Slow-release metoprolol in angina pectoris. A comparative study of a cardioselective beta-blocking drug, metoprolol, in ordinary and slow-release tablets (Durules) in the treatment of angina pectoris. A double-blind cross-over study was undertaken to compare the effects of ordinary metoprolol tablets (tablets) 0.1 g b.i.d. and metoprolol slow-release tablets (Durules) 0.2 g once daily in 16 patients with angina pectoris. Initially, the patients were treated with placebo for 2 weeks, and then during the cross-over periods with either 1 tablet morning and evening or 1 Durules in the morning and 1 placebo in the evening. Standardized bicycle ergometer exercise tests with heart rate and blood pressure measurements were performed 2 hours after placebo, 2 hours after tablets and Durules, 12 hours after tablets and 24 hours after Durules. The patients kept diaries of their anginal attacks throughout the study. There were no statistically significant differences in total work between tablets and Durules when the values at 12 hours and 24 hours were compared. However, total work was significantly greater at 2 hours and at 12 hours after tablets and 24 hours after Durules than after placebo. Heart rate and systolic blood pressure during exercise were significantly decreased 24 hours after Durules compared to placebo. The heart rate was, however, lower 12 hours after tablets than 24 hours after Durules (p less than 0.05), although this slight difference in the degree of beta-blockade did not seem to be of clinical importance in these patients.


The beta-adrenolytic component of antifibrillatory agents. Its therapeutic significance. The anti-fibrillatory ED50-values of a series of agents were determined. Upon administration of the agents in this ED50-dose (all agents then being equieffective in their antifibrillatory action) various side effects of each of them were quantitatively measured. The measured side effects were: the negative inotropic and chronotropic action, the conduction retarding, refractory period prolonging, excitability decreasing and ectopic automaticity depressing action. The substrate for these measurements was the isolated perfused rat heart. The series of agents tested consisted of a group possessing a beta-adrenolytic component and a group in which this component was absent. We compared quantitatively the side effects induced by the one group with those induced by the other. Differences were found in their influence on contractility and conductivity but not in their influence on the other parameters. The results obtained do not support the expectation that a beta-adrenolytic component will enlarge the therapeutic range of an antifibrillatory agent.


A spin label study of horseradish peroxidase. The topography of the active sites of native horseradish peroxidase and manganic horseradish peroxidase has been studied with the aid of a spin-labeled analog of benzhydroxamic acid (N-(1-oxyl-2,2,5,5-tetramethylpyrroline-3-carboxy)-p-aminobenzhydroxamic acid). The optical spectra of complexes between the spin-labeled analog of benzhydroxamic acid and Fe3+ or Mn3+ horseradish peroxidase resembled the spectra of the corresponding enzyme complexes with benzhydroxamic acid. Electron spin resonance (ESR) measurement indicated that at pH 7 the nitroxide moiety of the spin-labeled analog of benzhydroxamic acid became strongly immobilized when this label bound to either ferric or manganic horseradish peroxidase. The titration of horseradish peroxidase with the spin-labeled analog of benzhydroxamic acid revealed a single binding site with association constant Ka approximately 4.7 . 10(5) M-1. Since the interaction of ligands (e.g. F-, CN-) and H2O2 with horseradish peroxidase was found to displace the spin label, it was concluded that the spin label did not indeed bind to the active site of horseradish peroxidase. At alkaline pH values, the high spin iron of native horseradish peroxidase is converted to the low spin form and the binding of the spin-labeled analog of benzhydroxamic acid to horseradish peroxidase is completely inhibited. From the changes in the concentration of both bound and free spin label with pH, the pK value of the acid-alkali transition of horseradish peroxidase was found to be 10.5. The 2Tm value of the bound spin label varied inversely with temperature, reaching a value of 68.25 G at 0 degree C and 46.5 G at 52 degrees C. The dipolar interaction between the iron atom and the free radical accounted for a 12% decrease in the ESR signal intensity of the spin label bound to horseradish peroxidase. From this finding, the minimum distance between the iron atom and nitroxide group and hence a lower limit to the depth of the heme pocket of horseradish peroxidase was estimated to be 22 A.


Four-fold structural repeat in the acid proteases. The observation that the acid proteases contain two structurally equivalent lobes related by a dyad through the active centre has been extended to show that in endothiapepsin each lobe contains two similar halves related by a further local dyad. In lobe 1 22 pairs of alpha-carbons are equivalent with a root mean square deviation of 1.92 A. In lobe 2 17 pairs match within 2.31 A. Convergent evolution or gene quadruplication may have occurred.


[Purification, properties and regulation of urocaninase from rat liver]. Urocaninase (EC 4.2.1.4.9) from rat liver homogenate has been purified, using protein precipitation at pH 4,8, ammonium sulfate fractionation, gel-filtration through Sephadex G-200 and chromatography on DEAE-cellulose. Upon DEAE-cellulose chromatography urocaninase is separated from the proteins possessing the activity of 3',5'-AMP-dependent protein kinase. The purified enzyme becomes activated after addition of ATP and exogenous protein kinase or one of the fractions resulting from DEAE-cellulose chromatography. Using [gamma-32P]ATP, it has been shown that such activation is accompanied by incorporation of at least one phosphate residue into the enzyme molecule. The mol. weight of urocaninase as determined by gel-filtration is about 110 000. The Km value for urocanate is 15 . 10(-6) M, the isoelectric point lies at 5,6. The mechanism of regulation of the urocaninase activity in rat liver is discussed.


[Microsomal hemoprotein reduction by superoxide radical formed on NADPH-specific flavoprotein]. The superoxide radicals formed on NADPH-specific flavoprotein of liver microsomes can reduce cytochromes c, b5, and P-450. This reaction is inhibited under aerobic conditions by a low molecular weight analog of superoxide dismutase, e.g. the copper-tyrosine complex. The inhibitory effect of the complex is not observed under anaerobic conditions. Based on the results obtained a scheme of the electron transfer between the flavoprotein and haemoproteins involving superoxide radicals is proposed.


Extent and patterns of drug abuse among children in Malaysia. A field survey, based on a representative sample of children aged 12 to 16 years was carried out in three different areas of Malaysia. The data derived from the study have revealed that 10.5 per cent of them used drugs for non-medical reasons. Drug use was more common among boys (11.9 per cent) than girls (8.6 per cent). The highest frequency of drug was found in the youngest group--12-year-old children (13.5 per cent). The use of barbiturate and/or non-barbiturate sedatives (5.5 per cent) ranked first. This was followed in descending order by tranquillizers (4.5 per cent), simultants/amphetamines (3.9 per cent), heroin (3.6 per cent), morphine and/or opium (3.9 per cent), the hallucinogens (3.1 per cent) and cannabis (2.7 per cent).


Effects of pH on K depolarization and contracture in frog muscles. Membrane potential changes and mechanical tension provoked by 20 or 80 mM K at pH 8.0 or 4.5 were measured in muscle fiber bundles from Rana temporaria and Rana esculenta. The bathing solution contained Cl as the main anion. Low pH increased the depolarizing efficiency of high K to about the same degree in muscles of both species of frogs. The tension-[K] relationship was shifted toward lower [K] in muscles from R. temporaria and toward higher [K] in muscles from R. esculenta. It was concluded that the depolarization-contraction coupling was insensitive to pH changes in the former but not in the latter frog species.


Effect of colony type and pH on surface charge and hydrophobicity of Neisseria gonorrhoeae. The effect of colonial variation and growth at pH 7.2 or pH 6.0 on the surface properties of Neisseria gonorrhoeae was assessed by the use of two-phase partitioning and hydrophobic interaction chromatography. Cells grown at pH 7.2 tended to be both hydrophobic and to possess a slight negative charge. Growth at pH 6.0 appeared to decrease hydrophobicity and to increase the negative surface charge. Possession of a series of outer membrane proteins, termed the colony opacity-associated proteins, did not appear to significantly affect charge or hydrophobicity. Piliated cells tended to have a higher negative charge than nonpiliated variants. They also tended to be less hydrophobic at pH 7.2, but became more hydrophobic at pH 6.0. The implications of these findings are discussed.


Effect of iron on surface charge and hydrophobicity of Neisseria gonorrhoeae. The effect of iron concentration during growth on the physicochemical surface properties of the colonial variants of Neisseria gonorrhoeae has been assessed by aqueous two-phase partitioning in a dextran-polyethyleneglycol system containing positively charged trimethylamino-polyethyleneglycol or hydrophobic polyethyleneglycol-palmitate. The complex effects of iron, in combination with other variables known to affect surface charge and hydrophobicity, have provided some clues as to the properties of the gonococcal surface that are important in promoting virulence.


Factors influencing adherence of group B streptococci to human vaginal epithelial cells. Factors affecting the adherence of group B streptococci to human vaginal epithelial cells in vitro were examined. Maximal adherence was achieved within 15 min of incubation of bacteria with epithelial cells. Adherence was temperature and pH dependent; maximal adherence occurred at 37 degrees C and pH 5.5. Killing of streptococci with ultraviolet light or penicillin did not affect adherence. Similarly, adherence was not altered by preincubating epithelial cells at 65 degrees C for 30 min. Thus neither bacterial nor epithelial cell viability appears to be a prerequisite for adherence. Preincubation of streptococci at 65 degrees C for 30 min resulted in a marked decrease in adherence, whereas preincubation of group B streptococci with neuraminidase was associated with a significant increase in adherence. The adherence of strains belonging to five different group B streptococcal serotypes was not altered by group-specific or type-specific rabbit antisera. These findings suggest that the site for adherence on the bacterial cell wall is heat sensitive and is marked by sialic acid, but is not related to either group-specific or type-specific antigens.


In vitro adherence of radioactively labeled Escherichia coli in normal and cystitis-prone females. Numerous investigators report data obtained using an in vitro quantitative assay for measuring bacterial adherence to epithelial cells. We found this assay to contain significant sources of error in the large variation in number of bacteria bound per cell and in the dependence on the investigator's visual counting of bacteria bound per cell. In the modified assay described here, we eliminated the need for visual counting of bacteria by incorporating the use of radioactively labeled Escherichia coli. This allowed quantitation of bacterial adherence to as many as 50,000 vaginal cells, whereas the visual counting system limits the determination to perhaps 50 cells. We feel that the use of radioactively labeled bacteria in place of the visual counting system increases the validity and sensitivity of this assay. Using the modified method, we found no statistically significant differences among values for adherence of E. coli type 04 to the vaginal cells of control and cystitis-prone women at either pH 6.4 or 4.0.


