bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of methionine loading on pulse wave analysis in elderly volunteers
Authors: Hart S R , Mangoni A A , Swift C G , Jackson S H D
Published: August 2006

Objective

To test the hypothesis that an acute increase in plasma homocysteine produced by methionine is associated with an acute increase in pulse wave velocity.

Design

A double blind, cross over, placebo controlled design was used and pulse wave velocity, plasma homocysteine, total cholesterol: high density lipoprotein ratio, plasma triglyceride, oxidised low density lipoprotein cholesterol concentrations, apolipoproteins A1 and B, and C reactive protein were measured between 12.5 and 20 hours after methionine loading or placebo.

Results

Between 12.5 and 20 hours after exposure to a methionine loading test, arterial pulse wave velocity showed no significant difference compared with placebo. At 12 hours after exposure to the methionine loading test, in the presence of a controlled diet, triglyceride concentration significantly increased by 32.6% (p<0.02), cholesterol: high density lipoprotein ratio increased significantly by 22.5% (p<0.05) compared with placebo. Simultaneously, systolic blood pressure increased significantly by 4.9% (p<0.02).

Conclusion

In elderly volunteers, acute hyperhomocysteinaemia induced by methionine loading resulted in no overall significant delayed reduction in peripheral arterial distensibility. A significant deterioration in the lipid profile and increased blood pressure was seen during acute hyperhomocysteinaemia.
Acne: more than skin deep
Authors: Ayer J , Burrows N
Published: August 2006

Acne is one of the most prevalent skin conditions affecting teenagers. It is a disease of the pilosebaceous unit. Blockage of sebaceous glands and colonisation with Proionobacterium acnes leads to acne. Grading the severity of acne helps to determine the appropriate treatment. Treatment of acne should be started as early as possible to minimise the risk of scarring and adverse psychological effects. It should be tailored to the individual patient, the type of acne, its severity, the patient's ability to use the treatment, and the psychological state. Topical agents are the mainstay for treatment of mild acne. Moderate acne is treated with oral antibiotics. Resistance to antibiotics may be reduced by subsequent use of non-antibiotic topical medications. Severe acne is treated with isotretinoin, and this can lead to permanent remission. With better education and care given by medical profession, acne treatment could be significantly improved.
Interstitial lung disease: progress and problems
Authors: Bourke S J
Published: August 2006

Interstitial lung disease involves all areas of medicine as it often occurs in patients with comorbidities or as a consequence of systemic diseases and their treatment. Typically the physician is faced with a breathless patient, a diffusely abnormal chest radiograph, and a wide differential diagnosis. Progress has been made in using high resolution computed tomography as the key investigation in characterising the pattern and extent of the disease. Bronchoalveolar lavage is particularly important in excluding infection as a cause of diffuse lung infiltrates. Surgical lung biopsies have led to a new classification system for the range of histopathological patterns of disease that were previously known by the collective term cryptogenic fibrosing alveolitis. Problems persist in deciding when a surgical lung biopsy is clinically justified, in understanding the pathogenesis of these diseases, and in finding more effective treatments.
Surgical trainees benefit from good consultant working practices: an audit on the effect on training of a new consultant rota
Authors: Majed A R I , Riaz A A , Das-Purkayastha P , Martin W , Gregg-Smith S J
Published: August 2006

Purpose

To retrospectively assess operative supervision for orthopaedic trainees over an 18 week period when trauma and orthopaedic consultants changed their on call working practice from one week on call to a four day/three day block, during a fortnight period.

Outcome

The rota changes had important implications on workload and consultant availability to supervise juniors during operation with a positive effect upon training such that trauma surgery supervision rates increased significantly (p<0.001) after the introduction of these new working arrangements. Working life for consultants and ultimately patient care were also felt to improve and consultants' working hours were closer to the European working hours directives.
Chronic hepatitis B in hepatocarcinogenesis
Authors: Park N H , Song I H , Chung Y-H
Published: August 2006

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and has a wide geographical variation. Eighty per cent of HCC is attributed to hepatitis B virus (HBV). The predominant carcinogenic mechanism of HBV associated HCC is through the process of liver cirrhosis, but direct oncogenic effects of HBV may also contribute. Prevention of HBV infections as well as effective treatment of chronic hepatitis B is still needed for the global control of HBV associated HCC. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in the liver.
MOLECULAR MODEL CHECKING
Authors: EMERSON E. ALLEN , HAGER KRISTINA D. , KONIECZKA JAY H.
Published: August 2006

This paper shows how to perform model checking, a technique for automatic program verification, by a DNA algorithm. Our method depends on two ideas. First, Kripke structures can be compactly represented in a DNA substrate, coding each state and each edge by a strand of DNA. Second, satisfaction of temporal eventualities can be achieved through a self-propagating molecular chain reaction.
ENFORCING CONCURRENT TEMPORAL BEHAVIORS
Authors: PELED DORON , QU HONGYANG
Published: August 2006

