bluuebunny/crossref_metadata_2025 huggingface dataset:
Hibernating myocardium: pathophysiology, diagnosis, and treatmentThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).
Authors: Slezak Jan , Tribulova Narcis , Okruhlicova Ludmila , Dhingra Rimpy , Bajaj Anju , Freed Darren , Singal Pawan
Published: April 2009

Comprehensive management of patients with chronic ischemic disease is a critically important component of clinical practice. Cardiac myocytes have the potential to adapt to limited flow conditions by adjusting contractile function, reducing metabolism, conserving resources, and preserving myocardial integrity to cope with an oxygen and (or) nutrition shortage. A prime metabolic feature of cardiac myocytes affected by chronic ischemia is the return to a fetal gene pattern with predominance of carbohydrates as the substrate for energy. Structural adaptation with multiple intracellular changes is part of the remodeling process in hibernating myocardium. Transmural heterogeneity, which defines the pattern of injury in ventricular cardiomyocytes and the response to chronic ischemia, is a multifactorial process originating from functional, metabolic, and flow differences in subendocardial and subepicardial regions. Autophagy is typically activated in hibernating myocardium and has been identified as a prosurvival mechanism. Chronic ischemia is associated with changes in the number, size, and distribution of gap junctions and may give rise to conduction disturbances and arrhythmogenesis. Differentiation between viable and nonviable myocardium by assessing sensitivity of inotropic reserve is a crucial diagnostic tool that is correlated with the prognosis and outcome for improved contractility after restoration of blood perfusion in afflicted myocardium.Reliable and accurate diagnosis of ischemic, scar, and viable tissues is critical for recover strategies. Although early surgical reinstitution of blood flow is most effective in restoring physiologic function of the hibernating myocardium, several new approaches offer promising alternatives. Among others, vascular endothelial growth factor and fibroblast growth factor-2 (FGF-2), especially its lo-FGF-2 isoform, have been shown to be effective in rapid neovascularization. Substances such as statins, resveratrol, some hormones, and omega-3 fatty acids can improve recovery effect in chronically underperfused hearts. For patients with drug-refractory ischemia, intramyocardial transplantation of stem cells into predefined areas of the heart can enhance vascularization and have beneficial effects on cardiac function. This review of ischemic injury, its heterogeneity, accurate diagnosis, and newer methods of treatment, shows there is much information and tremendous hope for better management of patients with coronary heart disease.
Impaired regulation of cardiac function in sepsis, SIRS, and MODSThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).
Authors: Werdan Karl , Schmidt Hendrik , Ebelt Henning , Zorn-Pauly Klaus , Koidl Bernd , Hoke Robert Sebastian , Heinroth Konstantin , Müller-Werdan Ursula
Published: April 2009

In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which mediate the pacemaker current Ifand play an important role in transmitting sympathetic and vagal signals on heart rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endotoxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory reflex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppression of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of statins, β-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.
Altitudinal gradient of Eurasian otter (Lutra lutra) food niche in Mediterranean habitats
Authors: Remonti Luigi , Balestrieri Alessandro , Prigioni Claudio
Published: April 2009

The effects of geographical factors, such as latitude and altitude, on climate are known to influence the food habits of predator species distributed over a broad distribution range. A sharp latitudinal gradient in the diet of the Eurasian otter ( Lutra lutra (L., 1758)), that is an increase of trophic diversity from temperate to Mediterranean Europe, has been described recently. Altitude, affecting the diversity of fish assemblages and hence prey availability for otters, could also be a key factor influencing otter diet. With the aim of testing for the presence of an altitudinal gradient in otter diet in the Mediterranean area, we assessed the composition of diet at 24 sampling reaches spread in three main river catchments of southern Italy. The analysis of 1885 spraints revealed that fish were the main prey of otters, followed by amphibians, while other food items were of lesser significance, although crustaceans could be locally important. The altitude of the sampling station was negatively correlated with fish consumption and positively correlated with otter trophic diversity; at higher altitudes, alternative prey (particularly amphibians) were included in otter diet. The reduction of fish availability with elevation plays a major role in shaping this dietary pattern. The ability of otters to exploit alternative prey, such as amphibians, could allow the colonization of small rivers sustaining a low fish biomass.
Evaluating existing movement hypotheses in linear systems using larval stream salamanders
Authors: Cecala K. K. , Price S. J. , Dorcas M. E.
Published: April 2009

