Effect of zimeldine and its metabolites on [3H]thymidine incorporation in lymphocyte cultures from psychiatric patients with or without a hypersensitivity reaction during zimeldine therapy.

Lymphocyte transformation test (LTT) was applied to 28 patients who had developed a hypersensitivity syndrome (HSS) during treatment with the antidepressant drug zimeldine. Twenty-seven patients treated with zimeldine without any symptom of an HSS were matched controls. Zimeldine and its metabolites norzimeldine and CPP 200 all induced statistically significant increased [3H]thymidine incorporation in cultured lymphocytes from the HSS patients compared with the controls, norzimeldine being the most potent inducer. The results indicate an immunoreactive process in the development of the HSS induced by zimeldine.

Limited efficacy of inhibitors of herpes simplex virus DNA synthesis in murine models of recrudescent disease.

The herpesvirus DNA polymerase inhibitor foscarnet, applied topically, and the anti-herpesvirus guanosine analogue buciclovir, given orally, decreased virus replication and disease development in primary skin infections of mice caused by herpes simplex virus type 1 (HSV-1). If the same tissues were infected via sensory nerves, following zosteriform spread of the virus the same treatments showed strongly decreased efficacy, or were inefficacious, when started before development of clinical signs in the infected tissues. These results were obtained in murine models of zosteriform spread of HSV-1 to the ear (following inoculation of the ventral side of the neck) or to the lower flank (following inoculation of the upper flank). In these models the immune system played a dominant role in virus clearance. The topically applied foscarnet could not prevent disease development in these models of recrudescent disease even when applied before the virus was detected in the skin, but a decrease in virus titre was obtained. Orally administered buciclovir lost efficacy when administered at the time of virus entry into the skin, i.e. 1 or 2 days before development of clinical signs. In the flank model, measuring lesion development, orally administered acyclovir also had a strongly decreased efficacy, when compared with its effect during infections in which lesion development did not involve translocation of virus through nerves. In the presence of developing immunity the inhibitors could not accelerate the clearance of virus from infected tissues. Furthermore, all treatments (topical foscarnet and oral buciclovir or acyclovir) were without effect on disease development when treatment was initiated on appearance of the first clinical signs of disease. As disease development following zosteriform spread of HSV resembles that in recurrent herpes in humans, and as the limited efficacy of the inhibitors observed resembles the poor results obtained with inhibitors of herpesvirus DNA synthesis in clinical studies on the treatment of symptomatic recurrent herpes, we suggest the use of animal models of zosteriform spread for pre-clinical evaluation of new antiherpes drugs.

Effects of fibrinogen fragment and proteolytic enzyme on the immune system in mice.

The immunomodulating ability of fibrinogen fragment (Hol-DSK) and proteolytic enzyme with fibrinolytic activity from Aspergillus oryzae was analysed in CBA/Ca, C57Bl, C3H/HeJ and NMRI mice. Suppressive effects on the blastogenic response to mitogens were noted. No consistent suppressive effect, but sometimes an enhancing one, was recorded on the antibody responses to protein antigens. Administration of Hol-DSK or proteolytic enzyme shortly after the immunization resulted in a slight inhibition of the development of delayed hypersensitivity to picryl chloride in C57Bl but not in CBA mice. When similar administration was done simultaneously with administration of the challenging antigen of picryl chloride or sheep red blood cells in immunized mice, significant impairment of the delayed-type hypersensitivity reaction was noted. The modulating effects by Hol-DSK did not alter the in vitro bacteriocidal effects of peritoneal exudate cells from mice on Escherichia coli.

Protective effect of sublethal intraperitoneal Listeria infection secondary to intranasal influenza infection in aged immunodeficient mice.

Aged mice of the CBA/Ca strain, 15 months of age, and A/J mice, 17 months of age, exhibited impaired lymphoblastogenic response to concanavalin A but not to lipopolysaccharide. This defective cellular responsiveness was not accompanied by decreased antibody response to protein antigen or decreased ability to develop delayed hypersensitivity to picryl chloride. An increased susceptibility to influenza virus infection given intranasally was noted in the aged mice as compared with young animals. Such virus infection also impaired the lymphoblastogenic response to mitogens. Surprisingly, the virus infection in aged animals was less lethal after a subsequent infection with a small inoculum of Listeria bacteria.

Antigens of Escherichia coli, human immune response, and the pathogenesis of urinary tract infections.

Acute pyelonephritis (but not cystitis or "asymptomatic" bacteriuria) due to Escherichia coli induces serum antibodies to O-but rarely to K-antigens, especially not to the most common antigen, K1. Locally produced secretory IgA and IgG antibodies to O-and K-antigens appear in urine during most infections. The E. coli in urine of patients with asymptomatic bacteriuria are different from those in patients with acute pyelonephritis and cystitis and undergo continuous changes, presumably caused by the local antibody response. The E. coli become less virulent and are less able to attach to uroepithelial cells than E. coli causing acute symptomatic infections. Antibodies in urine prevent epithelial adherence. Parenteral and intravesicular injections of killed bacteria can protect against ascending pyelonephritis in rats. A few K-antigens dominate among E. coli that cause urinary tract infections. Vaccination of problem cases is a possibility because of the protective nature of K-antibodies. The mechanism of renal scarring that appears in some patients with urinary tract infections is unknown. Autoantibodies to the Tamm-Horsfall protein that increase after acute pyelonephritis or the cross-reactions noted between certain E. coli and antigens on the kidney may be involved.