bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlling Human Upright Posture: Velocity Information Is More Accurate Than Position or Acceleration
Authors: Jeka John , Kiemel Tim , Creath Robert , Horak Fay , Peterka Robert
Published: May 2004

The problem of how the nervous system fuses sensory information from multiple modalities for upright stance control remains largely unsolved. It is well established that the visual, vestibular, and somatosensory modalities provide position and rate (e.g., velocity, acceleration) information for estimation of body dynamics. However, it is unknown whether any particular property dominates when multisensory information is fused. Our recent stochastic analysis of postural sway during quiet stance suggested that sensory input provides more accurate information about the body's velocity than its position or acceleration. Here we tested this prediction by degrading major sources of velocity information through removal/attenuation of sensory information from vision and proprioception. Experimental measures of postural sway were compared with model predictions to determine whether sway behavior was indicative of a deficit in velocity information rather than position or acceleration information. Subjects stood with eyes closed on a support surface that was 1) fixed, 2) foam, or 3) sway-referenced. Six measures characterizing the stochastic structure of postural sway behaved in a manner consistent with model predictions of degraded velocity information. Results were inconsistent with the effect of degrading only position or acceleration information. These findings support the hypothesis that velocity information is the most accurate form of sensory information used to stabilize posture during quiet stance. Our results are consistent with the assumption that changes in sway behavior resulting from commonly used experimental manipulations (e.g., foam, sway-referencing, eyes closed) are primarily attributed to loss of accurate velocity information.
A combined in vitro/bioinformatic investigation of redox regulatory mechanisms governing cell cycle progression
Authors: Conour J. E. , Graham W. V. , Gaskins H. R.
Published: May 2004

The intracellular reduction-oxidation (redox) environment influences cell cycle progression; however, underlying mechanisms are poorly understood. To examine potential mechanisms, the intracellular redox environment was characterized per cell cycle phase in Chinese hamster ovary fibroblasts via flow cytometry by measuring reduced glutathione (GSH), reactive oxygen species (ROS), and DNA content with monochlorobimane, 2′,7′-dichlorohydrofluorescein diacetate (H2DCFDA), and DRAQ5, respectively. GSH content was significantly greater in G2/M compared with G1phase cells, whereas GSH was intermediate in S phase cells. ROS content was similar among phases. Together, these data demonstrate that G2/M cells are more reduced than G1cells. Conventional approaches to define regulatory mechanisms are subjective in nature and focus on single proteins/pathways. Proteome databases provide a means to overcome these inherent limitations. Therefore, a novel bioinformatic approach was developed to exhaustively identify putative redox-regulated cell cycle proteins containing redox-sensitive protein motifs. Using the InterPro ( http://www.ebi.ac.uk/interpro/ ) database, we categorized 536 redox-sensitive motifs as: 1) active/functional-site cysteines, 2) electron transport, 3) heme, 4) iron binding, 5) zinc binding, 6) metal binding (non-Fe/Zn), and 7) disulfides. Comparing this list with 1,634 cell cycle-associated proteins from Swiss-Prot and SpTrEMBL ( http://us.expasy.org/sprot/ ) revealed 92 candidate proteins. Three-fourths (69 of 92) of the candidate proteins function in the central cell cycle processes of transcription, nucleotide metabolism, (de)phosphorylation, and (de)ubiquitinylation. The majority of oxidant-sensitive candidate proteins (68.9%) function during G2/M phase. As the G2/M phase is more reduced than the G1phase, oxidant-sensitive proteins may be temporally regulated by oscillation of the intracellular redox environment. Combined with evidence of intracellular redox compartmentalization, we propose a spatiotemporal mechanism that functionally links an oscillating intracellular redox environment with cell cycle progression.
A role for Tbx5 in proepicardial cell migration during cardiogenesis
Authors: Hatcher Cathy J. , Diman Nata Y.S.-G. , Kim Min-Su , Pennisi David , Song Yan , Goldstein Marsha M. , Mikawa Takashi , Basson Craig T.
Published: May 2004

