Prediction of absolute rate coefficients and product branching ratios for the C(P-3) plus allene reaction system

Complex chemical reactions in the gas phase can be decomposed into a network of elementary (e.g., unimolecular and bimolecular) steps which may involve multiple reactant channels, multiple intermediates, and multiple products. The modeling of such reactions involves describing the molecular species and their transformation by reaction at a detailed level. Here we focus on a detailed modeling of the C(P-3)+allene (C3H4) reaction, for which molecular beam experiments and theoretical calculations have previously been performed. In our previous calculations, product branching ratios for a nonrotating isomerizing unimolecular system were predicted. We extend the previous calculations to predict absolute unimolecular rate coefficients and branching ratios using microcanonical variational transition state theory (mu-VTST) with full energy and angular momentum resolution. Our calculation of the initial capture rate is facilitated by systematic ab initio potential energy surface calculations that describe the interaction potential between carbon and allene as a function of the angle of attack. Furthermore, the chemical kinetic scheme is enhanced to explicitly treat the entrance channels in terms of a predicted overall input flux and also to allow for the possibility of redissociation via the entrance channels. Thus, the computation of total bimolecular reaction rates and partial capture rates is now possible. (C) 2002 American Institute of Physics.

Investigation of the flow field of a highly heated jet of air

Measurements of mean and fluctuating velocity and temperature and their self- and cross-products to the third-order are presented for a heated axisymmetric air jet. Froude numbers in the range of 3500 13,190, Reynolds numbers in the range of 3470-8500 and non-dimensional streamwise distances. X*, from 0.27 to 1.98 are covered by the data. It was found that turbulence intensity decreases for the heated jet in the region between the inertia dominated and the buoyancy dominated regions which is contrary to findings with helium jets mixing with ambient air to produce density fluctuations. The effects of heating on the turbulent kinetic energy budget and the temperature variance budget show small differences for the inertia dominated region and the intermediate region which help to explain the transition process to the far field plume region. Constants are evaluated for the isotropic eddy diffusivity and generalised gradient hypothesis models as well as the scalar variance model. No significant effect of heating on the dissipation time-scale ratio was found. A novel wire array with an inclined cold wire was used. Measurements obtained with this probe are found to lead to asymmetries in some of the higher-order products. Further investigation suggested that the asymmetries are attributable to an as yet unreported interference effect produced by the leading prong of the inclined temperature wire, The effect may also have implications for inclined velocity wires which contain a temperature component when used in heated flows. (C) 2002 Elsevier Science Inc. All rights reserved.

Are transitions in human gait determined by mechanical, kinetic or energetic factors?

It is currently unclear whether it is the need to maintain metabolic efficiency, the need to keep skeletal loading below critical force levels, or simple mechanical factors that drive the walk-to-run (W R) and run-to-walk (R-W) transitions in human gait. Eighteen adults (9 males and 9 females) locomoted on an instrumented treadmill using their preferred gait. Each completed 2 ascending (W-R) and 2 descending (R-W) series of trials under three levels of loading (0%, 15% and 30% body weight). For each trial, participants locomoted for 60 s at each of 9 different speeds -4 speeds both above and below their preferred transition speed (PTS) plus their PTS. Evidence was sought for critical levels of key kinetic (maximum vertical force, impulse, first peak force, time to first peak force and maximum loading rate), energetic (oxygen consumption, transport cost) and mechanical variables (limb lengths, strength) predictive of the gait transition. Analyses suggested the kinetic variables of time to first peak force and loading rate as the most likely determinants of the W-R and R-W transitions. (C) 2003 Elsevier Science B.V. All rights reserved.

The influence of a concurrent cognitive task on the compensatory stepping response to a perturbation in balance-impaired and healthy elders

This study investigated the influence of a concurrent cognitive task on the compensatory stepping response in balance-impaired elders and the attentional demand of the stepping response. Kinetic, kinematic and neuromuscular measures of a forward recovery step were investigated in 15 young adults, 15 healthy elders and 13 balance-impaired elders in a single task (postural recovery only) and dual task (postural recovery and vocal reaction time task) situation. Results revealed that reaction times were longer in all subjects when performed concurrently with a compensatory step, they were longer for a step than an in-place response and longer for balance-impaired older adults compared with young adults. An interesting finding was that the latter group difference may be related to prioritization between the two tasks rather than attentional demand, as the older adults completed the step before the reaction time, whereas the young adults could perform both concurrently. Few differences in step characteristics were found between tasks, with the most notable being a delayed latency and reduced magnitude of the early automatic postural response in healthy and balance-impaired elders with a concurrent task. (C) 2002 Elsevier Science B.V. All rights reserved.

