bluuebunny/crossref_metadata_2025 huggingface dataset:
The estrogen metabolite 17β-dihydroequilenin counteracts interleukin-1α induced expression of inflammatory mediators in human endothelial cells in vitro via NF-κB pathway
Authors: Kaun Christoph , Rega Gersina , Speidl Walter , Kastl Stefan , Weiss Thomas , Hohensinner Philipp , Dietrich Wolf , Tschugguel Walter , Bochkov Valery , Awad Ezzat , Maurer Gerald , Huber Kurt , Demyanets Svitlana , Pfaffenberger Stefan , Wojta Johann
Published: December 2005

In most studies showing cardio- and vasculoprotective effects of estrogens, 17β-estradiol was used and little information on possible effects of different estrogen metabolites is yet available. We investigated whether particular estrogen metabolites are effective in counteracting inflammatory activation of human endothelium. Human endothelial cells were incubated with 17α-dihydroequilenin, 17β-dihydroequilenin, δ-8,9-dehydroestrone, estrone and 17β-estradiol and stimulated with interleukin (IL)-1α.The expression of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) was determined. 17β-dihydroequilenin and 17β-estradiol at a concentration of 1µM reduced IL-1α-induced up regulation of IL-6, IL-8 and MCP-1 close to control levels. When both compounds were used in combination an additive effect was observed. 17α-dihydroequilenin and δ-8,9-dehydroestrone showed a similar anti-inflammatory effect only when used at 10µM whereas estrone had no effect. The effect of 17β-dihydroequilenin on IL-1α-induced production of IL-6, IL-8 and MCP-1 was reversed by the estrogen receptor antagonist ICI 182,780. 17β-dihydroequilenin also inhibited IL-1α-induced translocation of p50 and p65 to the nucleus of the cells. We have identified the estrogen metabolite 17β-dihydroequilenin, as an inhibitor of inflammatory activation of human endothelial cells. Characterization of specific estrogens – as shown in our study – could provide the basis for tailored therapies, which might be able to achieve vasoprotection without adverse side effects.
Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP)
Authors: Liu Tongyao , Scallan Ciaran , Broze George , Patarroyo-White Susanna , Pierce Glenn , Johnson Kirk
Published: December 2005

Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, severe von Willebrand disease, and other rare factor deficiencies. A novel approach to improve coagulation in such clotting disorders has been identified that, parodoxically, involves heparinlike sulfated polysaccharides.Select molecules of this broad class are largely devoid of anticoagulant activity and are here denoted Non-Anticoagulant Sulfated Polysaccharides (NASPs).A mechanism involving blockade of the extrinsic pathway downregulator,Tissue Factor Pathway Inhibitor (TFPI) by NASPs, was conceived as an approach for improving procoagulant behavior in hemophilic settings.A subset of NASPs, including pentosan polysulfate (PPS) and fucoidan inhibited both full-length and Kunitz 1 and 2 (K1K2) TFPI and, at concentrations from 4-500 nM, improved (i.e. accelerated) the clotting time of human hemophilia A and hemophilia B plasmas or plasma with reduced factor VII levels when tested in dilute prothrombin time (dPT) assays. Fucoidan did not reduce normal plasma APTT times implying specificity for extrinsic pathway control. Improved hemostasis in vivo was observed in mice with hemophilias A orB following low dose subcutaneous administration of PPS or fucoidan, or a combination of NASP plus factor supplement. Increased survival of factor deficient mice following a bleeding challenge was observed. Accordingly, administration of select NASP(s), via mechanism(s) not fully understood, represents a unique means of improving coagulation in bleeding disorders.
The death of human platelets during incubation in citrated plasma involves shedding of CD42b and aggregation of dead platelets
Authors: Savill John , Brown Simon , Hartley Paul
Published: December 2005

The ability to readily identify dead platelets is invaluable to studies examining the means of their death, factors affecting their lifespan and their means of clearance by phagocytes. The aim of the present work was to develop a vital staining procedure for the rapid and objective discrimination of live from dead platelets that accrued in citrated platelet rich plasma (cPRP) incubated at 37°C for several days. By transmission electron microscopy it was noted that platelet death was morphologically similar to necrosis and associated with aggregate formation. The vital dyes calcein-AM and FM 4–64 were found to robustly report the death of platelets and indicated that the aggregates which formed during incubation were populated exclusively by dead platelets. Additionally, platelet death was associated with the shedding of CD42b. Microscopic and cytometric analyses of incubated cPRP indicated that shedding of CD42b and aggregate formation by dead platelets were completely inhibited by the metalloproteinase inhibitor GM6001. Automated counting of platelets incubated in the presence of GM6001 revealed that death did not lead to a loss in cellularity. It is proposed that calcein-AM and FM4–64 are effective as vital stains for the reliable assessment of platelet viability and that platelet aggregation can occur by a novel mechanism dependent upon platelet death and metalloproteinase activity.
Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells
Authors: Fiori Anna , Bari Monica , Granata Filippo , Gasperi Valeria , De Stefano M. , Finazzi-Agrò Alessandro , Strom Roberto , Maccarrone Mauro
Published: December 2005