Mannose-sensitive interaction of Escherichia coli with human peripheral leukocytes in vitro. The ability of Escherichia coli which possess or lack mannose-sensitive adherence factors (adhesins) to associate with human peripheral leukocytes in vitro in the absence of serum was studied. E. coli 19+, which have mannose-sensitive adhesins, were derived from E. coli strain 19 by culturing in static Trypticase soy broth at 37 degrees C. E. coli 19-, which lack mannose-sensitive adhesins, were derived from E. coli 19 by culturing in agitated Trypticase soy broth at 30 degrees C. E. coli 19+ attached to leukocytes and stimulated the release of lysozyme but not beta-glucuronidase or lactate dehydrogenase. In contrast, E. coli 19- showed poor attachment to the leukocytes and failed to stimulate lysosomal enzyme release. During a 60-min incubation with the leukocytes, the number of viable 19+ organisms decreased, whereas the number of viable 19- remained constant. Purified type 1 pili from E. coli 19+ agglutinated the leukocytes but did not stimulate lysosomal enzyme release. Pretreatment of leukocytes with type 1 pili failed to prevent the adherence of E. coli 19+. The association of 19+ with leukocytes and subsequent release of lysozyme could be blocked by alpha-methyl-D-mannoside but not by equivalent concentrations of dextrose and sucrose. These results show that mannose-sensitive adhesins on E. coli mediate association of the organisms with leukocytes in the absence of serum components. The identity of the adhesins involved in leukocyte association has yet to be determined.


Human monocyte killing of Staphylococcus aureus: modulation by agonists of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate. This study was designed to test whether cyclic nucleotides play a role in the regulation of bacterial killing by human monocytes. Agents were tested for their ability to activate monocyte adenylate or guanylate cyclase in cell-free preparations, to increase cyclic adenosine 3',5'-monophosphate (cAMP) or cyclic guanosine 3',5'-monophosphate (cGMP) in intact human monocytes, and to modulate monocyte-induced killing of Staphylococcus aureus in vitro. Prostaglandin E1 and cholera toxin activated monocyte adenylate cyclase and inhibited monocyte killing of S. aureus. An adenylate cyclase inhibitor, RMI 12330A, reversed the prostaglandin E1-mediated inhibition of bacterial killing, thus implicating cAMP as the intracellular mediator of this inhibition. In contrast, monocyte cGMP levels were increased 5- and 17-fold by 5-hydroxytryptamine and N-methyl-N' -nitro-N-nitrosoguanidine, respectively, but neither agent was effective in modulating monocyte bactericidal activity. Thus, modulation of bactericidal activity in human monocytes did not conform to the yin/yang theory of opposing actions by cAMP and cGMP, for although monocyte-mediated killing of S. aureus was inhibited by cAMP agonists, it was not enhanced by cGMP agonists.


Quantitation of the adherence of an enteropathogenic Escherichia coli to isolated rabbit intestinal brush borders. Two assays were developed to quantitate the adherence of an Escherichia coli strain (RDEC-1) known to colonize the mucosal surface of the small intestine of rabbits to brush borders isolated from rabbit intestinal epithelial cells. In the first assay, the mean adherence per rabbit brush border was determined by counting the number of organisms adhering to each of 40 brush borders under phase microscopy. The mean adherence of RDEC-1 (11.5 +/- 0.7 per rabbit brush border) was significantly greater than adherence of two nonpathogenic strains: HS (2.7 +/- 0.4 per rabbit brush border) and 640 (0.8 +/- 0.1 per rabbit brush border). A similar distinction between the adherence of RDEC-1 and the control (nonadherent) organisms could be made more rapidly by determining the percentage of the total number of brush borders which had 10 or more adherent organisms; this second assay was used to define the optimum conditions for adherence. Maximum adherence was seen within 15 min. Adherence was temperature dependent, with adherence after 1 min at 37 degrees C being fourfold greater than that at 4 degrees C. The pH optimum for adherence was between 6.5 and 7.0, and adherence was abolished below pH 5.0. With the first, more sensitive assay, the effect of electrolytes and a number of hexoses and hexosamines on adherence was analyzed. RDEC-1 adherence was inhibited at high ionic strengths; however, adherence was not influenced at moderately high concentrations (20 mg/ml) by either d-mannose or l-fucose, in contrast to the case for other reported enteric pathogens. These two quantitative in vitro assays for adherence produce consistent results and have been used to partially characterize the adherence of RDEC-1 to rabbit brush borders.


Isoelectric focusing of Chlamydia trachomatis. HeLa-229 cells and the elementary bodies of Chlamydia trachomatis had a net negative electrical surface charge at neutral pH when measured by isoelectric focusing. Inclusion-forming and non-inclusion-forming elementary bodies focused in one band at pI 4.64.


Hydrophobic high-performance liquid chromatography of hormonal polypeptides and proteins on alkylsilane-bonded silica. Thirty-two hormonal polypeptides and nine proteins (8-65 kD) have been used to evaluate the potential of high-performance liquid chromatography on alkylsilane-bonded silica for separating and recovering biologically active compounds of this type. The basic method used was gradient elution with acetonitrile in an acid phosphate buffer. Variation of key chromatographic parameters demonstrated that low pH (less than 4.0) and high buffer molarity (greater than 0.1 M) are mandatory for reproducible high efficiency polypeptide chromatography. Simple NaCl-HCl mixtures of appropriate acidity and molarity could be substituted for the acid phosphate buffer, with the advantage of minimising non-physiological ion contributions to eluted materials. Minor selective effects were noted with different organic modifiers, but variation of other parameters, including choice of specific alkylsilane packings, did not materially influence separations. Under optimal conditions all of the polypeptides tested could be efficiently chromatographed, and many simultaneously resolved, as could most of the proteins tested. Three of the more hydrophobic proteins could not, however, be eluted from the alkylsilane packings. Retention orders of smaller compounds (less than 15 residues) generally correlated with the sum of the Rekker fragmental constants of their strongly hydrophobic residues. Larger polypeptides showed numerous anomalies when ranked by this means, however, limiting its predictive value. The separation of at least eighteen discrete components from a partially-purified posterior pituitary extract has demonstrated the capability of alkylsilane-type reversed-phase packings for the hydrophobic high-performance liquid chromatography of complex biological mixtures.


Determination of sulthiame, tetrahydro-2-p-sulphamoyl-phenyl-2h-1,2-thiazine-1,1-dioxide, in plasma at therapeutic concentrations, using high-performance liquid chromatography. A specific and sensitive liquid chromatographic method for the determination of sulthiame in small (0.5 ml) plasma samples is described. After adding an internal standard, a direct extract of the sample is examined by reversed-phase liquid chromatography with ultraviolet spectrophotometric detection. The method is rapid, simple and capable of determining plasma levels after therapeutic ingestion of sulthiame.


Simple high-performance liquid chromatographic method for the separation of 3,6-diacetylmorphine hydrochloride (heroin) and hydrolysis products. The application of reversed-phase high-performance liquid chromatography to the measurement of 3,6-diacetylmorphine (DAM) hydrochloride and its degradation products is described. This method has been applied to study the kinetics of the DAM hydrolysis at 26 +/- 0.1 degrees and 48 +/- 0.1 degrees. The hydrolysis of DAM involved a two-step first-order sequential mechanism between pH 3 and 8.6. The first-order rate constants of each step at all pH levels have been determined. The pH rate profile was constructed from kinetic measurements and demonstrated that stability of DAM hydrochloride solutions was optimal at pH 4.3. This information is being applied to the development of parenteral dosage forms of DAM hydrochloride.


Separation of drugs by high-performance liquid chromatography with porous polymer resins. The separation of cold drugs and neuroleptics by high-performance liquid chromatogarphy with the porous polymer resin DVB-MCL-O (or 11-30-0), which is a styrene-divinylbenzene-methyl methacrylate copolymer substituted with hydroxymethyl groups, was studied. This copolymer was compared with the commercial porous polymers Hitachi gel 3011, 3011-0 and 3030. A very small theoretical plate height was obtained by using DVB-MCL-O and methanol-ammonia solution (99:1) as the stationary and mobile phases, respectively. This combination was found to be the most suitable for the rapid separation of condensed aromatic ring compounds.


Displacement electrophoresis in gel as a technique for separating proteins on a preparative scale. A preparative displacement electrophoresis apparatus has been developed for the fractionation of proteins and other macromolecules. The separation is carried out down a vertical annular gel which is supported by a cylindrical glass cooler. The gel is protected from evaporation by a heavy inert insulating liquid with the terminating electrolyte floating on it. Very high potential drops and instabilities in the terminating electrolyte are avoided by continuously lowering the level of the inert liquid during the course of the separation. Fluorescent mobility markers have been synthesized, which make it possible to follow the progress of the separation and to divide the gel into fractions, once the separation is complete.


Synthesis of highly diversified carrier ampholytes. Evaluation of the resolving power of isoelectric focusing in the Pi system (alpha-1-antitrypsin genetic polymorphism). The use of condensing reagents such as epoxypropanol, diepoxyoctane, acrylamide and N,N'-methylenebisacrylamide in the synthesis of carrier ampholytes increased the diversity of amphoteric components. The quality of these synthetic carrier ampholytes has been tested in the separation of variants of alpha-1-anti-trypsin, a genetic polymorphism called the Pi system. A resolving power of the order of 0.005 pH unit was obtained.


Analysis of therapeutic and commonly abused drugs in serum and urine by gas-liquid chromatography using a photoionization detector. A simple, rapid and sensitive gas chromatographic procedure using the photoionization detector (PID) was developed for the detection and quantitation of several drugs in serum and urine. In order to evaluate the performance of the PID, the results were compared with those of the flame-ionization detector (FID). The data indicate that the PID is 8-16 times more sensitive than the FID for the drugs studied in the barbiturate group. Excellent reproducibility was found for samples quantitated with the PID on a routine basis. The PID and FID produced statistically similar results on extracted serum samples. The correlation coefficient was 0.99. The PID also produced chromatograms with less background than those obtained with the FID for many extracted serum samples. The advantages of the PID for drug analysis in biological fluids include simplicity of operation, lack of solvent response, universal drug response, non-destructive character and stability.


