bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Blood Rheology in Obstructive Sleep Apnea as a Mediator of Cardiovascular Risk
Authors: Steiner Stephan , Jax Thomas , Evers Stefanie , Hennersdorf Marcus , Schwalen Andreas , Strauer Bodo E.
Published: July 2005

Background: Cardiovascular complications are common in patients with obstructive sleep apnea (OSA). Blood rheology is a major determent of coagulation and an established risk factor for cardiovascular events. Since nocturnal hypoxemia could influence parameters of blood rheology, we hypothesized that OSA alters blood rheology independent of other cardiovascular risk factors. Methods: One hundred and ten consecutive patients admitted to the sleep laboratory were included. The association of plasma fibrinogen and viscosity (as parameters of blood rheology) with OSA was evaluated. Results: One hundred and ten patients aged 61.4 ± 10.1 years (body mass index 28.4 ± 4.1 kg/m2) were included. OSA was confirmed in 63 patients (57.2%) with an apnea-hypopnea index (AHI) of 28.7 ± 14.9 events/hour. Patients with OSA showed higher levels of plasma viscosity (1.36 ± 0.09 vs. 1.31 ± 0.08 mPas, p = 0.005). Nevertheless, hypertensive apneics have even higher levels of plasma viscosity than nonapneics (1.38 ± 0.091 vs. 1.32 ± 0.028 mPas, p = 0.018). Similar results were found in patients with coronary artery disease, where OSA was associated with elevated plasma viscosity (1.36 ± 0.076 vs. 1.31 ± 0.081 mPas, p = 0.007). Plasma fibrinogen was correlated with nocturnal minimal oxygen saturation (r = –0275, p = 0.0036) and AHI (r = 0.297, p = 0.001). OSA was associated with higher plasma fibrinogen (353 ± 83 vs. 317 ± 62 mg/dl, p = 0.015). These differences persist with control for cardiovascular risk factors. Conclusions: Patients with OSA have elevated morning fibrinogen levels and a higher plasma viscosity, which correlate positively with indices of sleep apnea severity. These changes in blood rheology are independent of cardiovascular risk factors, and therefore, might be specific mechanisms of OSA. This supports the pathophysiological concept that sleep apnea is a cardiovascular risk factor.
Weekly Dose-Dense Cisplatin-Epirubicin-Paclitaxel Administration with Granulocyte Colony-Stimulating Factor Support Does Not Substantially Improve Prognosis in Extensive Disease Small-Cell Lung Cancer
Authors: Frasci Giuseppe , Comella Pasquale , Carreca Ignazio , DeCataldis Giuseppe , Muci Domenico , Brunetti Cosimo , Russo Anna , Palmeri Sergio , D’Aniello Roberta , Giordano Renato , D’Aiuto Massimiliano , Comella Giuseppe
Published: July 2005

Purpose: The present study was aimed at defining the antitumor activity of the cisplatin-epirubicin-paclitaxel (PET) weekly administration with granulocyte colony-stimulating factor (G-CSF) support in chemonaive small-cell lung cancer patients with extensive disease (ED-SCLC). Methods: Chemonaive ED-SCLC patients received cisplatin 30 mg/sqm, epirubicin 50 mg/sqm and paclitaxel 120 mg/sqm, weekly, with G-CSF (5 µg/kg from day 3 to 5) support, for a maximum of 12 weeks. Results: Thirty-nine patients were treated, for a total of 354 cycles delivered. Eight complete (21%), and 22 partial responses (56%) were recorded, giving a 77% (95% CI = 61–89%) objective response rate (ORR). After 14 (range, 7–28)-month median follow-up, 24 deaths have occurred. Median progression-free and overall survival were 7 months and 11 months, with 1- and 2-year projected survivals of 45 and 24%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 4 (10%) and 1 (3%) patients, respectively. Only one case of neutropenic sepsis was recorded, while hemorrhagic thrombocytopenia was never observed. Emesis, loss of appetite, mucositis and fatigue were the main nonhematological toxicities, being severe in 9, 8, 4 and 7 patients, respectively. Conclusions: The weekly PET combination with G-CSF support represents an active therapeutic approach in chemonaive ED-SCLC patients. However, both ORR and median survival does not seem substantially better than those achievable with a standard regimen. In view of that, and in consideration of the relevant nonhematological toxicity, this approach should not be pursued outside clinical trials.
Clinical Significance of Nuclear Morphometry at the Invasive Front of T1 Colorectal Cancer and Relation to Expression of VEGF-A and VEGF-C
Authors: Kojima Motohiro , Shiokawa Akira , Ohike Nobuyuki , Ohta Yoshiki , Kato Hirotaka , Iwaku Kenji , Hayasi Ryoji , Morohoshi Toshio
Published: July 2005

