Upgrade of the beam extraction system of the GTS-LHC electron cyclotron resonance ion source at CERN.

Linac3 is the first accelerator in the heavy ion injector chain of the Large Hadron Collider (LHC), providing multiply charged heavy ion beams for the CERN experimental program. The ion beams are produced with GTS-LHC, a 14.5 GHz electron cyclotron resonance ion source, operated in afterglow mode. Improvement of the GTS-LHC beam formation and beam transport along Linac3 is part of the upgrade program of the injector chain in preparation for the future high luminosity LHC. A mismatch between the ion beam properties in the ion source extraction region and the acceptance of the following Low Energy Beam Transport (LEBT) section has been identified as one of the factors limiting the Linac3 performance. The installation of a new focusing element, an einzel lens, into the GTS-LHC extraction region is foreseen as a part of the Linac3 upgrade, as well as a redesign of the first section of the LEBT. Details of the upgrade and results of a beam dynamics study of the extraction region and LEBT modifications will be presented.

Analysis of prostaglandins formed from endogenous and exogenous arachidonic acid in homogenates of human reproductive tissues.

Isotope-labelled arachidonic acid has been used to study in vitro formation of prostaglandins and other products in mammalian tissue. Quantitative conclusions about cyclooxygenase activity have been drawn from such studies. However, arachidonic acid is present in all tissues, free and esterified, and therefore it can be expected that endogenous arachidonate would interfere with transformation of the radioactive exogenous substrate. (1-14C)-labelled arachidonate was, therefore, incubated with homogenates of various human tissues (amnion, chrorion, placenta and myometrium), and the two molecular forms, 12C and 14C, of arachidonic acid as well as of prostaglandin E2 and prostaglandin F2 alpha were quantitated, before and after 30 min of incubation, using gas chromatography-mass spectrometry with multiple ion detection. The results demonstrate a substantial release of arachidonic acid into the medium during incubation. There was no correlation between either the initial concentration of [12C]arachidonic acid and initial concentration of [12C]prostaglandin E2 or the percent increase of those compounds during incubation. The net formation of [12C]prostaglandin E2 and [14C]prostaglandin E2 from endogenous and exogenous precursor, respectively, were also very different. The study shows that by simply incubating (1-14C)-labelled arachidonic acid in tissue homogenates and measuring the amount of radioactivity transformed into various prostaglandins only qualitative conclusions can be drawn.

Plasma levels of 15 (S) 15-methyl-PGF 2 alpha-methyl ester following vaginal administration for induction of abortion in women.

A single suppository containing 3.0 mg 15 (S)15-methyl-PGF2 alpha-methyl ester was administered vaginally in women to terminate mid-trimester pregnancy. Plasma levels of the drug (both methyl ester and free acid forms) were measured at different time intervals using deuterated carriers and gas chromatography-mass-spectrometry. 15(S)15-methyl PGF2 alpha (sum of methyl ester + free acid) was found to have a mean value of 1166 pg/ml plasma at 3 hrs after administration of the suppository. The mean levels were subsequently found to be maintained in the range of 1000 pg/ml. Preliminary studies showed that unlike the successfully aborted women, in those who did not abort within 30 hrs with this suppository, the plasma levels of the drug were not maintained for a sufficiently long time. The episodes of side effects, body surface area and the induction-abortion interval in relation to the plasma levels are discussed.

Immunomodulatory action of propolis. V. Anticomplementary activity of a water-soluble derivative.

The effect of a water-soluble derivative (WSD) of propolis on the classical pathway (CP) and the alternative (AP) complement activity has been investigated. The in vitro experiments show that WSD inhibits both pathways and the effect depends on the source of complement. The suppression of complement-mediated haemolysis proves to be time- and temperature-related. High WSD concentrations cause direct damage of the target erythrocytes. The estimation of C3-residual activity indicates that the preparation diminishes C3 functional activity.

Immunomodulatory action of propolis. VI. Influence of a water soluble derivative on complement activity in vivo.

