bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Evaluation of Particle Consumption in a Particle Seeded Solar Receiver
Authors: Klein Hanna Helena , Rubin Rachamim , Karni Jacob
Published: January 2008

This experimental study shows the behavior of a directly irradiated, high temperature, solar receiver seeded with a low concentration of carbon black particles as the radiation absorbing media in the presence of air or nitrogen as the working fluid. Experiments were conducted in the presence of highly concentrated solar energy with an energy flux of up to 3MW∕m2 at the aperture of the receiver. 99.9% of the particles had an equivalent diameter of <5μm, but the remaining larger agglomerates accounted for 51% of the overall projected surface area. The molar ratio of carbon to gas in the fluid entering the receiver was 0.004–0.008. The heat transfer from the solar radiation to the working gas was accomplished almost exclusively via the particles. The receiver behavior during steady-state operation was evaluated. The receiver gas exit temperatures achieved during the experiments were between 1000 and 1550°C. When nitrogen was used as working gas, its exit temperature exceeded the average wall temperature, whereas when air was used, its exit temperature was lower than the average wall temperature. The air flow may have been heated to some extent by the receiver walls, whereas in the case of nitrogen, the particle-to-gas heat transfer was dominant throughout the receiver. When the gas exit temperature was above 1200°C, the particle seeded nitrogen flow absorbed 12–20% more energy than particle seeded air flow under the same operating conditions (insolation, particle load, flow rate, close proximity in time). The air tests reached high exit temperatures despite the reduction of particle concentration due to combustion. This indicates that heat transfer mainly occurs over a relatively short time period after the particle seeded flow enters the cavity close to the receiver aperture, before significant particle burning takes place. The energy due to carbon combustion was 3–5% of total energy absorbed in the high temperature air experiments. The carbon particles’ oxidation rate in the presence of molecular oxygen was found to be significantly lower than values documented in the literature for high temperature carbon black combustion in air. The high solar flux, which promotes very high radiation→particle→gas heat transfer rate, might account for this retardation.
Imaging Nucleophilic Substitution Dynamics
Authors: Mikosch J. , Trippel S. , Eichhorn C. , Otto R. , Lourderaj U. , Zhang J. X. , Hase W. L. , Weidemüller M. , Wester R.
Published: January 2008

Anion-molecule nucleophilic substitution (S
N
2) reactions are known for their rich reaction dynamics, caused by a complex potential energy surface with a submerged barrier and by weak coupling of the relevant rotational-vibrational quantum states. The dynamics of the S
N
2 reaction of Cl
–
+ CH
3
I were uncovered in detail by using crossed molecular beam imaging. As a function of the collision energy, the transition from a complex-mediated reaction mechanism to direct backward scattering of the I
–
product was observed experimentally. Chemical dynamics calculations were performed that explain the observed energy transfer and reveal an indirect roundabout reaction mechanism involving CH
3
rotation.
Superconducting Vortices in CeCoIn
5
: Toward the Pauli-Limiting Field
Authors: Bianchi Andrea D. , Kenzelmann Michel , DeBeer-Schmitt Lisa , White Jon S. , Forgan Edward M. , Mesot Joel , Zolliker Markus , Kohlbrecher Joachim , Movshovich Roman , Bauer Eric. D. , Sarrao John L. , Fisk Zachary , Petrović Cedomir , Eskildsen Morten Ring
Published: January 2008

Many superconducting materials allow the penetration of magnetic fields in a mixed state in which the superfluid is threaded by a regular lattice of Abrikosov vortices, each carrying one quantum of magnetic flux. The phenomenological Ginzburg-Landau theory, based on the concept of characteristic length scales, has generally provided a good description of the Abrikosov vortex lattice state. We conducted neutron-scattering measurements of the vortex lattice form factor in the heavy-fermion superconductor cerium-cobalt-indium (CeCoIn
5
) and found that this form factor increases with increasing field—opposite to the expectations within the Abrikosov-Ginzburg-Landau paradigm. We propose that the anomalous field dependence of the form factor arises from Pauli paramagnetic effects around the vortex cores and from the proximity of the superconducting state to a quantum critical point.
Optimized Immune Response Elicited by a DNA Vaccine Expressing Pneumococcal Surface Protein A Is Characterized by a Balanced Immunoglobulin G1 (IgG1)/IgG2a Ratio and Proinflammatory Cytokine Production
Authors: Ferreira Daniela M. , Darrieux Michelle , Oliveira Maria Leonor S. , Leite Luciana C. C. , Miyaji Eliane N.
Published: January 2008