The outcome of verifying software is often a 'counterexample', i.e., a listing of the actions and states of a behavior not satisfying the specification. The verification is usually done using a model of the software (often also using some abstraction to reduce its complexity) rather than the actual code. In order to understand the reason for the failure manifested by such a counterexample, it is sometimes necessary to test such an execution using the actual code. In this way we also find out whether we have a genuine error or a "false negative". Due to nondeterminism in concurrent code, enforcing a particular behavior of an actual program is not guaranteed even when one starts the execution with the prescribed initial state. Testers are faced with a similar problem when they have to demonstrate that a suspicious scenario can actually be executed. Such a scenario may involve some intricate scheduling and thus be illusive to demonstrate. We describe here a transformation that allows us to repeat a selected execution sequences of concurrent code. Since the transformation implies changes to the original code, we strive to minimize its effect on the original program.
CONTROLLABILITY AND COOPERATIVENESS ANALYSIS FOR AUTOMATIC ABSTRACTION REFINEMENT
Authors: MANG FREDDY Y. C. , HO PEI-HSIN
Published: August 2006

We present a new abstraction refinement algorithm to better refine the abstract model for formal property verification. In previous work, refinements are selected either based on a set of counter examples of the current abstract model, as in [5, 6, 7, 8, 9, 20, 21], or independent of any counter examples, as in [18]. We (1) introduce a new controllability analysis that is independent of any particular counter examples, (2) apply a new cooperativeness analysis that extracts information from a particular set of counter examples and (3) combine both to better refine the abstract model. We implemented the algorithm and applied it to verify several real-world designs and properties. We compared the algorithm against the abstraction refinement algorithms in [20] and [21] and the interpolation-based reachability analysis in [15]. The experimental results indicate that the new algorithm outperforms the other three algorithms in terms of runtime, abstraction efficiency (as defined in [20]) and the number of proven properties.
HYBRID SYSTEM VERIFICATION IS NOT A SINECURE — THE ELECTRONIC THROTTLE CONTROL CASE STUDY
Authors: FEHNKER ANSGAR , KROGH BRUCE
Published: August 2006

Though model checking itself is a fully automated process, verifying correctness of a hybrid system design using model checking is not. This paper describes the necessary steps, and choices to be made, to go from an informal description of the problem to the final verification result for a formal model and requirement. It uses an automotive control system for illustration.
UNITARITY ISSUE IN BTZ BLACK HOLES
Authors: MYUNG Y. S. , LEE H. W.
Published: August 2006

We study the wave equation for a massive scalar in three-dimensional AdS-black hole spacetimes to understand the unitarity issues in a semiclassical way. Here we introduce four interesting spacetimes: the non-rotating BTZ black hole (NBTZ), pure AdS spacetime (PADS), massless BTZ black hole (MBTZ), and extremal BTZ black hole (EBTZ). Our method is based on the potential analysis and solving the wave equation to find the condition for the frequency ω exactly. In the NBTZ case, one finds the quasinormal (complex and discrete) modes which signals for a non-unitary evolution. Real and discrete modes are found for the PADS case, which means that it is unitary obviously. On the other hand, we find real and continuous modes for the two extremal black holes of MBTZ and EBTZ. It suggests that these could be candidates for the unitary system.
THE GEODESIC RULE AND THE SPECTRUM OF THE VACUUM
Authors: KALOGEROPOULOS NIKOS
Published: August 2006

We analyze the consequences of a recent argument justifying the validity of the "geodesic rule" which can be used to determine the density of global topological defects. We derive a formula that provides a rough estimate of the number of string-like defects formed in a phase transition. We apply this formula to vacua which are spheres. We provide some reasons for the deviation of our predictions from the corresponding accepted values.
TOMOGRAPHY OF THE SOLAR INTERIOR
Authors: GIZON L.
Published: August 2006

Solar oscillations consist of a rich spectrum of internal acoustic waves and surface gravity waves, stochastically excited by turbulent convection. They have been monitored almost continuously over the last ten years with high-precision Doppler images of the solar surface. The purpose of helioseismology is to retrieve information about the structure and the dynamics of the solar interior from the frequencies, phases and amplitudes of solar waves. Methods of analysis are being developed to make three-dimensional images of subsurface motions and temperature inhomogeneities in order to study convective structures and regions of magnetic activity, like sunspots.
SURFACE AND SUPERCONDUCTIVITY
Authors: GOR'KOV L. P.
Published: August 2006

Experiments reveal the existence of metallic bands at surfaces of metals and insulators. The bands can be doped externally. We review properties of surface superconductivity that may set up in such bands at low temperatures and various means of superconductivity defection. The fundamental difference as compared to the ordinary superconductivity in metals, besides its two-dimensionality lies in the absence of the center of space inversion. This results in mixing between the singlet and triplet channels of the Cooper pairing.
MANY-BODY PHYSICS AND SPONTANEOUS SYMMETRY BREAKING
Authors: BELYAEV SPARTAK T.
Published: August 2006

