Age-related differences in the effect of in vivo administration of indomethacin on hemopoietic cell lineages of the spleen and bone marrow of mice

During 21 days of indomethacin treatment, erythroid cells in the spleens of both young adult and older mice, and in the bone marrow of young adult mice, were increased significantly early, in treatment, relative to age-matched control organs, and remained high throughout treatment. During drug exposure, the numbers of myeloid cells in young adult bone marrow, but not spleen, were reduced, but in older mice these cells were elevated in both organs. Lymphoid cells in the young adult and older mouse spleens decreased and increased, respectively, during treatment, but were unchanged and decreased, respectively, in the bone marrow of young adult and older mice. Monocytemacrophage cells in the spleen were elevated but unchanged in the bone marrow of both age groups. During 14 days of indomethacin treatment of houng adult mice, the proportions of precursor cells in DNA synthesis of only the splenic erythroid lineage were increased. Thus, the major hemopoietic lineages in both the bone marrow and spleen are affected by exposure to indomethacin in a time-dependent and age-dependent manner. For all lineages studied, those of the bone marrow were least disturbed, and/or were first to recover, even during continued drug exposure.     

Deficiency of fibrinolytic enzyme activities in the serum of patients with Alzheimer-type dementia

Previously we reported that there is a kallikrein deficiency in the cerebral tissue of patients with Alzheimer-type dementia. The present study was performed to investigate protease changes in the serum of these patients. The results showed that the kallikrein activity was normal, but that the activities of plasmin and urokinase were significantly low. The present findings indicate a derangement in the clotting and fibrinolytic systems in Alzheimer patients.     

Effect of monensin and diabetes on asialoglycoprotein degradation in rat hepatocytes

We have studied the effects of two modulations — streptozotocin-induced diabetes in vivo, and the presence of the carboxylic proton ionophore monensin in vitro — on the degradation of³H-asialoorosomucoid ligand in isolated rat hepatocytes.The ligand was internalized by means of a synchronous wave procedure. Diabetes was associated with a marked decrease in the amount of total degraded radioactive ligand compared to that in normal cells (3.6% and 37.3% of internalized ligand respectively, at 60 min), together with increased secretion of degradation products into the incubation medium (87% and 46.3% of the total degraded ligand was secreted by diabetic and normal cells, respectively). Monensin induced similar effects in normal cells, but had no apparent effect in diabetic cells.     

The presence of free D-serine,D-alanine and D-proline in human plasma

Twelve neutral free amino acids, i. e., serine, threonine, glutamine, asparagine, alanine, proline, methionine, tyrosine, valine, leucine, isoleucine and phenylalanine, were surveyed for the presence of D-enantiomers in plasma samples from patients with renal diseases and from normal subjects. D-serine, D-alanine and D-proline were found in the patient's plasma. The highest concentrations (D/L ratio) of D-serine, D-alanine and D-proline were 0.2362, 0.2087 and 0.0986, respectively. The sum of the contents of the three D-amino acids in a plasma sample correlated with the serum creatinine level of the subject. No D-amino acid was shown to be present in the plasma proteins.     

Effects of the adenylate cyclase activator forskolin and its inactive derivative 1,9-dideoxyforskolin on insect cytochrome P-450 dependent steroid hydroxylase activity

The adenylate cyclase activator forskolin and its pharmacologically inactive derivative 1,9-dideoxyforskolin were found to inhibit in a dose-dependent fashion the ecdysone 20-monooxygenase activity associated with wandering stage larvae ofDrosophila melanogaster and fat body and midgut from last instar larvae of the tobacco hornworm,Manduca sexta. The concentrations of these labdane diterpenes required to elicit a 50% inhibition of the cytochrome P-450 dependent steroid hydroxylase activity in the insect tissues ranged from approximately 5×10^–6 to 5×10^–4 M.     

Blockade of GABAB receptors accelerates amygdala kindling development.

The aim of this study was to investigate the putative role of GABAB receptors in the development of amygdala kindling in rats. The effects of the GABAB blocker CGP 35348 and the GABAB agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1-5 classified by Racine) and duration of after-discharges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p., which blocks central GABAB receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABAB receptors and thereby exerted a depressant effect on kindling development.     

Evaluation of the hepatotoxicological effects of a drug in an in vivo/in vitro model.

Both in vivo and in vitro models have certain disadvantages for the study of the chronic hepatotoxicity of drugs. The aim of this work was to evaluate a new approach based on an in vivo/in vitro model. After chronic in vivo treatment of rats with Vincamine and Vindeburnol (an eburnamenine derivative which exhibits hepatotoxic properties in man) liver cells were isolated, and functional and metabolic disorders (metabolic utilization of fructose and protein biosynthesis) were studied to determine injury. The results showed no modification of blood parameters, but a direct relationship between the dose of Vindeburnol administered in vivo and the metabolic disorders observed in vitro, evidencing the high sensitivity and reliability of this model.     

Gastrointestinal transit and digestibility of maltitol, sucrose and sorbitol in rats: a multicompartmental model and recovery study.

Using data obtained with a dye marker and the gavage technique, the kinetics of gastrointestinal transit of different loads of sugar substitutes (maltitol, sorbitol) and sugar (sucrose) in the rat were analysed using a linear multicompartmental model over a range from the realistic to the non-physiologic high, of carbohydrate intake levels and using only a few experimental time points. The model gave detailed insight into intestinal propulsion and gastrocecal transit time. Rate constants of transport between the compartments investigated were determined; they showed characteristics which could be related to the substance and the dosage administered. Analyses of the gastrointestinal content and calculations of the intestinal net water movement showed that the digestibility and absorption of the disaccharide sugar alcohol, maltitol, in the small gut depended inversely on the dose ingested. For all substances tested, caloric availability in the small intestine was calculated. At a physiological low level of maltitol intake, the results also indicated an insignificant calorie-saving effect in comparison to sucrose, an effect based mainly on the slow absorption rate of the maltitol cleavage product sorbitol.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Rapid generation of region specific probes by chromosome microdissection and their application.

The strategy presented here to identify unequivocally cryptic chromosomal rearrangements has relevance to both prenatal and postnatal cytogenetic analysis as well as the analysis of tumour-associated chromosome rearrangements. Microdissection and in vitro amplification of specific chromosomal regions are performed, followed by labelling for fluorescent in situ hybridization (FISH) to normal metaphase chromosomes (Micro-FISH). Micro-FISH probes have been used successfully to determine the derivation of chromosome segments unidentifiable by standard chromosome banding analysis. Micro-FISH probes (created in less than 24 hours) now make it possible to identify explicitly the chromosome constitution of virtually all cytologically visible chromosome rearrangements.