bluuebunny/crossref_metadata_2025 huggingface dataset:
Methods for exploring implementation variation and local context within a cluster randomised community intervention trial
Authors: Hawe Penelope , Shiell Alan , Riley Therese , Gold Lisa
Published: August 2004

Insignificant or modest findings in intervention trials may be attributable to poorly designed or theorised interventions, poorly implemented interventions, or inadequate evaluation methods. The pre-existing context may also account for the effects observed. A combination of qualitative and quantitative methods is outlined that will permit the determination of how context level factors might modify intervention effectiveness, within a cluster randomised community intervention trial to promote the health of mothers with new babies. The methods include written and oral narratives, key informant interviews, impact logs, and inter-organisational network analyses. Context level factors, which may affect intervention uptake, success, and sustainability are the density of inter-organisational ties within communities at the start of the intervention, the centrality of the primary care agencies expected to take a lead with the intervention, the extent of context-level adaptation of the intervention, and the amount of local resources contributed by the participating agencies. Investigation of how intervention effects are modified by context is a new methodological frontier in community intervention trial research.
Applying systematic review methods to studies of people’s views: an example from public health research
Authors: Harden Angela , Garcia Jo , Oliver Sandy , Rees Rebecca , Shepherd Jonathan , Brunton Ginny , Oakley Ann
Published: August 2004

Methods for systematic reviews are well developed for trials, but not for non-experimental or qualitative research. This paper describes the methods developed for reviewing research on people’s perspectives and experiences (“views” studies) alongside trials within a series of reviews on young people’s mental health, physical activity, and healthy eating. Reports of views studies were difficult to locate; could not easily be classified as “qualitative” or “quantitative”; and often failed to meet seven basic methodological reporting standards used in a newly developed quality assessment tool. Synthesising views studies required the adaptation of qualitative analysis techniques. The benefits of bringing together views studies in a systematic way included gaining a greater breadth of perspectives and a deeper understanding of public health issues from the point of view of those targeted by interventions. A systematic approach also aided reflection on study methods that may distort, misrepresent, or fail to pick up people’s views. This methodology is likely to create greater opportunities for people’s own perspectives and experiences to inform policies to promote their health.
Disruption of CD40-CD40 ligand pathway inhibits the development of intestinal muscle hypercontractility and protective immunity in nematode infection
Authors: Khan W. I. , Motomura Y. , Blennerhassett P. A. , Kanbayashi H. , Varghese A. K. , El-Sharkawy R. T. , Gauldie J. , Collins S. M.
Published: August 2004

In our previous studies, we demonstrated that during Trichinella spiralis infection, T helper (Th) 2 cells contribute to the development of intestinal muscle hypercontractility and worm expulsion from the gut via STAT6. In addition, we have linked the altered muscle contractility to the eviction of the parasite and thereby to the host defense. However, the initial events linking infection to the development of muscle hypercontractility are poorly understood. In this study, we examined the contribution of CD40-CD40 ligand (CD40L) interaction in the development of intestinal muscle hypercontractility, in monocyte chemoattractant protein-1 (MCP-1) production, and in the Th2 response in CD40 ligand-deficient (CD40L −/−) mice infected with T. spiralis. Expulsion of intestinal worms was substantially delayed in CD40L −/− mice compared with the wild-type mice after T. spiralis infection. Consistent with delayed worm expulsion, there was a significant attenuation of intestinal muscle contractility in CD40L −/− mice. Infected CD40L −/− mice also exhibited marked impairment in the production of MCP-1, IL-4, IL-13, IgG1, IgE, and mouse mucosal MCP 1 (MMCP-1), and in goblet cell response. These results demonstrate that CD40-CD40 ligand interaction plays an important role in MCP-1 production, Th2 response, intestinal muscle hypercontractility, and worm expulsion in nematode infection. The present data suggest that the early events leading to the generation of Th2 response include CD40-CD40 ligand interaction, which subsequently influences the production of Th2 cytokines, most likely via upregulation of MCP-1.
Butyrate specifically modulatesMUCgene expression in intestinal epithelial goblet cells deprived of glucose
Authors: Gaudier E. , Jarry A. , Blottière H. M. , de Coppet P. , Buisine M. P. , Aubert J. P. , Laboisse C. , Cherbut C. , Hoebler C.
Published: August 2004

The mucus layer covering the gastrointestinal mucosa is considered the first line of defense against aggressions arising from the luminal content. It is mainly composed of high molecular weight glycoproteins called mucins. Butyrate, a short-chain fatty acid produced during carbohydrate fermentation, has been shown to increase mucin secretion. The aim of this study was to test 1) whether butyrate regulates the expression of various MUC genes, which are coding for protein backbones of mucins, and 2) whether this effect depends on butyrate status as the major energy source of colonocytes. Butyrate was provided at the apical side of human polarized colonic goblet cell line HT29-Cl.16E in glucose-rich or glucose-deprived medium. In glucose-rich medium, butyrate significantly increased MUC3 and MUC5B expression (1.6-fold basal level for both genes), tended to decrease MUC5AC expression, and had no effect on MUC2 expression. In glucose-deprived medium, i.e., when butyrate was the only energy source available, MUC3 and MUC5B increase persisted, whereas MUC5AC expression was significantly enhanced (3.7-fold basal level) and MUC2 expression was strikingly increased (23-fold basal level). Together, our findings show that butyrate is able to upregulate colonic mucins at the transcriptional level and even better when it is the major energy source of the cells. Thus the metabolism of butyrate in colonocytes is closely linked to some of its gene-regulating effects. The distinct effects of butyrate according to the different MUC genes could influence the composition and properties of the mucus gel and thus its protective function.
Mechanical compression elicits NO-dependent increases in coronary flow
Authors: Sun Dong , Huang An , Kaley Gabor
Published: August 2004