A study of the effects of nicotine in the intact dog and the propensity for arrhythmias. This is a study of the effects of nicotine exposure in the intact dog on the propensity for arrhythmias. The mean effective and total refractory periods were prolonged after nicotine. The diastolic current threshold was increased after nicotine in every animal, yet the threshold for repetitive firing was decreased in four animals, all of which had individually prolonged relative refractory periods. We conclude that nicotine may increase the propensity for arrhythmias when an appropriately timed premature stimulus, of sufficient strength, encounters a ventricle with sufficient dispersion of refractoriness to allow re-entrant arrhythmias to be sustained.


Influence of indicating enzyme reaction on apparent creatine kinase activity creatine kinase in serum, VII. Comparison of the indicative systems yeast glucose-6-phosphate dehydrogenase/NADP+, leuconostoc glucose-6-phosphate dehydrogenase/NADP+ and leuconostoc glucose-6-phosphate dehydrogenase/NAD+ showed excellent correlation and no differences in apparent creatine kinase activity with the two methods using NADP+. By using NAD+ with the leuconostoc enzyme enzyme relative recovery of apparent creatine kinase activity is lower due to interference of other serum constituents. The mean value of the relative differences versus methods using NADP+ was 5.8% in our experiments.


Fluorometric assay of the arylsulphatases in human urine. A method is described which differentiates arylsulphatase A and arylsulphatase B in human urine. 4-Methylumbelliferyl sulphate serves as the substrate, and silver ions are used to inhibit arylsulphatase A activity. Using fresh urine it is possible to obtain separate values for arylsulphatase A and B when both are present, thus providing a diagnostic test for metachromatic leucodystrophy.


Studies on the permeability of the glutamate receptor at the insect neuromuscular junction. Voltage clamp studies of the post-synaptic membrane of the locust neuromuscular junction have shown that the transmitter substance and L-glutamate cause an approximately equal increase in permeability to sodium and potassium. The changes in reversal potential caused by altering external potassium, but not external sodium, were similar to those predicted by the Goldman equation. The ionic channels of the glutamate receptor had a high permeability to a variety of inorganic and organic cations, indicating relatively non-selective channels of size approximately 0.6 x 0.4 nm.


Glutamate potential : differences from the excitatory junctional potential revealed by diltiazem and concanavalin A in crayfish neuromuscular junction. 1. The effect of diltiazem and concanavalin A (Con A) on the crayfish neuromuscular junction was investigated in order to compare the action of L-glutamate with that of the excitatory transmitter. 2. When diltiazem (0.3 nM) was added to the perfusion fluid, the iontophoretic glutamate potential was reduced to about half, whereas the amplitude of excitatory junctional potentials (EJPs) increased by about two times. 3. Dose-response curves of L-glutamate suggested that diltiazem acted in a non-competitive manner. The decrease in amplitude of the glutamate potential caused by diltiazem was not due to the acceleration of desensitization of the glutamate receptor. 4. The increase in amplitude of EJPs caused by diltiazem was due to the increase in membrane resistance. The quantal content and size of extracellular EJPs were not affected by diltiazem. 5. In normal saline, bath application of glutamate decreased the amplitude of both glutamate potentials and EJPs because of desensitization of the glutamate receptor. The decrease in amplitude of the glutamate potential was completely prevented by previous application of Con A (10(-6) M). On the other hand, Con A had no influence on the decrease in amplitude of EJPs. 6. Some possible explanations of these pharmacological differences between glutamate potentials and EJPs revealed by diltiazem and Con A are considered.


Is glutamate the transmitter of crustacean motoneurons? 1. Bath-application of L-glutamate to crayfish opener muscle causes depolarization and resistance changes which both increase with falling temperature. At temperatures above 15 degrees C there is usually a resistance increase, at lower temperatures the resistance is decreased. 2. Meso-gamma . gamma'-diaminosuberic acid-dihydrochloride (meso-di-GABA) and dl-diamino-nonanedicarboxylic acid dihydrochloride (C-9) were newly synthesized as potential glutamate blockers. 3. Meso-di-GABA (10(-4) to 10(-3)M) usually caused a significant increase (15 degrees C) or decrease (7 degrees C) of membrane resistance and slight depolarization. Excitatory junction potentials (ejps) were reversibly depressed or blocked while the effects of glutamate were potentiated. The depression or block of neuromuscular transmission was not prevented by picrotoxin or by concanavaline A. 4. C-9 (3 x 10(-4) M) depressed or blocked the effect of applied glutamate with little or no effect on ejps. 5. The results are best explained by assuming that bath-applied glutamate acts mainly on extrasynaptic receptors. Meso-di-GABA is assumed to block synaptic receptors and to activate non-synaptic receptors while C-9 seems to act mainly as a blocker of glutamate action on non-synaptic receptors.


[The monoamines in molluscs. I. Catecholamines: biosynthesis, disposition and inactivation (author's transl)]. The central nervous system of the mollusc Helix pomatia, like that of other molluscs, contains a very high level of dopamine. However, noradrenaline is weakly represented. These characteristics apply to the peripheral nervous system and more particularly to the heart. The study of the phenomena taking part in the synthesis and inactivation of catecholamines shows that these processes are not different in vertebrates and molluscs. Thus, in the particular case of Helix pomatia the synthesis of catecholamines is carried out by tyrosine hydroxylase, aromatic amino acid decarboxylase and dopamine-beta-hydroxylase. These enzymes are not only active in the ganglia and nerves, but also in the peripheral nervous system. The monoamines are associated with granules. The synthesized enzymes in the pericarya migrate due to the axonal flow and accumulate in the intracardiac nerve endings. In Helix pomatia, the enzymes participate actively in the local synthesis of catecholamines using the precursors tyrosine and DOPA. We have little information on the uptake of dopamine by nervous structures, but it would seem that this phenomenon seems to play an active role in the synaptic inactivation of dopamine. The glial elements also play a part in uptake and inactivation. In most species the nervous system has very little monoamine oxidase, and there is even less in the heart. The enzymic activity depends on substrates and is more active with dopamine than with 5-hydroxytryptamine. The exact localization of monoamine oxidase in the tissues is unknown. However, we believe that it plays a part in the neuronal regulation of dopamine levels and in its synaptic inactivation. The same applies for catechol O-methyltransferase.


Transgastric highly selective vagotomy (HSTRV) without drainage. Preliminary report of a new simplified procedure of treatment of duodenal ulcer. The technique of preserving the antral vagal nerve supply of the stomach and division of the gastric branches of the nerves of Latarjet is common to both operations, but by replacing the transection of the hiatal cardioesophageal vagus nerve branches (including the nerve branches accompanying the arteries entering the fundus of the stomach) with a transgastric intramural transection and excision of all nerve fibers entering the fundus, a highly selective vagotomy is achieved. Completeness of HSTRV is controlled intraoperatively by a gastric pH meter and by measuring the oxygen tension of the gastric mucosa. One year to 18 months after application of HSTRV in 74 patients with uncomplicated duodenal ulcers, mortality was nil, morbidity insignificant, the previous ulcer symptoms no longer present, and dumping syndrome, recurrence and other significant complications were not observed.


Evaluation of urinary alkaline ribonuclease activity in the assessment of subclinical malnutrition in weanling rats. The sensitivity of the hydroxyproline (OHP)/creatinine (Cr) index and the free urinary alkaline ribonuclease activity as indices of nutritional status have been compared using rats as an experimental model. The results have revealed that the OHP/Cr index is a better biochemical parameter than the urinary alkaline ribonuclease activity for indicating a subclinical degree of malnutrition.


[Severe pneumococcal infections of adults. 100 cases collected in three years (Claude Bernard Hospital, Paris) (author's transl)]. After retrospective in intensive care unit of 100 severe cases of pneumococcal infection in three years, the authors analyse the circumstances of onset (occurring in autumn of winter), the general status (without evident high risk population), the symptomatology (84% of meningitis, 30% of pneumonia), the origin of infection (essentialy otitis media in meningitis). The case fatality rate is 39%. Frequency of multiple visceral localisations and of bacteremias is emphasized.


[Pneumococcal infections in military quarters (author's transl)]. A retrospective study on prevalence of pneumococcal in French military recruits of two military districts has been made in 1976 and 1977. Among 185,000 adults, 19 pneumococcal diseases were registered (0,1%). 15 were respiratory infections (10 acute pneumonia). The agent has been isolated of blood (the half) and of others samples : expectoration... (the half). In despite of geographical and climatic differences of two districts, the incidence of pneumococcal pneumonia is the same. The low prevalence of that infection results from the age, selection, and medical surveillance of the population studied.


[Epidemiologic features of pneumococcal meningitis in Africa. Clinical and serotypical aspects (author's transl)]. Pneumococcal meningitis, because of their frequency and their severity, are regarded as an important problem of Public Health in Africa. In a great number of African countries, particularly Equatorial and Central Africa, the pneumococcus is the first agent of bacterial meningitis. The annual prevalence is estimated as about 14/100 000 persons. The case fatality rate (on 1 600 cases) is 49,5% ; the annual mortality reaches about 7/100 000 (28 000 annual deaths in Africa). The babies and the old persons are more exposed to the risk, with an annual prevalence of 28,5/100 000 before five years old, and of 16,1/100 000 after sixty years old. The risk is small between five and forty five years old. The risk is very high in patients homozygous for sickle-cell disease. The spread of all detected serotypes, by descending frequency is : 1, 5, 6, 3, 23, 12, 2, 14, 9, 18, 19, 4, 8, 29, 40, others (Danish system of nomenclature). The distribution according to age is indicated by the authors. A vaccine with only 8 serotypes (1, 5, 6, 3, 23, 12, 2, 14) could cover 80% of serotypes in Dakar. For the babies, addition to pneumococcal vaccine with polyribose phosphate of Haemophilus influenzae b, could be useful, because high prevalence of meningitis with this germ before five years old in Africa.


[Contribution of counter-immunoelectrophoresis (electro-immunodiffusion) to the diagnosis of pneumococcal meningitis (author's transl)]. The author has used the counter-immunoelectrophoresis (CIE) comparatively with the routine bacteriologic method, in 220 pneumococcal meningitis at Dakar hospital. The omni-serum of Statens Serum Institute Copenhague applied to CSF, leads to detection of the quasi whole of antigens. The use of serums-pools is not essential in routine because his small supplement of information. The score of CIE is the same that the results of bacteriologic method, but the CIE is alone positive in 10,9% of cases. The detection of antigens in blood is interesting for the diagnosis (+ 2,3%) and the prognosis.


