bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatigue as a predictor of sickness absence: results from the Maastricht cohort study on fatigue at work
Authors: Janssen N , Kant IJ , Swaen G M H , Janssen P P M , Schröer C A P
Published: June 2003

Objectives:To investigate whether there is a relationship between fatigue and sickness absence. Two additional hypotheses were based on the theoretical distinction between involuntary, health related absence and voluntary, attitudinal absence. In the literature, the former term is usually used to describe long term sickness absence, the latter relates to short term sickness absence. In line with this, the first additional hypothesis was that higher fatigue would correspond with a higher risk of long term, primarily health related absence. The second additional hypothesis was that higher fatigue would correspond with a higher risk of short term, primarily motivational absence.

Methods:A multidimensional fatigue measure, as well as potential sociodemographic and work related confounders were assessed in the baseline questionnaire of the Maastricht cohort study on fatigue at work. Sickness absence was objectively assessed on the basis of organisational absence records and measured over the six months immediately following the baseline questionnaire. In the first, general hypothesis the effect of fatigue on time-to-onset of first sickness absence spell during follow up was investigated. For this purpose, a survival analysis was performed. The effect of fatigue on long term sickness absence was tested by a logistic regression analysis. The effect of fatigue on short term sickness absence was investigated by performing a survival analysis with time-to-onset of first short absence spell as an outcome.

Results:It was found that higher fatigue decreased the time-to-onset of the first sickness absence spell. Additional analyses showed that fatigue was related to long term as well as to short term sickness absence. The effect of fatigue on the first mentioned outcome was stronger than the effect on the latter outcome. Potential confounders only weakened the effect of fatigue on long term absence.

Conclusions:Fatigue was associated with short term but particularly with long term sickness absence. The relation between fatigue and future sickness absence holds when controlling for work related and sociodemographic confounders. Fatigue as measured with the Checklist Individual Strength can be used as a screening instrument to assess the likelihood of sickness absence in the short term.
Comparative study of bone mineral density, calcium, and vitamin D status in the Gujarati and white populations of Leicester
Authors: Hamson C , Goh L , Sheldon P , Samanta A
Published: June 2003

Objectives

To evaluate differences in bone mineral density (BMD), calcium, and vitamin D status between the Gujarati (South Asian) and white populations resident in Leicester and to determine whether this was linked to lifestyle factors.

Design

An observational cross sectional study of randomly selected Gujarati and white volunteers aged from 20–40 years.

Setting

City of Leicester.

Participants

Subjects were randomly selected by age (20–40 years) and ethnicity. A total of 262 individuals volunteered to participate, of which 201 (51 white females, 71 Gujarati females, 37 white males, 42 Gujarati males) were eligible for the study.

Main outcome measures

Results of questionnaire, BMD at the hip and lumbar spine, and measurement of serum calcium, albumin, alkaline phosphatase, and 25-hydroxyvitamin D.

Results

Male and female white subjects were significantly taller and heavier than their Gujarati counterparts. There was a statistically significant difference in BMD both at the spine (p<0.001) and hip (p<0.001) between the white and Gujarati females with the Gujaratis having a lower BMD. There was a trend for Gujarati males to have a lower BMD at the hip and spine than their white counterparts but these figures did not reach statistical significance. The intensity of cigarette smoking and the amount of alcohol consumption were both higher in the white male and female subjects. Sunlight exposure (>4 hours per day) was significantly higher in white subjects compared with Gujaratis. There were no significant differences in the mean level of serum calcium or alkaline phosphatase between the Gujaratis and whites. A significantly higher proportion (p<0.001) of the Gujarati men and women had a vitamin D level that was not measurable (that is, below the lower limit of the laboratory range of normal). Of those who had a measurable level (that is, in the normal range) mean levels of vitamin D were lower (p<0.05) in the Gujarati men and women.

Conclusion

The present study is the first of its kind to note a low BMD in Gujarati subjects of South Asian origin compared with their white counterparts, living in Leicester. This study also confirms the presence of low serum vitamin D levels in Gujaratis. There is a need for more research in South Asians with regard to the collection of normal BMD values. This could provide a more meaningful reference range for identifying South Asians at risk of osteoporotic fractures and may have public health implications of relevance to this ethnic group.
Recurrent aseptic meningitis due to different non-steroidal anti-inflammatory drugs including rofecoxib
Authors: Ashwath M L , Katner H P
Published: June 2003

Aseptic meningitis can be caused by viruses, drugs, and connective tissue disorders. The most common drugs causing it include antibiotics like trimethoprim-sulfamethoxazole, non-steroidal anti-inflammatory drugs (NSAIDs), intravenous immunoglobulins, intrathecal agents, vaccines, and monoclonal antibodies. A patient who had aseptic meningitis from three different NSAIDs including rofecoxib is presented.
AN INTERACTIVE TOOL FOR THE RAPID DEVELOPMENT OF KNOWLEDGE BASES
Authors: MOLDOVAN DAN I. , GÎRJU ROXANA C.
Published: June 2003