The idea of spontaneous symmetry breaking in many-body physics from personal perspective (Bose-gas, nuclear structure and a new approach of Generalized Density Matrix).
QUANTUM MATTERS: PHYSICS BEYOND LANDAU'S PARADIGMS
Authors: SENTHIL T.
Published: August 2006

Central to our understanding of quantum many particle physics are two ideas due to Landau. The first is the notion of the electron as a well-defined quasiparticle excitation in the many body state. The second is that of the order parameter to distinguish different states of matter. Experiments in a number of correlated materials raise serious suspicions about the general validity of either notion. A growing body of theoretical work has confirmed these suspicions, and explored physics beyond Landau's paradigms. This article provides an overview of some of these theoretical developments.
SPIN–CHARGE SEPARATION AND TOPOLOGICAL PHASE TRANSITIONS IN AHARONOV–BOHM RINGS OF INTERACTING ELECTRONS
Authors: NORMAND B. , HALLBERG K. , ALIGIA A. A. , KAMPF A. P.
Published: August 2006

We investigate the properties of strongly correlated electronic models on a flux-threaded ring connected to semi-infinite free-electron leads. The interference pattern of such an Aharonov-Bohm ring shows sharp dips at certain flux values, determined by the filling, which are a consequence of spin-charge separation in a nanoscopic system. The conductance through such a molecule or nanodevice is related directly to its spectroscopic properties, opening new experimental possibilities for probing the phenomenology of strongly interacting systems. As a further example, for a ring described by the half-filled ionic Hubbard model we show that the weight of the first conductance peak as a function of gate voltage or external flux allows one to identify the topological charge transition between a correlated insulator and a band insulator.
CAN INCOMMENSURATION STABILIZE A SUPERFLUID PHASE OF PARA-HYDROGEN?
Authors: BONINSEGNI MASSIMO
Published: August 2006

Extensive Path Integral Monte Carlo simulations of two-dimensional para-Hydrogen embedded in a crystalline matrix of Alkali atoms, show no evidence of superfluid behavior at low temperature. Rather, the system is observed to form a commensurate (non superfluid) crystal.
NUCLEAR-STRUCTURE THEORY IN THE SEARCH FOR NEW FUNDAMENTAL PHYSICS
Authors: ENGEL JONATHAN
Published: August 2006

Nuclear-structure theory is an important ingredient in the interpretation of many experiments that look for physics beyond the Standard Model. I review the role of nuclear structure in attempts to learn more about neutrinos through double beta-decay and to discover new sources of CP violation through atomic electric-dipole moments.
NUCLEAR INTERACTIONS FROM THE RENORMALIZATION GROUP
Authors: SCHWENK ACHIM
Published: August 2006

We discuss how the renormalization group can be used to derive effective nuclear interactions. Starting from the model-independent low-momentum interaction V low k, we successively integrate out high-lying particle and hole states from momentum shells around the Fermi surface as proposed by Shankar. The renormalization group approach allows for a systematic calculation of induced interactions and yields similar contributions to the scattering amplitude as the two-body parquet equations. We review results for the 1 S 0 and 3 P 2 superfluid pairing gaps as well as the spin dependence of effective interactions in neutron matter. Implications for the cooling of neutron stars are discussed.
RANDOM INTERACTIONS AND GROUND STATE SPIN OF FINITE FERMI SYSTEMS
Authors: ZELEVINSKY VLADIMIR , VOLYA ALEXANDER
Published: August 2006

Numerical simulations show that the ground state spin of a finite many-body system with random but rotationally invariant interactions is predominantly zero. This means that it is not sufficient to explain the zero ground state spin of even-even nuclei only by pairing correlations. Simple explanations based on a statistical multiplicity, width of the level density, effective pairing, formation of condensates etc. do not work. We suggest statistical theory based on the effective mean field and geometric chaoticity of angular momentum coupling of individual particles. The results show a significant role of symmetry arguments in finite systems.
EFFECTS OF A SINGLE QUANTUM SPIN ON JOSEPHSON OSCILLATIONS
Authors: HRUŠKA MARINA , BULAEVSKII LEV , SHNIRMAN ALEXANDER , SMITH DARRYL
Published: August 2006

We consider a single localized spin-1/2 placed between singlet superconducting leads of a Josephson junction inserted in a superconducting ring, subject to a dc magnetic field B || z. Turning on the tunneling or a time-dependent flux in a superconducting ring, induces oscillations of the Josephson current, with an amplitude sensitive to the initial value of the z-component of the spin, Sz = ±1/2, which allows for a measurement of the initial spin state. At low temperatures when effects of quasiparticles are negligible, this procedure realizes a quantum-non-demolition (QND) measurement of Sz.
DISSIPATIVE QUANTUM DISORDERED MODELS
Authors: CUGLIANDOLO LETICIA F.
Published: August 2006

