1. Exposure of depilated skin of guinea-pig to ultraviolet (u.v.) light for 20 s produces a prolonged inflammatory response.2. The erythaema becomes evident within 15-30 min after the exposure and progressively increases in intensity reaching its maximum by 4-6 hours. The erythaema persists over 24 hours.3. Increase in vascular permeability is biphasic with an early short-lived rise peaking at 0.5 h and a prolonged secondary response peaking at 9-12 h and lasting over 48 hours.4. In presence of aspirin, phenylbutazone and indomethacin, administered prior to u.v. exposure, the inflammatory reaction is partially suppressed, depending upon the dose. The drugs are ineffective in aborting or minimizing the response when given after the inflammation is established. Corticosteroids fail to influence the u.v. inflammation in this test. The significance of these findings is discussed.

Animals↗

PubMed1973

The local graft versus host reaction in the rat as a tool for drug mechanism studies.

1. A local graft versus host reaction in rats permits the evaluation of drug action on (i) donor (parental) animals and (ii) recipient animals (F(1) hybrid) prior to establishing a lymphoid cell graft to detect drugs which might attenuate immunocompetence over a prolonged period (e.g. steroids).2. Treatment of the recipient animals after a lymphoid graft readily detects anti-proliferative agents and may disclose other agents which interfere with the recognition of non-self by viable graft cells.3. Treatment of the cell graft in vitro before innoculation into the recipient animal permits the detection of alkylating agents, which effectively deactivate graft cells at non-toxic concentrations.4. Examples are given of how this reaction may be used to evaluate functionally the effects of chemical modification of the cell surfaces of lymphocytes and to detect active metabolites generated from a precursor drug (e.g. cyclophosphamide).5. Some novel immunosuppressant drugs are described.

Alkylating Agents↗

PubMed1973

Mechanism by which hydnocarpic acid inhibits mycobacterial multiplication.

Recent work in this laboratory has shown that hydnocarpic acid (HA), a principal constituent of chaulmoogra oil, inhibits multiplication in vitro of a number of mycobacterial species. This activity of HA was not shared by several straight-chain fatty acids and by dihydrochaulmoogric acid. A study of the interaction of HA with biotin has been undertaken, based on a structural analogy between biotin and the cyclopentenyl fatty acid. The multiplication of a strain of Mycobacterium intracellulare susceptible to 2 mug of HA/ml was measured turbidimetrically in Dubos medium, in the presence and absence of biotin and several other compounds. Biotin and, to a lesser extent, adenine plus guanine, palmitic acid, and linoleic acid antagonized growth inhibition by HA. Desthiobiotin, thioctic acid, and succinic acid did not block inhibition of bacterial multiplication by HA. HA may act by blocking the coenzymatic activity of biotin, or it may inhibit microbial biotin synthesis. Resumption of multiplication of M. intracellulare after a period of inhibition by HA in broth culture was found to be accompanied by reduction of the effective concentration of the drug; this could have resulted from metabolism of HA or production of an antagonist to HA by the organisms. Also, those organisms that multiplied in the presence of HA were found to represent HA-resistant mutants of M. intracellulare.

Cyclopentanes↗

PubMed1973

Early response of mouse foot pads to Mycobacterium laprae.

The purpose of these experiments was to study the early response of mouse foot pads to Mycobacterium leprae. To accomplish this, mice were inoculated in both foot pads with large and small numbers of organisms. The animals were sacrificed at intervals from 2 hr to 27 days after inoculation. The microscopical results, which utilized normal BALB/c and thymectomized-irradiated B6C3F(1) mice, showed that the tissue responded first with an influx of polymorphonuclear cells and later lymphocytes and monocytes. The latter formed a diffuse infiltrate in the tissues. Under conditions where growth normally occurred, the mononuclear cell infiltrate did not persist. The organisms were found within phagocytic cells and the interstitial space. They were always contained within a phagosome and often fused with lysosomes. Most of the organisms appeared to be degenerating at all of the times studied. No organisms were observed in striated muscle fibers of tissues studied.

Animals↗

PubMed1973

Analogy of Mycobacterium marinum disease to Mycobacterium leprae infection in footpads of mice.

Because it appeared likely that the disease process that follows inoculation of footpads of mice with Mycobacterium marinum might serve as a useful model of mouse footpad infection with M. leprae for immunological studies. an attempt was made to establish an analogy between the two processes. As a second objective, the adequacy of measurements of mouse footpad thickness as an index of the total number of M. marinum and of the number of viable M. marinum was determined. The evolution of M. marinum disease in the footpads of BALB/c mice was observed, and the influences of mouse age and sex and of inoculum size were measured. Mice were challenged with M. marinum in one footpad at several intervals after inoculation of the contralateral hind footpad with the same organism. In all of these experiments, mouse footpad thickness was noted to parallel multiplication of M. marinum during the phase of increasing footpad swelling. Cessation of bacterial multiplication was noted to occur just before maximal swelling had been achieved, and was followed by rapid loss of viable M. marinum. The total number of organisms and mouse footpad thickness decreased only slowly and incompletely. Analogy between M. marinum disease and M. leprae infection of the mouse footpad was established by the self-limited nature of both processes, and by similar patterns of protection against homologous and heterologous challenge conferred by the two processes.

Age Factors↗

PubMed1973

Mutants of Escherichia coli K-12 "cryptic," or deficient in 5'-nucleotidase (uridine diphosphate-sugar hydrolase) and 3'-nucleotidase (cyclic phosphodiesterase) activity.

Mutants of Escherichia coli have been selected for the absence of 5'-nucleotidase (uridine diphosphate-sugar hydrolase) and 3'-nucleotidase (2',3'-cyclic phophodiesterase). Mutants selected for the absence of 5'-nucleotidase are of two kinds: those that lack detectable activity for the enzyme (Ush(-)), and those that possess activity when cell extracts are assayed, but not when intact cells are assayed (cryptic; Crp(-)). The latter class is probably identical to a type of mutant previously reported by Ward and Glaser. When mutants are selected for the absence of 3'-nucleotidase, Crp(-)mutants are also obtained. Thus far, however, mutants totally lacking this enzyme have not been found. The location on the genetic map of one ush mutation is at position 11 min and that of one crp mutation at approximately 67 min. In the crp mutant, 5'-nucleotidase and 3'-nucleotidase remain located in the periplasm. This mutant is also cryptic for alkaline phosphatase but not for acid hexose phosphatase. Treatment of cells with ethylenediamine-tetraacetate substantially alleviated crypticity. These data are discussed in terms of the organization of periplasmic enzymes and of the outer membrane as a permeability barrier.

Acid Phosphatase↗

PubMed1973