Investigation of hip abductor activation in subject with clinical unilateral hip osteoarthritis

Objectives: (a) To compare the magnitude of gluteus medius and tensor fascia lata activation between a group of subjects with clinical unilateral hip osteoarthritis and a group of healthy older adults. (b) To compare the magnitude of activation of the gluteus medius and tensor fascia lata between sides in a group of subjects with clinical unilateral hip osteoarthritis and a group of healthy older adults. Methods: 19 subjects with clinical unilateral hip osteoarthritis and 19 healthy controls were investigated. The subjects performed a stepping task during which recordings were obtained using surface electromyograms from the hip abductors, and kinetic data were obtained from a dual force platform. Results: Subjects with clinical hip osteoarthritis had higher gluteus medius activation than the healthy older adults (p=0.037). In addition, there were no differences in the magnitude of gluteus medius activation between the sides (p=0.733). There was no difference in the force platform data between the groups (p=0.078). Conclusions: The increased magnitude of gluteus medius activation in the group with hip osteoarthritis is evidence of a muscular dysfunction associated with hip disease. This has implications for the progressive nature of the disease and for its conservative management.

Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Comparison of an ELISA and an LC/MS/MS method for measuring tacrolimus concentrations and making dosage decisions in transplant recipients

This study compared an enzyme-linked immunosorbent assay (ELISA) to a liquid chromatography-tandem mass spectrometry (LC/MS/MS) technique for measurement of tacrolimus concentrations in adult kidney and liver transplant recipients, and investigated how assay choice influenced pharmacokinetic parameter estimates and drug dosage decisions. Tacrolimus concentrations measured by both ELISA and LC/MS/MS from 29 kidney (n = 98 samples) and 27 liver (n = 97 samples) transplant recipients were used to evaluate the performance of these methods in the clinical setting. Tacrolimus concentrations measured by the two techniques were compared via regression analysis. Population pharmacokinetic models were developed independently using ELISA and LC/MS/MS data from 76 kidney recipients. Derived kinetic parameters were used to formulate typical dosing regimens for concentration targeting. Dosage recommendations for the two assays were compared. The relation between LC/MS/MS and ELISA measurements was best described by the regression equation ELISA = 1.02 . (LC/MS/MS) + 0.14 in kidney recipients, and ELISA = 1.12 . (LC/MS/MS) - 0.87 in liver recipients. ELISA displayed less accuracy than LC/MS/MS at lower tacrolimus concentrations. Population pharmacokinetic models based on ELISA and LC/MS/MS data were similar with residual random errors of 4.1 ng/mL and 3.7 ng/mL, respectively. Assay choice gave rise to dosage prediction differences ranging from 0% to 30%. ELISA measurements of tacrolimus are not automatically interchangeable with LC/MS/MS values. Assay differences were greatest in adult liver recipients, probably reflecting periods of liver dysfunction and impaired biliary secretion of metabolites. While the majority of data collected in this study suggested assay differences in adult kidney recipients were minimal, findings of ELISA dosage underpredictions of up to 25% in the long term must be investigated further.

On the validity of thermogravimetric determination of carbon gasification kinetics

Thermogravimetric analysis has been widely applied in kinetic studies of carbon gasification, with the associated temporal weight change profiles being used to extract kinetic information and to validate gasification models. However the weight change profiles are not always governed by the intrinsic gasification activity because of the effect of chemisorption and its dynamics. In the present work we theoretically determine the criteria under which weight change profiles can be used to determine intrinsic kinetics for CO2 and O2 gasification by examining the region in which the chemisorption dynamics can be assumed pseudo-steady. It is found that the validity of the pseudo-steady assumption depends on the experimental conditions as well as on the initial surface area of carbon. Based on known mechanisms and rate constants an active surface area region is identified within which the steady state assumption is valid and the effect of chemisorption dynamics is negligible. The size of the permissible region is sensitive to the reaction temperature and gas pressure. The results indicate that in some cases the thermogravimetric data should be used with caution in kinetic studies. A large amount of literature on thermogravimetric analyzer determined char gasification kinetics is examined and the importance of chemisorption dynamics for the data assessed.

