Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Scale Effects in Hydraulic Model Tests of Rock Protected Structures, HR-119, 1970

A laboratory investigation was undertaken to determine the limiting model Reynolds number above which the scour behavior of rock protected structures can be reproduced in hydraulic models scaled according to the Froude criterion. A submerged jet was passed over an initially full scour pocket containing uniform glass spheres and the rate of scour was measured as a function of time. The dimensions of the scour pocket and jet and the particle diameters were varied as needed to maintain strict geometric similarity. For each of two different Froude numbers the Reynolds number was varied over a wide range. The normalized scour rate was found to be practically independent of the Reynolds number, R, (based on the jet velocity and particle diameter) at values of R above about 2.5 x 10^3, and to decrease with Rat smaller values. A grid placed in the jet was found to have a very strong effect on the scour rate. In an attempt to explain the effect of R on the scour behavior, turbulent pressure and velocity fluctuations were measured in air flows and water flows, respectively, over rigid scour pockets having the same geometry as those formed in the scour experiments. The normalized spectra of the fluctuations were found to be nearly independent of R, but the flow pattern was found to be very sensitive to the inlet condition, the jet deflecting upward or downward in a not wholly explainable manner. This indicates that scour behavior can be modeled only if the approach flow is also accurately modeled.

Hind limb ischemia in rabbit model: T2-prepared versus time-of-flight MR angiography at 3 T.

PURPOSE: To prospectively compare various parameters of vessels imaged at 3 T by using time-of-flight (TOF) and T2-prepared magnetic resonance (MR) angiography in a rabbit model of hind limb ischemia. MATERIALS AND METHODS: Experiments were approved by the institutional animal care and use committee. Endovascular occlusion of the left superficial femoral artery was induced in 14 New Zealand white rabbits. After 2 weeks, MR angiography and conventional (x-ray) angiography were performed. Vessel sharpness was evaluated visually in the ischemic and nonischemic limbs, and the presence of small collateral vessels was evaluated in the ischemic limbs. Vessel sharpness was also quantified by evaluating the magnitude of signal intensity change at the vessel borders. RESULTS: The sharpness of vessels in the nonischemic limbs was similar between the TOF and the T2-prepared images. In the ischemic limbs, however, T2-prepared imaging, as compared with TOF imaging, generated higher vessel sharpness in arteries with diminished blood flow (mean vessel sharpness: 44% vs 30% for popliteal arteries, 45% vs 28% for saphenous arteries; P < .001 for both comparisons) and enabled better detection of small collateral vessels (93% vs 36% of vessels, P < .001). CONCLUSION: T2-prepared imaging can facilitate high-spatial-resolution MR angiography of small vessels with low blood flow and thus has potential as a tool for noninvasive evaluation of arteriogenic therapies, without use of contrast material. Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2452062067/DC1.

Knowledge Licensing in a Model of R&D-driven Endogenous Growth

In this paper I present an endogenous growth model where the engine of growth is in-house R&D performed by high-tech firms. I model knowledge (patent) licensing among high-tech firms. I show that if there is knowledge licensing, high-tech firms innovate more and economic growth is higher than in cases when there are knowledge spillovers or there is no exchange of knowledge among high-tech firms. However, in case when there is knowledge licensing the number of high-tech firms is lower than in cases when there are knowledge spillovers or there is no exchange of knowledge.

Knowledge Licensing in a Model of R&D-driven Endogenous Growth

In this paper I present an endogenous growth model where the engine of growth is in-house R&D performed by high-tech firms. I model knowledge (patent) licensing among high-tech firms. I show that if there is knowledge licensing, high-tech firms innovate more and economic growth is higher than in cases when there are knowledge spillovers or there is no exchange of knowledge among high-tech firms. However, in case when there is knowledge licensing the number of high-tech firms is lower than in cases when there are knowledge spillovers or there is no exchange of knowledge.

Nonequilibrium phase transition in a model for the propagation of innovations among economic agents

We characterize the different morphological phases that occur in a simple one-dimensional model of propagation of innovations among economic agents [X. Guardiola et al., Phys. Rev E 66, 026121 (2002)]. We show that the model can be regarded as a nonequilibrium surface growth model. This allows us to demonstrate the presence of a continuous roughening transition between a flat (system size independent fluctuations) and a rough phase (system size dependent fluctuations). Finite-size scaling studies at the transition strongly suggest that the dynamic critical transition does not belong to directed percolation and, in fact, critical exponents do not seem to fit in any of the known universality classes of nonequilibrium phase transitions. Finally, we present an explanation for the occurrence of the roughening transition and argue that avalanche driven dynamics is responsible for the novel critical behavior.