This article reviews recent studies of mean-field and one dimensional quantum disordered spin systems coupled to different types of dissipative environments. The main issues discussed are: (i) The real-time dynamics in the glassy phase and how they compare to the behaviour of the same models in their classical limit. (ii) The phase transition separating the ordered – glassy – phase from the disordered phase that, for some long-range interactions, is of second order at high temperatures and of first order close to the quantum critical point (similarly to what has been observed in random dipolar magnets). (iii) The static properties of the Griffiths phase in random king chains. (iv) The dependence of all these properties on the environment. The analytic and numeric techniques used to derive these results are briefly mentioned.
REPLY TO: "ON COHEN'S CLASSICAL TELEPORTATION OF CLASSICAL STATES"
Authors: COHEN OLIVER
Published: August 2006

In response to a recently published protocol for classical teleportation of classical states [1], Hrasko [2] has made some remarks in connection with the impossibility of precise quantum teleportation if a classical mixture is used in place of the EPR state, and with regard to the epistemological interpretation of quantum states. The purpose of this note is to attempt to clarify these issues and their relevance for the argumentation presented in [1].
Experimental Methods for Measuring Gene Interactions
Authors: Demuth Jeffery P. , Wade Michael J.
Published: August 2006

The role of epistasis in evolution has long been contentious. Resolving the issue requires empirical measurements that are statistically adequate and evolutionarily relevant. We review experimental methods for measuring epistasis, some that are commonly used but weak and others that are less frequently used but stronger. We review statistical genetic methods based on analyses of variances and means as well as molecular genetic methods for detecting gene interactions. We also highlight relevant empirical studies that illustrate the implementation of particular methods. In spite of the inherent weaknesses of most methods, epistasis is surprisingly common. We conclude with a discussion of how technologies for investigating genome-wide epistasis are bridging the gap between physiological and statistical epistasis for model organisms.
Resource Exchange in the Rhizosphere: Molecular Tools and the Microbial Perspective
Authors: Cardon Zoe G. , Gage Daniel J.
Published: August 2006

The interface between living plant roots and soils (the rhizosphere) is a central commodities exchange, where organic carbon flux from roots fuels decomposers that, in turn, can make nutrients available to roots. This ongoing exchange operates in the path of vast, transpiration-driven water flow. How the spatio-temporal patterning in resource availability around plant roots affects rhizosphere community composition, activity, and nutrient cycling remains unknown. This review considers how molecular approaches contribute to the exploration of rhizosphere resource exchange, highlighting several recently developed methods linking microbial identity with substrate uptake and gene expression. In particular, strengths and weaknesses of genetically engineered bioreporters are discussed, because currently they alone provide in situ spatio-temporal information at scales of rhizosphere organisms. The soil spatial context is an emerging frontier in ecological soils research. We conclude with parallels linking empirical investigation in the rhizosphere with the quest for understanding general rhizosphere function in Earth's diverse ecosystems.
Has Vicariance or Dispersal Been the Predominant Biogeographic Force in Madagascar? Only Time Will Tell
Authors: Yoder Anne D. , Nowak Michael D.
Published: August 2006

Madagascar is one of the world's hottest biodiversity hot spots due to its diverse, endemic, and highly threatened biota. This biota shows a distinct signature of evolution in isolation, both in the high levels of diversity within lineages and in the imbalance of lineages that are represented. For example, chameleon diversity is the highest of any place on Earth, yet there are no salamanders. These biotic enigmas have inspired centuries of speculation relating to the mechanisms by which Madagascar's biota came to reside there. The two most probable causal factors are Gondwanan vicariance and/or Cenozoic dispersal. By reviewing a comprehensive sample of phylogenetic studies of Malagasy biota, we find that the predominant pattern is one of sister group relationships to African taxa. For those studies that include divergence time analysis, we find an overwhelming indication of Cenozoic origins for most Malagasy clades. We conclude that most of the present-day biota of Madagascar is comprised of the descendents of Cenozoic dispersers, predominantly with African origins.
The Population Biology of Large Brown Seaweeds: Ecological Consequences of Multiphase Life Histories in Dynamic Coastal Environments
Authors: Schiel David R. , Foster Michael S.
Published: August 2006

