bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Heterogeneity of Inflammatory Breast Cancer: A Hyperproliferative Phenotype
Authors: Nguyen Dang M. , Sam Kathy , Tsimelzon Anna , Li Xiaoxian , Wong Helen , Mohsin Syed , Clark Gary M. , Hilsenbeck Susan G. , Elledge Richard M. , Allred D. Craig , O'Connell Peter , Chang Jenny C.
Published: September 2006

Purpose: Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays.

Experimental Design: For gene expression analysis, IBC (n = 14) was clinically defined as rapid-onset cancer associated with erythema and skin changes, whereas non-IBC patients (n = 20) had stage III breast cancers, and cDNA analysis was carried out using the Affymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from >2,000 non-IBC.

Results: Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93% versus 11%; P < 0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P < 0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P = 0.002; progesterone receptor, 68% versus 42%; P = 0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different.

Conclusion: This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.
Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer
Authors: Kulp Samuel K. , Chen Chang-Shi , Wang Da-Sheng , Chen Ching-Yu , Chen Ching-Shih
Published: September 2006

Purpose: To assess the antitumor effects of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42, vis-à-vis suberoylanilide hydroxamic acid (SAHA) in in vitro and in vivo models of human prostate cancer.

Experimental Design: The in vitro effects of (S)-HDAC-42 and SAHA were evaluated in PC-3, DU-145, or LNCaP human prostate cancer cell lines. Cell viability, apoptosis, and indicators of HDAC inhibition were assessed. Effects on Akt and members of the Bcl-2 and inhibitor of apoptosis protein families were determined by immunoblotting. Immunocompromised mice bearing established s.c. PC-3 xenograft tumors were treated orally with (S)-HDAC-42 (50 mg/kg q.o.d. or 25 mg/kg q.d.) or SAHA (50 mg/kg q.d.) for 28 days. In vivo end points included tumor volumes and intratumoral changes in histone acetylation, phospho-Akt status, and protein levels of Bcl-xL and survivin.

Results: (S)-HDAC-42 was more potent than SAHA in suppressing the viability of all cell lines evaluated with submicromolar IC50 values. Relative to SAHA, (S)-HDAC-42 exhibited distinctly superior apoptogenic potency, and caused markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. The growth of PC-3 tumor xenografts was suppressed by 52% and 67% after treatment with (S)-HDAC-42 at 25 and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppressed growth by 31%. Intratumoral levels of phospho-Akt and Bcl-xL were markedly reduced in (S)-HDAC-42-treated mice, in contrast to mice treated with SAHA.

Conclusions: (S)-HDAC-42 is a potent orally bioavailable inhibitor of HDAC, as well as targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy and warrants further investigation in this regard.
High-Dose Celecoxib and Metronomic “Low-dose” Cyclophosphamide Is an Effective and Safe Therapy in Patients with Relapsed and Refractory Aggressive Histology Non–Hodgkin's Lymphoma
Authors: Buckstein Rena , Kerbel Robert S. , Shaked Yuval , Nayar Rakesh , Foden Cindy , Turner Ruth , Lee Christine R. , Taylor Diane , Zhang Liying , Man Shan , Baruchel Sylvain , Stempak Diana , Bertolini Francesco , Crump Michael
Published: September 2006

Purpose: Angiogenesis is increased in aggressive histology non–Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy.

Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non–Hodgkin's lymphoma in a multicenter phase II prospective study.

Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index, ≥2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted “antiangiogenic” levels.

Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non–Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.
DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer
Authors: Yu Jinsheng , Mallon Mary A. , Zhang Wanghai , Freimuth Robert R. , Marsh Sharon , Watson Mark A. , Goodfellow Paul J. , McLeod Howard L.
Published: September 2006

Background: The ability to maintain DNA integrity is a critical cellular function. DNA repair is conducted by distinct pathways of genes, many of which are thought to be altered in colorectal cancer. However, there has been little characterization of these pathways in colorectal cancer.

Method: By using the TaqMan real-time quantitative PCR, RNA expression profiling of 20 DNA repair pathway genes was done in matched tumor and normal tissues from 52 patients with Dukes' C colorectal cancer.

Results: The relative mRNA expression level across the 20 DNA repair pathway genes varied considerably, and the individual variability was also quite large, with an 85.4 median fold change in the tumor tissue genes and a 127.2 median fold change in the normal tissue genes. Tumor-normal differential expression was found in 13 of 20 DNA repair pathway genes (only XPA had a lower RNA level in the tumor samples; the other 12 genes had significantly higher tumor levels, all P < 0.01). Coordinated expression of ERCC6, HMG1, MSH2, and POLB (RS ≥ 0.60) was observed in the tumor tissues (all P < 0.001). Apoptosis index was not correlated with expression of the 20 DNA repair pathway genes. MLH1 and XRCC1 RNA expression was correlated with microsatellite instability status (P = 0.045 and 0.020, respectively). An inverse correlation was found between tumor MLH1 RNA expression and MLH1 DNA methylation (P = 0.003).

