bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic Suppression of Angiogenesis following Radiation Exposure Is Independent of Hematopoietic Reconstitution
Authors: Udagawa Taturo , Birsner Amy E. , Wood Mark , D'Amato Robert J.
Published: March 2007

Radiation can potentially suppress neovascularization by inhibiting the incorporation of hematopoietic precursors as well as damaging mature endothelial cells. The purpose of these studies was to quantify the effect of radiation on angiogenesis and to examine the relationship between bone marrow reconstitution and neovascularization. Immune competent, severe combined immunodeficient, RAG1-deficient, and green fluorescence protein transgenic mice in the C57 genetic background, as well as the highly angiogenic 129S1/SvlmJ strain of mice, underwent whole-body or localized exposure to radiation. The hematopoietic systems in the irradiated recipients were restored by bone marrow transfer. Hematopoietic reconstitution was assessed by doing complete blood counts. Angiogenesis was induced in the mouse cornea using 80 ng of purified basic fibroblast growth factor, and the neovascular response was quantified using a slit lamp biomicroscope. Following whole-body exposure and bone marrow transplantation, the hematopoietic system was successfully reconstituted over time, but the corneal angiogenic response was permanently and significantly blunted up to 66%. Localized exposure of the eyes to radiation suppressed corneal angiogenesis comparably to whole-body exposure. Whole-body irradiation with ocular shielding induced bone marrow suppression but did not inhibit corneal neovascularization. In mice exposed to radiation before tumor implantation, the reduced local angiogenic response correlated with significantly reduced growth of tumor cells in vivo. These results indicate that bone marrow suppression does not suppress neovascularization in the mouse cornea and that although hematopoietic stem cells can readily reconstitute peripheral blood, they do not restore a local radiation-induced deficit in neovascular response. [Cancer Res 2007;67(5):2040–5]
Serine-Arginine Protein Kinase 1 Overexpression Is Associated with Tumorigenic Imbalance in Mitogen-Activated Protein Kinase Pathways in Breast, Colonic, and Pancreatic Carcinomas
Authors: Hayes Gregory M. , Carrigan Patricia E. , Miller Laurence J.
Published: March 2007

Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serine-arginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. [Cancer Res 2007;67(5):2072–80]
Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine
Authors: Groth-Pedersen Line , Ostenfeld Marie Stampe , Høyer-Hansen Maria , Nylandsted Jesper , Jäättelä Marja
Published: March 2007

Vincristine is a microtubule-destabilizing antimitotic drug that has been used in cancer therapy for over 40 years. However, the knowledge on vincristine-induced cell death pathways is still sparse. Here, we show that vincristine induces dramatic changes in the lysosomal compartment and sensitizes cells to lysosomal membrane permeabilization. In HeLa cervix carcinoma cells, vincristine induced mitotic arrest and massive cell death associated with an early increase in the lysosomal volume and lysosomal leakage followed by the activation of the intrinsic apoptosis program. In contrast, the majority of vincristine-treated MCF-7 breast carcinoma cells resisted apoptosis. Instead, they adapted to the spindle assembly checkpoint and escaped the mitotic arrest as micronucleated and senescent cells with an increase in the volume and the activity of their lysosomal compartment. Consistent with its substantial effects on the lysosomes, vincristine greatly sensitized cultured cancer cells as well as orthotopic breast cancer xenografts in mice to the cytotoxicity induced by siramesine, a sigma-2 receptor ligand that kills cancer cells by destabilizing their lysosomes. Importantly, the combination of nontoxic concentrations of vincristine and siramesine resulted in massive cell death even in MCF-7 cells that were capable of escaping vincristine-induced spindle assembly checkpoint and cell death. Similar synergism was observed when siramesine was combined with a semisynthetic vincristine analogue, vinorelbine, or with microtubule-stabilizing paclitaxel. These data strongly suggest that combination therapies consisting of microtubule-disturbing and lysosome-destabilizing drugs may prove useful in the treatment of otherwise therapy-resistant human cancers. [Cancer Res 2007;67(5):2217–25]
Overexpression of Dicer in Precursor Lesions of Lung Adenocarcinoma
Authors: Chiosea Simion , Jelezcova Elena , Chandran Uma , Luo Jianhua , Mantha Geeta , Sobol Robert W. , Dacic Sanja
Published: March 2007