The endocannabinoid anandamide (AEA) has many neurovascular activities. However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the vascular and the cerebral compartments. The results reported in this article show that isolated bovine brain microvessels, an ex vivo model of the blood-brain barrier, have detectable levels of endogenous AEA and possess the biochemical machinery to bind and metabolize it, i. e. type-1 and type-2 cannabinoid receptors (CB1R and CB2R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase, and the AEA-synthesizing enzymes N-acyltransferase and N-acyl-phosphatidylethanolamines-specific phospholipase D. We also show that activation of CB1R enhances AMT activity through increased nitric oxide synthase (NOS) activity and subsequent increase of NO production. AMT activity is instead reduced by activation of CB2R, which inhibits NOS and NO release. In addition, binding experiments and immunoelectronmicroscopy demonstrate that different endothelial cells vary in the expression of CB1R and CB2R on the luminal and/or abluminal sides. The different localization of CBRs can lead to a diverse effect on AMT activity on the luminal and abluminal membranes, suggesting that the distribution of these receptors may drive AEA directional transport through the blood-brain barrier and other endothelial cells.
Impairment of adipose tissue development by hypoxia is not mediated by plasminogen activator inhibitor-1
Authors: Semeraro Fabrizio , Voros Gabor , Collen Désiré , Lijnen H.
Published: December 2005

Hypoxia in rodents and humans is associated with a reduction of body fat on the one hand, and with enhanced expression of plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of the fibrinolytic system, on the other hand. It was the objective of this study to investigate whether impairment of adipose tissue development by hypoxia may be mediated by PAI-1. Five week old male wild-type (WT) C57Bl/6 mice were fed a standard (SFD) or high fat (HFD) diet and kept under normoxic or hypoxic (10% O2) conditions. In addition, PAI-1 deficient mice and WT littermates were kept on HFD under normoxia or hypoxia. In vitro, the effect of hypoxia (2% O2) was investigated on differentiation of 3T3-L1 cells into adipocytes. Hypoxia induced a significant reduction of weight gain in WT mice on either SFD or HFD, accompanied by lower weights of subcutaneous (SC) and gonadal (GON) fat. Under hypoxic conditions, adipocytes in the adipose tissues were significantly smaller, whereas blood vessel size and density were larger. Serum PAI-1 levels were enhanced in hypoxic mice on SFD but not on HFD, and overall did not correlate with the observed changes in adipose tissue composition. Furthermore, the effects of hypoxia on adipose tissue in mice on HFD were not affected by deficiency of PAI-1. The inhibiting effect of hypoxia on in vitro preadipocyte differentiation was not mediated by PAI-1 activity. In conclusion, impairment of in vivo adipose tissue development and in vitro differentiation of preadipocytes by hypoxia is not mediated by PAI-1.
Right on the spot
Authors: Laudanna Carlo , Alon Ronen
Published: December 2005

The arrest of rolling leukocytes on various target vascular beds is crucial for their recruitment at inflammatory sites and secondary lymphoid tissues. Leukocyte arrest is predominantly mediated by integrins interacting with either constitutive or inducible endothelial ligands. Integrins are cytoskeletally regulated heterodimers maintained in largely low affinity conformational states on circulating leukocytes. For arrest to occur, the affinity of integrin heterodimers must be enhanced in situ upon leukocyte encounter with proper endothelial-displayed chemokines or chemoattractants which bind and signal through specific G-protein coupled receptors (GPCRs) on the leukocyte surface. Recent studies suggest that this integrin activation involves rapid conformational alterations locally induced at confined leukocyte-endothelial contact sites. Following binding, integrin microclustering reinforced by associations with the cortical actin cytoskeleton further enhances integrin-mediated adhesiveness under shear stress. These events are controlled by complex signaling events, involving a series of small GTPases, as well as protein and lipid kinases which are triggered by chemokine bound GPCRs. To rapidly mediate this specialized function, subsets of signaling proteins and their specific targets are thought to preexist in pre-assembled multi-molecular complexes or signalosomes. Recent in vitro dissection of chemokine-triggered integrin activation on lymphocytes and neutrophils suggests that these signalosomes may vary both in composition and mode of activity between different immune cell types and distinct integrins. We review in this article recent findings on key elements implicated in chemokine triggering of integrin activation on rolling leukocytes, and discuss the possible existence of preformed proadhesive signaling networks in different subsets of leukocytes.
Endothelial tight junctions: permeable barriers of the vessel wall
Authors: Bazzoni Gianfranco
Published: December 2005