Transcriptional regulatory cascades during epicardial and coronary vascular development from proepicardial progenitor cells remain to be defined. We have used immunohistochemistry of human embryonic tissues to demonstrate that the TBX5 transcription factor is expressed not only in the myocardium, but also throughout the embryonic epicardium and coronary vasculature. TBX5 is not expressed in other human fetal vascular beds. Furthermore, immunohistochemical analyses of human embryonic tissues reveals that unlike their epicardial counterparts, delaminating epicardial-derived cells do not express TBX5 as they migrate through the subepicardium before undergoing epithelial-mesenchymal transformation required for coronary vasculogenesis. In the chick, Tbx5 is expressed in the embryonic proepicardial organ (PEO), which is composed of the epicardial and coronary vascular progenitor cells. Retrovirus-mediated overexpression of human TBX5 inhibits cell incorporation of infected proepicardial cells into the nascent chick epicardium and coronary vasculature. TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration. Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium. Culture of explanted PEOs demonstrates that untreated chick proepicardial cells downregulate Tbx5 expression during cell migration. Therefore, we propose that Tbx5 participates in regulation of proepicardial cell migration, a critical event in the establishment of the epicardium and coronary vasculature.
Morphologic Findings of Coronary Atherosclerotic Plaques in Diabetics
Authors: Burke Allen P. , Kolodgie Frank D. , Zieske Arthur , Fowler David R. , Weber Deena K. , Varghese P. Jacob , Farb Andrew , Virmani Renu
Published: May 2004

Objective—Coronary atherosclerotic plaque composition of diabetic subjects and localization of receptor for advanced glycation end products (RAGE) and its ligands have not been extensively studied.

Methods and Results—Hearts from diabetic subjects and age, race, and sex-matched nondiabetic subjects dying suddenly were examined. Coronary arteries were dissected and lesions were evaluated for plaque burden, necrotic core size, and inflammatory infiltrate. The expression of RAGE, the RAGE-binding protein (S100-A12, EN-RAGE), and cell death (apoptosis) were also determined. Lesions from type II diabetic subjects had larger mean necrotic cores (P=0.01) and greater total and distal plaque load (P<0.001) than nondiabetic subjects. Necrotic core size correlated positively with diabetic status, independent of other risk factors. Intimal staining for macrophages, T-cells, and HLA-DR was also significantly greater in diabetic subjects (P=0.03,P=0.003, andP<0.0001), respectively. The association of increased macrophage infiltrate was independent of cholesterol levels and patient age. Expression of RAGE and EN-RAGE was significantly greater in diabetic subjects (P=0.004) and was associated with apoptotic smooth muscle cells and macrophages.

Conclusions—In sudden coronary death, inflammation and necrotic core size play a greater role in the progression of atherosclerosis in diabetic subjects. The expression of RAGE and EN-RAGE may further compromise cell survival and promote plaque destabilization.
Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression
Authors: Sugiyama Seigo , Kugiyama Kiyotaka , Aikawa Masanori , Nakamura Shinichi , Ogawa Hisao , Libby Peter
Published: May 2004

Objective—

Superficial erosion of coronary plaques due to endothelial loss causes acute coronary syndromes (ACS). Macrophages at erosive sites of human coronary atheroma present myeloperoxidase (MPO), an enzyme that produces hypochlorous acid (HOCl).

Methods and Results—

Activated MPO-positive macrophages or exogenous HOCl promoted detachment of endothelial cells (EC) from “Matrigel” substrata in vitro. Pathophysiologically relevant concentrations of HOCl caused EC death in a concentration-dependent manner: HOCl (20 to 50 μmol/L) induced rapid shrinkage of EC with nuclear condensation and disruption of EC monolayers, whereas concentrations >100 μmol/L immediately induced blebbing of the EC plasma membrane without shrinkage. HOCl (30 to 50 μmol/L) also induced caspase-3 activation, poly (ADP-ribose) polymerase degradation, and DNA laddering in EC. HOCl rapidly decreased endothelial Bcl-2 and induced cytochrome-C release, indicating that HOCl activates apoptotic EC death, partially via mitochondrial damage. Increased intracellular glutathione (GSH) levels after treatment with GSH monoethyl ester (GSH-MEE) attenuated HOCl-induced EC apoptosis. Sublethal concentrations of HOCl (1.0 to 15 μmol/L) increased tissue factor in EC and GSH-MEE treatment limited this effect of HOCl.

Conclusions—

HOCl can provoke EC death and desquamation by either apoptotic or oncotic cell-death pathways, and sublethal concentrations of HOCl can increase endothelial tissue factor. These results show that MPO-positive macrophage-derived HOCl in the subendothelium of atheromata may participate in ACS by promoting superficial erosion and increasing thrombogenicity.
Effect of Pravastatin on Low-Density Lipoprotein Oxidation and Myocardial Perfusion in Young Adults With Type 1 Diabetes
Authors: Janatuinen Tuula , Knuuti Juhani , Toikka Jyri O. , Ahotupa Markku , Nuutila Pirjo , Rönnemaa Tapani , Raitakari Olli T.
Published: May 2004

Objective—

Diabetes has been associated with increased oxidative stress and impaired vascular function. Statins have been shown to reduce low-density lipoprotein (LDL) oxidizability and improve myocardial perfusion in hypercholesterolemic nondiabetic subjects. We studied whether pravastatin decreases LDL oxidation and improves myocardial perfusion in normocholesterolemic subjects with type 1 diabetes.

