bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenylyl cyclase type 5 protein expression during cardiac development and stress
Authors: Hu Che-Lin , Chandra Rachna , Ge Hui , Pain Jayashree , Yan Lin , Babu Gopal , Depre Christophe , Iwatsubo Kousaku , Ishikawa Yoshihiro , Sadoshima Junichi , Vatner Stephen F. , Vatner Dorothy E.
Published: September 2009

Adenylyl cyclase (AC) types 5 and 6 (AC5 and AC6) are the two major AC isoforms expressed in the mammalian heart that mediate signals from β-adrenergic receptor stimulation. Because of the unavailability of isoform-specific antibodies, it is difficult to ascertain the expression levels of AC5 protein in the heart. Here we demonstrated the successful generation of an AC5 isoform-specific mouse monoclonal antibody and studied the expression of AC5 protein during cardiac development in different mammalian species. The specificity of the antibody was confirmed using heart and brain tissues from AC5 knockout mice and from transgenic mice overexpressing AC5. In mice, the AC5 protein was highest in the brain but was also detectable in all organs studied, including the heart, brain, lung, liver, stomach, kidney, skeletal muscle, and vascular tissues. Western blot analysis showed that AC5 was most abundant in the neonatal heart and declined to basal levels in the adult heart. AC5 protein increased in the heart with pressure-overload left ventricular hypertrophy. Thus this new AC5 antibody demonstrated that this AC isoform behaves similarly to fetal type genes, such as atrial natriuretic peptide; i.e., it declines with development and increases with pressure-overload hypertrophy.
Calpain inhibition preserves myocardial structure and function following myocardial infarction
Authors: Mani Santhosh K. , Balasubramanian Sundaravadivel , Zavadzkas Juozas A. , Jeffords Laura B. , Rivers William T. , Zile Michael R. , Mukherjee Rupak , Spinale Francis G. , Kuppuswamy Dhandapani
Published: September 2009

Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca2+-dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated ( n = 6) and untreated ( n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 ± 2% pre-MI to 30 ± 4% with MI only vs. 41 ± 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 ± 2 μl pre-MI to 73 ± 4 μl with MI only vs. 55 ± 4 μl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients.
Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite
Authors: Kupai Krisztina , Csonka Csaba , Fekete Veronika , Odendaal Louise , van Rooyen Jacques , Marais De Wet , Csont Tamás , Ferdinandy Péter
Published: September 2009

The aim of the present study was to investigate if hyperlipidemia interferes with the infarct size-limiting effect of postconditioning and to study the involvement of peroxynitrite in this phenomenon. Rats were fed a 2% cholesterol-enriched or normal diet for 12 wk. Infarct size by triphenyltetrazolium chloride staining was measured in hearts isolated from both groups and subjected to 30 min coronary occlusion followed by 120 min reperfusion with or without the postconditioning protocol induced by six cycles of 10 s coronary occlusion and 10 s reperfusion at the onset of the reperfusion. Postconditioning significantly decreased infarct size in the normolipidemic but not in the hyperlipidemic group. Postconditioning increased cardiac 3-nitrotyrosine concentration (a marker for peroxynitrite formation) in the normal but not in the cholesterol-fed group when measured at the 5th min of reperfusion. Next, we tested if the postconditioning-induced acute increase in peroxynitrite is involved in the cardioprotection in normolipidemic animals in separate experiments. Postconditioning failed to decrease infarct size in the presence of the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron [III] (20 mg/l) in normolipidemic animals. We conclude that an early increase in peroxynitrite after postconditioning plays a role in cardioprotection. Furthermore, hyperlipidemia blocks the cardioprotective effect of postconditioning at least in part via deterioration of the postconditioning-induced early increase in peroxynitrite formation.
Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide
Authors: Xue Baojian , Singh Minati , Guo Fang , Hay Meredith , Johnson Alan Kim
Published: September 2009

The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry implants. NG-nitro-l-arginine methyl ester (l-NAME; 100 μg·kg·−1day−1), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of l-NAME augmented the pressor effects of systemic ANG II in females (Δ21.5 ± 2.2 vs. Δ9.2 ± 1.5 mmHg) but not in males (Δ29.4 ± 2.5 vs. Δ30.1 ± 2.5 mmHg). Central administration of N5-(1-imino-3-butenyl)-l-ornithine (l-VNIO), a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (Δ17.5 ± 3.2 vs. Δ9.2 ± 1.5 mmHg). In gonadectomized mice, central l-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central l-NAME- or l-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were ∼12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to ∼51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a protective role against ANG II-induced hypertension in female mice.
O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death
Authors: Ngoh Gladys A. , Hamid Tariq , Prabhu Sumanth D. , Jones Steven P.
Published: September 2009