Conclusion: Our study provides an initial characterization of the DNA repair pathways for understanding the cellular DNA damage/repair system in human colorectal cancer.
Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting
Authors: Sok John C. , Coppelli Francesca M. , Thomas Sufi M. , Lango Miriam N. , Xi Sichuan , Hunt Jennifer L. , Freilino Maria L. , Graner Michael W. , Wikstrand Carol J. , Bigner Darell D. , Gooding William E. , Furnari Frank B. , Grandis Jennifer R.
Published: September 2006

Purpose: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting.

Experimental Design: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux.

Results: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells.

Conclusions: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.
The Effect of Enzyme-Inducing Antiseizure Drugs on the Pharmacokinetics and Tolerability of Procarbazine Hydrochloride
Authors: Grossman Stuart A. , Carson Kathryn A. , Batchelor Tracy T. , Lesser Glenn , Mikkelsen Tom , Alavi Jane B. , Phuphanich Surasak , Hammour Tarek , Fisher Joy D. , Supko Jeffrey G.
Published: September 2006

Purpose: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD).

Experimental Design: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (−) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay.

Results: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in −EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation.

Conclusions: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.
Effectiveness of Sealants in Adolescents with High and Low Caries Experience
Authors: Heyduck C. , Meller C. , Schwahn C. , Splieth C.H.
Published: September 2006

The aim of this 3-year longitudinal study was to analyze caries increment and the caries-preventive effect of sealants in adolescents in the setting of the German national health system. 434 pupils (193 male, 241 female) took part in compulsory school examinations at age 12 (mean 12.3 ± 0.4 years) and 15 (mean 15.6 ± 0.3 years) according to WHO criteria, including the examination of sealants. Mean DMFT increased from 1.78 (± 2.15) to 3.97 (± 3.68), mean DMFS from 2.79 (±4.07) to 6.94 DMFS (± 8.34), respectively. Logistic regression analysis showed that high caries incidence at the individual level was mostly associated with the type of school (’Gymnasium’, RR = 0.3), gender (female, RR = 2.08) and high baseline DMFS (RR = 1.2 per surface), but not with the number of sealants. In an interaction model, adolescents with high baseline DMFS values had an even higher risk of caries increment with an increasing number of sealants compared to adolescents with fewer sealants (p = 0.047). At the tooth level, this effect was detected for first permanent molars, while sealants in premolars and second permanent molars did not result in a statistically significant caries-preventive effect due to the low caries incidence on these surfaces. Thus, sealants on occlusal surfaces of first permanent molars were only protective in individuals with low or moderate caries activity (p = 0.006), which indicates the need for other measures to reduce caries activity in high risk adolescents. In addition, rates of 19% lost sealants and 18% carious or filled surfaces in 3 years suggest a discrepancy between sealant retention under real-life conditions and the results of controlled clinical trials.
Three-Year Evaluation of the ART Approach in Class III and V Restorations in Permanent Anterior Teeth
Authors: Cefaly D.F.G. , Tapety C.M.C. , Mondelli R.F.L. , Lauris J.R.P. , Phantumvanit P. , Navarro M.F.L.
Published: September 2006

This study evaluated the survival of class III and V restorations using the atraumatic restorative treatment (ART) approach in permanent anterior teeth, after 3 years. A total of 151 restorations were performed in 60 patients. After 3 years, 107 restorations (47 patients) were evaluated. Data were analyzed using exact 95% confidence interval. A total of 97 restorations (91% with 95% CI = 83–99), 76 class III (92% with 95% CI = 82–100) and 21 class V (88% with 95% CI = 77–98) were classified as successful. The survival rate of the ART approach in class III and V restorations in permanent anterior teeth was considered high.
Increased Salivary Fluoride Concentrations after Post-Brush Fluoride Rinsing Not Reflected in Dental Plaque
Authors: Heijnsbroek M. , Gerardu V.A.M. , Buijs M.J. , van Loveren C. , ten Cate J.M. , Timmerman M.F. , van der Weijden G.A.
Published: September 2006

