Evaluation of the Interaction of Three Genotoxic Agents in Eliciting Sister-Chromatid Exchanges Using Response Surface Methodology

Chinese hamster cells (V79) were treated with ethylnitrosourea(ENU), bischloroethylnitrosourea (BCNU), and cis-diamminedichloroplatinum(II)(DDP) alone and in combination. Sister chromatid exchanges (SCEs)were quantitated as measures of genotoxicity of the three agents.The combination experiment employed a factorial design in whichcells were treated, in various concentration combinations, withall agents simultaneously. Response surface methodology usinga polynomial model in treatment variables to approximate themean the distribution of SCE events was employed for analysisof the interactions of the three genotoxic agents. Due to unequalvariances of the number of SCEs in the various treatment groups,a weighted leastsquares analysis was used to estimate the parametersof the dose-response relationship. The single-agent resultssuggest that the DDP concentration-response curve has a muchsteeper slope than the ENU and BCNU curves, and is concave downwardas compared to the relatively linear concentration-responsecurves of ENU and BCNU. The combination results suggest thatENU and DDP are involved in a negative interaction. The BCNTJ/DDPinteraction, the ENU/BCNU interaction, and the three-factorinteraction are not statistically significant. The analysisof these data demonstrates the usefulness of a statistical procedurefor evaluating the biological effects resulting from exposureto multiple cytotoxic agents. The methodology can be used withmany other types of endpoints and is not limited by the numberof treatment agents.     

Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone

Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone.Kennedy, G. L., Jr., and Kaplan, A. M. (1984). Fundam. Appl.Toxicol. 4, 960–971. Hexazinone [3-cydohexyl-6-(dimethylammino)-1-methyl-1,3,5-triazine2,4(1H,3H)-dione; CAS 51235-04-2] was tested for oral toxicityin rats (both 90-day and 2-year feeding studies), mice (8-weekand 2-year feeding studies), and dogs (90-day feeding study).The teratogenic potential was evaluated in rabbits and ratsand functional reproductive capacity was studied in rats. Ninety-dayfeeding of up to 1000 ppm produced no signs of a toxic responsein rats. Rats fed 5000 ppm had growth curves slightly inferiorto those of the controls as the only detectable difference.Extending the feeding period to 2 years produced decreased bodyweights in males fed 2500 ppm (top level tested) and in femalesfed either 1000 or 2500 ppm. All other indices of response,including the type and distribution of tumors, were similarin the test and control rats with the no-effect level being200 ppm. Eight-week feeding of up to 10,000 ppm in mice producedincreased liver weight only at the highest level without anyother changes. Two-year feeding of either 200, 2500, or 10,000ppm resulted in sloughing of the distal tip of the tail andincreased liver weights among mice fed 10,000 ppm. Hypertrophyof centrilobular hepatocytes and hyperplasic nodules were increasedin mice fed either 2500 or 10,000 ppm. No evidence of a tumorigenicresponse was evident The no-effect level was 200 ppm. Dogs fed5000 ppm for 90 days had decreased rate of body weight gainwith clinical enzyme changes suggestive of liver damage. Microscopicexamination of the liver failed to reveal any alterations anddogs fed either 200 or 1000 ppm were indistinguishable fromcontrols. The no-effect level in the dog was 1000 ppm. No evidenceof a teratogenic response was seen in either rats or rabbitsand reproduction capacity in rats fed up to 2500 ppm for threegenerations was unaffected     

The Use of Heparin in Autoimmune Hemolytic Disease

Seven patients with various forms of autoimmune hemolytic anemia weretreated with parenteral heparin. A therapeutic failure resulted in all instances.Heparin therapy did not induce a clinical response or reduce the magnitude ofhemolysis. There was no demonstrable in vivo or in vitro effect of this drugon direct and indirect antiglobulin and bromelin tests. Serum complementlevels and the degree of erythrocyte mobility were unaffected by heparin during the therapeutic trial.

Submitted on July 8, 1969 Accepted on November 25, 1969     

BULK FLOW IN THE CEREBROSPINAL FLUID SYSTEM OF THE DOG

Ventriculo-cisternal, intracranial subarachnoid-to-subarachnoid space and spinal subarachnoid space perfusions were carried out on dogs. The perfusate contained inulin as a tracer and the design of these experiments was based upon the concept that inulin leaves cerebro-spinal fluid (CSF) compartments only by means of bulk absorption, and that actual diffusion and active transport of inulin is negligibly small. Inulin was removed from different CSF spaces by bulk absorption at rates which varied linearly with hydrostatic pressure. The rate of formation of CSF is equal to inulin clearance plus the difference between outflow and inflow rates. The total CSF formation in dogs weighing 12 to 17 kg was measured as 0.065 ml/min, and 58.5 per cent of this amount was found to come from extraventricular CSF space. The rates are independent of hydrostatic pressure in the range studied.     

CHILD HEALTH PROBLEMS AND PROGRAMMES IN TWO UNDERDEVELOPED AREAS OE THE USA

There are areas in the USA where the health problems of children a similar to those of children in some developing countries. Traditional US health programmes have contributed to an improvement in the health status of many of these children but there remains much more to be done.     

Immunological reactivity in dermatophytosis

Patients with Trichophyton mentagrophytes and T. rubrum infections were compared in terms of cutaneous responses and in vitro lymphocyte reactivity to trichophytin and other antigens. Twelve out of fourteen T. mentagrophytes patients exhibited delayed cutaneous hypersensitivity to trichophytin. Most T. rubrum patients (thirty-seven out of forty-nine) lacked delayed reactions to trichophytin specifically, but these patients frequently manifested immediate weal reactions to this antigen. Positive lymphocyte responses correlated with the presence of delayed but not immediate cutaneous reactions. Serum from chronic T. rubrum patients failed to inhibit lymphocyte responses. Possible mechanisms for selective anergy in chronic T. rubrum patients are discussed.     

GUIDELINES FOR AUTOPSY IN HIV POSITIVE CASES

Autopsy on a patient who had died as a consequence of acquired immune deficiency syndrome (AIDS) can be of great value in understanding the disease process. A potential risk to the prosector for acquiring the HIV exists, but if adequate preventive measures are undertaken, the risk is negligible. Indeed there is no documented evidence of a pathologist or an autopsy room attendant acquiring HIV infection while performing autopsy on a patient with AIDS. The procedures to be followed in the autopsy of the patient with AIDS are discussed.KEY WORDS: Acquired immune deficiency syndrome (AIDS), Autopsy in HIV Positive, Autopsy, Hospital acquired infections