We previously demonstrated that the O-linked β- N-acetylglucosamine ( O-GlcNAc) posttranslational modification confers cardioprotection at least partially through mitochondrial-dependent mechanisms, but it remained unclear if O-GlcNAc signaling interfered with other mechanisms of cell death. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we ascertained whether O-GlcNAc signaling could attenuate ER stress-induced cell death per se. Before induction of ER stress (with tunicamycin or brefeldin A), we adenovirally overexpressed O-GlcNAc transferase (AdOGT) or pharmacologically inhibited O-GlcNAcase [via O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino- N-phenylcarbamate] to augment O-GlcNAc levels or adenovirally overexpressed O-GlcNAcase to reduce O-GlcNAc levels. AdOGT significantly ( P < 0.05) attenuated the activation of the maladaptive arm of the unfolded protein response [according to C/EBP homologous protein (CHOP) activation] and cardiomyocyte death (reflected by percent propidium iodide positivity). Moreover, pharmacological inhibition of O-GlcNAcase significantly ( P < 0.05) mitigated ER stress-induced CHOP activation and cardiac myocyte death. Interestingly, overexpression of GCA did not alter ER stress markers but exacerbated brefeldin A-induced cardiomyocyte death. We conclude that enhanced O-GlcNAc signaling represents a partially proadaptive response to reduce ER stress-induced cell death. These results provide new insights into a possible interaction between O-GlcNAc signaling and ER stress and may partially explain a mechanism of O-GlcNAc-mediated cardioprotection.
Right ventricular pacing improves right heart function in experimental pulmonary arterial hypertension: a study in the isolated heart
Authors: Handoko M. Louis , Lamberts Regis R. , Redout Everaldo M. , de Man Frances S. , Boer Christa , Simonides Warner S. , Paulus Walter J. , Westerhof Nico , Allaart Cornelis P. , Vonk-Noordegraaf Anton
Published: September 2009

Right heart failure in pulmonary arterial hypertension (PH) is associated with mechanical ventricular dyssynchrony, which leads to impaired right ventricular (RV) function and, by adverse diastolic interaction, to impaired left ventricular (LV) function as well. However, therapies aiming to restore synchrony by pacing are currently not available. In this proof-of-principle study, we determined the acute effects of RV pacing on ventricular dyssynchrony in PH. Chronic PH with right heart failure was induced in rats by injection of monocrotaline (80 mg/kg). To validate for PH-related ventricular dyssynchrony, rats (6 PH, 6 controls) were examined by cardiac magnetic resonance imaging (9.4 T), 23 days after monocrotaline or sham injection. In a second group (10 PH, 4 controls), the effects of RV pacing were studied in detail, using Langendorff-perfused heart preparations. In PH, septum bulging was observed, coinciding with a reversal of the transseptal pressure gradient, as observed in clinical PH. RV pacing improved RV systolic function, compared with unpaced condition (maximal first derivative of RV pressure: +8.5 ± 1.3%, P < 0.001). In addition, RV pacing markedly decreased the pressure-time integral of the transseptal pressure gradient when RV pressure exceeds LV pressure, an index of adverse diastolic interaction (−24 ± 9%, P < 0.01), and RV pacing was able to resynchronize time of RV and LV peak pressure (unpaced: 9.8 ± 1.2 ms vs. paced: 1.7 ± 2.0 ms, P < 0.001). Finally, RV pacing had no detrimental effects on LV function or coronary perfusion, and no LV preexcitation occurred. Taken together, we demonstrate that, in experimental PH, RV pacing improves RV function and diminishes adverse diastolic interaction. These findings provide a strong rationale for further in vivo explorations.
Regulation of VASP phosphorylation in cardiac myocytes: differential regulation by cyclic nucleotides and modulation of protein expression in diabetic and hypertrophic heart
Authors: Sartoretto Juliano L. , Jin Benjamin Y. , Bauer Michael , Gertler Frank B. , Liao Ronglih , Michel Thomas
Published: September 2009

Vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cyclic nucleotide-dependent kinases that has been implicated in cardiac pathology, yet many aspects of VASP's molecular regulation in cardiomyocytes are incompletely understood. In these studies, we explored the role of VASP, both in signaling pathways in isolated murine myocytes, as well as in a model of cardiac hypertrophy in VASPnullmice. We found that the β-adrenergic agonist isoproterenol promotes the rapid and reversible phosphorylation of VASP at Ser157 and Ser239. Forskolin and the cAMP analog 8-(4-chlorophenylthio)-cAMP promote a similar pattern of VASP phosphorylation at both sites. The effects of isoproterenol are blocked by atenolol and by compound H-89, an inhibitor of the cAMP-dependent protein kinase. By contrast, phosphorylation of VASP only at Ser239 is seen following activation of particulate guanylate cyclase by atrial natriuretic peptide, or following activation of soluble guanylate cyclase by sodium nitroprusside, or following treatment of myocytes with cGMP analog. We found that basal and isoproterenol-induced VASP phosphorylation is entirely unchanged in cardiomyocytes isolated from either endothelial or neuronal nitric oxide synthase knockout mice. In cardiomyocytes isolated from diabetic mice, only basal VASP phosphorylation is increased, whereas, in cells isolated from mice subjected to ascending aortic constriction (AAC), we found a significant increase in basal VASP expression, along with an increase in VASP phosphorylation, compared with cardiac myocytes isolated from sham-operated mice. Moreover, there is further increase in VASP phosphorylation in cells isolated from hypertrophic hearts following isoproterenol treatment. Finally, we found that VASPnullmice subjected to transverse aortic constriction develop cardiac hypertrophy with a pattern similar to VASP+/+mice. Our findings establish differential receptor-modulated regulation of VASP phosphorylation in cardiomyocytes by cyclic nucleotides. Furthermore, these studies demonstrate for the first time that VASP expression is upregulated in hypertrophied heart.
Angiotensin II, mechanotransduction, and pulsatile arterial hemodynamics in hypertension
Authors: Lacolley Patrick , Safar Michel E. , Regnault Veronique , Frohlich Edward D.
Published: September 2009

The aortic blood pressure curve involves two components: a steady component, the mean arterial pressure (MAP), which is dependent on cardiac output and vascular resistance, and a pulsatile component pulse pressure (PP), which is dependent on arterial stiffness and pulse wave reflections. The transduction mechanisms of MAP and PP differ markedly, involving focal adhesion kinase for MAP and oxygen free radicals for PP. Angiotensin II (ANG II) and its blockade are associated with changed vascular resistance and MAP; however, their effects on PP (peripheral and mostly central PP) have been inadequately investigated. In hypertensive rats, when compared with their normotensive controls, ANG II blockade normalizes central PP (<50 mmHg) but not MAP when the same drug dosage is used for each. In hypertensive patients, ANG II blockade reduces arterial stiffness and pulse wave reflections, but with the same reduction in MAP, there is a greater reduction in central than peripheral PP, thereby increasing carotid-brachial PP amplification. With long-term ANG II blockade, the hypertensive arteriolar hypertrophy observed at baseline is corrected in association with reduced arteriolar reflection coefficients, reduced carotid arterial attachments linking α5-integrin to its ligand fibronectin, and decreased circulating C-reactive protein. When given a normal salt diet, each of these factors contributes separately in reducing arterial stiffness and wave reflections. These responses disappear with a high-salt diet, a condition that usually involves the activation of the local vascular renin-angiotensin-aldosterone system and can be prevented by its selective blockade. Thus ANG II inhibition seems to contribute independently in reducing central PP and aortic stiffness.
In vitro translocation of quantum dots and influence of oxidative stress
Authors: Geys Jorina , De Vos Rita , Nemery Benoit , Hoet Peter H. M.
Published: September 2009

In vivo, translocation of inhaled nanoparticles to the circulation has been demonstrated. However, the interaction of nanoparticles with the lung epithelium is not understood. In this study, we investigated, in vitro, the translocation of nano-sized quantum dots (QDs; 25 pmol/ml) through a tight monolayer of primary isolated rat alveolar epithelial cells. The influence of surface charge on translocation was examined using nonfunctionalized QDs, amine-QDs, and carboxyl-QDs. The interaction between nanoparticles and the lung epithelium was monitored by repeatedly measuring the transepithelial electrical resistance (TEER) and by examining the cell layer with confocal microscopy. The effect of oxidative stress was tested by incubating the cells with tert-butyl hydroperoxide (t-BOOH; 75 μM or 1 or 10 mM); the antioxidant N-acetyl-l-cysteine was also used to assess the role of particle-mediated oxidative stress. No translocation through a tight monolayer of primary rat alveolar epithelial cells was observed for any of the different types of QDs. In general, an increase in TEER was found after incubation with QDs. A condition of low oxidative stress did not enhance translocation. In contrast, conditions of high stress (1 or 10 mM t-BOOH or due to QDs toxicity) with disruption of the cell layer, as shown in a decreased TEER, resulted in substantial translocation. In conclusion, no translocation of QDs was found through a tight monolayer of primary rat alveolar epithelial cells, regardless of the QDs surface charge. QDs did not impair the barrier function of the epithelial cells. In conditions with disruption of the cell-cell barrier, translocation was demonstrated.
Peroxisome proliferator-activated receptor-γ ligands induce heme oxygenase-1 in lung fibroblasts by a PPARγ-independent, glutathione-dependent mechanism
Authors: Ferguson Heather E. , Thatcher Thomas H. , Olsen Keith C. , Garcia-Bates Tatiana M. , Baglole Carolyn J. , Kottmann R. M. , Strong Emily R. , Phipps Richard P. , Sime Patricia J.
Published: September 2009