Objectives: To better understand the metastatic potential of T1 colorectal cancer, we investigated variations in nuclear morphometry and expression of angiogenic factors in cancer cells at the invasive front. Sixty-five patients who had undergone curative resection were entered. Methods: Nuclear shape factor, area, width, and proportion of cells with large nucleoli in all cells were determined in two high-power magnification areas at the invasive front of the tumor. We then performed the Ward method for cluster analysis. A dendrogram revealed that cases fell into two clusters: cluster A with high atypical nuclei and cluster B with low atypical nuclei. Expression of vascular endothelial growth factor-A (VEGF-A) and -C were evaluated immunohistochemically at the invasive front of the tumor. Results: Nuclear atypia, and VEGF-C expression were associated significantly with lymph node metastasis by univariate analysis. Nuclear atypia was independently and significantly associated with lymph node metastasis by multivariate analysis. Whereas VEGF-A expression was associated with nuclear atypia, VEGF-C expression was not showed. Nuclear atypia, strong VEGF-A or -C expressions were not associated with the depth of invasion. Conclusion: Nuclear morphometry and expression of angiogenic factors at the invasive front are useful prognostic markers of lymph node metastasis, even cases with slight invasion.
Final Results of a Prospective Trial of a PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) Regimen Followed by Radiotherapy after Curative Surgery for Pancreatic Adenocarcinoma
Authors: Reni Michele , Passoni Paolo , Bonetto Elisa , Balzano Gianpaolo , Panucci Maria Grazia , Zerbi Alessandro , Ronzoni Monica , Staudacher Carlo , Villa Eugenio , Di Carlo Valerio
Published: July 2005

Background: Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial. Methods: The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18–70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) ≧70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (α 0.05; β 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery. Results: Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3–4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 ± 7%. Two-year overall survival was 53 ± 7%. Conclusion: Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome.
Prognostic and Predictive Relevance of DNAM-1, SOCS6 and CADH-7 Genes on Chromosome 18q in Colorectal Cancer
Authors: Storojeva Iana , Boulay Jean-Louis , Ballabeni Pierluigi , Buess Martin , Terracciano Luigi , Laffer Urban , Mild Gabriele , Herrmann Richard , Rochlitz Christoph
Published: July 2005

Purpose: Chromosome 18q deletion has been described as a negative prognostic factor in colorectal cancer (CRC). The relationship between its supposed negative prognostic influence and the inactivation of candidate tumor suppressors deleted in colorectal cancer, Smad2 and Smad4 has not been definitively established. The aim of the present study was to evaluate the genetic status of three novel putative tumor suppressors, Cadh-7, DNAX accessory molecule-1 (Dnam-1) and suppressor of cytokine signaling (Socs6) on chromosome 18q and to correlate molecular results with patient survival and benefit from adjuvant chemotherapy. Experimental Design: One hundred and ninety representative patient samples from a randomized multicenter study of the Swiss Group for Clinical Cancer Research of 5-fluorouracil (5-FU)- based adjuvant chemotherapy were screened for the gene copy status of Cadh-7, Socs6 and Dnam-1 using real-time quantitative PCR assay, and the molecular results were correlated with clinical outcome. Results: Loss of gene copy number was found in 26.8, 37.9 and 54.2% for Cadh-7, Dnam-1 and Socs6, respectively. Only Dnam-1 deletion was an independent negative prognostic factor for the 5-year overall survival (OS) in the untreated group of patients (hazard ratio = 2.44; p = 0.01). On the contrary, loss of Cadh-7 gene copy number was a favourable prognostic factor for disease-free survival (hazard ratio = 0.43; p = 0.03) and OS (hazard ratio = 0.29; p = 0.01) in the untreated control population. Furthermore and most importantly, patients with Dnam-1 deletion who received adjuvant chemotherapy had a significantly lower risk of death compared to untreated patients with Dnam-1 deletion (hazard ratio = 0.51; p = 0.05), whereas those with Dnam-1 retention did not derive any benefit from 5-FU-based treatment (hazard ratio = 1.68; p = 0.16). Conclusions: Loss of Dnam-1 gene copy number and retention of Cadh-7 might be indicators of worse prognosis, and Dnam-1 deletion might predict for a beneficial response to adjuvant 5-FU-based chemotherapy in patients with CRC. The confirmation of our findings in large independent randomized studies is needed.
Expression of KIT (CD117) in Renal Cell Carcinoma and Renal Oncocytoma
Authors: Krüger Stefan , Sotlar Karl , Kausch Ingo , Horny Hans-Peter
Published: July 2005

Objective: Overexpression of KIT (CD117), a tyrosine kinase receptor, has been reported in a variety of tumors, some of which are susceptible to therapy with imatinib mesylate. Our aim was to analyze KIT expression immunohistochemically in renal cell carcinomas (RCCs) and in oncocytomas. Methods: Routinely processed, paraffin-embedded specimens from 61 RCCs and 13 renal oncocytomas were investigated immunohistochemically. Cytoplasmic and membrane-bound KIT staining of tumor cells was determined semiquantitatively. A subset of cases was additionally analyzed for point mutations of c-kit exon 17 by peptide nucleic acid-mediated nested polymerase chain reaction-clamping. Results: All cases of oncocytomas and chromophobe RCCs showed membrane-bound KIT positivity, while about three-quarters of cases showed cytoplasmic reactivity. All other types of RCC were found KIT negative. Within the group of chromophobe RCCs, negative cytoplasmatic KIT reactivity was significantly correlated with advanced tumor stage (pT ≧ 2; p = 0.036). Analysis of c-kit exon 17 revealed no ‘gain-of-function’ mutation like the codon 816 Asp→Val mutation (D816V). Conclusions: KIT expression is a hallmark of oncocytoma and chromophobe RCC. Since all other types of RCC were found to be KIT negative, immunohistochemical KIT reactivity may be used as an additional diagnostic criterion to distinguish chromophobe RCC from other RCC types. KIT reactivity and the absence of c-kit mutation D816V in chromophobe RCC justify speculations that imatinib mesylate therapy could be effective in patients with advanced disease.
Dendritic Cells and Vascular Endothelial Growth Factor in Colorectal Cancer: Correlations with Clinicobiological Findings
Authors: Della Porta Matteo , Danova Marco , Rigolin Gian Matteo , Brugnatelli Silvia , Rovati Bianca , Tronconi Chiara , Fraulini Chiara , Russo Rossi Antonella , Riccardi Alberto , Castoldi Gianluigi
Published: July 2005