It is widely accepted that more knowledge means more intelligence. In many knowledge intensive applications, it is necessary to have extensive domain-specific knowledge in addition to general-purpose knowledge bases. This paper presents a methodology for discovering domain-specific concepts and relationships in an attempt to extend WordNet. The method was tested on five seed concepts selected from the financial domain: interest rate, stock market, inflation, economic growth, and employment. Queries were formed with each of these concepts and a corpus of 5000 sentences was extracted automatically from the Internet and TREC-8 corpora. On this corpus, the system discovered a total of 264 new concepts not defined in WordNet, of which 221 contain the seeds and 43 are other related concepts. The system also discovered 64 relationships that link these concepts with either WordNet concepts or with each other. The relationships were extracted with the help of 22 distinct lexico-syntactic patterns representing four semantic relations. It takes the system approximately 40 minutes per seed working in interactive mode to discover the new concepts and relationships on the 5000 sentence corpus.
GRAPH-BASED HIERARCHICAL CONCEPTUAL CLUSTERING
Authors: JONYER ISTVAN , HOLDER LAWRENCE B. , COOK DIANE J.
Published: June 2003

Hierarchical conceptual clustering has proven to be a useful, although greatly under-explored data mining technique. A graph-based representation of structural information combined with a substructure discovery technique has been shown to be successful in knowledge discovery. The SUBDUE substructure discovery system provides the advantages of both approaches. This work presents SUBDUE and the development of its clustering functionalities. Several examples are used to illustrate the validity of the approach both in structured and unstructured domains, as well as compare SUBDUE to earlier clustering algorithms. Results show that SUBDUE successfully discovers hierarchical clusterings in both structured and unstructured data.
High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors
Authors: Kimura Takao , Sato Koichi , Malchinkhuu Enkhzol , Tomura Hideaki , Tamama Kenichi , Kuwabara Atsushi , Murakami Masami , Okajima Fumikazu
Published: June 2003

Objective—

Plasma high-density lipoprotein (HDL) level is inversely correlated with the risk of atherosclerosis. However, the cellular mechanism by which HDL exerts antiatherogenic actions is not well understood. In this study, we focus on the lipid components of HDL as mediators of the lipoprotein-induced antiatherogenic actions.

Methods and Results—

HDL and sphingosine 1-phosphate (S1P) stimulated the migration and survival of human umbilical vein endothelial cells. These responses to HDL and S1P were almost completely inhibited by pertussis toxin and other specific inhibitors for intracellular signaling pathways, although the inhibition profiles of migration and survival were different. The HDL-stimulated migration and survival of the cells were markedly inhibited by antisense oligonucleotides against the S1P receptors EDG-1/S1P
1
and EDG-3/S1P
3
. Cell migration was sensitive to both receptors, but cell survival was exclusively sensitive to S1P
1
. The S1P-rich fraction and chromatographically purified S1P from HDL stimulated cell migration, but the rest of the fraction did not, as was the case of the cell survival.

Conclusions—

HDL-induced endothelial cell migration and survival may be mediated by the lipoprotein component S1P and the lipid receptors S1P
1
and S1P
3
.
Region- and Type-Specific Induction of Matrix Metalloproteinases in Post–Myocardial Infarction Remodeling
Authors: Wilson Eric M. , Moainie Sina L. , Baskin Julia M. , Lowry Abigail S. , Deschamps Anne M. , Mukherjee Rupak , Guy T. Sloane , St John-Sutton Martin G. , Gorman Joseph H. , Edmunds L. Henry , Gorman Robert C. , Spinale Francis G.
Published: June 2003

Background—

Induction of matrix metalloproteinases (MMPs) contributes to adverse remodeling after myocardial infarction (MI). Whether a region- and type-specific distribution of MMPs occurs within the post-MI myocardium remained unknown.

Methods and Results—

Ten sheep were instrumented with a sonomicrometry array to measure dimensions in 7 distinct regions corresponding to the remote, transition, and MI regions. Eight sheep served as reference controls. The relative abundance of representative MMP types and the tissue inhibitors of the MMPs (TIMPs) was quantified by immunoblotting. Segment length increased from baseline in the remote (24.9±5.4%), transition (18.0±2.9%), and MI (53.8±11.0%) regions at 8 weeks after MI (
P
<0.05) and was greatest in the MI region (
P
<0.05). Region- and type-specific changes in MMPs occurred after MI. For example, MMP-1 and MMP-9 abundance was unchanged in the remote, fell to 3±2% in the transition, and was undetectable in the MI region (
P
<0.05). MMP-13, MMP-8, and MT1-MMP increased by >300% in the transition and MI regions (
P
<0.05). TIMP abundance decreased significantly in the transition region after MI and fell to undetectable levels within the MI region.