[Distribution of Streptococcus pneumoniae serotypes in Nantes Hospital (1969-1978) (author's transl)]. Between 1969 and 1978 at the CHR of Nantes we isolated Streptococcus pneumoniae from 815 swabs taken from 591 patients and which provided 595 different strains. Serotyping of all the strains was carried out using the capsular reaction test. The prevalence of the different serovars varied according to the year and the type of swab. No resistant strains to benzylpenicillin or ampicillin were observed. There was significant resistance to sulphonamides and tetracycline : 24,3 and 29,6% respectively. The American vaccine containing the greatest number of serovars was effective for only 69,8% of the strains isolated in Nantes.


[Pneumococcal capsular types of clinical specimens. Lyon: 1972-1977 and 1978 (author's transl)]. 878 strains of Streptococcus pneumoniae were tested during two periods : 667 strains from 1972 to 1977 and 211 strains during 1978. Strains were isolated from spinal fluids, blood, peritoneal fluids, urines, exudate from respiratory tract except sputum. In polymicrobial specimens, only the predominant species were serotyped. From 1972 to 1977, 53,3% of strains are typed and 6 serotypes and pools are prevalent among 68,5% of typed strains, the most frequent are : 6 - D - 18 - 19. During the second period (1978) 82,5% of strains are typed, 9 serotypes are prevalent among 68,5% of typed strains, the most frequent are : 6 - 19 - 23 - 3. During 1978, 27,6% of strains are isolated from child wards, others from adults wards. A comparison of the relative frequencies of the serotypes in the two wards shows that the following 10 serotypes are the most frequent: 6 - 19 - 23 - 3 - 18 - 1 - 8 - 9 - 14 - 4.


[Pneumococcal serotyping. Multicentric inventory in hospital. Years 1977-1978 (author's transl)]. For a period of 17 months, 670 pneumococci, mostly isolated in the Paris area, have been typed with contercurrent-immunoelectrophoresis ; 338 of them come from cases of pneumonia, bacteremia, meningitis and acute otitis media. An important regrouping of the most frequent serotypes among the 83 known serotypes makes possible a vaccinal prophylaxis. The tetradecavalent vaccine which is now for sale in USA gives, in the four main pathologies of this enquiry, a coverage superior to 80 percent. Choosing the 14 most frequent serotypes of the four main pathologies of their data the authors propose the following vaccinal formula : 1, 3, 4, 5, 6, 7, 8, 10, 12, 14, 15, 18, 19, 23.


[Psychopharmacotherapy: present status and trends]. The psychotropic preparations developed and introduced in recent years are discussed in the form of a synoptical paper. The information given mainly concentrates on the attempts to find antidepressants without cardiotoxic side-effects, psychoneuroleptics without extrapyramidal side-effects and long-acting or depot preparations. The survey is restricted to psychotropics in a narrow sense (with an antipsychotic action) and to preparations that are produced in the GDR or imported or made available for the clinical testing of which the reporting clinic (Dresden) was in charge.


Changes in rat gastric proteases with age: effect of hydrocortisone. Gel filtration on Sephadex G-75 of rat gastric mucosal preparation shows two peaks of proteolytic activity. These peaks differ at different ages of animals. The proteolytic activity of the gastric mucosa is spread over a wider range of pH in younger animals than older ones with a shift from higher pH towards lower pH values with increasing age. Hydrocortisone injection to nine day-old rats results in qualitative changes of gastric mucosal proteases, the proteolytic activity pattern of young treated animals being similar to that of untreated adult rat.


Search for antiglucocorticoid activity in rat liver in vivo. Estradiol and testosterone both lowered endogenous liver glycogen and at 20-fold higher doses impaired triamcinolone acetonide mediated glyconeogenesis in adult adrenalectomized male rats. Neither steroid influenced liver tyrosine transaminase although tryptophan pyrrolase activity was depressed by testosterone. Progesterone increased liver tryptophan pyrrolase but did not influence other parameters. Cortexolone did not alter either of these processes whereas cortisol induced both enzymes and, at much higher dose levels, gluconeogenesis. Binding of 3H-triamcinolone acetonide to its cytoplasmic receptor in vitro was left unaffected in presence of 20-fold greater concentration of either sex steroid but almost totally abolished by cold, homologous molecules. Similar results were obtained by 3H-cortisol except that estradiol partially competed for 3H-cortisol binding sites even at 20-fold greater concentrations of cold estradiol. Separation on DEAE-cellulose-52 and Ultrogel 44 columns revealed binding of all steroids to macromolecules of comparable physicochemical properties although the ratios of binding to the various subpopulations of the receptor were a function of the steroid in question. These results are discussed in terms of sex steroid binding to different moieties of a complex, heterogeneous, polymorphic protein rather than inhibition of binding to the active configuration acquired in presence of an inducer.


Central action of narcotic analgesics. V. Participation of serotonin in the mechanism of action of narcotic analgesics. The influence of serotonergic system on the changes in locomotor activity of mice and rats brought about by morphine, fentanyl, codeine and pentazocine and on morphine induced catalepsy in rats was studied. p-Chlorophenylalanine (pCPA) did not affect the behavioral changes produced in mice by morphine, fentanyl, codeine and pentazocine but reduced the behavioral depression produced by these drugs in rats. 5-Hydroxytryptophan (5-HTP) but not tryptophan (TP) reversed the action of pCPA on the effect of morphine and fentanyl. After reserpine the depression produced in rats by morphine and fentanyl was more pronounced. TP did not change the depression produced by combination of reserpine and morphine but counteracted the depression observed after combination of reserpine and fentanyl. In mice reserpine protected against hypermotility produced by morphine or fentanyl and TP potentiated the depression produced by the combination of reserpine and morphine or reserpine and fentanyl. Serotonin precursors, 5-HTP and TP evidently potentiated the morphine induced catalepsy. pCPA counteracted only the enhancement of the catalepsy observed after TP administration. Naloxone abolished the catalepsy after combined treatment with morphine and TP. Similarly but weaker acted cyproheptadine. The results suggest that the serotonin system plays a role in the effects of morphine and fentanyl on rat locomotor activity. An increase in the cerebral serotonin level increases the morphine catalepsy in rats.


Comparative study of erythromycin, amoxicillin and ampicillin antimicrobial activity against human respiratory tract pathogens. An in vitro test system was used to compare the antimicrobial activity of erythromycin, amoxicillin and ampicillin against respiratory tract pathogens isolated from man. The minimum inhibitory concentrations (MICs) of fresh clinical isolates of Streptoccus pyogenes, Streptocuccus pneumoniae, Staphylococcus aureus and Haemophilus influenzae to the macrolide and penicillins ranged between 0.01 and 0.9 microgram/ml. The microbes were exposed to each antibiotic for approximately 3 h at 1x,2x and 5x the relevant MIC. Irreversible surface defects and intracellular lesions were resolved by scanning and transmission electron microscopy in all antibiotic-treated bacterial species, irrespective of the antimicrobial used. In each case, inhibition of growth was recorded by turbometric assay; no significant difference was observed among the declining slopes of post-dosing growth curves for either erythromycin-, amoxicillin- or ampicillin-treated pathogens. The experimental observations show that the onset of antimicrobial activity and the bactericidal effectiveness of equipotent concentrations of erythromycin, amoxicillin and ampicillin were comparable in this study. The results complement previous clinical, bacteriologic and ultrastructure studies in vivo and demonstrate the contribution of the combined in vivo/in vitro study design for better understanding of antimicrobial activity in human respiratory tract infections.


[The influence of a beta-adrenolytic premedication on cardiovascular parameters and plasma free fatty acids during esophago-gastro-duodenoscopy (author's transl)]. Three groups of patients with different premedications were examined for changes of blood pressure, heart rate, ECG and plasma free fatty acid levels during esophago-gastro-duodenoscopy: Group A was premedicated with Bunitrolol, group B was premedicated with Hyoscin-N-butyl-bromide and diazepam, group C was endoscopied without premedication. The pulse rate rose significantly less in group A than in groups A and C; the same phenomenon was observed with regard to the systolic blood pressure. Premature beats occurred in all 3 groups: 32 per cent of the patients in group A, 43 per cent in group B and 60 per cent in group C had at least occasional premature beats; an accumulation of premature beats however occurred significantly less frequently in group A than in groups B or C. A drop of the ST-part of the ECG occurred with about the same frequency in each group. An increase of the plasma free fatty acids, which was noted in groups B and C, could be observed in Group A. A pre-endoscopic medication of beta blocking agents could be a useful measure in patients with labile arterial hypertension, vegatative dysregulation and a hyperkinetic heart syndrome.


[Neurotropic anisamides (author's transl)]. Evolution of the opinion of the french clinicians, during the 10 last years, towards the chemical group of the neurotropic anisamides : metoclopramide, sulpiride, sultopride, and tiapride. The good tolerance of these neuroleptic compounds, their low degree of activity on vigilance, are original characteristics of this new group of psychotropic drugs : polyvalent, or "multiple potential" neuroleptic agents.


Alcohol-induced switching over of metabolic flux in Streptomyces noursei JA0 3890b. Short-chain alcohols, benzyl alcohol and Tween 20 were found capable of switching over the metabolic flux in Streptomyces noursei JA 3890b from the preference of oxidative deamination of alanine towards the reinforced acquisition of NH4+. These changes were correlated to the decrease of the ratio of saturated to olefinic fatty acids in the mycelium, suggesting that alcohols and other polar lipophilic compounds can interfere with the biosynthesis and the function of the cytoplasmic membrane in Streptomyces.


[Steroid-transforming enzymes from microorganisms. XI. Reversibility of the dehydrogenation reaction of the steroid-1-dehydrogenase from Nocardia opaca]. Highly purified preparations of the 4-en-3-oxosteroid: (acceptor)-1-en-oxidoreductase from Nocardia opaca have been investigated in both types of reactions: 1.2-dehydrogenation of the 4-en-3-oxo-derivative and 1.2-hydrogenation of the 1.4-dien-3-oxo-derivative. It was not possible to separate the hydrogenating activity from the dehydrogenating activity by affinity chromatography, disc electrophoresis, SDS-electrophoresis, and isoelectric focusing techniques. The pure enzyme preparation is discussed as only one FAD depending protein acting in response to the system as a dehydrogenase as well as a reductase.


[Selective proximal vagotomy (SVP); technical details (author's transl)]. At present the technique of selective proximal vagotomy (SVP) seems to be standardized. Nevertheless, the surgical procedure is practiced by many authors in a different way concerning the proximal and distal borderline of denervation. In our opinion pylorplasty should only be performed in those patients suffering from retention or stenoses.