Objective: Dendritic cells (DC) are central to the development of immune system responses. In a cohort of 54 patients affected by colorectal cancer, we prospectively investigated the number of peripheral blood (PB) DC type 1 (DC1) and type 2 (DC2) and correlated their counts and functionality to the stage of the disease and to vascular endothelial growth factor (VEGF) levels. Results: At diagnosis, compared with healthy controls, patients presented reduced PBDC1 and PBDC2 numbers (p < 0.001). Moreover, in cancer patients, PBDC showed low levels of DC-associated antigens (HLA DR, p = 0.004; CD11c, p < 0.001; CD83, p = 0.01; CD86, p = 0.007 and Mannose receptor, p = 0.029), an upregulation of CXCR4 (p = 0.017) and a reduced T cell stimulation capability (p < 0.001). DC1 and DC2 loss was higher in stage D versus stage ABC patients (p = 0.003 and p = 0.002, respectively); surgery and chemotherapy appeared to attenuate a DC defect, although the restoration of normal PBDC levels is completed only at 6 and 12 months after diagnosis, respectively. In this series of patients, PBDC1 and PBDC2 numbers inversely correlated with VEGF serum levels (p < 0.001), suggesting a possible effect of this cytokine on DC compartment. In culture, the exposure of monocyte-derived DC to VEGF produced a dramatic alteration of DC differentiation by (1) induction of apoptosis, (2) alteration of DC immunophenotypic profile and (3) increased CXCR4 expression. Exposure to anti-VEGF blocking antibodies reversed VEGF inhibitory effects in all cases. Conclusions: These findings suggest that in colorectal cancer patients there is a numerical and functional impairment of PBDC compartment possibly related to the stage of the disease and to VEGF levels.
Consumption of Ready-to-Eat Cereals in Relation to Health and Diet Indicators among School Adolescents in Crete, Greece
Authors: Kafatos Anthony , Linardakis Manolis , Bertsias George , Mammas Ioannis , Fletcher Reg , Bervanaki Frosso
Published: July 2005

Background/Aims: We aimed at examining the intake of ready-to-eat cereals (RTEC) among adolescents in Crete, Greece, and investigate relationships with health and diet indicators. Methods: A sample of 392 adolescents (183 boys, 209 girls) aged 15 ± 0.4 years, attending high schools of two major counties in Crete, was studied to determine consumption of RTEC using a frequency questionnaire. Anthropometric measurements were performed and blood was drawn for analysis of serum lipoproteins and blood glucose (BG). The physical fitness was assessed with the 20-meter shuttle run test (SRT) and the amount of time watching television was estimated. Nutrient intakes were calculated through 24-hour dietary recalls. Results: 42% (n = 77) of boys and 43% (n = 90) of girls reported consumption of RTEC at least once per week. Approximately 40% of the male and 47% of the female consumers reported eating RTEC only at meals other than breakfast. RTEC consumption was inversely related to the obesity indices and BG levels, and positively related to the SRT (p < 0.05 in all analyses). RTEC consumers had significantly higher intakes of fibre, magnesium, calcium, iron, folate, and vitamins A, B2 and B6 (p < 0.05 in all analyses). Conclusion: Our results demonstrated favourable associations between RTEC intake and health and diet indicators in Greek adolescents, with potential implications for improved health status and chronic disease risk reduction.
α-Melanophore-Stimulating Hormone (α-MSH) Antagonizes Interleukin-1β-Induced Hyperalgesia and Fos Expression in the Paraventricular and Arcuate Nucleus of the Rat
Authors: Tonosaki Yoshikazu , Nishiyama Keiji , Roubos Eric W. , Sugiura Yasuo
Published: July 2005

It is known that intracerebroventricular (ICV) administration of a low dose of interleukin-1β (IL-1β) induces hyperalgesia and that this effect can be inhibited by α-melanophore-stimulating hormone (α-MSH). To identify the part of the brain that is affected by hyperalgesia-induced IL-1β and the possible site of α-MSH inhibition, we have examined Fos expression in the rat brain in response to ICV microinjection of α-MSH and/or IL-1β. Following injection of 10 pg IL-1β, hyperalgesia was induced and Fos became expressed in the paraventricular nucleus (PVN) of the hypothalamus and in the arcuate nucleus (ARC), which contains α-MSH-producing neurons. IL-1β injection did not induce Fos expression in the pars intermedia of the pituitary gland, which contains endocrine melanotrope cells that release α-MSH into the systemic circulation. ICV co-injection of IL-1β with 30 ng α-MSH fully inhibited both hyperalgesia and Fos expression in the PVN and the ARC. We conclude that PVN neurons are activated by hyperalgesic IL-1β and propose that this effect is abolished by α-MSH possibly released from the ARC but not from the pituitary gland.
Treatment of Cryptosporidiosis in Immunocompromised Hosts
Authors: Zardi E.M. , Picardi A. , Afeltra A.
Published: July 2005