Differential microRNA (miR) expression is described in non–small cell lung carcinoma. miR biogenesis requires a set of proteins collectively referred to as the miR machinery. In the proposed multistep carcinogenesis model, peripheral adenocarcinoma of the lung develops from noninvasive precursor lesions known as atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC). The gene array analysis of BAC and adenocarcinoma showed a transient up-regulation of Dicer (a key effector protein for small interfering RNA and miR function) and PACT along with down-regulation of most genes encoding miR machinery proteins. Immunohistochemically, Dicer was up-regulated in AAH and BAC and down-regulated in areas of invasion and in advanced adenocarcinoma. A fraction of adenocarcinomas lose Dicer as a result of deletions at the Dicer locus. Expanded immunohistochemical and Western blot analysis showed higher Dicer level in squamous cell carcinoma (SCC) of the lung when compared with adenocarcinoma. Other proteins of the RNA-induced silencing complex (RISC; SND1, PACT, and FXR1) were also present at higher levels in a SCC cell line when compared with an adenocarcinoma cell line. In conclusion, the stoichiometry of miR machinery and RISC depends on histologic subtype of lung carcinoma, varies along the AAH-BAC-adenocarcinoma sequence, and might explain the observed abnormal miR profile in lung cancer. The status of the endogenous miR machinery in various histologic subtypes and stages of lung cancer may help to predict the toxicity of and susceptibility to future RNA interference–based therapy. [Cancer Res 2007;67(5):2345–50]
Breaking Chemoresistance and Radioresistance with [213Bi]anti-CD45 Antibodies in Leukemia Cells
Authors: Friesen Claudia , Glatting Gerhard , Koop Bernd , Schwarz Klaus , Morgenstern Alfred , Apostolidis Christos , Debatin Klaus-Michael , Reske Sven N.
Published: March 2007

Chemoresistance and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. Targeted radiotherapy using monoclonal antibodies radiolabeled with α-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the α-emitter 213Bi ([213Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks β-irradiation–, γ-irradiation–, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to β-irradiation–, γ-irradiation–, and doxorubicin-mediated apoptosis and DNA damage, [213Bi]anti-CD45–induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous end-joining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [213Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [213Bi]anti-CD45 reversed deficient activation of caspase-3, caspase-8, and caspase-9, deficient cleavage of poly(ADP-ribose) polymerase, and deficient activation of mitochondria in chemoresistant and in radioresistant and apoptosis-resistant leukemia cells. These findings show that [213Bi]anti-CD45 is a promising therapeutic agent to break chemoresistance and radioresistance by overcoming DNA repair mechanisms in leukemia cells and provide the foundation for discovery of novel anticancer compounds. [Cancer Res 2007;67(5):1950–8]
Combined Treatment with Temozolomide and Methoxyamine: Blocking Apurininc/Pyrimidinic Site Repair Coupled with Targeting Topoisomerase IIα
Authors: Yan Ling , Bulgar Alina , Miao Yanling , Mahajan Varun , Donze Jon R. , Gerson Stanton L. , Liu Lili
Published: March 2007

Purpose: Methoxyamine has been shown to potentiate the cytotoxic effect of temozolomide both in vitro and in human tumor xenograft models. We postulate that the enhanced cytotoxicity is mediated by methoxyamine-bound apurininc/pyrimidinic (MX-AP) site, a key lesion formed by the combination of temozolomide and methoxyamine. When located within topoisomerase IIα (topo II) cleavage sites in DNA, MX-AP sites act as dual lethal targets, not only functionally disrupting the base excision repair (BER) pathway but also potentially poisoning topo II.

Experimental Design: Using oligonucleotide substrates, in which a position-specific MX-AP site is located within topo II cleavage sites, we examined the effect of MX-AP site on both AP endonuclease– and topo II–mediated DNA cleavage in vitro.

Results: MX-AP sites were refractory to the catalytic activity of AP endonuclease, indicating their ability to block BER. However, they were cleaved by either purified topo II or nuclear extracts from tumor cells expressing high levels of topo II, suggesting that MX-AP sites stimulate topo II–mediated DNA cleavages. In cells, treatment with temozolomide and methoxyamine increased the expression of topo II and enriched the formation of γH2AX foci, which were colocalized with up-regulated topo II, confirming that DNA double-strand breaks marked by γH2AX foci are associated with topo II in cells.

Conclusions: Our findings identify a molecular mechanism of cell death whereby MX-AP sites that cumulated in cells due to resistance to BER potentially convert topo II into biotoxins, resulting in enzyme-mediated DNA scission and cell death.
Tubedown Expression Correlates with the Differentiation Status and Aggressiveness of Neuroblastic Tumors
Authors: Martin Darryl T. , Gendron Robert L. , Jarzembowski Jason A. , Perry Arie , Collins Margaret H. , Pushpanathan Chitra , Miskiewicz Ewa , Castle Valerie P. , Paradis Hélène
Published: March 2007

Purpose: The discovery and validation of new prognostic factors and further refinement of risk group stratification are needed to improve clinical interpretation of neuroblastoma. Our laboratory isolated and characterized a developmentally regulated gene named TUBEDOWN against which we have raised a monoclonal antibody (OE5). Tubedown becomes down-regulated postnatally yet remains strongly expressed in some neuroblastomas. The purpose of this study is to define the utility of Tubedown expression as a new measure of the differentiation status and aggressiveness of neuroblastic tumors.