The latex agglutination test in virus diagnostic: identification of poliomyelitis and coxsackie viruses. We examined the practical value of the Latex agglutination test (LA test) in diagnostic virology. Viruses isolated from 125 specimens were identified in the LA test. All results were in agreement with those observed by a neutralization test. The LA test appears to be superior to conventional methods because of its easy handling and a rapid and reliable identification.


A simple method of detecting staphylococcal hemolysins. A modification of the "one-plate method" for detection of staphylococcal hemolysins has been described. Bacterial strains of Staphylococcus aureus, Streptococcus agalactiae and Cornebacterium pseudotuberculosis were replaced by their prepurified hemolytically active exosubstances: beta-toxin, CAMP-factor, and, the exosubstance of Corynebacterium pseudotuberculosis called COREX. By means of the modification described, exact detection of hemolysins in possible with staphylococcal strains producing one type of hemolysin as well as with strains producing a combination of hemolysins.


[An oral enteritis-vaccine composed of twelve heat inactivated Enterobacteriaceae. 1. Communication: Theoretical and epidemiological considerations (author's transl)]. The infectious diseases of the human intestinal tract which are caused by bacteria must be distinguished into two groups on account of their different pathogenesis: the cyclic infections (typhoid fever, parathyphoid fever) and the local infections (cholera, dysentery, Salmonella enteritis, dyspepsia coli infections). The local infections of the intestine do not cause a systemic but only a local immunity of the intestinal mucosa. It is necessary therefore to induce local immunity as active immunoprophylaxis by orally administering inactivated antigens. The twelve-fold enteritis vaccine consists of full antigens of 6 Salmonella strains, 2 Shigella strains, and 4 enteropathogenic coli strains pretreated by heat-inactivation (3 min/100 degrees C). The following should be considered as indication to effect active immunoprophylaxis against enteritis: Travelling into tropical and subtropical countries, people in emergency areas, children in developing countries, workers in food industries, secondary hospital infections, and carriers. The active mouse protection test revealed that oral immunization with enterobacteriaceae does not only deliver the well-known specific effect but also a non-specific effect which included the protection against other related enterobacteriaceae. Moreover, the specific component of the combined vaccine is enhanced by heterologous components. The resulting synergism or the adjuvantal effect, respectively, allows to employ a relatively limited number of germs which are selected on the basis of high pathogenicity, good immunogenicity, and great frequency. The first field trial with the twelve-fold vaccine was completed successfully: Following an infection with Salmonella which affected the employees of a fowl slaughtery, eight different species could be demonstrated; the above described polyvalent vaccine was orally administered and proved to be successful. The latter case clearly demonstrates the fast-acting effect of the vaccine on account of the heterologous bacterial antigens contained therein. 51 out of 60 Salmonella carriers excreted germs of a different antigen pattern not contained in the vaccine. However, the good results obtained showed that the species chosen for the vaccine were still sufficiently effective to cover the wide spectrum of other species of related enterobacteriaceae.


Mammalian serum susceptibility of Serratia marcescens: detection of three human serum susceptibility categories. A total of 65 strains of S. marcescens, including 36 currently employed O- and H-antigen reference strains, were examined for their susceptibility to the bactericidal activity of 80 vol % of fresh human serum. The majority of strains (57 = 87.6%) proved 'delayed serum-sensitive' (DSS); 4 strains (6.2%) were 'promptly serum-sensitive' (PSS), whereas 4 strains (6.2%) resisted (NSS) complement-mediated killing by human serum. Fresh sera obtained from 7 adult human volunteers yielded essentially identical kinetic killing data against representative NSS, DSS and PSS strains of S. marcescens. These observations were interpreted as further justification for the assignment of clinical isolates of S. marcescens to 3 categories of human serum susceptibility: DSS, PSS and NSS. Species differences among fresh sera from sheep, rabbits and guinea pigs, as contrasted with fresh human serum, were noted. In general, PSS strains of S. marcescens were killed in a slightly delayed fashion; DSS strains of S. marcescens were killed in an unpredictable kinetic pattern by sheep and rabbit sera, whereas fresh guinea pig serum entirely failed to kill selected DSS isolates of S. marcescens.


[Comparison of four recently introduced cephalosporins with respect to probability of resistance in multiresistant strains of Escherichia coli, Proteus mirabilis and Klebsiella spec. (author's transl)]. Strains with the same number of resistances were arranged in so-called resistance classes. Nine classes of resistance (0 to greater to or equal to 8) were formed by means of ten standard chemotherapeutics; the four new cephalosporins were excluded. For every resistance class frequency of cephalosporinresistance was described as coefficient ranging from 0 to 1 (Fig. 1). In Cephalothin the coefficients were markedly rising only in 6 (7)-fold resistant strains of the species examined. Similar but somewhat reduced rising of coefficients was also observed in Cefaclor and Cefamandole. In Cefaclor this is particularly evident for E. coli, whereas in Cefamandole, it concerns Klebsiella spec. In the other species rising of coefficients of Cefaclor and Cefamandole are less marked. The probability of restance in multiresistant strains are therefore distinguished more clearly from that of Cephalothin. Cefuroxime and Cefoxitin take a special position because the probability of resistance does not rise in multiresistant strains. The coefficients of Cefoxitin do not show any recognizable dependance on multiresistance. For clinical purpose the following conclusions can be derived: Because of their effectiveness in multiresistant strains Cefoxitin and Cefuroxime are suitable for empiric use in intensive care units where many multiresistant Klebsiella-strains are to be expected. Cefamandole on the other hand is characterized by a rising probability of resistance in multiresistant strains. Therefore it should only be given after antibiotic testing. Cefaclor, a new oral cephalosporin, will be introduced specially for outpatients where multiresistant strains are rarely found.


[The distribution of minimal inhibitory concentrations of recently introduced cephalosporins in multiresistant strains of Escherichia coli, Proteus mirabilis and Klebsiella spec. as revealed by zone sizes of a standardized agar diffusion test (author's transl)]. Strains of a species were divided into two groups according to the number of resistances (less than or equal to 4, greater than or equal to 5) using 10 standard chemotherapeutics regularly examined, the new cephalosporins not being among them. These groups of less than or equal to 4- and greater than or equal to 5-fold resistant strains were compared for each cephalosporin tested (Fig. 1). The most different distributions of zone diameters (of both groups) were seen in Cephalothin, whereas in Cefoxitin and - with little limitations - also in Cefuroxime in the main these distributions did not differ; they covered the same field. The distributions of Cefaclor and Cefamandole took an intermediate position. With respect to the two groups similar observations were made for E. coli, proteus mirabilis and Klebsiella spec. The differences between the two groups were most marked in Klebsiella strains. E. coli exhibited the smallest differences (Fig 1). On the assumption that the distribution of zone diameters reflect that of MIC's it can be concluded that nearly all of the Cefaclor- and Cefamandole-sensitive multiresistant strains have more elevated MIC's than those with only less than or equal to 4 resistances. On the other hand it must not be expected that MIC'S OF Cefoxitin and Cefuroxim are rising in multiresistant strains. It could be demonstrated that the different qualities of the recently introduced cephalosporins revealed in multiresistant strains can be explained by different dependences on mechanisms of Cephalothin-resistance (Fig. 2). This resistance is much more frequent in greater than or equal to 5-fold resistant strains. Recommendations for clinical use derived from these results are discussed.


Identification of anaerobes on the Minitek System, compared to a conventional system. The Minitek Miniaturized System (BBL) was compared to a conventional method (V.P.I.) for the indentification of anaerobes. Anaerobiosis was achieved by using the GasPak system (BBL) and a glove box. Gram staining, colonial morphology, gas-liquid chromatography and biochemical reactions as detailed in the Virginia Polytechnic Institute anaerobe laboratory manual were compared to the biochemical results obtained on the Minitek system. A total of 32 anaerobes was used. The percentage of correlation was an overall 98.2%. Discrepancies were found mostly in the production of indole, the reduction of nitrate, and the hydrolysis of aesculin. A further 95 anaerobes were tested on these three reactions, and found to give an overall agreement of 92.9%. It was found necessary to use some additional tests as well as gas-liquid chromatography for definitive identification. The microsystem was also evaluated as to time saved, cost and ease of use.


[Studies of the purification of the exotoxin of Bacillus cereus (author's transl)]. The exotoxins of Bacillus cereus show haemolytic, lethal, Phospholipase-C- and enterotoxigenic activities. The enterotoxigenic activity is regarded to be the factor which causes food poisoning in man. Efforts to purify the B. cereus exotoxins by precipitation with ammonium sulphate and subsequent chromatography on Sephadex-G-75 and Biogel-P-60 columns were partially successfull. Haemolysin and Phospholipase-C could be separated by gel-chromatography, they demonstrated partial identity on gel-diffusion agar. The lethal and enterotoxigenic activities could not be separated from the other toxins and remained heterogenous. No immunological relationship was found between Clostridium Type A alpha toxin and enterotoxin and the exotoxins of B. cereus.


Isolation of antigenic variants from leptospiras grown in vitro and from heart blood of guinea pigs inoculated with a clonized strain of Leptospira. A clonized culture of Leptospira interrogans serovar copenhageni strain Shibaura (Cl-Shibaura) was inoculated into guinea pigs. The heart blood of the guinea pigs, obtained at the febrile stage and inoculated onto the solid serum medium containing the homologous immune serum, produced large and small colonies. The serological examinations revealed that the large colonies were found mainly to be the antigenic variants, while the small colonies were mostly the parent. The antigenic variants accounted for 16.4% of all the colonies from the blood of the guinea pigs infected with Cl-Shibaura, and for 1.2% of all the colonies from the blood of the guniea pigs infected with Cl-Shibaura, and for 1.2% of all the ll colonies. The serological examinations revealed that the large colonies were found mainly to be the antigenic variants, while the small colonies were mostly the parent. The antigenic variants accounted for 16.4% of all the colonies from the blood of the guniea pigs infected with Cl-Shibaura, and for 1.2% of all the colonies from the culture of Cl-Shibaura in the normal serum medium. Antigenic variants were also isolated in vitro from the culture of 2 other serovars. The fact that the frequency of the antigenic variants of leptospiras was higher in vivo than in vitro is discussed.


[Problems of serological diagnosis of chronic pyelonephritis (author's transl)]. Using the passive hemagglutination test, 588 sera of patients with chronic pyelonephritis and 163 sera of pregnant women with persistent bacteriuria were investigated for the presence of antibodies aginst the enterobacterial common antigen (ECA). 10.2 percent of titers in the pyelonephritis group and 6.1 percent of titers of the pregnant women showed values higher than 1:16. The results were compared to a group of blood donors where 0.9 percent of the sera had pathological titers. The demonstration of ECA antibodies does not seem to be suitable for the diagnosis of urinary tract infections.