The water soluble derivative (WSD) of propolis in a dose of 150 mg/kg was administered intravenously (i.v.), intraperitoneally (i.p.) and orally (p.o.) to mice. The alteration of serum alternative pathway (AP) complement level was observed. The WSD also influenced the process of acute inflammation provoked by zymosan in mice. The effect was strongly dependent on the route of WSD administration.

Linac4 low energy beam measurements with negative hydrogen ions.

Linac4, a 160 MeV normal-conducting H(-) linear accelerator, is the first step in the upgrade of the beam intensity available from the LHC proton injectors at CERN. The Linac4 Low Energy Beam Transport (LEBT) line from the pulsed 2 MHz RF driven ion source, to the 352 MHz RFQ (Radiofrequency Quadrupole) has been built and installed at a test stand, and has been used to transport and match to the RFQ a pulsed 14 mA H(-) beam at 45 keV. A temporary slit-and-grid emittance measurement system has been put in place to characterize the beam delivered to the RFQ. In this paper a description of the LEBT and its beam diagnostics is given, and the results of beam emittance measurements and beam transmission measurements through the RFQ are compared with the expectation from simulations.

Metabolism of prostaglandin F2 alpha in sheep.

The metabolism of prostaglandin F2 alpha (PGF2 alpha) in ewes was studied after im injection of 9 beta-3H-labeled PGF2 alpha. About 75% of injected radioactivity was excreted in urine within 6 hr, whereas less than 1% was excreted in the milk over 3 days. Most identified urinary metabolites were formed through well known reactions involving oxidation of the hydroxyl group at carbon 15, saturation of double bonds, and oxidation of both carbon chains. However, some metabolites underwent more extensive oxidation of the carbon chain than had been seen before in other species. This might have taken place through catabolic activity of the gastrointestinal microflora followed by reabsorption into the circulation.

Immunomodulatory action of propolis: IV. Prophylactic activity against gram-negative infections and adjuvant effect of the water-soluble derivative.

The efficacy of the water-soluble derivative (WSD) of natural propolis (bee glue) was examined for augmentation of host resistance against experimental infections caused by Gram-negative pathogens (Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa). The substance was found to induce significant non-specific protection, but did not inhibit the in vitro growth of the same strains. Pretreatment with WSD prior to the standard scheme for tumour necrosis factor (TNF) induction (BCG and two weeks later lipopolysaccharide (LPS)) provoked an interval-dependent reduction in the lytic capacity of serum against L 929 target cells. The replacement of the triggering or priming signal with WSD markedly increased TNF production. In vivo administration of WSD led to a rapid and route-dependent change in the alternative complement pathway haemolysis. The alteration in C1q complement component and total protein synthesis, and also in nitroblue tetrazolium reduction, suggests that macrophage activation makes a major contribution to the capacity of WSD to prevent infections.

[Results of impregnating cows and heifers on consolidated farms and the methods for synchronizing their estrus]. / Prouchvane na rezultatite po zaplozhdane na kravite i iunitsite v uedrenite fermi i metodi za sinkhronizirane na estrusa im.

Studied were the conception rate, milk productivity, calving period, and age at first conception with 3265 cows of 12 herds and 3 breed groups--Bulgarian Red Cattle (BRC), Holstein-Friesian Cattle (HFC), and HFC X BRC. The effect was followed up of the enzyme preparations Cytochrome 'C' and Beta-glucuronidase on the conception rate of cows. Tested was the action of prostaglandin F2 alpha and its analogues Equimate, Luteolysine, and Panazelen on the synchronization of the estrus and the conception. It was found that there was a considerable delay in the calving of the heifers (29 months). The calving period of the cows was prolonged and ranged in days from 369.17 +/- 3.17 up to 381.26 +/- 8.61 for BRC, 378.09 +/- 3.56 to 393.21 +/- 14.85--for HFC, and 339.75 +/- 6.56 to 390.42 +/- 3.51--for HFC X BRC. The use of Beta-glucuronidase and Cytochrome 'C' in the artificial insemination of the cows with deep-frozen semen raised the conception rate at first insemination by about 8-10 per cent.

