bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock
Authors: Childs Ed W. , Tharakan Binu , Byrge Nickolas , Tinsley John H. , Hunter Felicia A. , Smythe W. Roy
Published: March 2008

Studies from our laboratory demonstrated the involvement of intrinsic apoptotic signaling in hyperpermeability following hemorrhagic shock (HS). Angiopoietin 1 (Ang-1), a potent inhibitor of hyperpermeability, was recently shown to inhibit apoptosis. The purpose of our study was to determine the effectiveness of Ang-1 in attenuating HS-induced hyperpermeability and its relationship to apoptotic signaling. HS was induced in rats by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 h, followed by reperfusion. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. Mitochondrial release of second mitochondrial derived activator of caspases (smac) and cytochrome c were determined by Western blot and ELISA, respectively. Caspase-3 activity was determined by fluorometric assay. Parallel studies were performed in rat lung microvascular endothelial cell (RLMEC) monolayers, utilizing HS serum and the proapoptotic Bcl-2 homologous antagonist/killer [BAK (BH3)] peptide as inducers of hyperpermeability. In rats, Ang-1 (200 ng/ml) attenuated HS-induced hyperpermeability versus the HS group ( P < 0.05). Ang-1 prevented HS-induced collapse of mitochondrial transmembrane potential (ΔΨm), smac and cytochrome c release, and caspase-3 activity ( P < 0.05). In RLMEC monolayers, HS serum and BAK (BH3) peptide both induced hyperpermeability that was inhibited by Ang-1 ( P < 0.05). Ang-1 attenuated HS and BAK (BH3) peptide-induced collapse of ΔΨm, smac release, cytochrome c release, activation of caspase-3, and vascular hyperpermeability. In vivo, BAK (BH3) induced vascular hyperpermeability that was attenuated by Ang-1 ( P < 0.05). These findings suggest that Ang-1's role in maintaining microvascular endothelial barrier integrity involves the intrinsic apoptotic signaling cascade.
Posttranslational modification of voltage-dependent potassium channel Kv1.5: COOH-terminal palmitoylation modulates its biological properties
Authors: Jindal Hitesh K. , Folco Eduardo J. , Liu Gong Xin , Koren Gideon
Published: March 2008

The physiological function of ion channels is affected by protein-protein and protein-membrane interactions that modulate their activity and/or localization. Palmitoylation modulates protein function by facilitating targeted membrane association, interaction with other proteins, and determining subcellular localization. In this study, we demonstrate that the voltage-dependent potassium (Kv) channel Kv1.5 is palmitoylated and that the mutation of COOH-terminal cysteines is sufficient to abolish the palmitoylation of the Kv1.5 polypeptide in Chinese hamster ovary (CHO) cells. The labeling represented the thioester linkage of the labeled palmitic acid to cysteine rather than amide and oxygen ester linkages as judged by the release of the palmitic acid upon the treatment of the gel with hydroxylamine at a neutral pH. Site-directed mutagenesis and radiolabeling studies revealed that C593 was the sole site of palmitoylation. The elucidation of the biological function of palmitoylation revealed that the expression of the FLAG-Kv1.5 palmitoylation-deficient mutant (FL-Kv1.5Palm−) in stable CHO cells increased membrane expression as determined by the biotinylation of surface proteins and quantitative immunofluorescence analyses of these cells, in turn enhancing the outward potassium current. This enhanced surface expression and the currents were consequential to the slower rate of internalization, causing an increased localization of FL-Kv1.5Palm−in the plasma membrane compared with the wild-type FL-Kv1.5 channels. We conclude that the Kv1.5 channel is palmitoylated and that its palmitoylation modulates its biological functions and, therefore, might provide a physiological link between the metabolic state and the expression of Kv1.5 on the plasma membrane.
Differential arterial blood flow response of splanchnic and renal organs during low-intensity cycling exercise in women
Authors: Endo Masako Yamaoka , Suzuki Rie , Nagahata Naomi , Hayashi Naoyuki , Miura Akira , Koga Shunsaku , Fukuba Yoshiyuki
Published: March 2008

To investigate the regional hemodynamic responses of abdominal arteries at the onset of exercise and to focus on their transient responses, eight female subjects (21–30 yr) performed ergometer cycling exercise at 40 W for 4 min in a semi-supine position. Mean blood velocities (MBVs) in the right renal (RA), superior mesenteric (SMA), and splenic (SA) arteries were measured by pulsed echo-Doppler ultrasonography, with beat-by-beat measurements of heart rate (HR) and mean arterial pressure (MAP). The vascular resistance index (RI) of each artery was calculated from MBV/MAP. MAP (76 ± 9 to 83 ± 8 mmHg at 4 min) and HR (60 ± 7 to 101 ± 9 beats/min at 4 min) increased during exercise ( P < 0.05). The MBV of RA and SA rapidly decreased after the onset of exercise (30 s; −19 ± 5% and −19 ± 12%, respectively), reaching −27 ± 7% and −27 ± 15% at the end of exercise ( P < 0.05). RI did not change during the initial 30 s of exercise, reflecting a reduction in MAP, and increased toward the end of the exercise (+55 ± 21% and +59 ± 39%, respectively). In contrast, both the MBV and RI in the SMA remained constant throughout the exercise. The results indicate that, whereas the responses of renal and splenic vessels changed similarly throughout the protocol, the vascular response of SMA that mainly supplies blood to the intestinal tract was unchanged during exercise. We, therefore, conclude that low-intensity cycling exercise resulted in differential blood flow responses in arteries supplying the abdominal organs.
Transcription repression and blocks in cell cycle progression in hypoplastic left heart syndrome
Authors: Gambetta Katheryn , Al-Ahdab Mohamad K. , Ilbawi Michel N. , Hassaniya Nahidh , Gupta Madhu
Published: March 2008

