bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver cytokine production and ICAM-1 expression following bone fracture, tissue trauma, and hemorrhage in middle-aged mice
Authors: Matsutani Takeshi , Kang Shih-Ching , Miyashita Masao , Sasajima Koji , Choudhry Mashkoor A. , Bland Kirby I. , Chaudry Irshad H.
Published: September 2006

Although studies have indicated that hemorrhagic shock and resuscitation produces hepatic damage by mechanisms involving adhesion molecules in endothelial cells and hepatocytes, it is not known if there is any difference in the extent of hepatic damage following bone fracture, soft tissue trauma, and hemorrhage (Fx-TH) between young and middle-aged animals. To study this, young (6–8 wk) and middle-aged (∼12 mo) C3H/HeN male mice were subjected to a right lower leg fracture, soft tissue trauma, (i.e., midline laparotomy), and hemorrhage (blood withdrawal to decrease the blood pressure to 35 ± 5 mmHg for 90 min) followed by resuscitation with four times the shed blood volume in the form of lactated Ringer solution. Mice were euthanized 24 h later, and liver tissues were harvested. Total bilirubin levels in the hepatocyte extract increased markedly following Fx-TH in both groups of mice; however, the increase in middle-aged mice was significantly higher compared with young mice. TNF-α and IL-6 levels in the hepatocyte extract following Fx-TH increased significantly in middle-aged mice but remained unchanged in young mice. IL-10 levels significantly decreased in middle-aged mice following Fx-TH but remained unchanged in young mice. Kupffer cells from middle-aged mice produced significantly higher IL-6 and IL-10 levels compared with young mice. Protein levels and mRNA expression of ICAM-1 in hepatocytes were also significantly higher in middle-aged mice compared with young mice following Fx-TH. These results collectively suggest that the extent of hepatic damage following Fx-TH is dependent on the age of the subject.
Short-cycle hypoxia in the intact heart: hypoxia-inducible factor 1α signaling and the relationship to injury threshold
Authors: Ning Xue-Han , Chen Shi-Han , Buroker Norman E. , Xu Cheng-Su , Li Fu-Ren , Li Shu-Ping , Song De-Song , Ge Ming , Hyyti Outi M. , Zhang Min , Portman Michael A.
Published: September 2006

Hypoxia-inducible factor 1α (HIF-1α) transcriptionally activates multiple genes, which regulate metabolic cardioprotective and cross-adaptive mechanisms. Hypoxia and several other stimuli induce the HIF-1α signaling cascade, although little data exist regarding the stress threshold for activation in heart. We tested the hypothesis that relatively mild short-cycle hypoxia, which produces minimal cardiac dysfunction and no sustained or major disruption in energy state, can induce HIF-1α activation. We developed a short-cycle hypoxia protocol in isolated perfused rabbit heart to test this hypothesis. By altering cycling conditions, we identified a specific cycle with O2 content and duration that operated near a threshold for causing functional injury in these rabbit hearts. Mild short-cycle hypoxia for 46 min elevated HIF-1α mRNA and protein within 45 min after reoxygenation. Expression also increased for multiple HIF-1α target genes, such as VEGF and heme oxygenase 1. After mild hypoxia, VEGF protein accumulation occurred, although HIF-1α and VEGF protein accumulation were suppressed after more severe hypoxia, which also caused depletion of ATP and nondiffusible nucleotides. In summary, these results indicate that mild near-threshold hypoxia induces HIF-1α cascade, but more severe hypoxia suppresses protein accumulation for this transcription factor and the target genes. Posttranscriptional suppression of these proteins occurs under conditions of altered energy state, exemplified by ATP depletion.
Arterial pressure transfer characteristics: effects of travel time
Authors: Westerhof Berend E. , Guelen Ilja , Stok Wim J. , Wesseling Karel H. , Spaan Jos A. E. , Westerhof Nico , Bos Willem Jan , Stergiopulos Nikos
Published: September 2006

We investigated the quantitative contribution of all local conduit arterial, blood, and distal load properties to the pressure transfer function from brachial artery to aorta. The model was based on anatomical data, Young's modulus, wall viscosity, blood viscosity, and blood density. A three-element windkessel represented the distal arterial tree. Sensitivity analysis was performed in terms of frequency and magnitude of the peak of the transfer function and in terms of systolic, diastolic, and pulse pressure in the aorta. The root mean square error (RMSE) described the accuracy in wave-shape prediction. The percent change of these variables for a 25% alteration of each of the model parameters was calculated. Vessel length and diameter are found to be the most important parameters determining pressure transfer. Systolic and diastolic pressure changed <3% and RMSE <1.8 mmHg for a 25% change in vessel length and diameter. To investigate how arterial tapering influences the pressure transfer, a single uniform lossless tube was modeled. This simplification introduced only small errors in systolic and diastolic pressures (1% and 0%, respectively), and wave shape was less well described (RMSE, ∼2.1 mmHg). Local (arm) vasodilation affects the transfer function little, because it has limited effect on the reflection coefficient. Since vessel length and diameter translate into travel time, this parameter can describe the transfer accurately. We suggest that with a, preferably, noninvasively measured travel time, an accurate individualized description of pressure transfer can be obtained.
A reevaluation of the roles of hexokinase I and II in the heart
Authors: Southworth Richard , Davey Katherine A. B. , Warley Alice , Garlick Pamela B.
Published: September 2006

Hexokinase is responsible for glucose phosphorylation, a process fundamental to regulating glucose uptake. In some tissues, hexokinase translocates to the mitochondria, thereby increasing its efficiency and decreasing its susceptibility to product inhibition. It may also decrease free radical formation in the mitochondria and prevent apoptosis. Whether hexokinase translocation occurs in the heart is controversial; here, using immunogold labeling for the first time, we provide evidence for this process. Rat hearts (6 groups, n = 6/group), perfused with either glucose- or glucose + oleate (0.4 mmol/l)-containing buffer, were exposed to 30-min insulin stimulation, ischemia, or control perfusion. Hexokinase I (HK I) and hexokinase II (HK II) distributions were then determined. In glucose-perfused hearts, HK I-mitochondrial binding increased from 0.41 ± 0.04 golds/mm in control hearts to 0.71 ± 0.10 golds/mm after insulin and to 1.54 ± 0.38 golds/mm after ischemia ( P < 0.05). Similarly, HK II-mitochondrial binding increased from 0.16 ± 0.02 to 0.53 ± 0.08 golds/mm with insulin and 0.44 ± 0.07 golds/mm after ischemia ( P < 0.05). Under basal conditions, the fraction of HK I that was mitochondrial bound was five times greater than for HK II; insulin and ischemia caused a fourfold increase in HK II binding but only a doubling in HK I binding. Oleate decreased hexokinase-mitochondrial binding and abolished insulin-mediated translocation of HK I. Our data show that mitochondrial-hexokinase binding increases under insulin or ischemic stimulation and that this translocation is modified by oleate. These events are isoform specific, suggesting that HK I and HK II are independently regulated and implying that they perform different roles in cardiac glucose regulation.
Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide
Authors: Just Armin , Olson Andrea J. M. , Whitten Christina L. , Arendshorst William J.
Published: September 2006

NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved in vasoconstriction and vascular remodeling during hypertension produced by chronic angiotensin II (ANG II) infusion. These effects are thought to be mediated largely through superoxide anion (O2−) scavenging of nitric oxide (NO). Little is known about the role of ROS in acute vasoconstrictor responses to agonists. We investigated renal blood flow (RBF) reactivity to ANG II (4 ng), norepinephrine (NE, 20 ng), and α1-adrenergic agonist phenylephrine (PE, 200 ng) injected into the renal artery (ira) of anesthetized Sprague-Dawley rats. The NOX inhibitor apocynin (1–4 mg·kg−1·min−1 ira, 2 min) or the superoxide dismutase mimetic Tempol (1.5–5 mg·kg−1·min−1 ira, 2 min) rapidly increased resting RBF by 8 ± 1% ( P < 0.001) or 3 ± 1% ( P < 0.05), respectively. During NO synthase (NOS) inhibition ( Nω-nitro-l-arginine methyl ester, 25 mg/kg iv), the vasodilation tended to increase (apocynin 13 ± 4%, Tempol 10 ± 1%). During control conditions, both ANG II and NE reduced RBF by 24 ± 4%. Apocynin dose dependently reduced the constriction by up to 44% ( P < 0.05). Similarly, Tempol blocked the acute actions of ANG II and NE by up to 48–49% ( P < 0.05). In other animals, apocynin (4 mg·kg−1·min−1 ira) attenuated vasoconstriction to ANG II, NE, and PE by 46–62% ( P < 0.01). During NOS inhibition, apocynin reduced the reactivity to ANG II and NE by 60–72% ( P < 0.01), and Tempol reduced it by 58–66% ( P < 0.001). We conclude that NOX-derived ROS substantially contribute to basal RBF as well as to signaling of acute renal vasoconstrictor responses to ANG II, NE, and PE in normal rats. These effects are due to O2− rather than H2O2, occur rapidly, and are independent of scavenging of NO.
Secretory phospholipases A2stimulate mucus secretion, induce airway inflammation, and produce secretory hyperresponsiveness to neutrophil elastase in ferret trachea
Authors: Okamoto Kosuke , Kim Jung-Soo , Rubin Bruce K.
Published: September 2006

