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PubMed1990

A physiological model for renal drug metabolism: enalapril esterolysis to enalaprilat in the isolated perfused rat kidney.

A physiologically based kidney model was developed to describe the metabolism of enalapril and explain the observed discrepancies between generated and preformed enalaprilat (metabolite) elimination in the constant flow single-pass and recirculating isolated perfused rat kidney preparations (IPKs) as a result of the differing points of origin of the metabolite within the kidney, subsequent to the simultaneous delivery of 14C-enalapril and 3H-enalaprilat. The model incorporated clearances for diffusion/transport of drug and metabolite across the basolateral and luminal membranes of the renal cells, an intrinsic clearance for renal drug metabolism, in addition to physiological variables such as perfusate flow rate, glomerular filtration rate, and urine flow rate. Nonlinear curve fitting of single-pass and recirculating data was performed to estimate the rate-limiting step in the renal elimination of enalaprilat. Through fitting and simulation procedures, we were able to predict metabolic and excretory events for enalapril (renal extraction ratio approximately equal to 0.25-0.3; fractional excretion, FE, was less than unity) and the relatively constant pattern of urinary excretion of preformed enalaprilat (extraction ratio approximately equal to 0.07; FE approximately equal to 1). The extraction ratio of the intrarenally formed enalaprilat in single-pass IPK was about twofold that for the preformed metabolite, whereas the FEs of generated enalaprilat in recirculating IPKs were greater than 1, and tended to increase, then decrease with perfusion time. These observations were explained by the optimized parameters which indicated that efflux from cell to lumen was rate-controlling in the excretion of enalaprilat, and another small transport barrier also existed at the basolateral membrane; the lower extraction ratio of preformed enalaprilat was due to its poor transmembrane clearance at the basolateral membrane. The variable FEs for generated enalaprilat vs. the relatively constant FE for preformed metabolite in the recirculating IPK was explained by the changing contributions of both circulating and intrarenal metabolite to metabolite excretion.

Animals↗

PubMed1988

Methods for separating temporally overlapping sources of neuroelectric data.

The localization of intracranial sources of EEG or MEG signals can be misled by the combined effect of several sources, as illustrated by simulated MEG data in which two of the three dipolar sources have slightly out of phase activity and partly complementary scalp topographies. These data were analysed by three different source localization methods. Fitting a single source to each sequential topography worked perfectly when only one source was active; this could also account for as much as 95% of the spatial variance of topographies resulting from two overlapping sources, although the solution was then far from any source. A principal component analysis approach followed by an oblique rotation (fitting one source to the spatial aspect of each component) correctly localized two of the sources but severely mislocated the source that was never active alone. Spatio-temporal source modeling (simultaneously fitting a set of sources to all consecutive topographies) correctly localized all three sources, provided that the parameter optimization method could escape sub-optimal local minima of the error function. Temporally overlapping sources can thus be separated and correctly identified if the mathematical model is adequate and the optimization procedure is well adapted.

Algorithms↗

PubMed1992

The effect of platelet activating factor on different phases of murine in vitro fertilization.

PURPOSE: Our purpose was to examine the effect of platelet activating factor (PAF) in different phases of mouse in vitro fertilization and optimal parameters that would enhance the fertilization rate. DESIGN AND SETTINGS: Various PAF concentrations (10(-7) to 10(-5) M) were selected to investigate its effect on three phases of mouse in vitro fertilization (i.e., sperm capacitation, sperm/oocyte coincubation, and preimplantation embryo growth) in three experimental groups: (I) with PAF treatment in the first phase, (II) with PAF treatment adopted in the first and second phases, and (III) with PAF treatment implemented in all three phases. RESULTS: The improvement of the fertilization rate in PAF treatment groups over the control group ranges from 6.5 to 19.0% (P < 0.05-P < 0.001). The highest enhancement of fertilization rate was achieved under the condition of PAF treatment (10(-6) M) through sperm capacitation and sperm/oocyte coincubation phases. CONCLUSION: The PAF concentration of 10(-6) M in sperm capacitation and sperm/oocyte coincubation yielded the greatest improvement in fertilization. However, continuing PAF treatment after sperm/oocyte coincubation had no beneficial effect on fertilization and preimplantation development.