Our previous studies have demonstrated that a decrease in arteriolar diameter that causes endothelial deformation elicits the release of nitric oxide (NO). Thus we hypothesized that cardiac contraction, via deformation of coronary vessels, elicits the release of NO and increases in coronary flow. Coronary flow was measured at a constant perfusion pressure of 80 mmHg in Langendorff preparations of rat hearts. Hearts were placed in a sealed chamber surrounded with perfusion solution. The chamber pressure could be increased from 0 to 80 mmHg to generate extracardiac compression. To minimize the impact of metabolic vasodilatation and rhythmic changes in shear stress, nonbeating hearts, by perfusing the hearts with a solution containing 20 mM KCl, were used. After extracardiac compression for 10 or 20 s, coronary flow increased significantly, concurrent with an increased release of nitrite into the coronary effluent and increased phosphorylation of endothelial NO synthase in the hearts. Inhibition of NO synthesis eliminated the compression-induced increases in coronary flow. Shear stress-induced dilation could not account for this increased coronary flow. Furthermore, in isolated coronary arterioles, without intraluminal flow, the release of vascular compression elicited a NO-dependent dilation. Thus this study reveals a new mechanism that, via coronary vascular deformation, elicited by cardiac contraction, stimulates the endothelium to release NO, leading to increased coronary perfusion.
Effects of increased training load on vagal-related indexes of heart rate variability: a novel sleep approach
Authors: Buchheit M. , Simon C. , Piquard F. , Ehrhart J. , Brandenberger G.
Published: August 2004

There is little doubt that moderate training improves cardiac vagal activity and thus has a cardioprotective effect against lethal arrhythmias. Our purpose was to learn whether a higher training load would further increase this beneficial effect. Cardiac autonomic control was inferred from heart rate variability (HRV) and analyzed in three groups of young subjects (24.5 ± 3.0 yr) with different training states in a period free of stressful stimuli or overload. HRV was analyzed in 5-min segments during slow-wave sleep (SWS, a parasympathetic state that offers high electrocardiographic stationarity) and compared with data collected during quiet waking periods in the morning. Sleep parameters, fatigue, and stress levels checked by questionnaire were identical for all three groups with no signs of overtraining in the highly trained (HT) participants. During SWS, a significant ( P < 0.05) increase in absolute and normalized vagal-related HRV indexes was observed in moderately trained (MT) individuals compared with sedentary (Sed) subjects; this increase did not persist in HT athletes. During waking periods, most of the absolute HRV indexes indistinctly increased in MT individuals compared with controls ( P < 0.05) but did not increase in HT athletes. Normalized spectral HRV indexes did not change significantly among the three groups. Heart rate was similar for MT and Sed subjects but was significantly ( P < 0.05) lower in HT athletes under both recording conditions. These results indicate that SWS discriminates the state of sympathovagal balance better than waking periods. A moderate training load is sufficient to increase vagal-related HRV indexes. However, in HT individuals, despite lower heart rate, vagal-related HRV indexes return to Sed values even in the absence of competition, fatigue, or overload.
Role of lung macrophages on susceptibility to respiratory infection following short-term moderate exercise training
Authors: Murphy E. A. , Davis J. M. , Brown A. S. , Carmichael M. D. , Van Rooijen N. , Ghaffar A. , Mayer E. P.
Published: August 2004

Moderate exercise training is associated with a decreased risk for upper respiratory tract infection in human and animal studies, but the mechanisms have not been elucidated. Lung macrophages play an important role in resistance to respiratory infection, and moderate exercise can enhance macrophage antiviral resistance, but no studies have directly tested the role of lung macrophages in this response. This study tested the effect of lung macrophage depletion on susceptibility to infection following short-term moderate exercise training. Mice were assigned to one of four groups: exercise (Ex) and resting controls (Con) with and without clodronate encapsulated liposomes (CL2MDP-lip). Ex mice ran for 1 h on a treadmill for 6 days at 36 m/min, 8% grade. Fifteen minutes following exercise or rest on the last day of training, mice were intranasally inoculated with a standardized dose of herpes simplex virus type 1. Clodronate (Ex-CL2MDP-lip and Con-CL2MDP-lip) or PBS liposomes (Ex-PBS-lip and Con-PBS-lip) (100 μl) were intranasally administered following exercise or rest on the 4th day of training and again on the 4th day postinfection. Morbidity, mortality, and symptom severity were monitored for 21 days. Exercise decreased morbidity by 36%, mortality by 61%, and symptom severity score on days 5–7 ( P < 0.05). Depletion of lung macrophages negated the beneficial effects of moderate exercise. This was indicated by no differences between Ex-CL2MDP-lip and Con-PBS-lip in morbidity (89 vs. 95%), mortality (79 vs. 95%), or symptom severity. Results indicate that lung macrophages play an important role in mediating the beneficial effects of moderate exercise on susceptibility to respiratory infection.
Sympathetic and angiotensin-dependent hypertension during cage-switch stress in mice
Authors: Lee Dexter L. , Webb R. Clinton , Brands Michael W.
Published: August 2004