Secretory phospholipases A2(sPLA2) are increased in the bronchoalveolar lavage fluid of patients with asthma and acute respiratory distress syndrome. Intratracheal sPLA2instillation induces acute lung injury in the rat and guinea pig. We hypothesized that sPLA2would stimulate mucus secretion in vitro and that intratracheal sPLA2exposure would induce mucus hypersecretion and airway inflammation in the ferret trachea in vivo. In vitro, porcine pancreatic sPLA2at a concentration of 0.5 or 5 U/ml significantly increased mucous glycoconjugate (MG) secretion from the excised ferret trachea. P-bromophenacylbromide (a sPLA2inhibitor), quercetin (a lipoxygenase inhibitor), or MK-886 (a 5-lipoxygenase inhibitor), each at 10−4M, significantly reduced sPLA2-induced MG secretion. sPLA2-stimulated MG secretion was decreased in Ca2+-free medium. In vivo, ferrets were intubated for 30 min once per day for 3 days using an ETT coated with 20 units of porcine pancreatic sPLA2mixed in water-soluble jelly. Constitutive MG secretion increased 1 day after sPLA2exposure and returned to control 5 days later. Human neutrophil elastase (HNE) at 10−8M increased MG secretion in the sPLA2-exposed trachea compared with that in the control trachea, but methacholine at 10−7M did not. sPLA2-induced secretory hyperresponsiveness continued for at least 5 days after sPLA2exposure ended. sPLA2increased tracheal inflammation, MG secretion, and secretory hyperresponsiveness to HNE probably through enzymatic action rather than by activation of its receptor.
Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension
Authors: Case D. , Irwin D. , Ivester C. , Harral J. , Morris K. , Imamura M. , Roedersheimer M. , Patterson A. , Carr M. , Hagen M. , Saavedra M. , Crossno J. , Young K. A. , Dempsey E. C. , Poirier F. , West J. , Majka S.
Published: September 2006

Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in the ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible β-galactoside-binding lectin produced by vascular, interstitial, epithelial, and immune cells. Gal-1 regulates SMC differentiation, proliferation, and apoptosis via interactions with the ECM, as well as immune system function, and, therefore, likely plays a role in the pathogenesis of PH. We investigated the effects of Gal-1 during hypoxic PH by quantifying 1) Gal-1 expression in response to hypoxia in vitro and in vivo and 2) the effect of Gal-1 gene deletion on the magnitude of the PH response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found that acute hypoxia increases expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells. In wild-type (WT) mice, Gal-1 immunoreactivity increased after 6 wk of hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1−/−) mice showed a decreased PH response, as measured by right ventricular pressure and the ratio of right ventricular to left ventricular + septum wet weight compared with their WT counterparts. However, the number and degree of muscularized vessels increased similarly in WT and Gal-1−/−mice. In response to chronic hypoxia, the decrease in factor 8-positive microvessel density was similar in both groups. Vasoreactivity of WT and Gal-1−/−mice was tested in vivo and with use of isolated perfused lungs exposed to acute hypoxia. Acute hypoxia caused a significant increase in RV pressure in wild-type and Gal-1−/−mice; however, the response of the Gal-1−/−mice was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hypoxia-induced PH, which influences disease progression.
IGF-I and branchial IGF receptor expression and localization during salinity acclimation in striped bass
Authors: Tipsmark Christian Kølbæk , Luckenbach John Adam , Madsen Steffen Søndergaard , Borski Russell John
Published: September 2006

The initial response of the IGF-I system and the expression and cellular localization of IGF type-I receptor (IGF-IR) were studied in the gill of a euryhaline teleost during salinity acclimation. Exposure of striped bass ( Morone saxatilis) to hyperosmotic and hypoosmotic challenges induced small, transitory (<24 h) deflections in hydromineral balance. Transfer from freshwater (FW) to seawater (SW) induced an initial decrease in plasma IGF-I levels after 24 h in both fed and fasted fish. There was an overall decrease in liver IGF-I mRNA levels after SW transfer, suggesting that decreased plasma levels may be due to a decline in hepatic IGF-I synthesis. No changes were observed in gill IGF-I mRNA, but SW transfer induced an increase in gill IGF-IR mRNA after 24 h. Transfer from SW to FW induced an increase in plasma IGF-I levels in fasted fish. In fed fish, no significant changes were observed in either plasma IGF-I, liver, or gill IGF-I mRNA, or gill IGF-IR mRNA levels. In a separate experiment, FW-acclimated fish were injected with saline or IGF-I prior to a 24-h SW challenge. Rapid regain of osmotic balance following SW transfer was hindered by IGF-I. Immunohistochemistry revealed for the first time in teleosts that IGF-IR and Na+-K+-ATPase are localized in putative chloride cells at the base of the lamellae, identifying these cells in the gill as a target for IGF-I and IGF-II. Overall the data suggest a hyperosmoregulatory role of IGF-I in this species.
Self-Care Dimensions of Complementary and Alternative Medicine Use among Older Adults
Authors: Votova Kristine , Wister Andrew V.
Published: September 2006

