bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis
Authors: Vamvakopoulos Joannis E. , Petrov Lyubomir , Aavik Silja , Lehti Satu , Aavik Einari , Häyry Pekka
Published: January 2006

Background: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. Methods: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. Results: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5–1.5 mg/kg/day) or imatinib (2– 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. Conclusions: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.
Continuous Endothelial Cell Activation Increases Angiogenesis: Evidence for the Direct Role of Endothelium Linking Angiogenesis and Inflammation
Authors: Rajashekhar Gangaraju , Willuweit Antje , Patterson Carolyn E. , Sun Peichuan , Hilbig Andreas , Breier Georg , Helisch Armin , Clauss Matthias
Published: January 2006

There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-α (TNF-α), we have established models of stable TNF-α expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF-α in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF-α antibodies and the inability of conditioned media from stable TNF-α-expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF-α-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-α can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.
Human Placental Lactogen Decreases Regional Blood Flow in Anesthetized Pigs
Authors: Grossini E. , Molinari C. , Battaglia A. , Mary D.A.S.G. , Ribichini F. , Surico N. , Vacca G.
Published: January 2006

In 22 pigs anesthetized with sodium pentobarbitone, changes in blood flow caused by infusion of human placental lactogen into the left renal, external iliac, and anterior descending coronary arteries were assessed using electromagnetic flowmeters. In 17 pigs, infusion of human placental lactogen whilst keeping the heart rate and arterial pressure constant decreased coronary, renal and iliac flow. In 5 additional pigs, increasing the dose of human placental lactogen produced a dose-related decrease in regional blood flow. The mechanisms of the above response were studied in 15 of the 17 pigs by repeating the experiment of infusion. The human placental lactogen-induced decrease in regional blood flow was not affected by blockade of cholinergic receptors (5 pigs) or of α-adrenergic receptors (5 pigs), but it was abolished by blockade of β2-adrenergic receptors (5 pigs). The present study showed that intra-arterial infusion of human placental lactogen primarily decreased coronary, renal and iliac blood flow. The mechanism of this response was shown to be due to the inhibition of a vasodilatory β2-adrenergic receptor-mediated effect.
The Transcripts of SFRP1,CEP63 and EIF4G2 Genes Are Frequently Downregulated in Transitional Cell Carcinomas of the Bladder
Authors: Buim Marcilei E. , Soares Fernando A. , Sarkis Álvaro S. , Nagai Maria Aparecida
Published: January 2006

Objective: The aim of the present study was to identify differentially expressed genes that might be associated with the phenotype of superficial and invasive bladder cancer. Methods: Differential display reverse transcriptase PCR (DDRT-PCR) was used to compare the expression pattern between normal bladder tissue and 4 groups of transitional cell carcinomas of the bladder regarding clinical stage and grade. Results: We were able to identify 72 different transcripts, of which 57 (79%) showed homology to known genes, 12 (17%) to hypothetical proteins and 3 (4%) to human expressed sequence tags. Among the differentially expressed genes, SFRP1,CEP63 and EIF4G2 were further validated by quantitative RT-PCR in a series of 50 transitional cell carcinomas. Overall, the transcripts of these three genes were shown to be downregulated in the bladder tumors analyzed. In accordance with the DDRT-PCR results, the SFRP1 transcripts were shown to be downregulated in 90% (45/50) of the bladder tumors as compared with the normal bladder tissue. Although EIF4G2 and CEP63 transcripts exhibited three different expression patterns, downregulation was found in about 50% of the cases analyzed. In addition, downregulation of both CEP63 and EIF4G2 gene transcription was associated with invasive tumors. Conclusion: The use of DDRT-PCR analysis to compare expression patterns among different subgroups of bladder tumors allowed us to identify a significant number of genes implicated in different cellular pathways that, when up- or downregulated, might play a role in the tumorigenic process of the bladder.
Sequential Treatment with Exemestane and Non-Steroidal Aromatase Inhibitors in Advanced Breast Cancer
Authors: Bertelli Gianfilippo , Garrone Ornella , Merlano Marco , Occelli Marcella , Bertolotti Laura , Castiglione Federico , Pepi Fiorella , Fusco Ornella , Del Mastro Lucia , Leonard Robert C.F.
Published: January 2006

Background: The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression. Patients and Methods: Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for ≧24 weeks). Results: Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9–82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6–78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2–63.7%) with a median TTP of 5.1 months. Conclusions: Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.
Prognostic Relevance of Basal Cytokeratin Expression in Operable Breast Cancer
Authors: Potemski Piotr , Kusinska Renata , Watala Cezary , Pluciennik Elzbieta , Bednarek Andrzej K. , Kordek Radzislaw
Published: January 2006