The aim of the present study was to assess fluoride concentrations in unstimulated saliva and buccal dental plaque 6 h after an oral hygiene procedure that consisted of brushing with an AmF/SnF2 dentifrice and different post-brush rinsing protocols: expectorating the excess of dentifrice foam and rinsing with tap water, expectorating only, or rinsing with 10 ml AmF/SnF2 mouthwash. The fluoride concentrations in plaque and saliva were increased after all three experimental protocols compared to F-free periods. The increase of the fluoride concentration in saliva was more pronounced after AmF/SnF2 mouthrinse as compared to rinsing with water and expectorating the excess of dentifrice foam. Such an effect was not seen in dental plaque. It is concluded that the potentially beneficial effect of not rinsing or fluoride rinsing after tooth brushing is not reflected in an increased fluoride concentration in newly formed dental plaque 6 h after brushing.
Evidence of Haematopoiesis within the Developing Human Diencephalon
Authors: Seitz Volkhard , Hummel Michael , Stein Harald , Papadopoulos Nikolaos , Zemlin Michael , Joehrens Korinna , Anagnostopoulos Ioannis
Published: September 2006

Aim: The sites of haematopoiesis during human ontogeny can be correlated to the sites where haematopoiesis occurs in vertebrate phylogeny. As haematopoiesis has been described in the diencephalon and pituitary gland of water-inhabiting vertebrates we wanted to find out whether such a phenomenon also occurs in human embryos. Material and Methods: Paraffin-embedded specimens from the diencephalon and pituitary gland of human embryos at the 7th to 22nd gestational week and from adults were investigated by conventional histology and immunohistology for the presence of haematopoietic cells. Results: Cellular accumulations predominantly of erythroid and megakaryocytic lineage were identified in the floor of the developing diencephalon of the 7th/8th gestational week. At the older developmental stages of the 18th to 22nd gestational week loose aggregates of haematopoietic cells within the leptomeningeal spaces adjacent to the hypophyseal infundibulum were detected in 2 out of 7 cases analyzed. Conclusions: As it has been proposed that lymphohaematopoietic clusters occasionally occur within the brain in bone marrow-less vertebrates as a response to noxious agents, we speculate that this temporal appearance of haematopoietic cell clusters within the diencephalon floor in early human ontogeny could also be due to fetal immunomodulations.
Tissue-Specific Function of Lymph Node Fibroblastic Reticulum Cells
Authors: Vega Francisco , Coombes Kevin R. , Thomazy Vilmos A. , Patel Kaushali , Lang Wenhua , Jones Dan
Published: September 2006

Objective: We present the first characterization of the cytokine expression pattern of lymph node fibroblastic reticulum cells (FRC), which are the stromal cells responsible for maintaining the highly structured nodal reticular fiber framework. Methods: Microarray expression profiles of cultured nodal FRC and dermal fibroblasts (DF) were compared as well as their response to TNF, IL-4, IL-6 and IL-13, cytokines responsible for intranodal stromal activation. Results: Hierarchical clustering of FRC and DF short-term culture samples revealed genes that were differentially expressed in FRC and DF. Identified differently regulated genes were confirmed by RNase protection analysis, PCR or immunohistochemistry. At earlier culture time points, FRC showed higher levels of several chemokines, including CCL2/MCP-1, and cytokines, e.g. IL-6, whereas several genes related to the production of extracellular matrix and angiogenesis were preferentially expressed in early DF cultures. By 60 days in culture, FRC and DF showed similar expression patterns consistent with homogenization of specialized stromal subsets. FRC and DF showed nearly identical transcriptional responses to exogenous TNF stimulation. Conclusions: Cultured FRC showed an overall transcriptional profile similar to cultured DF, including parallel responsiveness to TNF, but with differences in the expression of chemotactic chemokines, which reflect their biological roles.
Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB
Authors: Paul Shelley Chireyath , Lv Peng , Xiao Yan-Jv , An Ping , Liu Shi-Quan , Luo He-Sheng
Published: September 2006

Background/Aims: Thalidomide inhibited tumor necrosis factor-α (TNF-α) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-ĸB (NF-ĸB), inhibitor of NF-ĸB (IĸB) and TNF-α in a rat model of liver cirrhosis. Methods: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-ĸBp65, α-smooth muscle actin (α-SMA) protein and TNF-α mRNA were studied in the liver, IĸBα and TNF-α protein in the cytoplasm and NF-ĸBp65 protein in the nucleus. Results: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-α mRNA and protein, NF-ĸBp65 and α-SMA were significantly decreased and IĸBα protein was also elevated (p < 0.01). Conclusion: Thalidomide downregulates NF-ĸB-induced TNF-α and activates hepatic stellate cells (HSC) via inhibition of IĸB degradation to prevent liver cirrhosis.
Anomalous Origin of the Entire Coronary System with Separate Ostia within the Right Sinus of Valsalva: A Rare Congenital Anomaly and a Review of the Literature
Authors: Gavrielatos Gerasimos , Letsas Konstantinos P. , Pappas Loukas K. , Antonellis Ioannis , Kardaras Fotis
Published: September 2006