The goal of this study was to determine the dependence of the acute hypertensive response to a novel model of acute psychosocial stress on the sympathetic and renin-angiotensin systems. Baseline mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured with telemetry in mice for a 1-h period and averaged 98 ± 1 mmHg, 505 ± 3 beats/min, and 5 ± 1 counts, respectively. Stress was induced by placing a mouse into a cage previously occupied by a different male mouse, and this increased MAP, HR, and activity in the control group by 40 ± 2 mmHg, 204 ± 25 beats/min, and 68 ± 6 counts, respectively. Each variable gradually returned to baseline levels by 90 min after beginning cage switch. Pretreatment with terazosin (10 mg/kg ip) significantly reduced the initial increase in MAP to 12 ± 6 mmHg, whereas MAP for the last 45 min was superimposable on control values. Atenolol (10 mg/ml drinking water) had no effect to blunt the initial increase in MAP but had a growing effect from 10 min onward, decreasing MAP all the way to baseline by 60 min after starting cage switch. Captopril (2 mg/ml drinking water) treatment caused a very similar response. All three treatments significantly decreased the area under the blood pressure curve, and the blood pressure effect could not be attributed uniformly to effects on HR or activity. These data suggest that our novel model of psychosocial stress causes an initial α1-receptor-dependent increase in MAP. The later phase of the pressor response is blocked similarly by a β1-receptor antagonist and an ACE inhibitor, independent of HR, suggesting that the β1-dependent blood pressure effect is due, in large part, to the renin-angiotensin system.
Ventilatory effects of gap junction blockade in the RTN in awake rats
Authors: Hewitt Amy , Barrie Rachel , Graham Michael , Bogus Kara , Leiter J. C. , Erlichman Joseph S.
Published: August 2004

We tested the hypothesis that carbenoxolone, a pharmacological inhibitor of gap junctions, would reduce the ventilatory response to CO2 when focally perfused within the retrotrapezoid nucleus (RTN). We tested this hypothesis by measuring minute ventilation (VE), tidal volume (VT), and respiratory frequency (FR) responses to increasing concentrations of inspired CO2 (FiCO2 = 0–8%) in rats during wakefulness. We confirmed that the RTN was chemosensitive by perfusing the RTN unilaterally with either acetazolamide (AZ; 10 μM) or hypercapnic artificial cerebrospinal fluid equilibrated with 50% CO2 (pH ∼6.5). Focal perfusion of AZ or hypercapnic aCSF increased VE, VT, and FR during exposure to room air. Carbenoxolone (300 μM) focally perfused into the RTN decreased VE and VT in animals <11 wk of age, but VE and VT were increased in animals >12 wk of age. Glyzyrrhizic acid, a congener of carbenoxolone, did not change VE, VT, or FR when focally perfused into the RTN. Carbenoxolone binds to the mineralocorticoid receptor, but spironolactone (10 μM) did not block the disinhibition of VE or VT in older animals when combined with carbenoxolone. Thus the RTN is a CO2 chemosensory site in all ages tested, but the function of gap junctions in the chemosensory process varies substantially among animals of different ages: gap junctions amplify the ventilatory response to CO2 in younger animals, but appear to inhibit the ventilatory response to CO2 in older animals.
Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image
Authors: Shen Wei , Punyanitya Mark , Wang ZiMian , Gallagher Dympna , St.-Onge Marie-Pierre , Albu Jeanine , Heymsfield Steven B. , Heshka Stanley
Published: August 2004

A single abdominal cross-sectional computerized axial tomography and magnetic resonance image is often obtained in studies examining adipose tissue (AT) distribution. An abdominal image might also provide additional useful information on total body skeletal muscle (SM) and AT volumes with related physiological insights. We therefore investigated the relationships between abdominal SM and AT areas from single images and total body component volumes in a large and diverse sample of healthy adult subjects. Total body SM and AT volumes were derived by whole body multislice magnetic resonance imaging in 123 men [age (mean ± SD) of 41.6 ± 15.8 yr; body mass index of 25.9 ± 3.4 kg/m2] and 205 women (age of 47.8 ± 18.7 yr; body mass index of 26.7 ± 5.6 kg/m2). Single abdominal SM and AT slice areas were highly correlated with total body SM ( r = 0.71–0.92; r = 0.90 at L4–L5 intervertebral space) and AT ( r = 0.84–0.96; r = 0.94 at L4–L5 intervertebral space) volumes, respectively. R2 increased by only 5.7–6.1% for SM and 2.7–4.4% for AT with the inclusion of subject sex, age, ethnicity, scanning position, body mass index, and waist circumference in the model. The developed SM and AT models were validated in an additional 49 subjects. To achieve equivalent power to a study measuring total body SM or AT volumes, a study using a single abdominal image would require 17–24% more subjects for SM and 6–12% more subjects for AT. Measurement of a single abdominal image can thus provide estimates of total body SM and AT for group studies of healthy adults.
Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl
l
-Arginine Accelerates Endothelial Cell Senescence
Authors: Scalera Fortunato , Borlak Jürgen , Beckmann Bibiana , Martens-Lobenhoffer Jens , Thum Thomas , Täger Michael , Bode-Böger Stefanie M.
Published: August 2004