Objective: We investigated whether basal cytokeratin (CK5/6 or CK17) expression had an impact on survival in patients with operable breast cancer. Methods: Expression of CK5/6 or CK17 was analyzed by immunohistochemistry in 195 women with breast cancer. Results: In total, 72 (37%) tumor samples were regarded as being positive for CK5/6 or CK17. The basal-like phenotype as defined by basal cytokeratin expression, lack of estrogen receptor (ER) and absence of HER2 overexpression was found in 48 (25%) cases. Positive staining for CK5/6 or CK17 was associated with worse prognosis when compared with patients negative for basal cytokeratins in all cases (5-year cancer-specific survival rate 59.4 vs. 77.5%, p = 0.0273) and in the node-negative group (70.5 vs. 90.8%, p = 0.0208) but not in the node-positive group (43.9 vs. 65.4%, p = 0.1182). To determine the real prognostic value of basal cytokeratins, survival in a group of ER-negative patients was analyzed depending on CK5/6 or CK 17 expression. No influence on survival was observed. The outcome of patients whose cancers were positive for cyclin E regardless of ER status was not changed by CK5/6 or CK17 expression. In multivariate analysis, independent prognostic factors affecting survival in the whole group included: nodal involvement, HER2 status and cyclin E expression. Neither ER status nor basal cytokeratin expression retained statistical significance. Conclusion: We demonstrated that the poor prognosis associated with the basal-like phenotype of breast cancer was determined by ER absence and cyclin E expression and not by CK5/6 or CK17 expression.
Leukocyte Transglutaminase 2 Expression Limits Atherosclerotic Lesion Size
Authors: Boisvert W.A. , Rose D.M. , Boullier A. , Quehenberger O. , Sydlaske A. , Johnson K.A , Curtiss L.K. , Terkeltaub R.
Published: January 2006

Objective—

Transglutaminase 2 (TG2), a broadly expressed regulator of protein cross-linking, wound healing, and tissue fibrosis, mediates apoptotic cell ingestion and transforming growth factor-β release by macrophages and thereby can limit leukocyte-mediated inflammation. In atherosclerosis, oxidative stress and accumulation of unesterified cholesterol stimulate atherosclerotic lesion cell apoptosis. Cell death in advanced atherosclerotic lesions promotes lesion expansion and vulnerable plaques prone to rupture. Hence, we tested the hypothesis that leukocyte TG2 expression limits atherosclerosis.

Methods and Results—

We transplanted TG2−/− or TG2+/+ bone marrow into lethally irradiated low-density lipoprotein receptor (LDLR)−/− mice and evaluated diet-induced atherosclerosis after 16 weeks. We subsequently studied cultured TG2−/− and congenic TG2+/+ mouse macrophages for selected atherogenesis regulatory functions. Atherosclerotic aortic valve lesions in LDLR−/− recipients of TG2−/− bone marrow were larger and more subintimal lesional macrophage penetration than in TG2+/+ marrow recipients. Lesion intimal TG2 expression appeared robust in TG2+/+ but not TG2−/− marrow recipients. Cultured TG2−/− macrophages demonstrated diminished phagocytosis of apoptotic leukocytes, unaltered endocytosis, and degradation of oxidized LDL but decreased retinoic acid induction of the reverse cholesterol transport and apoptotic cell uptake mediator ABCA1.

Conclusions—

We conclude that macrophage TG2 expression promotes both apoptotic cell clearance and ABCA1 expression in vitro and limits atherosclerotic lesion size in vivo.
Tetrapeptide AcSDKP Induces Postischemic Neovascularization Through Monocyte Chemoattractant Protein-1 Signaling
Authors: Waeckel Ludovic , Bignon Jérôme , Liu Jian-Miao , Markovits Delphine , Ebrahimian Téni G. , Vilar José , Mees Barend , Blanc-Brude Olivier , Barateau Véronique , Le ricousse-Roussanne Sophie , Duriez Micheline , Tobelem Gérard , Wdzieczak-Bakala Joanna , Lévy Bernard I , Silvestre Jean-Sébastien
Published: January 2006

Background—We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia.