Methods and Results—

In this randomized, double-blind study, myocardial perfusion was measured at rest and during dipyridamole stimulation with positron emission tomography and [
15
O]H
2
O during hyperinsulinemic euglycemia in 42 patients (age 30±6 years; LDL cholesterol 2.48±0.57 mmol/L) before and after 4-month treatment with pravastatin 40 mg/d or placebo. In addition, 12 healthy nondiabetic subjects were studied. LDL oxidation was measured by determining the level of baseline diene conjugation in lipids extracted from LDL. The level of LDL oxidation was similar in the pravastatin and placebo groups before treatment (23.9±4.6 versus 25.6±9.5 μmol/L, respectively) and decreased significantly during pravastatin treatment to 19.5±5.0 μmol/L (
P
<0.005). Myocardial perfusion reserve was significantly lower in diabetic patients compared with controls (4.15±1.29 versus 5.31±1.86,
P
<0.05) and did not change after treatment. Glycemic control and insulin sensitivity remained unchanged during treatment.

Conclusion—

Pravastatin treatment, resulting in decreased LDL oxidation, did not improve myocardial perfusion reserve in subjects with type 1 diabetes.
Prognostic Value of Pharmacological Stress Echocardiography Is Affected by Concomitant Antiischemic Therapy at the Time of Testing
Authors: Sicari Rosa , Cortigiani Lauro , Bigi Riccardo , Landi Patrizia , Raciti Mauro , Picano Eugenio
Published: May 2004

Background—

The aim of this study was to determine whether antianginal medications affect the prognostic value of pharmacological stress echocardiography.

Methods and Results—

From the EPIC-EDIC Data Bank, 7333 patients (5452 men; age; 59±10 years) underwent pharmacological stress echocardiography with either high-dose dipyridamole (0.84 mg/kg over 10 minutes; n=4984) or high-dose dobutamine (up to 40 μg · kg
−1
· min
−1
; n=2349) (DET) for diagnostic purposes. At the time of testing, 1791 patients were on antiischemic therapy (nitrates and/or calcium antagonists and/or β-blockers). Patients were followed up for a mean of 2.6 years (range, 1 to 206 months). DET was positive for myocardial ischemia in 2854 patients (39%) and negative in 4479 (61%). Total mortality was 336 (4.5%). Death was attributed to cardiac causes in 161 patients (2.1%). Survival was highest in patients with negative DET off therapy and lowest in patients with positive DET studied on therapy (95% versus 81%;
P
=0.0000). Survival was comparable in patients with a negative test on therapy and in patients with a positive test off therapy (88% versus 84%,
P
=NS).

Conclusions—

Ongoing antiischemic therapy at the time of testing heavily modulates the prognostic value of pharmacological stress echo. In the presence of concomitant antiischemic therapy, a positive test is more prognostically malignant, and a negative test less prognostically benign.
Clinical Correlates and Prognostic Significance of Exercise-Induced Ventricular Premature Beats in the Community
Authors: Morshedi-Meibodi Ali , Evans Jane C. , Levy Daniel , Larson Martin G. , Vasan Ramachandran S.
Published: May 2004

Background—

Recent investigations suggest that ventricular premature beats during exercise (EVPBs) are associated with increased cardiovascular mortality in asymptomatic individuals, but mechanisms underlying the association are unclear.

Method and Results—

We evaluated 2885 Framingham Offspring Study participants (1397 men; mean age, 43 years) who were free of cardiovascular disease and who underwent a routine exercise stress test; 792 participants (27%) had development of EVPBs (median, 0.22/min of exercise). Logistic regression was used to evaluate predictors of EVPBs. Cox models were used to examine the relations of infrequent (less than or equal to median) and frequent (greater than median) versus no EVPBs to incidence of hard coronary heart disease (CHD) event (recognized myocardial infarction, coronary insufficiency, or CHD death) and all-cause mortality, adjusting for vascular risk factors and exercise variables. Age and male sex were key correlates of EVPBs. During follow-up (mean, 15 years), 142 (113 men) had a first hard CHD event and 171 participants (109 men) died. EVPBs were not associated with hard CHD events but were associated with increased all-cause mortality rates (multivariable-adjusted hazards ratio, 1.86, 95% CI, 1.24 to 2.79 for infrequent, and 1.71, 95% CI, 1.18 to 2.49 for frequent EVPBs versus none). The relations of EVPBs to mortality risk were not influenced by VPB grade, presence of recovery VPBs, left ventricular dysfunction, or an ischemic ST-segment response.