Structural ordering of coal char during heat treatment and its impact on reactivity

The effect of heat treatment on the structure of an Australian semi-anthracite char was studied in detail in the 850-1150degreesC temperature range using XRD, HRTEM, and electrical resistivity techniques. It was found that the carbon crystallite size in the char does not change significantly during heat treatment in the temperature range studied, for both the raw coal and its ash-free derivative obtained by acid treatment. However, the fraction of the organized carbon in the raw coal chars, determined by XRD, increased with increase of heat treatment time and temperature, while that for the ash-free coal chars remained almost unchanged. This suggests the occurrence of catalytic ordering during heat treatment, supported by the observation that the electrical resistivity of the raw coal chars decreased with heat treatment, while that of the ash-free coal chars did not vary significantly. Further confirmatory evidence was provided by high resolution transmission electron micrographs depicting well-organized carbon layers surrounding iron particles. It is also found that the fraction of organized carbon does not reach unity, but attains an apparent equilibrium value that increases with increase in temperature, providing an apparent heat of ordering of 71.7 kJ mol(-1) in the temperature range studied. Good temperature-independent correlation was found between the electrical resistivity and the organized carbon fraction, indicating that electrical resistivity is indeed structure sensitive. Good correlation was also found between the electrical resistivity and the reactivity of coal char. All these results strongly suggest that the thermal deactivation is the result of a crystallite-perfecting process, which is effectively catalyzed by the inorganic matter in the coal char. Based on kinetic interpretation of the data it is concluded that the process is diffusion controlled, most likely involving transport of iron in the inter-crystallite nanospaces in the temperature range studied. The activation energy of this transport process is found to be very low, at about 11.8 kJ mol(-1), which is corroborated by model-free correlation of the temporal variation of organized carbon fraction as well as electrical resistivity data using the superposition method, and is suggestive of surface transport of iron. (C) 2002 Elsevier Science Ltd. All rights reserved.

Kinetics of adsorption on activated carbon: application of heterogeneous vacancy solution theory

The kinetics of single component adsorption on activated carbon is investigated here using a heterogeneous vacancy solution theory (VST) of adsorption. The adsorption isotherm is developed to account for the adsorbate non-ideality due to the size difference between the adsorbate molecule and the vacant site, while incorporating adsorbent heterogeneity through a pore-width-related potential energy. The transport process in the bidisperse carbon considers coupled mass transfer in both macropore and micropore phases simultaneously. Adsorbate diffusion in the micropore network is modeled through effective medium theory, thus considering pore network connectivity in the adsorbent, with the activation energy for adsorbate diffusion related to the adsorption energy, represented by the Steele 10-4-3 potential for carbons. Experimental data of five hydrocarbons, CO2 and SO2 on Ajax carbon at multiple temperatures, as well as three hydrocarbons on Norit carbon at three temperatures are first fitted by the heterogeneous VST model to obtain the isotherm parameters, followed by application of the kinetic model to uptake data on carbon particles of different sizes and geometry at various temperatures. For the hydrocarbons studied, the model can successfully correlate the experimental data for both adsorption equilibrium and kinetics. However, there is some deviation in the fit of the desorption kinetics for polar compounds such as CO2 and SO2, due to the inadequacy of the L-J potential model in this case. The significance of viscous transport in the micropores is also considered here and found to be negligible, consistent with recent molecular simulation studies. (C) 2002 Elsevier Science Ltd. All rights reserved.

Polyspecific malaria antibodies present at the time of infection inhibit the development of immunity to malaria but antibodies specific for the malaria merozoite surface protein, MSP1, facilitate immunity

Serum taken from mice immune to malaria as a result of infection and drug cure, or from mice immunized with a recombinant form of the merozoite surface protein, MSP1, can provide passive protection of recipient mice against the lethal parasite, Plasmodium yoelii YM. However, recipients of MSP1-immune serum go on to develop long-term immunity, whereas recipients of serum from mice naturally immune to malaria rapidly lose their resistance to infection. We demonstrate that 'infection/cure' serum suppresses the development of both antibody and cell-mediated parasite-specific responses in recipients, whereas these develop in recipients of MSP1-specific antibodies. These data have profound implications for our understanding of the development of malaria immunity in babies who passively acquire antibodies from their mothers.

Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Background The ability of T cells, acting independently of antibodies, to control malaria parasite growth in people has not been defined. If such cell-mediated immunity was shown to be effective, an additional vaccine strategy could be pursued. Our aim was to ascertain whether or not development of cell-mediated immunity to Plasmodium falciparum blood-stage infection could be induced in human beings by exposure to malaria parasites in very low density. Methods We enrolled five volunteers from the staff at our research institute who had never had malaria. We used a cryopreserved inoculum of red cells infected with P falciparum strain 3D7 to give them repeated subclinical infections of malaria that we then cured early with drugs, to induce cell-mediated immune responses. We tested for development of immunity by measurement of parasite concentrations in the blood of volunteers by PCR of the multicopy gene STEVOR and by following up the volunteers clinically, and by measuring antibody and cellular immune responses to the parasite. Findings After challenge and a extended period without drug cure, volunteers were protected against malaria as indicated by absence of parasites or parasite DNA in the blood, and absence of clinical symptoms. Immunity was characterised by absence of detectable antibodies that bind the parasite or infected red cells, but by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity in peripheral blood mononuclear cells, and a drop in the number of peripheral natural killer T cells. Interpretation People can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, in the absence of detectable parasite-specific antibodies, suggesting an additional strategy for development of a malaria vaccine.

Functional significance of a highly conserved glutamate residue of the human noradrenaline transportere

The aim of the study was to investigate the role of glutamate residue 113 in transmembrane domain 2 of the human noradrenaline transporter in determining cell surface expression and functional activity. This residue is absolutely conserved in all members of the Na+- and Cl--dependent transporter family. Mutations to alanine (hE113A), aspartate (hE113D) and glutamine (hE113Q) were achieved by site-directed mutagenesis and the mutants were expressed in transfected COS-7 or HEK-293 cells. Cell surface expression of IIE113A and hE113D, but not hE113Q, was markedly reduced compared with wild type, and functional noradrenaline uptake was detected only for the hE113Q mutant. The pharmacological properties of the hE113Q mutant showed very little change compared with wild type, except for a decrease in V-max values for noradrenaline and dopamine uptake of 2-3-fold. However, the hE113D mutant showed very marked changes in its properties, compared with wild type, with 82-260-fold decreases in the affinities of the substrates, noradrenaline, dopamine and MPP+, and increased Na+ affinity for stimulation of nisoxetine binding. The results of the study show that the size and not the charge of the 113 glutamate residue of the noradrenaline transporter seems to be the most critical factor for maintenance of transporter function and surface expression.

Capillaries within compartments: Microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow. (C) 2003 Elsevier Ltd. All rights reserved.

Determination of regional flow by use of intravascular PET tracers: Microvascular theory and experimental validation for pig livers

Today, the standard approach for the kinetic analysis of dynamic PET studies is compartment models, in which the tracer and its metabolites are confined to a few well-mixed compartments. We examine whether the standard model is suitable for modern PET data or whether theories including more physiologic realism can advance the interpretation of dynamic PET data. A more detailed microvascular theory is developed for intravascular tracers in single-capillary and multiple-capillary systems. The microvascular models, which account for concentration gradients in capillaries, are validated and compared with the standard model in a pig liver study. Methods: Eight pigs underwent a 5-min dynamic PET study after O-15-carbon monoxide inhalation. Throughout each experiment, hepatic arterial blood and portal venous blood were sampled, and flow was measured with transit-time flow meters. The hepatic dual-inlet concentration was calculated as the flow-weighted inlet concentration. Dynamic PET data were analyzed with a traditional single-compartment model and 2 microvascular models. Results: Microvascular models provided a better fit of the tissue activity of an intravascular tracer than did the compartment model. In particular, the early dynamic phase after a tracer bolus injection was much improved. The regional hepatic blood flow estimates provided by the microvascular models (1.3 +/- 0.3 mL min(-1) mL(-1) for the single-capillary model and 1.14 +/- 0.14 min(-1) mL(-1) for the multiple-capillary model) (mean +/- SEM mL of blood min(-1) mL of liver tissue(-1)) were in agreement with the total blood flow measured by flow meters and normalized to liver weight (1.03 +/- 0.12 mL min(-1) mL(-1)). Conclusion: Compared with the standard compartment model, the 2 microvascular models provide a superior description of tissue activity after an intravascular tracer bolus injection. The microvascular models include only parameters with a clear-cut physiologic interpretation and are applicable to capillary beds in any organ. In this study, the microvascular models were validated for the liver and provided quantitative regional flow estimates in agreement with flow measurements.