Seaweed population biology has received far less attention than trophic dynamics, yet is critically important in establishing and maintaining algal communities. Complex life histories of habitat-forming kelps and fucoids, including spores, gametophytes, gametes, and microscopic and macroscopic benthic stages, must be considered within the context of their highly dynamic nearshore environments. We evaluate differences within and between kelps and fucoids in life histories as they affect population biology; dispersal and potential limitations in population establishment; macroscopic stages and variations in survival and longevity affecting stand structure; and microscopic stage responses to disturbance and variation in the physical environment. We suggest that the commonly made comparisons of seaweeds with terrestrial seed plants are misleading because of large differences in morphology, environments, and the ephemeral nature of propagule banks in the sea. We conclude that progress in understanding algal populations depends on better knowledge of microscopic stages and on feedback through density-dependent reproductive processes, dispersal, and settlement.
Gastric accommodation and motility are influenced by the barostat device: assessment with magnetic resonance imaging
Authors: de Zwart Ingrid M. , Haans Jeoffrey J. L. , Verbeek Paul , Eilers Paul H. C. , de Roos Albert , Masclee Ad A. M.
Published: August 2006

The barostat is considered the gold standard for evaluation of proximal gastric motility especially for the accommodation response to a meal. The procedure is invasive because it involves the introduction of an intragastric catheter and bag and is not always well tolerated. Moreover, the barostat bag itself may influence motility. Nowadays magnetic resonance imaging (MRI) is able to measure several aspects of gastric motility noninvasively. To evaluate whether the accommodation response of the stomach, observed with the barostat, is present during MRI and whether the barostat interferes with gastric physiology, gastric accommodation, motility, and emptying were studied twice in 14 healthy subjects with MRI using three-dimensional volume scans and two-dimensional dynamic scans once in the presence of a barostat bag and once when the barostat bag was not present. Fasting and postprandial intragastric volumes were significantly higher in the experiment with barostat vs. without barostat (fasting: 350 ± 132 ml vs. 37 ± 21 ml, P < 0.0001; postprandial: 852 ± 126 ml vs. 361 ± 62 ml, P < 0.0001). No significant differences were found in gastric emptying (88 ± 41 vs. 97 ± 40 ml/h, not significant) and contraction frequency between both experiments. The accommodation response observed in the presence of the barostat bag was not observed in the absence of the barostat bag. In conclusion, the presence of an intragastric barostat bag does not interfere with gastric emptying or motility, but the accommodation response measured with the barostat in situ is not observed without the barostat bag in situ. Gastric accommodation is a nonphysiological barostat-induced phenomenon.
Morphogenic protein epimorphin protects intestinal epithelial cells from oxidative stress by the activation of EGF receptor and MEK/ERK, PI3 kinase/Akt signals
Authors: Iizuka Masahiro , Sasaki Kenji , Hirai Yohei , Shindo Kenichi , Konno Shiho , Itou Hiroaki , Ohshima Shigetoshi , Horie Yasuo , Watanabe Sumio
Published: August 2006

Epimorphin is a mesenchymal protein that regulates morphogenesis of epithelial cells. Our preliminary study suggested a novel function of epimorphin in enhancing survival of intestinal epithelial cells (IEC). Oxidative stress leads to cell injury and death and is suggested to be a key contributor to pathogenesis of inflammatory bowel disease. This study was conducted to determine whether epimorphin protects IEC from oxidative stress. Rat intestinal epithelial cell line IEC-6 was cultured with epimorphin (10 and 20 μg/ml), and the life span of IEC was assessed. The mean life span of IEC-6 cells was prolonged 1.9-fold ( P < 0.0006) by treatment with epimorphin. We then examined the epimorphin signaling pathways. Epimorphin phosphorylated epidermal growth factor (EGF) receptor, activated the MEK/extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and phosphatidylinositol 3 (PI3) kinase/Akt pathways, phosphorylated Bad, and induced Bcl-XL and survivin. Hydrogen peroxide (1 mM) induced cell death in 92% of IEC-6 cells, but epimorphin dramatically diminished (88.7%) cell death induced by hydrogen peroxide ( P < 0.0001). This protective effect of epimorphin was significantly attenuated by inhibitors of MEK and PI3 kinase ( P < 0.0001) or EGF receptor-neutralizing antibody ( P = 0.0007). In wound assays, the number of migrated cells in the wound area decreased (72.5%) by treatment with 30 μM hydrogen peroxide, but epimorphin increased the number of migrated cells 3.18-fold ( P < 0.0001). These results support a novel function of epimorphin in protecting IEC from oxidative stress. This anti-oxidative function of epimorphin is dramatic and is likely mediated by the activation of EGF receptors and the MEK/extracellular signal-regulated kinase and PI3 kinase/Akt signaling pathways and through the induction of anti-apoptotic factors.
Chemokine receptor CCR5 deficiency exacerbates cerulein-induced acute pancreatitis in mice
Authors: Moreno Christophe , Nicaise Charles , Gustot Thierry , Quertinmont Eric , Nagy Nathalie , Parmentier Marc , Louis Hubert , Devière Jacques
Published: August 2006