The most important species of Cryptosporidium in humans, C. parvum and C. hominis, cause severe and chronic life-threatening gastroenteritis in immunocompromised patients. Despite a certain efficacy shown by passive immunotherapy or by some chemotherapeutic agents (e.g. paromomycin and nitazoxanide), no significant benefit has been demonstrated. The use of highly active antiretroviral therapy (HAART) in persons with the acquired immunodeficiency syndrome drastically reduces the prevalence of Cryptosporidium infection. This result seems to be due to aspartyl protease inhibitors of the human immunodeficiency virus included in HAART, which directly interfere with the life cycle of the parasite. The identification of the C. parvum proteases involved in the host-cell interaction could lead to new therapeutic approaches using specific parasite protease inhibitors in immunocompromised persons.
Interactions of Anti-Infectives: A Review
Authors: Barcia E. , Negro S.
Published: July 2005

Drug interactions can be beneficial and valuable, but their consequences are usually adverse/undesirable, thus compromising the efficacy of drugs and enhancing their toxicity. Interactions can be divided into pharmaceutical incompatibilities, and pharmacokinetic and pharmacodynamic interactions. Unexpected drug responses can result from drug-excipient incompatibilities or erroneous technological processes. Pharmacokinetic interactions can affect the processes of drug absorption, distribution, metabolization and excretion. Pharmacodynamic interactions occur when the effects of one drug are changed by the presence of another drug at its site of action; such interactions are classified as synergistic and antagonistic. The clinically most relevant drug interactions following this classification and regarding the use of anti-infectives are reviewed. Knowledge, research and discussion of drug interactions will assist in giving the patient optimal care.
Effects of Clarithromycin on Inflammatory Cell Mediator Release and Survival
Authors: Borszcz Peter D. , Befus Dean , Moqbel Redwan , Sin Don D. , Adamko Darryl J. , Paul Man S.F. , Lacy Paige
Published: July 2005

Background: Clarithromycin exhibits anti-inflammatory as well as antimicrobial activity, leading to decreased symptoms of asthma and chronic sinusitis. The mode of anti-inflammatory effects of clarithromycin on inflammatory cells is not well understood. We hypothesized that clarithromycin inhibits inflammatory cell mediator release and survival. Methods: We investigated the effects of this drug on survival and mediator release from mast cells, eosinophils and neutrophils. Results: Human eosinophil and neutrophil respiratory burst was inhibited by up to 54% after 1–2 h pretreatment with 100 µg/ml clarithromycin. Similar doses of erythromycin did not affect respiratory burst responses in these cells. Clarithromycin at doses of up to 100 µg/ml had no effect on granule-derived mediators released from mast cells and neutrophils. However, we found that clarithromycin (100 µg/ml) induced cell death in mast cells and eosinophils after 16–48 h incubation. Conclusion: Clarithromycin inhibited inflammatory cell mediator release and survival, which may enhance its ability to reduce the symptoms of chronic sinusitis and asthma.
Induction of Antifertility with Lupeol Acetate in Male Albino Rats
Authors: Gupta R.S. , Bhatnager A.K. , Joshi Y.C. , Sharma M.C. , Khushalani Veena , Kachhawa J.B.S.
Published: July 2005

The present study was undertaken to evaluate the antifertility activity of the active principle, i.e. lupeol acetate, isolated from benzene extract of Alstonia scholaris in male albino rats. The treatment with lupeol acetateat the dose level of 10 mg/rat/day did not cause any significant change in the body weights, but significant reduction in the weight of reproductive organs, i.e. testes, epididymides, seminal vesicle and ventral prostate, was observed. Testicular sperm count, epididymal sperm count and motility were found significantly declined when compared with controls, which resulted in reduction of male fertility by 100%. Arrest of spermatogenesis was noted at various stages with production of primary spermatocytes (preleptotene and pachytene), secondary spermatocytes and step-19 spermatids were decreased by 52.36, 54.91, 55.67 and 69.65%, respectively. The seminiferous tubules appeared reduced in size by 24.62%. Cross-sectional surface area of Sertoli cells as well as their counts were found to be significantly depleted. Leydig cell nuclear area and number of mature Leydig cells were decreased by 27.65 and 35.47%. Biochemical parameters of tissues i.e. protein, sialic acid, glycogen and cholesterol content of testes and seminal vesicular fructose also showed significant reduction.
Once-Weekly Treatment of Anemia in Patients with Cancer: A Comparative Review of Epoetins
Authors: Pujade-Lauraine Eric , Topham Clare
Published: July 2005

Anemia is common in cancer patients, but its impact is often poorly appreciated. As well as the negative effect of anemia on the quality of life, there is strong evidence that it is associated with poor treatment outcome and reduced survival. The introduction of recombinant human erythropoietin (epoetin) has provided an effective treatment of anemia, without the risk associated with blood transfusion. A recent randomized study of patients with hematological malignancies showed that once-weekly epoetin β has comparable efficacy at the same overall weekly dose as three-times-weekly treatment. This once-weekly regimen of epoetin β (NeoRecormon®) has been approved by European Regulatory Authorities for patients with lymphoproliferative malignancies and relative erythropoietin deficiency, who are receiving anti-tumor therapy. Darbepoetin α (Aranesp®) has also recently been approved for once-weekly treatment of anemia in patients with nonmyeloid malignancies receiving chemotherapy. The improved convenience and reduced administration costs associated with a once-weekly treatment may result in more patients receiving the benefits of epoetin therapy.
Plasma Gelatinase Activity Does Not Reflect Disease Activity after Operation for Colorectal Cancer
Authors: Waas E.T. , Wobbes T. , Lomme R.M.L.M. , Hendriks T.
Published: July 2005