Conclusions—

The unique findings of this study were 2-fold. First, changes in regional geometry after MI were associated with changes in MMP levels. Second, a region-specific portfolio of MMPs was induced after MI and was accompanied by a decline in TIMP levels, indicative of a loss of MMP inhibitory control. Targeting the regional imbalance between specific MMPs and TIMPs within the post-MI myocardium holds therapeutic potential.
Distal Myocardial Protection During Percutaneous Coronary Intervention With an Intracoronary β-Blocker
Authors: Wang Fen Wei , Osman Abdulfatah , Otero Javier , Stouffer George A. , Waxman Sergio , Afzal Adnan , Anzuini Angelo , Uretsky Barry F.
Published: June 2003

Background—

Experimental studies have demonstrated that intravenous β-blocker administration before coronary artery occlusion significantly reduces myocardial injury. Clinical studies have shown that intracoronary (IC) propranolol administration before percutaneous coronary intervention (PCI) delays myocardial ischemia. The present study tested the hypothesis that IC propranolol treatment protects ischemic myocardium from myocardial damage and reduces the incidence of myocardial infarction (MI) and short-term adverse outcomes after PCI.

Methods and Results—

Patients undergoing PCI (n=150) were randomly assigned in a double-blind fashion to receive IC propranolol (n=75) or placebo (n=75). Study drug was delivered before first balloon inflation via an intracoronary catheter with the tip distal to the coronary lesion. Biochemical markers were evaluated through the first 24 hours and clinical outcomes to 30 days. Evidence of MI with creatine kinase–MB elevation after PCI was seen in 36% of placebo and 17% of propranolol patients (
P
=0.01). Troponin T elevation was seen in 33% of placebo and 13% of propranolol patients (
P
=0.005). At 30 days, the composite end point of death, postprocedural MI, non–Q-wave MI after PCI hospitalization, or urgent target-lesion revascularization occurred in 40% of placebo versus 18% of propranolol patients (hazard ratio 2.14, 95% CI 1.24 to 3.71,
P
=0.004).

Conclusions—

IC administration of propranolol protects the myocardium during PCI, significantly reducing the incidence of MI and improving short-term clinical outcomes.
Comparison of the Short-Term Survival Benefit Associated With Revascularization Compared With Medical Therapy in Patients With No Prior Coronary Artery Disease Undergoing Stress Myocardial Perfusion Single Photon Emission Computed Tomography
Authors: Hachamovitch Rory , Hayes Sean W. , Friedman John D. , Cohen Ishac , Berman Daniel S.
Published: June 2003

Background—

The relationship between the amount of inducible ischemia present on stress myocardial perfusion single photon emission computed tomography (myocardial perfusion stress [MPS]) and the presence of a short-term survival benefit with early revascularization versus medical therapy is not clearly defined.

Methods and Results—

A total of 10 627 consecutive patients who underwent exercise or adenosine MPS and had no prior myocardial infarction or revascularization were followed up (90.6% complete; mean: 1.9±0.6 years). Cardiac death occurred in 146 patients (1.4%). Treatment received within 60 days after MPS defined subgroups undergoing revascularization (671 patients, 2.8% mortality) or medical therapy (MT) (9956 patients, 1.3% mortality;
P
=0.0004). To adjust for nonrandomization of treatment, a propensity score was developed using logistic regression to model the decision to refer to revascularization. This model (χ
2
=1822, c index=0.94,
P
<10
−7
) identified inducible ischemia and anginal symptoms as the most powerful predictors (83%, 6% of overall χ
2
) and was incorporated into survival models. On the basis of the Cox proportional hazards model predicting cardiac death (χ
2
=539,
P
<0.0001), patients undergoing MT demonstrated a survival advantage over patients undergoing revascularization in the setting of no or mild ischemia, whereas patients undergoing revascularization had an increasing survival benefit over patients undergoing MT when moderate to severe ischemia was present. Furthermore, increasing survival benefit for revascularization over MT was noted in higher risk patients (elderly, adenosine stress, and women, especially those with diabetes).

Conclusions—

Revascularization compared with MT had greater survival benefit (absolute and relative) in patients with moderate to large amounts of inducible ischemia. These findings have significant consequences for future approaches to post–single photon emission computed tomography patient management if confirmed by prospective evaluations.
Enalapril Decreases the Incidence of Atrial Fibrillation in Patients With Left Ventricular Dysfunction
Authors: Vermes Emmanuelle , Tardif Jean-Claude , Bourassa Martial G. , Racine Normand , Levesque Sylvie , White Michel , Guerra Peter G. , Ducharme Anique
Published: June 2003

Background—

Atrial fibrillation (AF) is frequently encountered in patients with heart failure (HF) and is also a predictor of morbidity and mortality in this population. Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors (ACEi) on the development of AF. To verify the hypothesis that ACEi prevent the development of AF in patients with HF, we conducted a retrospective analysis of the patients from the Montreal Heart Institute (MHI) included in the Studies Of Left Ventricular Dysfunction (SOLVD).

Methods and Results—

Clinical charts were reviewed and serial ECGs interpreted by a single cardiologist blinded to drug allocation. Patients with AF or flutter on the baseline ECG were excluded. Baseline characteristics were obtained from the SOLVD databases. The mean follow-up was 2.9±1.0 years. Of the 391 patients randomly assigned at MHI, 374 were in sinus rhythm at the time of random assignment, with 186 taking enalapril and 188 taking placebo. Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infarction in the enalapril group. Fifty-five patients had AF during the follow-up: 10 (5.4%) in the enalapril group and 45 (24%) in the placebo group (
P
<0.0001). By Cox multivariate analysis, enalapril was the most powerful predictor for risk reduction of AF (hazard ratio, 0.22; 95% CI, 0.11 to 0.44;
P
<0.0001).