Genetic algorithm for sequencing in midex model non-permutation flowshops using constrained buffers

Este trabajo presenta un Algoritmo Genético (GA) del problema de secuenciar unidades en una línea de producción. Se tiene en cuenta la posibilidad de cambiar la secuencia de piezas mediante estaciones con acceso a un almacén intermedio o centralizado. El acceso al almacén además está restringido, debido al tamaño de las piezas.AbstractThis paper presents a Genetic Algorithm (GA) for the problem of sequencing in a mixed model non-permutation flowshop. Resequencingis permitted where stations have access to intermittent or centralized resequencing buffers. The access to a buffer is restricted by the number of available buffer places and the physical size of the products.

Continuous positive airway pressure causes lung injury in a model of sepsis.

Continuous positive airway pressure, aimed at preventing pulmonary atelectasis, has been used for decades to reduce lung injury in critically ill patients. In neonatal practice, it is increasingly used worldwide as a primary form of respiratory support due to its low cost and because it reduces the need for endotracheal intubation and conventional mechanical ventilation. We studied the anesthetized in vivo rat and determined the optimal circuit design for delivery of continuous positive airway pressure. We investigated the effects of continuous positive airway pressure following lipopolysaccharide administration in the anesthetized rat. Whereas neither continuous positive airway pressure nor lipopolysaccharide alone caused lung injury, continuous positive airway pressure applied following intravenous lipopolysaccharide resulted in increased microvascular permeability, elevated cytokine protein and mRNA production, and impaired static compliance. A dose-response relationship was demonstrated whereby higher levels of continuous positive airway pressure (up to 6 cmH(2)O) caused greater lung injury. Lung injury was attenuated by pretreatment with dexamethasone. These data demonstrate that despite optimal circuit design, continuous positive airway pressure causes significant lung injury (proportional to the airway pressure) in the setting of circulating lipopolysaccharide. Although we would currently avoid direct extrapolation of these findings to clinical practice, we believe that in the context of increasing clinical use, these data are grounds for concern and warrant further investigation.

The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration

Planarian flatworms are an exception among bilaterians in that they possess a large pool of adult stem cells that enables them to promptly regenerate any part of their body, including the brain. Although known for two centuries for their remarkable regenerative capabilities, planarians have only recently emerged as an attractive model for studying regeneration and stem cell biology. This revival is due in part to the availability of a sequenced genome and the development of new technologies, such as RNA interference and next-generation sequencing, which facilitate studies of planarian regeneration at the molecular level. Here, we highlight why planarians are an exciting tool in the study of regeneration and its underlying stem cell biology in vivo, and discuss the potential promises and current limitations of this model organism for stem cell research and regenerative medicine.

Local perception and use of the multifunctionality of water tanks in two villages of Tamil Nadu, South India

Using data from free listings and a survey in two villages of Tamil Nadu, India, we discuss local perceptions and uses of water tanks, a traditional irrigation infrastructure. We hypothesize that both farmers and nonfarmers perceive and use water tanks for purposes other than irrigation. We found that informants recognized the importance of water tanks for irrigation, but also acknowledged other socioeconomic uses and ecological functions. Marginal sectors (i.e., Scheduled Castes) use tank resources in more diverse ways than other sectors of the population. Findings are relevant for development. International organizations working on the revival of water tanks aim to transfer water management to farmers for the purpose of irrigation. By recognizing that tanks benefit people other than farmers and in ways other than providing irrigation water, organizations working on tank rejuvenation could achieve a more equitable management of tank resources.

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation.