Objective: To investigate if plasma matrix metalloproteinase (MMP)-2 or -9 are better markers for disease activity than carcinoembryonic antigen (CEA) in the postoperative follow-up of colorectal cancer patients. Methods: A prospective study was performed including 61 patients operated for primary colorectal cancer. The follow-up was for at least 2 years and postoperative blood samples were obtained periodically with 3-month intervals. Plasma gelatinase activity was measured with quantitative gelatin zymography and serum CEA with a specific immunoassay. Results: Zymographic analysis of plasma samples revealed the presence of the proforms, but not the active forms, of both MMP-2 and -9. Prior to the detection of recurrent disease or metastasis in potentially curatively operated colorectal cancer patients, the changes in proMMP-2, -9 and CEA blood levels were determined. ProMMP-2 and -9 plasma levels changed little in this period and changes between patients with and without disease relapse were not statistically significant. In contrast, patients with disease relapse showed a significant increase (p = 0.002) in CEA in the two consecutive serum samples prior to the detection of recurrent disease or metastasis. Similarly, prior to death due to colorectal cancer, proMMP-2 and -9 plasma levels showed no significant change, whereas CEA levels increased considerably and significantly (p < 0.001) when compared to changes found in survivors. Conclusion: Plasma proMMP-2 and -9 activities show no potential value as prognostic markers in the follow-up of colorectal cancer.
Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers
Authors: Hetzel Jürgen , Balletshofer Bernd , Rittig Kilian , Walcher Daniel , Kratzer Wolfgang , Hombach Vinzenz , Häring Hans-Ulrich , Koenig Wolfgang , Marx Nikolaus
Published: July 2005

Background—

Antidiabetic thiazolidinediones (TZDs), like rosiglitazone or pioglitazone, improve endothelial function in patients with type 2 diabetes or metabolic syndrome, but it is currently unknown, whether these beneficial effects of TZDs depend on their metabolic action or may be caused by direct effects on the endothelium. Therefore, the present study examined whether short-term rosiglitazone treatment influences endothelium-dependent vasodilation as well as serum levels of vascular disease biomarkers in healthy, nondiabetic subjects.

Methods and Results—

Short-term treatment (21 days) of healthy subjects (n=10) did not significantly change blood glucose levels or lipid profile. In contrast, rosiglitazone significantly increased flow-mediated, endothelium-dependent vasodilation already within the first day from 5.3±2.7% at baseline to 7.8±2.6%, further increasing it to 9.4±3.0% at day 21. In addition, the early improvement of endothelium-dependent vasodilation was paralleled by a rapid reduction of serum levels of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), and sE-selectin. Moreover, after drug withdrawal all markers remained suppressed for the whole follow-up period of 7 days. In contrast, rosiglitazone treatment did not significantly affect tumor necrosis factor (TNF)-α, interleukin (IL)-6, sICAM-1, sVCAM-1, and sCD40L levels.

Conclusions—

Our study suggests a direct effect of TZD treatment on endothelial function and inflammatory biomarkers of arteriosclerosis, promoting the concept that TZDs, independent of their metabolic action, may exhibit protective effects in the vessel wall.
Rho-Kinase Is an Important Therapeutic Target in Cardiovascular Medicine
Authors: Shimokawa Hiroaki , Takeshita Akira
Published: July 2005

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-κB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.
Complete Rescue of Lipoprotein Lipase–Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPLS447XBeneficial Mutation
Authors: Ross Colin J.D. , Liu Guoqing , Kuivenhoven Jan Albert , Twisk Jaap , Rip Jaap , van Dop Willemijn , Ashbourne Excoffon Katherine J.D. , Lewis Suzanne M.E. , Kastelein John J. , Hayden Michael R.
Published: July 2005

The naturally occurring human lipoprotein lipase S447X variant (LPLS447X) exemplifies a gain-of function mutation with significant benefits including decreased plasma triglycerides (TG), increased high-density lipoprotein (HDL) cholesterol, and reduced risk of coronary artery disease. The S447X variant may be associated with higher LPL catalytic activity; however, in vitro data supporting this hypothesis are contradictory. We wanted to investigate the in vivo mechanism by which the LPLS447Xvariant improves the lipid profile of S447X carriers. We conducted a functional assessment of human LPLS447Xcompared with LPLWTin mice. LPL variants were compared in the absence of endogenous mouse LPL in newborn LPL−/−mice by adenoviral-mediated gene transfer. LPL−/−mice normally exhibit severe hypertriglyceridemia and die within 48 hours of birth. LPLWTgene transfer prolonged the survival of mice up to 21 days. In contrast, LPLS447Xcompletely rescued 95% of the mice to adulthood and increased LPL catalytic activity in postheparin plasma 2.1-fold compared with LPLWTat day 3 (P=0.003). LPLS447Xalso reduced plasma TG 99% from baseline (P<0.001), 2-fold more than LPLWT, (P<0.01) and increased plasma HDL cholesterol 2.9-fold higher than LPLWT(P<0.01). These data provide in vivo evidence that the increased catalytic activity of LPLS447Ximproves plasma TG clearance and increases the HDL cholesterol pool compared with LPLWT.
Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease
Authors: Lawrie Allan , Spiekerkoetter Edda , Martinez Eliana C. , Ambartsumian Noona , Sheward W. John , MacLean Margaret R. , Harmar Anthony J. , Schmidt Ann-Marie , Lukanidin Eugene , Rabinovitch Marlene
Published: July 2005