We have previously shown that DNA immunization with PspA (pneumococcal surface protein A) DNA is able to elicit protection comparable to that elicited by immunization with PspA protein (with alum as adjuvant), even though the antibody levels elicited by DNA immunization are lower than those elicited by immunization with the protein. This work aims at characterizing the ability of sera to bind to the pneumococcal surface and to mediate complement deposition, using BALB/c wild-type and interleukin-4 knockout mice. We observed that higher anti-PspA levels correlated with intense antibody binding to the pneumococcal surface, while elevated complement deposition was observed with sera that presented balanced immunoglobulin G1 (IgG1)/IgG2a ratios, such as those from DNA-immunized mice. Furthermore, we demonstrated that gamma interferon and tumor necrosis factor alpha were strongly induced after intraperitoneal pneumococcal challenge only in mice immunized with the DNA vaccine. We therefore postulate that although both DNA and recombinant protein immunizations are able to protect mice against intraperitoneal pneumococcal challenge, an optimized response would be achieved by using a DNA vaccine and other strategies capable of inducing balanced Th1/Th2 responses.
Magnitude, Breadth, and Functional Profile of T-Cell Responses during Human Immunodeficiency Virus Primary Infection with B and BF Viral Variants
Authors: Turk Gabriela , Gherardi María Magdalena , Laufer Natalia , Saracco Mónica , Luzzi Renata , Cox Josephine H. , Cahn Pedro , Salomon Horacio
Published: January 2008

The molecular pattern of the human immunodeficiency virus (HIV) epidemic in Argentina provides an appropriate scenario to study cellular immune responses in patients with non-clade B infection. We aimed to map T-cell responses in patients infected with BF recombinant variants and compare them with those of clade B patients. Sixteen recently infected patients were enrolled and grouped by viral subtype. Nef-specific responses were evaluated with a peptide matrix-based gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay using B and BF overlapping peptides. Cross-clade and clade-specific responses were found. A correlation between B versus BF Nef-specific responses was identified. Detailed analysis at the single-peptide level revealed that BF patients show a narrower response but greater magnitude. Nef immunodominant responses agreed with previous publications, although the B loop was targeted at an unexpectedly high frequency. The putative HLA allele(s) restricting each positive response was determined. Single-peptide level screening with two different peptide sets uncovered discordant responses (mostly caused by peptide offsetting) and allowed detection of increased breadth. Positive responses identified by ELISPOT assay were further studied by intracellular cytokine staining. These were almost exclusively mediated by CD8 T cells. Characterization of concordant responses revealed that cells show distinct functional profiles, depending on the peptide presented. Last, quality (in terms of polyfunctionality) of T cells was associated with better viral replication containment. Overall, interclade differences in the frequency of epitopes recognized, structural domains targeted, and magnitude of responses were identified. Screening T-cell responses with multiple sets increased sensitivity. Further support for the notion of polyfunctional CD8+T-cell requirement to better control viral replication is also provided.
Exercise-induced increases in NT-proBNP are not related to the exercise-induced immune response: Figure 1
Authors: Scharhag J , Meyer T , Auracher M , Müller M , Herrmann M , Gabriel H , Herrmann W , Kindermann W
Published: January 2008

Objective:

To investigate if the exercise-induced immune response contributes to the exercise-induced increase in brain natriuretic peptide (BNP) in healthy athletes. This has previously been speculated, as elevated concentrations of BNP or N-terminal pro brain natriuretic peptide (NT-proBNP) in cardiovascular patients were found to be related to immune reactions and elevations in inflammatory cytokines such as interleukin 6 (IL-6).

Methods:

Stored serum samples were analysed for NT-proBNP concentrations of 14 healthy endurance athletes (mean age: 25 (SD 5) years; VO2peak67 (SD 6) ml/min/kg), who had been examined previously for exercise-induced immune reactions and their dependence on carbohydrate supplementation (6 or 12% carbohydrate vs placebo beverages) after three bouts of 4 h cycling at a given workload of 70% of the individual anaerobic threshold. Venous blood samples were taken before, immediately after, and 1 h and 1 day after exercise. Leucocyte subpopulations were determined immediately after blood sampling by flow cytometry. Serum samples for posterior analysis of C-reactive protein (CRP), IL-6, cortisol and NT-proBNP were stored at −80°C.

Results:

The exercise-induced increases in NT-proBNP (p<0.001) were not related to the exercise-induced immune response, although exercise induced marked (CHOS-dependent) increases in IL-6, CRP, cortisol, leucocytes, neutrophils, monocytes and natural killer cells.

Conclusion:

It is unlikely that the exercise-induced increases in NT-proBNP or BNP in healthy athletes are caused by the exercise-induced immune response. Therefore, exercise-induced increases in NT-proBNP or BNP in healthy athletes have to be differentiated from increases in cardiovascular patients with systemic inflammation.
Putting the Myth of Creatine Supplementation Leading to Muscle Cramps and Dehydration to Rest
Authors: Dalbo Vincent James , Roberts Mike , Kerksick Chad , Stout Jeff
Published: January 2008

AbstractCreatine is one of the most popular athletic supplements with sales surpassing 400 million dollars in 2004. Due to the popularity and efficacy of creatine supplementation over 200 studies have examined the effects of creatine on athletic performance. Despite the abundance of research suggesting the effectiveness and safety of creatine a fallacy appears to exist in the general public driven by media claims and anecdotal reports that creatine supplementation can result in muscle cramps and dehydration. Although, a number of published studies have refuted these claims, a recent position statement by the American College of Sports Medicine (ACSM) in 2001 advised individuals who are managing their weight and exercising intensely or in hot environments to avoid creatine supplementation. Recent reports now suggest that creatine may enhance performance in hot and or humid conditions by maintaining hematocrit, aiding thermoregulation and reducing exercising heart rate and sweat rate. Creatine may also positively influence plasma volume during the onset of dehydration. Considering these new published findings, little evidence exists that creatine supplementation in the heat presents additional risk and should be taken into consideration as position statements and other related documents are published.