Animals↗

PubMed1996

Testing of a GIS Model of Eucalyptus largiflorens Health on a Semiarid, Saline Floodplain

Irrigated agriculture has resulted in substantial changes in water flows to the lower reaches of the River Murray. These changes have led to large-scale occurrences of dieback in Eucalyptus largiflorens (black box) woodlands as well as increased inputs of salt to the river. Management options to address problems of this scale call for the use of spatial data sets via geographic information systems (GIS). A GIS exists for one floodplain of the River Murray at Chowilla, and a simple model predicted six health classes of Eucalyptus largiflorens based on groundwater salinity, flooding frequency, and groundwater depth.To determine the usefulness of the model for vegetation management, the quality of both the model and the GIS data sets were tested. Success of the testing procedure was judged by the degree of spatial matching between the model's predictions of health and that assessed from aerial photographs and by field truthing. Analyses at 80 sites showed that tree health was significantly greater where groundwater salinity was less than 40 dS/m or flooding occurred more frequently than 1 in 10 years or depth to groundwater exceeded 4 m. Testing of the GIS data sets found that vegetation was misclassified at 15% of sites. Association was shown between GIS-predicted values and field-truthed values of groundwater salinity but not groundwater depth. The GIS model of health is a useful starting point for future vegetation management and can be further improved by increasing the quality of the data coverages and further refining of the model to optimize parameters and thresholds.

Journal Article↗

PubMed1989

Noninvasive metabolic analysis of eye bank corneas: a magnetic resonance spectroscopic study.

Nondestructive, noninvasive metabolic analysis of corneal donor tissue preserved in modified McCarey-Kaufman medium was achieved using phosphorus-31 magnetic resonance spectroscopy (31 P MRS). Clear corneas (n = 10) with minimal Descemet's folds and an endothelial cell density of 2990 +/- 166 cells/mm2 from donors aged 26 to 89 years were used. Relative amounts of low- and high-energy phosphatic metabolites were quantitated during a 1-h period using the integral of the 31P spectrum. The following indicators of the tissue's energy status were determined: (1) 31P spectral energy modulus (ratio of high- to low-energy metabolites, average 0.95 +/- 0.14); (2) adenosine triphosphate/inorganic orthophosphate (ATP/Pi) ratio, 1.97 +/- 0.55; (3) sugar phosphate/inorganic orthophosphate (SP/Pi) ratio, average 1.07 +/- 0.12; and (4) intracorneal pH, calculated from the resonance shift position of inorganic orthophosphate, average 7.28 +/- 0.05. The 31P MRS technique measures key corneal metabolic processes (maintenance of the high-energy phosphate complement, interrelationship of inorganic orthophosphate and its bioesters, and pH). This study provides baseline data for eventually determining optimal parameters of eye bank corneal tissues and for evaluating the metabolic status, or health, of the cornea.

Adenosine Triphosphate↗

PubMedDate not supplied

Identification of the three-element windkessel model incorporating a pressure-dependent compliance.

A new one-step computational procedure is presented for estimating the parameters of the nonlinear three-element windkessel model of the arterial system incorporating a pressure-dependent compliance. The data required are pulsatile aortic pressure and flow. The basic assumptions are a steady-state periodic regime and a purely elastic compliant element. By stating two conditions, zero mean flow and zero mean power in the compliant element, peripheral and characteristic resistances are determined through simple closed form formulas as functions of mean values of the square of aortic pressure, the square of aortic flow, and the product of aortic pressure with aortic flow. The pressure across as well as the flow through the compliant element can be then obtained so allowing the calculation of volume variation and compliance as functions of pressure. The feasibility of this method is studied by applying it to both simulated and experimental data relative to different circulatory conditions and comparing the results with those obtained by an iterative parameter optimization algorithm and with the actual values when available. The conclusion is that the proposed method appears to be effective in identifying the three-element windkessel even in the case of nonlinear compliance.

Algorithms↗

PubMedDate not supplied

Magnetic stimulation in the recuperative therapy of patients with spondylogenic diseases of the nervous system.