Hypoplastic left heart syndrome (HLHS) is characterized by abnormally developed atrial septum and a severe underdevelopment of the left side of the heart. Despite significant advances in its surgical management, little is known about the molecular abnormalities in this syndrome. To gain molecular insights into HLHS, expression profiling by gene-chip microarray (Affymetrix U133 2.0) and by real-time RT-PCR was performed in the atrial septum of patients diagnosed with HLHS and compared with age-matched non-HLHS patients. Hierarchical clustering of all expressed genes with a P < 0.01 of all tissue samples showed two main clusters, one of HLHS and the other of non-HLHS, suggesting different expression patterns by the two groups. Net affix followed by real-time RT-PCR analysis identified the differentially expressed genes to be those involved in chromatin remodeling, cell cycle regulation, and transcriptional regulation. These included remodeling factors, histone deactylase 2 and SET and MYND domain containing 1; transcription factors, FoxP1, and components of the calcineurin-nuclear factor of activated T cells signaling pathway; and cell cycle regulators, cyclin-dependent kinase (CDK)-4, phosphatase and tensin homolog, and p18. Since these factors play essential roles in heart growth and development, the abnormal expression pattern suggests that these molecules may contribute to the pathogenesis of HLHS.
A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart
Authors: Cheng Guangmao , Zile Michael R. , Takahashi Masaru , Baicu Catalin F. , Bonnema D. Dirk , Cabral Fernando , Menick Donald R. , Cooper George
Published: March 2008

Contractile dysfunction in pressure overload-hypertrophied myocardium has been attributed in part to the increased density of a stabilized cardiocyte microtubule network. The present study, the first to employ wild-type and mutant tubulin transgenes in a living animal, directly addresses this microtubule hypothesis by defining the contractile mechanics of the normal and hypertrophied left ventricle (LV) and its constituent cardiocytes from transgenic mice having cardiac-restricted replacement of native β4-tubulin with β1-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac β4-tubulin with mutant hemagglutinin-tagged β1-tubulin was well tolerated in vivo. When LVs in intact mice and cardiocytes from these same LVs were examined in terms of contractile mechanics, baseline function was reduced in mice with genetically hyperstabilized microtubules, and hypertrophy-related contractile dysfunction was exacerbated. However, in mice with genetically hypostabilized cardiac microtubules, hypertrophy-related contractile dysfunction was ameliorated. Thus, in direct support of the microtubule hypothesis, we show here that cardiocyte microtubule network density, as an isolated variable, is inversely related to contractile function in vivo and in vitro, and microtubule instability rescues most of the contractile dysfunction seen in pressure overload-hypertrophied myocardium.
Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation
Authors: Kulkarni Amit , Das Kumuda C.
Published: March 2008

Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)- and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 (Ser6) and histone H2AX (Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.
Xanthine oxidoreductase in respiratory and cardiovascular disorders
Authors: Boueiz Adel , Damarla Mahendra , Hassoun Paul M.
Published: March 2008

In addition to its critical role in purine metabolism, xanthine oxidoreductase (XOR) has been implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders such as acute lung injury, ischemia-reperfusion injury, atherosclerosis, heart failure, and arterial hypertension. Although much remains to be clarified about the regulation and signaling pathways of this enzyme, it is quite evident from abundant investigation in animal models and some human trials that XOR inhibition can favorably alter critical disease processes and impact outcomes. From promising bench-to-bedside data, a better understanding of this enigmatic enzyme is emerging. However, the positive findings related to XOR inhibition need to be confirmed in large-scale, well-designed clinical trials. This will hopefully provide new opportunities for therapeutic intervention. This article reviews the available evidence involving XOR in oxidative states with specific emphasis on respiratory and cardiovascular diseases.
Apoetm1Unc mice have impaired alveologenesis, low lung function, and rapid loss of lung function
Authors: Massaro Donald , Massaro Gloria DeCarlo
Published: March 2008

