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At least 109 records · Page 6Linked to original sources

PubMed1982

Computerized rapid analysis of pulmonary function test: use of a least mean squares correlation for interpretation of data.

Although systems for automated calculation and interpretation of screening pulmonary function tests (PFT) have been discussed by previous investigators, these systems are often unavailable to other users, require large or hybrid computers, or are difficult to modify. The use of a branching decision tree for PFT interpretation may also limit the number of correlations possible and make revision of the program difficult because changes in the proximal branches of the tree require a rewriting of the entire distal program. We have developed a system based on a minicomputer which uses a least mean squares analysis for rapidly analyzing the patient's PFT data. This program considers the following types of PFT data singly and in combination: percentage predicted total lung capacity and/or alveolar volume, forced expiratory volume in one second to forced vital capacity ratio (before and after bronchodilator or 80% helium challenge), and percentage predicted single breath diffusing capacity for carbon monoxide. The interpretation program (IP) then selects the 'best interpretation' for the patient by computing the variance between the patient's data and data from a menu of over 120 interpretation statements. During the past two years we have used this system for screening over 3000 patients. In about 90% of patients the computer selected interpretation statements which were acceptable to a sub-specialty pulmonary physician. The use of this IP for screening purposes has facilitated the efficient use of laboratory personnel and equipment.

Diagnosis, Computer-Assisted↗

PubMed1984

Dietary and age influence on the pharmacokinetic parameters of 2-acetylaminofluorene in BALB/c mice.

In a chronic study conducted in our laboratories, we found dietary effects on 2-acetylaminofluorene (2-AAF) toxicity. To determine if the absorption, distribution, metabolism, or elimination of 2-AAF was altered by the age of the animals, diet, or 2-AAF treatment, pharmacokinetic studies were conducted on young (11 weeks) and old (78 weeks) BALB/c mice that had been fed one of four diets containing 4 or 24% fat and 12 or 24% protein. Blood, urine, and feces samples were obtained over a 31-hr period after dosing with 500 ppm 2-[14C]AAF (10 microCi/mouse). Total radioactivity was determined after combusting each sample in an oxygen atmosphere and counting in a scintillation counter. The data from each individual mouse was simulated on an analog-digital hybrid computer utilizing a two-compartment model with metabolism. The pharmacokinetic parameters within groups were analyzed to make statistical comparisons of the effects of diet, dose, age, and interactions among the groups. The pharmacokinetic predictions of a shorter elimination half-life, smaller area-under-the-curve value, and therefore a decreased exposure to 2-AAF and metabolites due to an increased elimination rate of the parent compound through the urine were consistent with the decreased pathological effects found from the chronic study for the low protein/low fat diet mice.

2-Acetylaminofluorene↗

PubMed1983

Impact of thermal vasomotor control on the heart rate variability of newborn infants.

The reactivity of the periodic heart rate variability (HRV) to the thermal vasomotor control was studied during quiet sleep in a total of 20 neonates which were classified in 5 groups according to their maturity. Thermal stimulation on the peripheral skin was applied by an air blower at the rates of 5, 2.5 and 1.5 cycles/min. The oscillation of successive R-R intervals of the ECG was determined by a hybrid computer technique during thermal stimulations and compared to spontaneous HRV activity. The indices of the HRV and the total power of the periodic HRV remained unchanged during thermal stimulations. The response of the periodic HRV was selective at the spectral band corresponding to the frequency of stimulation. It was maximal at 5 cycles/min. The relative response was highly significant (P less than 0.001) and it increased with increasing maturity. The state of SGA (small for gestational age) seemed to decrease the vasomotor response of the HRV. The results suggested that the thermal vasomotor control was functional already in small preterm infants and it tended to increase with increasing maturity as does the autonomic cardiac control in general.

Body Temperature Regulation↗

PubMedDate not supplied

Correlating pharmacokinetics and teratogenic endpoints.