Objectives—

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), and its accumulation has been associated with cardiovascular disease. We aimed to investigate the role of ADMA in endothelial cell senescence.

Methods and Results—

Endothelial cells were cultured until the tenth passage. ADMA was replaced every 48 hours starting at the fourth passage. ADMA significantly accelerated senescence associated β-galactosidase activity. Additionally, the shortening of telomere length was significantly accelerated and the telomerase activity was significantly reduced. This effect was associated with an increase of oxidative stress: allantoin, a marker of oxygen free radical generation, and intracellular reactive oxygen species (ROS) increased significantly after ADMA treatment compared with control, whereas cellular thiol status and NOx synthesis decreased. Furthermore, ADMA-increased oxidative stress was accompanied by a decrease in the activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA, which could be prevented by the antioxidant pyrrolidine dithiocarbamate. Exogenous ADMA also stimulated secretion of MCP-1 and interleukin-8. Coincubation with the methyltransferase inhibitor S-adenosylhomocysteine abolished the effects of ADMA.

Conclusions—

These data suggest that ADMA accelerates senescence, probably via increased oxygen radical formation by inhibiting nitric oxide elaboration. This study provides evidence that modest changes of intracellular ADMA levels are associated with significant effects on slowing endothelial senescence.
α(1,3)Fucosyltransferases FucT-IV and FucT-VII Control Susceptibility to Atherosclerosis in Apolipoprotein E−/− Mice
Authors: Homeister Jonathon W. , Daugherty Alan , Lowe John B.
Published: August 2004

Objective—These studies examine the contributions of α(1,3)fucosyltransferases (FucT) IV and VII to the generation of selectin counter-receptors necessary for selectin-dependent atherogenesis. They also determine the functional contribution of FucT-IV and FucT-VII to shear-dependent tethering of monocytes to P-selectin, a process believed to be required for atherogenesis.

Methods and Results—Atherosclerotic lesion size and histology were determined in apolipoprotein E−/− mice sufficient or deficient in FucT-IV or FucT-VII. Lesion size was subtly reduced in FucT-IV–deficient mice and significantly reduced in FucT-VII–deficient mice. FucT deficiency did not alter lesion histology, plasma total cholesterol, or the lipoprotein distribution profile. Atheroprotection in FucT-IV or FucT-VII deficiency aligned with subtle and profound reductions, respectively, of P-selectin counter-receptor activity on peripheral blood monocytes as determined by tethering to P-selectin-IgG in vitro under shear flow.

Conclusions—FucT-VII–mediated α(1,3)fucosylation of selectin ligands is a necessary concomitant to atherogenesis in apoE−/− mice and is required for P-selectin–dependent peripheral blood monocyte adhesion under shear stress. FucT-IV deficiency yields subtle deficits in monocyte P-selectin counter-receptor activity and is associated with a subtle decrement in atherosclerosis. These studies identify an important role for FucT-VII in atherogenesis, and a subsidiary role for FucT-IV, and implicate leukocyte selectin counter-receptors in the pathogenesis of atherosclerosis.
Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees
Authors: Cantor Rita M. , de Bruin Tjerk , Kono Naoko , Napier Susan , van Nas Atila , Allayee Hooman , Lusis Aldons J.
Published: August 2004

Objective—

Familial combined hyperlipidemia (FCHL) is a genetically complex lipid disorder that is diagnosed in families by combinations of increased cholesterol, triglycerides, and/or apolipoprotein B (apoB) levels in patients and their first-degree relatives. Identifying the predisposing genes promises to reveal the primary risk factors and susceptibility pathways and suggest methods of prevention and treatment. As with most genetically complex disorders, a clinical definition of disease may not be the most useful phenotype for finding the complement of predisposing genes, and the quantitative traits used to define the disorder can provide important information. This is a report of a quantitative trait loci (QTL) analysis of FCHL.

Methods and Results—

A full genome scan of 377 multi-allelic markers genotyped at ≈10 centimorgan (cM) intervals was conducted in 150 sibling pairs from 22 nuclear families in FCHL pedigrees. These data were analyzed by 2 multipoint QTL linkage methods using the nonparametric and Haseman–Elston procedures of the Genehunter software. Using a criterion of
P
<0.001 by the nonparametric analysis, we found evidence of 2 apoB QTL at 1p21-31 (
P
<0.000009) and 17p11-q21 (
P
<0.000009), a total serum cholesterol QTL at 12p13 (
P
<0.0001), and a serum triglycerides QTL at 4p15-16 (
P
<0.0002). Using the criterion of
P
<0.03 for at least 2 traits at the same locus, additional evidence for cholesterol (
P
<0.01) and a triglycerides
P
<0.02) was observed at 17p11-21, as well as suggestive evidence for apoB (
P
<0.02) and triglycerides (
P
<0.01) at 4q34-35, and cholesterol (
P
<0.01) and triglycerides (
P
<0.02) and a binary FCHL trait (lod=1.5) at 16p12-13.

