bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypertensive End-Organ Damage and Premature Mortality Are p38 Mitogen-Activated Protein Kinase–Dependent in a Rat Model of Cardiac Hypertrophy and Dysfunction
Authors: Behr Thomas M. , Nerurkar Sandhya S. , Nelson Allen H. , Coatney Robert W. , Woods Tina N. , Sulpizio Anthony , Chandra Sudeep , Brooks David P. , Kumar Sanjay , Lee John C. , Ohlstein Eliot H. , Angermann Christiane E. , Adams Jerry L. , Sisko Joseph , Sackner-Bernstein Jonathan D. , Willette Robert N. 
Published: September 2007

BackgroundNumerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage.Methods and ResultsIn spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-α concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063–treated groups.ConclusionsThese results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.
Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension
Authors: Hilgers Karl F. , Hartner Andrea , Porst Markus , Veelken Roland , Mann Johannes F.E. 
Published: September 2007

Background—Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect.Methods and Results—Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg · kg−1· d−1or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects.Conclusions—Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.
Regional Cerebral Hyperperfusion and Nitric Oxide Pathway Dysregulation in Fabry Disease
Authors: Moore David F. , Scott Leland T.C. , Gladwin Mark T. , Altarescu Gheona , Kaneski Christine , Suzuki Kinuko , Pease-Fye Meg , Ferri Raymond , Brady Roscoe O. , Herscovitch Peter , Schiffmann Raphael 
Published: September 2007

BackgroundFabry disease is an X-linked lysosomal deficiency of α-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure.Methods and ResultsUsing [15O] H2O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weightS-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weightS-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of α-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels.ConclusionsThese findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.
Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes
Authors: Ziolo Mark T. , Katoh Hideki , Bers Donald M. 
Published: September 2007

Background—β-Adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca2+release channel (ryanodine receptor, RyR) during β-adrenergic stimulation.Methods and Results—Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca2+spark frequency (CaSpF, reflecting resting RyR openings) and Ca2+transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 μmol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca2+transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca2+load).Conclusions—iNOS/NO depresses β-adrenergic–stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits β-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.
Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes
Authors: Iwai-Kanai Eri , Hasegawa Koji , Sawamura Tatsuya , Fujita Masatoshi , Yanazume Tetsuhiko , Toyokuni Shinya , Adachi Souichi , Kihara Yasuki , Sasayama Shigetake 
Published: September 2007

Background—Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1.Methods and Results—In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2′-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK.Conclusions—These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.
Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers
Authors: Verma Subodh , Raj Satish R. , Shewchuk Lana , Mather Kieren J. , Anderson Todd J. 
Published: September 2007

Background—From a cardiovascular standpoint, the safety of cyclooxygenase-2 (COX-2) blockers has been a topic of increasing concern. This concern stemmed from observations indicating that the COX-2 isoform is the major source of endothelium-derived prostacyclin and, hence, that selective blockade of this enzyme may impair endothelial health. To investigate this matter, we examined the effects of 7 days of treatment with rofecoxib versus naproxen on endothelial function in healthy volunteers.Methods and Results—Thirty-five healthy volunteers were randomized to receive 7-day treatment with either rofecoxib (25 mg/d, n=18) or naproxen (750 mg/d, n=17). Vascular response measurements were conducted using forearm strain-gauge plethysmography. Changes in forearm blood flow in response to the endothelium-dependent vasodilator acetylcholine (3, 10, and 30 μg/min) and the endothelium-independent vasodilator sodium nitroprusside (1 and 10 μg/min) were assessed before and after treatment. Acetylcholine evoked a dose-dependent increase in forearm blood flow in all groups. Importantly, treatment resulted in no change in acetylcholine-mediated increases in forearm blood flow in either group (naproxen,P=0.27; rofecoxib,P=0.58). Similarly, there was no change in forearm blood flow in response to sodium nitroprusside (naproxen,P=0.55; rofecoxib,P=0.63).Conclusions—We herein describe, for the first time, the effects of COX-2-selective inhibition on endothelium-dependent vasodilatation in healthy adults. COX-2 blockade, when used at the doses employed therapeutically (which are known to inhibit vascular prostacyclin production) did not result in significant changes in endothelial vasodilator responses in healthy volunteers. The effects of COX-2 inhibitors on vasodilator responses in patients with coronary artery disease remain to be determined.
NovelSCN5AMutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family
Authors: Kyndt Florence , Probst Vincent , Potet Franck , Demolombe Sophie , Chevallier Jean-Christophe , Baro Isabelle , Moisan Jean-Paul , Boisseau Pierre , Schott Jean-Jacques , Escande Denis , Le Marec Hervé 
Published: September 2007

