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Biomedical subjects

W Kessler

Publications and source records attributed to W Kessler.

At least 37 records · Page 2Linked to original sources
PubMed1997

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.

Contents of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of 16 further congeners--polychlorinated dibenzodioxins and dibenzofuranes (PCDD/PCDF)--were determined in lipids of adipose tissue and of livers of 3 stillborns and of 17 infants (0.43-44 weeks old) who died from sudden infant death syndrome. International toxic equivalents (I-TEq) calculated for the sum of TCDD together with all of the 16 congeners (1.55-29.63 ng/kg lipids of adipose tissue, n = 20; 2.05-57.73 ng/kg liver lipids, n = 19) were within the range of or lower than the values published for adults. TCDD concentrations in lipids of breast-fed infants were higher (0.38-4.1 ng/kg lipids of adipose tissue, n = 9; 0.49-3.9 ng/kg liver lipids, n = 8) compared to non breast-fed subjects (0.16-0.76 ng/kg lipids of adipose tissue, n = 8; 0.29-0.71 ng/kg liver lipids, n = 7). Neither I-TEq values nor TCDD concentrations exceeded values published for adults. Since even in stillborns PCDD/PCPF were found (I-TEq, 9.70-10.83 ng/kg lipids of adipose tissue, 6.17-8.83 ng/kg liver lipids; TCDD, 1.3-2.1 ng/kg lipids of adipose tissue, 0.76-1.5 ng/kg liver lipids; n = 3), transplacental exposure has to be deduced. All of the findings concerning TCDD concentrations in the organism become intelligible on the basis of a physiological toxicokinetic model which was developed to describe the body burden of TCDD for the entire human lifetime in dependence of TCDD uptake from contaminated nutrition. The model reflects sex and age dependent changes in the following parameters: body weight, volumes of liver, adipose and muscle tissue, food consumption, and excretion of faeces. TCDD is supposed to be taken up orally, to be distributed freely in lipids of the organism and to be eliminated unchanged by excretion in lipids of faeces as well as by metabolism in the liver. The model was used to predict the half-life of elimination of TCDD (4 months in newborns increasing to approximately 5 years in adults) and concentrations of this compound in lipids of adipose tissue, blood, liver and faeces at different ages. Furthermore, the influence of breast-feeding on the TCDD burden of a mother, her milk and her child was simulated. The model was validated by means of own data gained in adipose tissue and livers of infants and also using a series of values measured by other authors in mother's milk and in tissues and faeces of infants and adults. Predictions as well as experimental findings demonstrate a distinct increase in the TCDD body burden of breast-fed infants. Generally, it can be concluded for the excretion of unchanged, non-volatile, non protein bound highly lipophilic compounds that their half-life is short in infants (approximately 5 months) and increases to approximately 10 years reached between 40 and 60 years of age.

Adipose Tissue↗
PubMed1997

Preclinical evaluation of biotin labeling for red cell survival testing.

Biotin labeling of red cells was tested in dogs as a preclinical study for cell survival. Red cells were labeled with either spacered Biotin-X-NHS (BxNHS) or water-soluble biotin compounds. After reinfusion, biotinylated red cells were detected in small blood samples (5 microliters) with flow cytometry. Improved BxNHS labeling allows an easy detection of positive red cells for almost 100 days, whereas labeling with watersoluble compounds-despite strong labeling during the first days-results in a decrease of label, which prevented a discrimation between labeled and negative cells after about 4 weeks. When biotin labeling of red cells was compared with 51Cr labeling, slopes of red cell survival were quite similar after the latter were corrected for elution. Survival slopes were linear, and the mean survival time was t = 93 d. In two blood-donor dogs the slopes of red cell survival where log linear and the mean survival time was t = 45 d. In conclusion, BxNHS, but not the water-soluble biotin compounds, is a good nonradioactive, nontoxic alternative for red cell survival studies. No health hazards are to be expected from the very low dose of Dimethylformamide, which is used as a solvent for biotin-x-NHS.

Animals↗
PubMed1997

Visualization of the coronary arteries in three-dimensional reconstructions using respiratory gated magnetic resonance imaging.

OBJECTIVE: To assess the applicability of respiratory-gated magnetic resonance coronary angiography, combined with three-dimensional image reconstruction, for visualizing the coronary arteries. METHODS: Twenty subjects (three healthy volunteers and 17 patients without stenoses detected by coronary angiography) were investigated. Magnetic resonance imaging was performed in a 1.5 T scanner using ECG-triggered gradient-echo sequences to acquire a volume data set consisting of 24-48 contiguous axial cross-sections of the heart (2 mm slice thickness, 1.17 mm x 1.17 mm in-plane resolution). Navigator-echo-based retrospective respiratory gating was used to minimize respiratory motion artifacts. Three-dimensional reconstructions of the heart were rendered using surface-display techniques. The length of the visualized coronary arteries was measured in curved multiplanar reconstructions. RESULTS: In the three-dimensional reconstructions, the left main artery (LMA) and left anterior descending artery (LADA) were visualized in 17 cases, the left circumflex artery (LCXA) in 15, and the right coronary artery (RCA) in 16 cases. Vessel continuity was uninterrupted in all 17 cases for the LMA, in 14 for the LADA, eight for the LCXA, and 13 for the RCA. The mean lengths of the visualized vessels were 14 +/- 7 mm for the LMA, 65 +/- 13 mm for the LADA, 45 +/- 16 mm for the LCXA, and 37 +/- 26 mm for the RCA. Reasons for impaired visibility of the LCXA and RCA were poor image quality due to there being a low contrast:noise ratio, motion artifacts, and incomplete coverage by the imaging volume. CONCLUSIONS: Navigator-echo-based magnetic resonance imaging is a promising technique for investigating the coronary arteries. Acquisition of a volume data set permits three-dimensional displays of the coronary vessels.

Case-Control Studies↗
PubMed1997

[A survey on vaccine efficacy in the city of Bongor (Chad) and its operational consequences for the vaccination program].

A measles epidemic occurred in the city of Bongor, Chad, from 22 September 1993 to 26 June 1994. A total of 792 patients were hospitalized, with a case fatality rate of 5.2%. After the epidemic, the district management team evaluated the expanded programme on immunization (EPI). Through a cluster survey the attack rate was estimated to be 29.1% (95% confidence interval (CI) = 20.4-37.8%) for the age group 12-59 months (n = 206). For this same age group, the measles immunization coverage was estimated to be 44.2% (95% CI = 34.6-53.8%) and the vaccine efficacy 9.5% (95% CI = 0-41.5%). Several flaws in the logistic handling of the vaccines and especially in the cold chain were identified. These results indicated a serious management problem in the EPI, which the district team then immediately started to rectify. The method used to estimate the immunization coverage and efficacy in the study is rapid and low cost. Also, it is feasible at the district level and permits identification of management problems in the EPI.

Age Factors↗
PubMed1996

Toxicokinetics of isoprene in rodents and humans.

A physiological toxicokinetic model (PT model) was developed for inhaled isoprene in mouse, rat and man. Partition coefficients blood:air and tissue:blood were determined in vitro by a headspace method. Parameters of a saturable isoprene metabolism in B6C3F1 mice, Sprague-Dawley rats and volunteers were obtained from gas uptake experiments in closed systems, analyzed by means of a two-compartment model. Incorporation of these parameters into the PT model revealed that isoprene was metabolized not only in the liver but also in extrahepatic organs. Endogenous production of isoprene in man was quantified from experiments with volunteers breathing into a closed system. The PT model was validated for mice, rats and humans by comparing simulated values with data determined by other authors.

Adult↗
PubMed1995

The 1990 meningococcal meningitis epidemic of Sarh (Chad): how useful was an earlier mass vaccination?

A large outbreak of meningococcal meningitis (Serogroup A) occurred in southern Chad in 1990. We describe the epidemic in the town of Sarh, where a mass vaccination against meningococcal meningitis had taken place two years before, in 1988 (estimated coverage: 66%). Early warning that an epidemic was imminent was given at the end of February, following more than 15 recorded cases per 100,000 population on 3 consecutive weeks. This threshold proved to be adequate to predict the outbreak. A total of 721 cases were recorded at Sarh hospital and at a nearby health centre. Direct agglutination tests confirmed that Neisseria meningitis serogroup A was the only causative agent. The overall incidence rate in this population of 80,000 was 0.9%. The highest weekly incidence rate was 186 cases per 100,000 population. The mean age of the patients was 12.6 years and age-specific incidence rates ranged from 0.23% to 1.42%. The male/female sex ratio was 1.36. Overall, the mortality among hospitalized patients was 7.9%. Mortality increased during the epidemic. The major risk factor for dying was the delay until reaching hospital. Only 4 out of 29 interviewed parents said that their child had been vaccinated two years before. Among adult patients this proportion was 12/38 (32%). Because of the small numbers and because of the impossibility to check the vaccination records it was not possible to assess precisely the impact of earlier mass vaccination. However, the previous mass vaccination did not prevent this major epidemic and its impact is likely to have been unimportant.

Adolescent↗
PubMed1995

Heritable translocations induced by inhalation exposure of male mice to 1,3-butadiene.

Previously, we reported that dominant lethal mutations were induced in spermatids after inhalation exposure of male (102/El x C3H/El)F1 mice to 1300 ppm of 1,3-butadiene on 5 days for 6 h per day (exposure dose 39,000 ppm h). The same inhalation exposure was given to male C3H/El inbred mice which were mated to inbred line 102/El females 8-14 d after the end of exposure. Male and female F1 hybrid progeny were tested for the presence of heritable translocations by observation of litter sizes and by cytogenetic analyses in meiotic and somatic cells. 1,3-Butadiene induced heritable translocations in late spermatids. The translocation frequency after 1,3-butadiene exposure to 39,000 ppm h was 2.7% (16 translocation heterozygotes among 559 F1 offspring). This frequency is 54 times higher than the historical control frequency (0.05%; 5 translocation heterozygotes among 9500 F1 offspring). Thus, 1,3-butadiene causes heritable germ cell effects in mice.

Administration, Inhalation↗
PubMed1995

Toxicokinetic models for volatile industrial chemicals and reactive metabolites.

Two approaches of compartmental toxicokinetic modeling of gaseous compounds are presented which are suitable for kinetic analysis of concentration-time data measured in the air of closed exposure systems. The first approach is based on a two-compartment model with physiological gas uptake, the second on a physiologically-based toxicokinetic model. Both models can be used for the description of inhalation, accumulation, exhalation and metabolism of gaseous compounds together with the toxicokinetics of metabolites. Interspecies extrapolation is based on physicochemical, physiological and biochemical parameters. The advantage of the two-compartment model is its limited number of variables and its experimentally easy applicability. Its disadvantage is the impossibility to predict tissue specific concentrations. The advantage of the physiologically-based model is its usability for predictions and for the description of tissue specific concentrations. However, it entails great effort, since a series of parameters has to be determined before meaningful model calculations can be carried out.

Animals↗
PubMed1994

Mutagenicity of 1,3-butadiene inhalation in somatic and germinal cells of mice.

Inhalation exposure of mice to 50, 200, 500 or 1300 ppm of 1,3-butadiene for 6 h per day for 5 consecutive days caused micronuclei in mouse bone marrow and peripheral blood erythrocytes. The dose response was non-linear. The slope of the curve flattened with increasing exposure concentration. Coat color spots were found in the mouse spot test after exposure of pregnant females on pregnancy days 8-12 to 500 ppm of 1,3-butadiene. Dominant lethal mutations were induced in spermatozoa and late spermatids after exposure of male mice to 1300 ppm with the 5-day exposure regimen. Thus, in the mouse 1,3-butadiene is a somatic and germ cell mutagen.

Administration, Inhalation↗
PubMed1994

The AVL-mode: a safe closed loop algorithm for ventilation during total intravenous anesthesia.