Metabolism of 16, 16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester (ONO-802) following intravenous and vaginal administration to pregnant women.

Following iv and vaginal administration of (5,6-3H2)-ONO-802 (5,6-3H2-16, 16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester) the appearance of radiolabeled compounds in plasma and urine were studied in early pregnant patients. Following iv administration, ONO-802 was rapidly hydrolyzed to the free acid which disappeared from plasma with an approximate half-life of 10-15 min. About 50% of the injected amount of compound was excreted in urine during the first 24 hr after injection. The structures of 16 urinary metabolites were determined. These data demonstrated that, following hydrolysis of ONO-802 to the free acid, the latter can undergo beta- and omega-oxidation like other prostaglandin analogs where enzymatic attack of the 15-hydroxyl group has been blocked. Some of the metabolites were excreted as conjugates (sulfates, glucuronides?) and, in two, the oxo group at C-9 had been reduced to a hydroxyl. Following vaginal administration of ONO-802 (1 mg, 60 microCi) in suppository form, radioactivity corresponding to 100-200 pg/ml of ONO-802 equivalents was found in plasma. The profile of metabolites in urine was qualitatively very similar to that after iv injection of (5,6-3H2)-ONO-802. Based on the data on excretion of metabolites in urine it was calculated that 12-28% of the dose administered vaginally was resorbed into the circulation.

In vivo expression of monokine and inducible nitric oxide synthase in experimentally induced pulmonary granulomatous inflammation. Evidence for sequential production of interleukin-1, inducible nitric oxide synthase, and tumor necrosis factor.

The present study examined the temporal pattern and localization of interleukin-1, tumor necrosis factor-alpha, and inducible nitric oxide synthase expression in lung tissue undergoing foreign body granuloma formation. Pulmonary granulomas were induced by the intratracheal injection of dextran beads into genetically high granuloma responder, carrying Bcgs (BALB/c), and low responder, carrying Bcgr (C3H/HeJ and DBA/2), mice. There was a pattern of sequential expression of these molecules in BALB/c mice. Thus, interleukin-1 alpha and inducible nitric oxide synthase were induced mostly in the cells accumulated around the beads and also in some bronchiolar epithelial cells during the early phase (1 to 3 days), whereas tumor necrosis factor-alpha was induced in the cells around the beads at the later resolution phase (3 to 7 days). By contrast, in low responder mice, an increase in the expression of interleukin-1 alpha and inducible nitric oxide synthase was detected in lung macrophages as well as in alveolar cells and bronchiolar epithelial cells on day 1, but that of tumor necrosis factor-alpha was not detected throughout the period. These results together with our previous findings on cytokine activity in granuloma extract suggest that interleukin-1 and nitric oxide produced by recruited macrophages may take part in the early, macrophage-dependent phase of granuloma formation whereas tumor necrosis factor-alpha may be more crucial as a mediator responsible for the difference in innate resistance or susceptibility to granuloma formation.

Chemiluminescent activity of macrophages during phagocytosis of different bacterial forms.

Studies on the luminol-dependent chemiluminescent activity of rat peritoneal macrophages after in vitro interactions with E. coli WF+ L-form cells, their cytoplasmic membranes (CM) or parent bacterial cells were carried out. It was established that the phagocytosis of CM induce 20 time stronger light emission as compared to the L-form and 40 times compared to the parent bacterium cells respectively. Electron microscopical investigation of ultrathin sections of rat peritoneal macrophages after 24 h interaction in vitro with CM showed activation of the cell surfaces and vacuolisation of the cytoplasm. Inhibition of the phagolysosome fusion during phagocytosis of CM was observed. The mechanism of the immunostimulating activity of CM is discussed.

Polyphenols from Bulgarian medicinal plants with anti-infectious activity.