The endothelial lining of the vessel wall is a permeable barrier, which is located at the interface between the vascular and the perivascular compartments. Although the endothelium acts as an efficient barrier that strictly separates the two compartments,it may also act as a permeable filter which allows selective exchange of solutes and water between the luminal and abluminal sides of the barrier. Similarly to epithelia, also in the endothelium permeability follows two distinct routes, which have been termed transcellular pathway (across the apical and basolateral membranes of individual cells) and paracellular pathway (through the intercellular junctions and the lateral spaces between contacting cells). After an initial description of the two pathways, the review focuses on the cellular and molecular basis of the paracellular pathway, with emphasis on the role of intercellular tight junctions and tight junction-associated claudins. Finally, the signaling events that regulate paracellular permeability are discussed.
Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells
Authors: Ho-Tin-Noé Benoît , Meilhac Olivier , Rossignol Patrick , Lijnen H. , Anglés-Cano Eduardo
Published: December 2005

Because of its structural homology with plasminogen, the apolipoprotein(a) [apo(a)] component of the athero-thrombogenic lipoprotein(a) [Lp(a)] particle inhibits plasminogen binding and activation onto fibrin as well as the subsequent fibrinolysis. In a similar manner, apo(a) may also interfere with plasmin(ogen)-induced cell detachment and apoptosis of adherent cells. To investigate this hypothesis, we studied the effect of a recombinant apo(a) [r-apo(a)] on plasminogen activation-induced apoptosis of vascular smooth muscle cells (VSMCs) and fibroblasts-like CHO-K1 cells. We demonstrate for the first time that apo(a) displays a concentration-dependent biphasic, enhancing/preventing effect on plasmin(ogen) induced cell detachment of VSMCs and CHO-K1 cells. Our results show that r-apo(a) binds to these cells with higher affinity than plasminogen [Kd = 0.9 ± 0.2 µM for plasminogen, Kd = 1.77 ± 0.34 nM for r-apo(a)] in a lysine-dependent manner. At high r-apo(a)/plasminogen ratios, their competitive interaction results in a partial inhibition of plasminogen activation by cell-bound t-PA. As a consequence, r-apo(a) prevents plasmin(ogen)-induced cell detachment and apoptosis. Surprisingly,at low r-apo(a)/plasminogen ratios,an enhancement in plasmin(ogen)-induced cell detachment and apoptosis was observed. This effect was shown to be “plasmin-selective” as r-apo(a) was unable to potentiate cell detachment induced by human neutrophil elastase and trypsin. Altogether these data are consistent with a new mechanism of apo(a)/plasmin(ogen) interactions that may contribute to the atherothrombogenic potential of Lp(a).
Association of cardiovascular risk factors with markers of endothelial dysfunction in middle-aged men and women
Authors: Thorand Barbara , Baumert Jens , Döring Angela , Schneider Andrea , Chambless Lloyd , Löwel Hannelore , Kolb Hubert , Koenig Wolfgang
Published: December 2005

Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases and diabetes mellitus. However, the causes underlying endothelial dysfunction are not fully understood. Therefore, the aim of the present study was to investigate associations of cardiovascular risk factors with soluble adhesion molecules (sE-Selectin, sICAM-1), soluble thrombomodulin (sTM) and von Willebrand factor (vWF) as markers of endothelial dysfunction. The study population consisted of a subcohort of 2,168 men and women aged 35 to 74 years randomly drawn from three cross-sectional population-based MONICA/ KORA Augsburg surveys conducted between 1984 and 1995. In multivariable linear regression analysis, current smoking, high (versus moderate) alcohol consumption, ratio of total cholesterol/HDL-cholesterol (TC/HDL-C) and C-reactive protein (CRP) were significantly associated with elevated levels of sEselectin and sICAM-1. Increased levels of sE-selectin were also found in subjects with actual hypertension, high body mass index and prevalent diabetes mellitus. In addition, low physical activity and no (versus moderate) alcohol consumption were significantly associated with elevated concentrations of sICAM-1. Levels of sTM were higher in subjects with actual hypertension, no or high amounts of alcohol intake and a high ratio of TC/ HDL-C, but were lower in subjects witha history of myocardial infarction. VWF was significantly associated with CRP only. In conclusion, sE-selectin and sICAM-1 are more strongly associated with traditional cardiovascular risk factors than sTM and vWF.
Clinical relevance of distal deep vein thrombosis
Authors: Paris Samuel , Le Gal Grégoire , Laroche Jean-Pierre , Perrier Arnaud , Bounameaux Henri , Righini Marc
Published: December 2005