Diminished lung function, indicated by a low forced expiratory volume in one second (FEV1), and short physical stature, predict early mortality from all causes, including cardiovascular, among smokers and never smokers. The basis for these associations is unclear, and, it is not known if there is a pulmonary morphological component to the relationship between low FEV1 and early death in a general population. Some apolipoprotein E genotypes also predict atherosclerosis and early mortality. These considerations led us to examine the Apoe tm1Unc (Apoe) mouse, in which the apolipoprotein E gene is deleted, and that develops dyslipidemia, atherosclerosis at an early age, and has a shorter life span than the founder wild-type (wt) strain. We asked if Apoe mice have a morphological or functional pulmonary phenotype. We measured the size, number, and surface area of pulmonary gas-exchange units (alveoli) and mechanical properties of the lung. Compared with wt mice, Apoe mice had: 1) diminished developmental alveologenesis, 2) increased airway resistance in early adulthood, 3) high lung volume and high dynamic and static compliance in later adulthood, 4) more rapid loss of lung recoil with age, and 5) were less long than wt mice. These findings in mice indicate the association of a low FEV1 with early death in humans may have developmental, and accelerated ageing, related pulmonary components, and that dietary, genetic, or dietary and genetic influences, on lipid metabolism may be an upstream cause of inflammation and oxidative stress, currently considered to be major risk factors for COPD.
Differential effects of intravenous anesthetics on capacitative calcium entry in human pulmonary artery smooth muscle cells
Authors: Yang Mikyung , Ding Xueqin , Murray Paul A.
Published: March 2008

We assessed the roles of the protein kinase C (PKC) and the tyrosine kinase (TK) signaling pathways in regulating capacitative calcium entry (CCE) in human pulmonary artery smooth muscle cells (PASMCs) and investigated the effects of intravenous anesthetics (midazolam, propofol, thiopental, ketamine, etomidate, morphine, and fentanyl) on CCE in human PASMCs. Fura-2-loaded human PASMCs were placed in a dish (37°C) on an inverted fluorescence microscope. Intracellular Ca2+concentration ([Ca2+]i) was measured as the 340/380 fluorescence ratio in individual PASMCs. Thapsigargin, a sarcoplasmic reticulum Ca2+-adenosine triphosphatase inhibitor, was used to deplete intracellular Ca2+stores after removing extracellular Ca2+. CCE was then activated by restoring extracellular Ca2+(2.2 mM). The effects of PKC activation and inhibition, TK inhibition, and the intravenous anesthetics on CCE were assessed. Thapsigargin caused a transient increase in [Ca2+]i. Restoring extracellular Ca2+caused a rapid peak increase in [Ca2+]i, followed by a sustained increase in [Ca2+]i; i.e., CCE was stimulated in human PASMCs. PKC activation attenuated ( P < 0.05), whereas PKC inhibition potentiated ( P < 0.05), both peak and sustained CCE. TK inhibition attenuated ( P < 0.05) both peak and sustained CCE. Midazolam, propofol, and thiopental each attenuated ( P < 0.05) both peak and sustained CCE, whereas ketamine, etomidate, morphine, and fentanyl had no effect on CCE. Our results suggest that CCE in human PASMCs is influenced by both the TK and PKC signaling pathways. Midazolam, propofol, and thiopental each attenuated CCE, whereas ketamine, etomidate, morphine, and fentanyl had no effect on CCE.
Alterations to surfactant precede physiological deterioration during high tidal volume ventilation
Authors: Maruscak Adam A. , Vockeroth Daniel W. , Girardi Brandon , Sheikh Tanya , Possmayer Fred , Lewis James F. , Veldhuizen Ruud A. W.
Published: March 2008

Lung injury due to mechanical ventilation is associated with an impairment of endogenous surfactant. It is unknown whether this impairment is a consequence of or an active contributor to the development and progression of lung injury. To investigate this issue, the present study addressed three questions: Do alterations to surfactant precede physiological lung dysfunction during mechanical ventilation? Which components are responsible for surfactant's biophysical dysfunction? Does exogenous surfactant supplementation offer a physiological benefit in ventilation-induced lung injury? Adult rats were exposed to either a low-stretch [tidal volume (Vt) = 8 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O, respiratory rate (RR) = 54–56 breaths/min (bpm), fractional inspired oxygen (FiO2) = 1.0] or high-stretch (Vt = 30 ml/kg, PEEP = 0 cmH2O, RR = 14–16 bpm, FiO2 = 1.0) ventilation strategy and monitored for either 1 or 2 h. Subsequently, animals were lavaged and the composition and function of surfactant was analyzed. Separate groups of animals received exogenous surfactant after 1 h of high-stretch ventilation and were monitored for an additional 2 h. High stretch induced a significant decrease in blood oxygenation after 2 h of ventilation. Alterations in surfactant pool sizes and activity were observed at 1 h of high-stretch ventilation and progressed over time. The functional impairment of surfactant appeared to be caused by alterations to the hydrophobic components of surfactant. Exogenous surfactant treatment after a period of high-stretch ventilation mitigated subsequent physiological lung dysfunction. Together, these results suggest that alterations of surfactant are a consequence of the ventilation strategy that impair the biophysical activity of this material and thereby contribute directly to lung dysfunction over time.
Lie Group Analysis of a Flow with Contaminant-Modified Viscosity
Authors: Moitsheki Raseelo J.
Published: March 2008