Congenital coronary artery malformations occur infrequently in the general population. In this report, we describe a rare case of anomalous origin of all three coronary arteries from separate ostia within the right coronary sinus.
Amyotrophic Lateral Sclerosis and Exposure to Environmental Toxins: An Australian Case-Control Study
Authors: Morahan Julia M. , Pamphlett Roger
Published: September 2006

It has been suggested that environmental toxins could be risk factors for sporadic amyotrophic lateral sclerosis (SALS). We therefore analysed epidemiological data on 179 SALS cases and 179 age-, ethnicity- and sex-matched controls in Australia using self-reporting questionnaires. SALS was associated with solvent/chemical exposure (OR = 1.92, 95% CI: 1.26–2.93), overall herbicide/pesticide exposure (OR = 1.57, 95% CI: 1.03–2.41) and industrial herbicide/pesticide exposure (OR = 5.58, 95% CI: 2.07–15.06). Exposure to herbicides/pesticides showed a dose-response effect. All positive findings were more statistically significant in males. These findings support those from northern hemisphere studies, indicating that environmental toxins can be risk factors for SALS.
Effects of Post-Treatment with Direct Hemoperfusion Using a CTR Column on Mortality and Inflammatory Responses to Endotoxin-Induced Shock in Rats
Authors: Taniguchi Takumi , Takemoto Yasuhiro , Tsuda Kazunobu , Inaba Hideo , Yamamoto Ken
Published: September 2006

Background: To clarify the effects of post-treatment with direct hemoperfusion using a CTR column on the mortality and inflammatory responses to endotoxin-induced shock in rats. Methods: Thirty-six male rats were randomly assigned to 1 of 3 groups (n = 12/group): the endotoxemic group, receiving intravenous Escherichia coli endotoxin (15 mg/kg over 2 min); the control column group, treated without CTR for 120 min at 2 h after endotoxin injection, and CTR-post-treatment group, treated with CTR for 120 min at 2 h after endotoxin injection. Hemodynamics, arterial blood gases, and mortality were recorded for the 8-hour observation period, and plasma cytokine concentrations were measured every 4 h. Results: The mortality rates were 83, 83 and 33% for the endotoxemic, control column, and CTR post-treatment groups, respectively. The increases in IL-6 concentrations were less for the CTR post-treatment group than the other 2 groups. Conclusion: The present study shows that CTR post-treatment inhibited hypotension and elevations in IL-6 concentrations, reducing the mortality rate of rats with endotoxin-induced shock.
Increased Ratio of CD31
+
/CD42
−
Microparticles to Endothelial Progenitors as a Novel Marker of Atherosclerosis in Hypercholesterolemia
Authors: Pirro Matteo , Schillaci Giuseppe , Paltriccia Rita , Bagaglia Francesco , Menecali Cinzia , Mannarino Massimo R. , Capanni Marusca , Velardi Andrea , Mannarino Elmo
Published: September 2006

Objectives—

Atherosclerosis may be caused by increased endothelial damage and by a consumptive loss of endothelial repair capacity by endothelial progenitors. Arterial stiffness is a reliable marker of atherosclerosis and a positive correlate of endothelial damage. We investigated whether an increased ratio of CD31
+
/CD42
−
microparticles to endothelial progenitors, a possible indicator of endothelial damage and impaired endothelium reparation, may contribute to aortic stiffness in hypercholesterolemia. We also studied the in vitro effect of microparticles from hypercholesterolemic patients on endothelial progenitor survival.

Methods and Results—

Circulating CD31
+
/CD42
−
microparticles, endothelial progenitors, and aortic pulse wave velocity (aPWV), a measure of aortic stiffness, were measured in 50 patients with never-treated hypercholesterolemia and 50 normocholesterolemic controls. Hypercholesterolemic patients had more circulating CD31
+
/CD42
−
microparticles, less endothelial progenitors, and a stiffer aorta than controls. aPWV was associated with CD31
+
/CD42
−
microparticles (
r
=0.61;
P
<0.001), endothelial progenitors (
r
=−0.45,
P
<0.001), and with cholesterol levels (
r
=0.51;
P
<0.001). High plasma cholesterol and a high ratio of CD31
+
/CD42
−
microparticles to endothelial progenitors independently predicted an increased aPWV. Microparticles from hypercholesterolemic patients caused a significant endothelial progenitor loss in vitro.