The use of pharmacokinetics can improve the extrapolation of animal teratology data for human risk evaluation. Before one can extrapolate between species, however, the pharmacokinetic model must be predictable within the species for which it was developed. This article summarizes an approach being used for correlating pharmacokinetics and teratology endpoints in the same animal and predicting the teratogenic outcome for other animals of the same species. With the aid of micro-sampling procedures, and sensitive and rapid analytical techniques, blood, urine and feces samples are obtained from individual animals following dosing and the data are simulated using a hybrid computer to develop a pharmacokinetic model. The model is validated in other animals by measuring the parent compound and metabolites in various "compartments" predicted by the model. Then the pharmacokinetic model is tested by predicting the teratogenic outcome in single ani-analyses indicated the most predictive pharmacokinetic parameters to be two maternal blood concentration values. Prediction of the teratogenic outcome based on these parameters was accurate for 74% of the litters in the 95% confidence interval. This approach is discussed as it relates to its utility for other exposure routes and for extrapolation to other species.

Abnormalities, Drug-Induced↗

PubMed1975

The mechanism of ferrocytochrome C oxidation by a horseradish isoperoxidase.

The oxidation of ferrocytochrome c catalysed by highly purified horse-radish isoperoxidase P2 was studied kinetically. To take into account the low turnover number of the enzyme and the tendency to autocatalytic oxidation of ferrocytochrome c, experimental conditions were used which prevented us from using the steady-state treatment. According to kinetic results reported by several authors, a kinetic scheme involving a ternary complex between the enzyme and the substrates was postulated and simulated on a hybrid computer. By assuming that the interaction of peroxidase with hydrogen peroxide is much faster than the interaction with ferrocytochrome c, one can verify that this scheme explains the fact that initial velocity does not vary in relation to the hydrogen peroxide concentration and that a sudden change of slope occurs in the kinetic curve for an initial hydrogen peroxide/ferrocytochrome c ratio lower than 0.5.

Computers↗

PubMedDate not supplied

A hybrid machine model of rice blast fungus, Magnaporthe grisea.

The fungus, Magnaporthe grisea (Rice blast fungus) is a major agricultural problem affecting rice and related food crops. The way that the fungus invades the host plant and propagates itself is a very important scientific problem and recent advances in research into the genetic basis of these processes can be used to build a simple partial model using hybrid computational modelling techniques. The possible potential benefits of doing this include the use of computer simulation and automated analysis through techniques such as model checking to understand the complex behaviour of such systems. The example is a metaphor for the process of trying to integrate and understand much of the vast amounts of genomic and other data that is being produced in current molecular biology research.

Magnaporthe↗

PubMed1991

What's new in cytostatic drug resistance and pathology.

A major problem in cytostatic treatment of malignant tumors is the development of chemoresistant cell clones. An increased understanding of chemoresistance related mechanisms, improved methods for the detection and localization of resistant cell populations including predictive conclusions on the effectiveness of cytostatic drugs would contribute to the advancement of anti-tumor strategies. This paper reviews current concepts suggested for the development of cellular resistance to natural product drugs (anthracyclines, Vinca alkaloids, epipodophyllotoxines, antibiotics; so-called multidrug resistance substances), alkylating agents (nitrosureas, busulfan and mitomycin C), heavy metal compounds (cisplatin) and antifolates (5-fluorouracil, methotrexate) and describes the role of drug transporting and binding proteins (P-170-glycoprotein), detoxifying enzymes (glutathion-S-transferase, dihydrofolate reductase), DNA repair enzymes (topoisomerase I and II, polymerase alpha and beta), and genomic alterations (amplification, double minutes and homogeneous staining regions) due to resistance. It is focussed on the employment of morphological methods (light microscopy, immunocytochemistry, electron microscopy, fluorescence analysis, in situ hybridization, computer aided morphometric analysis) which will help to detect resistant cell clones in tumor biopsies. First correlations between histological data and clinical course will be reported. In the future, the morphological determination of chemoresistance may play an important role in applied functional tumor pathology.

Alkylating Agents↗

PubMed1982

Caffeine disposition after oral doses.