Because of their linear nature, streams provide a restrictive framework to understand the movement ecology of many animals. Stream movements have been characterized under two competing hypotheses. The colonization hypothesis dictates that small individuals experience passive drift, but concurrent, upstream movement by larger individuals replaces the loss of small individuals. Alternatively, the production hypothesis suggests that downstream movements are a consequence of limited resource availability. Previous research suggests that large larvae should move upstream and vice versa for small larvae, which should therefore be found downstream more often. We conducted a mark–recapture study of larval red salamanders ( Pseudotriton ruber (Sonnini de Manoncourt and Latreille, 1801)) to assess the validity of these hypotheses. We found that no larvae exhibited downstream movement (skew = 0.361, p = 0.019; biased upstream), and large larvae were the only size cohort to exhibit directional movement upstream (skew = 0.901, p = 0.035). Contrary to predictions under the colonization hypothesis, small larvae were found upstream more frequently than large larvae (N = 871, H = 16.29, df = 2, p < 0.001). Our results suggest that larval movements are related to abiotic stream conditions, and we conclude that neither hypothesis fully explains stream movement. In the absence of drift, new movement hypotheses are necessary to describe persistent upstream movement in streams. These hypotheses should consider individual causes of movement and the direction of movements that will improve the fitness of the organism.
Large-scale spatiotemporal variation in calf sex ratio in moose (Alces alces): an effect of density-dependent decrease in maternal condition?
Authors: Bjørneraas K. , Solberg E. J. , Herfindal I. , Sæther B.-E.
Published: April 2009

The harvest of Norwegian moose ( Alces alces (L., 1758)) is directed towards certain sex and age classes to maximize yield in terms of meat or number of animals. Observed side effects are declining numbers of calves per female and proportions of adult males, which may affect other demographic variables. Using long-term data, we examined whether spatiotemporal variation in the calf sex ratio was related to changes in (i) density of harvested moose, (ii) recruitment rate, and (or) (iii) the composition of the adult segment of the population. We found declining proportions of male calves in the autumn harvest over time associated with decreasing recruitment rates. Similarly, the proportion of male calves was lower when density of harvested moose was high. We suggest that the decrease in proportion of male calves was caused by increased prenatal or postnatal mortality rates of males, possibly owing to a density-dependent decline in maternal body condition. Proportion of male calves increased with the proportion of adult males in the population the previous year, indicating that low proportions of adult males may lead to lower male recruitment, particularly at high densities. Further declines in proportions of male calves recruited may be avoided by reducing the population density and changing the demographic composition of the harvest.
SPECTRAL AND SCATTERING THEORY FOR SOME ABSTRACT QFT HAMILTONIANS
Authors: GÉRARD C. , PANATI A.
Published: April 2009

We introduce an abstract class of bosonic QFT Hamiltonians and study their spectral and scattering theories. These Hamiltonians are of the form H = dΓ(ω) + V acting on the bosonic Fock space Γ(𝔥), where ω is a massive one-particle Hamiltonian acting on 𝔥 and V is a Wick polynomial Wick(w) for a kernel w satisfying some decay properties at infinity.

We describe the essential spectrum of H, prove a Mourre estimate outside a set of thresholds and prove the existence of asymptotic fields. Our main result is the asymptotic completeness of the scattering theory, which means that the CCR representations given by the asymptotic fields are of Fock type, with the asymptotic vacua equal to the bound states of H. As a consequence, H is unitarily equivalent to a collection of second quantized Hamiltonians.
KINETIC THEORY OF PLASMAS: TRANSLATIONAL ENERGY
Authors: GRAILLE BENJAMIN , MAGIN THIERRY E. , MASSOT MARC
Published: April 2009

In the present study, we derive from kinetic theory a unified fluid model for multicomponent plasmas by accounting for the electromagnetic field influence. We deal with a possible thermal nonequilibrium of the translational energy of the particles, neglecting their internal energy and reactive collisions. Given the strong disparity of mass between the electrons and heavy particles, such as molecules, atoms, and ions, we conduct a dimensional analysis of the Boltzmann equation and introduce a scaling based on a multiscale perturbation parameter equal to the square root of the ratio of the electron mass to a characteristic heavy-particle mass. We then generalize the Chapman–Enskog method, emphasizing the role of the perturbation parameter on the collisional operator, the streaming operator, and the collisional invariants of the Boltzmann equation. The system is examined at successive orders of approximation, each corresponding to a physical timescale. At the highest approximation order investigated, the multicomponent Navier–Stokes regime is reached for the heavy particles and is coupled to first-order drift-diffusion equations for the electrons. The transport coefficients are then calculated in terms of bracket operators whose mathematical structure allows for positivity properties to be determined and Onsager's reciprocal relations to hold. The transport coefficients exhibit an anisotropic behavior when the magnetic field is strong enough. We also give a complete description of the Kolesnikov effect, i.e. the crossed contributions to the mass and energy transport fluxes coupling the electrons and heavy particles. Finally, the first and second laws of thermodynamics are proved to be satisfied by deriving a total energy equation and an entropy equation. Moreover, the purely convective system of equations is shown to be hyperbolic.
A NONCONFORMING PENALTY METHOD FOR A TWO-DIMENSIONAL CURL–CURL PROBLEM
Authors: BRENNER SUSANNE C. , LI FENGYAN , SUNG LI-YENG
Published: April 2009