Conclusions—

Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction.
Transgenic Mice Overexpressing Mutant
PRKAG2
Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy
Authors: Arad Michael , Moskowitz Ivan P. , Patel Vickas V. , Ahmad Ferhaan , Perez-Atayde Antonio R. , Sawyer Douglas B. , Walter Mark , Li Guo H. , Burgon Patrick G. , Maguire Colin T. , Stapleton David , Schmitt Joachim P. , Guo X.X. , Pizard Anne , Kupershmidt Sabina , Roden Dan M. , Berul Charles I. , Seidman Christine E. , Seidman J.G.
Published: June 2003

Background—

Mutations in the γ
2
subunit (
PRKAG2
) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance.

Methods and Results—

To elucidate the mechanism by which
PRKAG2
mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the
PRKAG2
cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation.

Conclusions—

Our data establish
PRKAG2
mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.
New Three-Dimensional Echocardiographic System Using Digital Radiofrequency Data—Visualization and Quantitative Analysis of Aortic Valve Dynamics With High Resolution
Authors: Handke Michael , Jahnke Cosima , Heinrichs Gudrun , Schlegel Jörg , Vos Clemens , Schmitt Daniel , Bode Christoph , Geibel Annette
Published: June 2003

Background—

Common 3D systems have only limited spatial and temporal resolution (frame rate of 25 Hz). Thin structures such as cardiac valves are not imaged exactly; rapid movement patterns cannot be precisely recorded. The objective of the present project was to achieve radiofrequency (RF) data transmission to the 3D workstation to improve image resolution.

Methods and Results—

A commercially available echocardiographic system (5-MHz transesophageal echocardiography probe) with an integrated raw data interface enables transmission of RF data (up to 40 megabytes per second). A 3D data set may contain up to 3 gigabytes, so that all of the high-resolution ultrasound information of the 2D image is available. Frame rates of up to 168 Hz result in temporal resolution 6 times that of standard 3D systems. The applicability of the system and the image quality were tested in 10 patients. The structure of the aortic valve and the dynamic changes were depicted by volume rendering. The changes in the orifice areas were measured in frame-by-frame planimetry. The mean number of frames recorded per cardiac cycle was 122±16. The improved structural resolution enabled a detailed imaging of the morphology of the aortic cusps. The rapid systolic movement patterns were recorded with up to 51 frames. The high number of frames enabled creation of precise area-time diagrams. Thus, the individual phases of aortic valve movement (rapid opening, slow valve closing, and rapid valve closing) could be analyzed quantitatively.

Conclusion—

A 3D system based on RF data enables high-resolution imaging of cardiac movement patterns. This offers new perspectives for qualitative and quantitative analyses, especially of cardiac valves.
Locus for Atrial Fibrillation Maps to Chromosome 6q14–16
Authors: Ellinor Patrick T. , Shin Jordan T. , Moore Rachel K. , Yoerger Danita M. , MacRae Calum A.
Published: June 2003

Background—

Atrial fibrillation (AF), the most common clinical arrhythmia, is a major cause of morbidity and mortality. Although AF is often associated with other cardiovascular conditions, many patients present without an obvious etiology. Inherited forms of AF exist, but the causative gene has been defined only in a single family. We have identified a large family (family FAF-1) in which AF segregates as a Mendelian trait.

Methods and Results—

Thirty-four family members were evaluated by 12-lead ECG, echocardiogram, 24-hour Holter monitoring, and laboratory studies. Individuals with electrocardiographically documented AF were defined as affected. Subjects were considered unaffected if they were >60 years of age, had no personal history of AF, and had no offspring with a history of AF. DNA was extracted and genotypic analyses were performed using polymorphic microsatellite markers. Evidence of linkage was obtained on chromosome 6, with a peak 2-point logarithm of the odds (LOD) score of 3.63 (θ=0) at the marker
D6S1021
. A maximal multipoint LOD score of 4.9 was obtained between
D6S286
and
D6S1021
, indicating odds of ≈100 000:1 in favor of this interval as the location of the gene defect responsible for AF in this family. The LOD scores were robust to changes in penetrance and allele frequency. Haplotype analyses further supported this minimal genetic interval.

Conclusion—

We have mapped a novel locus for AF to chromosome 6q14–16. The identification of the causative gene in this interval will be an important step in understanding the fundamental mechanisms of AF.
Increased Renal Medullary H
2
O
2
Leads to Hypertension
Authors: Makino Ayako , Skelton Meredith M. , Zou Ai-Ping , Cowley Allen W.
Published: June 2003