Conclusions—

QTL analyses of the traits that define FCHL are effective for localizing disease-predisposing genes.
Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease
Authors: Melo Luis G. , Gnecchi Massimiliano , Pachori Alok S. , Kong Deling , Wang Kai , Liu Xiaoli , Pratt Richard E. , Dzau Victor J.
Published: August 2004

Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. “Proof-of-concept” for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized.
Finding Vulnerable Atherosclerotic Plaques
Authors: Madjid Mohammad , Zarrabi Alireza , Litovsky Silvio , Willerson James T. , Casscells Ward
Published: August 2004

Techniques to identify and treat vulnerable plaques are the focus of enormous research. Some have questioned the benefit of locating individual vulnerable plaque in a multifocal disease. On autopsy, it is found that most deaths are caused by thrombotic occlusion of a single plaque; simultaneous occurrence of 2 occlusive thrombi is rare, but a second vulnerable plaque is common, particularly in acute myocardial infarction (MI). Angiographic progression is poorly predicted by risk factors, and angiographic progression is a weak predictor of MI or death. Intravascular ultrasonography (intravascular ultrasound [IVUS]) studies find plaque rupture in most MI patients and in approximately half with unstable angina, but in only a minority of patients with stable angina. IVUS identifies a second vulnerable plaque in many patients with unstable angina, and in most MI patients. Angioscopy reveals a very low incidence of a second vulnerable plaque compared with angiography and IVUS, but identifies additional yellow plaques in many patients with stable angina and in most patients with unstable angina or MI. Using thermography catheters and a temperature cutoff of 0.1°C, approximately half the patients with stable angina have >1 hot lesion; however, if the cutoff is 0.2°C, only ≈15% have a second hot lesion. New imaging techniques may detect additional characteristics of plaques and new predictive models may assess the risk of vulnerable plaques and patients. This approach enables physicians to “buy time” by application of local therapies until systemic therapies stabilize plaques. This may also reduce the risk in subjects in whom systemic therapies do not work.
ADP Receptor P2Y
12
Is Expressed in Vascular Smooth Muscle Cells and Stimulates Contraction in Human Blood Vessels
Authors: Wihlborg Anna-Karin , Wang Lingwei , Braun Oscar Östberg , Eyjolfsson Atli , Gustafsson Ronny , Gudbjartsson Tomas , Erlinge David
Published: August 2004

Objective—

ADP plays an important role in platelet aggregation by activating P2Y
12
receptors. We assessed the hypothesis that P2Y
12
receptors are expressed in vascular smooth muscle cells (VSMC).

Methods and Results—

P2Y
12
receptor mRNA was found to have a high expression among the P2 receptors in human VSMC, significantly higher than the other 2 ADP receptors (P2Y
1
and P2Y
13
, real-time polymerase chain reaction). Western blots gave a band of 50 kD, similar to that in platelets. To unmask a P2Y
12
receptor-mediated vasoconstriction by simulating the in vivo situation, vessels were precontracted to a submaximal level. 2-MeSADP stimulated contractions in vessel segments from internal mammary artery (IM), IM branches and small veins (E
max
=15±6% of 60mmol/L K
+
contraction, pEC
50
=5.6±0.6, E
max
=21±1%, pEC
50
=6.8±0.1, and E
max
=48±9%, pEC
50
=6.6±0.4). The selective P2Y
12
antagonist AR-C67085 blocked 2-MeSADP contractions. The contraction was not reduced in patients using clopidogrel, a drug inhibiting ADP-induced platelet aggregation by blocking the P2Y
12
receptor. This may be explained by the high instability of the active clopidogrel metabolite that never reaches the systemic circulation.

Conclusion—

ADP acting on P2Y
12
receptors not only is important for platelet activation but also stimulates vasoconstriction. Stable drugs with antagonistic effects on P2Y
12
receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm.
Functional Adult Myocardium in the Absence of Na
+
-Ca
2+
Exchange
Authors: Henderson Scott A. , Goldhaber Joshua I. , So Jessica M. , Han Tieyan , Motter Christi , Ngo An , Chantawansri Chana , Ritter Matthew R. , Friedlander Martin , Nicoll Debora A. , Frank Joy S. , Jordan Maria C. , Roos Kenneth P. , Ross Robert S. , Philipson Kenneth D.
Published: August 2004

