decreased media degeneration, layering, macrophage content, and increased smooth muscle cells) than sedentary controls. Exercise did not affect blood pressure. Conversely, swimming significantly reduced aortic Ang II type 1 receptor mRNA levels, whereas Ang II type 2 receptor expression remained unaffected. Sympathetic tone also significantly diminished in exercised 2-kidney, 1-clip mice compared with sedentary ones; renin and aldosterone levels tended to increase. Ang II type 1 downregulation was not accompanied by improved endothelial function, and no difference in balance among T-helper 1, T-helper 2, and T regulatory cells was observed between sedentary and exercised mice. These results show for the first time, in a mouse model of Ang II–mediated vulnerable plaques, that swimming prevents atherosclerosis progression and plaque vulnerability. This benefit is likely mediated by downregulating aortic Ang II type 1 receptor expression independent from any hemodynamic change. Ang II type 1 downregulation may protect the vessel wall from the Ang II proatherogenic effects. Moreover, data presented herein further emphasize the pivotal and blood pressure–independent role of Ang II in atherogenesis.
Power without Influence: The Bush Administration's Foreign Policy Failure in the Middle East
Authors: Pressman Jeremy
Published: April 2009

The administration of President George W. Bush was deeply involved in the Middle East, but its efforts did not advance U.S. national security. In the realms of counterterrorism, democracy promotion, and nonconventional proliferation, the Bush administration failed to achieve its objectives. Although the United States did not suffer a second direct attack after September 11, 2001, the terrorism situation worsened as many other countries came under attack and a new generation of terrorists trained in Iraq. Large regional powers such as Egypt and Saudi Arabia did not become more democratic, with no new leaders subject to popular mandate. The model used in Iraq of democratization by military force is risky, costly, and not replicable. Bush's policy exacerbated the problem of nuclear proliferation, expending tremendous resources on a nonexistent program in Iraq while bolstering Iran's geopolitical position. The administration failed because it relied too heavily on military force and too little on diplomacy, disregarded empiricism, and did not address long-standing policy contradictions. The case of the Bush administration makes clear that material power does not automatically translate into international influence.
Helpful and Hindering Multicultural Events in Group Supervision
Authors: Kaduvettoor Anju , O'Shaughnessy Tiffany , Mori Yoko , Beverly Clyde , Weatherford Ryan D. , Ladany Nicholas
Published: April 2009

This study examines the relationship between multicultural events in group supervision, group climate, and supervisee multicultural competence using a mixed qualitative/quantitative design. The discovery-oriented approach yielded 196 helpful and hindering multicultural events among 136 participants. The most common events included multicultural learning and peer vicarious learning. Supervisees suggested improving their group supervision through better integration of multicultural issues and more supervisor involvement. Regarding group climate, supervisees reporting peer vicarious learning or multicultural learning experienced higher group engagement, whereas misapplications of multicultural theory related to higher reports of group conflict. Increased multicultural learning and extra-group multicultural events positively related to supervisees' multicultural competence whereas multicultural conflicts with supervisors, misapplication of multicultural theory, and the absence of multicultural events negatively related to supervisee multicultural competence. The findings of this study generated several suggestions for managing multicultural events as well as improving theory, research, and practice for group supervision.
The Effect of Gender Stereotypes on Explicit and Implicit Career Preferences
Authors: Gadassi Reuma , Gati Itamar
Published: April 2009

The present study compared gender differences in directly reported and indirectly derived career preferences and tested the hypothesis that individuals' implicit preferences would show less gender-biased occupational choices than their directly elicited ones. Two hundred sixty-six visitors to a career-related Internet site were asked to (a) list 5 to 10 suitable occupations (the directly reported list) and (b) report their preferences in terms of 31 career-related aspects. The latter were used to produce a short list of promising occupational alternatives (the indirectly derived list), using the occupational database of an Internet-based career planning system. Each occupation in the database rated for sex dominance. The findings indicated that the sex dominance ratings of the occupations on the directly reported list accorded with the participants' gender for both men and women: Men's lists included mostly “masculine” occupations, whereas women's lists included mostly “feminine” occupations. This gender bias was significantly lower for the implicit lists. The difference between the directly reported and the indirectly derived lists was larger for women than for men, suggesting that the impact of stereotypes is more pronounced in women's than in men's directly reported career preferences.
Quality Education for African Americans After Parents Involved
Authors: Brown Frank
Published: April 2009

This introduction discusses the possible impact of the 2007 Supreme Court decision in Parents Involved in Community Schools v. Seattle School District No. 1, which dismantled the ability of school boards to act affirmatively to desegregate their schools by assigning students to schools beyond their neighborhoods as sanctioned in the Court's 1971 decision in Swann v. Charlotte Mecklenburg Board of Education. In addition, because this action will lead to de facto segregated schools by race and ethnicity, what are the possible implications for quality education for all students? Finally, the role of economic globalization on the need for the highest quality of education for racially isolated schools is discussed.
Parents Involved in Community Schools v. Seattle School District No. 1
Authors: Thro William E. , Russo Charles J.
Published: April 2009

In Parents Involved in Community Schools v. Seattle School District No. 1, a highly contentious and divided Supreme Court invalidated race-conscious admissions plans in two urban school systems, Seattle and Louisville. As such, Parents Involved was the latest chapter in the Court's almost 40-year history of reaching mixed results in such far-reaching areas involving race-conscious remedies as admissions to higher education, employment in the general workforce and in education, minority set aside programs, and voting rights. In light of the impact that Supreme Court cases on race-conscious remedies have in education, particularly in urban settings, this article first reviews the opinions of the Supreme Court's justices in Parents Involved because of its potentially far-reaching effect. The second part of the article reflects on the meaning of Parents Involved.
Politics and School Desegregation Before and After Parents Involved
Authors: Brown Frank , Hunter Richard C.
Published: April 2009

The authors attempt to tell the story of Brown and Parents Involved on educational inequality and connect these topics to economic competition globally. Brown came about in the 1950s in a much different environment: America was less diverse racially and ethnically, and economic competition on a global scale was less than in today's economy. Today, America's future is closely tied to the large pool of minority children enrolled in its public schools. The authors explore the return of more public schools to the neighborhood concept and how these schools may produce high-quality graduates. Finally, they examine how legal challenges may shift to school inequality within school districts away from challenges to inequality between school districts in the past.
Parents Involved in Community Schools v. Seattle School District No. 1
Authors: Pitre Paul E.
Published: April 2009

This article examines the Parents Involved in Community Schools v. Seattle Public School District No . 1 decision in light of its impact on the Brown ruling that preceded it. The Supreme Court's 5-4 vote on the matter of desegregation and equal access to educational opportunity signals that a divide exists in the United States with respect to the underlying educational values of excellence and equity. The current policy environment was examined and found to be dominated by the value of excellence at the expense of equity. Policy implications of the Parents Involved decision are considered, and policy recommendations for improving equitable access to education in the present environment are offered.