Key Words:creatine supplementation, muscle cramping, dehydration
Expression of breeding coloration in European Green Lizards (Lacerta viridis): variation with morphology and tick infestation
Authors: Václav R. , Prokop P. , Fekiač V.
Published: January 2008

According to the hypothesis of parasite-mediated sexual selection, for a communication system to work reliably, parasites should reduce the showiness of sexual signals of their host. In this study, we examined whether the expression of breeding coloration in free-ranging adult European Green Lizards ( Lacerta viridis (Laurenti, 1768)) is linked with infestation by their common ectoparasite Ixodes ricinus (L., 1758) (Acari: Ixodidae). We found that tick infestation was higher in males than in females. Males showing relatively heavier body for their tail length (predominantly males with regenerated tails) and relatively thinner tail base experienced higher infestation rates. In turn, relatively heavier females for their snout–vent length were less tick infested. Although some components of throat and chest coloration varied significantly with relative tail length, tail-base thickness, body mass, and head size, a measure of male throat and female chest color saturation seemed independent of lizard morphology. After correcting for the effects of morphology on skin coloration and tick load, the saturation of blue throat color in male lizards decreased with increasing level of tick infestation. In contrast, yellow chest color saturation increased with residual tick numbers in females. Considering presumably different signaling functions of male and female lizard coloration, our work suggests that tick infestation might represent a handicap for Green Lizards.
Cryptic lineages and hybridization in freshwater mussels of the genus Pyganodon (Unionidae) in northeastern North America
Authors: Cyr Frédéric , Paquet Annie , Martel André L. , Angers Bernard
Published: January 2008

The distribution of freshwater mussels Pyganodon Crosse and P. Fischer, 1894 traditionally inferred from morphological characters was validated by a genetic characterization of the genus within the Quebec peninsula. Individuals were identified by comparing the sequences from the female mitochondrial genome (COI and 16S) with those of reference individuals, while hybridization was assessed with male mitochondrial (COI and COII) and nuclear genomes (ITS1 and ITS2). The results confirmed most of the previous morphological identifications but revealed unexpected results. Both male and female mitochondrial genomes support the distinction between Pyganodon fragilis (Lamarck, 1819) and Pyganodon cataracta (Say, 1817). However, only one lineage of Pyganodon grandis (Say, 1829), instead of the two expected, was detected in the sampled area. The genetic survey also revealed the presence of two unidentified Pyganodon lineages, previously unreported within the Quebec peninsula. These extremely rare lineages harbour the signature of ancestral hybridizations. Finally, recent divergence and hybridizations make shell characters only partially efficient in discriminating Pyganodon lineages.
Foraging effort of Surf Scoters (Melanitta perspicillata) wintering in a spatially and temporally variable prey landscape
Authors: Kirk Molly K. , Esler Daniel , Boyd W. Sean
Published: January 2008

We monitored foraging effort of radio-tagged Surf Scoters (Melanitta perspicillata (L., 1758)) in three different habitats: (1) shellfish farm structures with high densities of mussels and strong seasonal prey depletion, (2) soft-bottom clam beds with more stable but less available prey, and (3) rocky intertidal beds with moderate mussel densities and depletion rates. We predicted that foraging effort would vary uniquely by habitat, with effort increasing more where depletion was strongest. However, variation in both hourly and daily foraging efforts was best explained by date only. Effort per hour was lowest in early December (presumably owing to very high prey abundance), increased until mid-February as prey declined, and then decreased again in March (probably owing to increased daylight time for foraging). Foraging effort estimated over a full day increased steadily from December to March as prey were depleted. Temporal patterns of effort did not vary by habitat after accounting for seasonal effects. Instead of increasing foraging effort in habitats with strong depletion, Surf Scoters redistributed to habitats with lower degrees of prey reduction as the season progressed. We suggest that Surf Scoters respond to variation in prey by adjusting both foraging effort and habitat selection as the prey landscape changes.
EFFICIENT STRUCTURES OF ACHIEVEMENT FUNCTIONS FOR GOAL PROGRAMMING MODELS
Authors: CHANG CHING-TER
Published: January 2008

Following the idea of Li (1996), Romero (2004) and Chang (2006), this paper proposes several efficient structures of achievement functions for goal programming and interval goal programming models. These proposed structures of achievement functions are more efficient than the traditional structures of achievement functions such as Lexicographic, Weight, MINMAX (Chebyshev) and interval achievement functions. The structures of achievement functions are comprehensive in terms of the breath of goal programming and interval goal programming. In order to demonstrate the superiority of the proposed methods in terms of the number of iterations and execution time, a computational experiment was conducted on a set of generated test examples.
RESCHEDULING WITH RELEASE DATES TO MINIMIZE TOTAL SEQUENCE DISRUPTION UNDER A LIMIT ON THE MAKESPAN
Authors: YUAN JINJIANG , MU YUNDONG , LU LINGFA , LI WENHUA
Published: January 2008