Conclusions—

Hypercholesterolemia-related aortic stiffness is promoted by plasma cholesterol directly, increased endothelial damage, and reduced endothelium repair capacity by endothelial progenitors.
Direct Evidence for Endothelial Vascular Endothelial Growth Factor Receptor-1 Function in Nitric Oxide–Mediated Angiogenesis
Authors: Ahmad Shakil , Hewett Peter W. , Wang Ping , Al-Ani Bahjat , Cudmore Melissa , Fujisawa Takeshi , Haigh Jody J. , le Noble Ferdinand , Wang Ling , Mukhopadhyay Debabrata , Ahmed Asif
Published: September 2006

Vascular endothelial growth factor-A (VEGF) is critical for angiogenesis but fails to induce neovascularization in ischemic tissue lesions in mice lacking endothelial nitric oxide synthase (eNOS). VEGF receptor-2 (VEGFR-2) is critical for angiogenesis, although little is known about the precise role of endothelial VEGFR-1 and its downstream effectors in this process. Here we have used a chimeric receptor approach in which the extracellular domain of the epidermal growth factor receptor was substituted for that of VEGFR-1 (EGLT) or VEGFR-2 (EGDR) and transduced into primary cultures of human umbilical vein endothelial cells (HUVECs) using a retroviral system. Activation of HUVECs expressing EGLT or EGDR induced rapid phosphorylation of eNOS at Ser1177, release of NO, and formation of capillary networks, similar to VEGF. Activation of eNOS by VEGFR-1 was dependent on Tyr794 and was mediated via phosphatidylinositol 3-kinase, whereas VEGFR-2 Tyr951 was involved in eNOS activation via phospholipase Cγ1. Consistent with these findings, the VEGFR-1–specific ligand placenta growth factor-1 activated phosphatidylinositol 3-kinase and VEGF-E, which is selective for VEGFR-2–activated phospholipase Cγ1. Both VEGFR-1 and VEGFR-2 signal pathways converged on Akt, as dominant-negative Akt inhibited the NO release and in vitro tube formation induced following activation of EGLT and EGDR. The identification Tyr794 of VEGFR-1 as a key residue in this process provides direct evidence of endothelial VEGFR-1 in NO-driven in vitro angiogenesis. These studies provide new sites of modulation in VEGF-mediated vascular morphogenesis and highlight new therapeutic targets for management of vascular diseases.
Proteomic Analysis of Pharmacological Preconditioning
Authors: Arrell D. Kent , Elliott Steven T. , Kane Lesley A. , Guo Yurong , Ko Young H. , Pedersen Pete L. , Robinson John , Murata Mitsushige , Murphy Anne M. , Marbán Eduardo , Van Eyk Jennifer E.
Published: September 2006

Ischemic preconditioning is characterized by resistance to ischemia reperfusion injury in response to previous short ischemic episodes, a protective effect that can be mimicked pharmacologically. The underlying mechanism of protection remains controversial and requires greater understanding before it can be fully exploited therapeutically. To investigate the overall effect of preconditioning on the myocardial proteome, isolated rabbit ventricular myocytes were treated with drugs known to induce preconditioning, adenosine or diazoxide (each at 100 μmol/L for 60 minutes). Their protein profiles were then compared with vehicle-treated controls (n=4 animals per treatment) using a multitiered 2D gel electrophoresis approach. Of 28 significantly altered protein spots, 19 nonredundant proteins were identified (5 spots remained unidentified). The majority of these proteins are involved in mitochondrial energetics, including subunits of tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. These changes were not indiscriminate, with only a small number of enzymes or complex subunits altered, indicating a very specific and targeted affect of these 2 preconditioning mimetics. Among the changes were shifts in the extent of posttranslational modification of 4 proteins. One of these, the adenosine-induced phosphorylation of the ATP synthase β subunit, was fully characterized with the identification of 5 novel phosphorylation sites. This proteomics approach provides an overall assessment of the cellular response to pharmacological treatment with adenosine and diazoxide and identifies a distinct subset of enzymes and protein complex subunit that may underlie the preconditioned phenotype.
Stroke Propagates Bacterial Aspiration to Pneumonia in a Model of Cerebral Ischemia
Authors: Prass Konstantin , Braun Johann S. , Dirnagl Ulrich , Meisel Christian , Meisel Andreas
Published: September 2006

Background and Purpose—

Bacterial pneumonia is the most common cause of death in patients sustaining acute stroke and is believed to result from an increased aspiration. Recently, stroke-induced immunodeficiency was described in a mouse model of cerebral ischemia, which is primarily caused by overactivation of sympathetic nervous system. We tested if stroke-induced immunodeficiency increases the risk of pneumonia after aspiration in a newly developed model of poststroke pneumonia.

