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Biomedical subjects

P Netter

Publications and source records attributed to P Netter.

At least 91 records · Page 5Linked to original sources
PubMed1996

Local immunocompetence and salivary cortisol in confinement.

The present study describes the effects of a 60-day isolation period on the salivary levels of cortisol and secretory IgA. The study took place in the context of the EXEMSI project in which four volunteers were isolated in a space station-like chamber in the DLR Institute of Aerospace Medicine in order to examine the effects of long term isolation. Inspection of the individual immunoglobulin A secretion rates revealed different patterns of cyclic variation with respect to the weekday-weekend schedule, and different time lags for the adaptation leading to a plateau for this parameter. The salivary cortisol levels showed a circadian rhythm with high concentrations in the early morning (7:30 am) and lower concentrations in the late evening (11:00 pm). Moreover, in all subjects marked increases of salivary cortisol were observed in a 12- to 14-day cycle. In two subjects the marked morning-evening differences were only visible at the weekends. The salivary cortisol and immunoglobulin A levels were determined twice weekly before and after completion of a complex decision-making test. The results reveal a changed responsiveness in all subjects at different times.

Adult↗
PubMed1996

Serotonin and dopamine as mediators of sensation seeking behavior.

The purpose of the present paper was to investigate the relationship of the serotonergic and dopaminergic systems to subscales of sensation seeking (SS). Two of the subscales, Disinhibition (DIS) and Experience Seeking (ES), were chosen for analysis based on their representation of the two major factors obtained in a factor analysis: DIS represents a factor of lack of impulse control and ES a factor of novelty seeking. In studies 1 and 2 responsivity to a serotonergic (5-HT) challenge by a 5-HT1a receptor agonist (ipsapirone) was investigated by drug-induced prolactin (PRL) and cortisol responses, as well as by emotional states and behavioral measures. The dopaminergic (DA) response to a DA agonist (lisuride) and antagonist (fluphenazine) was analyzed in a condition of smoking deprivation (study 3) using PRL responses, emotional states, and behavioral measures of nicotine craving as dependent variables. In the studies of the serotonergic system, high ES subjects showed a blunted cortisol response in both studies and high DIS subjects demonstrated a blunted PRL response in study 2. A frequently observed side effect of serotonergic agonists, increase in emotional arousal, was not observable with ipsapirone in high ES and high DIS subjects as compared to low scorers. Behavioral aggression, which had been experimentally induced in study 2, was increased in high ES as well as in high DIS by the 5-HT1a agonist which exerted antiaggressive effects in low scorers. These findings were found compatible with the idea of a generally low responsivity of the serotonergic system in high ES as well as in high DIS types of sensation seekers of 5-HT1a subsensitivity in high DIS and subsensitivity of other postsynaptic 5-HT receptors in high ES. There was no association between SS subscales and DA-induced decrease of PRL, but high ES subjects seemed to tolerate nicotine deprivation better than low ES subjects indicating that they were less susceptible to deprivation of nicotine-induced DA. But craving for nicotine was increased in high ES subjects by the DA agonist lisuride as opposed to the antagonist, which was taken as evidence that DA stimulation may induce approach behavior in high ES. Although only two subscales had been selected for the investigation, this approach suggests both common and different relationships between SS subscales and neurotransmitter systems.

Adult↗
PubMed1996

Influence of severity of chronic inflammatory joint disease on the pharmacokinetics of indomethacin and etodolac.

The goal of this study was to look for correlations between the severity of chronic inflammatory joint disease and pharmacokinetic parameters of nonsteroidal antiinflammatory drugs. Disease severity data (pain severity and magnitude of abnormalities in laboratory tests for inflammation) and pharmacokinetic data (area under the curve in the morning (AUCm) and maximum plasma concentration (Cmax) were collected during a prospective, randomized, double-blind, parallel-group study. Two groups of nine and 11 patients, respectively, were given 300 mg etodolac b.i.d or 50 mg indomethacin b.i.d. by the oral route, for three days, after a 36-hour placebo washout. Univariate analyses demonstrated statistically significant negative correlations between pharmacokinetic parameters of both study drugs and a number of disease severity parameters. In the multivariate analysis of data for etodolac, the sigma erythrocyte sedimentation rate contributed significantly to variations in all pharmacokinetic parameters and explained 100% of the variations in free S-enantiomer AUCm and in total and free S-enantiomer Cmax. For indomethacin, pain contributed to variations in Cmax values of the total and free forms; the sigma erythrocyte sedimentation rate was also a factor in variations in total indomethacin. These negative correlations suggest that severity of chronic inflammatory joint disease may influence the pharmacokinetics of nonsteroidal antiinflammatory drugs.