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPARγ ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPARγ independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an α/β unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPARγ ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPARγ ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.
Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants
Authors: Fujinaga Hideshi , Baker Christopher D. , Ryan Sharon L. , Markham Neil E. , Seedorf Gregory J. , Balasubramaniam Vivek , Abman Steven H.
Published: September 2009

Exposure of preterm infants to hyperoxia impairs vascular growth, contributing to the development of bronchopulmonary dysplasia and retinopathy of prematurity. Disruption of vascular endothelial growth factor (VEGF)-nitric oxide (NO) signaling impairs vascular growth. Endothelial progenitor cells (EPCs) may play an important role in vascular growth. Endothelial colony-forming cells (ECFCs), a type of EPC, from human preterm cord blood are more susceptible to hyperoxia-induced growth impairment than term ECFCs. Therefore, we hypothesized that hyperoxia disrupts VEGF-NO signaling and impairs growth in preterm ECFCs and that exogenous VEGF or NO preserves growth in hyperoxia. Growth kinetics of preterm cord blood-derived ECFCs (gestational ages, 27–34 wk) were assessed in room air (RA) and hyperoxia (40–50% oxygen) with or without VEGF, NO, or Nω-nitro-l-arginine. VEGF, VEGF receptor-2 (VEGFR-2), and endothelial NO synthase (eNOS) protein expression and NO production were compared. Compared with RA controls, hyperoxia significantly decreased growth, VEGFR-2 and eNOS expression, and NO production. VEGF treatment restored growth in hyperoxia to values measured in RA controls and significantly increased eNOS expression in hyperoxia. NO treatment also increased growth in hyperoxia. Nω-nitro-l-arginine treatment inhibited VEGF-augmented growth in RA and hyperoxia. We conclude that hyperoxia decreases growth and disrupts VEGF-NO signaling in human preterm ECFCs. VEGF treatment restores growth in hyperoxia by increasing NO production. NO treatment also increases growth during hyperoxia. Exogenous VEGF or NO may protect preterm ECFCs from the adverse effects of hyperoxia and preservation of ECFC function may improve outcomes of preterm infants.
Mesenchymal stem cells produce Wnt isoforms and TGF-β1 that mediate proliferation and procollagen expression by lung fibroblasts
Authors: Salazar Keith D. , Lankford Susan M. , Brody Arnold R.
Published: September 2009

Studies have been carried out previously to determine whether mesenchymal stem cells (MSC) influence the progression of pulmonary fibrosis. Here, we asked whether MSC (derived from mouse bone marrow and human umbilical cord blood) produce factors that mediate lung fibroblast (LF) growth and matrix production. MSC-conditioned media (CM) were found by ELISA to contain significant amounts of PDGF-AA and transforming growth factor-β1 (TGF-β1). Proliferation was increased in a concentration-dependent manner in LF cell lines and primary cells cultured in MSC-CM, but neither anti-PDGF antibodies nor PDGF receptor-specific antibodies affected proliferation, nor did a number of other antibodies to well-known mitogenic factors. However, proliferation was significantly inhibited by the Wnt signaling antagonist, secreted frizzled related protein-1 (sFRP-1). In addition, anti-Wnt1 and anti-Wnt2 antibodies attenuated MSC-CM-induced proliferation, and increased expression of Wnt7b was identified. As would be expected in cells activated by Wnt, nuclear β-catenin was increased. The amount of TGF-β1 in MSC-CM and its biological activity were revealed by activation at acidic pH. The stem cells synthesized and released TGF-β1 that increased α1-procollagen gene expression by LF target cells. Addition of anti-TGF-β to the MSC-CM blocked upregulation of collagen gene expression. These data demonstrate that MSC from mice and humans produce Wnt proteins and TGF-β1 that respectively stimulate LF proliferation and matrix production, two hallmarks of fibroproliferative lung disease. It will be essential to determine whether these factors can play a role in attempts to use MSC for therapeutic approaches.
Lossless Image Compression Based on Multiple‐Tables Arithmetic Coding
Authors: Chen Rung-Ching , Pai Pei-Yan , Chan Yung-Kuan , Chang Chin-Chen
Published: September 2009

This paper is intended to present a lossless image compression method based on multiple‐tables arithmetic coding (MTAC) method to encode a gray‐level imagef. First, the MTAC method employs a median edge detector (MED) to reduce the entropy rate off. The gray levels of two adjacent pixels in an image are usually similar. A base‐switching transformation approach is then used to reduce the spatial redundancy of the image. The gray levels of some pixels in an image are more common than those of others. Finally, the arithmetic encoding method is applied to reduce the coding redundancy of the image. To promote high performance of the arithmetic encoding method, the MTAC method first classifies the data and then encodes each cluster of data using a distinct code table. The experimental results show that, in most cases, the MTAC method provides a higher efficiency in use of storage space than the lossless JPEG2000 does.
Simulation Algorithm That Conserves Energy and Momentum for Molecular Dynamics of Systems Driven by Switching Potentials
Authors: Jesudason Christopher G.
Published: September 2009