The standard diagnostic approach of suspected deep vein thrombosis (DVT) is serial lower limb compression ultrasound (CUS) of proximal veins. Although it only assesses the proximal veins, withholding anticoagulant treatment in patients with a negative CUS on day one and after one week has been proven to be safe. However, in many centres, distal DVT is systematically screened for and treated by anticoagulants. The objectives of the review were 1) to evaluate the rate of extension of distal DVTs to proximal veins 2) to compare the safety of proximal limited CUS versus single complete CUS. We performed a MEDLINE search covering the period from January 1983 to January 2005 by using the key-words “calf vein thrombosis”, “distal thrombosis” and “compression ultrasonography”. English, German and French language original studies were retrieved. Moreover, references of retrieved articles were screened in order to detect missed pertinent articles. We pooled data of management studies where proximal or complete (i. e. proximal and distal) CUS were used, respectively. Studies evaluating CUS limited to the proximal veins showed a good safety profile with a pooled estimate of the 3-month thromboembolic rate of 0.6% (95% CI: 0.4–0.9%) in patients in whom anticoagulation was withheld. Studies using proximal and distal CUS showed a similar pooled estimate of the 3-month thromboembolic rate (0.4%, 95% CI: 0.1–0.6%) but distal DVT accounted for as many as 50% of all diagnosed DVTs in those series. Therefore, searching for distal DVT potentially doubles the number of patients given anticoagulant therapy and entails a risk of over-treatment. Data suggesting that anticoagulation is indicated for distal DVT are limited, and realizing distal CUS entails a risk of over-treatment. There is an urgent need for randomised trials assessing the usefulness of anticoagulant treatment in distal DVT.
Marburg I polymorphism of factor VII-activating protease and risk of recurrent venous thromboembolism
Authors: Gulesserian Talin , Hron Gregor , Endler Georg , Eichinger Sabine , Wagner Oswald , Kyrle Paul
Published: December 2005

Whether a single nucleotide polymorphism (1601 G>A) in the factor VII-activating protease gene (FSAP Marburg I) is a risk factor for venous thromboembolism (VTE) is unclear. We investigated the relevance of the variant with respect to recurrent VTE. 854 patients with a first unprovoked VTE were followed for an average of 41 months after discontinuation of anticoagulation. Study endpoint was symptomatic recurrent VTE. VTE recurred in 7 of 41 patients (17%) with and in 106 of 813 patients (13%) without the variant. After3 years, the probability of recurrence was 20.0% (95% CI, 5.3% to 34.6%) among patients with and 12.2% (95% CI, 9.6% to 14.8%) among those without FSAP MarburgI (p = 0. 5). The relative recurrence risk among carriers of the variant was 1.3 (95% CI, 0.6 to 2.8; p = 0.5) before and 1.5 (95% CI, 0.7 to 3.3; p = 0. 3) after adjustment for potentially confounding factors. We conclude that FSAP Marburg I is, if at all, only a mild factor for recurrent VTE. Patients with FSAP Marburg I most probably will not benefit from extended anticoagulation.
Migration of dendritic cells across blood and lymphatic endothelial barriers
Authors: Del Prete Annalisa , Locati Massimo , Otero Karel , Riboldi Elena , Mantovani Alberto , Vecchi Annunciata , Sozzani Silvano
Published: December 2005

Dendritic cells (DC) are professional antigen presenting cells which playa pivotal role in the activation of adaptive immunity. Tissue invasion by pathogens induces the recruitment of blood DC to the site of infection and contributes to their subsequent migration to secondary lymphoid organs. This complex process relies on the expression and regulation of receptors for chemotactic factors on the surface of migrating DC and on the activation of adhesion molecules which allow DC to properly interact with both blood and lymphatic vessels. In the absence of correct tissue localization, DC fail to promote proper immune responses. Therefore, the interaction of DC with endothelial cells represents a fundamental step for DC biology.
Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome
Authors: Frustaci Andrea , Priori Silvia G. , Pieroni Maurizio , Chimenti Cristina , Napolitano Carlo , Rivolta Ilaria , Sanna Tommaso , Bellocci Fulvio , Russo Matteo Antonio
Published: December 2005

Background—

The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in Brugada syndrome is still debated.

Methods and Results—

We studied 18 consecutive patients (15 males, 3 females; mean age 42.0±12.4 years) with clinical phenotype of Brugada syndrome and normal cardiac structure and function on noninvasive examinations. Clinical presentation was ventricular fibrillation in 7 patients, sustained polymorphic ventricular tachycardia in 7, and syncope in 4. All patients underwent cardiac catheterization, coronary and ventricular angiography, biventricular endomyocardial biopsy, and DNA screening of the
SCN5A
gene. Biopsy samples were processed for histology, electron microscopy, and molecular screening for viral genomes. Microaneurysms were detected in the right ventricle in 7 patients and also in the left ventricle in 4 of them. Histology showed a prevalent or localized right ventricular myocarditis in 14 patients, with detectable viral genomes in 4; right ventricular cardiomyopathy in 1 patient; and cardiomyopathic changes in 3. Genetic studies identified 4 carriers of
SCN5A
gene mutations that cause in vitro abnormal function of mutant proteins. In these patients, myocyte cytoplasm degeneration was present at histology, whereas terminal dUTP nick end-labeling assay showed a significant increase of apoptotic myocytes in right and left ventricle versus normal controls (
P
=0.014 and
P
=0.013, respectively).