Background—TheSCN5Agene encoding the human cardiac sodium channel α subunit plays a key role in cardiac electrophysiology. Mutations inSCN5Alead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease).Methods and Results—In the present study, we report the identification of a novel singleSCN5Amissense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406RSCN5Amutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutatedSCN5Ashowed no detectable Na+current but normal protein trafficking.Conclusions—We conclude that the same mutation in theSCN5Agene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of aSCN5Amutation.
Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium
Authors: Horstick Georg , Berg Oliver , Heimann Axel , Götze Otto , Loos Michael , Hafner Gerd , Bierbach Benjamin , Petersen Steffen , Bhakdi Sucharit , Darius Harald , Horstick Marina , Meyer Jürgen , Kempski Oliver 
Published: September 2007

Background—Complement activation during reperfusion of ischemic myocardium augments myocardial injury, and complement inhibition with C1-esterase inhibitor (C1-INH) at the time of reperfusion exerts marked cardioprotective effects in experimental studies. Application of C1-INH in newborns, however, was recently reported to have dangerous and even lethal side effects. This study addresses the essential role of dosage in studies using C1-INH.Methods and Results—Cardioprotection by C1-INH was examined in a pig model with 60 minutes of coronary occlusion followed by 120 minutes of reperfusion. C1-INH was administered intravenously 5 to 10 minutes before coronary reperfusion without heparin at a dose of 40, 100, and 200 IU/kg body wt. Compared with the NaCl controls, C1-INH 40 IU/kg reduced myocardial injury (44.1±13.8% versus 76.7±4.6% necrosis of area at risk,P≤0.05) and significantly suppressed local C3a and C5a generation. Myocardial protection was accompanied by reduced plasma concentrations of creatine kinase and troponin T. In contrast, no beneficial effects were observed when 100 IU/kg C1-INH was used. Furthermore, application of 200 IU/kg C1-INH provoked severe side effects and coagulation disorders.Conclusions—When applied at the correct dose, C1-INH significantly protects ischemic tissue from reperfusion damage. However, overly high doses (≥100 IU/kg) of C1-INH will provoke detrimental side effects, probably via its procoagulatory action.
Physiological and Pathophysiological Functions of the AT2Subtype Receptor of Angiotensin II
Authors: Henrion Daniel , Kubis Nathalie , Lévy Bernard I. 
Published: September 2007

Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT1R) and type 2 (AT2R). Whereas the key role of AT2R in the development of the embryo has been extensively studied, the role of AT2R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT2R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT2R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT2R-dependent dilation. Sometimes, such as in large renal arteries, AT2R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT2R stimulation may also have a role in shear stress–induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT2R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT1R blockade in patients, overstimulation of AT2R might be beneficial, given their potential vasodilator effect.Concerning the possible role of AT2R in cardiovascular remodeling, the situation is more controversial. In vitro AT2R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT2R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT1R blockade, and thus AT2R overstimulation, require more in-depth analysis.
Accurate Liquid Water Path Retrieval from Low-Cost Microwave Radiometers Using Additional Information from a Lidar Ceilometer and Operational Forecast Models
Authors: Gaussiat Nicolas , Hogan Robin J. , Illingworth Anthony J. 
Published: September 2007

