Hippocampal Noradrenaline and Serotonin Release over 24 Hours as Measured by the Dialysis Technique in Freely Moving Rats: Correlation to Behavioural Activity State,Effect of Handling and Tail-Pinch

Hippocampal extracellular levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were monitored with the microdialysis technique in freely moving rats. In one experiment 30 min samples were collected during 24 h of continuous perfusion, and the monoamine output was compared to the behavioural activity state, as arbitrarily classified in three categories: sleep/rest, drowsiness and full alertness associated with complex behaviours. In the individual animal the hippocampal NA and 5-HT output showed pronounced fluctuations during the 24 h period, but the 30 min sampling times did not allow for a clear-cut correlation to behavioural activity state. However, the mean NA and 5-HT output for all animals during the dark period of the day was 43 and 38% higher, respectively, than during the light period, and the average NA and 5-HT levels in samples collected during periods of high behavioural activity was 34 and 45% higher, respectively, than during periods of rest or sleep. In contrast, there were no detectable changes in extracellular 5-HIAA. The selective serotonin uptake blocker indalpine, added to the perfusion fluid at 1 microM, increased the extracellular 5-HT levels 6-fold, with a similar correlation to behavioural activity state as without indalpine. In a second experiment the effect of handling and tail-pinch was studied in 15 min sample fractions. Gentle handling of the animals during the sampling period increased the hippocampal NA and 5-HT output by 32 and 72%, respectively, and a similar increase (63 and 48%) was obtained by application of tail-pinch. Maximum NA output was reached during the handling or tail-pinch period, whereas maximal 5-HT levels were detected in the subsequent 15 min sample fraction. No changes in extracellular 5-HIAA was observed. It is concluded (1) that intracerebral microdialysis provides a useful method for the study of extracellular NA and 5-HT in the hippocampal formation of conscious rats during active behaviour; (2) that there are substantial fluctuations in hippocampal NA and 5-HT output in freely moving rats which correlate with the light - dark cycle as well as with the activity state of the animals; (3) that the spontaneous variations in 5-HT output are maintained during reuptake blockade; and (4) that behavioural activation through gentle handling or tail-pinch elicits NA and 5-HT release. The present data support a role of the forebrain NA and 5-HT systems in behavioural state control and highlights the necessity of experimental designs in which the spontaneous fluctuations in transmitter release are controlled for in studies of, for example, drug effects on NA and 5-HT release in conscious animals.     

Treatment of craniopharyngiomas—the stereotactic approach in a ten to twenty-three years' perspective

Summary Fourty-two consecutive patients with craniopharyngioma were treated by stereotactic approach, i.e. preferentially stereotactic puncture and installation of colloid isotope into cystic tumours and external stereotactic single dose irradiation to solid tumour parts. In a minority of cases, such treatment was less suitable, and surgical removal and/or radiotherapy was used. There was no peroperative mortality. A long-term follow up (observation time 10–23 years) of the 31 patients alive indicated that they were socially well adapted with a high rate of fulltime work and a low rate of intercurrent disease. In spite of substitution therapy for pituitary insufficiency in most cases, the patients were subjectively seldom disturbed by their disease.Our results support a change in the choice of therapy for craniopharyngioma patients, from open neurosurgery to the less invasive stereotactic techniques.     

Possibilities of finger substitution

Authors deal, in connection with their clinical cases, with the replacement of the fingers of the hand. Attention is called to the fact, that a minimal requirement of the reconstruction, performed on the severe, multiply amputated hand, should be the formation of a "basic hand", and that at the planning of such operations the aim may be the reconstruction of the function of the hand only. Among the methods presented the most modern methods, requiring microvascular surgical technique, are also shown. Although the right of using these is obvious, the older, however well proved methods should not be forgotten either. The possibilities of finger replantation are described didactically; considering the extent of this theme however authors did not strive to completeness.     

