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Biomedical subjects

A Zwart

Publications and source records attributed to A Zwart.

At least 19 recordsLinked to original sources
PubMed2001

Muting of androgen negative feedback unveils impoverished gonadotropin-releasing hormone/luteinizing hormone secretory reactivity in healthy older men.

Plasma bioavailable testosterone concentrations decline in healthy older men without a uniformly commensurate rise in serum LH concentrations, which disparity is consistent with a hypothesis of relative hypogonadotropism. Likewise, preserved gonadotrope responsiveness to exogenous GnRH stimulation, despite an attenuated amplitude of endogenous LH pulses, points to reduced hypothalamic GnRH feedforward signaling in aging males. To appraise GnRH/LH secretory reserve more directly in older men, we have compared daily LH secretion, driven by profound short-term blockade of androgen biosynthesis by oral ketoconazole administration, in nine young (ages, 18-32 yr) and seven older (ages, 60-73 yr) volunteers. The ability to unleash endogenous GnRH-driven LH secretion in response to acute testosterone withdrawal was quantitated by sampling blood every 10 min, for 24 h, followed by high-precision immunoradiometric assay. The resultant serum LH concentration profiles were analyzed by: 1) model-free discrete peak detection (Cluster) analysis; 2) the approximate entropy statistic to quantitate pattern regularity; and 3) 24-h rhythmic (cosinor) analysis. At baseline, mean and integrated (24-h) serum LH concentrations were similar in both age cohorts. However, Cluster analysis established an elevated LH peak frequency [18 +/- 0.86 (older) vs. 13 +/- 1.3 pulses/24 h (young), P = 0.0028] and a reduced incremental LH pulse area [37 +/- 6.9 (older) vs. 106 +/- 20 (young) IU/L x min, P = 0.016] in older men. Approximate entropy calculations also revealed more irregular LH release patterns in older men before intervention (P = 0.00089). Feedback stress, achieved by ketoconazole-induced androgen deprivation, unmasked further neuroregulatory defects in older volunteers, who failed to equivalently increase the: 1) mean (24-h) serum LH concentration [i.e. to 5.0 +/- 0.99 (older men) vs. 9.0 +/- 1.1 (young) IU/L, P = 0.000071]; 2) maximal LH peak height (to 6.1 +/- 1.1 vs. 10.4 +/- 1.2 IU/L, P = 0.00043); 3) incremental LH pulse area (to 41 +/- 8.8 vs. 87 +/- 20 IU/L x min, P = 0.016); 4) interpeak nadir serum LH concentration (to 4.0 +/- 0.77 vs. 7.9 +/- 1.0 IU/L, P < 10(-6)); 5) the quantitable irregularity of LH release (P = 0.00089); and 6) the mesor of 24-h rhythmic LH secretion (P = 0.000062). In summary, experimental imposition of a novel hypoandrogenemic open-loop feedback stressor, for 48 h, to heighten hypothalamic GnRH feedforward drive, unveils impoverished augmentation of LH pulse mass, impaired orderliness of LH release, and diminished 24-h rhythmic LH secretion in older men. The foregoing trilogy of neuroregulatory defects identifies unequivocally attenuated hypothalamo-pituitary reactivity to muting of androgen negative feedback in the aging male.

Adolescent↗
PubMed2000

[A child without edema in spite of albumin deficiency].

During extended investigation of a newborn girl with recurrent respiratory tract infection a continuous elevated blood sedimentation rate was noted together with a normal level of C reactive protein. This abnormality could be explained by analbuminaemia, causing a change in concentration of several other proteins such as transferrin. It was striking that this girl without albumin showed no signs of oedema. This lack of oedema could be explained by a decrease of oncotic pressure in the interstitium. Analbuminaemia is an autosomal recessive disorder. At follow-up the girl was still without complaints after 6 years.

Blood Sedimentation↗
PubMed2000

Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists.

