1/c expansion of a separable model of direct-interaction type

The properties of a proposed model of N point particles in direct interaction are considered in the limit of small velocities. It is shown that, in this limit, time correlations cancel out and that Newtonian dynamics is recovered for the system in a natural way.

Continuous-time random-walk model for financial distributions

We apply the formalism of the continuous-time random walk to the study of financial data. The entire distribution of prices can be obtained once two auxiliary densities are known. These are the probability densities for the pausing time between successive jumps and the corresponding probability density for the magnitude of a jump. We have applied the formalism to data on the U.S. dollardeutsche mark future exchange, finding good agreement between theory and the observed data.

Tuning clustering in random networks with arbitrary degree distributions

We present a generator of random networks where both the degree-dependent clustering coefficient and the degree distribution are tunable. Following the same philosophy as in the configuration model, the degree distribution and the clustering coefficient for each class of nodes of degree k are fixed ad hoc and a priori. The algorithm generates corresponding topologies by applying first a closure of triangles and second the classical closure of remaining free stubs. The procedure unveils an universal relation among clustering and degree-degree correlations for all networks, where the level of assortativity establishes an upper limit to the level of clustering. Maximum assortativity ensures no restriction on the decay of the clustering coefficient whereas disassortativity sets a stronger constraint on its behavior. Correlation measures in real networks are seen to observe this structural bound.

Extended treatment of treatment-naive patients with chronic hepatitis c virus (HCV) genotype 1-infection and slow response to pegylated interferon-alfa and ribavirin: a meta-analysis

Aims: Recently, several clinical trials analyzed if extended duration of treatment with pegylated interferon-alfa and ribavirin over 48 weeks can improve sustained virologic response (SVR) rates in HCV genotype 1-infected patients with slow virologic response. Because results of these clinical trials are conflicting, we performed a metaanalysis to determine the overall impact of extended treatment compared to standard treatment on virologic response rates in treatment-naive HCV genotype 1 slow responders. Methods: Literature search was performed independently by two observers using Pub Med, EMBASE, CENTRAL and abstracts presented in English at international liver and gastroenterology meetings. Randomized controlled clinical trials (RCTs; but studies that re-analyzed data retrospectively RCTs were also allowed) were considered if they included monoinfected treatment-naive HCV genotype 1 patients and compared treatment with pegIFN-alfa 2a or 2b in combination with ribavirin for 48 weeks versus extended treatment (up to 72 weeks) in slow responders. Primary and secondary end points were SVR rates and end-of-treatment (EOT) and relapse rates, respectively. In the present meta-analysis, study endpoints were summarized with a DerSimonian-Laird estimate for binary outcome basing on a random effects model. Results: Literature search yielded seven RTCs addressing the benefit of extended treatment with pegylated interferon-alfa and ribavirin in treatment-naive HCV genotype 1 slow responders. In total, 1330 slow responders were included in our meta-analysis. We show that extended treatment duration compared to the standard of care significantly improves SVR rates in HCV genotype 1 slow responders (12.4% improvement of overall SVR rate, 95% CI 0.055- 0.193, P = 0.0005). In addition, we show that rates of viral relapse were significantly reduced by extended treatment (24.1% reduction of relapse, 95% CI −0.3332 to −0.1487, P < 0.0001), whereas no significant impact of extended treatment on EOT response rates was found. Though extended treatment was burdened with an enhanced rate of premature treatment discontinuation due to interferonalfa- and ribavirin-related side effects, the frequency of serious adverse events was not increased. Conclusions: Treatment extension in HCV genotype 1 slow responders can improve SVR rates in difficult to treat patients and should be considered in patients who need to be treated before specific antivirals will be approved.

Generation of uncorrelated random scale-free networks

Uncorrelated random scale-free networks are useful null models to check the accuracy and the analytical solutions of dynamical processes defined on complex networks. We propose and analyze a model capable of generating random uncorrelated scale-free networks with no multiple and self-connections. The model is based on the classical configuration model, with an additional restriction on the maximum possible degree of the vertices. We check numerically that the proposed model indeed generates scale-free networks with no two- and three-vertex correlations, as measured by the average degree of the nearest neighbors and the clustering coefficient of the vertices of degree k, respectively.