Acute pancreatitis (AP) is an inflammatory disease involving the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands [the CC chemokines CCL3/MIP-1α, CCL4/MIP-1β, and CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES)] regulate leukocyte chemotaxis and activation, we investigated the expression of CCR5 ligands and the role of CCR5 and its ligands in experimental AP in mice. AP was induced by hourly intraperitoneal injections of cerulein in CCR5-deficient (CCR5−/−) or wild-type (WT) mice. Induction of AP by cerulein resulted in an early increase of pancreatic CCL2, CCL3, and CCL4 mRNA expression, whereas CCL5 mRNA expression occurred later. CCR5−/−mice developed a more severe pancreatic injury than WT mice during cerulein-induced AP, as assessed by a more pronounced increase in serum amylase and lipase levels and by more severe pancreatic edema, inflammatory infiltrates (mainly neutrophils), and necrosis. CCR5−/−mice also exhibited increased production of CCL2/MCP-1, CCL3/MIP-1α, and CCL4/MIP-1β during the course of cerulein-induced AP. In vivo simultaneous neutralization of CC chemokines with monoclonal antibodies in CCR5−/−mice reduced the severity of cerulein-induced AP, indicating a role of CC chemokines in exacerbating the course of AP in the absence of CCR5. Moreover, simultaneous neutralization of CCR5 ligands in WT mice also reduced the severity of cerulein-induced AP. In conclusion, lack of the chemokine receptor CCR5 exacerbates experimental cerulein-induced AP and leads to increased levels of CC chemokines and a more pronounced pancreatic inflammatory infiltrate, suggesting that CCR5 expression can modulate severity of AP.
Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure
Authors: Reddy Maram K. , Schultz Harold D. , Zheng Hong , Patel Kaushik P.
Published: August 2006

Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6–8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25–100 μg/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, NG-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.
Cardiac myofibroblasts differentiated in 3D culture exhibit distinct changes in collagen I production, processing, and matrix deposition
Authors: Poobalarahi Felicitta , Baicu Catalin F. , Bradshaw Amy D.
Published: August 2006

Myofibroblasts are a differentiated fibroblast cell type characterized by increased contractile capacity and elevated production of extracellular matrix (ECM) proteins. In the heart, myofibroblast expression is implicated in fibrosis associated with pressure-overload hypertrophy, among other pathologies. Although enhanced expression of ECM proteins by myofibroblasts is established, few studies have addressed the nature of the ECM deposited by myofibroblasts. To characterize ECM production and assembly by cardiac myofibroblasts, we developed a three-dimensional (3D) culture system using primary cardiac fibroblasts seeded into a nylon mesh that allows us to reversibly interconvert between myofibroblast and fibroblast phenotypes. We report that an increase in collagen I production by myofibroblasts was accompanied by a significant increase in collagen deposition into insoluble ECM. Furthermore, myofibroblasts exhibited increased levels of procollagen α1(I) with C-propeptide attached (and N-propeptide removed) relative to procollagen α1(I) compared with fibroblast cultures. An increase in production of the myofibroblast-associated splice variant of fibronectin (EDA-Fn) was seen in myofibroblast 3D cultures. Because the regulation of procollagen I processing is known to have profound effects on ECM assembly, differences in procollagen I secretion and maturation coupled with expression of EDA-Fn are shown to contribute to the production of a distinct ECM by the cardiac myofibroblast.
Frequency-based analysis of the early rapid filling pressure-flow relation elucidates diastolic efficiency mechanisms
Authors: Wu Yue , Kovács Sándor J.
Published: August 2006

Stiffness- and relaxation-based diastolic function (DF) assessment can characterize the presence, severity, and mechanism of dysfunction. Although frequency-based characterization of arterial function is routine (input impedance, characteristic impedance, arterial wave reflection), DF assessment via frequency-based methods incorporating optimization/efficiency criteria is lacking. By definition, optimal filling maximizes (E wave) volume and minimizes “loss” at constant stored elastic strain energy (which initiates mechanical, recoil-driven filling). In thermodynamic terms, optimal filling delivers all oscillatory power (rate of work) at the lowest harmonic. To assess early rapid filling optimization, simultaneous micromanometric left ventricular pressure and echocardiographic transmitral flow (Doppler E wave) were Fourier analyzed in 31 subjects. A validated kinematic filling model provided closed-form expressions for E wave contours and model parameters. Relaxation-based DF impairment is indicated by prolonged E wave deceleration time (DT). Optimization was assessed via regression between the dimensionless ratio of 2nd (Q2) and 3rd flow harmonics (Q3) to the lowest harmonic (Q1), i.e., (Q2/Q1) or (Q3/Q1) vs. DT or c, the filling model’s viscosity/damping (energy loss) parameter. Results show that DT prolongation or increased c generated increased oscillatory power at higher harmonics (Q2/Q1 = 0.00091DT + 0.09837, r = 0.70; Q3/Q1 = 0.00053DT + 0.02747, r = 0.60; Q2/Q1 = 0.00614 c + 0.15527, r = 0.91; Q3/Q1 = 0.00396 c + 0.05373, r = 0.87). Because ideal filling is achieved when all oscillatory power is delivered at the lowest harmonic, the observed increase in power at higher harmonics is a measure of filling inefficiency. We conclude that frequency-based analysis facilitates assessment of filling efficiency and elucidates the mechanism by which diastolic dysfunction associated with prolonged DT impairs optimal filling.
Reduced susceptibility to ventricular tachyarrhythmias in rats selectively bred for high aerobic capacity
Authors: Lujan Heidi L. , Britton Steven L. , Koch Lauren G. , DiCarlo Stephen E.
Published: August 2006

Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Human epidemiological studies and experimental work with animals indicate that regular physical activity is associated with reductions in cardiovascular disease (CVD) risk factors and sudden cardiac death. Similarly, artificial selection of rats for high aerobic treadmill-running capacity (high-capacity runners; HCR) has been shown to reduce CVD risk factors relative to rats selected as low-capacity runners (LCR). Therefore, we tested the hypothesis that HCR, relative to LCR rats, would be less susceptible to ischemia-reperfusion-mediated ventricular tachyarrhythmias. To test this hypothesis, we measured the susceptibility to ventricular tachyarrhythmias produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious LCR and HCR rats. Results document a significantly lower incidence of ventricular tachyarrhythmias in HCR (3 of 11, 27.3%) relative to LCR (6 of 7, 85.6%) rats. The decreased susceptibility to tachyarrhythmias in HCR rats was associated with a reduced cardiac metabolic demand during ischemia (lower rate-pressure product and ST segment elevation) as well as a wider range for the autonomic control of heart rate. The HCR and LCR represent a unique substrate for evaluation of the mechanisms underlying ischemia-mediated cardiac arrhythmogenesis.
Short-term cardiac memory and mother rotor fibrillation
Authors: Baher Ali , Qu Zhilin , Hayatdavoudi Ashkan , Lamp Scott T. , Yang Ming-Jim , Xie Fagen , Turner Stephen , Garfinkel Alan , Weiss James N.
Published: August 2006

Short-term cardiac memory refers to the effects of pacing history on action potential duration (APD). Although the ionic mechanisms for short-term memory occurring over many heartbeats (also called APD accommodation) are poorly understood, they may have important effects on reentry and fibrillation. To explore this issue, we incorporated a generic memory current into the Phase I Luo and Rudy action potential model, which lacks short-term memory. The properties of this current were matched to simulate quantitatively human ventricular monophasic action potential accommodation. We show that, theoretically, short-term memory can resolve the paradox of how mother rotor fibrillation is initiated in heterogeneous tissue by physiological pacing. In simulated heterogeneous two-dimensional tissue and three-dimensional ventricles containing an inward rectifier K+ current gradient, short-term memory could spontaneously convert multiple wavelet fibrillation to mother rotor fibrillation or to a mixture of both fibrillation types. This was due to progressive acceleration and stabilization of rotors as accumulation of memory shortened APD and flattened APD restitution slope nonuniformly throughout the tissue.
GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress
Authors: Baleeiro Carlos E. O. , Christensen Paul J. , Morris Susan B. , Mendez Michael P. , Wilcoxen Steven E. , Paine Robert
Published: August 2006

We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.
Galectin-1 in secondary alveolar septae of neonatal mouse lung
Authors: Foster Jennifer J. , Goss Kelli L. , George Caroline L. S. , Bangsund Peter J. , Snyder Jeanne M.
Published: August 2006

In mice, alveolarization occurs during postnatal days 4 through 12, when secondary alveolar septae create thin-walled alveoli in the distal lung. We hypothesized that genes predominantly expressed in newly forming secondary alveolar septae influence the process of alveolarization. To address this hypothesis, tips of secondary alveolar septae were isolated from sections of postnatal day 6 mouse lung tissue using laser capture microdissection. Total RNA was isolated and amplified from the dissected alveolar septal tips and from intact postnatal day 6 lung tissue. Gene expression in the samples was characterized using Affymetrix mouse U74AN2 GeneChips. Galectin-1 was an abundantly expressed transcript that was enriched in the alveolar septal tips compared with levels in the whole lung tissue. Galectins are β-galactoside-binding proteins involved in the regulation of cell proliferation, differentiation, and apoptosis in fibroblasts, muscle cells and endothelial cells, cell types that are present in the alveolar wall. Immunostaining in postnatal day 6 lung tissue confirmed that galectin-1 protein is concentrated in the tips of secondary alveolar septae, predominantly in myofibroblasts. Fibroblasts isolated from day 6 neonatal mouse lung tissue contained galectin-1 protein. Real-time PCR demonstrated that galectin-1 mRNA levels in mouse lung tissue peak at postnatal day 6. Immunoblot analysis confirmed that peak levels of lung galectin-1 protein are found at postnatal days 6 to 12. The increased expression of galectin-1 at the site and time of ongoing alveolarization in the newborn mouse is suggestive that galectin-1 may play an important role in this critical aspect of lung development.
Epithelial-derived TGF-β2 modulates basal and wound-healing subepithelial matrix homeostasis
Authors: Thompson H. Garrett R. , Mih Justin D. , Krasieva Tatiana B. , Tromberg Bruce J. , George Steven C.
Published: August 2006