A nonconforming finite element method for a two-dimensional curl–curl problem is studied in this paper. It uses weakly continuous P1 vector fields and penalizes the local divergence. Two consistency terms involving the jumps of the vector fields across element boundaries are also included to ensure the convergence of the scheme. Optimal convergence rates (up to an arbitrary positive ∊) in both the energy norm and the L2 norm are established on graded meshes. This scheme can also be used in the computation of Maxwell eigenvalues without generating spurious eigenmodes. The theoretical results are confirmed by numerical experiments.
INFORMATION TECHNOLOGY INVESTMENT DECISIONS UNDER ASYMMETRIC INFORMATION: A MODIFIED RATIONAL EXPECTATION MODEL
Authors: NI JINLAN , KHAZANCHI DEEPAK
Published: April 2009

In this paper, we propose that information technology (IT) managers make investment decisions about new IT initiatives based on a modified rational expectation model. Unlike traditional rational expectation models, we emphasize the relevance of market uncertainty and its impact on the return of new IT investment. This results in information acquisition decisions by managers that can cause information asymmetry. This information asymmetry is endogenous and so the IT manager can become well informed if and only if it is beneficial to do so. We also capture different levels of IT investment across managers by introducing heterogeneity across managers in terms of different levels of initial capital. Based on a simulation analysis to validate our theoretical model, we find that it is the IT manager with larger initial capital outlay who is particularly interested in acquiring information about their IT investments in order to reduce any asymmetry with competitors. Furthermore, we find that holding other things constant, fewer IT investors are informed when information cost increases and in consequence the difference of investment level between the informed and uninformed investors is more pronounced.
DISCRIMINATIVE FEATURE EXTRACTION BASED ON SELF-ADAPTIVE FREQUENCY WARPING FOR ROBUST SPEAKER IDENTIFICATION
Authors: LI YANPING , TANG ZHENMIN , DING HUI , ZHANG YAN
Published: April 2009

This paper presents a new discriminative feature based on self-adaptive frequency warping. We analyze the discrimination power between frequency components and individual characteristics and quantify this dependency. This new feature is extracted by nonuniform sub-band filters designed according to self-adaptive frequency warping in different frequency bands. Furthermore, in order to overcoming the acoustics mismatch between training and testing data in the noise environment, we adopted pre-enhancement prior to feature extracted module. Using a series of controlled experiments, it is shown that the theory of this feature is reasonable and understandable, which is insensitive to spoken content and thus more discriminative and robust in comparison to the conventional Mel frequency cepstral coefficients. The experimental results demonstrate that combining pre-enhancement and discriminative feature leads to noticeable improvement on speaker recognition rate and robustness.
Ketamine-induced hepatoprotection: the role of heme oxygenase-1
Authors: Suliburk James W. , Ward Jeremy L. , Helmer Kenneth S. , Adams Sasha D. , Zuckerbraun Brian S. , Mercer David W.
Published: April 2009

Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 μmol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-κB and PPAR-γ analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-γ activity, it enhanced NF-κB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
cGMP does not activate two-pore domain K+ channels in cerebrovascular smooth muscle
Authors: Lloyd Eric E. , Marrelli Sean P. , Bryan Robert M.
Published: April 2009

Two-pore domain K+ (K2P) channels are a new channel family. The goal of this study was to determine if K2P channels are activated by the nitric oxide (NO)/cGMP/PKG pathway in vascular smooth muscle. Relative levels of message for K2P channels were assessed in rat middle cerebral arteries (MCAs) using quantitative RT-PCR, and K+ currents were measured in freshly dispersed vascular smooth muscle cells of the MCA. The rat MCA expresses a number of K2P channels. Message for TREK-1 was the most abundant K2P channel, followed by TASK-1 and TWIK-2, which were expressed at ∼10% of the level of TREK-1. Message for other K2P channels was 1% or less than that of TREK-1. A number of K2P channels, including TREK-1, TWIK-2, and TASK-1, have putative PKG phosphorylation sites in the intracellular domains. The NO donor sodium nitroprusside (100 μM) or the membrane permeable analog of cGMP 8-bromo-cGMP (10 μM) elicited transient increases in whole cell current of vascular smooth muscle from the rat MCA. However, after large-conductance Ca2+-activated K+ channels had been blocked with 10 mM tetraethylammonium (TEA), no increase in whole cell current was observed. Since K2P channels are resistant to the blocking effects of TEA, we conclude that K2P channels in vascular smooth muscle were not activated by the NO/cGMP/PKG pathway. Although K2P channels are highly expressed, K2P currents are not activated via the NO/cGMP pathway in rat MCA smooth muscle, despite the presence of numerous putative PKG phosphorylation sites.
Role of the MAPK/ERK pathway in valvular interstitial cell calcification
Authors: Gu Xiaoxiao , Masters Kristyn S.
Published: April 2009