Upregulation of the GABA transporter GAT-1 in the gracile nucleus in the spared nerve injury model of neuropathic pain.

Neuropathic pain is a major health issue and is frequently accompanied by allodynia (painful sensations in response to normally non-painful stimulations), and unpleasant paresthesia/dysesthesia, pointing to alterations in sensory pathways normally dedicated to the processing of non-nociceptive information. Interestingly, mounting evidence indicate that central glial cells are key players in allodynia, partly due to changes in the astrocytic capacity to scavenge extracellular glutamate and gamma-aminobutyric acid (GABA), through changes in their respective transporters (EAAT and GAT). In the present study, we investigated the glial changes occurring in the dorsal column nuclei, the major target of normally innocuous sensory information, in the rat spared nerve injury (SNI) model of neuropathic pain. We report that together with a robust microglial and astrocytic reaction in the ipsilateral gracile nucleus, the GABA transporter GAT-1 is upregulated with no change in GAT-3 or glutamate transporters. Furthermore, [(3)H] GABA reuptake on crude synaptosome preparation shows that transporter activity is functionally increased ipsilaterally in SNI rats. This GAT-1 upregulation appears evenly distributed in the gracile nucleus and colocalizes with astrocytic activation. Neither glial activation nor GAT-1 modulation was detected in the cuneate nucleus. Together, the present results point to GABA transport in the gracile nucleus as a putative therapeutic target against abnormal sensory perceptions related to neuropathic pain.

Interleukin-17 is a critical mediator of vaccine-induced reduction of Helicobacter infection in the mouse model.

BACKGROUND &amp; AIMS: Despite the proven ability of immunization to reduce Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. This study explores the possibility that interleukin (IL)-17 plays a role in the reduction of Helicobacter infection following vaccination of wild-type animals or in spontaneous reduction of bacterial infection in IL-10-deficient mice. METHODS: In mice, reducing Helicobacter infection, the levels and source of IL-17 were determined and the role of IL-17 in reduction of Helicobacter infection was probed by neutralizing antibodies. RESULTS: Gastric IL-17 levels were strongly increased in mice mucosally immunized with urease plus cholera toxin and challenged with Helicobacter felis as compared with controls (654 +/- 455 and 34 +/- 84 relative units for IL-17 messenger RNA expression [P &lt; .01] and 6.9 +/- 8.4 and 0.02 +/- 0.04 pg for IL-17 protein concentration [P &lt; .01], respectively). Flow cytometry analysis showed that a peak of CD4(+)IL-17(+) T cells infiltrating the gastric mucosa occurred in immunized mice in contrast to control mice (4.7% +/- 0.3% and 1.4% +/- 0.3% [P &lt; .01], respectively). Gastric mucosa-infiltrating CD4(+)IL-17(+) T cells were also observed in IL-10-deficient mice that spontaneously reduced H felis infection (4.3% +/- 2.3% and 2% +/- 0.6% [P &lt; .01], for infected and noninfected IL-10-deficient mice, respectively). In wild-type immunized mice, intraperitoneal injection of anti-IL-17 antibodies significantly inhibited inflammation and the reduction of Helicobacter infection in comparison with control antibodies (1 of 12 mice vs 9 of 12 mice reduced Helicobacter infection [P &lt; .01], respectively). CONCLUSIONS: IL-17 plays a critical role in the immunization-induced reduction of Helicobacter infection from the gastric mucosa.

Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model.

BACKGROUND: Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor. METHODS: A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 microg (n = 9) and 400 microg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors. RESULTS: The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (0.67 +/- 0.2 vs 0.54 +/- 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed. CONCLUSIONS: Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.