Background: There is a lack of understanding about the patterns and rates of CAM use among older adults owing to a lack of research on specific types of CAM. Objectives: This study examines several dimensions of self-care deemed to be associated with CAM. Unmet health care needs, self-care attitudes, and spirituality are interpreted as health belief structures underlying CAM. Methods: Logistic regression analysis was used to examine use of three groups of practitioner-based CAM: (a) chiropractic; (b) massage, and (c) acupuncture, homeopathy and/or naturopathy use. We analyze a subsample of 4,401 older adults drawn from the 1996/1997 and 1998/1999 waves of the Canadian National Population Health Survey. Results: The logistic regression analyses indicate that self-care attitude and spirituality represent important predictors of practitioner-based CAM use. The associations for unmet health care needs were not supported. The strongest factors associated with CAM use were the illness context variables, which suggest that measures of need are key factors in leading individuals to seek other forms of health care. Discussion: Practitioner-based CAM use among older adults is influenced by self-care attitude and spirituality, in addition to health status, but to varying degrees depending on the type of CAM. Support of these self-care facets suggests that there is a desire on the part of consumers to exercise choice and to participate in health care decisions when considering CAM.
CYP2C19 Polymorphism and Risk for Essential Tremor
Authors: Alonso-Navarro Hortensia , Martínez Carmen , García-Martín Elena , Benito-León Julián , García-Ferrer Isabel , Vázquez-Torres Pilar , Puertas Inmaculada , López-Alburquerque Tomás , Agúndez José A.G. , Jiménez-Jiménez Félix Javier
Published: September 2006

Many patients with essential tremor (ET) develop acute adverse effects to primidone. We investigated the association between CYP2C19 polymorphism (possibly related to primidone metabolism) and the risk for developing essential ET and acute adverse effects to primidone. Leukocytary DNA from 200 ET patients and 300 healthy controls was studied for the genotype CYP2C19 and the occurrence of CYP2C19 allelic variants by using allele-specific PCR amplification and Sma I and BamH I RFLP analyses. The frequencies of the genotype CYP2C19*1/CYP2C19*2 and of the allelic variant CYP2C19*2 were significantly higher in ET patients than in controls. The mean age at onset of ET did not differ significantly between patients with genotypes CYP2C19*1/CYP2C19*2andCYP2C19*1/CYP2C19*1. The frequencies of the genotype CYP2C19*1/CYP2C19*2 and the allelic variant CYP2C19*2 were similar in ET patients who developed acute adverse effects to primidone, in those who tolerated primidone and in controls; the frequencies were also similar in patients with head, voice, tongue and chin tremor compared with controls. These results suggest that heterozygosis CYP2C19*1/CYP2C19*2 is associated with the risk for ET, but not with the age at onset of ET, the presentation of acute side effects of primidone, or the existence of head, voice, tongue or chin tremor.
Hypertension Induces Oxidative Stress but Not Macrophage Infiltration in the Kidney in the Early Stage of Experimental Diabetes Mellitus
Authors: Biswas Subrata K. , Lopes de Faria Jose B.
Published: September 2006

Background: The combination of diabetes and hypertension increases the incidence and severity of kidney disease in an additive manner. Inflammatory and oxidative stress mechanisms contribute to renal damage in both diabetes and hypertension. Therefore, we investigated whether renal macrophage infiltration and oxidative stress events are additive from the beginning in diabetic animals with coexisting hypertension. Methods: Diabetes was induced in spontaneously hypertensive rats (SHRs) and their genetically normotensive control Wistar Kyoto (WKY) rats by streptozotocin injection at 12 weeks of age for 10 days, and the effects of hyperglycemia on renal macrophage infiltration and oxidative stress were evaluated. Results: Blood pressure was higher in SHR than in WKY groups. Markers of oxidative stress-induced DNA and protein modification, 8-hydroxy- 2′-deoxyguanosine (8-OHdG) and nitrotyrosine, respectively, and the antioxidant glutathione levels were found to be similar in WKY-control and WKY-diabetic groups. However, 8-OHdG was significantly elevated (p = 0.014), the nitrotyrosine level tended to be elevated (p = 0.068) and the glutathione level was significantly reduced (p = 0.034) in the SHR-diabetic group compared to the SHR-control group. On the other hand, glomerular and tubulointerstitial macrophage infiltration was significantly higher in both WKY-diabetic and SHR-diabetic groups than the respective control groups. Conclusions: A short duration of diabetes mellitus induces renal oxidative stress in the presence of hypertension; however, renal macrophage infiltration becomes evident in early diabetes regardless of the presence or absence of hypertension. We conclude that the combination of diabetes and hypertension adversely affects oxidative stress in the kidney, but the combination has no additive effect on renal macrophage infiltration, at least in early diabetes.
Intron 2 (T/C) CYP46 Polymorphism Is Associated with Alzheimer’s Disease in Chinese Patients
Authors: Li Y. , Chu L.W. , Chen Y.Q. , Cheung B.M.Y. , Leung R.Y.H , Yik P.Y. , Ng K.M. , Mak W. , Jin D.Y. , St. George-Hyslop P. , Song Y.Q.
Published: September 2006