[Hexacyanoferrate-compounds as indicator substances for the efficacy of antimicrobial agents to desulfuricants (author's transl)]. Hexacyanoferrate-compounds are suitable to indicate the efficacy of antimicrobial substances to sulfate-reducing bacteria. They act as a cytochemical indicator system. (Stübner, 9), e. g. K3FeIII(CN)6 showes FeS formation before any visible blackening of the medium. By using hexacyanoferrate compounds it is easier to determine the efficacy of antimicrobial agents. In addition a microscopical control is recommended to detect damaged or avital bacteria in the limiting concentrations of the agents.


The effect of Toxoplasma cell fractions and mycobacterial immunostimulants against virulent Toxoplasma gondii in mice. Toxoplasma gondii tachyzoites were disrupted in a Ribi cell fractionator and separated into cell walls and protoplasm by differential centrifugation. These products were used alone or combined with a mycobacterial glycolipid (P3) and injected either as oil-in-water emulsions or incorporated in Freund's incomplete adjuvant. Mice were vaccinated by intravenous or intradermal routes and challenged intraperitoneally with a highly virulent strain of Toxoplasma gondii. A local granuloma formation was induced after i.d. inoculation of Toxoplasma vaccines containing P3 as this glycolipid enabled an adherence of the antigens on the mineral oil droplets. The adjuvant effect of P3 on antibody formation was also observed. Most of the fractions showed a low, but statistically significant prolongation of survival time. Vaccination by the i.v. route with homologous or heterologous antigens, including Trypanosoma cruzi, were not significantly effective, with the exception of a high dose of Toxoplasma protoplasm associated with P3.


[The dynamics of humoral and cellular immunity changes in patients with acute phase of trichinellosis (author's transl)]. 21 patients with acute trichinellosis have been studied. The behaviour of IgG, IgA and IgM in the serum of patients as well as the percentage of lymphocytes T and B was the aim of these studies. Statistically significant increase of IgG in serum has been observed since the third week of the clinical observation. During the whole period of observation the level of IgA was lowered--though the decrease was not statistically significant--whereas the level of IgM increased considerably. Decreased percentage of lymphocyte B in the peripheral blood during the first week of the clinical observation, later on increased significantly. The percentage of T lymphocyte was lowered during the whole period of the clinical observation of patients.


[Virological diagnosis of epidemic keratoconjunctivitis (author's transl)]. Among 180 patients with proved adenovirus infection of the eye, 144 infections with adenovirus 8 (Ad 8) were found. 11 or 7 patients were infected with Ad 19 or Ad 4 respectively; further 18 cases were associated with 6 other serotypes. The main symptoms of epidemic keratoconjunctivitis (EKC) (pronounced inflammatory swelling of the plica and caruncula, nummular corneal infiltations) are not confined to Ad 8 infections. For the virological diagnosis, a combination of virus isolation and serology is recommended. Virus isolation is mostly successful from conjunctival swabs obtained during the first week of the disease. For serological investigation, the first blood specimen should be taken as early as possible, the second not earlier than 15 days after onset of disease. The mere application of the group-specific adenovirus complement-fixation is insufficient; it should be supplied by neutralization and hemagglutination-inhibition with Ad 8 (or Ad 19) virus, although these reactions are not invariably type-specific. A swifter diagnosis of the adenovirus infection by immunofluorescence performed in cell cultures inoculated with conjunctival material, 3 or 7 days after inoculation, was often successful; however, this procedure proved to be less sensitive than virus isolation.


pH-map of the stomach of normal and vagotomized dogs. By means of electrometric surface measurements a peculiar pH-map of the mucosa of normal and vagotomized dog stomachs was obtained illustrating the different acid producing capacities of the various regions of the stomach, on the one hand, and showing that all types of vagotomy will reduce local acid secretion.


[Pathophysiology and clinical significance of gut hormones]. The different mode of secretion of the gut hormones (paracrine secretion--somatostatin. endocrine and neurocrine secretion--gastrin, CCK; neurocrine secretion--VIP, substance P), obscures the physiological significance of these hormones. However, the pathophysiological role of autonomous secreted hormones by endocrine tumours, is well established. Gut hormones are used for routine evaluation of gastrointestinal diseases. The therapeutic value of these substances has recently engendered considerable interest.


Pharmacological evidence on the specialization of CNS mechanisms responsible for motor act inhibition by aversive events. Our use of selected pharmacological agents has now extended the range of treatment-behaviour interactions previously studied by other (e.g., lesion) approaches in the search for appropriate models of behaviour organization and underlying physiological mechanisms. The case of muscarinic blockers has special interest, because the drugs induce only one type of primary change. At present, it appears difficult to reconcile the evidence in favour of a motor (perseverative) deficit with other evidence favouring an impairment of sensory processes. However, critical experiments using several go-no go avoidance tasks show that the two deficits may be inseparable. The complex profile of cue-dependent disinhibitory effects of antimuscarinics suggests that separate sensori-motor mechanisms are employed for response suppression not simply as a function of cue type, response type, or response-reinforcement relation but as a joint function of all these factors. Sedative-tranquillizing agents with so-called anti-conflict properties add still another dimension to the problem of motor act inhibition. These agents are maximally effective in disrupting response withholding when both reward and punishment follow the emission of a particular response, less consistently effective in tests with CS paired with non-contingent shock (CER), and mostly ineffective in those go-no go avoidance tasks which show a very high sensitivity to muscarinic blockade.


Environmental chemical-induced modification of cell-mediated immune responses. It is therefore proposed that: 1) environmental chemicals can have specific mechanisms of toxicity and can influence antibody-mediated immunity while having no detectable effect on cell-mediated immunity, 2) immune dysfunction is related to exposure time to a chemical and the tissue concentration of that chemical, 3) recovery of immune function may occur even though chemical exposure continues, and 4) a single assay of immune function may not be appropriate to detect chemical induced immune dysfunction.


[Chronic pyelonephritis of older and old patients--a diagnostic problem in general medical practice (author's transl)]. Chronic pyelonephritis is the most common renal disease of old age. The number of registered cases of this disease is below current diagnostic possibilities, since chronic urinary tract infection and chronic pyelonephritis still too rarely play a role in differential diagnostic considerations. Because of the insecure reliability of anamnesis and complaints reported by the patients the uroscopic examination of the urine and bacteriologic diagnostics are of special importance. These examinations can be carried out in general medical practice and they will lead to a diagnosis of chronic pyelonephritis with relatively high probability.


[Recent advances in the treatment of nephrolithiasis (author's transl)]. The treatment of nephrolithiasis depends mainly on the type of stone present. Uric acid calculi can be dissolved by oral medication producing alkalinization of the urine. Cystin stones can only rarely be dissolved by oral administration of D-penicillamine. The best and least expensive prophylaxis is a high and constant fluid intake of 600 ml every 4 hours. This way the pathologically increased cystin excretion can be kept soluble. Calcium containing calculi and so-called "infection stones" need surgical intervention. Because of the high recurrence rate of renal stones every indication for an operative procedure has to be considered very carefully. For lasting results elimination of urinary obstruction is necessary. The treatment of choice of patients with staghorn calculus disease is surgical, even in the solitary kidney and in geriatric patients. As recent advances in the operative treatment of nephrolithiasis coagulum pyelolithotomy, intraoperative pyeloscopy, hypothermia and "bench surgery" (extra-corporeal renal surgery) are reviewed. Attempts to dissolve renal calculi by percutaneous nephrostomy as well as extraction of pelvic stones by the same procedure are mentioned. Finally, the importance of postoperative prophylaxis and the progress made in the medical treatment of calcium stones are pointed out.


[New possibilities in diagnosis and therapy of renal carcinoma (author's transl)]. A brief discussion of the aetiology and epidemiology of renal carcinomas is followed by a description of the clinical features. Attention is drawn to the significance of symptoms emphasizing the importance of early diagnosis. Intravenous urography still remains as the most important diagnostic procedure. It is pointed out that sonography and computer-tomography are now established as newer diagnostic methods, i.e. in distinguishing between cyst and tumor, in renal masses. Therapy, is still based upon surgical treatment. Transperitoneal, radical tumornephrectomy as compared with simple lumbar nephrectomy, has improved 5-year survival rate up to 16% especially in stage III tumors. Extracorporeal surgery for single kidney patients as hyperthermic surgery constitute new surgical methods, but only for specifically equiped urologic clinics. Embolisation of renal cell carcinoma is also used as therapeutic management in largely progressed tumors, and also used, as a preoperative measure, for the reducement of tumor size. Irradiation, before and after surgical treatment, as well as cytostatic therapy, revealed no significant improvement. We have reason to hope that progress in the research of hormonal- and immunotherapy will improve 5-year survival rate, in renal cell carcinoma.


Effects of adrenergic drugs on aqueous cAMP and cGMP and intraocular pressure. The following variously selective adrenergic agonists were tested for their effects on the concentration of adenosine 3',5' cyclic monophosphate and guanosine 3',5- cyclic monophosphate in the aqueous humor of treated and fellow eyes of rabbits one hour after topical unilateral application (2 mg, base): Epinephrine (alpha, beta 1.beta 2), phenylephrine alpha), isoproterenol (beta 1, beta 2), tazolol (beta 1) and terbutaline (beta 2). All drugs produced a significant increase in cAMP in the treated eyes and all but terbutaline produced a significant increase in the fellow eye. Terbutaline alone caused an increased in cGMP although a similar dose of pilocarpine, a cholinergic agonist, was ineffective in changing cGMP levels. We conclude that (1) diverse adrenoceptor stimulation can increase cAMP, but (2) not necessarily in direct relation to an agent's hypotension induced by pilocarpine is not accompanied by an increase in aqueous cGMP.


[Study of bilirubin- albumin binding. I.-In vitro study by partition of bilirubin between an aqueous solution and an immiscible organic solvent (author's transl)]. The partition of bilirubin in vitro between water and isobutyl-methylketone/n-heptane mictures is investigated at different pH, in the absence and the presence of albumin. Results are used to compute the concentrations of unbound ionized and unionized bilirubin and the bilirubin-albumin characteristics (association constant K and nomber n of primary binding sites per mole of albumin). The effect of various factors upon these characteristics is discussed.