A class of coupled system of diffusion equations is considered. Lie group techniques resulted in a rich array of admitted point symmetries for special cases of the source term. We also employ potential symmetry methods for chosen cases of concentration and a zero source term. Some invariant solutions are constructed using both classical Lie point and potential symmetries.
Endothelial Differentiation of Hematopoietic Stem and Progenitor Cells from Patients with Multiple Myeloma
Authors: Ria Roberto , Piccoli Claudia , Cirulli Teresa , Falzetti Franca , Mangialardi Giuseppe , Guidolin Diego , Tabilio Antonio , Di Renzo Nicola , Guarini Attilio , Ribatti Domenico , Dammacco Franco , Vacca Angelo
Published: March 2008

Purpose: Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines.

Experimental Design: Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture.

Results: HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII–related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance.

Conclusions: In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor.
Ataxia Telangiectasia Mutated and p21CIP1 Modulate Cell Survival of Drug-Induced Senescent Tumor Cells: Implications for Chemotherapy
Authors: Crescenzi Elvira , Palumbo Giuseppe , de Boer Jasper , Brady Hugh J.M.
Published: March 2008

Purpose: Premature or stress-induced senescence is a major cellular response to chemotherapy in solid tumors and contributes to successful treatment. However, senescent tumor cells are resistant to apoptosis and may also reenter the cell cycle. We set out to find a means to specifically induce senescent tumor cells to undergo cell death and not to reenter the cell cycle that may have general application in cancer therapy.

Experimental Design: We investigated the mechanisms regulating cell survival in drug-induced senescent tumor cells. Using immunofluorescence and flow cytometry–based techniques, we established the status of the ataxia telangiectasia mutated (ATM) signaling pathway in these cells. We assayed the requirement of ATM signaling and p21CIP1 expression for survival in premature senescent tumor cells using pharmacologic inhibitors and antisense oligonucleotides.

Results: The ATM/ATR (ATM- and Rad3-related) signaling pathway was found to be constitutively active in drug-induced senescent tumor cells. We found that blocking ATM/ATR signaling with pharmacologic inhibitors, including the novel ATM inhibitors KU55933 and CGK733, induced senescent breast, lung, and colon carcinoma cells to undergo cell death. We show that the mechanism of action of this effect is directly via p21CIP1, which acts downstream of ATM. This is in contrast to the effects of ATM inhibitors on normal, untransformed senescent cells.

Conclusions: Blocking ATM and/or p21CIP1 following initial treatment with a low dose of senescence-inducing chemotherapy is a potentially less toxic and highly specific treatment for carcinomas.
A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker
Authors: Crawford Shelby , Belajic Daniel , Wei Jianmei , Riley Jason P. , Dunford Paul J. , Bembenek Scott , Fourie Anne , Edwards James P. , Karlsson Lars , Brunmark Anders , Wolin Ronald L. , Blevitt Jonathan M.
Published: March 2008

B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAFV600E-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker. [Mol Cancer Ther 2008;7(3):492–9]
Gene-Viral Cancer Therapy Using Dual-Regulated Oncolytic Adenovirus with Antiangiogenesis Gene for Increased Efficacy
Authors: Su Changqing , Na Manli , Chen Jie , Wang Xinghua , Liu Yongjing , Wang Weiguo , Zhang Qi , Li Linfang , Long Ju , Liu Xinyuan , Wu Mengchao , Fan Xiaolong , Qian Qijun
Published: March 2008

Conditionally replicative adenovirus (CRAD) represents a promising approach for cancer therapy. Several CRADs controlled by the human telomerase reverse transcriptase promoter have been developed. However, because of their replicative capacity, the importance of cancer specificity for CRADs needs to be further emphasized. In this study, we have developed a novel dual-regulated CRAD, CNHK500-mE, which has its E1a and E1b gene controlled by the human telomerase reverse transcriptase promoter and the hypoxia response element, respectively. It also carries a mouse endostatin expression cassette controlled by the cytomegalovirus promoter. These properties allow for increased cancer cell targeting specificity and decreased adverse side effects. We showed that CNHK500-mE preferentially replicated in cancer cells. Compared with a replication-defective vector carrying the same endostatin expression cassette, CNHK500-mE–mediated transgene expression level was markedly increased via viral replication within cancer cells. In the nasopharyngeal tumor xenograft model, CNHK500-mE injection resulted in antitumor efficacy at day 7 after therapy. Three weeks later, it led to significant inhibition of xenograft tumor growth due to the combined effects of viral oncolytic therapy and antiangiogenesis gene therapy. Pathologic examination showed that most cancer cells were positive for adenoviral capsid protein and for apoptotic terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling in the CNHK500-mE–treated tumor tissues, and the microvessels in these tumor tissues were diminished in quantity and abnormal in morphology. These results suggest that, as a potential cancer therapeutic agent, the CNHK500-mE is endowed with higher specificity to cancer cells and low cytotoxicity to normal cells. (Mol Cancer Res 2008;6(4):568–75)
CXCL16 Functions as a Novel Chemotactic Factor for Prostate Cancer Cells In vitro
Authors: Lu Yi , Wang Jianhua , Xu Yang , Koch Alisa E. , Cai Zhong , Chen Xue , Galson Deborah L. , Taichman Russell S. , Zhang Jian
Published: March 2008