Conclusions—

Despite an apparently normal heart at noninvasive evaluation, endomyocardial biopsy detected structural alterations in all 18 patients with Brugada syndrome. Mutations in the
SCN5A
gene, identified in 4 of the 18 patients, may have induced concealed structural abnormalities of myocardiocytes that accounted for paroxysmal arrhythmic manifestations.
nNOS
Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction
Authors: Dawson Dana , Lygate Craig A. , Zhang Mei-Hua , Hulbert Karen , Neubauer Stefan , Casadei Barbara
Published: December 2005

Background—

The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and β-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI)

Methods and Results—

We compared LV remodeling at 1, 4, and 8 weeks after MI in
nNOS
-knockout mice (
nNOS
−/−
) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g
−1
· min
−1
) were also evaluated 8 weeks after MI. Sham-operated
nNOS
−/−
mice showed enhanced basal LV contractility (
P
<0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (
P
<0.01 versus WT). Both basal and β-adrenergic LV relaxations were significantly impaired in
nNOS
−/−
mice. Survival after MI did not differ between groups. However,
nNOS
−/−
mice developed a faster and more severe LV dilation compared with WT mice (
P
<0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted
nNOS
−/−
mice responded to dobutamine with a dramatic fall in LV contractility (
P
<0.01 for preload-recruitable stroke work).

Conclusions—

nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial β-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism.
Techniques, Evaluation, and Consequences of Linear Block at the Left Atrial Roof in Paroxysmal Atrial Fibrillation
Authors: Hocini Mélèze , Jaïs Pierre , Sanders Prashanthan , Takahashi Yoshihide , Rotter Martin , Rostock Thomas , Hsu Li-Fern , Sacher Frédéric , Reuter Sylvain , Clémenty Jacques , Haïssaguerre Michel
Published: December 2005

Background—

There are no reports describing the technique, electrophysiological evaluation, and clinical consequences of complete linear block at roofline joining the superior pulmonary veins (PVs) in patients with paroxysmal atrial fibrillation (AF).

Methods and Results—

Ninety patients with drug-refractory paroxysmal AF undergoing radiofrequency ablation were prospectively randomized into 2 ablation strategies: (1) PV isolation (n=45) or (2) PV isolation in combination with linear ablation joining the 2 superior PVs (roofline; n=45). In both groups, the cavotricuspid isthmus, fragmented peri-PV-ostial electrograms, and spontaneous non-PV foci were ablated. Roofline ablation was performed at the most cranial part of the left atrium (LA) with complete conduction block demonstrated during LA appendage pacing by the online mapping of continuous double potential and an activation detour propagating around the PVs to activate caudocranially the posterior wall of the LA. The effect of ablation at the LA roof was evaluated by the change in fibrillatory cycle length, termination and noninducibility of AF, and clinical outcome. PV isolation was achieved in all patients with no significant differences in the radiofrequency duration, fluoroscopy, or procedural time between the groups. Roofline ablation required 12±6 (median 11, range 3 to 25) minutes of radiofrequency energy delivery with a fluoroscopic duration of 7±2 minutes and was performed in 19±7 minutes. Complete block was confirmed in 43 patients (96%) and resulted in an activation delay that was shorter circumventing the left than the right PVs during LA appendage pacing (138±15 versus 146±25 ms, respectively;
P
=0.01). Roofline ablation resulted in a significant increase in the fibrillatory cycle length (198±38 to 217±44 ms;
P
=0.0005), termination of arrhythmia in 47% (8/17), and subsequent noninducibility of AF in 59% (10/17) of the patients inducible after PV isolation. However, LA flutter, predominantly perimitral, could be induced in 10 patients (22%) after roofline ablation. At 15±4 months, 87% of the roofline group and 69% with PV isolation alone are arrhythmia free without antiarrhythmics (
P
=0.04).

Conclusions—

This prospective randomized study demonstrates the feasibility of achieving complete linear block at the LA roof. Such ablation resulted in the prolongation of the fibrillatory cycle, termination of AF, and subsequent noninducibility and is associated with an improved clinical outcome compared with PV isolation alone.
Prediction of Type 2 Diabetes Mellitus With Alternative Definitions of the Metabolic Syndrome
Authors: Hanley Anthony J.G. , Karter Andrew J. , Williams Ken , Festa Andreas , D’Agostino Ralph B. , Wagenknecht Lynne E. , Haffner Steven M.
Published: December 2005

Background—

In addition to predicting cardiovascular disease (CVD) morbidity and mortality, the metabolic syndrome is strongly associated with the development of type 2 diabetes mellitus (DM), itself an important risk factor for CVD. Our objective was to compare the ability of various metabolic syndrome criteria (including those recently proposed by the International Diabetes Federation), markers of insulin resistance (IR) and inflammation, and impaired glucose tolerance (IGT) in the prediction of DM and to determine whether various proposed modifications to the National Cholesterol Education program (NCEP) metabolic syndrome definition improved predictive ability.