Methods—

Experimental stroke in mice was induced by occlusion of the middle cerebral artery (MCAO) for 60 minutes. Aspiration pneumonia was induced by intranasal application of 20 μL of a defined suspension of
Streptococcus pneumoniae
in phosphate-buffered saline 4 or 14 days after MCAO. Treatment comprised moxifloxacin (100 mg/kg body weight, six times every 2 hours after operation) or propranolol (30 mg/kg body weight, immediately before as well as 4 and 8 hours after MCAO). Readout was lung histology and bacterial counts in lung and blood.

Results—

Nasal inoculation of only 200 colony-forming units of
S pneumoniae
caused severe pneumonia and bacteremia after experimental stroke, whereas 200 000 colony-forming units are needed to induce comparable disease in sham animals. Aspiration pneumonia in stroke animals outlasted acute stroke state but was preventable by β-adrenoreceptor blockade.

Conclusions—

Experimental stroke propagates bacterial aspiration from harmless intranasal colonization to harmful pneumonia. Prevention of infections by β-adrenoreceptor blockade suggests that immunodepression by sympathetic hyperactivity is essential for progression of bacterial aspiration to pneumonia.
Population-Based Study of Determinants of Initial Secondary Care Costs of Acute Stroke in the United Kingdom
Authors: Luengo-Fernandez Ramon , Gray Alastair M. , Rothwell Peter M.
Published: September 2006

Background and Purpose—

To determine the cost-effectiveness of specific interventions to prevent or treat acute stroke, it is necessary to know the costs of stroke according to patient characteristics and stroke subtype and etiology. However, very few such data are available and none from population-based studies. We determined the predictors of resource use and acute care costs of stroke using data from a population-based study.

Methods—

Data were obtained from the Oxford Vascular study, a population-based cohort of all individuals in nine general practices in Oxfordshire, UK, which identified 346 patients with a first or recurrent stroke during April 1, 2002, to March 31, 2004. Univariate and multivariate analyses were performed to identify the main predictors of resource use and costs.

Results—

Acute care costs ranged from £326 (lower decile) to £19 901 (upper decile). There were multiple important univariate interrelations of patient characteristics, stroke subtype, and stroke etiology with hospital admission, length of stay, and 30-day case-fatality. For example, patients with primary intracerebral hemorrhage were more likely to be admitted than patients with partial anterior circulation ischemic stroke and less likely to survive without disability, but length of stay was reduced as a result of high early case-fatality such that cost was substantially less. However, the majority of univariate predictors of resource use, cost, and outcome were confounded by initial stroke severity as measured by the National Institutes of Health Stroke Scale score, which accounted for approximately half of the predicted variance in cost. Cost increased approximately linearly up to an National Institutes of Health Stroke Scale score of 18 and then fell steeply at higher scores as a result of rising early case-fatality.

Conclusions—

Several patient and event-related characteristics explained the wide range of initial secondary care costs of acute stroke, but stroke severity was by far the most important independent predictor.
Cerebral Microbleeds Are Associated With Lacunar Stroke Defined Clinically and Radiologically, Independently of White Matter Lesions
Authors: Wardlaw Joanna M. , Lewis Stephanie C. , Keir Sarah L. , Dennis Martin S. , Shenkin Susan
Published: September 2006

Background and Purpose—

Associations among microbleeds, white matter lesions (WMLs), and small deep infarcts on imaging have been reported. Because many of these imaging infarcts were asymptomatic, the relationship of microbleeds to clinical lacunar stroke is unclear. An association between microbleeds and clinically defined lacunar stroke might suggest a common causal microangiopathy.

Methods—

Patients with lacunar, partial anterior circulation or posterior circulation stroke syndromes and older healthy subjects underwent MRI. Microhemorrhages, infarcts, hemorrhages, and WMLs were coded blind to clinical details. A final clinicoradiologic stroke subtype diagnosis was assigned.

Results—

Among 308 subjects (67 older healthy and 241 with stroke), 54 patients had microbleeds (17%). Microbleeds were twice as frequent in lacunar than cortical strokes (26% versus 13%,
P
=0.03) or healthy older subjects (9%) and associated with increasing WML scores (
P
<0.0001). Lacunar and cortical stroke subtypes and healthy older subjects had similar WML scores.

Conclusions—

Microbleeds are associated with lacunar stroke defined clinicoradiologically more than other stroke subtypes but not simply by association with WMLs. This suggests that microbleeds and lacunar stroke have a similar microvascular abnormality.
Age-Related Changes in Carotid Artery Flow and Pressure Pulses
Authors: Hirata Kozo , Yaginuma Toshio , O’Rourke Michael F. , Kawakami Masanobu
Published: September 2006

Background and Purpose—

We sought to establish the relation between the pulsatile components of pressure and flow waveforms in the carotid artery and their change with age.