Experimental Design: Tubedown protein expression was quantitatively assessed in neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) and normal adrenal tissues using Western blot and OE5 immunohistochemistry. Regulation of Tubedown expression during retinoic acid–induced neuronal differentiation in neuroblastoma cell lines was assessed by Western blotting.

Results: High levels of Tubedown expression are observed in tumors with significant neuroblastic component, unfavorable histopathology, advanced stage, high-risk group, and poor outcome. In contrast, more differentiated subsets of neuroblastic tumors, ganglioneuroblastomas with favorable histopathology and ganglioneuromas, express low levels of Tubedown. In vitro, marked retinoic acid–induced neuronal differentiation responses of neuroblastoma cells are associated with a significant decrease in Tubedown expression, whereas limited neuronal differentiation responses to retinoic acid were associated with little or no decrease in Tubedown expression.

Conclusions: Our results indicate that the levels of Tubedown expression are linked to the differentiation status and aggressiveness of neuroblastic tumors and represent an independent prognostic factor for neuroblastoma. Tubedown expression may be useful to more accurately define different neuroblastic tumor subsets and ultimately provide more adequate assessment and treatment for neuroblastoma patients.
Amplified in Breast Cancer 1 in Human Epidermal Growth Factor Receptor–Positive Tumors of Tamoxifen-Treated Breast Cancer Patients
Authors: Kirkegaard Tove , McGlynn Liane M. , Campbell Fiona M. , Müller Sven , Tovey Sian M. , Dunne Barbara , Nielsen Kirsten V. , Cooke Timothy G. , Bartlett John M.S.
Published: March 2007

Purpose: Amplified in breast cancer 1 (AIB1) is a member of the p160/steroid receptor coactivators family and is involved in estrogen-dependent gene transcription by reducing the antagonistic activity of tamoxifen-bound estrogen receptor-α (ER-α). The present study was carried out to test the hypothesis that AIB1 protein expression and/or gene amplification mediates tamoxifen resistance in breast cancer.

Experimental Design: Immunohistochemistry using AIB1 antibody and fluorescence in situ hybridization using probes specific for AIB1 and chromosome 20 was done on 402 ER-α–positive tamoxifen-treated breast cancers.

Results: AIB1 overexpression was not associated with relapse during treatment with tamoxifen. In contrast, high AIB1 expression in patients with human epidermal growth factor receptor (HER) 2– and HER3-overexpressing tumors or tumors expressing one or more of HER1, HER2, or HER3 (HER1-3 positive) was associated with an increased risk of relapse on tamoxifen [hazard ratio, 2.20; 95% confidence interval, 1.07-3.52 (P = 0.0416); hazard ratio, 2.42; 95% confidence interval, 1.32-4.43 (P = 0.0030), respectively]. AIB1 gene amplification was observed in 18 of 362 (5%) patients. High AIB1 gene copy number had no effect on overall or disease-free survival.

Conclusions: Data presented here support a role for AIB1 expression on relapse during tamoxifen treatment in hormone-responsive HER-expressing clinical breast cancers and support clinical evidence, suggesting a cross-talk between ER-α and growth factor receptor pathways through changes in expression of specific coactivator proteins, such as AIB1. This study highlights the potential that tumor profiling, using multiple markers of treatment response, may improve patient selection for endocrine treatment, such as tamoxifen or aromatase inhibitors.
Mesothelin Expression in Human Lung Cancer
Authors: Ho Mitchell , Bera Tapan K. , Willingham Mark C. , Onda Masanori , Hassan Raffit , FitzGerald David , Pastan Ira
Published: March 2007

Purpose: To investigate mesothelin as a new target for immunotherapy in lung cancer.

Experimental Design: Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific for mesothelin was assessed for its cytotoxic activity against lung cancer cells.

Results: We found that mesothelin mRNA was expressed in 83% of lung adenocarcinomas (10 of 12 patients). The mesothelin precursor protein was detected in 82% of lung adenocarcinoma (9 of 11 patients), and its mature form was detected in 55% (6 of 11 patients). Immunohistochemistry showed strong and diffuse mesothelin staining in human lung adenocarcinomas and weak or modest staining in squamous cell carcinomas. We detected mesothelin mRNA in 78% of lung cancer cell lines (7 of 9) of the NCI-60 cell line panel. Mesothelin mRNA and proteins were expressed at a high level in non–small cell lung cancer lines EKVX, NCI-H460, NCI-H322M, and NCI-H522. Flow cytometric analysis showed high surface expression of mesothelin in NCI-H322M and EKVX cell lines. Immunotoxin SS1P showed high cytotoxic activity on NCI-H322M and EKVX cells with IC50 values ranging from 2 to 5 ng/mL.