We have recently reported that exaggerated oxidative stress in the renal medulla due to superoxide dismutase inhibition resulted in a reduction of renal medullary blood flow and sustained hypertension. The present study tested the hypothesis that selective scavenging of O
2
·−
in the renal medulla would prevent hypertension associated with this exaggerated oxidative stress. An indwelling, aortic catheter was implanted in nonnephrectomized Sprague-Dawley rats for daily measurement of arterial blood pressure, and a renal medullary interstitial catheter was implanted for continuous delivery of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC, 7.5 mg · kg
−1
· d
−1
) and a chemical superoxide dismutase mimetic, 4-hydroxytetramethyl piperidine-1-oxyl (TEMPOL, 10 mg · kg
−1
· d
−1
). Renal medullary interstitial infusion of TEMPOL completely blocked DETC-induced accumulation of O
2
·−
in the renal medulla, as measured by the conversion rate of dihydroethidium to ethidium in the dialysate and by urinary excretion of 8-isoprostanes. However, TEMPOL infusion failed to prevent DETC-induced hypertension, unless catalase (5 mg · kg
−1
· d
−1
) was coinfused. Direct infusion of H
2
O
2
into the renal medulla resulted in increases of mean arterial pressure from 115±2.5 to 131±2.1 mm Hg, which was similar to that observed in rats receiving the medullary infusion of both TEMPOL and DETC. The results indicate that sufficient catalase activity in the renal medulla is a prerequisite for the antihypertensive action of TEMPOL and that accumulated H
2
O
2
in the renal medulla associated with exaggerated oxidative stress might have a hypertensive consequence.
Imbalance of T-Cell Subsets in Angiotensin II–Infused Hypertensive Rats With Kidney Injury
Authors: Shao Jing , Nangaku Masaomi , Miyata Toshio , Inagi Reiko , Yamada Koei , Kurokawa Kiyoshi , Fujita Toshiro
Published: June 2003

Blockade of angiotensin (Ang) II is efficient in various renal diseases. Although interest has focused on the hemodynamic changes and reduction of proteinuria, recent studies emphasize the nonhemodynamic effects of Ang II on kidney injury. The aim of this study was to clarify the mechanisms of Ang II on the immune system that alter the balance of helper T-cell (Th) subsets. We used a continuous, Ang II infusion model of rats that develop hypertension, proteinuria, and tubulointerstitial damage, including de novo expression of α-smooth muscle actin and loss of endothelial cells. We isolated T cells from the spleen and measured cytokine levels by ELISA systems. Ang II–infused rats showed an increase in the Th1 cytokine γ-interferon and a decrease in the Th2 cytokine interleukin-4. The same change in cytokine mRNA expression in the spleen and kidney was confirmed by quantitative polymerase chain reaction analysis. Our ELISPOT assay showed an increase in the number of γ-interferon–secreting T cells by Ang II. To investigate whether these changes were specific effects of Ang II, we treated the model rats with the Ang II receptor blocker (ARB) olmesartan or the nonspecific vessel dilator hydralazine. Administration of the ARB ameliorated disease manifestations and the imbalance in Th subsets, whereas hydralazine did not, despite comparable effects on blood pressure. These results demonstrate a direct role of Ang II in the modification of Th balance. The imbalance of Th subsets was associated with hypertensive kidney injury induced by Ang II. Some of the beneficial effects of ARBs might be explained by their immunomodulatory reactions.
Pharmacological Modulation of Platelet Function in Hypertension
Authors: Blann Andrew D. , Nadar Sunil , Lip Gregory Y.H.
Published: June 2003

Platelets exert a considerable influence on human morbidity and mortality. The rationale for their study in hypertension follows the observation that the major consequences of hypertension are stroke and myocardial infarction. However, the etiology of these consequences in hypertension is, paradoxically, not hemorrhagic (as might be expected from the effects of high blood pressure), but occlusive, with thrombus being the culprit lesion. Mechanisms of platelet activation include high shear force, activation of the renin-angiotensin system, endothelial changes, and the presence of comorbidity, such as atrial fibrillation. The treatment of high blood pressure brings about a reversal of the changes seen in the cell. This could be in part due to the direct effect of the drug on the megakaryocyte and/or the platelets themselves, or it might simply be due to the reduction in blood pressure. Some drugs, such as calcium channel antagonists and angiotensin II receptor blockers, however, might have direct effects on platelet biochemistry other than reducing blood pressure. Finally, antiplatelet drugs are becoming an important part of the management of high-risk hypertensives, which aim to minimize vascular complications.
Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins
Authors: Lin Tong , Zeng Lingfang , Liu Yi , DeFea Kathryn , Schwartz Martin A. , Chien Shu , Shyy John Y.-J.
Published: June 2003

Previous studies have shown that integrin activation and fluid shear stress can modulate the activity of sterol regulatory element binding proteins (SREBPs) in vascular endothelial cells. We investigated the role of small GTPase Rho-mediated signal transduction pathway in this mode of SREBP activation. Fluid shear stress activates the Rho downstream effectors ROCK, LIM kinase (LIMK), and cofilin. The various negative mutants of RhoA, ROCK, LIMK, and cofilin can block the shear stress activation of SREBPs. The shear stress–activated SREBP depends on S2P proteases but not caspase-3. Mechanistically, the endoplasmic reticulum-to-Golgi transport of SREBP cleavage–activating protein requires the actin-based cytoskeleton and is enhanced by the Rho-ROCK-LIMK-cofilin pathway. By enhancing the SREBP-mediated cholesterol metabolism, this unique mechanism may contribute to endothelial cell functions under flow.
Dismantling of Cadherin-Mediated Cell-Cell Contacts Modulates Smooth Muscle Cell Proliferation
Authors: Uglow Elizabeth B. , Slater Sadie , Sala-Newby Graciela B. , Aguilera-Garcia Concepción M. , Angelini Gianni D. , Newby Andrew C. , George Sarah J.
Published: June 2003

Proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal thickening during atherosclerosis and restenosis. The cadherins are transmembrane proteins, which form cell-cell contacts and may regulate VSMC proliferation. In this study, N-cadherin protein concentration was significantly reduced by stimulation of proliferation with fetal calf serum (FCS) and platelet-derived growth factor-BB (PDGF-BB) in human saphenous vein VSMCs. Furthermore, overexpression of a truncated N-cadherin, which acts as a dominant-negative increased VSMC proliferation. The amount of an extracellular fragment of N-cadherin (≈90 kDa) in the media after 24 hours was increased by 12-fold by FCS and 11-fold by PDGF-BB, suggesting that N-cadherin levels are regulated by proteolytic shedding. Incubation with a synthetic metalloproteinase inhibitor or adenoviral overexpression of the endogenous tissue inhibitors of metalloproteinases (TIMPs) demonstrated that metalloproteinase activity was responsible in part for this proteolysis. Although total levels of β-catenin protein were not affected, β-catenin was translocated to the nucleus after stimulation with FCS and PDGF-BB. Our data indicates cadherin-mediated cell-cell contacts modulate proliferation in VSMCs. Furthermore, disruption of N-cadherin cell-cell contacts mediated in part by metalloproteinase activity occurs during VSMC proliferation, releasing β-catenin and possibly inducing β-catenin-mediated intracellular signaling.
EphA4-Mediated Rho Activation via Vsm-RhoGEF Expressed Specifically in Vascular Smooth Muscle Cells
Authors: Ogita Hisakazu , Kunimoto Satoshi , Kamioka Yuji , Sawa Hirofumi , Masuda Michitaka , Mochizuki Naoki
Published: June 2003

Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein–coupled receptors. In the present study, we demonstrate a novel cell-cell interaction–mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1–induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1–triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction–mediated RhoA activation that regulates vascular smooth muscle contractility.
Molecular Determinants of the Prothrombogenic and Inflammatory Phenotype Assumed by the Postischemic Cerebral Microcirculation
Authors: Ishikawa Mami , Cooper Dianne , Russell Janice , Salter James W. , Zhang John H. , Nanda Anil , Granger D. Neil
Published: June 2003

Background and Purpose—

Circulating blood cells have been implicated in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury and stroke. The objective of this study was to define the magnitude and molecular determinants of the platelet- and leukocyte–endothelial cell adhesive interactions induced by I/R in the mouse brain.

Methods—

Bilateral common carotid artery occlusion was induced for 1 hour in C57BL/6 mice, followed by either 40 minutes or 4 hours of reperfusion. Fluorescent platelets were administered intravenously, and the frontal brain surface was observed with intravital fluorescence microscopy. Leukocyte–endothelial cell adhesion was monitored with the use of rhodamine-6G.

Results—

Ischemia followed by 40 minutes of reperfusion resulted in the rolling (125.1±23.6/mm
2
) and firm adhesion (109.5±25.8/mm
2
) of leukocytes but not platelets in venules. However, with 4 hours of reperfusion, rolling (138.8±24.6/mm
2
) and firm adhesion (153.7±22.3/mm
2
) of platelets were detected, and this was accompanied by a more intense recruitment of rolling (374.5±54.6/mm
2
) and adherent (445.2±57.1/mm
2
) leukocytes. In mice deficient in either P-selectin (P-selectin
−/−
) or intercellular adhesion molecule-1 (ICAM-1) (ICAM-1
−/−
), the I/R-induced platelet–endothelial cell (by 80% and 60%, respectively) and leukocyte–endothelial cell (by 84% and 78%, respectively) interactions were significantly blunted compared with those of wild-type mice.

Conclusions—

These findings indicate that I/R promotes the adhesion of both platelets and leukocytes in cerebral venules, with the accumulation of adherent leukocytes preceding the recruitment of platelets. Both P-selectin and ICAM-1 contribute to the inflammatory and prothrombogenic state induced by cerebral I/R.
High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor-prognosis chronic lymphocytic leukemia
Authors: McCarthy Helen , Wierda William G. , Barron Lynn L. , Cromwell Candy C. , Wang Jing , Coombes Kevin R. , Rangel Roberto , Elenitoba-Johnson Kojo S. J. , Keating Michael J. , Abruzzo Lynne V.
Published: June 2003