Conclusions—

In our large, community-based sample of asymptomatic individuals, EVPBs were associated with increased risk of death at a much lower threshold than previously reported. Additional studies are needed to confirm these findings and to clarify the underlying mechanisms.
Arginine Vasopressin Levels Are Elevated and Correlate With Functional Status in Infants and Children With Congestive Heart Failure
Authors: Price Jack F. , Towbin Jeffrey A. , Denfield Susan W. , Clunie Sarah , Smith E.O. , McMahon Colin J. , Radovancevic Branislav , Dreyer William J.
Published: May 2004

Background—

Arginine vasopressin (AVP) is a vasoactive hormone that acts on the kidney to conserve solute-free water and produces a potent vasoconstrictive effect during hypovolemic states. AVP levels are elevated in adults with congestive heart failure (CHF), and early clinical trials using AVP antagonists are being conducted. The purpose of this study was to determine if AVP levels (1) are elevated in children with CHF attributable to left ventricular dysfunction or pulmonary overcirculation attributable to large left-to-right shunts and (2) can predict functional clinical status.

Methods and Results—

AVP levels were measured in patients with dilated cardiomyopathy (DCM) and CHF and in patients with large left-to-right intracardiac shunts. Each patient with DCM (ejection fraction percent <40%) was classified as NYHA functional class I through IV when the AVP level was drawn. Serum sodium was measured, serum osmolality was calculated, and echocardiograms and chest radiographs were performed on all study patients. AVP levels were also measured in age-matched controls. Mean AVP level in children with DCM (n=27) was 10.3 pg/mL (±12.8) versus 3.7 pg/mL (±2.4) in controls (n=15) (
P
<0.01). Mean AVP level in children with left-to-right shunts (n=14) was 13.9 pg/mL (±17.3) versus 3.5 pg/mL (±1.3) in controls (n=8) (
P
<0.04). In patients with DCM, AVP levels correlated directly with NYHA functional class (
r
2
=0.73,
P
<0.001).

Conclusions—

Arginine vasopressin levels are elevated in infants and children with CHF attributable to left ventricular dysfunction and in infants with large left-to-right intracardiac shunts. Furthermore, there is a direct relationship between AVP level and the severity of heart failure in patients with DCM.
In Vivo Induction of Endothelial Apoptosis Leads to Vessel Thrombosis and Endothelial Denudation
Authors: Durand E. , Scoazec A. , Lafont A. , Boddaert J. , Al Hajzen A. , Addad F. , Mirshahi M. , Desnos M. , Tedgui A. , Mallat Z.
Published: May 2004

Background—

The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis.

Methods and Results—

Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43±0.30 versus 0.93±0.44, respectively;
P
=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (
P
<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%,
P
=0.04). These results were confirmed in balloon-injured atheromatous arteries.

Conclusions—

In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.
β-Adrenoceptor Blocker Carvedilol Provides Cardioprotection via an Adenosine-Dependent Mechanism in Ischemic Canine Hearts
Authors: Asanuma Hiroshi , Minamino Tetsuo , Sanada Shoji , Takashima Seiji , Ogita Hisakazu , Ogai Akiko , Asakura Masanori , Liao Yulin , Asano Yoshihiro , Shintani Yasunori , Kim Jiyoong , Shinozaki Yoshiro , Mori Hidezo , Node Koichi , Kitamura Soichiro , Tomoike Hitonobu , Hori Masatsugu , Kitakaze Masafumi
Published: May 2004

Background—

Carvedilol is a β-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other β-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts.

Methods and Results—

In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0±2.8% versus 40.9±4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2±5.4%) or by an inhibitor of ecto-5′-nucleotidase (44.4±3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4±5.6 to 73.5±7.5 mL · 100 g
−1
· min
−1
;
P
<0.05) and adenosine release (112.3±22.2 to 240.6±57.1 nmol/L;
P
<0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5′-nucleotidase activity.

Conclusions—

Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.
Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy
Authors: Cardinale Daniela , Sandri Maria T. , Colombo Alessandro , Colombo Nicola , Boeri Marina , Lamantia Giuseppina , Civelli Maurizio , Peccatori Fedro , Martinelli Giovanni , Fiorentini Cesare , Cipolla Carlo M.
Published: May 2004

Background—

In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously.