The excitation–contraction coupling cycle in cardiac muscle is initiated by an influx of Ca
2+
through voltage-dependent Ca
2+
channels. Ca
2+
influx induces a release of Ca
2+
from the sarcoplasmic reticulum and myocyte contraction. To maintain Ca
2+
homeostasis, Ca
2+
entry is balanced by efflux mediated by the sarcolemmal Na
+
-Ca
2+
exchanger. In the absence of Na
+
-Ca
2+
exchange, it would be expected that cardiac myocytes would overload with Ca
2+
. Using Cre/loxP technology, we generated mice with a cardiac-specific knockout of the Na
+
-Ca
2+
exchanger, NCX1. The exchanger is completely ablated in 80% to 90% of the cardiomyocytes as determined by immunoblot, immunofluorescence, and exchange function. Surprisingly, the NCX1 knockout mice live to adulthood with only modestly reduced cardiac function as assessed by echocardiography. At 7.5 weeks of age, measures of contractility are decreased by 20% to 30%. We detect no adaptation of the myocardium to the absence of the Na
+
-Ca
2+
exchanger as measured by both immunoblots and microarray analysis. Ca
2+
transients of isolated myocytes from knockout mice display normal magnitudes and relaxation kinetics and normal responses to isoproterenol. Under voltage clamp conditions, the current through L-type Ca
2+
channels is reduced by 50%, although the number of channels is unchanged. An abbreviated action potential may further reduce Ca
2+
influx. Rather than upregulate other Ca
2+
efflux mechanisms, the myocardium appears to functionally adapt to the absence of the Na
+
-Ca
2+
exchanger by limiting Ca
2+
influx. The magnitude of Ca
2+
transients appears to be maintained by an increased gain of sarcoplasmic reticular Ca
2+
release. The myocardium of the NCX1 knockout mice undergoes a remarkable adaptation to maintain near normal cardiac function.
Gene Transfer of NAD(P)H Oxidase Inhibitor to the Vascular Adventitia Attenuates Medial Smooth Muscle Hypertrophy
Authors: Liu Jianhua , Ormsby Adrian , Oja-Tebbe Nancy , Pagano Patrick J.
Published: August 2004

We previously showed that a systemic inhibitor of gp91

phox

(nox2)-based NAD(P)H oxidase abolishes angiotensin II (Ang II)–induced vascular hypertrophy. In the present study, we tested whether perivascular transfection with Ad-gp91ds-eGFP (an adenoviral bicistronic construct targeting NAD(P)H oxidase in fibroblasts) or controls Ad-CMV-eGFP and Ad-scrmb-eGFP would affect medial hypertrophy in response to Ang II. In C57BL/6J mice, we applied Ad-gp91ds-eGFP or controls to the left carotid adventitia, and 2 days later we implanted minipumps delivering vehicle or Ang II (750 μg/kg per day) for 7 days. None of the viral treatments affected Ang II–induced systolic blood pressure elevation. Immunohistochemical staining showed marker eGFP in adventitial fibroblasts and some macrophages, indicating expression of the gp91ds inhibitor. As expected, Ang II induced medial hypertrophy (medial cross-sectional area, 32.96±2.04 versus 20.57±1.00×10
3
μm
2
, Ang II versus control;
P
<0.001) that was significantly inhibited by Ad-gp91ds-eGFP (26.23±0.90×10
3
μm
2
;
P
<0.01) but not control viruses. Application of viruses alone did not change medial size under control conditions. Immunohistochemical staining and semiquantitative analysis showed a 70% increase in reactive oxygen species levels measured by the lipid peroxidation byproduct 4-hydroxynonenal (4-HNE) throughout the carotid wall in the Ang II group versus vehicle. After treatment with Ad-gp91ds-eGFP, 4-HNE generation was normalized. Thus NAD(P)H oxidases in adventitial fibroblasts and macrophages appear to modulate Ang II–induced medial hypertrophy.
Underfunding of Stroke Research
Authors: Pendlebury Sarah T. , Rothwell Peter M. , Algra Ale , Ariesen Marie-José , Bakac Goksel , Czlonkowska Anna , Dachenhausen Alexandra , Krespi Yakup , Kõrv Janika , Krolikowski Konrad , Kulesh Sergey , Michel Patrik , Thomassen Lars , Bogousslavsky Julien , Brainin Michael
Published: August 2004

Background and Purpose—

Previous studies in the United States and the United Kingdom have shown that stroke research is underfunded compared with coronary heart disease (CHD) and cancer research despite the high clinical and financial burden of stroke. We aimed to determine whether underfunding of stroke research is a Europe-wide problem.

Methods—

Data for the financial year 2000 to 2001 were collected from 9 different European countries. Information on stroke, CHD, and cancer research funding awarded by disease-specific charities and nondisease-specific charity or government- funded organizations was obtained from annual reports, web sites, and by direct communication with organizations.

Results—

There was marked and consistent underfunding of stroke research in all the countries studied. Stroke funding as a percentage of the total funding for stroke, CHD, and cancer was uniformly low, ranging from 2% to 11%. Funding for stroke was less than funding for cancer, usually by a factor of ≥10. In every country except Turkey, funding for stroke research was less than that for CHD.