Background: Cholesterol metabolism has been implicated in the pathophysiology of Alzheimer’s disease (AD), and cholesterol-related genes are plausible candidate genes for AD. Genetic association of CYP46A1 polymorphisms with AD had been under extensive investigations; however, observations on intron 2 T→C (rs754203) generated inconclusive results. Objective: To analyse an independent data set in a Chinese population to see whether the polymorphic site rs754203 of the CYP46A1 gene is associated with AD. Methods: We analysed 130 sporadic AD patients and 110 healthy controls of the Southern Chinese origin. Results: An association between the genotype frequency and AD was suggested in the general population (p = 0.047, odds ratio, OR = 1. 61, 95% confidence interval, CI = 0.96–2.70), while the association was most significant in the apolipoprotein E (ApoE) Ε4-negative group (p = 0.004, OR = 2.54, 95% CI =1.31–4.95). Linkage disequilibrium block prediction results also favoured this association. Consistent with previous reports, intron 3 C→T (rs4900442) polymorphism did not show any evidence of association; in our data set ApoEΕ4 was confirmed to be a genetic risk factor for AD (p = 0.0016, OR = 2.76, 95% CI = 1.50–5.11).
Characterization of Patients with Schizophrenia and Related Psychoses: Evaluation of Different Diagnostic Procedures
Authors: Vares Maria , Ekholm Andreas , Sedvall Göran C. , Hall Håkan , Jönsson Erik G.
Published: September 2006

Background: We aimed at estimating the value of structured interviews, medical records and clinical diagnoses for assessing lifetime diagnosis of patients with schizophrenia. In addition, the validity of the Operational Criteria Checklist (OPCRIT) system was analysed. Sampling and Methods: Swedish patients (n = 73), diagnosed with schizophrenia and related disorders by their treating physician, were scrutinized. Independent research diagnoses according to the Diagnostic and Statistical Manual, ed. 3, revised (DSM-III-R) were obtained by (1) a structured interview; (2) the OPCRIT algorithm, based on record analysis only; (3) the OPCRIT algorithm, based on record and interview analysis, or (4) a separate traditional research diagnosis based on both record and interview analysis. In addition, clinical International Classification of Diseases (ICD) diagnoses, given by the treating physician, were obtained from the case notes. Concordance rates for the different psychosis diagnoses were calculated. Results: Diagnoses based on interviews only showed poor to fair agreement with the other research diagnoses, but patients diagnosed with schizophrenia or schizophrenic psychoses (i.e. schizophrenia, schizophreniform or schizoaffective disorder) at the interview almost always also obtained a corresponding research diagnosis based on record or combined sources. Diagnoses based on records only showed a good to excellent agreement with diagnoses based on records and interviews. Clinical ICD diagnoses generally displayed poor agreement with the research diagnoses, but 94% of patients ever given a clinical ICD diagnosis of schizophrenic psychosis received a corresponding traditional research diagnosis. OPCRIT diagnoses and independently assigned research diagnoses, based on the same information, displayed excellent concordance. Conclusions: Structured interviews performed with Swedish long-term-treated psychosis patients during non-hospitalization are a poor source for the evaluation of psychosis diagnoses, but a good screening instrument for the detection of DSM-III-R schizophrenia. In the investigated population, medical records are a valuable source for diagnostic assessment of psychoses and may serve as a stand-alone procedure in this patient category. Swedish clinical ICD diagnoses have a high positive predictive power identifying DSM-III-R diagnoses of schizophrenic psychoses, indicating validity of register-based research focusing on these diagnoses. The OPCRIT system is a valid tool for assessing DSM-III-R psychosis diagnoses. It should be emphasized that the present conclusions are based on the investigated Swedish psychosis population and cannot be generalized to populations composed of other patient groups or sampled in other settings, with other traditions regarding the use and availability of medical records.
Nonendothelial Mesenchymal Cell–Derived MCP-1 Is Required for FGF-2–Mediated Therapeutic Neovascularization
Authors: Fujii Takaaki , Yonemitsu Yoshikazu , Onimaru Mitsuho , Tanii Mitsugu , Nakano Toshiaki , Egashira Kensuke , Takehara Takako , Inoue Makoto , Hasegawa Mamoru , Kuwano Hiroyuki , Sueishi Katsuo
Published: September 2006

Objective—Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated.