Methods and Results—

In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values ≥0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were <0.08 ng/mL (TnI
−/−
group); in 145, there was only an early increase (TnI
+/−
group); and in 63 patients, both values increased (TnI
+/+
group). In the TnI
−/−
group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI
+/+
group (84% versus 37% in the TnI
+/−
group;
P
<0.001).

Conclusions—

TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter. This stratification allows us to differentiate the monitoring program and to plan, in selected patients, preventive strategies aimed at improving clinical outcome.
Neutrophils Infiltrate Resistance-Sized Vessels of Subcutaneous Fat in Women With Preeclampsia
Authors: Leik Courtney E. , Walsh Scott W.
Published: May 2004

We examined if there is systemic vascular inflammation and neutrophil infiltration in women with preeclampsia. Resistance-sized vessels (10 to 200 μm) of subcutaneous fat were evaluated from normal nonpregnant women, normal pregnant women, and preeclamptic women. Immunohistochemical staining was performed for: (1) interleukin-8 (IL-8), a potent neutrophil chemokine; (2) intercellular adhesion molecule-1 (ICAM-1; CD54), an endothelial cell adhesion molecule; and (3) CD66b, a neutrophil antigen. Vessels of preeclamptic patients had intense IL-8 staining in the endothelium and vascular smooth muscle, as compared with little or no staining for normal pregnant and normal nonpregnant patients. ICAM-1 was expressed on the endothelium of all patient groups. In preeclamptic patients, ICAM-1 was also expressed on vascular smooth muscle. Vessels of preeclamptic patients had significantly more CD66b staining of neutrophils than did normal pregnant or normal nonpregnant patients. There were significantly more vessels stained, more vessels with neutrophils flattened and adhered to endothelium, more vessels with neutrophils infiltrated into the intima, and more neutrophils per vessel. In conclusion, in women with preeclampsia, there was significant infiltration of neutrophils into maternal systemic vasculature associated with inflammation of the vascular smooth muscle indicated by increased expression of IL-8 and ICAM-1. Neutrophil infiltration provides a reasonable explanation for endothelial and vascular smooth muscle dysfunction in preeclampsia because neutrophils produce toxic substances, which may explain clinical symptoms.
Expression of Mutant p193 and p53 Permits Cardiomyocyte Cell Cycle Reentry After Myocardial Infarction in Transgenic Mice
Authors: Nakajima Hidehiro , Nakajima Hisako O. , Tsai Shih-Chong , Field Loren J.
Published: May 2004

Previous studies have demonstrated that expression of p193 and p53 mutants with dominant-interfering activities renders embryonic stem cell–derived cardiomyocytes responsive to the growth promoting activities of the E1A viral oncoproteins. In this study, the effects of p53 and p193 antagonization on cardiomyocyte cell cycle activity in normal and infarcted hearts were examined. Transgenic mice expressing the p193 and/or the p53 dominant-interfering mutants in the heart were generated. Transgene expression had no effect on cardiomyocyte cell cycle activity in uninjured adult hearts. In contrast expression of either transgene resulted in a marked induction of cardiomyocyte cell cycle activity at the infarct border zone at 4 weeks after permanent coronary artery occlusion. Expression of the p193 dominant-interfering mutant was also associated with an induction of cardiomyocyte DNA synthesis in the interventricular septa of infarcted hearts. A concomitant and marked reduction in hypertrophic cardiomyocyte growth was observed in the septa of hearts expressing the p193 dominant-interfering transgene, suggesting that cell cycle activation might partially counteract the adverse ventricular remodeling that occurs after infarction. Collectively these data suggest that antagonization of p193 and p53 activity relaxes the otherwise stringent regulation of cardiomyocyte cell cycle reentry in the injured adult heart.
Cerebrovascular Mortality 10 Years After Stroke
Authors: Terént Andreas
Published: May 2004

Objectives—

Cerebrovascular mortality has declined in the general population of Sweden. The objective of the present study was to investigate causes of death among stroke patients in a long-term perspective.

Research Design and Methods—

A population-based study was conducted of first-ever strokes in the municipality of Söderhamn, Sweden. Standardized mortality ratios were calculated for comparison with the general population. Three time periods (1975 to 1978, 1983 to 1986, and 1987 to 1990) were analyzed. All 1186 patients were followed up for at least 10 years.

Results—

Cerebrovascular mortality was greatly increased (more than 10-fold) in comparison with the general population during all study periods. The mortality from ischemic heart disease and some other diseases was moderately raised (3- to 8-fold), whereas the mortality from malignant disorders was normal.