A clinical profile of 100 child-patients with schizophrenia. This is a retrospective study of 100 child-patients with schizophrenia seen in the Child Psychiatric Clinic over a period of 4 years. Some personal and family characteristics of this group of patients are presented. Their clinical features, management and outcome are also presented and discussed.


[Diagnostic significance of lactose level in milk. 1. Lactose level in first quarter milk samples following artificial udder irritation and infection]. Studies were conducted into lactose levels of milk in response to experimentally irritated or artificially infected udder quarters. Milk lactose was found to be suitable as a model parameter by which to objectivate pathophysiological processes in the udder in the context of research, such as experiments on artificial udder infection or testing of udder tolerance of certain medicaments.


[Diagnostic significance of lactose level of milk. 2. Lactose level in first quarter milk samples in various udder disorders]. The behaviour of lactose levels in first quarter milk was studied in the context of a large dairy herd in the presence of various udder health defects. The results were related to other criteria generally used in mastitis diagnosis. The lactose level in first quarter milk was found to be a diagnostic criterion which was properly applicable to detecting and identifying clinical and subclinical mastitis. A limit value of 4.6 per cent has been commonly assumed in literature and proved to be a sound basis for udder health assessment, provided that the given phase of lactation is taken into due consideration (exclusion of cows in the first month post partum as well as of aged milking cows from the seventh month of lactation). Also reported in this paper are results regarding milk lactose and its correlations with other criteria for mastitis diagnosis. A close correlation was found to exist between lactose level and electric conductivity of first quarter milk.


Restricted chimerism of peripheral blood cells after transplantation of allogeneic hemopoietic tissue in rabbits. Allogeneic bone marrow or spleen cells were transplanted in rabbits treated with a single dose of 110 kmg/g of cyclophosphamide or four doses of 50 mg/kg. Chimerism of peripheral blood cells occurred in about 50% of the recipients, lasting from about the 14th day until 180 days after transplantation. The chimerism was limited to some kinds of cells since dissociation of proliferation of hemopoietic cells and split chimerism of lymphocytes were observed. Dissociation of proliferation of hemopoietic cells consisted in the appearance of only one cell line, namely lymphocytes, whereas the erythrocyte cells did not proliferate. Split chimerism occurred within lymphocytes, manifested by the presence of the donor's T lymphocytes but absence of proliferation of the donor's B lymphocytes.


Seasonal abundance of Culex annulirostris and other mosquitoes at Kowanyama, north Queensland, and Charleville, south west Queensland. At Kowanyama, 104,006 adult female mosquitoes of a probable 47 species were collected on twelve occasions from April, 1972, to April, 1976. At Charleville, 71,791 adult females of 20 taxa were taken during thirteen periods from February, 1974, to February, 1976. Culex annulirostris was predominant at Kowanyama and especially at Charleville where it comprised up to 99% of dry season collections. Culex fatigans, Ae normanensis, An annulipes and, at Kowanyama only, An bancroftii were the other major species collected. Several bait trapping methods were suitable for monitoring densities of Cx annulirostris and other species but mammalian baits were best. Because Cx annulirostris activity continued throughout winter even at Charleville, continuous cycles of arbovirus transmission are possible, although the potential of dormant Aedes eggs also bears investigation as a method of arbovirus survival.


Isolation of virus strains from mosquitoes collected in Queensland, 1972-1976. 171,348 mosquitoes and 4,353 other arthropods collected at three centres in Queensland in 1972-1976 yielded 151 strains of 18 viruses. Culex annulirostris was the major source of virus isolation but 42 strains from Aedes normanensis indicate it to be a vector of importance. Ross River and Kokobera viruses were isolated at Kowanyama in the dry season, a finding of interest as being compatible with year-round survival in vector-vertebrate cycles. Culex fatigans has in part replaced Culex annulirostris in peridomestic breeding sites at Kowanyama; the infrequency of virus isolation from it suggests that this replacement may lower arbovirus infection rates. Twelve strains were identified as viruses antigenically distinct from any previously isolated in Australia or New Guinea: Ch16129, showed by the International Reference Centre for Arboviruses to be a previously undescribed member of the Simbu Group (Facey's Paddock virus), Ch16313 (Murweh), Ch19520 (Parker's Farm) and Ch19546 (little Sussex). The remaining strains were identified as viruses previously known in Australia, but included many new host or geographical records.


[Beta-glucuronidase activity in the gastric juice and gastric mucosa of rats subjected to protein deficiency]. The experiment was performed in order to evaluate the beta-glucuronidase activity in gastric juice and gastric mucosa of rats submitted to protein-free diet. A group of 36 young adult male wistar rats was fed a protein-free diet ad libitum for five weeks; a second group of 36 wistar rats ingested a purified isocaloric 12,5% casein diet for the same period. The concentration of proteins in plasma, gastric juice and gastric glandular mucosa and the beta-glucuronidase activity in the gastric juice and gastric glandular mucosa were determined. Protein deficient rats had lower plasma protein concentration and also a lower protein concentration in gastric juice and gastric mucosa. In these animals there was no significant change of beta-glucuronidase activity in the gastric juice, but there was a significant increase of the specific enzimatic activity in the gastric mucosa. The results suggest that protein restriction in young adult rats affects the gastric mucosa. The increase of the specific beta-glucuronidase activity might be due to heightened local catabolism or to a comparatively more severe protein depletion.


Canine Gaucher disease--the enzymic defect. beta-Glucosidase activity was investigated in tissues from a case of canine Gaucher disease and from a normal dog. In the latter, enzyme activity showed two pH optima at pH 4-0-4-25 and pH 5-0-5-5. In Gaucher disease tissues, negligible activity could be measured at the mouse acidic pH.


[Reciprocal responses to macular stimulation of neurons localized in the region of the forelimb and of the hindlimb of Deiters nucleus]. In decerebrate cats with cerebellum intact the frequency response of 102 neurons located within the lateral vestibular nucleus (NVL) to sinusoidal stimulation of vestibular receptors was analyzed. Positional sensitive units, showing a reciprocal pattern of response to lateral tilting characterized by an excitation during ipsilateral and a depression during contralateral tilt, were equally found in the rostroventral (forelimb) and dorsocaudal (hindlimb) divisions of the NVL. No unit was found to be excited during both ipsilateral and contralateral tilts. A comparison between these findings and those reported in cerebellectomized preparations indicates that the reciprocal pattern of response to tilt of neurons, particularly located in the hindlimb region of the NVL, depends upon the anatomical integrity of the cerebellum.


Effect of antihistamines on anaphylactoid oedema in rats using a modified plethysmometer for measuring foot volume. This study reports the quantitative effect of the H1--and H2--receptor antagonists on dextran-induced anaphylactoid oedema in rats. The findings indicate that mepyramine, promethazine and chlorpromazine which are H1--receptor antagonists significantly inhibited this anaphylactoid oedema. While on the other hand burimamide an H2--receptor antagonist at doses below 500 micrograms/kg inhibit dextran-induced oedema but at higher doses enhances oedema formation in the test rats. E.D50 values obtained for mepyramine, chlorpromazine and promethazine are 5.01 mg/kg, 0.36 mg/kg, 1.78 mg/kg respectively. The dual effects of burimamide on dextran-induced oedema merits further investigation and confirmation with the aid of other H1--and/or H2--receptor systems. A modification of the plethysmometric method of Buttle et. al. (1957) is also described.


The role of ATP and lactic acid for mitochondrial function during myocardial ischemia. Phosphorylation rates of canine heart mitochondria isolated after various periods of myocardial ischemia after cardioplegic arrest were correlated with the myocardial ATP-, lactate- and undissociated lactic acid content as well as with interstitial H+-concentration. The following correlation coefficients were found: ATP: 0.87, lactate: 0.93, interstitial H+: 0.73. The calculated undissociated lactic acid content and the mitochondrial phosphorylation rate during ischemia showed a correlation coefficient of r = 0.95. Swelling measurements of mitochondria, isolated immediately after cardioplegic arrest, demonstrated that an undissociated lactic acid- and an ATP-concentration of 70 microM and 28 microM respectively are necessary for a half maximal swelling reaction under anaerobic conditions. The results suggest that the accumulation of undissociated lactic acid during myocardial ischemia could play an important role for mitochondrial damage in vivo.


[Effect of transmembrane potential on noradrenaline transport in chromaffin granules]. Imposing a transmembrane potential positive with respect to the medium on chromaffin granule ghosts increased the initial rate of the delta pH-induced uptake of noradrenaline, whereas imposing a negative potential decreased this rate. The increase of the uptake rate was proportional to the potential. The ATP-induced uptake of noradrenaline was also sensitive to the potential since imposing a transient negative potential onto the positive potential generated by the membrane ATPase induced a latency in this transport.


[Evolution in time of transmitter release at frog neuromuscular junction]. It has previously been shown that the unitary quantal end-plate potentials observed at synapses blocked by low Ca++ high Mg++ ringer, belong to distinct clusters according to their amplitude, time to peak and latency characteristics. These clusters correspond probably to distinct releasing units dispersed along the presynaptic terminal branches. The distribution versus time of the occurence of unitary potentials belonging to one latency cluster has been studied over long lasting evoked nerve activity (stimulation frequencies: 1 to 10 Hz). It was observed that transmitter release at one releasing site is statistically periodic with emitting periods separated by rest periods. At a given end-plate the period of emitting activity seems to be independent from one emitting site to another.


Schizophrenia: the nature of the psychological disturbance and its possible neurochemcial basis. The diagnosis of schizophrenia is established principally by the presence of certain psychological symptoms which although subjective can be reliably assessed by standardized interviewing procedures. The most characteristic symptoms (Schneider's first-rank symptoms) fall into three groups: (a) auditory hallucinations of particular types, (b) 'ego-boundary disturbances', including intrusions into the stream of consciousness attributed to external agencies, and (c) delusional perception. Symptoms closely resembling those seen in schizophrenia can be induced in non-schizophrenic individuals by amphetamine-like drugs, and both these symptoms and those of schizophrenia are ameliorated by neuroleptic drugs (the major tranquillizers). Amphetamines facilitate and neuroleptic drugs diminish neural transmission mediated by the chemical substance dopamine. In recent post-mortem studies on patients who had suffered brom schizophrenia, it was found that dopamine release was not increased. However, in some cases there was evidence of increased sensitivity of the dopamine receptor.