Methods and Results—Hindlimb ischemia was induced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (0.12 mg/kg per day) or high (1.2 mg/kg per day) doses of AcSDKP, for 7 or 21 days. Angiography scores, arteriole density, capillary number, and foot perfusion were increased at day 21 in the high-dose AcSDKP-treated mice (by 1.9-, 1.8-, 1.3-, and 1.6-fold, respectively) compared with control animals (P<0.05,P<0.01,P<0.01, respectively). AcSDKP treatment for 24 hours upregulated the monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels by 1.5-fold in cultured endothelial cells (P<0.01). In the ischemic hindlimb model, administration of AcSDKP also enhanced MCP-1 mRNA levels by 90-fold in ischemic leg (P<0.001) and MCP-1 plasma levels by 3-fold (P<0.001 versus untreated ischemic control mice). MCP-1 levels upregulation were associated with a 2.3-fold increase in the number of Mac3-positive cells in ischemic area of AcSDKP-treated mice (P<0.001 versus untreated animals). Interestingly, AcSDKP-induced monocyte/macrophage infiltration and postischemic neovascularization was fully blunted in MCP-1-deficient animals.

Conclusion—AcSDKP stimulates postischemic neovascularization through activation of a proinflammatory MCP-1-related pathway.
Effect of Rosiglitazone Treatment on Plaque Inflammation and Collagen Content in Nondiabetic Patients
Authors: Meisner Franz , Walcher Daniel , Gizard Florence , Kapfer Xaver , Huber Roman , Noak Anja , Sunder-Plassmann Ludger , Bach Helga , Haug Cornelia , Bachem Max , Stojakovic Tatjana , März Winfried , Hombach Vinzenz , Koenig Wolfgang , Staels Bart , Marx Nikolaus
Published: January 2006

Background—

Therapeutic strategies to stabilize advanced arteriosclerotic lesions may prevent plaque rupture and reduce the incidence of acute coronary syndromes. Thiazolidinediones (TZDs), like rosiglitazone, are oral antidiabetic drugs with additional antiinflammatory and potential antiatherogenic properties. In a randomized, placebo-controlled, single-blind trial, we examined the effect of 4 weeks of rosiglitazone therapy on histomorphological characteristics of plaque stability in artery specimen of nondiabetic patients scheduled for elective carotid endarterectomy.

Methods and Results—

A total of 24 nondiabetic patients with symptomatic carotid artery stenosis were randomly assigned to rosiglitazone (4 mg BID) or placebo in addition to standard therapy. In this population of nondiabetic patients, rosiglitazone treatment did not significantly change fasting blood glucose, fasting insulin, or lipid parameters. In contrast, rosiglitazone significantly reduced CD4-lymphocyte content as well as macrophage HLA-DR expression in the shoulder region, reflecting less inflammatory activation of these cells by lymphocyte interferon-γ. Moreover, rosiglitazone significantly increased plaque collagen content (7.7±1.6% versus 3.7±0.7% of plaque area;
P
=0.036) compared with placebo, suggesting that TZD treatment may stabilize arteriosclerotic lesions. In addition, rosiglitazone reduced serum levels of 2 inflammatory arteriosclerosis markers: C-reactive protein and serum amyloid A.

Conclusions—

Four weeks of treatment with rosiglitazone significantly reduces vascular inflammation in nondiabetic patients, leading to a more stable type of arteriosclerotic lesion.
Lipoprotein Lipase Bound to Apolipoprotein B Lipoproteins Accelerates Clearance of Postprandial Lipoproteins in Humans
Authors: Zheng Chunyu , Murdoch Susan J. , Brunzell John D. , Sacks Frank M.
Published: January 2006

Objectives—

Experiments in cells and animal models show that lipoprotein lipase (LpL) bound to apolipoprotein (apo)B lipoproteins enhances their uptake by receptor mediated pathways. It is unknown whether this pathway is important in humans.

Methods and Results—

ApoB lipoproteins with LpL were isolated from normal subjects after oral fat loading by immunoaffinity chromatography and were further separated into apoB100 and apoB48 lipoproteins. Postprandially, apoB lipoproteins with LpL had significantly greater increases (4- to 10-fold) and faster rates of clearance (5- to 8-fold) percentage-wise than those without LpL. apoB lipoproteins with LpL had enhanced clearance regardless of whether they also contained apoE. LpL was particularly important for the clearance of apoB48 lipoproteins, of which 25% (range, 11% to 31%) could be removed from circulation together with LpL during the postprandial state. apoB lipoproteins with LpL were larger in size and were enriched in triglyceride, cholesterol, and apoE compared with those without LpL. However, neither size nor apoE content explained the faster clearance rates of LpL-containing lipoproteins.

Conclusion—

Plasma LpL may act like an apolipoprotein to enhance the clearance of apoB lipoproteins in humans, a mechanism particularly important for intestinal lipoproteins in the postprandial state.
Differential Healing Activities of CD34
+
and CD14
+
Endothelial Cell Progenitors
Authors: Awad Ola , Dedkov Eduard I. , Jiao Chunhua , Bloomer Steven , Tomanek Robert J. , Schatteman Gina C.
Published: January 2006

Objective—

Peripheral blood contains primitive (stem cell-like) and monocytic-like endothelial cell progenitors. Diabetes apparently converts these primitive progenitors, from a pro-angiogenic to anti-angiogenic phenotype. Monocytic progenitors seem to be less affected by diabetes, but potential pro-angiogenic activities of freshly isolated monocytic progenitors remain unexplored. We compared the ability of primitive and monocytic endothelial cell progenitors to stimulate vascular growth and healing in diabetes and investigated potential molecular mechanisms through which the cells mediate their in vivo effects.