Conclusions: Mesothelin is expressed on the surface of most lung adenocarcinoma cells. Immunotoxin SS1P is cytotoxic against mesothelin-expressing lung cancer cell lines and merits evaluation as a new therapeutic agent in treating non–small cell lung cancer.
April 16th: The World Voice Day
Authors: Švec Jan G. , Behlau Mara
Published: March 2007

Although the voice is used as an everyday basis of speech, most people realize its importance only when a voice problem arises. Increasing public awareness of the importance of the voice and alertness to voice problems are the main goals of the World Voice Day, which is celebrated yearly on April 16th. The event started as a national initiative in Brazil in 1999 and quickly spread internationally. The article provides a brief history of the World Voice Day, together with basic background information.
Effects of Two Conventional Preoperative Radiation Schedules on Anastomotic Healing in the Rat Colon
Authors: Bedirli Abdulkadir , Kerem Mustafa , Karahacioglu Eray , Ofluoglu Ebru , Yilmaz T. Utku , Pasaoglu Hatice , Tater O. Petek , Sakrak Omer , Pak Yucel
Published: March 2007

Background: Preoperative radiotherapy (RT) is an increasingly popular form of adjunct therapy for rectal cancer; however, little is known about its effects on matrix metalloproteinase (MMP) expression in colonic anastomotic healing. Methods: Wistar rats were irradiated to a total dose of 25 or 40 Gy. Four days after the end of RT, an end-to-end colorectal anastomosis was performed. Animals were sacrificed at 1, 3, and 7 days after the anastomosis. A control group was studied similarly, but was not irradiated. Results: No significant differences were found in peritonitis rate and anastomotic complications. The average bursting pressure and breaking strength were only reduced significantly in the rats irradiated with 40 Gy. However, the concentration and the content of hydroxyproline in anastomotic tissues were unchanged. In irradiated rats, MMP-2 and MMP-9 were significantly increased at 40 Gy, but not at 25 Gy. On the other hand, 25-Gy irradiation induced a smaller increase in the levels of the tissue inhibitors of metalloproteinase-1 compared with the controls. Conclusion: Anastomotic strength is adversely affected by high-dose fractionated preoperative RT. In contrast, preoperative RT at 25 Gy in five fractions over 5 days is safe with regard to the maintenance of wound strength in colorectal anastomosis.
Enhanced Reactivity and Delayed Recovery of Sensorimotor Cortex in the Novelty Seeking Personality
Authors: Shishida Kazuhiro , Hashizume Akira , Onoda Keiichi , Okamoto Yasumasa , Yamawaki Shigeto
Published: March 2007

Background: The novelty seeking (NS) personality trait is hypothesized to be associated with high cortical reactivity, poor inhibitory control and/or varied dopaminergic neurotransmission in the basal ganglia. After somatosensory stimulation, electrical oscillations in alpha and beta bands generated in the sensorimotor cortex show a short duration decrease (event-related desynchronization) and a subsequent increase (event-related synchronization) that is thought to reflect cortical activation and the inhibitory/recovery process, respectively. These oscillatory changes are also believed to be affected by the status of the basal ganglia and by dopaminergic functions. In the present study, we investigated the association between the NS personality trait and somatosensory oscillatory changes after median nerve stimulation assessed by magnetoencephalography. Methods: From 48 healthy subjects, we selected 14 high scorers and 14 age- and sex-matched low scorers on the NS dimension of the Temperament and Character Inventory. Magnetic fields were recorded while subjects received electrical stimulation of either the right or left median nerve with equal probability and with a randomized interstimulus interval. Frequency analysis was performed on the alpha and beta bands. Results: Compared with the low NS group, the high NS group showed larger magnitude of beta event-related desynchronization and larger latencies of the alpha and beta event-related synchronization. Conclusion: These results suggest that individuals with high degrees of the NS trait have greater reactivity and delayed recovery of the sensorimotor cortex in response to simple somatosensory stimulation. This may be significant for the understanding of their exploratory and impulsive behavior.
Factors Associated with Seven-Year Incidence of Diabetes Complications among Older Mexican Americans
Authors: Kaushik Vinod P. , Al Snih Soham , Ray Laura A. , Raji Mukaila A. , Markides Kyriakos S. , Goodwin James S.
Published: March 2007