Methods and Results—Using murine models of fibroblast growth factor-2 (FGF-2)–mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-α stimulated MCP-1 expression in all cell types tested, whereas FGF-2–mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo.

Conclusions—These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2–mediated therapeutic neovascularization.
RhoA Mediates Angiotensin II–Induced Phospho-Ser536 Nuclear Factor κB/RelA Subunit Exchange on the Interleukin-6 Promoter in VSMCs
Authors: Cui Ruwen , Tieu Brian , Recinos Adrian , Tilton Ronald G. , Brasier Allan R.
Published: September 2006

The vasoconstrictor angiotensin II (Ang II) accelerates atherosclerosis by inducing vascular gene expression programs, producing monocyte recruitment, and vascular remodeling. In vascular smooth muscle cells (VSMCs), Ang II signaling activates interleukin (IL)-6 expression, a cytokine producing acute-phase inflammation, mediated by the transcription factor nuclear factor κB (NF-κB). The classical NF-κB activation pathway involves cytoplasmic-to-nuclear translocation of the potent RelA transactivating subunit; however, because nuclear RelA is present in VSMCs, the mechanism by which NF-κB activity is controlled is incompletely understood. In this study, we focus on early activation steps controlling RelA activation. Although Ang II only weakly induces ≈1.5-fold RelA nuclear translocation, RelA is nevertheless required because short interfering RNA–mediated RelA knockdown inhibits inducible IL-6 expression. We find instead that Ang II stimulation rapidly induces RelA phosphorylation at serine residue 536, a critical regulatory site in its transactivating domain. Chromatin immunoprecipitation assays indicate no significant changes in total RelA binding to the native IL-6 promoter, but an apparent increase in fractional binding of phospho-Ser536 RelA. Inactivation of RhoA by treatment with
Clostridium botulinum
exoenzyme C3 exotoxin or expression of dominant negative RhoA blocks Ang II–inducible RelA Ser536 phosphorylation and IL-6 expression. Finally, enhanced phospho-Ser536 RelA formation in the aortae of rats chronically infused with Ang II was observed. Together, these data indicate a novel mechanism for Ang II–induced NF-κB activation in VSMCs, mediated by RhoA-induced phospho-Ser536 RelA formation, IL-6 expression, and vascular inflammation.
Pacing-induced Heterogeneities in Intracellular Ca
2+
Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart
Authors: Aistrup Gary L. , Kelly James E. , Kapur Sunil , Kowalczyk Michael , Sysman-Wolpin Inbal , Kadish Alan H. , Wasserstrom J. Andrew
Published: September 2006

Optical mapping studies have suggested that intracellular Ca
2+
and T-wave alternans are linked through underlying alternations in Ca
2+
cycling-inducing oscillations in action potential duration through Ca
2+
-sensitive conductances. However, these studies cannot measure single-cell behavior; therefore, the Ca
2+
cycling heterogeneities within microscopic ventricular regions are unknown. The goal of this study was to measure cellular activity in intact myocardium during rapid pacing and arrhythmias. We used single-photon laser-scanning confocal microscopy to measure Ca
2+
signaling in individual myocytes of intact rat myocardium during rapid pacing and during pacing-induced ventricular arrhythmias. At low rates, all myocytes demonstrate Ca
2+
alternans that is synchronized but whose magnitude varies depending on recovery kinetics of Ca
2+
cycling for each individual myocyte. As rate increases, some cells reverse alternans phase, giving a dyssynchronous activation pattern, even in adjoining myocytes. Increased pacing rate also induces subcellular alternans where Ca
2+
alternates out of phase with different regions within the same cell. These forms of heterogeneous Ca
2+
signaling also occurred during pacing-induced ventricular tachycardia. Our results demonstrate highly nonuniform Ca
2+
signaling among and within individual myocytes in intact heart during rapid pacing and arrhythmias. Thus, certain pathophysiological conditions that alter Ca
2+
cycling kinetics, such as heart failure, might promote ventricular arrhythmias by exaggerating these cellular heterogeneities in Ca
2+
signaling.
Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure
Authors: Kang Yu-Ming , Zhang Zhi-Hua , Johnson Ralph F. , Yu Yang , Beltz Terry , Johnson Alan Kim , Weiss Robert M. , Felder Robert B.
Published: September 2006

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-α in heart failure (HF) rats. TNF-α and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E
2
by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-α, interleukin (IL)-1β and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-α, IL-1β, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E
2
in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo
Authors: Hizume Takatoshi , Morikawa Keiko , Takaki Aya , Abe Kohtaro , Sunagawa Kenji , Amano Mutsuki , Kaibuchi Kozo , Kubo Chiharu , Shimokawa Hiroaki
Published: September 2006

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, PO) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, PO) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.
Early Coronary Revascularization Diminishes the Risk of Ischemic Stroke With Acute Myocardial Infarction
Authors: Van De Graaff Eric , Dutta Monisha , Das Pranab , Shry Eric A. , Frederick Paul D. , Blaney Martha , Pasta David J. , Steinhubl Steven R.
Published: September 2006

Background and Purpose—

Ischemic stroke is an uncommon but devastating complication of myocardial infarction (MI). It is possible that delay in the acute revascularization of these patients influences the risk of peri-MI ischemic stroke independent of size of infarction or residual ventricular function. The influence of the timing and type of revascularization on risk of ischemic stroke in the patient with MI has not previously been assessed.