Conclusions—

This study confirms that stroke research is grossly underfunded, compared with CHD and cancer, throughout Europe. Similar data have been obtained from the United States suggesting that relative underfunding of stroke research is likely to be a worldwide phenomenon.
Proinflammatory Genetic Profiles in Subjects With History of Ischemic Stroke
Authors: Flex Andrea , Gaetani Eleonora , Papaleo Pierangelo , Straface Giuseppe , Proia Anna S. , Pecorini Giovanni , Tondi Paolo , Pola Paolo , Pola Roberto
Published: August 2004

Background and Purpose—

Proinflammatory genetic profiles, resulting from the combination of single nucleotide polymorphisms in genes encoding inflammatory molecules, may contribute to the development and progression of cardiovascular diseases. We evaluated the association between history of ischemic stroke and genetic profiles determined by the synergistic effects of polymorphisms in genes encoding prototypical inflammatory proteins.

Methods—

The study included 237 individuals with history of ischemic stroke and 223 age-matched and gender-matched controls. The polymorphisms of the C-reactive protein (
CRP
), interleukin-6 (
IL-6
), macrophage migration inhibitory factor (
MIF
), monocyte chemoattractant protein-1 (
MCP-1
), intercellular adhesion molecule-1 (
ICAM-1
), E-selectin (
E-sel
), and matrix metalloproteinase-3 (

MMP-3

) genes were studied.

Results—

IL-6
GG,
IL-6
GC,
MCP-1
GG,
ICAM-1
EE,
E-sel
AA, and

MMP-3

5A5A genotypes were significantly and independently associated with stroke history. The odds of stroke increased with the number of high-risk genotypes: carrying 1 proinflammatory gene variant conferred a risk of 3.3 (1.6 to 6.9), whereas individuals concomitantly carrying 2 and 3 proinflammatory gene variants had adjusted odds ratios of 21.0 (7.6 to 57.5) and 50.3 (10.2 to 248.1), respectively.

Conclusions—

Proinflammatory genetic profiles are significantly more common in subjects with stroke history. Synergistic effects between proinflammatory genotypes might be potential markers for cerebrovascular diseases.
Gushist and Qutbian Approaches to Government: A Comparative Analysis of Religious Assassination
Authors: Kiener Ronald
Published: August 2004

The disciples and pseudo-followers of the religious ideologues Sayyid Qutb and Rabbi Zvi Yehudah Kook have now lived without their mentors for more than twentyfive years (in the case of Qutb) and for more than a decade (in the case of Kook). In both instances, putative “disciples” of these thinkers committed assassinations of the acknowledged domestic leader of a sitting government: Sadat in 1981 by al-Jihad al-Islami; Rabin in 1995 by Eyal. In this paper, the theories of both mentors and their ersatz disciples on the issue of violence against the sitting government will be examined for possible comparative results. Rather than finding a symmetry in these examples of Middle Eastern fundamentalist violence, the author elaborates a sharp difference between the two: one (Islam) is centered on the issue of apostasy, while the other (Judaism) is centered on the issue of communal rights and protections. Rather than providing a point for drawing similarities, fundamentalist-inspired assassination points out the differences between Israeli-Jewish and Egyptian-Islamic fundamentalisms.
Gift and Return Gift, Greeting and Return Greeting in India.
Authors: Michaels Axel
Published: August 2004

In a remarkable, often quoted footnote of his famous “Essai sur le don,” Marcel Mauss wonders that traditional Hindu law does not really prescribe the obligation to return a gift (Skt. dāna). According to some authors (J. Parry, Th. Trautmann, G. Raheja et al.) Mauss has demonstrated by this footnote his lack of a firm grasp of the theory of dāna since he did not notice that a dāna contains too much impurity or inauspiciousness to return to its donor. On the basis of striking parallels between the Śāstric theories of greeting (abhivādanadharma) and gift-giving (dānadharma), this paper questions the aspect of impurity in the gift and argues that kingly generosity or liberality and the meritious attitudes of asceticism have been the major source for giving gifts.
Ergogenic Aids: A Review of Basic Science, Performance, Side Effects, and Status in Sports
Authors: Tokish John M. , Kocher Mininder S. , Hawkins Richard J.
Published: August 2004

The use of drugs and supplements to enhance performance has become a part of mainstream athletics. Many team physicians and sports medicine practitioners are unfamiliar with the benefits and risks of these products and thus are unable to educate young athletes on this topic. In spite of numerous reports on the health risks of anabolic steroid use, 1 to 3 million Americans have used them. Human growth hormone has been tried by up to 5% of 10th graders, although no scientific study has shown that it is an effective performance-enhancing drug. Amphetamines and similar compounds may be the most widely abused drug in baseball; recently, they have come under increased scrutiny in sport. Erythropoietin is a highly effective aerobic enhancer that has been linked to multiple deaths in cyclists and other endurance athletes. The neutraceutical industry, led by supplements such as creatine, ephedra, and androstenedione, remains unregulated by the Food and Drug Administration and has serious issues with quality and side effects. An understanding of these products is essential for the sports medicine practitioner to provide sound, safe advice to the athlete.
Nonoperative and Operative Management of Snapping Scapula
Authors: Manske Robert C. , Reiman Michael P. , Stovak Mark L.
Published: August 2004