The value and optimal parameters of a new method of therapy, magnetic impulse stimulation, was studied in 225 patients with neurological manifestations of osteochondrosis and vertebral spondyloarthrosis. Electromyography, thermography, rheovasography, and assays of lipid peroxidation were used to assess the mechanisms of the therapeutic actions of magnetic impulse stimulation.

Adult↗

PubMed1998

Estimation of evoked potentials using total least squares prony technique.

The authors investigate the applicability of Prony modelling to the estimation of evoked potentials. Four types of total least squares (TLS) model are considered and their optimal parameters are defined based on ten visual averaged EPs. Simulations with various signal and noise characteristics show that the TLS-Prony estimation is superior to averaging for two of the models, namely the unconstrained and the stable models. Application of the TLS-Prony estimator as a post-processor to moderate averaging allows a reduction in the number of responses averaged, or equivalently of recording time, by a factor of two.

Evoked Potentials, Visual↗

PubMed1992

DNA-mediated gene transfection into primary cultures of adult mouse keratinocytes.

An efficient and reproducible technique for the transfection of primary cultures of adult mouse keratinocytes has been developed. The procedure involves culturing the primary adult mouse epidermal cells at 32 degrees C in an enriched media until they reach 70 to 95% confluency, followed by transfection with exogenous DNA in a low potassium environment. Using chloramphenicol acetyl transferase (CAT) transient gene expression assays and various strong viral promoter/CAT constructs, the transfection procedure was optimized for media formulation, plasmid DNA concentration, carrier DNA concentration, incubation temperature, incubation period, and cell density. Optimized parameters include the use of 6 micrograms plasmid DNA and 10 micrograms pUC19 carrier DNA per 60-mm tissue culture dish. Since primary keratinocytes undergo a well-characterized pattern of differentiation in vitro in response to extracellular calcium concentrations, this transfection procedure should provide a useful model in which to study both tissue- and differentiation-specific gene expression.

Animals↗

PubMedDate not supplied

Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors.

Clinical trials for binary therapies, like boron neutron capture therapy (BNCT), pose a number of unique problems and challenges in design, performance, and interpretation of results. In neutron beam development, different groups use different optimization parameters, resulting in beams being considerably different from each other. The design, development, testing, execution of patient pharmacokinetics and the evaluation of results from these studies differ widely. Finally, the clinical trials involving patient treatments vary in many aspects such as their dose escalation strategies, treatment planning methodologies, and the reporting of data. The implications of these differences in the data accrued from these trials are discussed. The BNCT community needs to standardize each aspect of the design, implementation, and reporting of clinical trials so that the data can be used meaningfully.

Boron Compounds↗

PubMed1998

Significance of magnetic resonance image and blood manganese measurement for the assessment of brain manganese during total parenteral nutrition in rats.

In this study, we report on the influence of trace elements (TE) on signal intensities of nuclear magnetic resonance images (MRI), both in vivo and in vitro. Optimal parameters for the assessment of Mn concentration in the brain of rats on total parenteral nutrition were established. For the in vitro study, Mn and trace element solutions, one containing Zn, Cu, Fe, and I (TE-4) and another containing the above elements plus Mn (TE-5), were diluted with physiological saline or with rat brain homogenate and used to measure signal intensities in MRI. Concentration-dependent signal hyperintensity was observed in both cases in the Mn and the TE-5 solutions, but no effect was observed with the TE-4 solution. The signal increase was greater for brain tissue homogenates. In the in vivo study, the experimental animals were maintained under total parenteral nutrition (TPN) with a standard clinical dose of TE-5 and/or with 10-fold the clinical dose of TE-4 and TE-5 for 1 wk. Only rats that were receiving the increased TE-5 dose showed signal hyperintensity on MRI. Positive correlations were observed among the signal hyperintensity, the blood Mn concentrations, and that of the rat brain. Our results suggest that Mn in TE preparations may be the cause of signal hyperintensity on MRI in a concentration-dependent fashion, and that MRI and measurement of blood Mn may be used to estimate Mn accumulation in brain tissue.

Animals↗

PubMed2004

Detection of multiple human herpes viruses by DNA microarray technology.