A variety of tumor cells produce chemokines that promote tumor cell proliferation and chemotaxis. We previously reported that CXCL16 production is increased in aggressive prostate cancer cells compared with the less aggressive tumor cells and benign cells as identified in a cytokine antibody array. The functional contribution of CXCL16 in prostate cancer development has not yet been evaluated. Accordingly, mRNA expression of CXCL16 and its receptor, CXCR6, were determined by real-time reverse transcription-PCR in various cancer cell lines, including prostate cancer and tissues obtained from localized and metastatic prostate cancer. Consistent with our finding on CXCL16 protein production by prostate cancer cells, aggressive prostate cancer C4-2B and PC3 cells, as well as bone and liver metastatic tissues, expressed higher levels of both CXCL16 and CXCR6 mRNA compared with the less aggressive prostate cancer LNCaP cells, nonneoplastic PrEC and RWPE-1 cells, and benign prostate tissues, respectively. Furthermore, CXCR6 and CXCL16 protein expressions were examined in tissue specimens by immunohistochemistry. Immunohistochemical examination of CXCR6 expression showed strong epithelial staining that correlated with Gleason score, whereas CXCL16 staining was not. Finally, we found that both interleukin-1β and tumor necrosis factor α significantly induced CXCL16 production by prostate epithelial cells, thereby indicating that inflammatory cytokines may play a role in the CXCL16 induction. CXCL16 was found to promote prostate cancer cell migration and invasion in vitro. Therefore, we concluded that CXCL16 functions, through CXCR6, as a novel chemotactic factor for prostate cancer cells. (Mol Cancer Res 2008;6(4):546–54)
Glycaemic control improves fibrin network characteristics in type 2 diabetes – A purified fibrinogen model
Authors: Covic Namukolo , van der Westhuizen Francois , Nagaswami Chandrasekaran , Baras Yelena , Loots Du , Jerling Johann , Elgar Dale , Edmondson Kathryn , van Zyl Danie , Rheeder Paul , Weisel John , Pieters Marlien
Published: March 2008

Diabetic subjects have been shown to have altered fibrin network structures. One proposed mechanism for this is non-enzymatic glycation of fibrinogen due to high blood glucose. We investigated whether glycaemic control would result in altered fibrin network structures due to decreased fibrinogen glycation. Twenty uncontrolled type 2 diabetic subjects were treated with insulin in order to achieve glycaemic control. Twenty age- and body mass index (BMI)-matched non-diabetic subjects were included as a reference group. Purified fibrinogen, isolated from plasma samples was used for analysis. There was a significant decrease in fibrinogen glycation (6.81 to 5.02 mol glucose/mol fibrinogen) with a corresponding decrease in rate of lateral aggregation (5.86 to 4.62) and increased permeability (2.45 to 2.85 × 10−8 cm2) and lysis rate (3.08 to 3.27 μm/min) in the diabetic subjects after glycaemic control. These variables correlated with markers of glycaemic control. Fibrin clots of non-diabetic subjects had a significantly higher ratio of inelastic to elastic deformation than the diabetic subjects (0.10 vs. 0.09). Although there was no difference in median fiber diameter between diabetic and non-diabetic subjects, there was a small increase in the proportion of thicker fibers in the diabetic samples after glycaemic control. Results from SDS-PAGE indicated no detectable difference in factor XIIIa-crosslinking of fibrin clots between uncontrolled and controlled diabetic samples. Diabetic subjects may have altered fibrin network formation kinetics which contributes to decreased pore size and lysis rate of fibrin clots. Achievement of glycaemic control and decreased fibrinogen glycation level improves permeability and lysis rates in a purified fibrinogen model
Mild Induced Hypertension Improves Blood Flow and Oxygen Metabolism in Transient Focal Cerebral Ischemia
Authors: Shin Hwa Kyoung , Nishimura Masaki , Jones Phillip B. , Ay Hakan , Boas David A. , Moskowitz Michael A. , Ayata Cenk
Published: March 2008

Background and Purpose—

In focal ischemic cortex, cerebral blood flow autoregulation is impaired, and perfusion passively follows blood pressure variations. Although it is generally agreed that profound hypotension is harmful in acute stroke, the hemodynamic and metabolic impact of increased blood pressure on the ischemic core and penumbra are less well understood. We, therefore, tested whether pharmacologically induced hypertension improves cerebral blood flow and metabolism and tissue outcome in acute stroke using optical imaging with high spatiotemporal resolution.

