Development of an auxotrophic oral live Shigella flexneri vaccine

An oral live attenuated Shigella flexneri vaccine candidate strain was constructed by making it auxotrophic and dependent on aromatic metabolites not available in mammalian tissues. An aroD gene of Escherichia coli K12 strain NK 5131, inactivated by insertion in it of the Tn 10 transposon, was transduced using phage P1 into a virulent S. flexneri serotype Y strain (Sfl 1) isolated from a patient with bacillary dysentery. One of the transductant strains Sfl 114 was found to invade HeLa cells in vitro, to cause plaque formation in HeLa monolayers (i.e. maintain intracellular multiplication in vitro), but to be unable to cause keratoconjunctivitis in guinea-pig eyes. When the strain was fed to Macacca fascicularis monkeys it was well tolerated, excreted for 1-4 days, and found to elicit a local intestinal sIgA and serum IgA, IgM and IgG responses. Monkeys challenged with 100 ID50 dose (1 X 10(11) bacteria) of the virulent parent Sfl 1 strain were completely protected from development of diarrhoea. Coloscopy of the monkeys and the sampling of intestinal biopsies showed that the vaccine protected against the surface epithelial erosions and ulcerations seen in unimmunized monkeys. Killing of invading virulent shigellae apparently took place intracellularly in the mucosa suggesting that cellular immune mechanisms played a role in the elicited host defence. The constructed S. flexneri Sfl 114 strain has the properties of a promising shigella vaccine and will next be the subject of studies with human volunteers.     

Myalgia Epidemica und Poliomyelitis

Ohne Zusammenfassung     

The incidence of Crohn's disease is not decreasing in Sweden

An epidemiologic study of the incidence of Crohn's disease during the 25-year period 1963-1987 within a geographically well defined area has been performed. The mean annual incidence during the 25 years was 6.1/10(5) inhabitants. During the first quinquennium the incidence was 4.3/10(5) inhabitants, but during the next four quinquennia the incidence was very stable around 6.6/10(5) inhabitants. The point prevalence on 31 December 1987 was 146/10(5), with a male to female ratio of 1:1.15. An analysis of birth cohorts could not reveal any cohort more prone to develop the disease. Of the 246 incidence cases 5 patients had died of Crohn's disease. The percentage of small-bowel disease only was very stable during the whole study period. The proportion of large-bowel disease decreased only slightly, and combined small- and large-bowel disease increased somewhat towards the end of the study period, probably because of better diagnostic methods.     

Metabolism of nomifensine after oral and intravenous administration

The metabolism of nomifensine was studied after single oral and intravenous administration and after 2 weeks of oral dosing. The three principal metabolites reached maximum plasma concentrations rapidly (in 1 to 1.5 hours) after nomifensine administration. Less than 10% was detected as a free, unconjugated form. All three metabolites were eliminated rapidly (elimination t1/2 values between 6.8 and 9.0 hours). Only very low concentrations of free metabolites were found in plasma after 24 hours of nomifensine administration. AUC values for free metabolites were between 0.27 to 0.46 hr X mumol/L after all nomifensine schedules. Two weeks of dosing had no significant influence on the elimination t1/2 or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions. In addition, there were no changes in the conjugation reactions during prolonged nomifensine dosing. Nomifensine has a very short t1/2 and no tendency for accumulation after repeated doses. We conclude that nomifensine's clinical pharmacokinetic profile is not significantly changed by the kinetic behavior of its three main metabolites after the usual maintenance doses.     

Lithotripsy of urinary bladder stones with a mechanical lithotriptor inserted through a narrow introducer. An experimental study in pigs.

Mechanical lithotripsy of urinary bladder stones was performed with the RotoLith lithotriptor in 8 pigs with implanted human stones or artificial stones after open cystotomy. The effect of the treatment on the urinary bladder was investigated macro- and microscopically immediately after the lithotripsy in 4 animals and 4 weeks after the lithotripsy in the other 4 animals. The stones were fragmented into very small pieces which would have been possible to pass with the urine. The histopathologic examination immediately after the procedure showed slight mucosal edema, patches of erosions in the mucosa, and minor submucosal bleeding. Microscopic examination of the bladders removed 4 weeks after lithotripsy showed slight chronic inflammation. The experimental results have encouraged us to plan to use this lithotripsy procedure in selected patients with bladder stones.