Methods and Results—

We examined 822 subjects in the Insulin Resistance Atherosclerosis Study aged 40 to 69 years who were nondiabetic at baseline. After 5.2 years, 148 individuals had developed DM. IGT, metabolic syndrome definitions, and IR markers all significantly predicted DM, with odds ratios ranging from 3.4 to 5.4 (all
P
<0.001), although there were no significant differences in the areas under the receiver operator characteristic (AROC) curves between the definitions. Modifying or requiring obesity, glucose, or IR components in NCEP-defined metabolic syndrome did not significantly alter the predictive ability of the definition under AROC curve criteria (all
P
>0.05). Similarly, although IR and inflammation variables were significantly associated with incident DM when included in multivariate models with NCEP-defined metabolic syndrome (all
P
<0.01), expanding the definition by adding these variables as components did not significantly alter the predictive ability of the definition under AROC curve criteria (all
P
>0.05).

Conclusions—

The International Diabetes Federation and NCEP metabolic syndrome definitions predicted DM at least as well as the World Health Organization definition, despite not requiring the use of oral glucose tolerance testing or measures of IR or microalbuminuria. Modifications or additions to the NCEP metabolic syndrome definition had limited impact on the prediction of DM.
Cost-Effectiveness of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine Therapy for Blacks With Heart Failure
Authors: Angus Derek C. , Linde-Zwirble Walter T. , Tam S. William , Ghali Jalal K. , Sabolinski Michael L. , Villagra Victor G. , Winkelmayer Wolfgang C. , Worcel Manuel
Published: December 2005

Background—

Fixed-dose combination of isosorbide dinitrate/hydralazine (ISDN/HYD) improved clinical outcomes in the African-American Heart Failure Trial (A-HeFT). We assessed the resource use, costs of care, and cost-effectiveness of ISDN/HYD therapy in the A-HeFT trial population.

Methods and Results—

We obtained resource use data from A-HeFT, assigning costs through the use of US federal sources. Excluding indirect costs, we summarized the within-trial experience and modeled cost-effectiveness over extended time horizons, including a US societal lifetime reference case. During the mean trial follow-up of 12.8 months, the ISDN/HYD group incurred fewer heart failure–related hospitalizations (0.33 versus 0.47 per subject;
P
=0.002) and shorter mean hospital stays (6.7 versus 7.9 days;
P
=0.006). When study drug costs were excluded, both heart failure–related and total healthcare costs were lower in the ISDN/HYD group (mean per-subject heart failure–related costs, $5997 versus $9144;
P
=0.04; mean per-subject total healthcare costs, $15 384 versus $19 728;
P
=0.03). With an average daily drug cost of $6.38, ISDN/HYD therapy was dominant (reduced costs and improved outcomes) over the trial duration. Assuming that no additional benefits accrue beyond the trial, we project the cost-effectiveness of ISDN/HYD therapy using heart failure–related costs to be $16 600/life-year at 2 years after enrollment, $37 100/life-year at 5 years, and $41 800/life-year over lifetime (reference case).

Conclusions—

ISDN/HYD therapy, previously shown to improve clinical outcomes, also reduced resource use and costs in A-HeFT, primarily because of a large reduction in hospitalizations. Long-term use of ISDN/HYD therapy should be associated with a favorable cost-effectiveness profile in this population.
Nuclear Factor-κB–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes
Authors: Baetz Delphine , Regula Kelly M. , Ens Karen , Shaw James , Kothari Shilpa , Yurkova Natalia , Kirshenbaum Lorrie A.
Published: December 2005

Background—

A survival role for the transcription factor nuclear factor-κB (NF-κB) in ventricular myocytes has been reported; however, the underlying mechanism is undefined. In this report we provide new mechanistic evidence that survival signals conferred by NF-κB impinge on the hypoxia-inducible death factor BNIP3.

Methods and Results—

Activation of the NF-κB signaling pathway by IKKβ in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKKβ or p65 NF-κB suppressed basal and hypoxia-inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF-κB elements to be crucial for inhibiting basal and inducible BNIP3 gene activity. Cells derived from p65
−/−
-deficient mice or ventricular myocytes rendered defective for NF-κB signaling with a nonphosphorylative IκB exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF-κB–defective myocytes rescued them from mitochondrial defects and cell death.

Conclusions—

The data provide new compelling evidence that NF-κB suppresses mitochondrial defects and cell death of ventricular myocytes through a mechanism that transcriptionally silences the death gene BNIP3. Collectively, our data provide new mechanistic insight into the mode by which NF-κB suppresses cell death and identify BNIP3 as a key transcriptional target for NF-κB–regulated expression in ventricular myocytes.
Consumer Vulnerability to Perceived Product Similarity Problems: Scale Development and Identification
Authors: Walsh Gianfranco , Mitchell Vincent-Wayne
Published: December 2005