Methods—

Cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen were measured noninvasively using simultaneous multispectral reflectance imaging and laser speckle flowmetry during distal middle cerebral artery occlusion in mice. Hypertension was induced by phenylephrine infusion starting 10 or 60 minutes after ischemia to raise blood pressure by 30% for the duration of ischemia; control groups received saline infusion.

Results—

Mild induced hypertension rapidly increased cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen in both the core and penumbra and prevented the expansion of cerebral blood flow deficit during 1 hour distal middle cerebral artery occlusion. Induced hypertension also diminished the deleterious effects of periinfarct depolarizations on cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen without altering their frequency. Consistent with this, mild induced hypertension reduced infarct volume by 48% without exacerbating tissue swelling when measured 2 days after 1 hour transient distal middle cerebral artery occlusion.

Conclusions—

Our data suggest that mild induced hypertension increases collateral cerebral blood flow and oxygenation and improves cerebral metabolic rate of oxygen in the core and penumbra, supporting its use as bridging therapy in acute ischemic stroke until arterial recanalization is achieved.
Racial and Ethnic Differences in Postacute Rehabilitation Outcomes After Stroke in the United States
Authors: Ottenbacher Kenneth J. , Campbell Joanna , Kuo Yong-Fang , Deutsch Anne , Ostir Glenn V. , Granger Carl V.
Published: March 2008

Background and Purpose—

Incidence, prevalence, and mortality for stroke vary by race and ethnicity with higher rates for blacks compared with non-Hispanic whites. Little information is available regarding differences in postacute care outcomes for racial and ethnic groups after a stroke.

Methods—

A retrospective analysis was conducted of 161 692 patients from the Uniform Data System for Medical Rehabilitation who received inpatient medical rehabilitation after a first stroke in 2002 and 2003. Multivariable models examined the effects of race and ethnicity on length of stay, functional status, rehabilitation efficiency, and discharge setting.

Results—

The mean age was 70.97 years (SD=12.87), 53% were female, and 76% were non-Hispanic white. Mean length of stay was similar for all groups ranging from 17.39 days (SD=10.86) to 17.93 (SD=10.59). Non-Hispanic white patients had higher admission and discharge functional status ratings compared with patients in the minority groups (
P
<0.01). Differences in functional status across racial/ethnic groups were related to age (F=20.49,
P
<0.001); the older the comparison group, the greater the difference in functional status. Non-Hispanic whites were discharged home less often than blacks (OR=0.64, 95% CI=0.62 to 0.66), Hispanics (OR=0.58, 95% CI=0.55 to 0.62), or other minority groups (OR=0.67, 95% CI=0.57 to 0.67).

Conclusions—

The findings suggest racial and ethnic disparities exist in postacute care outcomes for persons with stroke.
Severity of Leukoaraiosis and Susceptibility to Infarct Growth in Acute Stroke
Authors: Ay Hakan , Arsava E. Murat , Rosand Jonathan , Furie Karen L. , Singhal Aneesh B. , Schaefer Pamela W. , Wu Ona , Gonzalez R. Gilberto , Koroshetz Walter J. , Sorensen A. Gregory
Published: March 2008

Background and Purpose—

Leukoaraiosis (LA) is associated with structural and functional vascular changes that may compromise tissue perfusion at the microvascular level. We hypothesized that the volume of LA correlated with the proportion of initially ischemic but eventually infarcted tissue in acute human stroke.

Methods—

We studied 61 consecutive patients with diffusion-weighted imaging–mean transit time mismatch. All patients were scanned twice within 12 hours of symptom onset and between days 4 and 30. We explored the relationship between the volume of white matter regions with LA on acute images and the proportion of diffusion-weighted imaging–mean transit time mismatch tissue that progressed to infarction (percentage mismatch lost).

Results—

Bivariate analyses showed a statistically significant correlation between percentage mismatch lost and LA volume (
r
=0.33,
P
<0.01). A linear regression model with percentage mismatch lost as response and LA volume, acute diffusion-weighted imaging and mean transit time volumes, age, admission blood glucose level, admission mean arterial blood pressure, etiologic stroke subtype, time to acute MRI, and time between acute and follow-up imaging as covariates revealed that LA volume was an independent predictor of infarct growth (
P
=0.04). The adjusted percentage mismatch lost in the highest quartile of LA volume was 1.9-fold (95% CI: 1.2 to 3.1) greater than the percentage mismatch lost in the lowest quartile.

Conclusion—

LA volume at the time of acute ischemic stroke is a predictor infarct growth. Because LA is associated with factors that modulate tissue perfusion as well as tissue capacity for handling of ischemia, LA volume appears to be a composite predictive marker for the fate of acutely ischemic tissue.
Functional MRI Correlates of Lower Limb Function in Stroke Victims With Gait Impairment
Authors: Enzinger Christian , Johansen-Berg Heidi , Dawes Helen , Bogdanovic Marko , Collett Jonathan , Guy Claire , Ropele Stefan , Kischka Udo , Wade Derick , Fazekas Franz , Matthews Paul M.
Published: March 2008

Background and Purpose—

Although knowledge concerning cortical reorganization related to upper limb function after ischemic stroke is growing, similar data for lower limb movements are limited. Previous studies with hand movement suggested increasing recruitment of motor areas in the unlesioned hemisphere with increasing disability. We used ankle movement as a lower limb analog to test for similarities and differences in recovery patterns.