Mechanistic population Models in Biology: Model Derivation and Application

In general, models of ecological systems can be broadly categorized as ’top-down’ or ’bottom-up’ models, based on the hierarchical level that the model processes are formulated on. The structure of a top-down, also known as phenomenological, population model can be interpreted in terms of population characteristics, but it typically lacks an interpretation on a more basic level. In contrast, bottom-up, also known as mechanistic, population models are derived from assumptions and processes on a more basic level, which allows interpretation of the model parameters in terms of individual behavior. Both approaches, phenomenological and mechanistic modelling, can have their advantages and disadvantages in different situations. However, mechanistically derived models might be better at capturing the properties of the system at hand, and thus give more accurate predictions. In particular, when models are used for evolutionary studies, mechanistic models are more appropriate, since natural selection takes place on the individual level, and in mechanistic models the direct connection between model parameters and individual properties has already been established. The purpose of this thesis is twofold. Firstly, a systematical way to derive mechanistic discrete-time population models is presented. The derivation is based on combining explicitly modelled, continuous processes on the individual level within a reproductive period with a discrete-time maturation process between reproductive periods. Secondly, as an example of how evolutionary studies can be carried out in mechanistic models, the evolution of the timing of reproduction is investigated. Thus, these two lines of research, derivation of mechanistic population models and evolutionary studies, are complementary to each other.

Comparison of a deterministic and a data driven model to describe MBR fouling

Membrane bioreactors (MBRs) are a combination of activated sludge bioreactors and membrane filtration, enabling high quality effluent with a small footprint. However, they can be beset by fouling, which causes an increase in transmembrane pressure (TMP). Modelling and simulation of changes in TMP could be useful to describe fouling through the identification of the most relevant operating conditions. Using experimental data from a MBR pilot plant operated for 462days, two different models were developed: a deterministic model using activated sludge model n°2d (ASM2d) for the biological component and a resistance in-series model for the filtration component as well as a data-driven model based on multivariable regressions. Once validated, these models were used to describe membrane fouling (as changes in TMP over time) under different operating conditions. The deterministic model performed better at higher temperatures (>20°C), constant operating conditions (DO set-point, membrane air-flow, pH and ORP), and high mixed liquor suspended solids (>6.9gL-1) and flux changes. At low pH (<7) or periods with higher pH changes, the data-driven model was more accurate. Changes in the DO set-point of the aerobic reactor that affected the TMP were also better described by the data-driven model. By combining the use of both models, a better description of fouling can be achieved under different operating conditions

Temporal variability of soil CO2 emission after conventional and reduced tillage described by an exponential decay in time model

To study Assessing the impact of tillage practices on soil carbon losses dependents it is necessary to describe the temporal variability of soil CO2 emission after tillage. It has been argued that large amounts of CO2 emitted after tillage may serve as an indicator for longer-term changes in soil carbon stocks. Here we present a two-step function model based on soil temperature and soil moisture including an exponential decay in time component that is efficient in fitting intermediate-term emission after disk plow followed by a leveling harrow (conventional), and chisel plow coupled with a roller for clod breaking (reduced) tillage. Emission after reduced tillage was described using a non-linear estimator with determination coefficient (R²) as high as 0.98. Results indicate that when emission after tillage is addressed it is important to consider an exponential decay in time in order to predict the impact of tillage in short-term emissions.

Anaerobic-aerobic treatment of swine wastewater in uasb and batch reactors in series

In this work it was evaluated the performance of two systems of swine wastewater treatment consisting of two-stage upflow anaerobic sludge blanket (UASB) reactors, with and without post-treatment in sequencing batch reactor (SBR), fed continuously, with aerobic phase. The UASB reactors in the first stage had 908 L in the sets I and II, and in the second stage 350 and 188 L, respectively. In the set II the post-treatment was performed in a SBR of 3,000 L. The hydraulic detention times in the anaerobic treatment systems were 100, 75 and 58 h in the set I; 87, 65 and 51 h in the set II; and 240 and 180 h in the SBR. The volumetric organic load applied in the first stage UASB reactors ranged from 6.9 to 12.6 g total COD (L d)-1 in the set I and 7.5 to 9.8 g total COD (L d)-1 in the set II. The average removal efficiencies of total COD, total phosphorus (Ptotal), and Kjeldahl and organic nitrogen (KN and Norg) in the anaerobic treatment systems were similar and reached maximum values of 97%, 64%, 68%, and 98%. In the SBR, the removal efficiencies of total COD and thermotolerant coliforms were up to 62 and 92% resulting, respectively, in effluent concentrations of 135 mg L-1 and 2x10(4)MPN (100 mL)-1. For Ptotal, total nitrogen (TN) and Norg, the average removal efficiencies in the SBR were up to 58, 25 and 73%, respectively.