The epithelium influences the mesenchyme during dynamic processes such as embryogenesis, wound healing, fibrosis, and carcinogenesis. Since transforming growth factor-β (TGF-β) modulates these processes, we hypothesized that epithelial-derived TGF-β also plays a critical role in maintaining the extracellular matrix at basal conditions. We utilized an in vitro model of the epithelial-mesenchymal trophic unit in the human airways to determine the role of epithelial-derived TGF-β in modulating the extracellular matrix under basal and wound-healing conditions. When differentiated at an air-liquid interface, the human bronchial epithelium produces active TGF-β2 at a concentration of 50–70 pg/ml, whereas TGF-β1 is undetectable. TGF-β2 increases two- to threefold following scrape injury in a dose-dependent fashion and significantly enhances both α-smooth muscle actin expression in the underlying collagen-embedded fibroblasts and secretion of tenascin-C into the matrix. Multiphoton microscopy demonstrates substantially enhanced second harmonic generation from fibrillar collagen in the matrix. Pretreatment of the matrix with either sirolimus (2.5 nM) or paclitaxel (10 nM) abolishes the increases in both TGF-β2 and second harmonic generation in response to epithelial injury. In the absence of the epithelium, exogenous active TGF-β2 (0–400 pg/ml) produces a biphasic response in the second harmonic signal with a minimum occurring at the epithelial-derived basal level. We conclude that epithelial-derived TGF-β2 is secreted in response to injury, significantly alters the bulk optical properties of the extracellular matrix, and its tight regulation may be required for normal collagen homeostasis.
Ras association domain family 1C protein stimulates human lung cancer cell proliferation
Authors: Amaar Yousef G. , Minera Marlon G. , Hatran Laurice K. , Strong Donna D. , Mohan Subburaman , Reeves Mark E.
Published: August 2006

Recently, the Ras association domain family 1 gene ( RASSF1) has been identified as a Ras effector encoding two major mRNA forms, RASSF1A and RASSF1C, derived by alternative promoter selection and alternative mRNA splicing. RASSF1A is a tumor suppressor gene. However, the function of RASSF1C, both in normal and cancer cells, is still unknown. To learn more about the function of RASSF1C in human cancer cells, we tested the effect of silencing RASSF1C mRNA with small interfering RNA on lung cancer cells (NCI H1299) that express RASSF1C but not RASSF1A. Small interfering RNA specific for RASSF1C reduced RASSF1C mRNA levels compared with controls. This reduction in RASSF1C expression caused a significant decrease in lung cancer cell proliferation. Furthermore, overexpression of RASSF1C increased cell proliferation in lung cancer cells. Finally, we found that RASSF1C, unlike RASSF1A, does not upregulate N-cadherin 2 and transglutaminase 2 protein expression in NCI H1299 lung cancer cells. This suggests that RASSF1C and RASSF1A have different effector targets. Together, our findings suggest that RASSF1C, unlike RASSF1A, is not a tumor suppressor but rather stimulates lung cancer cell proliferation.
Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA
Authors: Bulau Patrick , Zakrzewicz Dariusz , Kitowska Kamila , Leiper James , Gunther Andreas , Grimminger Friedrich , Eickelberg Oliver
Published: August 2006

Protein arginine methylation is catalyzed by a family of enzymes called protein arginine methyltransferases (PRMTs). Three forms of methylarginine have been identified in eukaryotes: monomethylarginine (l-NMMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), all characterized by methylation of one or both guanidine nitrogen atoms of arginine. l-NMMA and ADMA, but not SDMA, are competitive inhibitors of all nitric oxide synthase isoforms. SDMA is eliminated almost entirely by renal excretion, whereas l-NMMA and ADMA are further metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To explore the interplay between methylarginine synthesis and degradation in vivo, we determined PRMT expression and DDAH activity in mouse lung, heart, liver, and kidney homogenates. In addition, we employed HPLC-based quantification of protein-incorporated and free methylarginine, combined with immunoblotting for the assessment of tissue-specific patterns of arginine methylation. The salient findings of the present investigation can be summarized as follows: 1) pulmonary expression of type I PRMTs was correlated with enhanced protein arginine methylation; 2) pulmonary ADMA degradation was undertaken by DDAH1; 3) bronchoalveolar lavage fluid and serum exhibited almost identical ADMA/SDMA ratios, and 4) kidney and liver provide complementary routes for clearance and metabolic conversion of circulating ADMA. Together, these observations suggest that methylarginine metabolism by the pulmonary system significantly contributes to circulating ADMA and SDMA levels.