Much remains to be discovered about the etiology of heart valve disease and the molecular level mechanisms that drive it. The MAPK/ERK pathway influences calcification in many cell types and has been linked to the expression of a contractile phenotype in valvular interstitial cells (VICs). However, a direct correlation between MAPK/ERK pathway activity and VIC calcification has not been previously described. Thus the role of the MAPK pathway in the calcification of VIC cultures was investigated by measuring ERK activation in both calcifying and noncalcifying VIC environments and then, conversely, analyzing the effects of ERK pathway inhibition on VIC calcification and phenotype. Prolonged elevation of phosphorylated ERK-1/2 was found in calcifying VIC cultures, whereas directly blocking phosphorylation of ERK-1/2 resulted in a dramatic decrease in nodule number, nodule size, and total calcified area. Application of the ERK pathway inhibitor was also associated with a dramatic decrease in apoptosis, which may have contributed to the decreased nodule formation obtained via ERK inhibition. Real-time PCR analysis revealed that calcified samples exhibited significantly elevated expression of several myofibroblastic and osteoblastic markers, while ERK inhibition substantially reduced the expression of these markers, often to levels comparable to the noncalcifying control. These data suggest that the MAPK pathway plays an important role in regulating the phenotype and calcification of VICs, wherein sustained pathway activation is associated with increased VIC calcification. These findings may be used to further elucidate the mechanisms of valvular disease and identify potential treatment targets.
Active stiffening of mitral valve leaflets in the beating heart
Authors: Itoh Akinobu , Krishnamurthy Gaurav , Swanson Julia C. , Ennis Daniel B. , Bothe Wolfgang , Kuhl Ellen , Karlsson Matts , Davis Lauren R. , Miller D. Craig , Ingels Neil B.
Published: April 2009

The anterior leaflet of the mitral valve (MV), viewed traditionally as a passive membrane, is shown to be a highly active structure in the beating heart. Two types of leaflet contractile activity are demonstrated: 1) a brief twitch at the beginning of each beat (reflecting contraction of myocytes in the leaflet in communication with and excited by left atrial muscle) that is relaxed by midsystole and whose contractile activity is eliminated with β-receptor blockade and 2) sustained tone during isovolumic relaxation, insensitive to β-blockade, but doubled by stimulation of the neurally rich region of aortic-mitral continuity. These findings raise the possibility that these leaflets are neurally controlled tissues, with potentially adaptive capabilities to meet the changing physiological demands on the heart. They also provide a basis for a permanent paradigm shift from one viewing the leaflets as passive flaps to one viewing them as active tissues whose complex function and dysfunction must be taken into account when considering not only therapeutic approaches to MV disease, but even the definitions of MV disease itself.
Clinical cardioprotection and the value of conditioning responses
Authors: Peart Jason N. , Headrick John P.
Published: April 2009

Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research, the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning and postconditioning have proven fertile in identification of experimental means of cardioprotection and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end effectors, may be poor choices for clinical exploitation. This includes evidence of age dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly used drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.
Superoxide-mediated inactivation of nitric oxide and peroxynitrite formation by tobacco smoke in vascular endothelium: studies in cultured cells and smokers
Authors: Peluffo Gonzalo , Calcerrada Pablo , Piacenza Lucia , Pizzano Nelson , Radi Rafael
Published: April 2009

Tobacco smoke is known to cause nitric oxide (·NO) inactivation and endothelial dysfunction. In this work we evaluated the interplay between·NO and superoxide (O2·−) radicals and the consequent impact on·NO bioavailability and nitroxidative stress in bovine aortic endothelial cells exposed to cigarette smoke extract (CSE) and in smokers. Bovine aortic endothelial cells in the presence of CSE triggered O2·−production as indicated by spin-trapping electron paramagnetic resonance experiments. O2·−was produced both extracellulary (3.4 vs. 1.0 nmol·h−1·mg−1; CSE vs. control; cytochrome c3+reduction assay) and intracellularly (40% inhibition of cytosolic aconitase). CSE also led to the production of peroxynitrite as evaluated by dihydrorhodamine oxidation and protein tyrosine nitration on cells. O2·−and peroxynitrite formation were decreased by ascorbate and α-tocopherol. Additionally, CSE led to the oxidation of endothelial nitric oxide synthase increasing the monomeric inactive form of endothelial nitric oxide synthase. Smokers and age-matched healthy volunteers were supplemented orally with 500 mg ascorbate plus 400 IU all-rac-α-tocopherol every 12 h for 165 days. Smokers had endothelial dysfunction compared with control subjects (95% confidence interval: 2.5, 8.3 vs. 10.6, 14.2; P < 0.05) as assessed by flow-mediated dilation of the brachial artery, and plasma levels of protein 3-nitrotyrosine were 1.4-fold higher. The loss of flow-mediated dilation in smokers reverted after a long-term antioxidant supplementation (95% confidence interval: 13.9, 19.9; P < 0.05), reaching values comparable with the control population. Our data indicate that elements on tobacco smoke, most likely through redox cycling, divert·NO toward peroxynitrite by inducing O2·−production in vascular endothelial cells both in vitro and in vivo.
Lateralization of expression of neural sympathetic activity to the vessels and effects of carotid baroreceptor stimulation
Authors: Diedrich André , Porta Alberto , Barbic Franca , Brychta Robert J. , Bonizzi Pietro , Diedrich Laura , Cerutti Sergio , Robertson David , Furlan Raffaello
Published: April 2009