Previous research has shown that beta-adrenoceptor (beta-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines. Aim of this research was to determine whether the effects of beta-agonists on LPS-induced TNFalpha and IL-10 release are influenced by their different stereochemistry. In addition, the role of the beta-AR subtypes was studied. The effect of two stereoisomers of the selective beta2-AR agonist TA2005 [(R,R)- and (S,S)-] on the LPS-induced TNFalpha and IL-10 release by U937 macrophages was compared. The (R,R)-stereoisomer was 277 times more potent in inhibiting the TNFalpha release than the (S,S)-form. The (R,R)-stereoisomer also appeared to be more potent in increasing the IL-10 release. In radioligand binding studies the affinity of (R,R)-TA2005 for the beta-adrenoceptor was 755 times higher than the (S,S)-TA2005 stereoisomer. In addition, the elevation of intracellular cAMP in U937 cells appeared to be stereoselective: (R,R)-TA2005 was more potent in elevating intracellular cAMP. The effect of both stereoisomers on the LPS-induced TNFalpha release could almost completely be antagonized by preincubation with the selective beta2-AR-antagonist ICI-118551. Further evidence that the effect of the beta-agonists is mediated via the beta2-adrenoceptor subtype exclusively was acquired by incubation of U937 cells with selective beta1- and beta3-agonists. None of these receptor subtype agonists showed significant suppressive effect on TNFalpha release. This study provides additional proof that the anti-inflammatory effects of beta2-agonists are mediated via the beta2-adrenoceptor and indicates that these effects are highly dependent on the stereoselectivity of the ligand.

Adrenergic beta-Agonists↗
PubMed1995

Repeated measurement of respiratory function and bronchoconstriction in unanesthetized mice.

A noninvasive forced oscillation technique was used to determine respiratory function in unanesthetized and spontaneously breathing mice. Pseudorandom noise pressure variations in a frequency range of 16-208 Hz were applied to the body surface, and the flow response was measured at the nose. From the pressure-flow relationship, respiratory transfer impedance was calculated. Study of intra-animal variability on a short- and a long-term basis revealed that the real part of respiratory transfer impedance was reproducible within 9%. The imaginary part appeared less reproducible (within 22%). Furthermore, bronchoconstrictive responses were investigated and analyzed by evaluation of respiratory resistance as measured at 16 Hz (Rrs16). During the first 15 min after ovalbumin challenge in ovalbumin-sensitized mice, Rrs16 was significantly increased [49 +/- 7% (SE)]. Inhalation of methacholine in untreated mice induced an increase in Rrs16 of 75 +/- 16% (SE). In saline-challenged animals, no significant changes were observed. This method enables evaluation of long-term respiratory function in mice and appeared to be a sensitive measure for bronchoconstriction.

Administration, Inhalation↗
PubMed1994

Airway responses during and directly after single-time exposure to ozone.

Breathing pattern and lung mechanical parameters were measured in 7 female Wistar rats (ca. 200 g) during exposure to 1.0 (n = 5) or 1.3 (n = 2) ppm ozone in air for 2 h and during a 2-h post-exposure observation period. Changes in breathing pattern showed a gradual decrease from 3 to 2 Hz at constant minute ventilation during the first hour of exposure. During the second hour of exposure 6 out of 7 animals developed post-expiratory apnoea (resulting from interstitial oedema), which took about half the breathing cycle concomitant with a decrease of ca. 50% of the minute volume. The breathing pattern returned to normal at the end of the post-exposure observation period. Lung mechanical properties were determined by the forced oscillation method in the restrained, unanaesthetized, spontaneously breathing rats. Airway resistance, inertia and compliance were calculated at regular time intervals during exposure and during the observation period. Overall resistance increased significantly by a factor of 1.76 (P < 0.05); compliance decreased significantly by a factor of 3 (P < 0.05). Airway inertia showed individual increases or decreases. The mean increase (1.23) did not reach the level of significance. At the end of the exposure period the stable changes were interrupted by short-lasting periods of bronchospasms during which the airway resistance increased by a factor of 8 or more.

Airway Resistance↗
PubMed1993

A new ventilation inhomogeneity index from multiple breath indicator gas washout tests in mechanically ventilated patients.

OBJECTIVES: a) To determine the validity of a new method to analyze indicator gas washout tests on mechanically ventilated patients. This method takes into account the difference between the end-expiratory gas fraction and the mean gas fraction in the lung and provides the end-expiratory lung volume and a new index of ventilation inhomogeneity called volumes regression index. b) To determine the validity of this index as a predictor of chronic obstructive pulmonary disease. c) To compare this index with the moment ratio index and Becklake index. DESIGN: Prospective study of diagnostic test. Criterium standards: Closed-circuit indicator gas dilution technique and Tiffeneau index. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: A total of 38 mechanically ventilated postoperative patients, divided into two groups: the obstructive group (n = 21) and the nonobstructive group (n = 17), based on their preoperative lung function. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: a) The mean coefficient of variation of all lung volume measurements in a group of nine healthy volunteers was 5%, and the difference between this technique and the closed-circuit helium dilution measurements was -2 +/- 5%. In patients, the mean coefficient of variation of the lung volume measurements was 3.5%. The volumes regression index was measured as 0.02 +/- 0.04 in a dummy lung, 0.37 +/- 0.08 in the healthy volunteers, 0.64 +/- 0.23 in the nonobstructive patients, and 1.1 +/- 0.3 in the obstructive patients. The volumes regression index provided a better correlation (r2 = .46) with preoperatively determined Tiffeneau index than the Becklake index (r2 = .11) or the moment ratio index (r2 = .18). CONCLUSION: The proposed technique provides a means for accurate measurement of the end-expiratory lung volume and the amount of ventilation inhomogeneity in mechanically ventilated intensive care unit patients.