Caffeine (TMX) disposition was studied in mean after 1, 5, and 10 mg/kg in water, as mocha coffee (1.54 mg/kg) and as a soft drink (0.22 mg/kg). TMX and its metabolites were analyzed in plasma and urine by high-pressure liquid chromatography. The design permitted confirmation of most of the partial results in various experimental settings and contributed new data on the metabolic disposition of TMX, with specific reference to main dimethylxanthine metabolite found in plasma, paraxanthine (1,7-dimethylxanthine). Different analysis methods were compared for the calculated parameters (absorption and elimination rate constants and renal clearance)to assess the consistency of results. The kinetics of TMX and of its dimethylated metabolites in plasma were described with a model that used an analogdigital hybrid computing system. In addition to providing a comprehensive profile of TMS disposition in the healthy adult, the results indicate tha TMX exhibits dose-independent kinetics at the levels at which man normally takes TMX.

Administration, Oral↗

PubMed1986

Model systems for pharmacokinetics of steroid drugs subject to enterohepatic circulation.

A number of drugs including steroid hormones undergo enterohepatic circulation (EHC) which influences the drug disposition parameters. EHC of drugs leads to prolonged drug exposition which may enhance the risk of liver incompatibility. The extent of EHC expressed by the reabsorption rate of a given drug is of interest from the clinical and toxicological point of view. A two-compartment model with an additional time lag was realized by a hybrid computer system to study the influence of EHC on the shape of plasma concentration-time profiles and pharmacokinetic parameters. Reabsorption rates of potential steroid drugs were calculated by model-simulation and the results compared with the experimentally found ones. Although the lag time model is only a simplified approximation to the underlying physiological processes it reflects sufficiently the pharmacokinetic profile of steroid drugs subject to EHC.

Animals↗

PubMed2005

Modeling the flow of fluid/particle mixtures in microchannels: encapsulating nanoparticles within monodisperse droplets.

We develop a hybrid computational approach for simulating mixtures of binary fluids and mobile, submicron particles. The model couples a lattice Boltzmann method for the binary fluid with a Brownian dynamics model for the particles. The particles can exhibit preferential wetting interactions with the different components of the fluid. As an illustration of the method, we carry out simulations in two dimensions to compare the spinodal decomposition of a pure binary fluid with the phase separation of binary blends that contain either fixed or mobile particles. We then isolate conditions where the flow of a binary fluid/particle mixture past surfaces with well-defined asperities leads to the formation of monodisperse droplets, which encapsulate the nanoparticles. The findings provide guidelines for creating multiphase emulsions with well-controlled morphologies.

Journal Article↗

PubMed1979

Coupling interval, exit block, and periodicity of ventricular parasystolic rhythm.

The electrocardiograms in this study of parasystolic rhythm were tape recorded and then analysed with a special purpose hybrid computer. The rate of appearance of specific inter-ectopic intervals was shown to change significantly with small changes in either the sinus or parasystolic pacemaker period. Natural changes in the period of the ectopic pacemakers were observed over several hours. Changes amounting to 14% within 10 min and 18% overall were observed in one patient, and a gradual lengthening of 10% over 3 h in another. A previously undescribed form of exit block has been discovered in one patient where the block remained active for a given time only after propagation from the parasystolic focus. Different interectopic intervals were shown to contribute to specific and restricted coupling interval locations in diastole. Hence this form of exit block, by preventing some inter-ectopic intervals from propagating, limited the locations in diastole in which parasystolic ectopic complexes could appear. In this case later diastolic complexes were inhibited and hence fusion complexes were completely absent. Parasystolic rhythm, with and without the exit block described, was simulated successfully by a digital computer. The simulations aided our understanding of the clinical data.

Aged↗

PubMed1982

Sleep spindles: pharmacological effects in humans.

In the present paper we summarize the effects of a variety of drugs on sleep spindle activity in humans. The data are derived from 16 studies conducted in our laboratories during the past several years. The Sleep Analyzing Hybrid Computer was utilized to score each record for sleep stage and spindle activity. To the best of our knowledge, this collection of data is the largest currently available on the relationship between drug administration and standardized sleep spindle parameters in normal human subjects. Ten of the studies are dose-response evaluations. We consider this design a powerful and useful approach for basic sleep pharmacology research. Marked spindle enhancement was produced by flurazepam. WE-941 (a new benzodiazepine hypnotic), methaqualone, and secobarbital. Smaller differences were found for atropine, scopolamine, and caffeine. The results are discussed with respect to drug-class differences, sleep induction properties, the current literature, and the benzodiazepine hypothesis. Some of our future research plans with respect to spindle pharmacology also are presented.