BACKGROUND: The detailed characterization of virus DNA is a challenge, and the genotyping that has been achieved to date has only been possible because researchers have sent a great deal of time and effort to do so. Instead of the simultaneous detection of hundreds of viruses on a single high-density DNA-chip at very high costs per chip, we present here an alternative approach using a well-designed and tailored microarray which can establish whether or not a handful of viral genes are present in a clinical sample. METHODS: In this study we applied a new concept of microarray-based, optimized and robust biochemistry for molecular diagnostics of the herpesviruses. For comparison, all samples were genotyped using standard procedures. RESULTS: The biochemical procedure of a knowledge-based, low-density microarray was established based on the molecular diagnostics of human herpes viruses: herpes simplex virus (HSV) HSV-1, HSV-2, varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV-6. The study attempted to optimize parameters of microarray design, surface chemistry, oligonucleotide probe spotting, sample labeling and DNA hybridization to the developed DNA microarray. The results of 12 900 hybridization reactions on about 150 configured herpes virus microarrays showed that the established microarray-based typing procedure was reproducible, virus-specific and sufficiently sensitive with a lower limit of 100 viral copies per mL sample. CONCLUSIONS: The developed method utilizes low-fluorescence background coverslips, epoxy surface chemistry, standardized oligonucleotide probe spotting, PCR-labeling with Cy3 of isolated DNA, array hybridization, and detecting of specific spot fluorescence by an automatic microarray reader. We expect the configured microarray approach to be the method for high-throughput associated studies on human herpes viruses.

Carbocyanines↗

PubMed2001

How many antibiotics are produced by the genus Streptomyces?

Streptomyces is the largest antibiotic-producing genus in the microbial world discovered so far. The number of antimicrobial compounds reported from the species of this genus per year increased almost exponentially for about two decades, followed by a steady rise to reach a peak in the 1970s, and with a substantial decline in the late 1980s and 1990s. The cumulative number shows a sigmoid curve that is much flatter than what a logistic equation would predict. We attempted to fit a mathematical model to this curve in order to estimate the number of undiscovered antimicrobials from this genus as well as to predict the trends in the near future. A model assuming that the screening efforts are encouraged by a previous year's success and that the probability of finding a new antibiotic is a function of the fraction of antibiotics undiscovered so far offered a good fit after optimizing parameters. The model estimated the total number of antimicrobial compounds that this genus is capable of producing to be of the order of a 100,000 - a tiny fraction of which has been unearthed so far. The decline in the slope appeared to be due to a decline in screening efforts rather than an exhaustion of compounds. Left to itself, the slope will become zero in the next one or two decades, but if the screening efforts are maintained constant, the rate of discovery of new compounds will not decline for several decades to come.

Anti-Bacterial Agents↗

PubMed2004

LC-MS/MS method for the confirmatory determination of aromatic amines and its application in textile analysis.

A confirmation method for the determination of 18 aromatic amines originating from azo dyes after reductive cleavage was developed. The method is based on the use of high-performance liquid chromatography/tandem mass spectrometry with atmospheric-pressure chemical ionization. For the identification of the analytes one precursor ion and two daughter ions (multi-reaction monitoring, MRM) were selected and the LC-MS/MS parameters optimized to obtain high sensitivity and selectivity. The linear ranges varied from 0.1-1 to 30-50 microg mL(-1) with correlation coefficients of 0.99 or better. The applicability of the method to determine o-tolidine (3,3'-dimethylbenzidine) and 3,3'-dimethoxybenzidine in textiles following reductive cleavage of acid red 114, trypan blue, and Chicago sky blue 6B was demonstrated.

Journal Article↗

PubMed2002

An improved stereoselective reduction of a bicyclic diketone by Saccharomyces cerevisiae combining process optimization and strain engineering.

The stereoselective reduction of the bicyclic diketone bicyclo[2.2.2]octane-2,6-dione, to the ketoalcohol (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octane-2-one, was used as a model reduction to optimize parameters involved in NADPH-dependent reductions in Saccharomyces cerevisiae with glucose as co-substrate. The co-substrate yield (ketoalcohol formed/glucose consumed) was affected by the initial concentration of bicyclic diketone, the ratio of yeast to glucose, the medium composition, and the pH. The reduction of 5 g l(-1) bicyclic diketone was completed in less than 20 h in complex medium (pH 5.5) under oxygen limitation with an initial concentration of 200 g l(-1) glucose and 5 g l(-1) yeast. The co-substrate yield was further enhanced by genetically engineered strains with reduced phosphoglucose isomerase activity and with the gene encoding alcohol dehydrogenase deleted. Co-substrate yields were increased 2.3-fold and 2.4-fold, respectively, in these strains.