Adult↗
PubMed1992

Multi-compartment model to study the effect of air-blood and blood-tissue partition coefficients on concentration-time-effect relationships.

The influence of the air-blood (lambda) and blood-tissue partition coefficients of substances on the concentration-time-effect relationship E = [aCnT]b was studied by model simulation of uptake and distribution of gases. The model consisted of a lung compartment and four tissue compartments. Rat and human model parameters were obtained from physiological data, and substance-dependent variables. The observable effect E (righting reflex, mortality, etc.) for directly acting systemic agents was supposed to be related to the (arbitrarily chosen) concentration of the substance in the arterial blood or in the liver compartment. We conclude that for a directly acting systemic agent n greater than or equal to 1. If n less than 1 other mechanisms such as metabolism must be incorporated in the model which, however, should not be excluded when n greater than or equal to 1. If the observable effect is related to arterial concentration of the substance, n increases with decreasing lambda. If the liver concentration is related to the observable effect, man and rat may behave quite differently. This has major consequences for the extrapolation of animal results to the human situation in risk assessment.

Air↗
PubMed1992

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 testing.

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40-50) as the conventional LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1992

Respiratory transfer impedance and derived mechanical properties of conscious rats.

A setup is described for measuring the respiratory transfer impedance of conscious rats in the frequency range 16-208 Hz. The rats were placed in a restraining tube in which head and body were separated by means of a dough neck collar. The restraining tube was placed in a body chamber, allowing the application of pseudorandom noise pressure variations to the chest and abdomen. The flow at the airway opening was measured in a small chamber connected to the body chamber. The short-term reproducibility of the transfer impedance was tested by repeated measurements in nine Wistar rats. The mean coefficient of variation for the impedance did not exceed 10%. The impedance data were analyzed using different models of the respiratory system of which a three-coefficient resistance-inertance-compliance model provided the most reliable estimates of respiratory resistance (Rrs) and inertance (Irs). The model response, however, departed systematically from the measured impedance. A nine-coefficient model best described the data. Optimization of this model provided estimates of the respiratory tissue coefficients and upper and lower airway coefficients. Rrs with this model was 13.6 +/- 1.0 (SD) kPa.l-1.s, Irs was 14.5 +/- 1.3 Pa.l-1.s2, and tissue compliance (Cti) was 2.5 +/- 0.5 ml/kPa. The intraindividual coefficient of variation for Rrs and Irs was 11 and 18%, respectively. Because most of the resistance and inertance was located in the airways (85 and 81% of Rrs and Irs, respectively), the partitioning in tissue and upper and lower airway components was rather poor. Our values for Rrs and Irs of conscious rats were much lower and our values for Cti were higher than previously reported values for anesthetized rats.

Airway Resistance↗
PubMed1991

PDPS: a pulmonary data processing system for assessment of gas exchange properties by multiple gas wash-out.

A data acquisition and processing system for the analysis of inert gas wash-out tests is described. The described system is in clinical use on spontaneously breathing patients as well as on mechanically ventilated Intensive Care patients. It combines several analysis techniques with an aim to provide a deeper insight into the nature of existing ventilation inhomogeneity than the individual techniques alone can provide. The signals measured are the respiratory flow, the fractions of one or two indicator gases washing out and the fractions of the metabolic gases oxygen and carbon dioxide. Analysis of these signals provides information concerning the end-expiratory lung-volume, distribution of ventilation and perfusion in the lung, the role of diffusion in the ventilation process and the metabolic oxygen uptake and CO2 release. This article describes the algorithms used and the results that are presented.

Algorithms↗
PubMed1991

Evaluation of the sensory irritation test for the assessment of occupational health risk.