Administration, Oral↗
PubMed1996

Stereoselective irreversible binding of ketoprofen glucuronides to albumin. Characterization of the site and the mechanism.

We have previously shown that the acyl glucuronide of racemic ketoprofen can irreversibly bind in vitro to plasma proteins (Dubois, N., et ai., Drug Metab. Dispos. 21, 617-623, 1993), but the mechanism of the reaction has not been characterized. In the present study, the reactivity toward albumin of the glucuronide of both ketoprofen enantiomers was investigated. The extent of binding increased with the concentration of both protein and glucuronide. However, the two diastereoisomers showed different reactivities toward human serum albumin (HSA): the maximum yield of adducts with the glucuronide of the S-enantiomer was twice that obtained with the glucuronide of its antipode. The maximum extent of irreversible binding was at 4 hr for the R-ketoprofen conjugate, but was later for the S-form. Chemical modifications of albumin indicated that the glucuronide of the S-isomer reacted only with lysine residues, whereas the R-form linked covalently mainly with tyrosine residues and secondarily with lysine residues. A competition study using specific binding probes and fatty acids showed that the conjugates of S- and R-ketoprofen reacted with amino acids located in sites I and II of HSA, respectively. Taken together, these findings suggest that the irreversible binding of ketoprofen to albumin depends on the stereochemistry of the aglycon: the R-enantiomer binds to site II of the protein probably by a nucleophilic attack by tyrosine and/or lysine residues, whereas adduct formation via the conjugate of the S-enantiomer could occur at site I of HSA by the Schiff base mechanism. This irreversible binding at sites I and II may affect the major function of albumin (i.e. the transport of drugs and endogenous compounds).

Animals↗
PubMed1995

Genetic analysis of the folded structure of yeast mitochondrial cytochrome b by selection of intragenic second-site revertants.

The mutations C133-->Y133, L282-->F282 and G340-->E340 in yeast mitochondrial cytochrome b each lead to a dysfunction of the cytochrome bc1 complex and, consequently, to the absence of growth on non-fermentable substrates. We isolated and characterized, from these mutants, fourteen different intragenic pseudo-revertants of various respiratory sufficient phenotypes. Both first-site and second-site suppressor mutations were found. A novel type of suppressor mutation consisted of the three-base-pair deletion of the parental mutated codon (E340 delta). The results provide, for the first time, evidence for the transmembrane disposition of helices F and G of the current eight-helix cytochrome b model. These two helices are presumably in contact with helix C in the folded protein. A simple modelisation study suggests that the packing of helices C, F and G in cytochrome b may be similar to that of helices I, II and VII in bacteriorhodopsin, respectively. We observed from the study of second-site revertants that compensation across the membrane never occurs. For each revertant, the suppressor mutation and the corresponding target mutation are on the same side of the membrane. This membrane sidedness strengthens the topological constraints imposed by the Q-cycle, namely the necessity of spatial separation of two catalytic reaction sites for ubiquinone.

Amino Acid Sequence↗
PubMed1995

[Inducible cyclooxygenase. New relationships between non-steroidal anti-inflammatory agents and inhibition of synthesis of prostaglandins].

After a brief history of the main discoveries concerning the research on arachidonic acid and its biologically active derivatives, recent findings related to the identification of 2 isoenzymes of the prostaglandin-H synthase (PGHS) are reviewed. These isoenzymes play different roles within the body, since PGHS-1 is involved in homeostasis when PGHS-2 is mainly expressed during the inflammatory reaction. Non-steroidal anti-inflammatory drugs classically inhibit the biosynthesis of prostaglandins but this inhibitory effect depends on the considered isoenzyme. This discovery may have pharmacological and clinical impact but, at the present time, research is focused more on new pharmacological targets than on improving drug prescription.

Adrenal Cortex Hormones↗
PubMed1995

Mutations in the mitochondrial split gene COXI are preferentially located in exons: a mapping study of 170 mutants.