Whenever there exists a crossover from one potential to another, computational problems are introduced in Molecular Dynamics (MD) simulation. These problem are overcome here by an algorithm, described in detail. The algorithm is applied
to a 2‐body particle potential for a hysteresis loop reaction model. Extreme temperature
conditions were applied to test for algorithm effectiveness by monitoring
global energy, pressure and temperature discrepancies in an equilibrium system.
No net rate of energy and other flows within experimental error should be observed,
in addition to invariance of temperature and pressure along the MD cell for the said
system. It is found that all these conditions are met only when the algorithm is applied.
It is concluded that the method can easily be extended to Nonequilibrium
MD (NEMD) simulations and to reactive systems with reversible, non‐hysteresis
loops.
Anti‐Hepatitis B Virus X Protein in Sera Is One of the Markers of Development of Liver Cirrhosis and Liver Cancer Mediated by HBV
Authors: Zhang Hang , Wu Lian-Ying , Zhang Shuai , Qiu Li-Yan , Li Nan , Zhang Xuan , Zhang Xue-Zhi , Shan Chang-Liang , Ye Li-Hong , Zhang Xiao-Dong
Published: September 2009

Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the significance of circulating antibody to hepatitis B virus X antigen (anti‐HBx) in sera remains unclear. In the present study, we examined the titers of anti‐HBx (IgG) in the sera from 173 patients with chronic hepatitis B (CHB), 106 liver cirrhosis (LC), and 61 HCC by enzyme‐linked immunosorbent assay (ELISA), respectively. Our data showed that the positive rates of anti‐HBx were higher in sera of LC (40.6%) and HCC (34.4%) than those of CHB (10.4%), P < .05. In all 40 patients with anti‐HBx+ out of 340 patients, 39 (97.5%) were HBsAg/HBeAg/anti‐HBc+ and 1 (2.5%) was anti‐HBs+ (P < .01), suggesting that anti‐HBx in sera is a marker of HBV replication rather than a protective antibody. Thus, our findings reveal that circulating anti‐HBx in sera is one of the markers of development of LC and HCC mediated by HBV.
Risk Factors for Age-Related Maculopathy
Authors: Connell Paul P. , Keane Pearse A. , O'Neill Evelyn C. , Altaie Rasha W. , Loane Edward , Neelam Kumari , Nolan John M. , Beatty Stephen
Published: September 2009

Age-related maculopathy (ARM) is the leading cause of blindness in the elderly. Although beneficial therapeutic strategies have recently begun to emerge, much remains unclear regarding the etiopathogenesis of this disorder. Epidemiologic studies have enhanced our understanding of ARM, but the data, often conflicting, has led to difficulties with drawing firm conclusions with respect to risk for this condition. As a consequence, we saw a need to assimilate the published findings with respect to risk factors for ARM, through a review of the literature appraising results from published cross-sectional studies, prospective cohort studies, case series, and case control studies investigating risk for this condition. Our review shows that, to date, and across a spectrum of epidemiologic study designs, only age, cigarette smoking, and family history of ARM have been consistently demonstrated to represent risk for this condition. In addition, genetic studies have recently implicated many genes in the pathogenesis of age-related maculopathy, including Complement Factor H, PLEKHA 1, and LOC387715/HTRA1, demonstrating that environmental and genetic factors are important for the development of ARM suggesting that gene-environment interaction plays an important role in the pathogenesis of this condition.
Warped Product Semi‐Invariant Submanifolds in Almost Paracontact Riemannian Manifolds
Authors: Atçeken Mehmet
Published: September 2009

We show that there exist no proper warped product semi‐invariant submanifolds in almost paracontact Riemannian manifolds such that totally geodesic submanifold and totally umbilical submanifold of the warped product are invariant and anti‐invariant, respectively. Therefore, we consider warped product semi‐invariant submanifolds in the form N = N⊥×fNT
by reversing two factor manifolds NT
and N⊥. We prove several fundamental properties of warped product semi‐invariant submanifolds in an almost paracontact Riemannian manifold and establish a general inequality for an arbitrary warped product semi‐invariant submanifold. After then, we investigate warped product semi‐invariant submanifolds in a general almost paracontact Riemannian manifold which satisfy the equality case of the inequality.
Robust and Unbiased Variance of GLM Coefficients for Misspecified Autocorrelation and Hemodynamic Response Models in fMRI
Authors: Waldorp Lourens
Published: September 2009