Field Evaluation of Compaction Monitoring Technology: Phase II Volumes 1 and 2, TR-495, 2006

This report documents an extensive field program carried out to identify the relationships between soil engineering properties, as measured by various in situ devices, and the results of machine compaction monitoring using prototype compaction monitoring technology developed by Caterpillar Inc. Primary research tasks for this study include the following: (1) experimental testing and statistical analyses to evaluate machine power in terms of the engineering properties of the compacted soil (e.g., density, strength, stiffness) and (2) recommendations for using the compaction monitoring technology in practice. The compaction monitoring technology includes sensors that monitor the power consumption used to move the compaction machine, an on-board computer and display screen, and a GPS system to map the spatial location of the machine. In situ soil density, strength, and stiffness data characterized the soil at various stages of compaction. For each test strip or test area, in situ soil properties were compared directly to machine power values to establish statistical relationships. Statistical models were developed to predict soil density, strength, and stiffness from the machine power values. Field data for multiple test strips were evaluated. The R2 correlation coefficient was generally used to assess the quality of the regressions. Strong correlations were observed between averaged machine power and field measurement data. The relationships are based on the compaction model derived from laboratory data. Correlation coefficients (R2) were consistently higher for thicker lifts than for thin lifts, indicating that the depth influencing machine power response exceeds the representative lift thickness encountered under field conditions. Caterpillar Inc. compaction monitoring technology also identified localized areas of an earthwork project with weak or poorly compacted soil. The soil properties at these locations were verified using in situ test devices. This report also documents the steps required to implement the compaction monitoring technology evaluated.

A Gain Scheduling Model Predictive Controller for Blood Glucose Control in Type 1 Diabetes

This paper presents a control strategy for blood glucose(BG) level regulation in type 1 diabetic patients. To design the controller, model-based predictive control scheme has been applied to a newly developed diabetic patient model. The controller is provided with a feedforward loop to improve meal compensation, a gain-scheduling scheme to account for different BG levels, and an asymmetric cost function to reduce hypoglycemic risk. A simulation environment that has been approved for testing of artificial pancreas control algorithms has been used to test thecontroller. The simulation results show a good controller performance in fasting conditions and meal disturbance rejection, and robustness against model–patient mismatch and errors in mealestimation

An improved approach for predicting the distribution of rare and endangered species from occurrence and pseudo-absence data

1. Few examples of habitat-modelling studies of rare and endangered species exist in the literature, although from a conservation perspective predicting their distribution would prove particularly useful. Paucity of data and lack of valid absences are the probable reasons for this shortcoming. Analytic solutions to accommodate the lack of absence include the ecological niche factor analysis (ENFA) and the use of generalized linear models (GLM) with simulated pseudo-absences. 2. In this study we tested a new approach to generating pseudo-absences, based on a preliminary ENFA habitat suitability (HS) map, for the endangered species Eryngium alpinum. This method of generating pseudo-absences was compared with two others: (i) use of a GLM with pseudo-absences generated totally at random, and (ii) use of an ENFA only. 3. The influence of two different spatial resolutions (i.e. grain) was also assessed for tackling the dilemma of quality (grain) vs. quantity (number of occurrences). Each combination of the three above-mentioned methods with the two grains generated a distinct HS map. 4. Four evaluation measures were used for comparing these HS maps: total deviance explained, best kappa, Gini coefficient and minimal predicted area (MPA). The last is a new evaluation criterion proposed in this study. 5. Results showed that (i) GLM models using ENFA-weighted pseudo-absence provide better results, except for the MPA value, and that (ii) quality (spatial resolution and locational accuracy) of the data appears to be more important than quantity (number of occurrences). Furthermore, the proposed MPA value is suggested as a useful measure of model evaluation when used to complement classical statistical measures. 6. Synthesis and applications. We suggest that the use of ENFA-weighted pseudo-absence is a possible way to enhance the quality of GLM-based potential distribution maps and that data quality (i.e. spatial resolution) prevails over quantity (i.e. number of data). Increased accuracy of potential distribution maps could help to define better suitable areas for species protection and reintroduction.