Many occupational exposure limits (OELs) are based on irritation. A sensory irritation test has been developed based on trigeminal nerve stimulation in the nasal mucosa of rodents which results in a decreased respiratory frequency. The RD50, the concentration inducing a 50% decrease in the respiratory rate, was proposed for the assessment of OELs. The reproducibility within one laboratory appeared to be satisfactory, but interlaboratory differences may be larger. Intra- and interspecies differences were inconsistent. Other effects (pulmonary irritation, toxicity) may interfere with trigeminal nerve stimulation. The effects of mixed and repeated exposures (the occurrence of "sensitization" and "(cross-)tolerance") are evaluated. Severe toxicity was observed in animals exposed below the RD50 for some compounds. A quantitative evaluation with respect to human data was not possible. The suitability of the test for the assessment of an OEL is doubted. The best purpose will be as an upper range-finding study for subacute or chronic toxicity experiments.

Air Pollutants, Occupational↗
PubMed1991

Collateral ventilation by diffusion across the alveolar walls and the exchange of inert gases in the lung.

The underlying hypothesis of this study is that collateral ventilation by diffusion of occluded air spaces in the lungs of patients with chronic obstructive pulmonary disease (COPD) may play a substantial role in the pulmonary gas exchange of these patients. Using a related lung model we have simulated: a) the multiple-breath washout of helium (He) and sulphur hexafluoride (SF6) from the alveolar space, and b) the washout of inert tracer gases with different blood-gas partition coefficients, range 0.01-330, from mixed venous blood. These computations were carried out for different values of the collateral diffusion capacity (CDC). Next, the results obtained at each individual value of CDC were used to compute the breath number (NCR) at the crossing-over of the He-SF6 washout curves and the inert gas shunt fraction QS/QC. NCR and QS/QC range up to about 100 and 0.04, respectively, when CDCSF6 ranges down to about 0.1 ml.min-1.mmHg-1. These ranges for NCR and QS/QC, and the typical finding of relatively large values for NCR in combination with small values for QS/QC, are also reported in the literature for patients with COPD. These agreements thus support our hypothesis. In line with the small values for QS/QC, our results further indicate that even large, well-perfused, occluded air spaces in the lung will hardly affect the recovered ventilation/perfusion distribution obtained from inert gas data when CDCSF6 exceeds 0.1 ml.min-1.mmHg-1.

Computer Simulation↗
PubMed1990

Interactive effects of ozone and formaldehyde on the nasal respiratory lining epithelium in rats.

The combined effects on the nasal epithelium of mixtures of ozone and formaldehyde at cytotoxic and noncytotoxic concentrations were examined. Male Wistar rats were exposed by inhalation during 22 h/d for 3 consecutive days to 0.3, 1.0, or 3.0 ppm formaldehyde, or to 0.2, 0.4, or 0.8 ppm ozone, or to mixtures of 0.4 ppm ozone and 0.3, 1.0, or 3.0 ppm formaldehyde, or to 1.0 ppm formaldehyde and 0.2, 0.4, or 0.8 ppm ozone, or they were sham-exposed to clean air. The noses were examined for pathological changes at six standard cross levels by light microscopy and for epithelial cell proliferation by counting [3H-methyl]thymidine-labeled cells at cross levels II and III. Ozone at 0.4 ppm or 0.8 ppm or formaldehyde at 3 ppm enhanced cell proliferation at cross level II at all locations, except for the epithelium of the septum, which was not affected by ozone. At cross level III ozone alone did not induce cell proliferation, but formaldehyde at 0.3 and 1 ppm tended to reduce cell proliferation while at 3 ppm proliferation was slightly stimulated. The combined exposure to 0.4 ppm ozone and 0.3 ppm formaldehyde induced less cell proliferation at cross levels II and III when compared with that of 0.4 ppm ozone alone. Less cell proliferation was also seen at cross level II when animals were exposed to 0.4 or 0.8 ppm ozone in combination with 1 ppm formaldehyde than when exposed to these ozone concentrations alone. A more than additive increase in cell proliferation was found at cross level II after exposure to 0.4 ppm ozone in combination with 3 ppm formaldehyde, and at cross level III in animals exposed to 0.4 ppm ozone and 1 or 3 ppm formaldehyde. Treatment-related histopathological nasal changes, such as disarrangement, loss of cilia, and hyper/metaplasia of the epithelium were seen at 0.2, 0.4, and 0.8 ppm ozone and at 3 ppm formaldehyde. Simultaneous exposure to both materials did not noticeably affect type, degree, and size of the microscopic nasal lesions.