Human studies suggest that cardiovascular neural sympathetic control is predominantly modulated by the right cerebral hemisphere. It is unknown whether post-ganglionic sympathetic activity [muscle sympathetic nerve activity (MSNA)] shows any functional asymmetry. Eight right-handed volunteers (3 women and 5 men, 32 ± 2 yr of age) underwent ECG, beat-by-beat blood pressure, respiratory activity, and simultaneous right and left MSNA recordings during spontaneous and controlled breathing (CB, 15 breaths/min, 0.25 Hz). Dynamic carotid baroreceptor stimulation was obtained by 0.1-Hz sinusoidal suction, from 0 to −50 mmHg, randomly applied to the right, left, and combined right and left sides of the neck during CB. Laterality was assessed by changes in the MSNA burst rate (in bursts/min, and bursts/100 beats), strength [amplitude (A) and area (AA)], and the oscillatory component at 0.1 Hz during baroreceptor stimulation. Amplitude parameters were normalized by CB burst mean amplitude and area of the same side. At rest, the right and left MSNA burst rate and total MSNA activity were similar. Conversely, the right MSNA normalized burst AN(1.36 ± 0.18) and AAN(1.31 ± 0.16) were larger than the left MSNA AN(1.04 ± 0.09) and AAN(1.02 ± 0.08). Unilateral and bilateral carotid baroreflex stimulation abolished the right prevalence of ANand AAN. In conclusion, the right lateralization of sympathetic activity to the vessels is indicated by normalized burst strength parameters of bilateral MSNA recordings at rest during spontaneous breathing. Carotid baroreceptor stimulation disrupted such expression of MSNA lateralization possibly by disturbing the synchronizing action of right cerebral hemisphere.
Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone
Authors: Johnson Christopher D. , Melanaphy Donal , Purse Andrew , Stokesberry Susan A. , Dickson Paula , Zholos Alexander V.
Published: April 2009

The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 μM). However, both menthol and another agonist icilin (50 μM) caused relaxation of vessels precontracted with KCl (60 mM) or the α-adrenoceptor agonist phenylephrine (2 μM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca2+-independent phospholipase A2 activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either Nω-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 μM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 μA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.
Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice
Authors: Yang Jiyeon , Park Yoonjung , Zhang Hanrui , Xu Xiangbin , Laine Glen A. , Dellsperger Kevin C. , Zhang Cuihua
Published: April 2009

We hypothesized that the interaction between tumor necrosis factor-α (TNF-α)/nuclear factor-κB (NF-κB) via the activation of IKK-β may amplify one another, resulting in the evolution of vascular disease and insulin resistance associated with diabetes. To test this hypothesis, endothelium-dependent (ACh) and -independent (sodium nitroprusside) vasodilation of isolated, pressurized coronary arterioles from mLepr db (heterozygote, normal), Lepr db (homozygote, diabetic), and Lepr db mice null for TNF-α ( dbTNF−/ dbTNF−) were examined. Although the dilation of vessels to sodium nitroprusside was not different between Lepr db and mLepr db mice, the dilation to ACh was reduced in Lepr db mice. The NF-κB antagonist MG-132 or the IKK-β inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in Lepr db mice, but the responses in mLepr db mice were unaffected. The protein expression of IKK-α and IKK-β were higher in Lepr db than in mLepr db mice; the expression of IKK-β, but not the expression of IKK-α, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF-α in diabetic mice. Lepr db mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF-α and NF-κB and the protein modification of phosphorylated (p)-IKK-β and p-JNK were greater in Lepr db mice, but NaSal attenuated TNF-α, NF-κB, p-IKK-β, and p-JNK in Lepr db mice. The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Lepr db compared with mLepr db mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Lepr db mice. MG-132 or the neutralization of TNF-α reduced superoxide production in Lepr db mice. In conclusion, our results indicate that the interaction between NF-κB and TNF-α signaling induces the activation of IKK-β and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.
IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation
Authors: Kolliputi Narasaiah , Waxman Aaron B.
Published: April 2009