Abstract
Water clouds have an important impact on the radiative balance of the earth. The use of ground-based dual-frequency microwave radiometers to derive both liquid water path (LWP) and water vapor path (WVP) is well established, but uncertainties over the dry, water vapor, and liquid water absorption coefficients and the radiometric calibration can lead to errors in the retrieved LWP. A method in which additional information from a lidar ceilometer is used to identify the presence of liquid water clouds and their altitude is described. When such clouds are absent, the radiometric calibrations of the two frequencies are optimally adjusted so that the retrieved LWP is forced to zero; when they are present the calibrations are interpolated from the nearest clear-sky periods before and after, and the temperature of the cloud is used to refine the liquid water absorption coefficient (with the temperature profile taken from a forecast model). This procedure is insensitive to the choice of absorption model, removes the troublesome negative values of LWP that can be retrieved, and provides more accurate values of low LWP in thin clouds. Analysis shows that LWP as low as 10 g m−2 can be reliably retrieved, 90% of the time the error being less than 50%, and for LWP greater than 20 g m−2 the error is less than 10%. An additional advantage is that the retrieval can tolerate uncertainties in the various absorption coefficients and is unaffected by slow drifts in brightness temperature errors of up to 5 K. Previous techniques have required that these temperatures be accurate to 0.5 K or better, which entails careful calibration and can be quite difficult to achieve.
Analysis of Abnormal Wave Records by the Hilbert–Huang Transform Method
Authors: Veltcheva Albena D. , Soares C. Guedes 
Published: September 2007

AbstractThe Hilbert–Huang transform method is used in this work to analyze wave records from the North Sea, which include abnormal waves. The analysis of the characteristics of abnormal waves is based on the local decomposition of wave data by using the intrinsic mode functions. The variations of amplitude of intrinsic mode functions around the time of the occurrence of abnormal waves are examined in order to investigate the contribution of different intrinsic mode functions on the abnormal waves’ profile, in an attempt to find relationships between them. The changes of local frequency of each intrinsic mode function in the vicinity of abnormal waves are examined. The essential nonlinearity of abnormal waves is considered as intrawave frequency modulation, a variation of the instantaneous frequency within one oscillation cycle. The Hilbert spectrum is used as a detector of abnormal waves.
Surface Salinity Measurements—COSMOS 2005 Experiment in the Bay of Biscay
Authors: Reverdin G. , Boutin J. , Lourenco A. , Blouch P. , Rolland J. , Niiler P. P. , Scuba W. , Rios A. F. 
Published: September 2007

Abstract
Sea surface salinity (SSS) data were collected in the Bay of Biscay between April and November 2005. The major source of data is 15 surface drifters deployed during the COSMOS experiment in early April and early May 2005 [12 from the Scripps Instution of Oceanography (SIO) and 3 from METOCEAN]. This is complemented by thermosalinograph (TSG) data from four French research vessels and four merchant vessels, from salinity profiles collected by Argo profiling floats and CTD casts, and from surface samples during two cruises. Time during the two cruises was dedicated to direct inspection of the drifters, recovering some, and providing validation data. This dataset provides a unique opportunity to estimate the accuracy of the SSS data and to evaluate the long-term performance of the drifter salinities. Some of the TSG SSS data were noisy, presumably from bubbles. The TSG data from the research vessels needed to be corrected from biases, which are very commonly larger than 0.1 pss-78 (practical salinity scale), and which in some instances evolved quickly from day to day. These corrections are only available when samples were collected or ancillary data are available (e.g., from CTD profiles). The resulting accuracy of the corrected TSG dataset, which varies strongly in time, is discussed. The surface drifter SSS data presented anomalous daytime values during days with strong surface warming. These data had to be excluded from the dataset. The drifter SSS presented initial biases in the range 0.009 to −0.026 pss-78. The (usually) negative bias increased by an average of −0.007 pss-78 during the average 65-day period before the COSMOS-2 cruise on 22–27 June. High chlorophyll derived from satellite ocean color, and therefore high density of phytoplanktonic cells, is observed in Medium Resolution Imaging Spectrometer (MERIS)/Moderate Resolution Imaging Spectroradiometer (MODIS) composites during part of the period, in particular in late April or early May. No correlation was found between the change in bias and the estimated surface chlorophyll. Evolution during the following summer months is harder to ascertain. For three buoys, there is little change in bias, but for two others, there could have been an increase in bias by up to 0.03 or 0.04 pss-78 during July–August. Seven drifters were recovered in the autumn, which provide recovery or postrecovery estimates of the biases, suggesting in three cases (out of seven) a large (0.02–0.03 pss-78) increase in bias during the autumn months, but no significant increase for the other four drifters.