Use of Pharmacokinetic Modeling to Design Studies for Pathway-Specific Exposure Model Evaluation

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes and pathways. The purpose of this article is to demonstrate a method to use pharmacokinetic (PK) modeling and computer simulation to guide the design of field studies to validate pathway models. The children’s dietary intake model is discussed in detail as an example. Three important aspects are identified for a successful design to evaluate the children’s dietary intake model: a) longitudinally designed study with significant changes in the exposure for the route/pathway of interest, b) short biologic half-life of the selected chemical, and c) surface loading of the selected chemical at sufficient levels. Using PK modeling to guide a study design allowed a path-specific exposure model to be evaluated using urinary metabolite biomarkers

A 3D computed tomography based tool for orthopedic surgery planning

Series : Lecture notes in computational vision and biomechanics, vol. 19The preparation of a plan is essential for a surgery to take place in the best way possible and also for shortening patient’s recovery times. In the orthopedic case, planning has an accentuated significance due to the close relation between the degree of success of the surgery and the patient recovering time. It is important that surgeons are provided with tools that help them in the planning task, in order to make it more reliable and less time consuming. In this paper, we present a 3D Computed Tomography based solution and its implementation as an OsiriX plugin for orthopedic surgery planning. With the developed plugin, the surgeon is able to manipulate a three-dimensional isosurface rendered from the selected imaging study (a CT scan). It is possible to add digital representations of physical implants (surgical templates), in order to evaluate the feasibility of a plan. These templates are STL files generated from CAD models. There is also the feature to extract new isosurfaces of different voxel values and slice the final 3D model according to a predefined plane, enabling a 2D analysis of the planned solution. Finally, we discuss how the proposed application assists the surgeon in the planning process in an alternative way, where it is possible to three-dimensionally analyze the impact of a surgical intervention on the patient.(undefined

Combinations of β-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections

Wideband THz time domain spectroscopy based on optical rectification and electro-optic sampling

We present an analytical model describing the full electromagnetic propagation in a THz time-domain spectroscopy (THz-TDS) system, from the THz pulses via Optical Rectification to the detection via Electro Optic-Sampling. While several investigations deal singularly with the many elements that constitute a THz-TDS, in our work we pay particular attention to the modelling of the time-frequency behaviour of all the stages which compose the experimental set-up. Therefore, our model considers the following main aspects: (i) pump beam focusing into the generation crystal; (ii) phase-matching inside both the generation and detection crystals; (iii) chromatic dispersion and absorption inside the crystals; (iv) Fabry-Perot effect; (v) diffraction outside, i.e. along the propagation, (vi) focalization and overlapping between THz and probe beams, (vii) electro-optic sampling. In order to validate our model, we report on the comparison between the simulations and the experimental data obtained from the same set-up, showing their good agreement

Research on supply chain optimization considering consumer subsidy mechanism in the context of carbon neutrality

With the proposal of China’s “carbon peak, carbon neutral” strategy, the increasing awareness of low carbon production among consumers, and the government’s introduction of carbon trading mechanism and low carbon consumption subsidy policies, enterprises are facing good opportunities for development. However, how the government can reasonably formulate low carbon policies and how enterprises can implement optimal low-carbon production decisions are still key issues in China’s low-carbon transition development. In this context, this paper is based on the carbon trading mechanism and carbon consumption subsidies. In this context, based on the car-bon trading mechanism, this paper focuses on green production and green consumption, considers the impact of low-carbon consumer preferences and government subsidies on enterprises’ low-carbon production decisions, and uses the optimal theory to study the optimal pricing strategy and the optimal carbon reduction strategy. The study shows that the increase in carbon price has a positive effect on the increase in enterprise profit; the increase of carbon emission has a negative effect on the increase of enterprise profit and the high carbon price will intensify this effect. In addition, changing the intensity of government subsidies to consumers will lead to the change of enterprise carbon emission strategy. The study of this paper provides a certain reference for the government to reasonably formulate carbon trading prices and consumer low-carbon subsidies. In addition, considering consumer low-carbon preferences is also conducive to promoting green production practices of enterprises, thus promoting the realization of the carbon neutral strategy

The role of GRIP1 and ephrin B3 in blood pressure control and vascular smooth muscle cell contractility

This work was supported by grants from the Canadian Institutes of Health Research to J.W. (MOP57697, MOP69089 and MOP 123389), H.L. (MOP97829), and G.C. (CMI72323). It was also financed by grants from the Natural Sciences and Engineering Research Council of Canada (203906-2012), and the J.-Louis Levesque Foundation to J.W. This study was also made possible by a group grant from the National Sciences Foundation of China (#81361120264) to J.S., S.H. T.W. and J.W. The funders provided support in the form of salaries for authors [Y.W.; Z.W.; H.L.; J.P.; J.R.], and experimental costs, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “author contributions”. The authors thank Regeneron Pharmaceuticals for generously providing Efnb3 KO mice. The authors thank all the authors of the International Consortium for Blood Pressure Genome-Wide Association Studies for allow us to mine the study dataset

Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations

Facilitating Joint Chaos and Fractal Analysis of Biosignals through Nonlinear Adaptive Filtering

Background: Chaos and random fractal theories are among the most important for fully characterizing nonlinear dynamics of complicated multiscale biosignals. Chaos analysis requires that signals be relatively noise-free and stationary, while fractal analysis demands signals to be non-rhythmic and scale-free. Methodology/Principal Findings: To facilitate joint chaos and fractal analysis of biosignals, we present an adaptive algorithm, which: (1) can readily remove nonstationarities from the signal, (2) can more effectively reduce noise in the signals than linear filters, wavelet denoising, and chaos-based noise reduction techniques; (3) can readily decompose a multiscale biosignal into a series of intrinsically bandlimited functions; and (4) offers a new formulation of fractal and multifractal analysis that is better than existing methods when a biosignal contains a strong oscillatory component. Conclusions: The presented approach is a valuable, versatile tool for the analysis of various types of biological signals. Its effectiveness is demonstrated by offering new important insights into brainwave dynamics and the very high accuracy in automatically detecting epileptic seizures from EEG signals

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP