Purified protein derivative of tuberculin induces immunoglobulin production in normal mouse spleen cells.

Purified protein derivative (PPD) tuberculin induced immunoglobulin production in cultures of nonimmune mouse spleen cells, as measured by plaque-forming cells (PFC) against sheep erythrocytes (SRBC), horse erythrocytes, and 4-hydroxy-3,5-dinitrophenacetyl-SRBC. The increase started between 15 and 20 h of culture and reached a peak at 48-72 h. Higher PPD concentrations resulted in earlier peak responses than low concentrations. The Ig produced was mainly 19S and of very low avidity. The response elicited by PPD was of the same type as that caused by lipopolysaccharide of bacterial origin. Mitomycin treatment of cells before culture did not change the numbers of PFC/10(6) recovered cells but the cell recovery was considerably lower. Also injection of PPD in vivo resulted in increased numbers of PFC. On the basis of these results it is suggested that PPD nonspecifically activates a majority of the B cell population to proliferation and immunoglobulin synthesis.

Influence of fibrinogen fragments on human lymphocyte thymidine uptake.

Fragments of human fibrinogen were tested for ability to suppress activation of human blood lymphocytes by the lectin phytohaemagglutinin (PHA). Measurement of cellular 14C-thymidine uptake was used as an indicator of DNA synthesis and cell proliferation. The tested fragments were obtained by plasmin digestion or by CNBr fragmentation of fibrinogen. Inhibition of uptake, with good dose response relationship, was demonstrated for the plasmic fragment PL-3 and for the CNBr fragment Hol-DSK. Digests of the latter with trypsin and plasmin gave the same effects as the intact fragment. However, reproducibility was poor with PL-3. Hol-DSK gave better reproducibility, but with pronounced interbatch variations. Other fragments of fibrinogen were tested, but gave no effect in the studied concentrations. The reason for the poor reproducibility is discussed.

Placebo in clinical drug trials--a multidisciplinary review.

The use of placebo in controlled clinical trials is a very difficult matter from an ethical point of view. Scientifically it offers probably the best way of obtaining fast and valid conclusions, thus promoting medical progress for the benefit of future patients. On the other hand, some patients may stand the risk of obtaining a suboptimal therapy in a placebo-controlled trial. In general, this latter aspect must be given precedence. Therefore the use of placebo control should be minimized and other control methods encouraged. However, in certain well-defined instances the use of a placebo control can be justified, provided the ethical implications can be handled.

Adverse reactions in connection with zimeldine treatment--a review.

The results of clinical trials have shown that the general level of side-effects is substantially lower with zimeldine than with tricyclic antidepressants. Data from ordinary clinical usage in Sweden and the U.K. (as opposed to clinical research experience) shows a similar picture. Hypersensitivity reactions, characterized by fever, myalgia and/or arthralgia, and transient increases in transaminases, occur in approximately 1.5% of patients. In rare cases potentially serious neuropathies have been reported.

Evaluation of methods for recording adverse drug reactions in clinical trials.

Four methods used for obtaining information from patients on adverse drug reactions are reviewed on the basis of personal experience. In the development of new therapeutic drugs the method which records all events experienced by a patient during drug treatment is to be preferred as it increases the possibility of detecting unanticipated or previously unreported adverse reactions. Disadvantage of this method is that a high number of events not related to drug treatment may be recorded, causing problems in analysis of the data.

A pilot study on the effect of BCG vaccination in patients with bronchial carcinoma.

Eight patients with non-resectable bronchial carcinoma were treated with a combination of cyclophosphamide and BCG. No effect on survival was noted; mean survival was 11 months from the first admission to hospital.

Low in vitro response to PPD and PHA in lymphocytes from BCG-induced pleurisy in guinea pigs.

In order to study any correlation between functional properties of lymphocytes in BCG-induced pleural exudation and the development of the pleurisy a previously described experimental model was used. This model with a duration of effusion of more than 17 days has characteristic stages. From the third day and onwards there are lymphocytes in sufficient amount for in vitro cultures. Proliferation of lymphocytes from the fluid was measured as uptake of 14C-thymidine. The response of the lymphocytes to PPD tuberculin and to phytohemagglutinin (PHA) was studied, and their spontaneous activity was measured. Comparisons were made with lymphocytes from regional lymph nodes. Pleural lymphocytes sampled on the third post-induction day did not respond to PPD or PHA stimulation. In later stages, pleural lymphocytes were stimulated by PPD to approximately the same degree as the lymph node lymphocytes. The response to PHA was weak at all stages of pleurisy, though in later stages there were some cases with high values. Variations in activation ability, related to disease staging, were demonstrated. However, low activities, and variability of the responses, without concomitant variations in disease, speak against a connection between the course of disease and functional status of the lymphocytes as measured in this study.

Pleurisy induced by intrapleural BCG in immunized guinea pigs.

Guinea pigs immunized with intracutaneous BCG more than 10 weeks previously responded with pleurisy to a large dose (2 mg) of BCG injected into the right pleural cavity. The pleurisy was characterized by an initial stage in which the effusion contained predominantly granulocytes. From day 3 to day 17 after induction, lymphocytes were the dominant white cells. From the day 11 onwards there was decrease of fluid volumes and cell numbers, with concomitant induration and subsequent necrosis of regional lymph nodes, swelling of the pleural wall and formation of adhesions. Fluid volumes of 4-15 ml and total lymphocyte yields of, in general, 10-100 million during days 3-11 after induction of pleurisy, make the model suitable for chemical analyses and immunologic studies.

Intravenous use of rifampicin.

Nineteen seriously ill patients with suspected or verified tuberculosis were treated with a new formulation of rifampicin for intravenous use. The normal dosage was 300 mg twice a day. Local reactions at the injection site were noted in four patients but no serious adverse reactions were observed. The serum concentrations were similar to those after the same dose given orally.

Immunological function in patients operated on with small intestinal shunts for morbid obesity.

Obese individuals, operated on with intestinal shunts, have been investigated with regard to immunological functions. After operation strong increases in skin reactions of immediate and delayed type were observed. Analysis of total WBC and differential counts, percentage T lymphocytes, immunoglobulin concentrations, and lymphocyte reactivity yielded no explanation of the findings.

Nonspecific stimulation of lymphocytes by tuberculin.

Lymphocytes from uninfected, nonimmune mice can be stimulated to proliferate and produce antibody to diverse antigens in culture when exposed to the purified protein derivative of tuberculin or unheated tuberculin culture filtrate. Lymphocytes from numerous inbred strains of mice respond to tuberculin, but no true low responder strain has been found as yet. The evidence presented suggests that a subpopulation of B cells, which are distinct from those activated by lipopolysaccharide endotoxin, respond to tuberculin. The results of digestion experiments with insolubilized enzymes suggest that the nonspecific activating principles in tuberculin are protein.

Fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A in pleural effusions. High turnover of fibrinogen in pleurisy.

Fibrinogen, fibrin(ogen) degradation products (FDP) and fibrinopeptide A (FPA) were analysed in pleural fluids from 20 consecutive patients with major effusions of various aetiology. FPA is a short-lived polypeptide which is split off from fibrinogen, whereafter fibrin is formed. FDP are formed through lysis of fibrin or fibrinogen. In 18 patients no fibrinogen could be detected in pleural fluid, whereas two (both having malignant tumours) had detectable but low concentrations. High FPA concentrations, interpreted as reflecting very recent fibrin formation, were found in all pleural fluids except for one case of empyema and one transudate. Plasma concentrations were low in most cases. The same pattern was found with regard to FDP, i.e. exudates showed high concentrations, whereas plasma concentrations were low. The only patient with a transudate showed absence of fibrinogen and low concentrations of FDP and FPA. We interpret our findings as indicative of a high rate of fibrin formation and degradation in pleural exudates and have not found any differences between various types of pleural exudates. Consequently, the findings may illustrate the close association between the coagulation system and inflammatory reactions which may be common to most pleural diseases.

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.

Dipyridamole suppresses uptake of thymidine in human and bovine cells in vitro.

Dipyridamole has been shown to induce proliferative activity in heart muscle capillary wall cells in the rat. To test whether this effect is due to direct cellular stimulation we tested the substance in various in vitro systems (human lymphocytes, glial cells and endothelial cells; and bovine endothelial cells). During these conditions dipyridamole did not influence cellular proliferation. In all cell systems tested, uptake of labelled thymidine showed an inhibition by dipyridamole. This confirms the earlier finding that dipyridamole inhibits nucleoside uptake, and extends the finding to human cells.