In chronic lymphocytic leukemia (CLL), analysis of immunoglobulin heavy chain variable regions for somatic hypermutation identifies 2 prognostic subsets, mutated and unmutated. Investigators have postulated that unmutated and mutated CLL arises from malignant transformation of pre– and post–germinal center (GC) B cells, respectively. Alternatively, unmutated cases may arise from B cells stimulated by T-cell–independent antigens or from GC B cells with inactive somatic hypermutation. Activation-induced cytidine deaminase (AID), a protein essential for somatic hypermutation, is expressed by GC B cells in which this process occurs. We investigated AID mRNA expression in 20 CLL cases. In 8 cases we detected high expression of wild-type AID mRNA and 2 splice variants; in 12 cases and 5 normal peripheral blood B-cell samples we detected no expression using standard conditions. Of 8 CLL cases that highly expressed AID, 7 were unmutated, suggesting that this subset may arise from GC-experienced B cells with inactive somatic hypermutation, and may predict prognosis.
Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells
Authors: Jiang Ning , Reich Charles F. , Pisetsky David S.
Published: June 2003

After apoptosis or necrosis, macrophages clear dead cells by phagocytosis. Although this process is efficient, circulating nucleosomes can occur in certain diseases, presumably reflecting either increased production or impaired clearance. To investigate the generation of blood nucleosomes, graded numbers of apoptotic and necrotic cells were administered to healthy mice, and levels of blood nucleosomes and DNA were determined. Using Jurkat cells as a model, nucleosomes and DNA were detected in the blood after the administration of 108 apoptotic or necrotic cells per mouse by the intraperitoneal route. The kinetics of the response were similar for both types of cells. The role of macrophages was assessed by eliminating these cells with clodronate liposomes or silica. Although clodronate treatment alone produced a peak level of blood DNA, the subsequent administration of dead cells caused no change in DNA levels. In contrast, silica treatment alone did not elicit a blood DNA response, though this treatment limited the rise in DNA from administered cells. Molecular studies showed that the blood DNA following the administration of apoptotic or necrotic cells arose from the mouse and the Jurkat cells, and its size distribution was consistent with apoptosis. Together, these findings suggest that the generation of blood nucleosomes depends on macrophages, with apoptosis a concomitant of a high burden of dead and dying cells.
Distribution of marrow repopulating cells between bone marrow and spleen early after transplantation
Authors: Plett P. Artur , Frankovitz Stacy M. , Orschell Christie M.
Published: June 2003

Whether hematopoietic stem cells (HSCs) home selectively to bone marrow (BM) early after transplantation remains an issue of debate. Better understanding of homing mechanisms may benefit BM transplantation protocols in cases of limited graft cell number or nonmyeloablative conditioning regimens. Using flow cytometry and serial transplantation to stringently identify HSCs, trafficking patterns of long-term engrafting cells were mapped between BM and spleen early after transplantation. Low-density BM cells were tracked in irradiated or nonirradiated mice 1, 3, 6, and 20 hours after transplantation, at which time recipient BM and spleen were analyzed for recovery of primitive donor cells by phenotype and adhesion molecule expression. In addition, phenotypically defined HSC-enriched or HSC-depleted grafts were tracked 20 hours after transplantation in recipient BM and spleen and analyzed for recovery and long-term repopulating potential in mice undergoing serial transplantation. Regardless of irradiation status, recovery of donor Sca-1+ lin- cells was higher at most time points in recipient BM than in spleen, while recovery of total Sca-1+ cells was variable. A significantly higher percentage of BM-homed donor Sca-1+ cells expressed CD43, CD49e, and CD49d 20 hours after transplantation than spleen-homed cells, which contained significantly more non-HSC phenotypes. Furthermore, BM-homed cells were significantly enriched for cells capable of secondary multilineage hematopoiesis in mice undergoing serial transplantation compared with spleen-homed cells. These results support the notion of specific homing of HSCs to BM by 20 hours after transplantation and provide a basis for the enhanced engraftment potential afforded some Sca-1+ lin- cells subfractionated on the basis of adhesion molecule expression.
A controlled assessment of an asthma self-management plan involving a budesonide dose regimen. OPTIONS Research Group
Authors: Ayres JG , Campbell LM
Published: June 2003

Our aim was to assess the efficacy of budesonide (Pulmicort Turbohaler Astra) used as part of a self-management plan in a group of patients with chronic asthma. One hundred and twenty five patients with nocturnal asthma symptoms, despite the use of inhaled prophylactic and beta 2-agonist therapy, were randomized to inhaled budesonide 200, 400 or 800 micrograms b.i.d. either with dose adjustments made by the physician, i.e. doctor-managed (DM; n = 64), or as part of a self-management plan (SM; n = 61). The SM group were allowed to adjust their dose according to written guidelines based on morning peak flow. At the end of the 6 month treatment period, there were no significant differences detected between the DM and the SM groups either from the clinic or diary card data. Both groups demonstrated a significant reduction in the number of sleep-disturbed nights, by 75% in the DM group and 77% in the SM group, at the end of the study. In conclusion, for patients with mild-to-moderate asthma, either a doctor-adjusted dose regimen or a peak flow based self-management plan involving budesonide is equally efficacious. For some patients, a simple regimen, adjusted by the physician at clinic visits, may be easier to follow.
Endobronchial secretion of interleukin-13 following local allergen challenge in atopic asthma: relationship to interleukin-4 and eosinophil counts
Authors: Kroegel C , Julius P , Matthys H , Virchow JC  , Luttmann W
Published: June 2003