Methods—

Eighteen subjects were selected with chronic residual gait impairment due to a single subcortical ischemic stroke. Functional MRI scans were obtained at 3.0 T during active and passive ankle dorsiflexion in the patients (8 females, 10 males; mean age, 59.9±13.5 years; range, 32 to 74 years) and 18 age-matched healthy control subjects.

Results—

We observed substantial neocortical activity associated with foot movement both in the patients with stroke and in the healthy control subjects. Our primary finding was increased cortical activation with increasing functional impairment. The extent of activation (particularly in the primary sensorimotor cortex and the supplementary motor area of the unlesioned hemisphere) increased with disability. The changes were most prominent with the active movement task.

Conclusions—

Using ankle movement, we observed increased activation in the unlesioned hemisphere associated with worse function of the paretic leg, consistent with studies on movement of paretic upper limbs. We interpret this finding as potentially adaptive recruitment of undamaged ipsilateral motor control pathways from the supplementary motor area and (possibly maladaptive) disinhibition of the ipsilateral sensorimotor cortex.
Endovascular Thrombectomy and Thrombolysis for Severe Cerebral Sinus Thrombosis
Authors: Stam Jan , Majoie Charles B.L.M. , van Delden Otto M. , van Lienden Krijn P. , Reekers Jim A.
Published: March 2008

Background and Purpose—

Most patients with cerebral sinus thrombosis (CST) recover after treatment with heparin, but a subgroup has a poor prognosis. Those patients may benefit from endovascular thrombolysis.

Methods—

Prospective case series. Patients with sinus thrombosis were selected for thrombolysis if they had an altered mental status, coma, straight sinus thrombosis, or large space-occupying lesions. Urokinase was infused into the sinuses (bolus 120 to 600×10
3
U; then 100×10
3
U/h) via a jugular catheter, in 15 cases combined with mechanical thrombus disruption or removal.

Results—

We treated 20 patients (16 women), mean age 32 years. Twelve patients were comatose and 14 had hemorrhagic infarcts before thrombolysis. Twelve patients recovered (Rankin score 0 to 2), 2 survived with handicaps, and 6 died. Factors associated with a fatal outcome were leukemia (3/6 versus 0/14,
P
=0.02) and large hemorrhagic infarcts (4/6 versus 2/14,
P
=0.04). Seizures were less frequent in the fatal cases (
P
=0.05). Patients who died had a larger mean lesion surface than survivors (30.5 versus 13.6 cm
2
;
P
=0.03), larger midline shift (5.2 versus 1.7 mm;
P
=0.02), and a more rapid course (2.7 versus 8.2 days;
P
=0.01). Five patients who died had large hemispheric infarcts and edema before thrombolysis, causing herniation. Five patients had increased cerebral hemorrhage (3 minor, 2 major) after thrombolysis.

Conclusions—

Thrombolysis can be effective for severe sinus thrombosis, but patients may deteriorate because of increased cerebral hemorrhage. Patients with large infarcts and impending herniation did not benefit.
Morphological But Not Functional Changes of the Carotid Artery Are Associated With the Extent of Coronary Artery Disease in Patients With Preserved Left Ventricular Function
Authors: Sugioka Kenichi , Hozumi Takeshi , Iwata Shinichi , Oe Hiroki , Okuyama Takuhiro , Shirai Nobuyuki , Yamashita Hajime , Ehara Shoichi , Kataoka Toru , Yoshikawa Junichi , Ueda Makiko , Yoshiyama Minoru
Published: March 2008

Background and Purpose—

The atherosclerotic process is associated with both morphological and functional changes in the carotid artery. We evaluated the relationship between these parameters of the carotid artery and the extent of coronary artery disease (CAD) in patients with preserved left ventricular function.

Methods—

The study population consisted of 104 stable patients with CAD who had preserved left ventricular function (left ventricular ejection fraction ≥45%). All patients underwent carotid ultrasound for evaluation of carotid artery plaque score defined by the sum of plaque thickness, maximum percent area stenosis, and carotid arterial stiffness index β calculated by a combination of changes in carotid arterial diameter and blood pressure.

Results—

Plaque score and percent area stenosis correlated with the extent of CAD defined as the number of diseased coronary vessels (
P
<0.001 and 0.002, respectively), but arterial stiffness β did not (
P
=0.39). Using logistic regression analyses adjusting for confounding coronary risk factors and arterial stiffness β, plaque score and percent area stenosis were independently correlated with multivessel CAD (
P
=0.001 and 0.004, respectively).