Background: Diabetes is common in elderly persons and is highly prevalent in Mexican Americans. Little is known about factors associated with the incidence of diabetes complications. Objective: To examine the social, demographic and health factors associated with a 7-year incidence of diabetes complications among older Mexican Americans with diabetes. Methods: A 7-year prospective cohort of 536 non-institutionalized Mexican Americans aged ≧65 years with diabetes residing in the Southwest of USA. Measures included socio-demographic factors, duration of diabetes, diabetes treatment, medical conditions and body mass index. Diabetes complications were assessed by self-reports of any kidney, eye and circulation problems or amputation due to diabetes over a 7-year period. Results: Subjects with disease duration of ≧10 years were found to have an increased incidence of kidney, eye and circulation problems or amputation over a 7-year period. Hazard ratio (HR) for circulation problems was significantly higher in foreign-born subjects with >15 years in the USA. Foreign-born subjects with <15 years in the USA and those with a frequent number of physician visits were at increased risk of kidney complications. Subjects with baseline eye complications had a higher HR for incidence of amputations in the next 7 years. Subjects with baseline circulation complications had a higher incidence of amputations, eye and kidney complications in the next 7 years. Conclusions: Our data suggest that risks of diabetes complications are influenced by different factors. Prolonged diabetes duration, being foreign-born, living in the USA for a longer period, and frequent physician visits were factors associated with diabetes complications. Designing intervention strategies to reduce diabetes complication risks requires an understanding of the differences in demographic and health predictors of such risks.
Expression of Tumor Necrosis Factor Receptor-1 in Arterial Wall Cells Promotes Atherosclerosis
Authors: Zhang Lisheng , Peppel Karsten , Sivashanmugam Perumal , Orman Eric S. , Brian Leigh , Exum Sabrina T. , Freedman Neil J.
Published: March 2007

Objective—

Mechanisms by which tumor necrosis factor-α (TNF) contributes to atherosclerosis remain largely obscure. We therefore sought to determine the role of the arterial wall TNF receptor-1 (TNFR1) in atherogenesis.

Methods and Results—

Carotid artery-to-carotid artery interposition grafting was performed with
tnfr1
−/−
and congenic (C57Bl/6) wild-type (WT) mice as graft donors, and congenic chow-fed apolipoprotein E-deficient mice as recipients. Advanced atherosclerotic graft lesions developed within 8 weeks, and had 2-fold greater area in WT than in
tnfr1
−/−
grafts. While the prevalence of specific atheroma cells was equivalent in WT and
tnfr1
−/−
grafts, the overall abundance of cells was substantially greater in WT grafts. WT grafts demonstrated greater MCP-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression at both early and late time points, and proliferating cell nuclear antigen expression at early time points. Aortic atherosclerosis was also reduced in 14-month-old
apoe
−/−
/
tnfr1
−/−
mice, as compared with cognate
apoe
−/−
mice. In coculture with activated macrophages, smooth muscle cells expressing the TNFR1 demonstrated enhanced migration and reduced scavenger receptor activity.

Conclusions—

TNFR1 signaling, just in arterial wall cells, contributes to the pathogenesis of atherosclerosis by enhancing arterial wall chemokine and adhesion molecule expression, as well as by augmenting medial smooth muscle cell proliferation and migration.
Hydrogen Peroxide Derived From Beating Heart Mediates Coronary Microvascular Dilation During Tachycardia
Authors: Kokusho Yasunori , Komaru Tatsuya , Takeda Satoru , Takahashi Katsuaki , Koshida Ryoji , Shirato Kunio , Shimokawa Hiroaki
Published: March 2007

Objective—

Coronary flow is closely correlated to the myocardial metabolic demand. We tested the hypothesis that hydrogen peroxide (H
2
O
2
) derived from beating hearts mediates metabolic coronary microvascular dilation.

Methods and Results—

We used a bioassay method in which an isolated microvessel is placed on a beating heart to detect myocardium-derived vasoactive mediators. A rabbit coronary arterial microvessel (detector vessel [DV], n=25) was pressurized and placed on a canine beating heart. After intrinsic tone of DV had developed, we observed DV at rest (heart rate, 120 bpm) and during tachypacing (heart rate, 240 bpm) using an intravital microscope equipped with a floating objective. The tachypacing produced DV dilation by 8.2% (
P
<0.01 versus baseline), and the dilation was abolished by cell-impermeable catalase (a H
2
O
2
scavenger, 500 U/mL). We performed myocardial biopsy at rest and tachypacing. The biopsy specimens were loaded with 2′,7′-dichlorodihydrofluorescein diacetate (10 μmol/L) to visualize H
2
O
2,
and observed with confocal microscopy. Dichlorofluorescein fluorescence was diffusely identified in the myocardium and the tachypacing increased the fluorescence intensity (
P
<0.01). Exogenous H
2
O
2
caused vasodilation of arterial microvessels in vitro in a concentration-dependent manner that was abolished by catalase.