The Adaptive Lung Ventilation Controller (ALV-Controller) represents a new approach to closed loop control of ventilation. It is based on a pressure controlled ventilation mode. Adaptive lung ventilation signifies automatic breath by breath adaptation of breathing patterns to the lung mechanics of an individual patient. The specific goals are to minimize work of breathing, to maintain a preset alveolar ventilation and to prevent the occurrence of intrinsic PEEP. We ventilated 5 patients undergoing major abdominal procedures using ALV. ALV was tolerated well in all patients. Alveolar ventilation was preset between 5500 and 6500 ml/min. Serial dead space (Vds) and respiratory time constant (resistance * compliance) of the patients ranged from 104 to 164 ml and 0.74 to 1.5 s, respectively. The resulting respiratory rates ranged from 8 to 15 breaths/min, the tidal volumes from 542 to 829 ml, and the applied maximum inspiratory pressures from 15.5 to 18.9 mbar. Expiratory time was sufficient in all cases to allow complete expiration and to avoid intrinsic PEEP. I: E-relations ranged from 0.36 to 0.76. After a step change in alveolar ventilation rise times of the breathing patterns were recorded at values from 7 to 67 s. Overshoot did not reach statistic significance compared to the variations in breathing patterns which occurred during stable measuring periods. Accuracy of the controller was high (27.8 ml difference between preset and applied alveolar ventilation in the mean) and stability was sufficient for clinical purposes. The results of this preliminary study show that the breathing patterns selected by the controller were well adapted to the lung mechanics of the patients. Respiratory rates, inspiratory pressures and tidal volumes were within the clinically acceptable range in all patients.

Adult↗
PubMed1994

Styrene-7,8-oxide in blood of workers exposed to styrene.

A field study was carried out on 13 workers exposed to styrene vapors at time-weighted average concentrations between 10 and 73 ppm. The reactive intermediate styrene-7,8-oxide was determined in blood samples using a direct gas chromatographic method. Styrene-7,8-oxide concentrations were in the range between 0.9 and 4.1 micrograms/l blood. Linear correlations were found between styrene-7,8-oxide in blood and styrene in ambient air and blood. For an exposure concentration of 20 ppm styrene (German MAK value) a steady-state level of about 1 microgram styrene-7,8-oxide/l blood was calculated.

Adult↗
PubMed1993

Species-specific pharmacokinetics of styrene in rat and mouse.

The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 mumol/(h.kg) and 625 mumol/(h.kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil:air and water:air which have been determined in vitro at 37 degrees C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K'st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K'st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K'st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K'st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1993

A pharmacokinetic model to describe toxicokinetic interactions between 1,3-butadiene and styrene in rats: predictions for human exposure.

Co-exposure to vapours of 1,3-butadiene and styrene occurs in the styrene-butadiene polymer manufacturing industry. Both compounds are biotransformed during a first step by cytochrome P450-dependent mono-oxygenases to epoxides--intermediates which are proven carcinogens. In a previous publication, we reported that metabolism of butadiene in rats was inhibited by simultaneous exposure to styrene, whereas butadiene had no effect on the kinetics of styrene. In order to translate these results into conditions of human exposure, we developed a physiologically based pharmacokinetic (PBPK) model, which is presented here. Maximal metabolic rates (Vmax) and Ostwald's partition coefficients were obtained using liver microsomes and tissues from rat and man. Apparent Michaelis (Km) and inhibition (Ki) constants were derived from previously published data on rats and were considered to be species-independent. The model was used to simulate human exposure to atmospheric mixtures of 5 and 15 ppm butadiene with 0.20 and 50 ppm styrene. It predicts that the presence of styrene significantly inhibits butadiene metabolism in man: At exposures up to 15 ppm, the amounts of butadiene metabolized can be expected to be reduced to 81 and 63% with co-exposure to styrene at 20 and 50 ppm, respectively.

Administration, Inhalation↗
PubMed1992

Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P.