Methods and Results—

Human CD34
+
primitive progenitors and CD14
+
monocytic progenitors were injected locally into the ischemic limbs of diabetic mice. CD14
+
cell therapy improved healing and vessel growth, although not as rapidly or effectively as CD34
+
cell treatment. Western blot analysis revealed that cell therapy modulated expression of molecules in the VEGF, MCP-1, and angiopoietin pathways.

Conclusions—

Injection of freshly isolated circulating CD14
+
cells improves healing and vascular growth indicating their potential for use in acute clinical settings. Importantly, CD14
+
cells could provide a therapeutic option for people with diabetes, the function of whose CD34
+
cells may be compromised. At least some progenitor-induced healing probably is mediated through increased sensitivity to VEGF and increases in MCP-1, and possibly modulation of angiopoietins.
Relative Contributions of ABCA1 and SR-BI to Cholesterol Efflux to Serum From Fibroblasts and Macrophages
Authors: Duong MyNgan , Collins Heidi L. , Jin Weijun , Zanotti Ilaria , Favari Elda , Rothblat George H.
Published: January 2006

Objectives—

Cholesterol efflux is achieved by several mechanisms. This study examines contributions of these pathways to efflux to human serum.

Methods and Results—

Human fibroblasts were stably transfected with SR-BI while ABCA1 was upregulated. Quantitation of cholesterol efflux to human serum demonstrated that there was efflux from cells without either protein. Expression of ABCA1 produced a small increase in efflux, whereas SR-BI expression had a dramatic impact. To quantitate ABCA1 and SR-BI contribution, fibroblasts were pretreated with Probucol and BLT-1 to, respectively, inhibit these efflux proteins. Exposing SR-BI–expressing fibroblasts to BLT-1 inhibited efflux by 67%. Probucol pretreatment of ABCA1-expressing fibroblasts reduced efflux to serum by 26%. A large fraction of total efflux was uninhibited. For both J774 and mouse peritoneal macrophages, contributions of either ABCA1 or SR-BI to efflux to serum were low, with background/uninhibited efflux contributing from 70% to 90% of total efflux.

Conclusions—

We have shown that ABCA1-mediated efflux to serum responds to the pool of lipid-free/poor apolipoproteins, whereas phospholipid-containing particles mediate SR-BI efflux. Although SR-BI and ABCA1 contribute to efflux from fibroblasts and cholesterol-enriched macrophages, a large proportion of the total efflux to human serum is mediated by a mechanism that is neither SR-BI nor ABCA1.
Apolipoproteins C-III and A-V as Predictors of Very-Low-Density Lipoprotein Triglyceride and Apolipoprotein B-100 Kinetics
Authors: Chan Dick C. , Watts Gerald F. , Nguyen Minh N. , Barrett P. Hugh R.
Published: January 2006

Objective—

We investigated the associations between plasma very-low-density lipoprotein (VLDL)–apolipoprotein (apo)C-III and apoA-V concentrations and the kinetics of VLDL–apoB-100 and VLDL triglycerides in 15 men. We also explored the relationship between these parameters of VLDL metabolism and VLDL–apoC-III kinetics.

Methods and Results—

ApoC-III, apoB, and triglyceride kinetics in VLDL were determined using stable isotopes and multicompartmental modeling to estimate production rate (PR) and fractional catabolic rate (FCR). Plasma VLDL–apoC-III concentration was significantly and inversely associated with the FCRs of VLDL triglycerides (
r
=−0.610) and VLDL–apoB (
r
=−0.791), and positively correlated with the PR of VLDL–apoC-III (
r
=0.842). However, apoA-V concentration was not significantly associated with any of the kinetic variables. There was a significant association (
P
<0.01) between the PRs of VLDL triglycerides and VLDL–apoB (
r
=0.641), and between the FCRs of VLDL triglycerides and VLDL–apoB (
r
=0.737). In multiple regression analysis, plasma VLDL–apoC-III concentration was a significant predictor of VLDL triglyceride FCR (β-coefficient=−0.575) and VLDL–apoB FCR (β-coefficient=−0.839).