Conclusions—

H
2
O
2
derived from the beating heart mediates tachypacing-induced metabolic coronary vasodilation in vivo.
Critical Role of the NAD(P)H Oxidase Subunit p47

phox

for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction
Authors: Doerries Carola , Grote Karsten , Hilfiker-Kleiner Denise , Luchtefeld Maren , Schaefer Arnd , Holland Steven M. , Sorrentino Sajoscha , Manes Costantina , Schieffer Bernhard , Drexler Helmut , Landmesser Ulf
Published: March 2007

Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). An increased myocardial activity of the NAD(P)H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD(P)H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type (WT) mice (n=46) and mice lacking the cytosolic NAD(P)H oxidase component p47

phox

(p47

phox

−/− mice) (n=32). Infarct size was similar among the groups. NAD(P)H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice (83±8 versus 16.7±3.5 nmol of O
2
− ·
μg
−1
·min
−1
;
P
<0.01) but not in p47

phox

−/− mice after MI (13.5±3.6 versus 15.5±3.5 nmol of O
2
− ·
μg
−1
·min
−1
), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47

phox

−/− mice after MI, suggesting NAD(P)H oxidase–dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47

phox

−/− mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47

phox

−/− mice as compared with WT mice, as assessed by echocardiography (LV end-diastolic diameter: 4.5±0.2 versus 6.3±0.3 mm,
P
<0.01; LV ejection fraction, 35.8±2.5 versus 22.6±4.4%,
P
<0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47

phox

−/− mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47

phox

−/− mice as compared with WT mice after MI (72% versus 48%;
P
<0.05). These results suggest a pivotal role of NAD(P)H oxidase activation and its subunit p47

phox

for LV remodeling/dysfunction and survival after MI. The NAD(P)H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI.
Rho Kinase–Mediated Vasoconstriction Is Important in Severe Occlusive Pulmonary Arterial Hypertension in Rats
Authors: Oka Masahiko , Homma Noriyuki , Taraseviciene-Stewart Laimute , Morris Kenneth G. , Kraskauskas Donatas , Burns Nana , Voelkel Norbert F. , McMurtry Ivan F.
Published: March 2007

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase–mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia (≈10% O2) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase–mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.
CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation Through Suppression of Ectopic Atrial Gene Expression
Authors: Koibuchi Nobutaka , Chin Michael T.
Published: March 2007

We previously reported that mice lacking the hairy-related basic helix–loop–helix (bHLH) transcription factor
CHF1/Hey2
develop a thin-walled left ventricle. To explore the basis for this phenotype, we examined regional gene expression patterns in the developing myocardium. We found that atrial natriuretic factor (
ANF
), which is normally expressed in the atria and trabeculae and is restricted from the developing compact myocardium beginning at embryonic day 13.5, is persistently expressed in the left ventricular compact myocardium of the knockout animals. We also examined the expression pattern of the T-box transcription factor
Tbx5
, a known regulator of
ANF
, and an additional
Tbx5
-dependent gene, connexin 40 (
Cx40
), both of which share a similar expression pattern to
ANF
during development.
Tbx5
and
Cx40
were similarly expressed ectopically in the compact myocardium of the
CHF1/Hey2
knockout mouse. The atrial contractile genes
mlc1a
and
mlc2a
were also expressed ectopically in the left ventricular compact myocardium, providing evidence for a general dysregulation of atrial gene expression. Crossing of a myocardial-specific
CHF1/Hey2
transgenic mouse with the knockouts led to rescue of the thin-walled myocardial phenotype and restoration of the normal patterns of gene expression. Myocardial cell proliferation, which has been shown previously to be suppressed by
Tbx5
, was also decreased in the knockout mice and rescued by the transgene. Our findings suggest that
CHF1/Hey2
suppresses atrial identity in the left ventricular compact myocardium, facilitates myocardial proliferation by suppressing
Tbx5
, and thereby promotes proper ventricular myocardial maturation.
Absence of the Chemokine Receptor CCR2 Protects Against Cerebral Ischemia/Reperfusion Injury in Mice
Authors: Dimitrijevic Oliver B. , Stamatovic Svetlana M. , Keep Richard F. , Andjelkovic Anuska V.
Published: March 2007

Background and Purpose—The chemokine, monocyte chemoattractant protein-1 (CCL2), is a major factor driving leukocyte infiltration into the brain parenchyma in a variety of neuropathologic conditions associated with inflammation, including stroke. In addition, recent studies indicate that CCL2 and its receptor (CCR2) could have an important role in regulating blood-brain barrier (BBB) permeability. This study evaluated the role of the CCL2/CCR2 axis in regulating postischemic inflammation, BBB breakdown, and vasogenic edema formation.

Methods—CCR2−/−and CCR2+/+mice were subjected to focal transient cerebral ischemia. BBB permeability and brain edema formation were observed at days 1 and 5 of reperfusion by evaluating the product surface area for fluorescein isothiocyanate–albumin and measuring water and electrolyte contents. Immunohistochemistry was used to assess leukocyte infiltration. cDNA gene and protein arrays for inflammatory cytokines were used to assess inflammatory profiles in CCR2+/+and CCR2−/−mice.