A broad mixture of inflammatory mediators ("inflammatory soup") was used to investigate the responsiveness of primary afferents from rat hairy skin in an in vitro skin-saphenous nerve preparation. In addition, a conditioning effect of the tachykinin substance P on chemosensitivity of nociceptors was examined. Inflammatory soup (IS) was made up in synthetic interstitial fluid from bradykinin, serotonin, histamin and prostaglandin E2 (all 10(-5) M). In addition, the potassium and the hydrogen ion concentration (7 mM, pH 7.0) and the temperature (39.5 degrees C) were elevated. The latter agents, in a control solution, did not excite nociceptors (n = 5). IS was repeatedly superfused over the receptive fields for 5 min at 10 min intervals; substance P (SP 10(-6) and 10(-5) M) was applied during the last 5 min of the interval and during the subsequent IS stimulation. IS excited more than 80% of the mechano-heat sensitive ("polymodal") afferents with slowly conducting nerve fibres (n = 72), but none of the low-threshold mechanoreceptive slow and fast conducting units (n = 17). Slow conducting afferents with high mechanical threshold (n = 35) were weakly, and less frequently (< 20%), driven by IS. A majority, but not all, of the responsive units showed tachyphylaxis upon repeated IS application. None, however, lost its responsiveness completely. Conditioning heat stimulation (32-46.5 degrees C in 20 s) did not enhance the subsequent IS response, which may indicate that sensitizing substances normally released by a noxious heat stimulus were already contained in IS. No sensitization to mechanical (von Frey) or heat stimulation could be established in the period after the IS response had subsided and after the washout was completed, respectively. A short-lived sensitization may have been overlooked under these temporal restrictions. Conditioning SP in 10(-5) M but not in 10(-6) M concentration significantly increased the IS response of polymodal C fibres, by 58% on average (n = 14). SP did not excite the units. Comparing with previous data, we conclude that there is a significant synergism between inflammatory mediators, acting to induce more intense and more sustained discharge via many nociceptors than single mediators alone could achieve. Conditioning substance P can further enhance this algogenic action. Mechanisms of interaction and relative contributions of single substances remain to be elucidated.

Animals↗
PubMed1992

Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene.

The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient "body/air" being 0.53 +/- 0.23 (mean +/- SD) and the accumulation factor "body/air" at steady-state being 0.33 +/- 0.13 (mean +/- SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32 +/- 12 nmol/h (mean +/- SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44 +/- 0.19 nmol/kg (mean +/- SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five non-smokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20 +/- 5 pmol/g Hb (mean +/- SD) found in the non-smokers corroborated the steady-state level of 18 +/- 3 pmol/g Hb (mean +/- SD) calculated from the pharmacokinetic approach.

Adult↗
PubMed1991

Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man.

Kinetics of the metabolism of 1,2-epoxybutene-3 (butadiene monoxide) were investigated in liver fractions of mouse, rat, and man. In these species similar enzyme characteristics were found. In microsomes, no NADPH-dependent metabolism of butadiene monoxide was detectable. Epoxide hydrolase activity was found only in microsomes. The Vmax [nmol butadiene monoxide/(mg protein x min)] was 19 in mouse, 17 in rat, and 14 in man and the apparent Km (mmol butadiene monoxide/l incubate) was 1.5 in mouse. 0.7 in rat, and 0.5 in man. Glutathione S-transferase activity was found in cytosol only, revealing first order kinetics in the measured range. The ratio Vmax/Km [(nmol butadiene monoxide x 1)/(mg protein x min x mmol of butadiene monoxide)] was 15 in mouse, 11 in rat, and 8 in man. The data obtained were used to extrapolate on the total rate of butadiene monoxide metabolism for each species in vivo: it was calculated to be 1.3 times higher in mice and 2.3 times lower in man compared to rats, when corrected for body weight.

Animals↗
PubMed1990

Direct determination of styrene-7,8-oxide in blood by gas chromatography with flame ionization detection.

A simple capillary gas chromatographic method is described for direct determination of styrene-7,8-oxide (styrene oxide) in blood samples of 1 ml, with a detection limit of 1 ng/ml. After the addition of 1-phenylpropylene oxide as internal standard, blood samples were extracted with n-hexane, the n-hexane phases were concentrated under nitrogen, and up to 25 microliters of the resulting solution were injected on-column using a retention gap. Separation was carried out on a fused-silica capillary column coupled to a flame ionization detector. Using this method the metabolism of styrene oxide in rat blood was investigated. Concentrations of styrene oxide in the blood of rats exposed to styrene at atmospheric concentrations between 20 and 800 ppm for 3 h at steady-state conditions are reported.

Animals↗