Atropine↗

PubMed1982

Impedance loading servo pump system for excised canine ventricle.

To investigate ventricular-arterial system interaction, we have developed a hybrid-computer-controlled impedance loading servo pump system that enables us to impose a simulated arterial hydraulic impedance on an excised canine ventricle. An analog computer programmed to simulate a three-element Windkessel model of the arterial system computes instantaneous aortic flow from the instantaneous ventricular pressure. The time integral of this flow is used to command a volume servo pump system that controls the instantaneous ventricular volume. All parameter values in the loading system are controlled by a digital computer. The actual impedance spectrum generated by the system was reasonably close to that expected from the arterial model. The unique features of this system are the following. 1) The instantaneous volume of the ventricle, which is crucial information, can be measured. 2) If needed, the arterial impedance model can easily be reprogrammed to generate more complex impedance spectra. 3) The vascular parameters can be made nonlinear or time varying through the digital computer control.

Animals↗

PubMed1979

Clinical pharmacokinetics of nitroxoline.

14C-Nitroxoline was given orally to the rats, and its distribution as well as plasma and bile levels were determined autoradiographically and by the aid of radioactivity measurements, respectively. Nitroxoline was also given to the human volunteers orally and intravenously in three various doses and the corresponding urine concentrations of unconjugated and conjugated nitroxoline were determined spectrophotometrically. A pharmacokinetical model was generated on the basis of the results. The curve fitting procedure between total nitroxoline cumulative quantities in urine and the model response simulated on analog-hybrid computer enabled the evaluation of the validity of the chosen model as well as of the identification of its parameters.

Adult↗

PubMed2002

[Genomic structure of low density lipoprotein receptor related protein 5 gene].

OBJECTIVE: To determine the genomic structure of low density lipoprotein receptor related protein 5 (LRP5) gene. METHODS: cDNA sequence encoding LRP5 was used to screen genomic clones containing LRP5 gene by computer hybridization approach. By comparing the cDNA sequence of LRP5 with the genomic sequences, the genomic structure of LRP5 was determined, and then it was conformed by amplifying and sequencing the sequences of exons and splicing junction. RESULTS: The genomic sequence of LRP5 gene was 131.6 kb in length, containing 23 exons and 22 introns. Three single nucleotide polymorphisms were detected within the coding sequences of LRP5 gene, namely A459G in exon 2, C2220T in exon 10 and G4416C in exon 21. Four polymorphic markers, D11S1917, D11S4087, D11S1337 and D11S4178, located in the 5' flank sequence, introns 1, 4, and 13 of the LRP5 gene, respectively. CONCLUSION: The characterization of genomic structure of LRP5 gene allows the investigators to detect disease-causing mutation within the gene and further study the function of LRP5 gene.

Base Sequence↗

PubMed1991

Frequency of urination and its effects on metabolism, pharmacokinetics, blood hemoglobin adduct formation, and liver and urinary bladder DNA adduct levels in beagle dogs given the carcinogen 4-aminobiphenyl.

The human urinary bladder carcinogen, 4-aminobiphenyl (ABP), is known to undergo hepatic metabolism to an N-hydroxy arylamine and its corresponding N-glucuronide. It has been proposed that these metabolites are both transported through the blood via renal filtration to the urinary bladder lumen where acidic pH can facilitate the hydrolysis of the N-glucuronide and enhance the conversion of N-hydroxy-4-aminobiphenyl (N-OH-ABP) to a reactive electrophile that will form covalent adducts with urothelial DNA. Blood ABP-hemoglobin adducts, which have been used to monitor human exposure to ABP, are believed to be formed by reactions within the erythrocyte involving N-OH-ABP that has entered the circulation from the liver or from reabsorption across the urothelium. To test these hypotheses directly, experimental data were obtained from female beagles given [3H]ABP (p.o., i.v., or intraurethrally). [3H]N-OH-ABP (i.v. or intraurethrally), or [3H]N-OH-ABP N-glucuronide (i.v.). Analyses included determinations of total ABP in whole blood and plasma, ABP-hemoglobin adducts in blood erythrocytes, ABP and N-OH-ABP levels (free and N-glucuronide) in urine, urine pH, frequency of urination (controlled by urethral catheter), rates of reabsorption of ABP and N-OH-ABP across the urothelium, and apparent volumes of distribution in the blood/tissue compartment. The major ABP-DNA adduct, N-(guan-8-yl)-4-aminobiphenyl, was also measured in urothelial and liver DNA using a sensitive immunochemical method. An analog/digital hybrid computer was then utilized to construct a multicompartmental pharmacokinetic model for ABP and its metabolites that separates: (a) absorption; (b) hepatic metabolism and distribution in blood and tissues; (c) ABP-hemoglobin adduct formation; (d) hydrolysis and reabsorption in the urinary bladder lumen; and (e) excretion. Using this model, cumulative exposure of the urothelium to free N-OH-ABP was simulated from the experimental data and used to predict ABP-DNA adduct formation in the urothelium. The results indicated that exposure to N-OH-ABP and subsequent ABP-DNA adduct formation are directly dependent on voiding frequency and to a lesser extent on urine pH. This was primarily due to the finding that, after p.o. dosing of ABP to dogs, the major portion of the total N-OH-ABP entering the bladder lumen was free N-OH-ABP (0.7% of the dose), with much lower amounts as the acid-labile N-glucuronide (0.3% of the dose).(ABSTRACT TRUNCATED AT 400 WORDS)

Aminobiphenyl Compounds↗

PubMedDate not supplied

A pharmacokinetic model to predict exposure of the bladder epithelium to urinary N-hydroxyarylamine carcinogens as a function of urine pH, voiding interval, and resorption.

Estimation of urinary levels of N-hydroxyarylamines, which are believed to be ultimate carcinogens for the bladder epithelium, has been complicated by the rapid resorption of these metabolites across the bladder wall and by their formation in the urine upon hydrolysis of N-hydroxyarylamine N-glucuronide conjugates. Therefore, a three-compartment pharmacokinetic model was developed with an analog-digital hybrid computer to separate absorption, metabolism, and distribution in the whole animal from events in the bladder lumen (deposition, hydrolysis, and resorption). The total bladder exposure to the carcinogen, N-hydroxy-2-naphthylamine, was then simulated from experimental data; and urine pH and voiding interval, both of which differ widely among species, were tested as variables. For humans and dogs, urine pH was found to be considerably more acidic than monkeys or rats; while voiding intervals in rats were considerably shorter than in monkeys, dogs, or humans. The relative species susceptibilities, indicated by the model as total bladder exposure to the N-hydroxyarylamine metabolite under conditions of normal urine pH and frequency of micturition for each species, were in the order: human greater than or equal to dog greater than monkey greater than rat. This is consistent with the reported carcinogenic potency of 2-naphthylamine in these species and suggests that urine pH and voiding interval are important determinants in aromatic amine-induced bladder cancer.

Absorption↗

PubMed1982

Digital and sampled-data control of arterial blood pressure during halothane anesthesia.

A control system that maintains mean arterial pressure (MAP) at a desired level by automatically controlling halothane input has been developed. The control system is a discrete, digital type and is implemented with a small desk-top programmable calculator. Essentially, if MAP decreases, the inspired concentration of halothane will decrease; if MAP increases, the system will compensate by increasing inspired halothane concentration. The control system was tested in two ways: with a hybrid computer model of uptake and distribution of halothane and with dog experiments. The results indicate that (a) the model can be used to predict the response of the animal-anesthesia machine control system, and (b) the proposed algorithm is successful in controlling one anesthetic agent with one physiologic variable.

Anesthesiology↗