IL-6 overexpression protects mice from hyperoxic acute lung injury in vivo, and treatment with IL-6 protects cells from oxidant-mediated death in vitro. The mechanisms of protection, however, are not clear. We characterized the expression, localization, and regulation of Bax, a proapoptotic member of the Bcl-2 family, in wild-type (WT) and IL-6 lung-specific transgenic (Tg+) mice exposed to 100% O2 and in human umbilical vein endothelial cells (HUVEC) treated with H2O2 and IL-6. In control HUVEC treated with H2O2 or in WT mice exposed to 100% O2, a marked induction of Bax translocation and dimerization was associated with increased JNK and p38 kinase activity. In contrast, specific JNK or p38 kinase inhibitors or treatment with IL-6 inhibited Bax mitochondrial translocation and apoptosis of HUVEC. IL-6 Tg+ mice exposed to 100% O2 exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser184 compared with WT mice. The PI3K-specific inhibitor LY-2940002 blocked this IL-6-induced Bax phosphorylation and promoted cell death. Furthermore, IL-6 potently blocked hyperoxia- or oxidant-induced Bax insertion into mitochondrial membranes. Thus IL-6 functions in a cytoprotective manner, in part, by suppressing Bax translocation and dimerization through PI3K/Akt-mediated Bax phosphorylation.
Activated protein C protects against ventilator-induced pulmonary capillary leak
Authors: Finigan James H. , Boueiz Adel , Wilkinson Emily , Damico Rachel , Skirball Jarrett , Pae Hyun Hae , Damarla Mahendra , Hasan Emile , Pearse David B. , Reddy Sekhar P. , Grigoryev Dmitry N. , Cheadle Christopher , Esmon Charles T. , Garcia Joe G. N. , Hassoun Paul M.
Published: April 2009

The coagulation system is central to the pathophysiology of acute lung injury. We have previously demonstrated that the anticoagulant activated protein C (APC) prevents increased endothelial permeability in response to edemagenic agonists in endothelial cells and that this protection is dependent on the endothelial protein C receptor (EPCR). We currently investigate the effect of APC in a mouse model of ventilator-induced lung injury (VILI). C57BL/6J mice received spontaneous ventilation (control) or mechanical ventilation (MV) with high (HVT; 20 ml/kg) or low (LVT; 7 ml/kg) tidal volumes for 2 h and were pretreated with APC or vehicle via jugular vein 1 h before MV. In separate experiments, mice were ventilated for 4 h and received APC 30 and 150 min after starting MV. Indices of capillary leakage included bronchoalveolar lavage (BAL) total protein and Evans blue dye (EBD) assay. Changes in pulmonary EPCR protein and Rho-associated kinase (ROCK) were assessed using SDS-PAGE. Thrombin generation was measured via plasma thrombin-antithrombin complexes. HVTinduced pulmonary capillary leakage, as evidenced by significant increases in BAL protein and EBD extravasation, without significantly increasing thrombin production. HVTalso caused significant decreases in pulmonary, membrane-bound EPCR protein levels and increases in pulmonary ROCK-1. APC treatment significantly decreased pulmonary leakage induced by MV when given either before or after initiation of MV. Protection from capillary leakage was associated with restoration of EPCR protein expression and attenuation of ROCK-1 expression. In addition, mice overexpressing EPCR on the pulmonary endothelium were protected from HVT-mediated injury. Finally, gene microarray analysis demonstrated that APC significantly altered the expression of genes relevant to vascular permeability at the ontology (e.g., blood vessel development) and specific gene (e.g., MAPK-associated kinase 2 and integrin-β6) levels. These findings indicate that APC is barrier-protective in VILI and that EPCR is a critical participant in APC-mediated protection.
Tristetraprolin regulates IL-8 mRNA stability in cystic fibrosis lung epithelial cells
Authors: Balakathiresan Nagaraja Sethuraman , Bhattacharyya Sharmistha , Gutti Usha , Long Robert P. , Jozwik Catherine , Huang Wei , Srivastava Meera , Pollard Harvey B. , Biswas Roopa
Published: April 2009