Conclusions—

Our findings suggest that increased VLDL–apoC-III concentrations resulting from an overproduction of VLDL–apoC-III are strongly associated with the delayed catabolism of triglycerides and apoB in VLDL. We also demonstrated that the kinetics of VLDL triglycerides and apoB are closely coupled. Our data do not support a role for plasma apoA-V in regulating VLDL kinetics.
Oxidative Stress and Vascular Disease
Authors: Heistad Donald D.
Published: January 2006

There is compelling evidence that oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases. In atherosclerosis, hypertension, stroke, diabetes, and heart failure, expression of superoxide is increased in blood vessels, and endothelial vasomotor function is impaired, presumably caused in large part by inactivation of nitric oxide by superoxide. Endothelial dysfunction is predictive of cardiovascular risk, and probably plays a key role in the pathophysiology of atherosclerosis and its complications. In preliminary studies in hypercholesterolemic mice and in older humans, we have found high levels of superoxide in the aortic valve, as well as aorta. We speculate that superoxide, in addition to playing a key role in atherogenesis, may play a key role in signaling that leads to calcific aortic valvular stenosis. Antioxidant enzymes, especially the three isoforms of superoxide dismutase (SOD), modulate basal levels of superoxide and protect against vasomotor dysfunction. A common gene variant of extracellular SOD (ecSOD) is associated with increased risk of ischemic heart disease. We have made recombinant adenoviruses to examine cardiovascular effects of ecSOD and its heparin-binding domain. This approach might be used to study the almost 500 other proteins with a heparin-binding domain. Finally, several key unanswered questions in relation to oxidative stress and atherosclerosis are raised, and proposed as fruitful areas of research.
Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques
Authors: Rodgers Kenneth J. , Watkins Deborah J. , Miller Alastair L. , Chan Peter Y. , Karanam Sharada , Brissette William H. , Long Clive J. , Jackson Christopher L.
Published: January 2006

Objective—

Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization.

Methods and Results—

Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (
P
=0.026) and were 46% smaller (
P
=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (
P
=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (
P
=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques.

Conclusion—

These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.
Direct Interaction of the Cell Division Cycle 37 Homolog Inhibits Endothelial Nitric Oxide Synthase Activity
Authors: Harris M. Brennan , Bartoli Manuela , Sood Sarika G. , Matts Robert L. , Venema Richard C.
Published: January 2006

Endothelial NO synthase (eNOS) via the production of NO in the endothelium plays a key role in cardiovascular biology and is tightly regulated by co- and posttranslational mechanisms, phosphorylation, and protein–protein interactions. The cell division cycle 37 homolog (Cdc37) is a key heat shock protein 90 (Hsp90) cochaperone for protein kinase clients, and Akt/Hsp90 interaction is dependent on Cdc37. Because both Hsp90 and Akt are key eNOS regulatory proteins, we hypothesized that Cdc37 interacts with eNOS as part of the regulatory complex. In the present study, we demonstrate by coimmunoprecipitation and affinity purification in bovine aortic endothelial cells (BAECs) that Cdc37 is complexed with eNOS, Hsp90, and Akt. In addition, cell fractionation data indicate that Cdc37 is found in caveolae with eNOS. Further analysis by in vitro binding assays reveals a direct interaction between purified Cdc37 and eNOS. Incubation of purified Cdc37 with purified wild-type eNOS decreases eNOS activity in vitro. Overexpression of wild-type Cdc37 in BAECs inhibits eNOS activity and NO release, whereas overexpression of S13A-Cdc37 mutant in BAECs increases eNOS activity and NO release. Taken together, these data suggest that Cdc37 has a direct regulatory interaction with eNOS and may play an important role in mediating the eNOS protein complex formation as well as subsequent eNOS phosphorylation and activation.
Are There Patients With Acute Ischemic Stroke and Atrial Fibrillation That Benefit From Low Molecular Weight Heparin?
Authors: O’Donnell Martin J. , Berge Eivind , Sandset Per Morten
Published: January 2006

Background and Purpose—

Treatment doses of heparins are not recommended for acute ischemic stroke. Despite this, their use in this setting is widespread. We investigated whether subgroups of patients with acute ischemic stroke and atrial fibrillation, identified by clinical, hemostatic (
d-
dimer, prothombin fragments
1+2
[F
1+2
], soluble fibrin monomer), or inflammatory (C-reactive protein [CRP]) variables might have a differential response to low molecular weight heparin (LMWH) over aspirin. In addition, we sought to identify factors associated with a poor clinical outcome at 3 months.

Methods—

We conducted a post hoc subgroup analysis of a randomized, placebo-controlled, double-blind trial (Heparin in Acute Embolic Stroke Trial) designed to test the hypothesis that treatment doses of LMWH (dalteparin; 100 IU/kg BID) would be superior to aspirin (160 mg per day) in patients with acute ischemic stroke and atrial fibrillation. For the current analysis, 431 participants were included. The primary outcome measure was a poor outcome at 3 months, defined as death or dependency in activities of daily living. Using regression analysis, we determined whether any of the chosen variables were associated with a differential response to dalteparin (treatment interaction) or with poor outcome.

Results—

In the multivariable logistic regression model, none of the clinical, hemostatic, or inflammatory variables were associated with a significant treatment interaction. Stroke severity (odds ratio [OR], 1.09 [95% CI, 1.07 to 1.12]), increasing age (OR, 1.09 [CI, 1.05 to 1.14]), CRP level (OR, 1.32 [CI, 1.04 to 1.66]), and F
1+2
level (OR, 1.77 [CI, 1.07 to 2.91]) were independently associated with a poor outcome at 3 months.

Conclusions—

Our study does not support the use of treatment doses of LMWH in any of the studied subgroups of patients with acute ischemic stroke and atrial fibrillation. Age, stroke severity, CRP, and F
1+2
were predictive of poor outcome at 3 months.
A Randomized Controlled Trial of Supervised Versus Unsupervised Exercise Programs for Ambulatory Stroke Survivors
Authors: Olney Sandra J. , Nymark Jennifer , Brouwer Brenda , Culham Elsie , Day Andrew , Heard Joan , Henderson Margaret , Parvataneni Krishna
Published: January 2006

Background and Purpose—

Little is known about the relative efficacy of supervised versus unsupervised community exercise programs for stroke survivors. This study compared the effectiveness of a 10-week supervised strengthening and conditioning program (supervised) with a 1-week supervised instruction program followed by a 9-week unsupervised home program (unsupervised) and evaluated retention of changes at 6 months and 1 year after program completion.

Methods—

Seventy-two subjects retained at baseline (27 women, 45 men; mean±SD age, 64.6±11.8 years) were randomly allocated to receive the supervised or unsupervised program. The primary outcome was walking speed over 6 minutes, and secondary outcome measures were Human Activity Profile, Medical Outcome Study 36-Item Short-Form survey (SF-36), Physiological Cost Index, and lower extremity muscle strength.

Results—

The 6-minute walking speed increased significantly in both groups and remained significantly improved by 1 year. The Human Activity Profile demonstrated an increasing trend only in the supervised group that was significant by 1 year. The SF-36 Physical Component summary score increased significantly in the supervised group and remained improved by 1 year; the unsupervised group showed significant improvement at 1 year. Women made greater gains in supervised programs, but men made greater gains in unsupervised programs.

Conclusions—

Supervised exercise programs and unsupervised programs after initial supervised instruction were both associated with physical benefits that were retained for 1 year, although supervised programs showed trends to greater improvements in self-reported gains. Gender differences require further research.
Relationship Between Cerebral Circulatory Reserve and Oxygen Extraction Fraction in Patients With Major Cerebral Artery Occlusive Disease
Authors: Yata Kenichiro , Suzuki Akifumi , Hatazawa Jun , Shimosegawa Eku , Nagata Ken , Sato Mika , Moroi Junta
Published: January 2006

Background and Purpose—

The present study examined the relationship between circulatory and metabolic reserve in patients with hemodynamic impairment.

Methods—

Positron emission tomography was used to investigate 40 patients with major cerebral artery occlusive disease. The ratio of cerebral blood volume to cerebral blood flow (CBV/CBF) and vasoreactivity in response to hypercapnia (%CBF
hypercapnia
) and acetazolamide (ACZ) stress (%CBF
ACZ
) were measured to evaluate circulatory reserve. Oxygen extraction fraction (OEF) was measured to evaluate metabolic reserve. To detect relationships between circulation reserve and OEF, cerebral hemispheres were grouped into 5 or 6 stepwise groups based on reduction of circulation reserve.

Results—

OEF was significantly elevated in hemispheres with CBV/CBF ≥0.11 minutes and in hemispheres with %CBF
hypercapnia
<0%. OEF was significantly increased according to %CBF
ACZ
in hemispheres with %CBF
ACZ
<15% and plateaued at levels below −15%.