Heightened expression of the S100 calcium–binding protein, S100A4/Mts1, is observed in pulmonary vascular disease. Loss of serotonin (5-hydroxytryptamine [5-HT]) receptors or of the serotonin transporter (SERT) attenuates pulmonary hypertension in animals, and polymorphisms causing gain of SERT function are linked to clinical pulmonary vascular disease. Because 5-HT induces release of S100β, we investigated the codependence of 5-HT receptors and SERT in regulating S100A4/Mts1 in human pulmonary artery smooth muscle cells (hPA-SMC). 5-HT elevated S100A4/Mts1 mRNA levels and increased S100A4/Mts1 protein in hPA-SMC lysates and culture media. S100A4/Mts1 in the culture media stimulated proliferation and migration of hPA-SMC in a manner dependent on the receptor for advanced glycation end products. Treatment with SB224289 (selective antagonist of 5-HT
1B
), fluoxetine (SERT inhibitor), SERT RNA-interference, and iproniazid (monoamine oxidase-A inhibitor), blocked 5-HT–induced S100A4/Mts1. 5-HT signaling mediated phosphorylation (p) of extracellular signal–regulated kinase 1/2 (pERK1/2), but pERK1/2 nuclear translocation depended on SERT, monoamine oxidase activity, and reactive oxygen species. Nuclear translocation of pERK1/2 was required for pGATA-4–mediated transcription of S100A4/Mts1. These data provide evidence for a mechanistic link between the 5-HT pathway and S100A4/Mts1 in pulmonary hypertension and explain how the 5-HT
1B
receptor and SERT are codependent in regulating S100A4/Mts1.
Inhibition of Lipopolysaccharide-Induced Inflammatory Responses by an Apolipoprotein AI Mimetic Peptide
Authors: Gupta Himanshu , Dai Lijun , Datta Geeta , Garber David W. , Grenett Hernan , Li Yanbing , Mishra Vinod , Palgunachari Mayakonda N. , Handattu Shaila , Gianturco Sandra H. , Bradley William A. , Anantharamaiah G.M. , White C. Roger
Published: July 2005

Previous studies suggest that high-density lipoprotein and apoAI inhibit lipopolysaccharide (LPS)-induced inflammatory responses. The goal of the current study was to test the hypothesis that the apoAI mimetic peptide L-4F exerts antiinflammatory effects similar to apoAI. Pretreatment of human umbilical vein endothelial cells (HUVECs) with LPS induced the adhesion of THP-1 monocytes. Incubation of cells with LPS and L-4F (1 to 50 μg/mL) reduced THP-1 adhesion in a concentration-dependent manner. This response was associated with a significant reduction in the synthesis of cytokines, chemokines, and adhesion molecules. L-4F reduced vascular cell adhesion molecule-1 expression induced by LPS or lipid A, whereas a control peptide (Sc-4F) showed no effect. In contrast to LPS treatment, L-4F did not inhibit IL-1β- or tumor necrosis factor-α–induced vascular cell adhesion molecule-1 expression. The inhibitory effect of L-4F on LPS induction of inflammatory markers was associated with reduced binding of LPS to its plasma carrier molecule, lipopolysaccharide binding protein, and decreased binding of LPS to HUVEC monolayers. LPS and L-4F in HUVEC culture medium were fractionated by fast protein liquid chromatography and were localized to the same fractions, suggesting a physical interaction between these molecules. Proinflammatory responses to LPS are associated with the binding of lipid A to cell surface receptors. The current studies demonstrate that L-4F reduces the expression of inflammatory markers induced by LPS and lipid A and suggest that apoAI peptide mimetics may be useful in the treatment of inflammation associated with endotoxemia.
Carotid Atherosclerotic Plaque Characteristics Are Associated With Microembolization During Carotid Endarterectomy and Procedural Outcome
Authors: Verhoeven B.A.N. , de Vries J.P.P.M. , Pasterkamp G. , Ackerstaff R.G.A. , Schoneveld A.H. , Velema E. , de Kleijn D.P.V. , Moll F.L.
Published: July 2005

Background and Purpose—

During carotid endarterectomy (CEA), microemboli may occur, resulting in perioperative adverse cerebral events. The objective of the present study was to investigate the relation between atherosclerotic plaque characteristics and the occurrence of microemboli or adverse events during CEA.

Methods—

Patients (n=200, 205 procedures) eligible for CEA were monitored by perioperative transcranial Doppler. The following phases were discriminated during CEA: dissection, shunting, release of the clamp, and wound closure. Each carotid plaque was stained for collagen, macrophages, smooth muscle cells, hematoxylin, and elastin. Semiquantitative analyses were performed on all stainings. Plaques were categorized into 3 groups based on overall appearance (fibrous, fibroatheromatous, or atheromatous).