Cystic fibrosis (CF) is due to mutations in the CFTR gene and is characterized by hypersecretion of the proinflammatory chemokine IL-8 into the airway lumen. Consequently, this induces the highly inflammatory cellular phenotype typical of CF. Our initial studies revealed that IL-8 mRNA is relatively stable in CF cells compared with those that had been repaired with [WT]CFTR (wild-type CFTR). Relevantly, the 3′-UTR of IL-8 mRNA contains AU-rich sequences (AREs) that have been shown to mediate posttranscriptional regulation of proinflammatory genes upon binding to ARE-binding proteins including Tristetraprolin (TTP). We therefore hypothesized that very low endogenous levels of TTP in CF cells might be responsible for the relative stability of IL-8 mRNA. As predicted, increased expression of TTP in CF cells resulted in reduced stability of IL-8 mRNA. An in vitro analysis of IL-8 mRNA stability in CF cells also revealed a TTP-induced enhancement of deadenylation causing reduction of IL-8 mRNA stability. We conclude that enhanced stability of IL-8 mRNA in TTP-deficient CF lung epithelial cells serve to drive the proinflammatory cellular phenotype in the CF lung.
Numerical Blow‐Up Time for a Semilinear Parabolic Equation with Nonlinear Boundary Conditions
Authors: Assalé Louis A. , Boni Théodore K. , Nabongo Diabate
Published: April 2009

We obtain some conditions under which the positive solution for
semidiscretizations of the semilinear equation ut = uxx − a(x, t)f(u),   0 < x < 1,   t ∈ (0, T), with boundary conditions ux(0, t) = 0, ux(1, t) = b(t)g(u(1, t)), blows up in a finite time and estimate its semidiscrete blow‐up time. We also establish
the convergence of the semidiscrete blow‐up time and obtain some results about
numerical blow‐up rate and set. Finally, we get an analogous result taking
a discrete form of the above problem and give some computational results to
illustrate some points of our analysis.
Health Care Utilisation and Attitudes towards Health Care in Subjects Reporting Environmental Annoyance from Electricity and Chemicals
Authors: Eek Frida , Merlo Juan , Gerdtham Ulf , Lithman Thor
Published: April 2009

Environmentally intolerant persons report decreased self-rated health and daily functioning. However, it remains unclear whether this condition also results in increased health care costs. The aim of this study was to describe the health care consumption and attitudes towards health care in subjects presenting subjective environmental annoyance in relation to the general population, as well as to a group with a well-known disorder as treated hypertension (HT).Methods. Postal questionnaire (n= 13 604) and record linkage with population-based register on health care costs.Results. Despite significantly lower subjective well being and health than both the general population and HT group, the environmentally annoyed subjects had lower health care costs than the hypertension group. In contrast to the hypertension group, the environmentally annoyed subjects expressed more negative attitudes toward the health care than the general population.Conclusions. Despite their impaired subjective health and functional capacity, health care utilisation costs were not much increased for the environmentally annoyed group. This may partly depend on negative attitudes towards the health care in this group.
Peroxisome Proliferator‐Activated Receptors in HBV‐Related Infection
Authors: Dubuquoy Laurent , Louvet Alexandre , Hollebecque Antoine , Mathurin Philippe , Dharancy Sébastien
Published: April 2009

Thirty years after its discovery, the hepatitis B virus (HBV) still remains a major global public health problem. Worldwide, two billion subjects have been infected, 350 million have a chronic infection and more than 600 000 die annually of HBV‐related liver disease or hepatocellular carcinoma; new infections occur because of the presence of a large reservoir of chronic carriers of the virus. Since a decade several studies describe the interrelations between HBV and nuclear receptors and more particularly the peroxisome proliferator‐activated receptors (PPARs). After a brief introduction, this review will make a rapid description of HBV incidence and biology. Then a report of the literature on the role of PPARs on viral transcription and replication will be developed. Finally, the role of HBV on PPARγ expression and activity will be discussed. Concluding remarks and perspectives will close this review.
Extensive Sclerosing Mesenteritis of the Rectosigmoid Colon Associated with Erosive Colitis
Authors: Nobili C. , Degrate L. , Caprotti R. , Franciosi C. , Leone B. E. , Romano F. , Dinelli M. , Uggeri Fr.
Published: April 2009

Sclerosing mesenteritis is a rare, idiopatic, usually benign, inflammatory process of the mesenteric adipose tissue. The most common site of involvement is the small bowel mesentery. We present a case of sclerosing mesenteritis of the rectosigmoid colon as a cause of severe abdominal pain, abdominal obstruction, and ischemic colic mucosal lesions. Contrast enema, colonoscopy, angiography, and CT were the imaging modalities used. A 20 cm diameter, fibrotic mass causing extensive compression of rectosigmoid colon was found at laparotomy. Histological examination showed extended fibrosis, inflammatory cells infiltration, lipophages, and granulomas within the mesenteric adipose tissue associated with erosive colitis. Clinical presentation and treatment are discussed.
Processing and Structure of Carbon Nanofiber Paper
Authors: Zhao Zhongfu , Gou Jihua , Khan Aurangzeb
Published: April 2009