In this paper, we consider the rescheduling problem for jobs on a single machine with release dates to minimize total sequence disruption under a limit on the makespan. We show that the considered problem can be solved in polynomial time. Consequently, the rescheduling problem for jobs on a single machine with release dates to minimize makespan under a limit on the total sequence disruption can also be solved in polynomial time.
A BRANCH-AND-BOUND ALGORITHM FOR FINDING ALL OPTIMAL SOLUTIONS OF THE ASSIGNMENT PROBLEM
Authors: FU ZHUO , EGLESE RICHARD , WRIGHT MIKE
Published: January 2008

Alternative optimal solutions can give more choice for practical decision making. Therefore, the provision of methods for finding alternative optimal solutions is an important component part of the solution techniques for optimization models. The aim of this paper is to present a branch-and-bound algorithm for finding all optimal solutions of the linear assignment problem. Numerical experimental results are also given.
POTENTIALS OF COUPLED QUINTESSENCE BASED ON A DILATON
Authors: HUANG Z. G. , SUN Q. Q. , FANG W. , LU H. Q.
Published: January 2008

In this paper, we regard dilaton in Weyl-scaled induced gravitational theory as coupled quintessence, which is called DCQ model by us. Parametrization of the dark energy model is a good method by which we can construct the scalar potential directly from the effective equation of state function ωσ(z) describing the properties of the dark energy. Applying this method to the DCQ model, we consider four parametrizations of ω(z) and investigate the features of the constructed DCQ potentials, which possess two different evolutive behaviors called "O" mode and "E" mode. Lastly, we comprise the results of the constructed DCQ model with those of quintessence model numerically.
MULTI-GeV NEUTRINOS DUE TO $n\bar n$ OSCILLATION IN GAMMA-RAY BURST FIREBALLS
Authors: SAHU SARIRA
Published: January 2008

The long and short gamma-ray bursts are believed to be produced due to collapse of massive stars and merger of compact binaries respectively. All these objects are rich in neutron and the jet outflow from these objects must have a neutron component in it. By postulating the [Formula: see text] oscillation in the gamma-ray burst fireball, we show that, 19–38 GeV neutrinos and anti-neutrinos can be produced due to annihilation of anti-neutrons with the background neutrons. These neutrinos and anti-neutrinos will be produced before the 5–10 GeV neutrinos due to dynamical decoupling of neutrons from the rest of the fireball. Observation of these neutrinos will shed more light on the nature of the GRB progenitors and also be a unique signature of physics beyond the standard model. A possible way of detecting these neutrinos in future is also discussed.
The FDA Critical Path Initiative and Its Influence on New Drug Development
Authors: Woodcock Janet , Woosley Raymond
Published: January 2008

Societal expectations about drug safety and efficacy are rising while productivity in the pharmaceutical industry is falling. In 2004, the US Food and Drug Administration introduced the Critical Path Initiative with the intent of modernizing drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. An important part of the initiative is the use of public-private partnerships and consortia to accomplish the needed research. This article explicates the reasoning behind the Critical Path Initiative and discusses examples of successful consortia.
Appropriate Use of Cervical Cancer Vaccine
Authors: Zimet Gregory D. , Shew Marcia L. , Kahn Jessica A.
Published: January 2008

Human papillomavirus (HPV) is a necessary, though not sufficient, cause of cervical cancer. Two vaccines have been developed that prevent two HPV types associated with 70% of cervical cancers. One of the vaccines (a quadrivalent vaccine) also prevents two HPV types associated with 90% of genital warts. Both HPV vaccines have shown very good efficacy and safety. This review summarizes the guidelines for use of the quadrivalent vaccine published by the Advisory Committee on Immunization Practices, presents data on vaccine efficacy and safety, and gives an overview of the findings of cost-effectiveness studies. In addition, we summarize the research on the attitudes of parents and health care providers toward HPV vaccine and critically evaluate controversial and challenging issues surrounding HPV vaccination, including concerns about sexual disinhibition and potential obstacles to vaccine distribution and uptake.
TAT-mediated PRDX6 protein transduction protects against eye lens epithelial cell death and delays lens opacity
Authors: Kubo Eri , Fatma Nigar , Akagi Yoshio , Beier David R. , Singh Sanjay P. , Singh Dhirendra P.
Published: January 2008

A diminished level of endogenous antioxidant in cells/tissues is associated with reduced resistance to oxidative stress. Peroxiredoxin 6 (PRDX6), a protective molecule, regulates gene expression/function by controlling reactive oxygen species (ROS) levels. Using PRDX6 protein linked to TAT, the transduction domain from human immunodeficiency virus type 1 TAT protein, we demonstrated that PRDX6 was transduced into lens epithelial cells derived from rat or mouse lenses. The protein was biologically active, negatively regulating apoptosis and delaying progression of cataractogenesis by attenuating deleterious signaling. Lens epithelial cells from cataractous lenses bore elevated levels of ROS and were susceptible to oxidative stress. These cells harbored increased levels of active transforming growth factor (TGF)-β1 and of α-smooth muscle actin and βig-h3, markers for cataractogenesis. Importantly, cataractous lenses showed a 10-fold reduction in PRDX6 expression, whereas TGF-β1 mRNA and protein levels were elevated. The changes were reversed, and cataractogenesis was delayed when PRDX6 was supplied. Results suggest that delivery of PRDX6 can postpone cataractogenesis, and this should be an effective approach to delaying cataracts and other degenerative diseases that are associated with increased ROS.
Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction
Authors: Huang Shijun , Patterson Eugene , Yu Xichun , Garrett Marion W. , De Aos Isabel , Kem David C.
Published: January 2008

Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G protein-coupled receptor kinase-2 (GRK2) activity and increased sensitivity to isoproterenol 6–24 h after coronary artery ligation in the dog. We previously demonstrated that the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1 h before the onset of ischemia, and this was associated with significant cardioprotection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine whether a clinical window exists following the onset of ischemia for such a protective effect. The treatment of six dogs with the selective proteasome inhibitor bortezomib 1 h after the surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against the loss of GRK2 at 24 h. There was no significant increase of heat shock protein 70(72) in the EBZ of bortezomib-treated animals compared with control. There was a striking absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that is highly predictive of sudden cardiac deaths (SCDs) during electrocardiogram monitoring of the first 24 h in the bortezomib-treated animals in contrast with nontreated infarcted animals. There were no SCDs in the 6 treated animals (0%) and five SCDs in the 14 control animals (36%). Assay of whole blood proteasome activity demonstrated the expected decrease over the 24-h observation period. These data support the concept that proteasome inhibition within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.
Placental growth factor is a potent vasodilator of rat and human resistance arteries
Authors: Osol George , Celia Gerard , Gokina Natalia , Barron Carolyn , Chien Edward , Mandala Maurizio , Luksha Leonid , Kublickiene Karolina
Published: January 2008

The objectives of this study were to determine whether placental growth factor (PlGF) exerts a vasodilatory effect on rat uterine vessels (arcuate arteries and veins) and to examine regional differences in reactivity by comparing these responses to those of comparably sized mesenteric vessels. We also sought to examine and compare its effects on human uterine and subcutaneous vessels. All vessels were studied in vitro, under pressurized (rat) or isometric wire-mounted (human) conditions, and exposed to a range of PlGF concentrations. Inhibitors of nitric oxide and prostaglandin synthesis were included in an effort to understand the causal mechanism(s). In rat uterine arteries, the effects of receptor inhibition and activation using selective ligands for VEGFR-1 (PlGF) vs. VEGFR-2 (VEGF-E) were determined, and real-time RT-PCR was performed to evaluate the effect of pregnancy on relative abundance of VEGFR-1 and VEGFR-2 message in the vascular wall. PlGF was a potent vasodilator of all vessels studied, with greatest sensitivity observed in rat uterine arteries. Pregnancy significantly augmented dilator sensitivity to PlGF, and this effect was associated with selective upregulation of VEGFR-1 message in the pregnant state. The contribution of nitric oxide was appreciable in rat and human uterine arteries, with lesser effects in rat uterine veins and mesenteric arteries, and with no observable effect in human subcutaneous vessels. Based on these results, we conclude that PlGF is a potent vasodilator of several vessel types in both humans and rats. Its potency and mechanism vary with physiological state and vessel location and are mediated solely by the VEGFR-1 receptor subtype. Gestational changes in the uterine circulation suggest that this factor may play a role in modulating uterine vascular remodeling and blood flow during the pregnant state.
Up4A stimulates endothelium-independent contraction of isolated rat pulmonary artery
Authors: Gui Yu , Walsh Michael P. , Jankowski Vera , Jankowski Joachim , Zheng Xi-Long
Published: January 2008

Extracellular nucleotides, such as ATP, UDP, and UTP, regulate pulmonary vascular tone through P2X and P2Y receptors. Recently, uridine adenosine tetraphosphate (Up4A) was reported as a novel endothelium-derived vasoconstrictive factor. Up4A contains both purine and pyrimidine moieties, which potentially activate P2X and P2Y receptors. The present study examined the effect of Up4A on contractility of isolated rat pulmonary artery. Up4A at 1–100 μM stimulated contraction in a concentration-dependent manner. Up4A was equipotent as UTP and UDP in the endothelium-denuded artery while much more effective than UTP and UDP in endothelium-intact preparations. The vasoconstrictor effect of Up4A was inhibited by suramin but not IP5I or desensitization of P2X receptors with α,β-methylene-ATP (α,β-Me-ATP). Up4A-induced contraction was also inhibited by pretreatment with thapsigargin, nitrendipine, or EGTA but unaffected by H1152. Furthermore, unlike ATP and UTP, Up4A did not induce relaxation of endothelium-intact preparations precontracted with phenylephrine. These results suggest that Up4A is a potent vasoconstrictor, but not a vasodilator, of the rat pulmonary artery. Up4A likely acts through a suramin-sensitive P2Y receptor. The contractile effect of Up4A involves the entry of extracellular Ca2+ and release of Ca2+ from intracellular stores but not Ca2+ sensitization via the RhoA/Rho kinase pathway. Up4A, therefore, potentially plays an important role in the regulation of pulmonary vascular tone.
A mechanism for arteriolar remodeling based on maintenance of smooth muscle cell activation
Authors: Jacobsen Jens Christian Brings , Mulvany Michael John , Holstein-Rathlou Niels-Henrik
Published: January 2008