Methods—

Distention (pressure) and axial flow velocity waveforms were recorded noninvasively and simultaneously from the common carotid artery of 56 healthy subjects aged 20 to 72 years.

Results—

There was a close relation between the time intervals of pressure and flow waves: from foot to first shoulder or peak, to second shoulder or peak, and to incisura (
r
=0.97,
P
<0.0001 for each), which approximated the line of identity. The peak and nadir of flow velocity decreased with age, but late systolic flow augmentation increased substantially (1.6 times in the older group); this can be attributed to earlier wave reflection from the lower body. Pressure augmentation index (PAI) and flow augmentation index (FAI) increased similarly with age (PAI (%)=0.84×age−26.6; FAI (%)=0.75×age+11.9; both
P
<0.0001).

Conclusions—

Arterial stiffening with aging increases carotid flow augmentation and can explain the increasing flow fluctuations in cerebral blood vessels. Measurement of carotid FAI may provide a gauge for risk of cerebral microvascular damage, just as PAI provides a gauge for risk of left ventricular hypertrophy and failure.
The Unchanging Incidence and Case-Fatality of Stroke in the 1990s
Authors: Kleindorfer Dawn , Broderick Joseph , Khoury Jane , Flaherty Matthew , Woo Daniel , Alwell Kathleen , Moomaw Charles J. , Schneider Alexander , Miller Rosie , Shukla Rakesh , Kissela Brett
Published: September 2006

Background and Purpose—

Many advances were made in stroke prevention strategies during the 1990s, and yet temporal trends in stroke incidence and case-fatality have not been reported in the United States. Blacks have a 2-fold higher risk of stroke; however, there are no data over time showing if any progress has been made in reducing racial disparity in stroke incidence. The objective of this study was to examine temporal trends in stroke incidence and case-fatality within a large, biracial population during the 1990s.

Methods—

Within a biracial population of 1.3 million, all strokes were ascertained at all local hospitals using International Classification of Diseases, 9th Revision codes during July 1993 to June 1994 and again in 1999. A sampling scheme was used to ascertain cases in the out-of-hospital setting. Race-specific incidence and case-fatality rates were calculated and standardized to the 2000 US Census population. A population-based telephone survey regarding stroke risk factor prevalence and medication use was performed in 1995 and 2000.

Results—

There were 1954 first-ever strokes in 1993–1994 and 2063 first-ever strokes in 1999. The annual incidence of first-ever hospitalized stroke did not significantly change between study periods: 158 per 100 000 in both 1993–1994 and 1999 (
P
=0.97). Blacks continue to have higher stroke incidence than whites, especially in the young; however, case-fatality rates continue to be similar between races and are not changing over time. Medication use for treatment of stroke risk factors significantly increased in the general population between study periods.

Conclusions—

Despite advances in stroke prevention treatments during the 1990s, the incidence of hospitalized stroke did not decrease within our population. Case-fatality also did not change between study periods. Excess stroke mortality rates seen in blacks nationally are likely the result of excess stroke incidence and not case-fatality, and the racial disparity in stroke incidence did not change over time.
Self-Control, Native Traditionalism, and Native American Substance Use: Testing the Cultural Invariance of a General Theory of Crime
Authors: Morris Gregory D. , Wood Peter B. , Dunaway R. Gregory
Published: September 2006

Usinga sample of White and Native Americanhigh school students, the authors provide a test of (a) self-control theory's invariance thesis and (b) native traditionalism as an explanation of Native American substance use. Self-control significantly influenced all forms of substance use when controlling for race and in race-specific analyses. However, z tests by race revealed that self-control is a stronger predictor of marijuana and serious drug use among Native Americans. Beyond this simple comparison across groups, the authors control for native traditionalism (as a proxy for cultural variation) among the Native American respondents. In doing so, self-control remained a consistent predictor of their substance use. Although these findings largely support the invariance thesis of self-control, the racial difference related to marijuana and serious drug use poses a theoretical challenge. With regard to native traditionalism, results suggest that those most attached to their native traditions engage in greater substance use.
Effects of Motivation and Problem Severity on Court-Based Drug Treatment
Authors: Cosden Merith , Basch Janice E. , Campos Emily , Greenwell Ashley , Barazani Sivan , Walker Sara
Published: September 2006