[Present nosology of the affective disorders (author's transl)]. The present nosology of the affective disorders seems accurate enough to enable valid definitions and classifications to be made, despite the differences between the countries and the methods of approach. Nevertheless, there has been much controversy regarding different clinical types, similar or opposite, and notably about whether the pathogenesis and etiology are single multiple. Consideration must be given not only to the clinical form presenting but also to the course (episodic, recurrent or chronic) and to the circadian variations. Moreover, it is absolutely essential to distinguish in the nosology, on the one hand, the clinical picture proper and, on the other hand, the aetiology or the psychic structure. Thus, a simple depression may be related to an endogenous process and a melancholic state may be reactive. The theoretical problems of classification may justify the use of multivariate analysis. However, it is doubtful whether sophisticated methods are absolutely necessary in clinical practice.


[The inversion of mood (author's transl)]. It is for a good reason that the colloquium is entitled Affective disorders and not Depression: in reality there is a profound unity between elation and depression and we have to ask ourselves whether there may be inversion of mood in any case of elation and vice-versa. Mood inversion occurs in various conditions: depression sets in a previously elated person, finally overwhelmed by the consequences of his acts; or elation may occur as an over-compensation for the pain of loss. These two situations lead either to a paradoxical content of the patient's talk or to a metapsychological elaboration. Finally, the change may take place without there being a clear psychological formulation. The concomitants of these phenomena, involving the biological amines or the neurotransmitters, must be elucidated. Clinically, there are two types of problem: the problem of the premonitory signs of inversion of mood and the problem of attempting to prevent it.


[Biochemical methodology for studying affective disorders]. Defects in brain neurotransmitter function are believed to be involved in the aetiology of mood disorders, and model systems are based on this concept. Abnormalities in synthesis, storage, release, reuptake or catabolism of monamines, GABA, glycine, taurine, peptides and purines may occur. There may also be an endogenous psychotogen--an aberrant metabolite of a transmitter. Models are divided into two groups. 1. Human. Brain, CSF, blood cells (platelets, erythrocytes), plasma and urine have been analysed for neurotransmitters or metabolites. Particular emphasis has been given to serotonin (5-HT) and the catecholamines, dopamine and noradrenaline. 2. Animal. Human mood disorders may be stimulated by drug-induced behavioural changes in animals (hyperactivity, stereotyped behaviour sedation). The above biochemical parameters relating to neuronal function can then be assessed. Brain neuronal pathways can be stimulated in animals with monoamine precursors and MAO inhibitor drugs. This drug-induced hyperactivity can be used to "evaluate" therapeutic techniques such as electroconvulsive therapy (ECT). Model analogues of mood disorder have limited use until human disease aetiology is known, currently the best use of models may be for demonstration and evaluation of particular similarities between human mood disorders and drug-induced alterations of animal behavioural patterns.


[Depression and sleep (author's transl)]. Sleep is affected in depression; insomnia is common, sleep of normal duration and hypersomnia less common. All-night studies have shown changes of the two types of sleep. Deep non-REM sleep is abolished during the course of the illness and sometimes also after remission. Paradoxical sleep, which may be reduced or increased in duration, starts sooner after the onset of sleep. According to Kupfler, ease of production of that sleep is specific to primary depression, unipolar or bipolar. A possible relationship between paradoxical sleep and certain types of depression is suggested by the fact that the tricyclic and MAOI antidepressant drugs and lithium reduce or suppress that sleep. Finally, deprivation of paradoxical sleep by repeated waking during the night has been put forward as a form of treatment. Despite the heterogeneous nature of depression, findings at present which show paradoxical sleep pressure provide a pathophysiological basis for the biological problems posed.


[Iatrogenic depression (author's transl)]. A number of drugs are traditionally blamed for causing depression: in general medicine, the antihypertensives, the oral contraceptives and the appetite suppressants; in psychiatry, the neuroleptics. The identification of iatrogenic depression is difficult methodologically, for two reasons: 1. Detection of the depression. 2. Linking convincingly that state of depression with the administration of a particular drug, given the presence of many non-pharmacological factors. The literature and the experience of clinicians provide fairly contradictory evidence, but an analysis of published work calls for the following observations: --the type and severity of depression are rarely specified;--a history of psychiatric disorder is commonly stressed;--the specific role of the disability caused by physical or mental illness and the need to use palliative rather than curative measures are usually underestimated;--biochemically, it is surprising that the effects which some of these drugs are known to have upon the cerebral amines do not cause more depression of mood. In fact, if we consider how widely the drugs incriminated are used, it is clear that real drug-caused depression is rather uncommon.


[Classification of the antidepressants (author's transl)]. The antidepressants can be classified chemically. The standard division is between the tricyclic antidepressants and the chemically heterogeneous MAOIs. Many other compounds can be included among the antidepressants, e.g. the bicyclics and possibly also the beta-stimulants, the alpha-blockers and ions such as rubidium. As regards the mechanisms of action, we have the antidepressants which act selectively upon serotonin and those which act more particularly upon noradrenaline. This notion must be extended. Dopamine may be involved in certain depressive syndromes and also other systems may have a role, such as electrolyte systems, cell permeability and the multiple influences which have a bearing upon the monoamines. Finally, the effect upon receptors and their nature are discussed. A third type of classification refers to the therapeutic spectrum of the drug. We have the sedative antidepressants, active in agitated depression and the stimulant antidepressants which are active in retarded depression. However, the two categories of antidepressants have the same global antidepressant action.


[Unilateral and bilateral shock therapy: mechanism of action (author's transl)]. The unilateral and bilateral therapy differ in psycho-organic effects but have the same antidepressive efficiency. This is due to the facts that the organic effects are mainly caused by the electrical current whereas the antidepressive effect is dependent on the seizure activity. Compared to the bilateral treatment, unilateral gives reduced confusion, anterograde and retrograde amnesia as well as reduced experience of memory impairment. The difference is explained by a lower density of current in the brain. The unilateral treatment should be the treatment to be chosen. The antidepressive action of ECT fits the amine hypothesis, ECT causes a sustained increase of the synthesis of norepinephrine and of the sensitivity of amine receptors and creates conditions for alleviating both "low-output" and "low-sensitivity" depression. The antidepressive action is probably mediated by release of hypothalamic neurohormones.


[Depressive symptomatology and type of treatment (author's transl)]. Details of treatment remain imprecise in depression, as the trials of antidepressants have been more concerned with overall effectiveness than with specificity. The aetiology in depression does not provide sufficient guidance for treatment, even though drugs are preferred for endogenous depression and psychotherapy for neurotic depression. An unitary formulation of depression can be postulated on the basis of the concept of regression; endogenous and reactive depression would then stem from the nature of the depressed subject's personality. Such an approach can encompass the various possible aetiologies in depression: biochemical, psychological and social, without necessarily contrasting them. In this connection, depression is a psychobiological syndrome within which there may be different symptomatic pictures, depending notably upon the various monoamine hypotheses raised in numerous studies. In that event, possible correlations between biochemical abnormalities and certain clinical manifestations may better guide the selection of drugs.


[The research of new antidepressants: present orientations (author's transl)]. A number of promising antidepressant compounds are presently either being developed in the laboratory or are being tested clinically by pharmaceutical firms and universities around the world. New compounds are sought which will provide: 1. fewer side effects, particularly anticholinergic and cardiovascular effects; 2. more rapid onset of action than 7-10 days required of most antidepressants now used; 3. efficacy in a higher percentage of patients than the 65-70 per cent estimated to respond to currently available antidepressant therapies. Compounds now being investigated include: new tricyclics which are unlike those commonly in use; the tetracyclics; the salts of naturally occurring cations such as lithium and rubidium; and various chemically unrelated new compounds. In addition, several drugs currently being tested as anorectics seem promising for future antidepressant drugs research.


[Mechanisms of action of the antidepressants (author's transl)]. The tricyclic and related antidepressants reduce monoamine uptake at the synapses, block the presynaptic receptors and, after chronic administration, act upon the synthesis of the monoamines and the sensitivity of the post-synaptic receptors. The NA and 5-HT synapses are influenced to different degrees by the antidepressants: for example, desipramine has a preponderance of activity at NA synapses and clomipramine at 5-HT synapses. By combining these findings and by highlighting one or other of these properties, it is possible to come to diametrically opposite conclusions upon the effect of the antidepressants upon monoamine performance (activation or inhibition) and to develop many models of the mechanisms of antidepressant action. The authors describe some of these and stress the model which is at the basis of the studies being carried out at the Department of Psychiatry of the University of Geneva.


[Amineptine, a new antidepressant: pharmacological review (author's transl)]. Amineptine is a tricyclic derivative with a 7-carbon chain of aminoacids. Chemical alterations of the aminoacid chain have revealed its importance in the shaping of the pharmacological effects. The drug is rapidly absorbed. Amineptine is metabolised principally by beta-hydroxylation of the chain. The pharmacological profile at different doses is as follows: a. 0.1 mg/kg: reduction of exploratory behaviour, b. 1 mg/kg: reduction of serum prolactin level, c. 5 mg/kg: potentiation of L-5 HTP, d. 10 mg/kg: antagonism of the effects of reserpine and of tetrabenazine, e. increased activity and social behaviour, EEG alerting effect limited to 1 hour and increase in paradoxical sleep (15 to 20 mg/kg). This pharmacological profile suggests an effect of amineptine upon certain dopamine structures. At synapse, neurobiochemistry confirms a mechanism of inhibition of DA incorporation and inhibition of uptake and/or release of 5 HT. Amineptine is virtually devoid of peripheral activity, particularly anticholinergic Amineptine may be indicated for the treatment of depression where retardation is dominant.


Allogeneic marrow grafting for acute leukemia: a follow-up of long-term survivors. We have reported 100 consecutive patients with refractory acute leukemia treated with chemotherapy, total body irradiation (TBI) and marrow from an HLA identical sibling. At the time of the report 17 patients were alive after 11-53 months. All patients have now been followed more than 3 years. At the time of the last report 4 of the 17 patients had relapsed: two in the marrow, one in the central nervous system and one in the testicle. Three of these four patients have died of their disease 27, 34 and 50 months following transplant. The patient with a solitary testicular relapse remains in complete remission 49 months after local irradiation without concomitant systemic therapy. One other patient died 26 months following transplantation from cardiopulmonary complications following multiple respiratory infections. Of the 13 surviving patients, three suffer from chronic graft-versus-host disease. Summaries of the problems encountered in these patients after the first 100 days are presented. Ten of the original 100 patients are living productive lives 36-80 months after transplantation. The data clearly demonstrate that long-term unmaintained remissions are possible in a small fraction of patients with terminal leukemia treated with various chemotherapy regimens and TBI followed by marrow transplantation.