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P Netter

Publications and source records attributed to P Netter.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1995

Stereoselective esterase activity of human serum albumin toward ketoprofen glucuronide.

Many carboxylic acid-containing drugs undergo conjugation with D-glucuronic acid in humans, leading to the formation of acyl glucuronides, which are excreted into urine. However, these metabolites can be hydrolyzed back to the parent aglycon; this reaction can be accelerated by human serum albumin (HSA). Although this phenomenon of interaction between the acyl glucuronide and HSA has been described for various drugs, the kinetics of the protein have not been characterized. The aim of this study was to investigate the HSA-mediated mechanism involved in the in vitro hydrolysis by albumin of the acyl glucuronides of (R)- and (S)-ketoprofen (a nonsteroidal anti-inflammatory drug), as model compounds. The conjugates of both ketoprofen enantiomers were incubated, separately or together, with increasing concentrations of albumin (14.5-145 microM) at pH 7.4 and 37 degrees. The reaction followed Michaelis-Menten kinetics and was stereoselective; the (R)-ketoprofen glucuronide was a better substrate than the S-conjugate. To identify the HSA domain involved in the hydrolysis reaction, specific probes of HSA binding sites were used as potential inhibitors. These probes, added at an equimolar probe/glucuronide ratio (145 microM), slightly decreased the hydrolysis (by up to 30%). They affected the reversible binding of (R)-ketoprofen glucuronide to HSA, as shown by CD studies. Because iodoacetic acid did not modify the single free cysteine residue on HSA, this amino acid residue cannot be the reactive one. In addition, the chemical modification of a single tyrosine residue (probably Tyr-411) on HSA by diisopropyl fluorophosphate significantly but weakly affected the hydrolysis of (R)-ketoprofen glucuronide, suggesting that this residue also is not involved in the catalysis. In contrast, the R-conjugate was not bound to modified albumin, as revealed in CD experiments. These results support the existence of distinct sites on HSA for reversible binding and hydrolysis of (R)-ketoprofen glucuronide.

Binding Sites↗
PubMed1994

Stereoselective binding of the glucuronide of ketoprofen enantiomers to human serum albumin.

Since acyl glucuronides are known to undergo deconjugation, especially in the presence of human serum albumin (HSA), only a few reports have described their reversible binding to plasma proteins. The aim of this study was to investigate the reversible binding of R and S ketoprofen glucuronides to HSA by a rapid technique, such as ultraviolet circular dichroism. Binding of R ketoprofen glucuronide only induced an extrinsic Cotton effect at 340 nm. Scatchard plot analysis revealed that R ketoprofen and its glucuronide are bound to one site of albumin with an association constant of 28.1 x 10(4) and 6.1 x 10(4) M-1, respectively. Modification of one tyrosine residue by diisopropylfluorophosphate prevented the access of ligands to sites I and II of albumin, and also fully inhibited the binding of R ketoprofen and that of its conjugate. Displacement experiments with specific probes of albumin binding sites suggested that R ketoprofen and the glucuronide are bound to site II rather than site I. However, R ketoprofen was not displaced by its conjugate. S ketoprofen glucuronide is also bound to HSA, since it decreased the binding of the antipode conjugate. However, the binding of this metabolite to albumin did not induce an extrinsic Cotton effect large enough to determine the binding constants. D-Glucuronic acid did not bind to sites I or II of albumin. This moiety is likely responsible for the lower affinity of HSA for the R ketoprofen glucuronide when compared to that for R ketoprofen, due to the hydrophilicity and/or the bulkiness of this group.

Binding Sites↗
PubMed1994

[Treatment of acute microcrystalline inflammation].

The treatment of acute crystal-induced inflammatory episodes is based on two major classes of drugs, colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs). In its capacity to inhibit leukocyte influx into the inflammatory site, colchicine demonstrates its remarkable anti-inflammatory properties in gouty attacks, for which it is a real therapeutic test. Nevertheless, at usual dosages, colchicine often induces gastrointestinal irritation manifested by diarrhoea. Other side effects (in particular haematologic) are rare but severe in case of liver or kidney failure, which are classic contraindications to this treatment. NSAIDs, by inhibiting local prostaglandin synthesis, are also highly effective in gouty attacks. This ubiquitous property nonetheless leads to side effects, mainly gastro-intestinal and renal. In gouty attacks, clinical steps include a diagnostic work-up seeking an aetiological cause, whereas episodes of chondrocalcinosis or apatite-induced rheumatism are treated symptomatically (rest of the joint, NSAIDs, sometimes colchicine, or local infiltration of cortisone derivatives).

Acute Disease↗
PubMed1994

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid.

Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days. The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose. Eicosanoids (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTC4) in synovial fluid were determined by immunoenzymatic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests. Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE2 and LTB4 concentrations. The decrease in 6-keto-PGF1 alpha and TXB2 was not significant. No significant change was found for LTC4 and hyaluronic acid. Total concentrations of sodium naproxen were equivalent in plasma (16.1 micrograms.ml-1) and synovial fluid (18.9 micrograms.ml-1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11%), as shown by binding of the drug to human serum albumin, at various protein concentrations. Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

The influence of nicotine on performance, mood, and physiological parameters as related to smoking habit, gender, and suggestibility.