Alcohol Dehydrogenase↗

PubMed2003

Modeling lipid accumulation and degradation in Yarrowia lipolytica cultivated on industrial fats.

A modeling approach was used to quantify the kinetic behavior of a Yarrowia lipolytica strain capable of producing significant lipid amounts when cultivated on industrial fats. Biomass and cellular lipid evolution were successfully simulated, while the optimized parameter values were similar to those experimentally measured. The maximum specific formation rate of fat-free biomass seemed unaffected by the substrate fatty acid composition. On the contrary, the maximum concentration of lipid accumulated inside the yeast cell, as well as the maximum specific accumulation rate of cellular lipids, was favored in high stearic acid content media. The microorganism presented the tendency to degrade its accumulated lipids, although remarkable substrate fat amounts remained unconsummated in the culture medium. This degradation slowly occurred in the yeast cell as the specific rate of the intracellular carbon pool (storage lipid consumption) was significantly lower compared with that of the extracellular carbon pool (substrate fat). However, the fat-free biomass yield on storage lipids (g of fat-free biomass formed per g of storage lipids consumed) was higher than the one on the substrate (g of fat-free biomass formed per g of medium fat consumed).

Biomass↗

PubMed2006

Influence of glucose and saturated free-fatty acid mixtures on citric acid and lipid production by Yarrowia lipolytica.

In the present report, the effect of glucose and stearin (substrate composed by saturated free-fatty acids) on the production of biomass, reserve lipid, and citric acid by Yarrowia lipolytica ACA-DC 50109 was investigated in nitrogen-limited cultures. Numerical models that were used in order to quantify the kinetic behavior of the above Yarrowia lipolytica strain showed successful simulation, while the optimized parameter values were similar to those experimentally measured and the predictive ability of the models was satisfactory. In nitrogen-limited cultures in which glucose was used as the sole substrate, satisfactory growth and no glucose inhibition occurred, although in some cases the initial concentration of glucose was significantly high (150 g/l). Citric acid production was observed in all trials, which was in some cases notable (final concentration 42.9 g/l, yield 0.56 g per g of sugar consumed). The concentration of unsaturated cellular fatty acids was slightly lower when the quantity of sugar in the medium was elevated. In the cases in which stearin and glucose were used as co-substrates, in spite of the fact that the quantity of cellular lipid inside the yeast cells varied remarkably (from 0.3 to 2.0 g/l-4 to 20% wt/wt), de novo fatty acid biosynthesis was observed. This activity increased when the yeast cells assimilated higher sugar quantities. The citric acid produced was mainly derived from the catabolism of sugar. Nevertheless, citric acid yield on sugar consumed and citrate specific production rate, as evaluated by the numerical model, presented substantially higher values in the fermentation in which no fat was used as glucose co-substrate compared with the cultures with stearin used as co-substrate.

Citric Acid↗

PubMed2005

Establishment of embryogenic cell suspension cultures of garlic (Allium sativum L.), plant regeneration and biochemical analyses.

Embryogenic cell suspension cultures of garlic (Allium sativum L.) were initiated in liquid medium from friable embryogenic tissue. The optimal parameters for culture maintenance were: (1) an initial cell density of 1-4% (v/v); (2) medium renewal every 14 days and subculturing every 28 days; (3) a low 2,4-dichlorophenoxyacetic acid concentration (0.1-0.3 mg/l). Cultures regenerated during a 14-month period. The cell suspension cultures differentiated embryos following transfer to a semi-solid embryo induction medium, with histological studies confirming and characterising the embryogenic nature of the process. Forty percent of these embryos converted into plantlets, which produced micro bulbs in vitro. The composition of the sulphur compounds of the micro bulbs obtained from cell suspension embryo-derived plantlets differed slightly from those produced by in vitro shoot proliferation-derived plantlets, but after two cycles of multiplication in the field these differences had disappeared.

2,4-Dichlorophenoxyacetic Acid↗