Results—

Fibrous plaques were associated with the occurrence of more microemboli during clamp release and wound closure compared with atheromatous plaques (
P
=0.04 and
P
=0.02, respectively). Transient ischemic attacks and minor stroke occurred in 5 of 205 (2.4%) and 6 of 205 (2.9%) patients, respectively. Adverse cerebral outcome was significantly related to the number of microembolic events during dissection (
P
=0.003) but not during shunting, clamp release, or wound closure. More cerebrovascular adverse events occurred in patients with atheromatous plaques (7/69) compared with patients with fibrous or fibroatheromatous plaques (4/138) (
P
=0.04).

Conclusions—

Intraoperatively, a higher number of microemboli were associated with the presence of a fibrous but not an atheromatous plaque. However, atheromatous plaques were more prevalent in patients with subsequent immediate adverse events. In addition, specifically the number of microemboli detected during the dissection phase were related to immediate adverse events.
Serum Ferritin Is a Risk Factor for Stroke in Postmenopausal Women
Authors: van der Daphne L. , Grobbee Diederick E. , Roest Mark , Marx Joannes J.M. , Voorbij Hieronymus A. , van der Schouw Yvonne T.
Published: July 2005

Background and Purpose—

Iron is an essential element for the human body. It has, however, been suggested that excessive iron stores may increase the risk of vascular disease. So far, epidemiologic studies on stroke are sparse.

Methods—

We studied the association between iron status and stroke risk in a population-based cohort of 11 471 Dutch postmenopausal women between 49 and 70 years of age. Women were included between 1993 and 1997 and followed up until January 1, 2000, for cerebrovascular events. We conducted a case-cohort study by using all stroke cases (n=63) and a random sample of the baseline cohort (n=1134). Serum ferritin, serum iron, and transferrin saturation were measured as markers of iron status. A weighted Cox proportional-hazards model was used to estimate crude and multivariate-adjusted hazard ratios for tertiles of different iron parameters in relation to stroke.

Results—

In a multivariate model, the highest tertile of serum ferritin concentration was associated with an increased risk of stroke (hazard ratio [HR], 1.45; 95% confidence interval [CI], 0.87 to 2.42) compared with the lowest tertile. For ischemic stroke, the increase was more pronounced (HR, 2.23; 95% CI, 1.05 to 4.73) and reached statistical significance.

Conclusions—

Neither serum iron nor transferrin saturation was associated with an increased stroke risk. However, higher serum ferritin concentrations in postmenopausal women are associated with an increased risk of ischemic stroke.
Polymorphisms in Genes of the Endothelin System and Cerebral Small-Vessel Disease
Authors: Gormley Kelly , Bevan Steve , Hassan Ahamad , Markus Hugh S.
Published: July 2005

Background and Purpose—

Endothelial dysfunction has been implicated in the pathogenesis of cerebral small-vessel disease (SVD). Endothelin (ET), released by the endothelium, plays a crucial role in vasoconstriction in the cerebral circulation and could contribute to the pathogenesis of cerebral SVD. Circulating ET levels may not reflect vascular production of endothelin-1 (ET-1), most of which is abluminal. Studying genetic associations, particularly of functional polymorphisms that alter activity of the ET system, is an attractive method of determining whether ET plays a role in SVD pathogenesis. We determined whether genetic variants in components of the ET system are a risk factor for cerebral SVD.

Methods—

Three hundred SVD patients and 600 community controls were genotyped. Polymorphisms in the ET-1 gene (K198N), the ET receptor type A (ET
A
), (−231
G
>
A
and +1222
C
>
T
), and the ET type B (ET
B
) receptor (G57S and L277L) were genotyped. Polymorphisms were studied both individually and as haplotypes. With brain imaging, cases were subtyped into those with lacunar infarct without leukoaraiosis and those with leukoaraiosis.

Results—

No significant differences were observed between SVD cases and controls for any individual single-nucleotide polymorphism or the ET
A
haplotype. There were no differences between cases with isolated lacunar infarct or with lacunar infarct and leukoaraiosis.

Conclusions—

This study, in a well-phenotyped population, does not support a role for genetic variation in the ET system as a risk factor for cerebral SVD.
“Clinical-CT Mismatch” and the Response to Systemic Thrombolytic Therapy in Acute Ischemic Stroke
Authors: Kent David M. , Hill Michael D. , Ruthazer Robin , Coutts Shelagh B. , Demchuk Andrew M. , Dzialowski Imanuel , Wunderlich Olaf , von Kummer Rudiger
Published: July 2005

Background and Purpose—

Mismatch between clinical deficits and imaging lesions in acute stroke has been proposed as a method of identifying patients who have hypoperfused but still have viable brain, and may be especially apt to respond to reperfusion therapy. We explored this hypothesis using a combined database including 4 major clinical trials of intravenous (IV) thrombolytic therapy.

Methods—

To determine what the radiological correlates of a “matched” functional deficit are, we calculated the relationship between the ASPECT score of the 24-hour (follow-up) CT scan and the 24-hour National Institutes of Health Stroke Scale (NIHSS) score on the subsample with ASPECT scores performed at this time (n=820). Based on this empirical relationship, we computed the absolute difference between the observed baseline ASPECT score and the “expected” score (ie, matched) based on baseline NIHSS for all patients (n=2131). We tested whether patients with better than expected baseline ASPECTS were more likely to benefit from IV recombinant tissue plasminogen activation (rtPA).