Branding and product differentiation should lead to distinct product positioning in the minds of consumers, which helps them to choose between products. However, the increasing numbers of similar products make it more difficult for consumers to distinguish between brands, which can lead to a loss of utility through mistaken and misinformed purchases. Despite this risk, little research has addressed the perceived product similarity construct, and there is no accepted measure or any idea of which consumers are vulnerable to it. This research develops a parsimonious scale for measuring consumers’ orientation for inferring that all products within a category are similar and identifies those vulnerable to it. Support was found for a one-dimensional six-item measure, and its reliability and validity were assessed. Cluster analysis identified three similarity groups of which one appeared highly vulnerable to seeing products as similar. Implications for consumer policy and marketplace trust are discussed.
Critical Consumer Education: Empowering the Low-Literate Consumer
Authors: Adkins Natalie Ross , Ozanne Julie L.
Published: December 2005

Consumer education programs assume that consumers have the right to full product information, and well-informed consumers will be able to get their needs met in the marketplace. Adults with limited literacy abilities, however, enter the marketplace without the literacy resources of other consumers and are potentially more vulnerable. Many adult literacy programs assume adult literacy students lack both literacy and consumer skills. The results from an interpretative study suggest adult literacy learners combine a range of social skills and resources and an ability to manage the shame of the low-literacy stigma to get their needs met in the marketplace. Four consumer literacy profiles are discussed, and an alternative form of consumer education tailored to each profile is proposed. We discuss the role of a more critical consumer educational approach in literacy assistance programs and its impact on adult learners’ feelings of self-esteem, empowerment, and agency.
Functional Illiteracy and Nutritional Education in the United States: A Research-Based Approach to the Development of Nutritional Education Materials for Functionally Illiterate Consumers
Authors: Viswanathan Madhu , Gau Roland
Published: December 2005

Nutritional education programs are at the intersection of two important macro-level issues; the rate of functional illiteracy among individuals in the United States and disturbing health and nutrition-related trends in the last two decades. Functionally illiterate consumers form a sizable portion of the population in the United States and a sizable portion of the likely target audience for nutritional education programs. However, until recently, research on functionally illiterate consumer behavior has essentially been nonexistent. This study’s analysis of materials currently used in nutritional education programs suggests that such materials should be modified to convey information in a more user-friendly manner. On the basis of a case study of a nutrition educational program and interviews and observations of teachers and clients, the authors develop and recommend educational materials using visual displays emphasizing the marketplace context rather than using verbal and numerical modes emphasizing abstract information.
Vulnerable Women on Screen and at Home: Soap Opera Consumption
Authors: Stern Barbara B. , Russell Cristel Antonia , Russell Dale W.
Published: December 2005

Daytime television soap operas primarily appeal to women, providing emotional release, personal gratification, companionship, and an escape from reality. This article reviews the extant literature on soap opera consumption to reveal a vulnerability system in which industry profits flow from a genre that specializes in conveying images of vulnerable women living in luxury to downscale viewers living in constrained circumstances and repeatedly exposed to unrealistic and inappropriate role models. The soap industry has recently acknowledged its audience’s vulnerability and has attempted to bring together producers, writers, and network executives to encourage awareness of the industry’s role in shaping consumers’ attitudes and behavior.
Vulnerability in the Marketplace: Concepts, Caveats, and Possible Solutions
Authors: Ringold Debra Jones
Published: December 2005

Vulnerable consumers fail to understand their preferences and/or lack the knowledge, skills, or freedom to act on them. To protect them, some want to censor information, restrict choices, and mandate behaviors. One-fifth of the American public is functionally illiterate, K-12 performance is declining, and yet a substantial majority of American consumers (adolescents included) appear to be marketplace literate. Rather than curtail consumer prerogatives to protect a vulnerable minority, education reform focused on the values, knowledge, and skills necessary to create and navigate responsive markets is proposed. Reformed adult and K-12 education can refine, expand, and accelerate learners’ informal and experiential understanding of marketplace fundamentals. The aim is to significantly replace trial and error with a robust understanding of markets, markets habitually governed by social virtues. Evidence suggests that these aims can be better achieved via K-12 choice and should be the focus of adult basic education reform.
Clinical intervention rates in community pharmacy: a randomised trial of the effect of education and a professional allowance
Authors: Benrimoj Shalom I , Langford Jane H , Ward Paul R , Berry Geoffrey , Collins David , Lauchlan Roberta , Stewart Kay
Published: December 2005

Objectives

To quantify the rate of clinical interventions by community pharmacists, and to determine the effect of providing targeted education and/or fee-for-service professional remuneration on the rate of clinical interventions.

Methods

A randomised trial involving four groups of 10 community pharmacies: group A served as a control and received neither education nor remuneration; group B received education and professional remuneration; group C received “advanced” education and professional remuneration; and group D received professional remuneration with no education. Pharmacists in all groups documented interventions for three one-week periods. Types of intervention were pre-specified by the researchers and logged as such by the pharmacists. Interventions were categorised as “reactive” or “proactive” by a panel comprising a community pharmacist and a hospital pharmacist. Logistic regression analysis was used to compare differences in intervention rates between the groups at baseline, between groups over time (six weeks), and within groups over time.