As a consequence of misspecification of the hemodynamic response and noise variance models, tests on general linear model coe cients are not valid. Robust estimation of the variance of the general linear model (GLM) coecients in fMRI time series is therefore essential. In this paper an alternative method to estimate the variance of the GLM coe cients accurately is suggested and compared to other methods. The alternative, referred to as the sandwich, is based primarily on the fact that the time series are obtained from multiple exchangeable stimulus presentations. The analytic results show that the sandwich is unbiased. Using this result, it is possible to obtain an exact statistic which keeps the 5% false positive rate. Extensive Monte Carlo simulations show that the sandwich is robust against misspeci cation of the autocorrelations and of the hemodynamic response model. The sandwich is seen to be in many circumstances robust, computationally efficient, and flexible with respect to correlation structures across the brain. In contrast, the smoothing approach can be robust to a certain extent but only with specific knowledge of the circumstances for the smoothing parameter.
Cardiac Sarcoidosis Culminating in Severe Biventricular Failure
Authors: Ozaki Takefumi , Ohnuma Noritomo , Shimizu Norihiro , Hasegawa Atsushi , Horimoto Masashi
Published: September 2009

A 59-year-old woman with a history of lung sarcoidosis developed general edema and exertional dyspnea. An electrocardiogram showed first-degree atrioventricular block with complete right bundle branch block. Chest X-ray showed cardiomegaly. Echocardiography showed diffuse and severe hypokinesis of the left ventricle (LV) and biventricular enlargement with severe tricuspid regurgitation. Myocardial scintigraphy disclosed a perfusion defect at the ventricular septum and hypoperfusion at the posterior wall and the apex. On cardiac catheterization, pulmonary capillary wedge pressure, right ventricular, and right atrial pressures were elevated. Coronary angiograms were normal. Myocardial biopsy of the right ventricle histologically revealed epithelioid cell granuloma with infiltration of fibrous cells. The patient's symptom and LV function were improved with conventional medical therapy for heart failure. This is a rare case of cardiac sarcoidosis resulting in biventricular failure.
Ovarian Cancer Pathogenesis: A Model in Evolution
Authors: Karst Alison M. , Drapkin Ronny
Published: September 2009

Ovarian cancer is a deadly disease for which there is no effective means of early detection. Ovarian carcinomas comprise a diverse group of neoplasms, exhibiting a wide range of morphological characteristics, clinical manifestations, genetic alterations, and tumor behaviors. This high degree of heterogeneity presents a major clinical challenge in both diagnosing and treating ovarian cancer. Furthermore, the early events leading to ovarian carcinoma development are poorly understood, thus complicating efforts to develop screening modalities for this disease. Here, we provide an overview of the current models of ovarian cancer pathogenesis, highlighting recent findings implicating the fallopian tube fimbria as a possible site of origin of ovarian carcinomas. The ovarian cancer model will continue to evolve as we learn more about the genetics and etiology of this disease.
Atypical Protein Kinase Cι Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis
Authors: Regala Roderick P. , Davis Rebecca K. , Kunz Alyssa , Khoor Andras , Leitges Michael , Fields Alan P.
Published: September 2009

Protein kinase Cι (PKCι) is an oncogene required for maintenance of the transformed phenotype of non–small cell lung cancer cells. However, the role of PKCι in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic KrasG12D is activated by Cre-mediated recombination in the lung with or without simultaneous genetic loss of the mouse PKCι gene, Prkci. Genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. This effect correlates with a defect in the ability of Prkci-deficient bronchioalveolar stem cells to undergo Kras-mediated expansion and morphologic transformation in vitro and in vivo. Furthermore, the small molecule PKCι inhibitor aurothiomalate inhibits Kras-mediated bronchioalveolar stem cell expansion and lung tumor growth in vivo. Thus, Prkci is required for oncogene-induced expansion and transformation of tumor-initiating lung stem cells. Furthermore, aurothiomalate is an effective antitumor agent that targets the tumor-initiating stem cell niche in vivo. These data have important implications for PKCι as a therapeutic target and for the clinical use of aurothiomalate for lung cancer treatment. [Cancer Res 2009;69(19):7603–11]
Bone Marrow–Derived Cell-Specific Chemokine (C-C Motif) Receptor-2 Expression is Required for Arteriolar Remodeling
Authors: Nickerson Meghan M. , Song Ji , Meisner Joshua K. , Bajikar Sameer , Burke Caitlin W. , Shuptrine Casey W. , Owens Gary K. , Skalak Thomas C. , Price Richard J.
Published: September 2009

Objective—

Bone marrow-derived cells (BMCs) and inflammatory chemokine receptors regulate arteriogenesis and angiogenesis. Here, we tested whether arteriolar remodeling in response to an inflammatory stimulus is dependent on BMC-specific chemokine (C-C motif) receptor 2 (CCR2) expression and whether this response involves BMC transdifferentiation into smooth muscle.