Results—CCR2−/−mice had reduced infarct sizes and significantly reduced BBB permeability and brain edema formation in the affected ischemic hemisphere compared with CCR2+/+mice. This reduction in injury was closely associated with reduced infiltration of not only monocytes but also neutrophils (7- and 4-fold decreases, respectively). In addition, CCR2−/−mice had reduced expression/production of inflammatory cytokines during reperfusion.

Conclusions—These data suggest that inhibiting the CCL2/CCR2 axis affects brain reperfusion outcome by reducing brain edema, leukocyte infiltration, and inflammatory mediator expression.
The Case for Modality-Specific Outcome Measures in Clinical Trials of Stroke Recovery-Promoting Agents
Authors: Cramer Steven C. , Koroshetz Walter J. , Finklestein Seth P.
Published: March 2007

Clinical trials for acute stroke treatments have often used composite clinical rating scales as primary outcome measures of treatment efficacy. Recent preclinical and clinical studies highlight the opportunity to administer treatments in the subacute and chronic phase of stroke to promote neurological recovery. Because different neurological deficits recover to different extents at different rates after stroke, putative stroke recovery-promoting treatments may exert differential effects on various functional aspects of stroke recovery. For this reason, we propose that the use of modality-specific outcome measures may be best suited as primary end points in clinical trials of stroke recovery-promoting agents. The use of such end points may result in a more selective labeling of stroke recovery treatments.
Punding as a Complication of Brain Stem Stroke?
Authors: Nguyen Frederic N. , Pauly Rebecca R. , Okun Michael S. , Fernandez Hubert H.
Published: March 2007

Background and Purpose—

Stereotyped motor behaviors, known as “punding,” originally described among amphetamine abusers have only recently been reported in Parkinson disease associated with both pro-(eg, levodopa) or anti-(eg, quetiapine) dopaminergic therapy. We describe a non–Parkinson disease case of nonpharmacologically induced punding as a complication of a brain stem cardiovascular accident.

Summary of Case—

A 54-year-old man, after an episode of brain stem cardiovascular accident secondary to basilar artery thrombosis, was noted to endlessly purchase and hoard food items and to write, copy and organize recipes. His activity was excessive, disruptive and affected his interaction with family members. The patient’s punding behaviors significantly improved with an increased dose of sertraline from 100 mg to 150 mg per day.

Conclusion—

Our patient’s presentation was most consistent with punding, but interestingly was not a result of dopaminergic therapy. Moreover, improvement of his behavior was noted with a selective serotonin reuptake inhibitor, further questioning the dopaminergic hypothesis of punding.
IL1RN
VNTR Polymorphism in Ischemic Stroke
Authors: Worrall Bradford B. , Brott Thomas G. , Brown Robert D. , Brown W. Mark , Rich Stephen S. , Arepalli Sampath , Wavrant-De Vrièze Fabienne , Duckworth Jaime , Singleton Andrew B. , Hardy John , Meschia James F.
Published: March 2007

Background and Purpose—

Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene (
IL1RN
) and cerebrovascular disease.

Methods—

An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race.

Results—

After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11;
P
=0.03) for the white participants. The effect of allele 2 of
IL1RN
on stroke risk most closely fits a recessive genetic model (
P
=0.009). For the smaller sample of nonwhite participants, the results were not significant.

Conclusions—

Allele 2 of
IL1RN
, present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted.
Local Field Potentials and Spikes in the Human Medial Temporal Lobe are Selective to Image Category
Authors: Kraskov Alexander , Quiroga Rodrigo Quian , Reddy Leila , Fried Itzhak , Koch Christof
Published: March 2007

Local field potentials (LFPs) reflect the averaged dendrosomatic activity of synaptic signals of large neuronal populations. In this study, we investigate the selectivity of LFPs and single neuron activity to semantic categories of visual stimuli in the medial temporal lobe of nine neurosurgical patients implanted with intracranial depth electrodes for clinical reasons. Strong selectivity to the category of presented images was found for the amplitude of LFPs in 8% of implanted microelectrodes and for the firing rates of single and multiunits in 14% of microelectrodes. There was little overlap between the LFP- and spike-selective microelectrodes. Separate analysis of the power and phase of LFPs revealed that the mean phase was category-selective around the θ frequency range and that the power of the LFPs was category-selective for high frequencies around the γ rhythm. Of the 36 microelectrodes with amplitude-selective LFPs, 30 were found in the hippocampus. Finally, it was possible to readout information about the category of stimuli presented to the patients with both spikes and LFPs. Combining spiking and LFP activity enhanced the decoding accuracy in comparison with the accuracy obtained with each signal alone, especially for short time intervals.
Human-Nonhuman Animal Relationships in Australia: An Overview of Results from the First National Survey and Follow-up Case Studies 2000-2004
Authors: Franklin Adrian
Published: March 2007