Results

87,130 prescription items were dispensed in the study period, and there were 762 clinical interventions, an intervention rate of 0.87%. Of the total, 375 (0.43%) were proactive and 387 (0.44%) were reactive. Groups B and C showed increases in clinical intervention rates immediately after the educational intervention, but these rates then decreased between week 1 and 2. Over the study period, group D had statistically significant reductions in intervention rates from baseline (total, reactive and proactive), and group A showed statistically significant reductions in reactive intervention rates.

Conclusions

The results from this study show that providing remuneration alone or maintaining the status quo (ie, neither remuneration nor education) did not lead to an increase in clinical interventions in community pharmacies. Increases in rates within the groups receiving education and remuneration were short lived. Developing and implementing educational programmes in addition to fee-for-service remuneration packages may have a positive impact on clinical intervention rates. Longitudinal work is required to investigate the sustainable effects of longer-term education strategies on clinical interventions in community pharmacy.
A national survey of pharmacist transcribing of discharge prescriptions
Authors: Hobson Rachel J , Sewell Graham J
Published: December 2005

Objective

To provide quantitative data on pharmacist discharge prescription transcription service (PDPTS) provision in UK hospitals.

Method

Postal questionnaire survey of clinical pharmacy managers.

Setting

Selection criteria included one hospital in each acute trust in the UK.

Key findings

The response rate was 66% (135/206). In mid-2001, a PDPTS was provided by 49 hospital pharmacy departments (36%). PDPTS was the most common prescribing activity undertaken by pharmacists, followed by a prescription amendment policy (29%), prescribing in pre-admission clinics (18%) and re-writing drug charts (15%). 59 departments (44%) did not undertake any prescribing activity.

Of the 86 non-transcribing hospitals, 69% undertook no prescribing activity (range = 0 to 3 prescribing activities). Transcribing hospitals offered a wider range of prescribing activities (range = 1 to 8 prescribing activities). A weak relationship was found between the number of pharmacists employed per hospital and the number of prescribing activities undertaken (correlation coefficient = 0.208, P = 0.018). The most frequently used PDPTS model (78%) involved pharmacists transcribing the discharge prescriptions for their own wards. The number of pharmacists transcribing discharge prescriptions per hospital ranged from 1 to 89 (mean = 8, mode = 2, median = 5, 25% percentile = 2, 75% percentile = 10). The majority of pharmacists (52%) reported writing less than five prescriptions per day; 35% were writing 5–10 prescriptions per day. The most common training requirement for pharmacists to start transcribing was an in-house training programme (55%). The majority of departments (80%) did not re-assess the ability of their pharmacists to transcribe.

Conclusion

Hospital pharmacy departments in the UK have started to take on prescribing roles, especially transcribing discharge prescriptions. However, it would appear that the majority of the PDPTS schemes are not being run extensively throughout the hospitals. It is of concern that the principles of clinical governance are not being met in terms of training and re-assessment of the pharmacists who are undertaking this service. The reasons why the service has developed in some hospitals and not others are not known. In order to extend this service, funding, resources and skill-mix maximisation need to be considered. This will enable patients to gain the maximum benefit from this service development.
Clinical significance of clinical interventions in community pharmacy: a randomised trial of the effect of education and a professional allowance
Authors: Benrimoj Shalom I , Langford Jane H , Ward Paul R , Berry Geoffrey , Collins David , Lauchlan Roberta , Stewart Kay
Published: December 2005

Objectives

To assess the clinical significance of clinical interventions undertaken by community pharmacists, and to explore the effect of providing education and/or remuneration on the clinical significance of interventions.

Design

Randomised trial involving four groups of community pharmacists; expert panel to assess the clinical significance of the interventions.

Methods

The “proactive” clinical interventions undertaken by community pharmacists during the trial were reviewed by an expert panel for assessment of avoided adverse health consequences and clinical significance. The panel used a validated assessment instrument developed from the existing research literature and a pilot study by the authors.

Data analysis

Agreement between experts was determined using the kappa statistic. In addition, the results of the expert panel were analysed for cases where the majority of experts provided the same assessment of clinical significance (ie, consensus).

Results

Overall, there was no statistically significant difference in the clinical significance of clinical interventions undertaken by the four study groups. However, there were significant differences (95% CI) in the types of proactive interventions undertaken, with the two groups that received an educational intervention being more likely to engage in more complex intervention areas, such as drug/drug interactions and adverse/side effects. Analysis of consensus revealed that 52% of proactive clinical interventions were deemed to be “clinically significant” and 2% were deemed to be either “clinically very significant” or “potentially life-saving”. When extrapolated to national Australian prescribing figures, a mean of 3,752 potentially life-saving interventions by community pharmacists could be expected per year (95% CI 454 to 13,554).

Conclusion

The results of this study provide the first estimates of the potential clinical benefits associated with clinical interventions in Australian community pharmacies. The study contributes evidence on the value of pharmaceutical services to the health care system. As such, it is expected that the study findings will provide a platform for discussion and decision-making.