Results—

At 24 hours, there was a strong, linear, negative correlation between NIHSS and ASPECTS (r
2
=0.33,
P
<0.0001); on average, an increase of 10 points on NIHSS corresponded to a decrease of ≈3 points on ASPECTS. At baseline, the average degree of mismatch between the observed and “expected” ASPECTS was 2.1 points (interquartile range, 1.0 to 3.4). However, multiple analyses failed to reveal a consistent relationship between the degree of clinical-CT mismatch at baseline and a patient’s likelihood of benefiting from IV rtPA.

Conclusion—

Clinical-CT mismatch using ASPECT scoring does not reliably identify patients more or less likely to benefit from IV rtPA.
The Lexicon-Syntax Parameter: Reflexivization and Other Arity Operations
Authors: Reinhart Tanya , Siloni Tal
Published: July 2005

We argue that crosslinguistic variation regarding verbal reflexivization is parametric, reflecting a broader lexicon-syntax parameter: arity operations—operations on θ-roles, which affect the valence of a predicate—can apply in the lexicon or in the syntax. The significant empirical coverage of this parameter supports the view that the lexicon must be an active component of the grammar. The discussion focuses mainly on the formation of reflexive verbs. We argue that the prevailing view that reflexive verbs have an unaccusative derivation cannot be maintained. Rather, the reflexivization operation bundles a θ-role with an external θ-role, forming a combination that must merge externally. Next, we also briefly review other arity operations: (a) reciprocalization, (b) decausativization, and (c) saturation, which is involved in the formation of passives, middles, and impersonals. Variation in auxiliary selection, owing to the application of reflexivization or other arity operations, is independent of the lexicon-syntax parameter and follows under our approach from a structural accusative Case parameter.
On the Acquisition of Principle B
Authors: Elbourne Paul
Published: July 2005

Chien and Wexler (1990) reported that children obeyed Principle B of binding theory when the antecedent was a quantifier but not when the antecedent was referential. This was argued by Grodzinsky and Reinhart (1993) to support Reinhart's (1983) theory according to which Principle B affects only bound pronouns. Since then, other studies have supported the asymmetry between referential and quantifier antecedents. This article, however, argues that previously unremarked experimental factors lessen the force of all these studies, and it points to other relevant experiments that seem to showthat children do not obey Principle B at all. It reviews previously offered theories on the acquisition of Principle B that are compatible with the latter view of the facts.
Seeing Oneself in the Mirror: Critical Reflections on the Visual Experience of the Reflected Self
Authors: Macke Frank
Published: July 2005

Merleau-Ponty, in his well-known essay, "Eye and Mind," startlingly comments: "A Cartesian does not see himself in the mirror; he sees a dummy, an 'outside,' which, he has every reason to believe, other people see in the very same way but which, no more for himself than for others, is not a body in the flesh." This essay opens up a discourse on this very problem: the question of what one sees when looks at oneself in the mirror. As well, the now-common assumption that we have arrived at a postmodern condition of experience, knowledge, and interpretation comes into question when we consider the possibility that the human sciences have not sufficiently embraced a post-Cartesian perspective on mind, body, self, and vision. The essay closes with a reflection on the contact of the self and the other in vision. The self and the other are not "signs" that are "read" in the context of a perceptual field. Rather, the interpersonal world embodied through the vital flesh of self in communion with other is reflected to the eye only if the observer cares to take note, to imaginatively flesh-out the world embodied in the moment of a thoughtful glance.
Revamping Sartre's Original Project: Freedom's Narcissistic Wound
Authors: Borchers Scott
Published: July 2005

This essay is divided into three parts. In the first, I develop a new interpretation of Sartre's notion of an original project, or original choice, by emending his initial position in Being and Nothingness, and by extrapolating from his autobiography and his psychobiographies on Baudelaire and Flaubert. In the second part, I examine the early and late Sartre's paradoxical commitment to self-analysis, and go on to draw taut the tension in the late Sartre between individual freedom and relations to others. I demonstrate that the tension in the thought of the late Sartre can be explained and resolved only with reference to Sartre's own original projects. The third part is devoted to briefly analyzing what combination of factors in Sartre's developmental history led to his original projects, in view of a possible psychobiography on Sartre. Nearly everything covered in this essay is an attempt by Sartre to appropriate Freud as an instrument in his own thought (Pontalis, 1986). In the third part, I also try to show that Freud resists Sartre's analysis, as it were, and that Sartre only proves Freud right.
The Role of Dialogue, Otherness and the Construction of Insight in Psychosis: Toward a Socio-Dialogic Model
Authors: Dolson Mark
Published: July 2005

The focus is on the intersubjective, narrative and dialogic aspects of the clinical phenomenon of insight in psychosis. By introducing a socio-dialogic model for the clinical production of insight, it can be learned how insight, as a form of self-knowledge (of a morbid alteration in one's relation to the world/others), is a product of the clinical interview, namely the dialogic relation between patient and clinical interviewer. Drawing upon the philosophy of Emmanuel Levinas, expressly his notion of the ethical encounter, the production of insight in the clinical interview is elucidated as both a synchronic and diachronic phenomenon—a provisional form of self-knowledge based on historically-produced frames of meaning which are recalled and narrated, i.e., produced at a specific moment in time. The production of insight, based on auto-biographical memory, is ultimately a processual and transactional phenomenon which arises out of the narrative construction of experience and the dialogic negotiation of the individual's "authored" experience. This process may be understood as a synergistic dynamic between intersubjective micro-processes (dialogue) and symbolic macro-processes (such as "culture"), which may, when crystallized at the individual level, precipitate a subjectively insightful account of the prodromal illness experience.