Conclusions—

Metabolic reserve consumption began at CBV/CBF ≥0.11 minutes, CBF
hypercapnia
<0%, and CBF
ACZ
<15%.
Access to Higher Education
Authors: Briscoe Felecia M. , De Oliver Miguel
Published: January 2006

This case study researches the degree to which the location and services offered by a multicampus university, geographically situated consistent with the commercial principles of a large mass-market enterprise, facilitate access for educationally underserved groups. First, the necessity of democratizing educational access to an underprivileged population is contrasted against real estate market forces that regularly influence the positioning of such large municipal infrastructure to the detriment of the target population. Based on the site selected for the main campus and the degree of educational services offered by the later establishment of a branch campus, the costs of access for both privileged and underprivileged groups are compared, illustrating the continuing institutional marginalization of the underprivileged in the face of repeated attempts to equitably serve this population.
Choosing Segregation or Integration?
Authors: Karsten Sjoerd , Felix Charles , Ledoux Guuske , Meijnen Wim , Roeleveld Jaap , Van Schooten Erik
Published: January 2006

Across Europe, urban education systems are struggling with the process of integration of immigrants in schools. The process of inclusion and exclusion in European cities shows many similarities with earlier experiences in U.S. cities. This article explores the most important aspects of this new urban phenomenon and its impact on urban school systems. It clearly shows that ethnic segregation in elementary and secondary schools is widespread in Dutch cities. This ethnic segregation is caused by a combination of residential segregation and parental choice. The article also deals with recent Dutch studies on the effects of segregation. Finally, it treats the question of how schools and authorities, in a long-standing tradition of parental choice, are dealing with this segregation. Given the debate of choice in the United States, the Dutch case offers an ideal opportunity for empirically testing some assumptions in the discussion concerning the relationship between choice and segregation.
Professional Development for Urban Principals in Underperforming Schools
Authors: Houle Judith C.
Published: January 2006

Principals in America’s lowest performing urban schools face many challenges, including public scrutiny as a consequence of being identified as such by state and federal legislation. These special circumstances have implications for the professional development of the leaders of these schools. This article chronicles the work of the Connecticut State Department of Education, local districts, faculty from a private university, and the principals of Connecticut’s 28 priority schools as they created coherence from state-mandated and district-mandated programs intended to bring about school improvement. A yearlong Urban Principals’ Academy (UPA) was devoted to addressing the instructional leadership, capacity building, and personal renewal needs of these principals. Details regarding the content of the UPA are presented with data gathered from the sessions. The article concludes with lessons learned regarding professional development for urban principals of underperforming schools in context of the No Child Left Behind Act of 2001.
The Role of Administrator Characteristics on Perceptions of Innovativeness among Public School Administrators
Authors: Hite Julie M. , Williams Ellen J. , Hilton Sterling C. , Baugh Steven C.
Published: January 2006

Pressures for reform require greater innovativeness among public school administrators than in the past. Perceptions of innovativeness, which function as administrators’ reality and influence participation in innovation, are reflected in their informal network relationships. Using network methods and descriptive statistics, this article explores a public school administrator network, highlighting the relationship of administrator characteristics (personal demographics, position, experience) on three different types of perceptions of innovativeness: (a) being perceived by others as innovative, (b) perceiving others as innovative, and (c) mutually perceiving each other as innovative. Findings indicate demographics of age and experience were related to administrators being perceived as innovative, suggesting the value of increased visibility and administrative stability. No association was found between administrator characteristics and either perceiving others or having mutual perceptions of innovation suggesting a potential lack of bias in who perceives others as innovative or in establishing mutual perceptions of innovation.
Two Dimensions of Parent Participation in an Inner School District
Authors: Flaugher Paul
Published: January 2006

An exploratory study finds that parents who meet frequently with teachers about their child’s school are not also likely to report they attend evening school or parenting programs. The research is based upon a take-home survey administered to parents of elementary school children in an inner-city type school district that is close to a major metropolitan area but separated from it by a major river. Parents in the district have, in the aggregate, fewer years of education, and less income than those in the surrounding county, yet typically report frequent contacts with school personnel. The author concludes that these parents distinguish between meeting with school personnel for the welfare of their children and all other programs that do not have this pragmatic utility.
A Sociocultural Perspective on Acculturation
Authors: Monzó Lilia D. , Rueda Robert
Published: January 2006

This article conceptualizes acculturation from a sociocultural theoretical framework. Drawing on data from a 2-year ethnographic study of immigrant families, specifically their beliefs and practices related to discipline, the authors show that acculturation is a complex, dynamic, and interactive process that cannot be easily measured through typical acculturation scales. Indeed, this study shows that families actively choose and negotiate the U.S. practices they adopt and that children are active agents in this process.
Putting the Learning in Service Learning
Authors: Manley Theodoric , Buffa Avery S. , Dube Caleb , Reed Lauren
Published: January 2006