We have analysed the precise location of a large number (170) of mutations affecting the structural gene for subunit I of the cytochrome c oxidase complex. This gene, COXI, is 12.9 kb long and the major part of the sequence (i.e. 11.3 kb) is composed of introns. Several conclusions can be drawn from this study: (1) A significant proportion (84/170) of the mutations cannot be assigned to a single position within the gene by deletion mapping, in spite of clearly being located in it. These mutations are probably large deletions or multiple mutations. (2) Four mutants carry distant double mutations, which have been individually localized. (3) Eighty-two mutants have lesions that are restricted to very short regions of the gene and we therefore conclude that they are most probably due to single hits; amongst these single mutations, 41 are unambiguously located in exons and 28 in introns. This result implies that, at least in this particular split gene, the probability of selection of a mutant phenotype in an exon is, on the average, 13.3 times greater than in an intron, in spite of the existence, within most of these introns, of open reading frames specifying intronic proteins. The evolutionary significance and biological implications of these results are discussed.

Base Sequence↗
PubMed1995

Zymosan-induced arthritis in rats. II. Effects of anti-inflammatory drugs.

As zymosan-induced arthritis in rats combines dual activation of early prostaglandin-dependent processes (edema, fever, pain) and IL-1 related effects on cartilage metabolism, we compared the respective influences of indomethacin (IMT) and dexamethasone (DEX) on its course. Different parameters were assessed: knee swelling, febrile response, loss of activity, cartilage metabolism and histology. DEX improved all these parameters, while IMT exerted only light beneficial effects on fever and knee swelling without obvious beneficial influence on cartilage metabolism and histological lesions. These results suggest that anti-inflammatory activities of DEX and IMT are due to interferences with different pathways during zymosan-induced arthritis in rats.

Animals↗
PubMed1995

Suppression of HPA-axis activity by haloperidol after experimentally induced heat stress.

1. Healthy male volunteers were exposed to either a heat condition (52 degrees C) or normal temperature (28 degrees C) receiving a single oral dose of 3 mg haloperidol or placebo in a double-blind design. 2. Ratings on aversiveness as well as on intensity of ambient temperature and saliva samples for determination of cortisol were sampled at defined intervals. Body core temperature and sweat loss were measured continuously throughout the three hour experiment. 3. Results indicate increased levels of cortisol after exposure to heat but not after a pretreatment with haloperidol. 4. The findings of this study suggest that D2-receptors of tuberoinfundibular neurons are blocked by haloperidol which suppresses the dopamine mediated release of vasopressin induced by dehydration and the subsequent stimulation of CRH.

Adult↗
PubMed1995

Experimental models for aggression and inventories for the assessment of aggressive and autoaggressive behavior.

This paper reviews principles realized in questionnaires for the assessment of aggression as well as in experimental models suitable for inducing aggression for the validation of questionnaire scales and for providing experimental models for testing aggression-reducing drug effects. Existing self-rating scales based on factor analysis were shown to measure certain parameters of reactions concerning modes of expression of aggression and its objects. In observer rating scales situations are usually also specified. A final scale containing 9 situations and 17 reactions grouped into seven factors is presented. It could be shown to differentiate between certain types of aggression provoking situations. Furthermore, models suitable for eliciting aggression were developed in three different departments of psychology. They are based on frustration by blockade of goals and critique or subtraction of positive reinforcers ("Tower of Hanoi" and "Superball Game" in Würzburg, "Unsolvable Maze Computer Task" in Berlin) and by a competitive condition combined with application of aversive stimuli by a coplayer ("Modified Buss Machine" in Giessen). All experimental conditions were suitable for inducing anger and emotional arousal, negative ratings of confederates or experimenters, and partly also physiological changes. The results seem promising enough to test the relationship between artificially induced aggression and pathologiocal aggression in further research.

Aggression↗
PubMed1995

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Since both (R)- and (S)-enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve-root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac-ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half-lives of (R)- and (S)-ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)- and (S)-forms, respectively.

Administration, Oral↗
PubMed1995

Magnetic resonance imaging may be an asset to diagnose and classify fluoroquinolone-associated Achilles tendinitis.

The aim of this study was to document the accuracy of magnetic resonance imaging (MRI) during fluoroquinolone-associated Achilles tendinitis. Fourteen Achilles tendons were examined by MRI (T1 and T2 or T2*-weighted sequences) in nine patients with typical tendinopathy (13 cases of tendinitis and 1 rupture) during fluoroquinolone therapy. Tendinous involvement was classified according to the prominence of intra- or peritendinous changes. The most typical feature was the presence of intratendinous changes, longitudinal or transversal, detected on T1 or T2-weighted sequences. Peritendinitis was most visible in two cases and nodular involvement in three cases. It was concluded that MRI appears a helpful and accurate method in identifying and classifying such iatrogenic tendinitis. In addition, MRI indicates orthopedic management when detecting risk of rupture.

Achilles Tendon↗