Methods—

We used the National Registry of Myocardial Infarction 3 and 4 databases to identify 45 997 subjects who received thrombolytic therapy and 47 876 patients who were treated with primary percutaneous transluminal coronary angioplasty for MI. In-hospital ischemic stroke occurred in 248 (0.54%) and 150 (0.31%) patients in the two groups, respectively. Patients were stratified based on time from presentation to initial therapy.

Results—

A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes was associated with a lower risk of ischemic stroke (odds ratio, 0.58; 95% CI, 0.36–0.94). Primary angioplasty within 90 minutes of arrival was associated with a nonsignificant trend toward lower stroke risk (odds ratio, 0.68; 95% CI, 0.41–1.12). Interestingly, his benefit of early reperfusion therapy did not appear to be related to improvements in left ventricular function.

Conclusion—

Risk of in-hospital ischemic stroke with MI is closely tied to the time to revascularization with both thrombolytic and percutaneous transluminal coronary angioplasty therapies. Early revascularization is independently predictive of a lower risk of ischemic stroke, but the mechanism of this does not appear to be related to improved cardiac function. The records of 45 997 subjects who received thrombolytic therapy and 47 876 patients who were treated with primary percutaneous transluminal coronary angioplasty for myocardial infarction were analyzed to determine the relationship between time to revascularization and the occurrence of ischemic stroke. A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes of presentation was associated with a lower risk of ischemic stroke, and angioplasty within 90 minutes was similarly associated with a nonsignificant trend toward lower stroke risk.
The Effect of Behavioral Realism and Form Realism of Real-Time Avatar Faces on Verbal Disclosure, Nonverbal Disclosure, Emotion Recognition, and Copresence in Dyadic Interaction
Authors: Bailenson Jeremy N , Yee Nick , Merget Dan , Schroeder Ralph
Published: September 2006

The realism of avatars in terms of behavior and form is critical to the development of collaborative virtual environments. In the study we utilized state of the art, real-time face tracking technology to track and render facial expressions unobtrusively in a desktop CVE. Participants in dyads interacted with each other via either a video-conference (high behavioral realism and high form realism), voice only (low behavioral realism and low form realism), or an “emotibox” that rendered the dimensions of facial expressions abstractly in terms of color, shape, and orientation on a rectangular polygon (high behavioral realism and low form realism). Verbal and non-verbal self-disclosure were lowest in the videoconference condition while self-reported copresence and success of transmission and identification of emotions were lowest in the emotibox condition. Previous work demonstrates that avatar realism increases copresence while decreasing self-disclosure. We discuss the possibility of a hybrid realism solution that maintains high copresence without lowering self-disclosure, and the benefits of such an avatar on applications such as distance learning and therapy.
Pietro Della Valle's Latin Geography of Safavid Iran (1624-1628): Introduction
Authors: Schüller Volkmar , Brentjes Sonja
Published: September 2006

This article argues that Pietro della Valle's Latin geography of the Safavid Empire is important for taking a middle ground between two common tendencies of early modern authors in Catholic and Protestant Europe when writing about Western Asia and Northern Africa. While cartographers and mapmakers—in Venice, Antwerp, Amsterdam, and Paris—privileged new information (from travelers) in their choice of place names, those who wrote on the history or geography of these regions often suppressed local knowledge, giving preference to terms from ancient Greek and Latin history and geography, enriched by reference to the Bible. Della Valle, while traveling in Ottoman and Safavid territories, made intensive efforts to learn major local languages and acquire information about contemporary political, cultural, and physical geography, as documented in his diary and the original copies of his letters written during the long years of travel. The approach he takes in his geography of the Safavid Empire is thus close to choices made by the cartographers and mapmakers.
Peacekeepers and Prostitutes
Authors: Allred Keith J.
Published: September 2006