Conclusion—

Cerebrovascular disease was the predominant cause of death among Swedish stroke patients in the 1970s and the 1980s.
Insidious Cognitive Decline in CADASIL
Authors: Amberla Kaarina , Wäljas Minna , Tuominen Susanna , Almkvist Ove , Pöyhönen Minna , Tuisku Seppo , Kalimo Hannu , Viitanen Matti
Published: May 2004

Background and Purpose—

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes repeated ischemic attacks leading to subcortical vascular dementia. The aim of this study was to characterize cognitive function in subjects with a C475T (R133C) mutation in the
Notch3
gene, leading to CADASIL.

Methods—

Prestroke (n=13) and poststroke (n=13) mutation carriers and mutation carriers with dementia (n=8) were compared with healthy noncarriers from the same families using a comprehensive set of neuropsychological tests.

Results—

Changes in working memory and executive function were observed in the very early phase of the disease before transient ischemic attack (TIA) or stroke. Later, in the poststroke phase, the cognitive impairment concerned also mental speed and visuospatial ability. Finally, the subjects with dementia had multiple cognitive deficits, which engaged even verbal functions, verbal episodic memory, and motor speed. The 2 mutation carrier groups without dementia and the controls could be reliably distinguished using 3 tests that assessed working memory/attention, executive function, and mental speed. Episodic memory was relatively well-preserved late in the disease.

Conclusion—

A deterioration of working memory and executive function was already observed in the prestroke phase, which means that cognitive decline may start insidiously before the first onset of symptomatic ischemic episodes.
Ischemic Stroke in Young Women
Authors: Nightingale Alison L. , Farmer Richard D.T.
Published: May 2004

Background and Purpose—

Estimates of the incidence of ischemic stroke in young women vary widely from 0.9 to 8.9 per 100 000 per year. This study was conducted to determine the incidence and risk factors for ischemic stroke in young women in the UK.

Methods—

Women aged 15 to 49 with a first diagnosis and supporting evidence of ischemic stroke between January 1, 1992, and December 31, 1998, were identified from the UK General Practice Research Database. Age-specific incidence rates were calculated and a nested case-control study was conducted with up to 6 controls randomly selected and matched to each case by year of birth and general practice. Crude and adjusted odds ratios (ORs) were calculated using conditional logistic regression.

Results—

The incidence of ischemic stroke was 3.56/100 000 per year. Factors associated with an increased risk were heart disease (OR, 10.5), heavy alcohol consumption (OR, 8.5), previous venous thromboembolism (OR, 6.2), treated diabetes mellitus (OR, 4.7), hypertension (OR, 4.6), migraine (OR, 2.3), and use of combined oral contraceptives (OR, 2.3). Light alcohol consumption was found to be protective (OR, 0.17).

Conclusions—

The crude incidence rate was lower than previously reported for the USA and Europe but higher than that reported for the UK Oxford Region. This could be because of an under-representation of mild cases or because of a true lower incidence in the UK compared with the USA and the rest of Europe. The results of the case-control study are consistent with previous studies of ischemic stroke in young women.
Osteoprotegerin and Osteopontin Are Expressed at High Concentrations Within Symptomatic Carotid Atherosclerosis
Authors: Golledge Jonathan , McCann Moira , Mangan Simone , Lam Alfred , Karan Mirko
Published: May 2004

Background and Purpose—

The aim of this study was to compare the concentration of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), and osteopontin (OPN) in stable (asymptomatic) and unstable (symptomatic) carotid atherosclerosis. In addition, we were interested in the effect of angiotensin II blockade on the secretion of these proteins by unstable atherosclerosis.

Methods—

Endarterectomy samples removed from patients with recent (within 6 weeks) or no previous focal neurological symptoms were assessed by immunohistochemistry, Western analysis, and explant culture. Concentrations of OPG, RANKL, and OPN were measured by mean optical density (MOD), densitometry of protein bands, and enzyme-linked immunosorbent assay of supernatants from explant culture, and compared between symptomatic and asymptomatic patients.

Results—

The concentration of OPG and OPN within the proximal internal carotid (PIC) part of the endarterectomy specimen removed from symptomatic patients was elevated 2- and 4-fold, respectively. Although the concentration of RANKL did not differ according to patients’ symptoms, the quantity of OPG secreted by explants of the PIC was greater in explants from symptomatic patients and could be significantly reduced within 48 hours of incubation with the angiotensin II blocker irbesartan.

Conclusion—

OPG and OPN are upregulated in symptomatic human carotid atherosclerosis with possible implications for plaque stability. Angiotensin II blockade is able to downregulate OPG secretion in vitro.
Stroke Care Delivery in Institutions Participating in the Registry of the Canadian Stroke Network
Authors: Kapral Moira K. , Laupacis Andreas , Phillips Stephen J. , Silver Frank L. , Hill Michael D. , Fang Jiming , Richards Janice , Tu Jack V.
Published: May 2004

Background and Purpose—

Guidelines and performance indicators have been established for acute stroke care. However, little is known about the process of stroke care delivery in Canada.

