Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells

VP-16-213, a semisynthetic derivative of podophyllotoxin, is an active antitumor agent. In this paper, the effects of VP-16-213 and podophyllotoxin on microtubule assembly in vitro and nucleoside transport in HeLa cells are compared. At 100 muM, VP-16-213 does not inhibit microtubule assembly in vitro, while 5 muM podophyllotoxin completely prevents the formation of microtubules. The presence of the glucoside moiety in VP-16-213 is responsible for the inactivity of VP-16-213 in this system because 4'-demethylepipodo-phyllotoxin, the nonglucoside congener of VP-16-213, inhibits microtubule assembly. In HeLa cells, VP-16-213 and podophyllotoxin share a common biological property; both agents inhibit the uptake of thymidine and uridine into cells by inhibiting the facilitated diffusional component of nucleoside transport. The conncentrations of drug necessary to inhibit thymidine and uridine uptake into HeLa cells by 50% are 10 and 5 muM, respectively, for podophyllotoxin, and 25 and 20 muM for VP-16-213. The action of podophyllotoxin on nucleoside transport appears unrelated to its effect on microtubule assembly, since VP-16-213, which does not inhibit microtubule assembly, inhibits nucleoside transport.     

Marital sexual dysfunction: ejaculation disturbances

The three clinically encountered disturbances of the male orgasmic phase--that is, premature ejaculation, inability to ejaculate, and retrograde ejaculation--are discussed. The problem of defining premature ejaculation is explained and the possible pathogenic mechanisms of its origin are reviewed. The classic premature ejaculator is described. Also included are an elaboration of the newer therapeutic approaches to the problem and a suggested clinical protocol for screening patients. The other two, less common dysfunctions are briefly discussed.     

Detection and quantitation of multiple volatile compounds in tissues by GC and GC/MS

Qualitative and quantitative analysis of tissues and body fluids for multiple volatile organic compounds were performed by a combination of packed and open tubular capillary GC and GC/MS. This paper describes methods for such analyses in a case involving the exposure of two persons to methyl ethyl ketone, methyl isobutyl ketone, toluene and the three isomeric xylenes. Tissue and body fluid concentrations of these substances in the two decedents are presented and discussed briefly.     

Alcohol consumption and major depression in the Canadian population

OBJECTIVE: Various clinical studies have documented associations between alcohol consumption and depressive disorders. In some circumstances, alcohol ingestion may cause or worsen depression, whereas in other circumstances the direction of causal effect may be reversed. The objective of this study was to evaluate associations between alcohol consumption and major depression in the Canadian population. METHOD: Data from the Canadian National Population Health Survey (NPHS) were analyzed. This survey, conducted by Statistics Canada in 1994, used a probability sample of 17,626 subjects. The NPHS included measures of alcohol ingestion and a diagnostic screen for major depression (Composite International Diagnostic Interview [CIDI] Short Form). RESULTS: Subjects reporting any drinking in the year preceding the interview were more likely to have experienced an episode of major depression during that time than subjects reporting no drinking. Subjects reporting maximal ingestions of 5 or more drinks (and especially 10 or more drinks) on at least 1 occasion during the preceding year were also at greater risk of major depression than nondrinking subjects or subjects reporting smaller maximal ingestions. Neither the average amount consumed daily nor the frequency of drinking was associated with major depression. CONCLUSIONS: In the general population, there is no simple relationship between the quantity or frequency of alcohol consumption and the prevalence of major depression. Any drinking and maximal consumption on 1 occasion, however, are related to the prevalence of major depression. Further research is needed to delineate causal mechanisms so that clinical and public-health interventions can be formulated.     

Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.