Animals↗
PubMed1990

A new method for the determination of carboxyhemoglobin in blood of newborns. Possible clinical implications of elevated levels.

Spectral differences between hemoglobin derivatives from adult-(HbA) and fetal-hemoglobin (HbF) make the accurate determination of carboxyhemoglobin (COHb) troublesome in blood of newborns. Only the newest dedicated instruments for the determination of COHb take these differences into account. However, since there are virtually no spectral differences between both hemoglobins in the deoxygenated state, reduction of neonatal blood with sodium dithionite eliminates that spectrophotometric error. Based on this principle, an easy, fast and accurate method for the determination of COHb in minimal amounts of blood was developed; equally well suited for blood of newborns and adults. The instrument used with this new method is a general purpose centrifugal clinical chemistry analyzer (COBAS-FARA, Roche, Basle, Switzerland). After the reduction of blood with sodium dithionite, a simple two component system (Hb and COHb) is formed, which can be spectrophotometrically quantitated by measuring at two suitable wavelengths, i.e., 579 nm and 534 nm. The COHb fraction is calculated with the help of: COHb % = 177.73.(A534/A579)-176.66. Comparison with the OSM3 Hemoximeter (Radiometer A/S, Denmark) for 145 adult blood samples with varying COHb levels (0-30%) yielded a mean difference in COHb % of about 0.06% (SD = 0.38). For fetal blood (N = 63) about the same difference was found when the OSM3 was used in the so-called fetal mode, while comparison with the regular adult mode yielded a difference of about 3.1%. This indicates that the new method is indeed not disturbed by the spectral differences between HbA and HbF.(ABSTRACT TRUNCATED AT 250 WORDS)

Carboxyhemoglobin↗
PubMed1989

Nasal tumours in rats after severe injury to the nasal mucosa and prolonged exposure to 10 ppm formaldehyde.

To study the significance of damage to the nasal mucosa for the induction of nasal tumours by formaldehyde in rats, a long-term inhalation study was conducted in which male rats with severely damaged or undamaged nose were exposed 6 h/day for 5 days/week to 0, 0.1, 1.0 or 10 ppm formaldehyde vapour for 28 months, or for 3 months followed by a 25-month observation period. The damage to the nasal mucosa was induced by bilateral intranasal electrocoagulation. The total number of rats used was 720, 480 with damaged and 240 with intact nose. Compound-related degenerative, inflammatory and hyperplastic changes of the nasal respiratory and olfactory mucosa were invariably observed when rats with intact nose were exposed to 10 ppm but not when exposed to 1.0 or 0.1 ppm formaldehyde. Nasal electrocoagulation increased the incidences of formaldehyde-induced rhinitis, hyper- and metaplasia of the respiratory epithelium, and degeneration and hyper- and metaplasia of the olfactory epithelium. In addition, exposure to 10 ppm formaldehyde for 28 months produced nasal squamous cell carcinomas in rats with damaged nose (15/58) but not in rats with intact nose. Three months of exposure to 10 ppm formaldehyde or exposure to 0.1 or 1.0 ppm formaldehyde for 28 months had no such effect. It was concluded that severe damage to the nasal mucosa may contribute to the induction of nasal tumours by formaldehyde.

Animals↗
PubMed1989

The excretion of highly soluble gases by the lung in man.

The excretion (E) of inert gases by the lung depends on, among other things, their blood-gas partition coefficients (lambda). According to conventional gas exchange models, E should increase with increasing lambda. However, recent models that take into account the tidal character of breathing and the buffering capacity of lung tissue predict that E will show a minimum in the range of large lambda values (lambda greater than 10). Further, this local minimum should shift to larger lambda values in exercise conditions as compared to rest conditions. The aim of this study is to verify this predicted behaviour of E. The experiments were carried out with seven healthy subjects at rest and at three work loads (50 W, 100 W and 150 W) on a bicycle ergometer. The behaviour of E was determined from the results of a simultaneous washin of four tracer gases: ethyl acetate (lambda approximately 75), acetone (lambda approximately 330), ethanol (lambda approximately 2000) and acetic acid (lambda approximately 20000). The washin lasted 4 min, and E was calculated from E = 1 - PE-/PI, where PI and PE- are the partial pressures of the tracer gas in inspired and mixed expired gas determined from the recordings obtained during the last minute of washin. PI and PE- were measured with a mass spectrometer. Comparison of the E values of the four gases shows that at rest a minimum value for E is found for acetone. In exercise conditions, however, the smallest E value is found for the more soluble ethanol or acetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