Results of the Black Metropolis Model (BMM) of service learning are analyzed and illustrated in this article to explain how to “put the learning in service learning.” There are many soup kitchens or nontransforming models of service learning where students are asked to serve needy populations but internalize and learn little about the service in their service learning. The results of a successful transforming model of service learning are presented to demonstrate how to put the learning in service learning for all students. The model integrates community institutions, residents, university faculty, staff, and undergraduate and high school students in hands-on service learning experiences that document uneven changes in the Black Metropolis of Chicago. The results reveal that the information and knowledge acquired by students transforms student knowledge as they internalize how uneven development in housing impacts community residents and their future in the original Black Metropolis of Chicago.
Educational Change Over Time? The Sustainability and Nonsustainability of Three Decades of Secondary School Change and Continuity
Authors: Hargreaves Andy , Goodson Ivor
Published: January 2006

Purpose: This article presents the conceptual framework, methodological design, and key research findings from a Spencer Foundation-funded project of long-term educational change over time.

Research Design: Based on more than 200 interviews, supplementary observations, and extensive archival data, it examines perceptions and experiences of educational change in eight high schools in the United States and Canada among teachers and administrators who worked in the schools in the 1970s, 1980s, and 1990s.

Findings: The article indicates that most mainstream educational change theory and practice in the field of educational administration neglects the political, historical, and longitudinal aspects of change to their detriment. Educational change, it finds, is shaped by the convergence of large-scale economic and demographic shifts that produce five change forces (waves of reform, changing student demographics, teacher generations, leadership succession, and school interrelations) that have defined three distinct periods of educational change during the past 30 years.

Conclusions: These forces and their convergence have ultimately reaffirmed the traditional identities and practices of conventional high schools and pulled innovative ones back toward the traditional norm in an age of standardization (though to a lesser extent where the schools are professional learning communities or have anactivist orientation). Conclusions are drawn in the form of a strategic theory of sustainable change.
Teacher Nostalgia and the Sustainability of Reform: The Generation and Degeneration of Teachers’ Missions, Memory, and Meaning
Authors: Goodson Ivor , Moore Shawn , Hargreaves Andy
Published: January 2006

Purpose : This article focuses on the sustainability of reform through the lens of teachers’ nostalgia—the major form of memory among a demographically dominant cohort of experienced older teachers. Unwanted change evokes senses of nostalgia for these lost missions that take two forms: social and political. As teachers age, their responses to change are influenced not only by processes of degeneration (loss of commitment, energy, enthusiasm, etc.) but also by the agendas of the generation—historically situated missions formed decades ago that teachers have carried with them throughout their careers.

Findings: Findings indicate that the effects of cumulative demographic and educational change and the resulting nostalgias have left teachers feeling resistant to mandated reform, insecure about their own professional capacity, disenchanted with their students, and pessimistic about their schools’ future. The results of this research have practical implications for policy makers, administrators, and classroom teachers.
School Leadership Succession and the Challenges of Change
Authors: Fink Dean , Brayman Carol
Published: January 2006

Background: Throughout the Western world, the fallout from the standards/standardization agenda has resulted in potential leaders questioning educational leadership as a career path. Moreover, the aging of the baby boom generation has created a shortage of qualified principals in many educational jurisdictions. Policy makers have responded to these twin pressures by initiating major programs to identify, recruit, and prepare future leaders. Leadership succession, whether planned or unplanned, has become an accelerated and cumulative process that is including people of increasing levels of inexperience. Succession is now a chronic process rather than an episodic crisis.

Purpose: This article argues that succession is not the key issue. What is crucial is the degree of autonomy that principals can exercise on behalf of their school community.

Findings: During the 30 years of the Change Over Time? study (described elsewhere), we have seen this autonomy eroded to the point that leaders have become managers of systems’ agendas rather than serving their schools and students. Staff members have become cynical about both leaders and leadership succession in the face of cumulative and accelerated succession and perceived changes in their principals’ roles and obligations—increasing the degree of resistance to change. Only when young people begin to see that leadership roles in schools once again make a difference to students learning not just test scores, then quality leaders will emerge and effective succession planning policies developed.
Changing Spaces: Urban School Interrelationships and the Impact of Standards-Based Reform
Authors: Baker Michael , Foote Martha
Published: January 2006

Background: This article is an historical sociospatial analysis of change during the past three decades within and between three high schools in a deindustrialized city in the northeastern United States. Sociospatial relations are the everyday spatial practices, perceptions, and representations that constitute social worlds. Interrelated with the continued economic decline and spatial segregation in many U.S. cities, state standards-based reform policies are reinforcing and furthering a more hierarchical, homogeneous, and fragmented educational space, increasing the marginalization of some urban schools, teachers, and students.

Purpose: This historical sociospatial analysis of urban secondary schools will describe the conjunction of demographic and policy changes contributing to patterns of uneven development that raise questions about the consequences and sustainability of the current state and federal standards-based reform initiatives.