Preclinical evaluation of the immunogenicity of C-type HIV-1-based DNA and NYVAC vaccines in the Balb/C mouse model.

As part of a European initiative (EuroVacc), we report the design, construction, and immunogenicity of two HIV-1 vaccine candidates based on a clade C virus strain (CN54) representing the current major epidemic in Asia and parts of Africa. Open reading frames encoding an artificial 160-kDa GagPolNef (GPN) polyprotein and the external glycoprotein gp120 were fully RNA and codon optimized. A DNA vaccine (DNA-GPN and DNA-gp120, referred to as DNA-C), and a replication-deficient vaccinia virus encoding both reading frames (NYVAC-C), were assessed regarding immunogenicity in Balb/C mice. The intramuscular administration of both plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial T-cell responses against both antigens as well as Env-specific antibodies. Whereas low doses of NYVAC-C failed to induce specific CTL or antibodies, high doses generated cellular as well as humoral immune responses, but these did not reach the levels seen following DNA vaccination. The most potent immune responses were detectable using prime:boost protocols, regardless of whether DNA-C or NYVAC-C was used as the priming or boosting agent. These preclinical findings revealed the immunogenic response triggered by DNA-C and its enhancement by combining it with NYVAC-C, thus complementing the macaque preclinical and human phase I clinical studies of EuroVacc.

Monte Carlo study of a kinetic lattice model with random diffusion of disorder

We report Monte Carlo results for a nonequilibrium Ising-like model in two and three dimensions. Nearest-neighbor interactions J change sign randomly with time due to competing kinetics. There follows a fast and random, i.e., spin-configuration-independent diffusion of Js, of the kind that takes place in dilute metallic alloys when magnetic ions diffuse. The system exhibits steady states of the ferromagnetic (antiferromagnetic) type when the probability p that J>0 is large (small) enough. No counterpart to the freezing phenomena found in quenched spin glasses occurs. We compare our results with existing mean-field and exact ones, and obtain information about critical behavior.

A random linear functional approach to efficiency bounds

This paper suggests a method for obtaining efficiency bounds in models containing either only infinite-dimensional parameters or both finite- and infinite-dimensional parameters (semiparametric models). The method is based on a theory of random linear functionals applied to the gradient of the log-likelihood functional and is illustrated by computing the lower bound for Cox's regression model

Bactericidal synergism between daptomycin and the phage lysin Cpl-1 in a mouse model of pneumococcal bacteraemia.

Combination therapy may improve the outcome of Streptococcus pneumoniae-induced bacteraemia. Here we tested the combination of two antipneumococcal agents, daptomycin and Cpl-1 (the pneumococcal Cp-1 bacteriophage lysin), in a mouse model of pneumococcal bacteraemia. Mice were challenged intraperitoneally (i.p.) with 10(6)CFU of the extremely virulent serotype 2 S. pneumoniae D39 isolate. Subtherapeutic doses of daptomycin (0.4mg/kg) and Cpl-1 (0.4mg/kg and 1mg/kg) were administrated i.p. either alone or in combination by a single bolus injection 1h after bacterial challenge. Survival rates of animals were followed over a period of 7 days. Daptomycin (0.4mg/kg) in combination with Cpl-1 (0.4mg/kg) significantly increased the percentage of surviving mice at Day 7 (80%) compared with the untreated control (0%) and daptomycin or Cpl-1 monotherapy (35% and 0%, respectively). Whilst increasing the concentration of Cpl-1 to 1.0mg/kg did not improve survival when injected alone, its combination with 0.4mg/kg daptomycin further increased the survival rate to 95%. Thus, it was found that the combination of daptomycin with Cpl-1 was synergistic and bactericidal against S. pneumoniae in a mouse model of pneumococcal bacteraemia. To our knowledge, this is the first report of synergism between daptomycin and a phage lysin demonstrated in vivo. Such a combination could represent an interesting alternative therapy for the treatment of pneumococcal bacteraemia/sepsis and possibly other severe pneumococcal infections.