Methods and Results—

Dorsal skinfold window chambers were implanted into C57Bl/6 wild-type (WT) mice, as well as the following bone marrow chimeras (donor-host): WT-WT, CCR2
−/−
-WT, WT-CCR2
−/−
, and EGFP
+
-WT. One day after implantation, tissue MCP-1 levels rose from “undetectable” to 463pg/mg, and the number of EGFP
+
cells increased more than 4-fold, indicating marked inflammation. A 66% (28 μm) increase in maximum arteriolar diameter was observed over 7 days in WT-WT mice. This arteriolar remodeling response was completely abolished in CCR2
−/−
-WT mice but largely rescued in WT-CCR2
−/−
mice. EGFP
+
BMCs were numerous throughout the tissue, but we found no evidence that EGFP
+
BMCs transdifferentiate into smooth muscle, based on examination of >800 arterioles and venules.

Conclusions—

BMC-specific CCR2 expression is required for injury/inflammation-associated arteriolar remodeling, but this response is not characterized by the differentiation of BMCs into smooth muscle.
The Soering reshold: Why Only Fundamental Values Prohibit Refoulement in ECHR Case Law
Authors: Battjes Hemme
Published: September 2009

According to ECHR case-law, the Convention prohibits expulsion if violations of Articles 2 and 3 are risked upon return. Feared violations of other rights such as the freedom of religion do normally not prohibit expulsion. This article explores how the Court delimits violations that prohibit expulsion from those that do not, and which reasons the Court has put forward for justifying this distinction. It focuses on the consistency in the Court's reasoning. It is submitted that balancing human rights to inter alia the economic well-being of the Contacting states determines the outcome of expulsion cases, although this balancing is in many cases invisible, and that this balancing test rests upon the relevance of the alien status of those who invoke the prohibition on expulsion, although this relevance has not been substantiated in the case-law.
Still Silencing the Racism Suffered by Migrants . . . The Limits of Current Developments under Article 14 ECHR
Authors: Dembour Marie-Bénédicte
Published: September 2009

The European Court of Human Rights has recently developed its jurisprudence related to racial discrimination in highly significant ways. The Court has rightly been applauded for abandoning its requirement that racial discrimination be proved 'beyond reasonable doubt' and for endorsing the concept of indirect discrimination, allowing it, in the last five years, to begin to find states from 'eastern Europe' in violation of the Convention for having discriminated against especially Roma applicants. While welcome, these new developments should not detract from the need to continue asking difficult questions, including the following: why has it taken decades for the Court to start finding a violation of Article 14 on grounds of race? Why are cases, such as Menson v. United Kingdom concerning the slow reaction of the police in investigating the lethal attack of a black man, not found admissible? Can we expect the Court, created in a region which largely built itself upon colonialism, to generate mechanisms fit to tackle racism? In the past, judges themselves have provided the most virulent critique of the Court's inability to tackle racism. Migrants still remain to benefit from their progressive stance in relation to Article 14 claims based on grounds of race.
Love Thy Neighbour: Family Reunification and the Rights of Insiders
Authors: de Hart Betty
Published: September 2009

This article looks at the extent and way in which the European Court of Human Rights takes the interests of insider spouses (citizens or permanent residents) into account in Article 8 ECHR cases (right to family life). It uses Caren's three moral principles for family reunification policies as an analysing tool for the evaluation of the Court's first admission and expulsion cases, and looks at the underlying notions of gender and ethnicity. The author concludes that insiders' interests play only a marginal role in the case law and offers several explanations. Although the Court has acknowledged that family reunification is about insiders, it has not taken the consequences of such a position into account. It does not look at the ties of the insider spouse to his or her country of citizenship or residence. It sees the relationships of insider women with migrant partners as a more serious threat to restrictive immigration policies than relationships of insider men with migrant women. Furthermore, the Court thinks of nation-states as closed units to which migrants may be admitted as an exception to the rule, and does not acknowledge that insiders develop family relations with outsiders either within or outside the nation-state.
The Exclusiveness of Inclusion: On the Boundaries of Human Rights in Protecting Transnational and Second Generation Migrants
Authors: Farahat Anuscheh
Published: September 2009

This article analyses the treatment of so-called transnational migrants in expulsion cases reviewed under Article 8 of the European Convention on Human Rights before the European Court of Human Rights (hereinafter: the Court). By regularly crossing national borders and maintaining cultural and social ties to more than one country these migrants are in fact not effectively protected by the Court. This disadvantaging treatment can be explained as being the result of the Court's doctrine of margin of appreciation which allows domestic political preference in immigration policy to dominate the balancing process before the Court. The margin of appreciation doctrine is interpreted as the Court's way of dealing with the more general tension it faces in acting as a guardian on the one hand and respecting domestic legislation on the other. This tension is strengthened by the institutional arrangement under which the Court is acting. Against this background, this article submits two possible amendments on the doctrinal and procedural level, suggesting that the Court should follow a more inclusive reasoning and should replace the margin of appreciation doctrine by the concept of core content.
Structural Instability: Strasbourg Case Law on Children's Family Reunion
Authors: Spijkerboer Thomas
Published: September 2009