This study addresses the effects of motivation and problem severity on outcomes in two court-baseddrug treatment programs. Data were examined for 578 offenders served by a drug court and223served by a drug treatment court mandated through California's Substance Abuse Crime Prevention Act (SACPA). It was hypothesized that client-reported motivation would be associated with severity of drug problems and that motivation would be positively associated, and severity negatively associated, with program completion and 12-month, postdischarge recidivism. The first hypothesis was supported— motivation for treatment, measured by client-reported need for treatment and acknowledgementof problemseverity, was associatedwith severity of druguse. Program completion in drug court was predicted by client motivation and prior jail time, whereas SACPA completion was predicted by severity of drug problems and prior employment. Recidivism was associated with program completion and problem severity but not treatment motivation in either program. Implications for court-based treatment programs and future research are discussed.
How Does Tacit Knowledge Proliferate? An Episode-Based Perspective
Authors: D’Eredita Michael A. , Barreto Charmaine
Published: September 2006

Evidence has accrued that tacit knowledge is personal and ineffable as proposed by Polanyi (1958). Proponents of this view do not explain the mechanism responsible for the proliferation of tacit knowledge. This paper introduces a cognitive perspective to the process of tacit knowledge proliferation while maintaining that tacit knowledge is personal, ineffable and context-specific. Three propositions are discussed: tacit knowledge is episodic, thus personal, context-specific and acquired through experience; experience results from the construction or relating of episodes, but does not necessarily result in specifically ‘intended’ tacit knowledge; and the proliferation of tacit knowledge within an organization is the result of a constructive and collaborative process. The crux of this perspective has three assumptions: constructing and relating of tacit knowledge is episodic, constructing new episodes is obligatory upon attention, and relating to past episodes is obligatory upon attention.
Health behaviour modelling for prenatal diagnosis in Australia: a geodemographic framework for health service utilisation and policy development
Authors: Muggli Evelyne E , McCloskey David , Halliday Jane L
Published: September 2006

Background

Despite the wide availability of prenatal screening and diagnosis, a number of studies have reported no decrease in the rate of babies born with Down syndrome. The objective of this study was to investigate the geodemographic characteristics of women who have prenatal diagnosis in Victoria, Australia, by applying a novel consumer behaviour modelling technique in the analysis of health data.

Methods

A descriptive analysis of data on all prenatal diagnostic tests, births (1998 and 2002) and births of babies with Down syndrome (1998 to 2002) was undertaken using a Geographic Information System and socioeconomic lifestyle segmentation classifications.

Results

Most metropolitan women in Victoria have average or above State average levels of uptake of prenatal diagnosis. Inner city women residing in high socioeconomic lifestyle segments who have high rates of prenatal diagnosis spend 20% more on specialist physician's fees when compared to those whose rates are average. Rates of prenatal diagnosis are generally low amongst women in rural Victoria, with the lowest rates observed in farming districts. Reasons for this are likely to be a combination of lack of access to services (remoteness) and individual opportunity (lack of transportation, low levels of support and income). However, there are additional reasons for low uptake rates in farming areas that could not be explained by the behaviour modelling. These may relate to women's attitudes and choices.

Conclusion

A lack of statewide geodemographic consistency in uptake of prenatal diagnosis implies that there is a need to target health professionals and pregnant women in specific areas to ensure there is increased equity of access to services and that all pregnant women can make informed choices that are best for them. Equally as important is appropriate health service provision for families of children with Down syndrome. Our findings show that these potential interventions are particularly relevant in rural areas.

Classifying data to lifestyle segments allowed for practical comparisons of the geodemographic characteristics of women having prenatal diagnosis in Australia at a population level. This methodology may in future be a feasible and cost-effective tool for service planners and policy developers.
Awareness and practice of patient's rights law in Lithuania
Authors: Ducinskiene Danute , Vladickiene Jurgita , Kalediene Ramune , Haapala Irja
Published: September 2006

Background

Patient's rights law is intended to secure good medical practice, but it can also serve to improve understanding between patients and medical staff if both were aware of their rights.

Methods

Awareness and practice of the new patient's rights law in Lithuanian health care institutions was explored through a survey of 255 medical staff and 451 patients in the four Kaunas city medical units in 2002. Participation rates were 74% and 66%, respectively.

Results

Majority of the medical staff (85%) and little over one half of the patients (56%) had heard or read about the Law on Patient's Rights (p < 0.001). Only 50% of professionals compared to 69% of patients thought information for patients about diagnosis, treatment results and alternative treatments is necessary (p < 0.001). A clear discrepancy was indicated between physicians informing the patients (80% – 98% of physicians) and patients actually knowing (37% – 54%) their treatment prognosis, disease complications or possible alternative treatment methods.

Conclusion

These results suggest a need for awareness-raising among patients to improve the practical implementation of the Patient's Rights Law in Lithuania.