Structural adaptation in arterioles is part of normal vascular physiology but is also seen in disease states such as hypertension. Smooth muscle cell (SMC) activation has been shown to be central to microvascular remodeling. We hypothesize that, in a remodeling process driven by SMC activation, stress sensitivity of the vascular wall is a key element in the process of achieving a stable vascular structure. We address whether the adaptive changes in arterioles under different conditions can arise through a common mechanism: remodeling in a stress-sensitive wall driven by a shift in SMC activation. We present a simple dynamic model and show that structural remodeling of the vessel radius by rearrangement of the wall material around a lumen of a different diameter and driven by differences in SMC activation can lead to vascular structures similar to those observed experimentally under various conditions. The change in structure simultaneously leads to uniform levels of circumferential wall stress and wall strain, despite differences in transmural pressure. A simulated vasoconstriction caused by increased SMC activation leads to inward remodeling, whereas outward remodeling follows relaxation of the vascular wall. The results are independent of the specific myogenic properties of the vessel. The simulated results are robust in the face of parameter changes and, hence, may be generalized to vessels from different vascular beds.
Long-term effects of the perinatal environment on respiratory control
Authors: Bavis Ryan W. , Mitchell Gordon S.
Published: January 2008

The respiratory control system exhibits considerable plasticity, similar to other regions of the nervous system. Plasticity is a persistent change in system behavior triggered by experiences such as changes in neural activity, hypoxia, and/or disease/injury. Although plasticity is observed in animals of all ages, some forms of plasticity appear to be unique to development (i.e., “developmental plasticity”). Developmental plasticity is an alteration in respiratory control induced by experiences during “critical” developmental periods; similar experiences outside the critical period will have little or no lasting effect. Thus complementary experiments on both mature and developing animals are generally needed to verify that the observed plasticity is unique to development. Frequently studied models of developmental plasticity in respiratory control include developmental manipulations of respiratory gas concentrations (O2and CO2). Environmental factors not specifically associated with breathing may also trigger developmental plasticity, however, including psychological stress or chemicals associated with maternal habits (e.g., nicotine, cocaine). Despite rapid advances in describing models of developmental plasticity in breathing, our understanding of fundamental mechanisms giving rise to such plasticity is poor; mechanistic studies of developmental plasticity are of considerable importance. Developmental plasticity may enable organisms to “fine tune” their phenotype to optimize the performance of this critical homeostatic regulatory system. On the other hand, developmental plasticity could also increase the risk of disease later in life. Future directions for studies concerning the mechanisms and functional implications of developmental plasticity in respiratory motor control are discussed.
Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation
Authors: Strempel Sebastian , Schroeder Christoph , Hemmersbach Ruth , Boese Andrea , Tank Jens , Diedrich André , Heer Martina , Luft Friedrich C. , Jordan Jens
Published: January 2008

Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 ± 1 yr, body mass index 24 ± 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.
Predicting cisplatin and trabectedin drug sensitivity in ovarian and colon cancers
Authors: Stevens Ellen V. , Nishizuka Satoshi , Antony Smitha , Reimers Mark , Varma Sudhir , Young Lynn , Munson Peter J. , Weinstein John N. , Kohn Elise C. , Pommier Yves
Published: January 2008

Molecular profiling of markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in patients and can also provide a basis for individualization of therapy. Toward those ends, we have used reverse-phase protein lysate microarrays to evaluate expression of protein components of the nucleotide excision repair (NER) pathways. Those pathways strongly influence the anticancer activities of numerous drugs, including those that are the focus here, cisplatin and ecteinascidin 743 (Et-743; Yondelis, Trabectedin). Cisplatin is generally more active in cell types deficient in NER, whereas Et-743 tends to be less active in those cells. We measured protein expression and sensitivity to those drugs in 17 human ovarian and colon cancer cell lines (13 of them from the NCI-60 panel) and five xeroderma pigmentosum (XP) patient cell types, each containing a different NER defect. Of the NER proteins giving reliable signals, XPF and XPG showed the highest correlations of protein expression with drug activity across all three tissue-of-origin groups. When we compared protein expression data with mRNA expression data from Affymetrix U133A chips, we found no consistent correlation between the two across the cell lines studied, which reinforces the conclusion that protein measurements can give more interpretable mechanistic information than can transcript measurements. The work reported here provides motivation for larger proteomic studies with more cell types focused on potential biomarkers in additional pharmacologically pertinent pathways. [Mol Cancer Ther 2008;7(1):10–8]
Influence of Human Skin Specimens Consisting of Different Skin Layers on the Result of in vitro Permeation Experiments
Authors: Henning A. , Neumann D. , Kostka K.-H. , Lehr C.-M. , Schaefer U.F.
Published: January 2008