Methods—

The Registry of the Canadian Stroke Network (RCSN) captured detailed clinical data on patients with stroke and transient ischemic attack seen at 21 acute care institutions across Canada. Data from phase 1 of the RCSN (June 2001 to February 2002) were used to determine the use of evidence-based acute stroke care interventions in participating institutions.

Results—

Overall, 4439 patients were seen during the study time frame and 1701 (38%) consented to full data collection. Thirty-one percent received care on a stroke unit or from a mobile stroke team. Among patients with ischemic stroke, 7% received thrombolysis, 80% underwent carotid imaging, 89% received antithrombotic agents, and 54% of those with atrial fibrillation received warfarin. There were significant intersite variations in the delivery of all of these interventions except for the use of antithrombotic agents, and these persisted after adjustment for age, sex, stroke type, and other comorbid conditions.

Conclusions—

Patients in institutions participating in the RCSN received high-quality stroke care based on a number of performance measures. However, gaps exist in the provision of other elements of stroke care, particularly organized inpatient stroke care and warfarin for atrial fibrillation. Future research should explore explanations for these findings and focus on solutions to deficiencies in care.
Sodium Intake and Risk of Death From Stroke in Japanese Men and Women
Authors: Nagata Chisato , Takatsuka Naoyoshi , Shimizu Natsuki , Shimizu Hiroyuki
Published: May 2004

Background and Purpose—

Despite the evidence for a positive association of dietary salt and blood pressure, the few prospective studies that have assessed the association between dietary salt and stroke have reported inconsistent results. The purpose of this study was to examine the relation between sodium intake and death from stroke in a population-based cohort of Japanese men and women.

Methods—

In 1992, usual diet including sodium intake was determined in 13 355 men and 15 724 women in Takayama City, Gifu, with the use of a validated food frequency questionnaire.

Results—

There were 269 stroke deaths (137 men and 132 women) between baseline and 1999. In men, the highest compared with the lowest tertile of sodium intake was significantly positively associated with death from total stroke after controlling for covariates (hazard ratio [HR]), 2.33; 95% CI, 1.23 to 4.45). Significantly positive associations were also observed between sodium intake and death from ischemic stroke (HR, 3.22; 95% CI, 1.22 to 8.53) as well as death from intracerebral hemorrhage (HR, 3.85; 95% CI, 1.16 to 12.7). A positive association between sodium intake and death from stroke in women was suggested, although the associations for total stroke and ischemic stroke were of borderline significance (HR, 1.70; 95% CI, 0.96 to 3.02 and HR, 2.10; 95% CI, 0.96 to 4.62, respectively).

Conclusions—

These prospective data support the hypothesis that dietary salt increases the risk of death from stroke.
Validation of the Aphasic Depression Rating Scale
Authors: Benaim Charles , Cailly Bruno , Perennou Dominic , Pelissier Jacques
Published: May 2004

Background and Purpose—

The Aphasic Depression Rating Scale (ADRS) was developed to detect and measure depression in aphasic patients during the subacute stage of stroke.

Methods—

Six experts selected an initial sampling of behavioral items from existing depression rating scales. Stroke patients (aphasic and nonaphasic) were assessed with these items by the rehabilitation staff, with the Hamilton Depression Rating Scale (HDRS) for nonaphasic patients only, by a psychiatrist, and by the rehabilitation staff with Visual Analog Scales (VAS). A second item selection was conducted after a regression algorithm was run including VAS as independent variables (criterion validity) and after their factorial structure was analyzed with a principal component analysis (factorial validity). The construct validity was evaluated with respect to the other depression assessments. A threshold for the diagnosis of depression was computed with respect to the psychiatrist’s diagnosis. Interrater and test-retest reliability were assessed in 2 additional groups of aphasic patients.

Results—

Eighty patients participated in the study (59 aphasic). Fifteen behavioral items from existing depression rating scales were selected, and 9 were retained after the validation process. ADRS correlated highly with VAS and HDRS (
r
=0.60 to 0.78,
P
=10
−4
to 10
−6
). With respect to the psychiatrist’s diagnosis, the sensitivity and specificity of ADRS were 0.83 and 0.71, respectively, when the threshold was set at 9/32. Its factorial structure was comparable to HDRS structure. Interrater and test-retest reliability were high (average κ coefficient of the 9 items=0.69).

