A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs

A multi-measurand fibre-optic sensor system for process and health monitoring of fibre reinforced composites

Advanced fibre reinforced composites (AFRCs) are being used extensively in areas where weight is at a premium, for example, aerospace, automotive, marine and civil engineering. Autoclave-based processing of this class of material can be influenced by a number of factors including the temperature, chemical integrity of the resin system and the thermal properties of the constituent materials. Therefore, simultaneous monitoring of multiple measurands is essential to enable cross-correlation of evolving chemo-physical properties of the material as a function of the processing parameters. Majority of the fibre optic-based sensors reported to-date are suitable for single or at the most, dual-measurand systems. This paper presents an overview of the design, fabrication and deployment of a novel multi-measurand optical fibre sensor (MMS). The MMS is capable of simultaneously monitoring strain, temperature, refractive index and cross-linking chemistry. The sensor design is based on the extrinsic fibre Fabry-Perot interferometer. A unique feature of this sensor system is that a conventional multi-channel fibre-coupled near-infrared spectrometer is used to monitor the four independent parameters. The MMS was embedded in between the fourth and fifth plies of an eight-ply E-glass fabric laminate. A commercially-available thermosetting epoxy/amine resin system was used to impregnate the fabric layers which were laminated manually. The laminated preform was cured in an autoclave and the results on the simultaneous monitoring of the specified functional groups in the resin system, evolution of fabrication strain, temperature and the refractive index are reported in this paper. Attention is drawn to the effect of processing and post-processing on the output from the embedded optical fibre sensors.</p

A multi-measurand fibre-optic sensor system for process and health monitoring of fibre reinforced composites

Advanced fibre reinforced composites (AFRCs) are being used extensively in areas where weight is at a premium, for example, aerospace, automotive, marine and civil engineering. Autoclave-based processing of this class of material can be influenced by a number of factors including the temperature, chemical integrity of the resin system and the thermal properties of the constituent materials. Therefore, simultaneous monitoring of multiple measurands is essential to enable cross-correlation of evolving chemo-physical properties of the material as a function of the processing parameters. Majority of the fibre optic-based sensors reported to-date are suitable for single or at the most, dual-measurand systems. This paper presents an overview of the design, fabrication and deployment of a novel multi-measurand optical fibre sensor (MMS). The MMS is capable of simultaneously monitoring strain, temperature, refractive index and cross-linking chemistry. The sensor design is based on the extrinsic fibre Fabry-Perot interferometer. A unique feature of this sensor system is that a conventional multi-channel fibre-coupled near-infrared spectrometer is used to monitor the four independent parameters. The MMS was embedded in between the fourth and fifth plies of an eight-ply E-glass fabric laminate. A commercially-available thermosetting epoxy/amine resin system was used to impregnate the fabric layers which were laminated manually. The laminated preform was cured in an autoclave and the results on the simultaneous monitoring of the specified functional groups in the resin system, evolution of fabrication strain, temperature and the refractive index are reported in this paper. Attention is drawn to the effect of processing and post-processing on the output from the embedded optical fibre sensors.</p

The DOE Water Cycle Pilot Study

A Department of Energy (DOE) mutli-laboratory Water Cycle Pilot Study (WCPS) investigated components of the local water budget at the Walnut River Watershed in Kansas to study the relative importance of various processes and to determine the feasibility of observational water budget closure. An extensive database of local meteorological time series and land surface characteristics was compiled. Numerical simulations of water budget components were generated and, to the extent possible, validated for three nested domains within the Southern Great Plains; the DOE Atmospheric Radiation Measurement/Cloud Atmospheric Radiation Testbed (ARM/CART), the Walnut River Watershed (WRW), and the Whitewater Watershed (WW), Kansas A 2-month Intensive Observation Period (IOP) was conducted to gather detailed observations relevant to specific details of the water budget, including fine-scale precipitation, streamflow, and soil moisture measurements not made routinely by other programs. Event and seasonal water isotope (delta 18O, delta D) sampling in rainwater, streams, soils, lakes, and wells provided a means of tracing sources and sinks within and external to the WW, WRW, and the ARM/CART domains. The WCPS measured changes in leaf area index for several vegetation types, deep groundwater variations at two wells, and meteorological variables at a number of sites in the WRW. Additional activities of the WCPS include code development toward a regional climate model with water isotope processes, soil moisture transect measurements, and water level measurements in ground water wells

The DOE Water Cycle Pilot Study

A Department of Energy (DOE) mutli-laboratory Water Cycle Pilot Study (WCPS) investigated components of the local water budget at the Walnut River Watershed in Kansas to study the relative importance of various processes and to determine the feasibility of observational water budget closure. An extensive database of local meteorological time series and land surface characteristics was compiled. Numerical simulations of water budget components were generated and, to the extent possible, validated for three nested domains within the Southern Great Plains; the DOE Atmospheric Radiation Measurement/Cloud Atmospheric Radiation Testbed (ARM/CART), the Walnut River Watershed (WRW), and the Whitewater Watershed (WW), Kansas A 2-month Intensive Observation Period (IOP) was conducted to gather detailed observations relevant to specific details of the water budget, including fine-scale precipitation, streamflow, and soil moisture measurements not made routinely by other programs. Event and seasonal water isotope (delta 18O, delta D) sampling in rainwater, streams, soils, lakes, and wells provided a means of tracing sources and sinks within and external to the WW, WRW, and the ARM/CART domains. The WCPS measured changes in leaf area index for several vegetation types, deep groundwater variations at two wells, and meteorological variables at a number of sites in the WRW. Additional activities of the WCPS include code development toward a regional climate model with water isotope processes, soil moisture transect measurements, and water level measurements in ground water wells