In this article, the case law of the European Court of Human Rights on children's family reunion is examined. The argument is that the Court's case law is necessarily inconsistent. This is so in part as a consequence of the structure of international legal argument, and partly as a consequence of the seeming normative conflict about the legitimacy of migration control. On both points, the Court is torn between two equally legitimate and equally untenable extremes, which forces the Court to take a centrist position and to acknowledge both the legitimacy and the untenable nature of any position. The main part of the article analyses how this takes shape in the legal technicalities in the judgements under review.
Against All Odds: How Single and Divorced Migrant Mothers were Eventually able to Claim their Right to Respect for Family Life
Authors: van Walsum Sarah
Published: September 2009

Feminist and post-colonial theorists challenge the supposed neutrality of international human rights law which, in their view, should be seen as a product of asymmetrical power relations. On the basis of this premise, it seems unlikely that single and divorced migrant mothers from outside of the EU will be able to mobilize international human rights law to their advantage. And yet, after twenty years of litigation, single and divorced migrant mothers in the Netherlands are now finally able to claim their right to respect for family life and reunite with children left behind in their countries of origin. This chapter seeks to explain how this increase in human rights protection could come about. While some litigants are less powerful than others, they do not always stand alone. Increasing the scope of analyses makes it possible to include case law produced by more powerful actors. Their gains can offer strategic opportunities to those less powerful.
Writing About Patients: What Clinical and Literary Writers Share
Authors: Miller Elise
Published: September 2009

Anyone who seeks publication wants readers, but self-expression, self-assertion, and self-promotion have consequences, especially for those who draw on clinical material and who must honor publication standards of integrity and reliability, as well as ethical codes governing confidentiality, consent, disguise, and collaboration. This paper employs tools of literary analysis, principles of moral philosophy, and psychoanalytic theories about writing to show that writers of fiction and autobiography also struggle with these dilemmas. They worry about their responsibilities to the sources of their stories, and wonder if changing names and dates will prevent friends and family, whose lives get used as material, from feeling embarrassed, betrayed, or exploited. Because they understand that the composing process blurs boundaries between fiction and nonfiction, fantasy and memory, self and other, they recognize that an author’s relationship with his or her subject (matter) can disable the capacity to recognize when self-interest has taken over a concern for the welfare of others. More important, literary authors are free to write about writing, and what they render transparent about primitive, unconscious processes suggests that what clinical writing has in common with fiction and autobiography should be included in efforts to update ethical standards and procedures regarding psychoanalytic publication.
Clinical Strategies for the Management of Acute Mastoiditis in the Pediatric Population
Authors: Lin Harrison W. , Shargorodsky Josef , Gopen Quinton
Published: September 2009

Although the incidence of acute mastoiditis has been substantially reduced since the introduction of antibiotic therapy, mastoiditis complications are still commonly seen in the pediatric population. Many of these cases require lengthy hospitalizations and extensive medical and surgical interventions. Accordingly, a safe, effective, and resourceful diagnostic and therapeutic plan must be executed for the workup and treatment of each patient suspected of having acute mastoiditis. With thorough clinical evaluations, early diagnosis, and close follow-up, a large proportion of children with severe acute otitis media or early stage mastoiditis can be managed in the primary care setting without immediate surgical specialty involvement. This review presents an overview of the anatomical and pathophysiological considerations in acute mastoiditis and offers pediatricians a practical, evidence-based algorithm for the diagnostic and therapeutic approach to this disease.
Psychopathology, Defence Mechanisms, and the Psychosocial Work Environment
Authors: Larsen Anelia , Bøggild Henrik , Mortensen Jens Tølbøll , Foldager Leslie , Hansen John , Christensen Anders , Arendt Mikkel , Rosenberg Nicole , Munk-Jørgensen Povl
Published: September 2009

Background: The body of evidence verifies the predictive value of certain work characteristics for mental health problems and that various levels of adaptation mechanisms are employed when dealing with adversity. Data on the relationships between employees’ mental health status, their perceptions of work, and their psychological defences are scarce.

Aims: To examine the role that personal defences play in the relationship between psychiatric symptoms among working people and their working environment.

Methods: Nine hundred and seventy six employees (mean age = 42.4 years, SD = 11.3) participated in a questionnaire study that included the Defence Style Questionnaire, the Symptom Checklist 90 revised, and the Copenhagen Psychosocial Questionnaire .

Results: Data showed that greater maturity of psychological defences was associated with higher level of psychological functioning and there were strong associations between presence of psychopathology and the three defence clusters. Results indicated a strong positive correlation between the mature defence style and the perception of a satisfactory workplace. There was no interaction between psychopathology and defences in relation to work environment.

Conclusion: Psychopathology and defences were significantly associated with work conditions, which could suggest that adaptation mechanisms and psychopathology are two independent forms of adjustment to the rapidly changing world of work.