The literature exhibits high variation in results from drug permeation experiments across human skin. Our purpose was to investigate the influence of human skin specimens, consisting of different skin layers and resulting from different skin preparation techniques, on the in vitro permeation of a model drug, i.e. flufenamic acid (FFA). FFA permeation across human (1) trypsin-isolated stratum corneum, (2) heat-separated epidermis and (3) dermis, (4) dermatomized skin and (5) full-thickness skin (FTS) from either a hydrophilic or lipophilic donor was investigated in Franz-type diffusion cells. Cumulative permeated drug amounts were plotted versus time, and a fit to Fick’s 2nd law of diffusion was performed. Since performing skin diffusion experiments in the laboratory is time consuming and expensive, especially when using FTS, we also investigated the possibility of calculating the resistances of composite skin layers from the diffusion resistances of the individual skin layers. Due to short lag time, practical handling and economic preparation, heat-separated epidermis appears to be superior in human skin in vitro permeation experiments compared to separated stratumcorneum sheets, dermatomized skin and FTS. Furthermore, we found a good correlation between calculated and experimental resistances which underlines that calculation of the total diffusion resistance of composed skin preparations from resistances of individual skin layers is legitimate and useful. Considering our findings, improved interpretation of literature data and more consistent results for future permeation experiments are possible.
Residual Renal Function – One of the Factors Associated with Arterial Stiffness in Peritoneal Dialysis Patients
Authors: Huang Wen-Hung , Chen Kuan-Hsing , Hsu Ching-Wei , Chen Yung-Chang , Hung Cheng-Chieh , Huang Jeng-Yi , Lin Ja-Liang , Yang Chih-Wei
Published: January 2008

Background: Arterial stiffness as determined by brachial-ankle pulse wave velocity (baPWV) has been demonstrated to predict cardiovascular events or mortality in patients with end-stage renal disease. Peritoneal function and residual renal function (RRF) both are important for patients undergoing peritoneal dialysis (PD). No association has yet been established between arterial stiffness, and RRF and peritoneal function in patients undergoing PD. Methods: 146 PD patients received PD lasting over 4 months. baPWV was determined using an automated, non-invasive, waveform analysis device. Results: This retrospective study revealed independent correlations between baPWV and mean arterial pressure, age, status of diabetes mellitus and RRF as well as an inverse correlation with body mass index. Conclusion: This retrospective study showed that arterial stiffness is independently correlated with RRF. Interestingly, peritoneal function test is not associated with baPWV value.
Cost Consequences of Adjuvant Capecitabine, Mayo Clinic and de Gramont Regimens for Stage III Colon Cancer in the French Setting
Authors: Douillard J.Y. , Tilleul P. , Ychou M. , Dufour P. , Perrocheau G. , Seitz J.F. , Maes P. , Lafuma A. , Husseini F.
Published: January 2008

Background/Aims: To compare the cost consequences of oral capecitabine and two different intravenous regimens of 5-fluorouracil/folinic acid (de Gramont and Mayo Clinic regimens) as adjuvant therapy in stage III colon cancer in France. Methods: Clinical efficacy and safety data were taken from published clinical trials. Medical resource use was estimated from published data and expert opinion. Direct costs (drug acquisition, inpatient and home drug administration, laboratory tests, transportation, and management of adverse events) were considered over a time horizon of 46 months (3.8 years). The perspective taken was that of the French Sickness Funds. Results: In patients treated with capecitabine, relapse-free survival was 1.3 months longer than with the Mayo Clinic regimen, which has been shown to be as effective as the de Gramont regimen. In the base case analysis, capecitabine was less costly (3,654 EUR/patient) than the Mayo Clinic (10,481 EUR/ patient) and de Gramont (7,204 EUR/patient) regimens. In the sensitivity analysis, capecitabine remained dominant except when the intravenous regimens were assumed to be administered at home in all patients. Conclusions: In France, capecitabine is more effective and less costly than both the Mayo Clinic and de Gramont regimens as adjuvant therapy for colon cancer.
A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults with Nonmetastatic and Extremity Osteosarcomas
Authors: Basaran Mert , Bavbek E. Sevil , Saglam Sezer , Eralp Levent , Sakar Burak , Atalar Ata Can , Bilgic Bilge , Ozger Harzem , Onat Haluk
Published: January 2008

Background: Osteosarcoma is a rare malignancy, and patients with this disease benefit from adjuvant chemotherapy. While cisplatin, anthracyclines and ifosfamide are the most commonly used agents in the treatment of osteosarcoma, a search for the best combination with higher efficacy and minimal toxicity continues. We planned to evaluate the efficacy of epirubicin combined with cisplatin and ifosfamide in patients with localized primary osteosarcoma. Methods: Patients with nonmetastatic extremity osteosarcoma who were older than 15 years were included in the study. The preoperative chemotherapy regimen consisted of epirubicin 90 mg/m2, cisplatin 100 mg/m2 on day 1 and ifosfamide 2.0 g/m2/day with an equivalent dose of mesna on days 2–4, repeated every 21 days. Six cycles of this combination regimen were administered (3 cycles prior to surgery and 3 cycles postoperatively). Results: Forty-five patients with localized osteosarcoma entered this phase II trial. Median follow-up was 64 months. Thirty-two patients (84%) received the assigned 6 cycles of chemotherapy. Complete and good histological response to neoadjuvant chemotherapy was 26 and 37%, respectively. The 5-year disease-free and overall survival rates were 41.9% (95% CI 33.6–50.2) and 48.2% (95% CI 39.6–56.8). The most prominent grade 4 toxicity was neutropenia occurring in 32% of patients. The lungs were the most frequent site of relapse (32%). Conclusions: The combination of cisplatin, ifosfamide and epirubicin is an active, reasonably well-tolerated regimen without grade 3 or 4 cardiac toxicity in patients with nonmetastatic extremity osteosarcoma and deserves further investigation in the context of prospective phase III trials.
Successful Pregnancy in Stage IE Primary Non-Hodgkin’s Lymphoma of Uterine Cervix Treated with Neoadjuvant Chemotherapy and Conservative Surgery
Authors: Lorusso D. , Ferrandina G. , Pagano L. , Gagliardi M.L. , Scambia G.
Published: January 2008