Three Bulgarian medicinal plants--Geranium macrorrhizum L. and G. sanguineum L. (Geraniaceae), and Epilobium hirsutum L. (Onagraceae) were analyzed phytochemically. Different polyphenols like flavonoids and tannis have been found to be principal constituents of the plants. A series of water or alcohol extracts was obtained, and their anti-infectious activity was tested. A significant inhibitory effect of water-alcohol extract and of four fractions from the polyphenolic mixture of E. hirsutum on the reproduction of influenza viruses in vitro, in ovo, and in vivo was established. Four extracts from G. macrorrhizum and three extracts from G. sanguineum were studied for in vitro inhibition of the growth of some Gram-negative bacteria (Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa), Gram-positive bacterium (Staphylococcus aureus), and fungus (Candida albicans). Some geranium extracts caused a strong increase of the survival rate in an infection with K. pneumoniae in mice. Augmentation of the nonspecific host resistance in relation to the influence of the extracts on the classical complement activation pathway was also studied.

[Immunosuppression in an experimental infection with the infectious rhinotracheitis virus]. / Imunosupresiia pri eksperimentalna infektsiia s virusa na zarazniia rinotrakheit.

The changes in the immune status of the calves infected with bovine herpes virus-1 inducing infectious rhinotracheitis were studied. The virus was introduced by intratracheal inoculation of 5 cm3 suspension with minimal concentration of 10(-7) CPU50 per 1 cm2 from the Cervena voda strain cultivated in calf kidney culture. An infection of moderate seriousness and characteristic clinical manifestations was caused. On the 2nd, 5th, 10th and 15th day after the infection lung lavage was carried out and samples were taken from the peripheral blood. The number, viability and differential distribution of the alveolar macrophages and phagocytic and microbicidal ability showed a tendency to decrease during the acute phase of the infection (the 2nd-5th day) followed by a slow restoration in the period of convalescence (the 15th day). Some parameters of the systemic immunity--number of the plaque-forming and the rosette-forming cells, differential and absolute number of leucocytes in the peripheral blood--also had similar dynamics. The changes in the local and in the systemic, in the cell and humoral immunity were connected to the pathogenesis of the infection and the immune suppressive properties of the agent. The rhinotracheitis infection is indicative of the character of changes in the immune status at herpes virus infections and, on the other hand, it can be used as a model for testing immunostimulators of recovery effect.

Gas chromatographic--mass spectrometric quantitation of 16, 16-dimethyl-trans-delta 2-PGE1.

Di-deuterated and di-tritiated 16,16-dimethyl-trans-delta 2-PGE1 has been synthesized and used for development of a GC-MS method for quantitation of corresponding unlabelled drug in patient plasma. Although these carrier/internal standard molecules only contain 2 deuterium atoms the lower limit of detection at each injection is as low as about 40 pg. The maximum plasma levels of this drug following administration of vaginal suppositories used in clinical studies (1 mg 16,16-dimethyl-trans-delta 2-PGE1 methyl ester in 0.8 g Witepsol S-52) were 100-350 pg/ml i.e. in the same order of magnitude as earlier seen for 16,16-dimethyl-PGE2.

Effect of oxadiarrhot on some mechanisms of the immune system.

The preliminary application of the preparation Oxadiarrhot has no effect on the progress and the result of bacterial and mixed (bacterial-viral) infections. In animals treated with the preparation antigen-reactive and antibody-productive cells show insignificant decrease in number. There is no essential influence of the preparation on the mononuclear phagocytes system--the alveolar macrophages and polymorphonuclears do not change their functions.

Immunological and biochemical investigations of the infectious bovine rhinotracheitis. III. Alterations in pulmonary surfactant lipids.

The effect of experimental bovine herpes virus (BHV) type I rhinotracheitis on the surfactant system phospholipids in calves was examined. A stimulated exocytosis of pulmonary surfactant phospholipids in the acute phase of the disease was documented biochemically and ultrastructurally. The data presented were assumed as an evidence of the involvement of pulmonary surfactant in lung defense.