Conclusions—

Carotid artery plaque burden, but not arterial stiffness, is associated with the extent of CAD, suggesting morphological rather than functional changes in the carotid artery may be a more accurate predictor of the extent of CAD and multivessel CAD independent of left ventricular function.
Whole Genome Analyses Suggest Ischemic Stroke and Heart Disease Share an Association With Polymorphisms on Chromosome 9p21
Authors: Matarin Mar , Brown W. Mark , Singleton Andrew , Hardy John A. , Meschia James F.
Published: March 2008

Background and Purpose—

Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near
CDKN2A
and
CDKN2B
genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population.

Methods—

We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400 000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block.

Results—

In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65).

Conclusions—

These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.
Sonothrombolysis With Transcranial Color-Coded Sonography and Recombinant Tissue-Type Plasminogen Activator in Acute Middle Cerebral Artery Main Stem Occlusion
Authors: Eggers Jürgen , König Inke R. , Koch Björn , Händler Götz , Seidel Günter
Published: March 2008

Background and Purpose—

Sonothrombolysis is a new treatment approach in acute ischemic stroke. The results of a monocenter, randomized clinical study are presented.

Methods—

Subjects with acute middle cerebral artery main stem occlusion were randomized into a target group receiving 1-hour transcranial continuous insonation using a 1.8-MHz Doppler ultrasound (US) probe or a control group. All underwent standard thrombolysis with intravenous recombinant tissue-type plasminogen activator.

Results—

Thirty-seven subjects were included; 19 subjects were treated in the target (US) group and 18 in the control (no-US) group, all with no residual flow in the middle cerebral artery main stem occlusion (Thrombolysis in Brain Ischemia recanalization grade 0). Compared with the no-US group, the US group showed greater improvement in National Institutes of Health Stroke Scale values at days 1 and 4 and a higher median Thrombolysis in Brain Ischemia grade 1 hour after recombinant tissue-type plasminogen activator initiation. Recanalization (complete or partial) after 1 hour occurred in 57.9% of the US group and 22.2% of the no-US group (
P
=0.045). After 90 days, 4 subjects from the US group had a modified Rankin Score ≤1 (none from the no-US group) and 8 had a Barthel Index ≥95 (none from the no US group;
P
=0.106 and
P
=0.003, respectively). Three subjects from the US group (15.8%) developed a symptomatic intracranial hemorrhage as did one (5.6%) in the no-US group (
P
=0.60).

Conclusions—

This small randomized study indicates a beneficial impact of transcranial ultrasound on recanalization and short-term outcome in subjects with middle cerebral artery main stem occlusion and recombinant tissue-type plasminogen activator treatment.
Middle Cerebral Artery Occlusion in the Rabbit Using Selective Angiography
Authors: Jahan Reza , Stewart Daphne , Vinters Harry V. , Yong William , Vinuela Fernando , Vandeberg Pete , Marder Victor J.
Published: March 2008

Background and Purpose—

An animal model of selective middle cerebral artery (MCA) occlusion is needed for evaluation of intra-arterial (IA) delivery of thrombolytic agents. We describe a technique for MCA thrombo-occlusion in the rabbit with real-time angiographic documentation of occlusion and thrombolytic recanalization.

Methods—

After femoral artery cutdown, a microcatheter was advanced from the internal carotid artery to the MCA. MCA occlusion was achieved by IA thrombin and reperfusion by IA plasmin.

Results—

The terminal internal carotid artery was successfully catheterized in 12 of 13 animals. Stable (2-hour) MCA occlusion was induced and verified angiographically in all 12 animals; 2 animals also had distal internal carotid artery thrombus. Recanalization was achieved rapidly after IA plasmin in 3 of 3 animals.

Conclusions—

We describe a new animal model of selective MCA occlusion documented by real-time angiography and used to demonstrate recanalization with IA plasmin.
Observation of the Lenticulostriate Arteries in the Human Brain In Vivo Using 7.0T MR Angiography
Authors: Cho Zang-Hee , Kang Chang-Ki , Han Jae-Yong , Kim Sang-Hoon , Kim Kyoung-Nam , Hong Suk-Min , Park Cheol-Wan , Kim Young-Bo
Published: March 2008

Background and Purpose—

We sought to examine the feasibility of observing the lenticulostriate arteries (LSAs) noninvasively by ultrahigh-field MRI with 7.0T.

Methods—

We used 3-dimensional time-of-flight MR angiography with a radiofrequency coil optimized for 7.0T MRI. We examined the LSAs of 6 healthy subjects and compared 7.0T MR angiography images with 1.5T ones to examine the potentials of ultrahigh-field MRI for angiography.

Results—

The results show clear details of LSAs and their distribution in the normal healthy subjects with large variations in the shapes, the number of branches and the sites of origin. We also observed substantial differences between the left and right sides within each subject. Although we studied only 6 subjects, we found no age- or gender-related differences in the LSAs.

Conclusions—

The visualization of microvasculature of the brain, such as LSAs, using 7.0T MR angiography, is possible in in vivo human studies noninvasively. We, therefore, believe that it could play a major role in the study of small vascular abnormalities, such as the early stages of cerebral strokes.