Background: Primary non-Hodgkin’s lymphoma involving the uterine cervix is extremely rare with a frequency of 0.008% of all cervical tumors. No standard treatment has been defined for this disease. Case: A 29-year-old Caucasian woman with primary non-Hodgkin stage IE lymphoma of the uterine cervix was treated with neoadjuvant chemotherapy and conservative surgery. Three years after completion of primary treatment, she became pregnant and successfully delivered a full-term healthy baby. Conclusion: This case report supports the data that a conservative strategy consisting of neoadjuvant chemotherapy followed by a uterine-preserving approach represents an adequate option for young highly motivated patients who desire to preserve the childbearing potential.
Irinotecan plus Gemcitabine and 5-Fluorouracil in Advanced Pancreatic Cancer: A Phase II Study
Authors: Endlicher E. , Troppmann M. , Kullmann A. , Gölder S. , Herold T. , Herfarth H. , Grossmann J. , Schlottmann K. , Kullmann F.
Published: January 2008

Aims: The aim of the present study was to evaluate the 6-month survival rate of patients with inoperable or metastatic pancreatic cancer treated with irinotecan and gemcitabine plus 5-fluorouracil. Secondary efficacy end points included response rate, time to progression (TTP), overall survival (OS) and toxicity. Patients and Methods: 30 patients with histologically proven pancreatic carcinoma and at least one bidimensionally measurable lesion were enrolled. Of the patients, 83% had metastatic and 17% locally advanced disease. One cycle, lasting 21 days, comprised treatment on days 1 and 8 consisting of 75 mg/m2 irinotecan i.v. for 90 min, 1,000 mg/m2 gemcitabine i.v. for 30 min and 2,000 mg/m2 fluorouracil (5-FU) for 24 h. A total of six cycles was planned for each patient. Results: 28 patients competed at least one treatment cycle and were therefore assessable for efficacy, and 75% of them achieved the primary end point of the study (survival after 6 months). One-year survival was 25%. Stabilization (partial response and stable disease) was observed in 35.7% (10/28) and partial remission in 7.1% (2/28). The objective response rate was 7.1% (2/28) after completion of the six cycles. Median TTP was 3.4 months (1.2–11.5), and median OS was 8.3 months (2.1–36.2). Regarding severe hematological toxicities, only neutropenia was observed (grade 3 20.7%, 6/29, and grade 4 3.5%, 1/29). In spite of anti-emetic supportive care, nausea affected most of the patients: 79.3% (23/29). Grade 3 vomiting was observed in 4 of the 29 patients (13.8%) and grade 4 in 1 patient (3.5%). Only 1 patient experienced diarrhea grade 3 (3.5%) and 1 patient (3.5%) suffered from a grade 3 peroneal nerve enervation. Conclusions: A combination of irinotecan, gemcitabine and 5-FU is feasible and shows considerable efficacy in patients with inoperable or metastatic pancreatic cancer. Due to its low toxicity, this combination might be an interesting cytotoxic regimen in addition to targeted therapies.
Efficacy of Percutaneous Cementoplasty for Bone Metastasis from Hepatocellular Carcinoma
Authors: Kodama Hideaki , Aikata Hiroshi , Uka Kiminori , Takaki Shintaro , Mori Nami , Waki Koji , Jeong Soo Cheol , Kawakami Yoshiiku , Shirakawa Hiroo , Takahashi Shoichi , Toyota Naoyuki , Ito Katsuhide , Chayama Kazuaki
Published: January 2008

Objective: To assess the efficacy of percutaneous cementoplasty for painful bone metastasis from hepatocellular carcinoma (HCC). Methods: Cementoplasty was performed for 22 metastatic bone tumors in 13 patients. All patients had intractable pain and were diagnosed as metastatic bone tumor from HCC. The ostyneedle was inserted in the center of the site of bone metastasis under CT guidance. VAS score, Tokuhashi score and Frankel score were used for assessment of the efficacy of cementoplasty. We also assessed the response to treatment, adverse events and prognosis. Results: Only the VAS score, but not Tokuhashi and Frankel scores, improved after cementoplasty. Cementoplasty for painful bone metastasis provided relief of severe pain but did not improve prognosis, neurological function or survival. Eleven of 13 (85%) patients showed CR or PR and the mean pain-free period was 5 months, including a 10-month pain-free period in one case. No major complications were encountered. Conclusions: Percutaneous cementoplasty can provide pain relief and improvement of quality of life, though without survival benefits, for HCC patients with painful bone metastasis.