Based on previous observations that sensory suggestibility might be related to cholinergic drug effects, and that individual susceptibility to nicotine as defined by response differences to various doses is lower in males, nonsmokers, and highly suggestible subjects, the present study investigated whether nicotine serum blood levels, cardiovascular responses, and sensory suggestibility show differences according to gender and smoking habit, and whether differences in nicotine susceptibility measured by a discrimination task by subjective ratings on activation can be reproduced in the direction predicted by the previous data. In a double-blind threefold cross-over design 48 subjects divided according to smoking habit, gender, and sensory suggestibility were tested in balanced order under the influence of an oral dose of 0, 0.014, or 0.028 mg/kg body weight of nicotine. Results revealed higher serum levels of nicotine in males and smokers, a dose-dependent increase in heart rate and systolic and diastolic blood pressure, partly interacting with gender or smoking habit (females and nonsmokers showing larger increase with the low doses), and a change in suggestibility in the expected direction (decrease with the low dose, increase with the large one only in female nonsmokers). A fourfold interaction among dose, smoking habit, gender, and suggestibility for the discrimination task partly reproduced the observations of higher nicotine susceptibility in females and non-smokers, whereas suggestibility did not seem to reveal the expected changes. Also, on a subjective level larger doses were necessary to make male smokers feel activated, while the other groups showed the biphasic response pattern to the two nicotine doses. In conclusion, the data justify further research on the concept of nicotine susceptibility defined by biphasic effects of nicotine on vigilance.

Administration, Oral↗
PubMed1994

Anti-inflammatory properties of IL-1 in carrageenan-induced paw oedema.

To evaluate any inhibitory effect of a single dose of human recombinant interleukin-1 beta (hrIL-1 beta) on the severity of carrageenan-induced oedema in rats (a commonly used model of acute inflammation), we first injected 0.1 ml of carrageenan (0.2%, 0.5%, or 2%) to induce mild, moderate, or severe inflammation, respectively into the right rear footpad. Then we promptly injected the interleukin (0.02, 0.2, or 2 micrograms) subcutaneously into the flank. The initial rapid increase in volume of the injected paw (within 2 h of the subplantar injection) was independent of the dose of carrageenan, whereas the increase in volume by 6 to 10 h was dose-dependent. All doses of HrIL-1 beta inhibited the carrageenan-induced swelling at the 6th hour. In the moderate and severe carrageenan-induced oedemas, the higher dose of HrIL-1 beta induced a delayed inflammation peaking at 10 h instead at 6 h.

Animals↗
PubMed1994

Extraversion as a modifying factor in catecholamine and behavioral responses to ethanol.

Individual differences in catecholamine response to stress and ethanol were tested in extraverts and introverts on the basis of Eysenck's drug postulate claiming that introverts would be less susceptible to sedative drugs like ethanol. Forty-four healthy males received either 0.8 g/kg ethanol mixed into a drink of caffeine-free cola or a respective placebo and were tested with a stressful mental arithmetic task before and 40 min after the intake of the drink. Plasma catecholamines were determined from blood samples drawn at five defined intervals from an indwelling cannula and self-ratings on deactivation, relaxation, and anxiety were obtained as well as quality and quantity of performance in the arithmetic task. Results showed that there was no difference in catecholamine stress responses between introverts (Ex -) and extraverts (Ex +) before the drink, but that the intake of the fluid (both ethanol and placebo) resulted in higher norepinephrine (NE) increases in Ex - than in Ex +. The combined effects of ethanol and stress yielded larger responses of longer durations in Ex - than in Ex +. The concomitant psychological changes showed larger reductions in anxiety and increases in relaxation as well as larger decrements in quality of performance (% errors) in introverts in spite of their higher catecholamine increases. Thus, the predictions on the basis of arousal theory could not be verified experimentally and the drug postulate has to be modified in the sense that introverts probably have a higher depletion of NE in the central nervous system under physical but not under mental stress which is reflected by higher levels in the plasma and respective decreases in performance and activation.

Adult↗
PubMed1994

Characterization of zymosan-induced arthritis in the rat: effects on joint inflammation and cartilage metabolism.

A single intra-articular (ia) injection of 2 mg zymosan on D0 led to the production of acute periarticular edema followed by subacute erosive synovitis. The development of the zymosan-induced arthritis was associated with an initial loss of running activity and with an initial decrease of proteoglycan synthesis. Febrile response was present only on D1. In addition, on D20 synovial pannus led to a marked depletion of the proteoglycan content in the articular cartilage. When injected ia, IL1 beta (1 microgram) provoked similar fever and similar changes in cartilage anabolism, but did not affect cartilage proteoglycan content (D20). These results suggest that zymosan-induced synovitis in the rat combines early prostaglandin-dependent processes (edema, pain, fever) with IL1-related effects on cartilage metabolism, thus allowing evaluation of chondroprotective drugs.

Animals↗