On numerous occasions in the past fifteen years, U.N. peacekeepers have been accused of sexually assaulting or abusing the populations they serve. A Comprehensive Review of peacekeeper misconduct completed in 2005 identified significant problems and recommended numerous changes to address them. The U.S. Army and NATO, in a response to the possibility that their deployed troops will be engaged in or facilitate human trafficking, have enacted new policies intended to remove their troops from the demand for women trafficked for sexual services. The Department of Defense and NATO initiatives are similar to those being considered by the United Nations for preventing sexual misconduct by its peacekeepers. Because the United States, NATO, and the United Nations are all addressing the problems of sexual misconduct by deployed troops, their efforts should be mutually reinforcing. The examples of American and NATO armed forces offer hope that the United Nations will also enact strong measures to prevent future misconduct by its peacekeepers.
When Sanctions Fail to Increase Cooperation in Social Dilemmas: Considering the Presence of an Alternative Option to Defect
Authors: Mulder Laetitia B. , van Dijk Eric , De Cremer David , Wilke Henk A. M.
Published: September 2006

Previous social dilemma research has shown that sanctioning defection may enhance cooperation. The authors argue that this finding may have resulted from restricting participants to two behaviors (cooperation and defection). In this article, the authors introduce the concept of a “social trilemma” (a social dilemma in which an alternative option to defect is present) and tested the effect of a sanction. The authors show that a sanction only increased cooperation and collective interests in the traditional social dilemma. In a social trilemma, the sanction failed because it caused some people to choose the alternative option to defect. Moreover, the results indicate that this was especially the case when people did not expect fellow group members to cooperate. In this case, the sanction even worked counterproductive because it decreased collective interests. It is concluded that allowing individuals to consider alternative options to defect can reveal the potential detrimental effects of sanctioning systems for the collective.
The Mediating Role of Perceptual Validation in the Repentance–Forgiveness Process
Authors: Eaton Judy , Struthers C. Ward , Santelli Alexander G.
Published: September 2006

This research focuses on one potential mechanism by which repentance leads to forgiveness. Two studies demonstrate that repentance leads to increased perceptual validation (social verification that one is correct about one's interpretation of an event) and, ultimately, more forgiveness. Participants reported more perceptual validation when they received repentance than when they did not (Studies 1 and 2), particularly repentance that included an acknowledgement of the transgression and the harm done (Study 2). In addition, in Study 2, acknowledgement of the transgression by a third party also had a positive effect on forgiveness. There was evidence that perceptual validation mediated the repentance–forgiveness relationship. These findings suggest that repentance facilitates forgiveness, at least in part, because it makes victims feel validated.
Phospholipase C, calcium, and calmodulin are critical for α4β1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants
Authors: Hyduk Sharon J. , Chan, Jason R. , Duffy Stewart T. , Chen Mian , Peterson Mark D. , Waddell Thomas K. , Digby Genevieve C. , Szaszi Katalin , Kapus Andras , Cybulsky Myron I.
Published: September 2006

During inflammation, monocytes roll on activated endothelium and arrest after stimulation by proteoglycan-bound chemokines and other chemoattractants. We investigated signaling pathways downstream of G protein–coupled receptors (GPCRs) that are relevant to α4β1 integrin affinity up-regulation using formyl peptide receptor-transfected U937 cells stimulated with fMLP or stromal-derived factor-1α and human peripheral blood monocytes stimulated with multiple chemokines or chemoattractants. The up-regulation of soluble LDV peptide or vascular cell adhesion molecule-1 (VCAM-1) binding by these stimuli was critically dependent on activation of phospholipase C (PLC), inositol 1,4,5-triphosphate receptors, increased intracellular calcium, influx of extracellular calcium, and calmodulin, suggesting that this signaling pathway is required for α4 integrins to assume a high-affinity conformation. In fact, a rise in intracellular calcium following treatment with thapsigargin or ionomycin was sufficient to induce binding of ligand. Blockade of p44/42 and p38 mitogen-activated protein (MAP) kinases, phosphoinositide 3-kinase, or protein kinase C (PKC) signaling did not inhibit chemoattractant-induced LDV or VCAM-1 binding. However, activation of PKC by phorbol ester up-regulated α4β1 affinity with kinetics distinct from those of GPCR signaling. A critical role for PLC and calmodulin was also established for leukocyte arrest and adhesion strengthening.
Durable responses to imatinib in patients with PDGFRB fusion gene–positive and BCR-ABL–negative chronic myeloproliferative disorders
Authors: David Marianna , Cross Nicholas C. P. , Burgstaller Sonja , Chase Andrew , Curtis Claire , Dang Raymond , Gardembas Martine , Goldman John M. , Grand Francis , Hughes George , Huguet Francoise , Lavender Louise , McArthur Grant A. , Mahon Francois X. , Massimini Giorgio , Melo Junia , Rousselot Philippe , Russell-Jones Robin J. , Seymour John F. , Smith Graeme , Stark Alastair , Waghorn Katherine , Nikolova Zariana , Apperley Jane F.
Published: September 2006

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL–negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL–negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase–polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion–positive, BCR-ABL–negative CMPDs.