A unique concept of making nanocomposites from carbon nanofiber paper was explored in this study. The essential element of this method was to design and manufacture carbon nanofiber paper with well‐controlled and optimized network structure of carbon nanofibers. In this study, carbon nanofiber paper was prepared under various processing conditions, including different types of carbon nanofibers, solvents, dispersants, and acid treatment. The morphologies of carbon nanofibers within the nanofiber paper were characterized with scanning electron microscopy (SEM). In addition, the bulk densities of carbon nanofiber papers were measured. It was found that the densities and network structures of carbon nanofiber paper correlated to the dispersion quality of carbon nanofibers within the paper, which was significantly affected by papermaking process conditions.
TGF-β1-Induced Expression of the Poor Prognosis SERPINE1/PAI-1 Gene Requires EGFR Signaling: A New Target for Anti-EGFR Therapy
Authors: Samarakoon Rohan , Higgins Craig E. , Higgins Stephen P. , Higgins Paul J.
Published: April 2009

Increased transforming growth factor-β(TGF-β) expression and epidermal growth factor receptor (EGFR) amplification accompany the emergence of highly aggressive human carcinomas. Cooperative signaling between these two growth factor/receptor systems promotes cell migration and synthesis of stromal remodeling factors (i.e., proteases, protease inhibitors) that, in turn, regulate tumor invasion, neo-angiogenesis and inflammation. ranscript profiling of transformed human cells revealed that genes encoding wound healing, matrix remodeling and cell cycle proteins (i.e., the “tissue repair” transcriptome) are significantly up-regulated early after growth factor stimulation. The major inhibitor of plasmin generation, plasminogen activator inhibitor-1 (PAI-1), is among the most highly induced transcripts during the phenotypic transition initiated by TGF-βmaximal expression requires EGFR signaling. PAI-1 induction occurs early in the progression of incipient epidermal squamous cell carcinoma (SCC) and is a significant indicator of poor prognosis in epithelial malignancies. Mouse modeling and molecular genetic analysis of complex systems indicates that PAI-1 regulates the temporal/spatial control of pericellular proteolysis, promotes epithelial plasticity, inhibits capillary regression and facilitates stromal invasion. Defining TGF-β1-initiated signaling events that cooperate with an activated EGFR to impact the protease-protease inhibitor balance in the tumor microenvironment is critical to the development of novel therapies for the clinical management of human cancers.
Conjunctivitis and Total IgE in Lacrimal Fluid: Lacrytest Screening
Authors: Monzón Susana , Arrondo Elena , Bartra Joan , Torres Ferran , Basagaña María , San Miguel M. del Mar , Alonso Rosario , Cisteró-Bahima Anna
Published: April 2009

Total tear IgE has been considered to play an important role in allergic conjunctivitis, and measurement has been considered useful for diagnosis. The aim of this study was to ascertain whether Lacrytest®, a new commercialised method to detect IgE levels in lacrimal fluid, could constitute a screening test for the diagnosis of allergic conjunctivitis. This was a cross-sectional study. Patients with seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis and a control group were included. Clinical history, ophthalmic examination, skin prick test and conjunctival provocation test were obtained. Lacrytest®was later performed in all groups. Fifty-four patients were enrolled: thirty with IgE-mediated conjunctivitis and, nine with vernal keratoconjunctivitis and fifteen controls. Lacrytest®was negative in all controls, positive in 20% of the IgE-mediated conjunctivitis group and in 88.9% of the vernal keratoconjunctivitis group. Global statistically-significant differences were found among the three groups (). Sensitivity of the test in the IgE-mediated conjunctivitis group was 20%, specificity 100%, positive predictive value 100%, and negative predictive value 38.46%, while in VKC sensitivity was 88.88%, specificity 100%, positive predictive value 100%, and negative predictive value 93.75%. Our data confirm that this test is not useful for screening allergic conjunctivitis. Lacrytest®, while not providing any useful information to an allergist, could be helpful for ophthalmologists to confirm an IgE-mediated or VKC conjunctivitis.
Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer
Authors: Flynn John F. , Wong Christina , Wu Joseph M.
Published: April 2009

This review will focus on recent advances in the application of antiepidermal growth factor receptor (anti-EGFR) for the treatment of breast cancer. The choice of EGFR, a member of the ErbB tyrosine kinase receptor family, stems from evidence pinpointing its role in various anti-EGFR therapies. Therefore, an increase in our understanding of EGFR mechanism and signaling might reveal novel targets amenable to intervention in the clinic. This knowledge base might also improve existing medical treatment options and identify research gaps in the design of new therapeutic agents. While the approved use of drugs like the dual kinase inhibitor Lapatinib represents significant advances in the clinical management of breast cancer, confirmatory studies must be considered to foster the use of anti-EGFR therapies including safety, pharmacokinetics, and clinical efficacy.