This paper provides an overview of results from an Australian Research Council-funded project "Sentiments and Risks: The Changing Nature of Human-Animal Relations in Australia." The data discussed come from a survey of 2000 representative Australians at the capital city, state, and rural regional level. It provides both a snapshot of the state of involvement of Australians with nonhuman animals and their views on critical issues: ethics, rights, animals as food, risk from animals, native versus introduced animals, hunting, fishing, and companionate relations with animals. Its data point to key trends and change. The changing position of animals in Australian society is critical to understand, given its historic export markets in meat and livestock, emerging tourism industry with its strong wildlife focus, native animals' place in discourses of nation, and the centrality of animal foods in the national diet. New anxieties about risk from animal-sourced foods and the endangerment of native animals from development and introduced species, together with tensions between animals' rights and the privileging of native species, contribute to the growth of a strongly contested animal politics in Australia.
More Than a Furry Companion: The Ripple Effect of Companion Animals on Neighborhood Interactions and Sense of Community
Authors: Bulsara Max , Wood Lisa , Giles-Corti Billie , Bosch Darcy
Published: March 2007

Companion animals (pets) exemplify the affinities possible between humans and nonhuman animals. Evidence documenting a diversity of emotional, physical, and therapeutic benefits of pet guardianship (ownership) substantiates sentimental anecdotes from pet owners. Although the literature focuses primarily on the "one to one" benefits accruing from interactions with pets, this paper explores the potential role of pets as facilitators of social interactions and sense of community. The paper uses triangulation to synthesize findings from qualitative and quantitative research undertaken in three Western Australian suburbs. The qualitative data derive from 12 focus groups and quantitative data, from a survey of 339 residents. In both qualitative and quantitative research, pet ownership positively associated with social interactions, favor exchanges, civic engagement, perceptions of neighborhood friendliness, and sense of community. Pets appeared to ameliorate some determinants of mental health such as loneliness. Findings suggest pets have a ripple effect extending beyond their guardians (owners) to non-pet owners and the broader community. Given the high rates of pet residency in neighborhoods, there is merit in further considering the nexus between pets and community health and well being.
Uses of Places and Setting Preferences in a French Antarctic Station
Authors: Weiss Karine , Feliot-Rippeault Marie , Gaud Richard
Published: March 2007

The various uses of space as well as the environmental preferences of wintering people were investigated during 1 year in a French Antarctic station using daily participant observation (for uses of places) and a repeated measure of the perception and evaluation of the settings. The uses of places varied according to occupational and age subgroups: The young scientists expressed a higher need for privacy and a strong investment in their working areas, whereas the technicians preferred the social leisure area (main hall). These places were used as different behavior settings and thus corresponded to flexible environments. Flexibility was a characteristic of all the preferred places. A change in the preferences among the settings and the uses of places was also observed: After midwinter, the preferences evolved from private places to working areas. At the end of the mission, a behavioral change reflecting a stronger need for privacy was also observed.
The Correlates of Community Attractiveness
Authors: Lekwa Verl L. , Rice Tom W. , Hibbing Matthew V.
Published: March 2007

Anyone familiar with American communities knows that they vary significantly in terms of their physical attractiveness. In this study, the authors explore the community-level correlates of attractiveness using data from all of Iowa’s 954 cities and towns. Each of the communities was visited by a researcher who scored it in terms of its attractiveness. The authors correlate these ratings with a variety of community-level sociodemographic, economic, and attitudinal indicators. The results show that attractive communities tend to be larger, wealthier, and more civic-minded than other communities. Attractive communities also tend to have a higher percentage of elderly and college-educated residents. Further analysis revealed that population, wealth, and education are correlated less strongly with attractiveness as community size increases, whereas civic mindedness is correlated more strongly with attractiveness as community size increases. The authors discuss what their findings mean for communities trying to become more attractive.
Competency in Child Care Settings
Authors: Maxwell Lorraine E.
Published: March 2007

A rating scale is developed for preschool classrooms to assess the physical environment’s role in children’s development of cognitive and social competency. The scale is tested in 98 classrooms, and children are assessed on two measures of competency in a subsample of these classrooms. Findings indicate that the physical environment is related to measures of competency, one of which is a self-perception measure. Younger children’s competency, those in the 3-year-olds’ classrooms as opposed to the 4-year-olds’ classrooms, is most affected by the physical environment. Assessment of quality child care must include thorough assessment of the physical environment.
Assisted Living as a New Place Schema
Authors: Imamoğlu Çağrı
Published: March 2007

This study examines how the new place type of assisted living is represented in terms of its visual and verbal attributes and in comparison with the well-established schemata of home and nursing homes. Ninety-eight respondents (with a mean age of 62 years) are surveyed. Results indicate that home and nursing home are conceived in opposite terms, whereas assisted living is represented in between but with more homelike than institution-like attributes, except for its visual representation, which seems to involve rather institution-like exteriors and undifferentiated interiors. Results are discussed with regard to basic attributes of assisted living and possible differences between schemata of newly developing and well-established place types.