We investigated the secretion of interleukin (IL)-13 into the airways in 10 mild allergic asthmatics by employing local allergen challenge, and compared the data both to IL-4 levels and eosinophil numbers obtained by bronchoalveolar lavage (BAL). Appropriate allergen or saline were endoscopically instilled into different airway segments, which were lavaged 10 min and 18 h after allergen or sham challenge. IL-4 and IL-13 were measured in unconcentrated BAL fluid using a double sandwich enzymes-linked immunosorbent assay (ELISA). Endobronchial allergen challenge induced a highly significant increase in the numbers of eosinophils after 18 h in the allergen exposed segment. Ten minutes following allergen exposure, low levels of IL-4 and IL-13 could be detected, whilst concentrations of both cytokines were significantly raised 18 h following local allergen exposure. In contrast to IL-4, the concentration of IL-13 strongly correlated with the eosinophil numbers found 18 h post-allergen challenge. The results suggest that interleukin-13 is actively secreted during the late asthmatic response in mild asthmatic subjects. In view of its action on eosinophils and other cell types, we conclude that interleukin-13, in addition to interleukin-4, may play an important role in the pathogenesis of eosinophil-related inflammation, such as bronchial asthma.
Effect of nitrogen dioxide and other combustion products on asthmatic subjects in a home-like environment
Authors: Salome CM , Brown NJ , Marks GB , Woolcock AJ , Johnson GM , Nancarrow PC , Quigley S , Tiong J
Published: June 2003

Nitrogen dioxide (NO2) is one of a number of nitrogen compounds that are by-products of combustion and occur in domestic environments following the use of gas or other fuels for heating and cooking. In this study, we examined the effect of two levels of NO2 on symptoms, lung function and airway hyperresponsiveness (AHR) in asthmatic adults and children. In addition, in the same subjects, we examined the effects of the same levels of NO2 mixed with combustion by-products from a gas space heater. The subjects were nine adults, aged 19-65 yrs, and 11 children, aged 7-15 yrs, with diagnosed asthma which was severe enough to require daily medication. All subjects had demonstrable AHR to histamine. Exposures were for 1 h on five separate occasions, 1 week apart, to: 1) ambient air, drawn from outside the building; 2) 0.3 parts per million (ppm) NO2 in ambient air; 3) 0.6 ppm NO2 in ambient air; 4) ambient air+combustion by-products+NO2 to give a total of 0.3 ppm; and 5) ambient air+combustion by-products+NO2 to give a total of 0.6 ppm. Effects were measured as changes in lung function and symptoms during and 1 h after exposure, in AHR 1 h and 1 week after exposure, and in lung function and symptoms during the week following exposure. Exposure to NO2 either in ambient air or mixed with combustion by-products from a gas heater, had no significant effect on symptoms or lung function in adults or in children. There was a small, but statistically significant, increase in AHR after exposure to 0.6 ppm NO2 in ambient air. However, there was no effect of 0.6 ppm NO2 on AHR when the combustion by-products were included in the test atmosphere nor of 0.3 ppm NO2 under either exposure condition. We conclude that a 1 h exposure to 0.3 or 0.6 ppm NO2 has no clinically important effect on the airways of asthmatic adults or children, but that 0.6 ppm may cause a slight increase in airway hyperresponsiveness.
Serum house dust mite antibodies: predictor of increased bronchial responsiveness in adults of a community
Authors: Omenaas E , Bakke P , Eide GE , Elsayed S , Gulsvik A
Published: June 2003

The purpose of this study was to determine whether the presence of serum specific immunoglobulin E (IgE) antibodies was associated with increased bronchial responsiveness in adults. We studied cross-sectionally a random community sample of 18-73 year old adults, of whom 83% (n = 489) performed bronchial responsiveness testing as well as serum measurements of five specific IgE antibodies. In the crude data, 39% of those with house dust mite antibodies (n = 18) had a bronchial responsiveness < or = 32 g.L-1 methacholine compared with 19% in subjects without any of the five specific IgE antibodies (n = 453). The corresponding percentages for subjects with timothy antibodies (n = 16) was 25%, birch antibodies (n = 13) 23%, cat antibodies (n = 10) 40% and mould antibodies (n = 2) 50%. When assessing the multivariate relationship between the presence of one specific IgE antibody and degree of bronchial responsiveness we used a semi-proportional hazards model with the response as a 20% fall in forced expiratory volume in one second (FEV1) from pretest value. Covariates included in the model were: gender, age, pretest FEV1, smoking habits, pack-years, season and other specific IgE antibodies than that examined. The presence of house dust mite antibodies was a significant predictor (p < 0.01) of increased bronchial responsiveness in never- and ex-smokers. Indoor allergic sensitization (house dust mite, cat and mould) was a significant predictor of increased bronchial responsiveness, while outdoor allergic sensitization (timothy and birch) was not. Excluding subjects with obstructive lung disease (n = 39) or including the covariate log total serum IgE as a potential confounder yielded the same result. Thus, in this community, indoor allergic sensitization rather than allergic sensitization per se was related to increased bronchial responsiveness after adjusting for other relevant covariates.