Conclusions—

ADRS is a valid, reliable, sensitive, and specific tool for the evaluation of depression in aphasic patients during the stroke subacute phase.
Nerve Injury about the Shoulder in Athletes, Part 2
Authors: Safran Marc R.
Published: May 2004

Nerve injuries about the shoulder in athletes are being recognized with increasing frequency. Prompt and correct diagnosis of these injuries is important to treat the patient and to understand the potential complications and natural history, so as to counsel our athletes appropriately. This 2-part article is a review and an overview of the current state of knowledge regarding some of the more common nerve injuries seen about the shoulder in athletes, including long thoracic nerve, spinal accessory nerve, burners and stingers, and thoracic outlet syndrome. Each of these clinical entities will be discussed independently, reviewing the anatomy, mechanism of injury, patient presentation (history and examination), the role of additional diagnostic studies, differential diagnosis, and management.
Catastrophic Cervical Spine Injuries in the Collision Sport Athlete, Part 1
Authors: Banerjee Rahul , Palumbo Mark A. , Fadale Paul D.
Published: May 2004

Catastrophic cervical spine injuries can lead to devastating consequences for the collision athlete. Improved understanding of these injuries can facilitate early diagnosis and effective on-field management. This article is the first of a 2-part series. The first part reviews the current concepts regarding the epidemiology, functional anatomy, and diagnostic considerations relevant to cervical spine trauma in collision sports. In the second part, to be published later, the principles of emergency care of the cervical spine-injured athlete are reviewed. This article provides a rational approach to the early recognition of the different clinical syndromes associated with catastrophic cervical spine injury. Rapid on-field diagnosis can help to optimize the outcomes of these catastrophic injuries.
Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer
Authors: Yu Phyllis W. , Tabuchi Ruby S. , Kato Roberta M. , Astrakhan Alexander , Humblet-Baron Stephanie , Kipp Kevin , Chae Keun , Ellmeier Wilfried , Witte Owen N. , Rawlings David J.
Published: May 2004

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacterial infections. Using Btk- and Tec-deficient mice (BtkTec–/–) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)–treated BtkTec–/– mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec–/– recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, recovery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG3 levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA.
Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation
Authors: Srivastava Alok , Poonkuzhali Balasubramanian , Shaji Ramachandran V. , George Biju , Mathews Vikram , Chandy Mammen , Krishnamoorthy Rajagopal
Published: May 2004

Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with β-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P = .001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 ± 0.06 vs 0.33 ± 0.071 L/h/kg, Student t test P value = .000 01; and 508 ± 125 vs 656 ± 255 ng/mL, t test P value = .001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.
Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis
Authors: Zaza Gianluigi , Yang Wenjian , Kager Leo , Cheok Meyling , Downing James , Pui Ching-Hon , Cheng Cheng , Relling Mary V. , Evans William E.
Published: May 2004

Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 ± 57 versus 1001 ± 31 or versus 1315 ± 76 fmol/nmol/h, P < .0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1–positive and TEL-AML1–negative ALL (P < .001, false discovery rate [FDR] = 5%). The pattern of expression of these 16 genes discriminated TEL-AML1–positive ALL with a true accuracy of 84% in an independent test set (n = 17, confidence interval 70% to 94%, P < .001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism.
Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia
Authors: Harris Michael N. , Ozpolat Bulent , Abdi Fadi , Gu Sheng , Legler Allison , Mawuenyega Kwasi G. , Tirado-Gomez Maribel , Lopez-Berestein Gabriel , Chen Xian
Published: May 2004

All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor–α (PML-RARα) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid–coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant down-regulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-δ, eEF1γ, 14-3-3ϵ, and 14-3-3ζ/δ (P < .05). The translational inhibitor DAP5/p97/NAT1 (death-associated protein 5) and PML isoform-1 were found to be up-regulated (P < .05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P < .05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these proteomic findings were validated by Western blot analysis. Our data in comparison with previous cDNA microarray studies and our reverse transcription–polymerase chain reaction (RT-PCR) experiments demonstrate that broad networks of posttranscriptional suppressive pathways are activated during ATRA-induced growth inhibition processes in APL.
Identification of a novel mutation (C321X) in HJV
Authors: Huang Franklin W. , Rubio-Aliaga Isabel , Kushner James P. , Andrews Nancy C. , Fleming Mark D.
Published: May 2004

Juvenile hemochromatosis is a rare autosomal recessive disorder characterized by the early onset of severe iron overload. We report the occurrence of compound heterozygous mutations in hemojuvelin (HJV), including a termination codon, in a patient with juvenile hemochromatosis but no family history of iron disorders. (Blood. 2004;104:2176-2177)