Connective tissue metabolism in children with chronic renal failure

To assess the characteristics of connective tissue metabolism in chronic renal failure (CRF), urinary excretion of glycosaminoglycan (GAG) fractions and hydroxyproline (HYP) was determined in ten patients with CRF and in ten age-matched healthy children. CRF was found to be associated with elevated free HYP (19.9±6.1 vs 9.8±3.6 mol/day,P<0.05) and depressed peptide HYP excretion (33.1±13.5 vs 225.2±17.7 mol/day,P<0.01), a low rate of total GAG excretion (7.0±2.4 vs 16.1±1.9 mol uronic acid/day,P<0.05) with low chondroitin 4 — sulphate + chondroitin 6 — sulphate (Ch-Ss) (14.0±9.9 vs 65.0±22.1%) and a high proportion of non-sulphated or under-sulphated fractions, i.e. hyaluronic acid + chondroitin + heparan sulphate (HA+Ch+HS) (75.3±11.4 vs 31.5±5.7%). Urinary 3-methyl-histidine (3-met-HIS) excretion and plasma essential free amino acids did not differ in the two groups. In response to haemodialysis no consistent change occurred in urinary excretion of 3-met-HIS, peptide-bound HYP, total GAG or percentage distribution of individual GAG fractions. After haemodialysis all plasma amino acids decreased significantly, and there was a significant increase in urinary excretion of free HYP (P<0.05). We conclude that the alterations in urinary excretion of total and individual GAGs observed in CRF may reflect disturbed connective tissue metabolism which does not appear to be accounted for by protein malnutrition or enhanced protein breakdown and remains uninfluenced by haemodialysis therapy.     

Experience with a new "reserve protocol" in advanced and pretreated Hodgkin's disease

Between 1983-1987 16 patients with advanced stage Hodgkin disease, most of whom in an immunsuppressed, immundeficient state, were treated with a new "post-COPP", or "post-ABVD" reserve-protocol. In all cases megavoltage Co radiotherapy and COPP (CVPP) or ABVD polychemotherapy had previously been. Compared with the previously administered polychemotherapy the new 3-component cytostatic agent was well tolerated by the patients. The LEAMP-protocol therapy is therefore recommended in cases of ineffective combined radiochemotherapy (chemoresistance) or intolerance to chemotherapy. In four cases prolonged, complete, in nine cases partial remission was achieved and in more than a half of the patients favourable clinical effects and changes were experienced. In two cases temporary, partial remission was seen. One cases, because of the short period of treatment could not be evaluated. On the basis of the longitudinal observations the results achieved seemed subjectively and objectively favourable. The LEAMP-protocol was found to be well tolerated and satisfactorily effective.     

A developmental study of low birth weight infants in 1986

Evolution of the newborn infant weighing 1,000-1,499 g, was studied in 1986 in the "Mariana Grajales" Gynecologic and Obstetric Teaching Provincial Hospital, Department of Neonatology, Santa Clara. Data was obtained from the clinical histories of the newborns and of their mothers. A control group was selected in order to analyze and compare the causes of low birthweight, and as causes of it were determined age and height, and as associated diseases, urinary sepsis, anemia and toxemia of pregnancy. Premature rupture of membranes was significant. Half of the infants of the group under study was severe and moderately depressed. At the somatic evolution was observed a trend to increment and a high coefficient of correlation within the three variables under study. Main nursing actions offered fit up to the attention of these neonates.     

A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity

The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.     

Superoxide dismutase in cestodes. Isoenzymatic characterization and studies of inhibition by a series of benzimidazoles and by pyrimidine derivatives of recent synthesis

The activities of superoxide dismutase (SOD) (E.C.1.15.1.1) in extracts of five cestode parasites (Moniezia expansa, M. benedeni, Avitellina centripunctata. Taenia hydatigena and Dipylidium caninum) were investigated. The polyacrylamide gel electrophoretic patterns revealed that each of the five species had four isoenzyme bands; they could be differentiated principally by their displacements and, less clearly, by their intensities. Determinations were made of the inhibitory activities of four benzimidazoles and six recently synthesised pyrimidine derivatives on the SOD enzymes from the cestodes. The results confirm that the percentage of inhibitions of SOD by the same pyrimidine derivatives are markedly superior to those of the benzimidazoles.     

Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study

Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neurotoxicity and dermatotoxicity of cyanomorpholinyl adriamycin

Summary The highly lipophilic cyanomorpholinyl adriamycin (CMA) is the most potent antineoplastic anthracycline yet described. CNS distribution and toxicity were examined after i.v. administration of CMA to mice. At doses 0.1 mg/kg, a neurotoxic syndrome including ataxia, hypokinesia, and tremors appeared. At doses of 0.05 mg/kg, which have been reported to be antineoplastic, no neurotoxicity was observed. On histopathologic examination, no changes were observed in the brain, spinal cord, or dorsal root ganglia. Unlike adriamycin (ADR), which rapidly appears in the nuclei of several tissues, CMA showed no fluorescence, suggesting a different cellular microcompartmentalization. The i.d. injection of CMA disclosed a 200-fold increase in toxicity compared with that of adriamycin. In comparisons of CMA and ADR, neurotoxicity and cardiotoxicity occurred equally only at higher doses; however, the dermatotoxicity and antineoplastic activity of CMA were increased several hundred-fold.