Snapping scapula is a painful crepitus of the scapulothoracic articulation. This crepitus is a grinding or snapping noise with scapulothoracic motion that may or may not accompany pain. This condition is commonly seen in overhead-throwing athletes. Treatment of patients with this syndrome begins with nonoperative methods; when nonoperative treatment fails, several surgical options exist. This article will discuss both nonoperative and operative management of this common shoulder condition.
Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment
Authors: Rivollier Aymeric , Mazzorana Marlène , Tebib Jacques , Piperno Muriel , Aitsiselmi Tarik , Rabourdin-Combe Chantal , Jurdic Pierre , Servet-Delprat Christine
Published: August 2004

Dendritic cells (DCs), the mononuclear cells that initiate immune response, and osteoclasts, the multinucleated bone-resorbing cells, are derived from monocyte/macrophage precursor cells. Granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor (M-CSF) reciprocally regulate the differentiation of both lineages in mice. Using human monocyte-derived DCs generated in vitro, we show that immature DCs transdifferentiate into functional osteoclasts (OCs) in the presence of M-CSF and receptor activator of nuclear factor-κB ligand (RANKL). Transdifferentiation operates through fusion of intermediate adherent bipolar fusiform mononuclear cells expressing CD14, CD1a, and RANKL and able to induce RANKL+ T-cell proliferation. Surprisingly, DC fusion in vitro is faster and more efficient than monocyte fusion to form multinucleated giant cells. The transdifferentiation process reported here supports the existence of a high cellular plasticity within differentiated myeloid phagocytes. Importantly, this process is greatly enhanced by rheumatoid arthritis synovial fluid and involves proinflammatory cytokines such as interleukin 1 or tumor necrosis factor α, as well as components of the extracellular matrix such as hyaluronic acid. Our data therefore suggest that DC-derived OCs may be directly involved in the osteolytic lesions observed in human inflammatory bone diseases such as rheumatoid arthritis or in particular forms of Langerhans cell histiocytosis, characterized by accumulation of immature skin DCs and chronic lytic bone lesions. (Blood. 2004;104:4029-4037)
Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB
Authors: Wolach Baruch , Scharf Yitshak , Gavrieli Ronit , de Boer Martin , Roos Dirk
Published: August 2004

Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92] → GGT), predicting Tyr30Arg31 → stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow.
Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway
Authors: Chuang Kuo-Pin , Huang Ya-Fang , Hsu Yi-Ling , Liu Hsiao-Sheng , Chen Hong-Chen , Shieh Chi-Chang
Published: August 2004

Monocyte-endothelial adhesion plays an important role in monocyte trafficking and hence is important for immune responses and pathogenesis of inflammatory diseases including atherosclerosis. The cross-talk between different integrins on monocytes may be crucial for a coordinated regulation of the cellular adhesion during the complex process of transendothelial migration. By using monoclonal antibodies and recombinant intercellular adhesion molecule 1 (ICAM-1) to engage lymphocyte function-associated antigen 1 (LFA-1) on monocytic cells, we found that the cellular adhesion to vascular cell adhesion molecule 1 (VCAM-1) mediated by very late antigen 4 (VLA-4) was suppressed after this treatment and the suppression depended on the presence of reactive oxygen species (ROSs). Inhibition of production of ROSs through the use of inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, but not inhibitors of mitochondrial electron transport chain or xanthine oxidase, revealed that this suppression on VLA-4-mediated cellular binding was mediated by ROSs produced by phagocyte NADPH oxidase. Activation of phosphoinositol-3 kinase and Akt appears to mediate this NADPH oxidase activation through p47phox phosphorylation and Rac-1 activation. Our results provide a novel pathway in which ROSs play a critical role in integrin cross-talk in monocytes. This signaling pathway may be important for cellular transition from firm arrest to diapedesis during monocyte trafficking. (Blood. 2004;104:4046-4053)
Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628
Authors: Dhodapkar Madhav V. , Hussein Mohamad A. , Rasmussen Erik , Solomon Alan , Larson Richard A. , Crowley John J. , Barlogie Bart
Published: August 2004

Current therapy of primary systemic (AL) amyloidosis with oral melphalan and prednisone remains unsatisfactory, with a median survival of only 13 months. Between 1996 and 2003, 93 patients with biopsy-proven AL amyloidosis were enrolled in a prospective US national cooperative group trial. Treatment schema consisted of induction therapy with pulse dexamethasone (DEX), followed by maintenance therapy with DEX and alpha interferon. Hematologic complete remissions were observed in 24% and improvement in AL amyloidosis–related organ dysfunction occurred in 45% of patients evaluable for response. Median survival of the entire cohort is 31 months, with an estimated 2-year overall survival (OS) and event-free survival (EFS) of 60% and 52%, respectively. Presence of congestive heart failure and increased level of serum β2 microglobulin (≥ 0.0035 g/L [3.5 mg/L]) were dominant predictors of adverse outcome. Estimated 2-year OS in patients who are eligible to receive transplants with this approach was 78%. These data demonstrate for the first time in the context of a US multicenter prospective clinical trial that front-line therapy with a DEX-based regimen in AL amyloidosis can lead to durable reversal of AL amyloidosis–related organ dysfunction and prolonged survival.