Confounders contributing to the reported associations of coffee or caffeine with disease

The role of caffeine or coffee in causing or promoting the incidence of serious disease is equivocal. Two design factors may account for the discrepancies in reported findings on the effects of coffee drinking: (a) imprecision of measurement and (b) confounding variables. A study of 2,714 white U.S. adults disclosed that, of 32 risk factors analyzed by linear and logistic regression, only sex and cigarette smoking were found to be important potential confounders of caffeine and coffee intake. Partial R2 values of the other 30 risk factors were relatively small and were inconsistent for each sex. It is unlikely that any of these factors could explain any of the reported associations between caffeine or coffee consumption and certain diseases. However, certain weak associations with caffeine or coffee intake should be included in the study design when they are known to be risk factors of a disease under investigation. These factors for men are dietary fat intake, vitamin C intake, and body mass index; and for women are vitamin use, alcohol intake, stress, and perceived health status.     

Inhibition of phosphoribosylpyrophosphate synthetase by 4-methoxy-(MRPP) and 4-amino-8-(D-ribofuranosylamino) pyrimido[5,4-d]pyrimidine (ARPP)

The basis for the antitumor activities of the exocyclic amino nucleosides 4-amino-(ARPP) and 4-methoxy-8-(D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (MRPP) was investigated. The primary target of these nucleosides appeared to be 5-phospho-alpha-D-ribofuranose-1-pyrophosphate (PRPP) synthetase. MRPP-5'-monophosphate was a competitive inhibitor (Ki = 40 microM) of the activation of this enzyme by the cofactor inorganic phosphate (K alpha = 2.2 mM). Consequently, ARPP and MRPP treatment of WI-L2 cultures rapidly inhibited both de novo pyrimidine and purine synthesis as well as the nucleotide salvage reactions dependent on PRPP, ARPP or MRPP treatment completely prevented [14C]bicarbonate incorporation into acid-soluble pyrimidine and purine nucleotides. The rate of salvage of [8-14C]hypoxanthine to form IMP was decreased by 85%. Treatment of cells with these agents caused a 50% reduction in the steady-state level of PRPP. When the capacity of the treated cells for sustained synthesis of PRPP was examined by adenine incorporation, the rate of adenine uptake was inhibited by greater than 50%. In vivo treatment of BDF1 mice with a single dose of ARPP (173 mg/kg) or MRPP (62 mg/kg) extended the mean life span of the mice, which had been inoculated intraperitoneally 1 day earlier with 1 x 10(6) L1210 murine leukemia cells, by 62 and 82% respectively. These studies indicate that MRPP and ARPP inhibit PRPP synthetase, and that PRPP synthetase may be a viable target in the development of certain antitumor agents.     

Moderate drinking in ex-alcoholics: recent studies

The literature on the occurrence of moderate drinking in ex-alcoholics that has been published since the Rand report in 1976 is reviewed. Although differences in diagnosis, definitions of moderate drinking and length of follow-up make strict comparisons of the studies difficult, the majority of studies seem to indicate that the earlier reports of the frequency of such moderate drinking may be overly optimistic. Depending on the definition of moderate drinking that is used, the longer the interval required for alcoholics to sustain moderate, problem-free drinking, the less likely is such an outcome. Among treated alcoholics, the percentage probably ranges from about 2 to 12%; the percentage may be higher among alcoholics identified in community population samples. Thus far, the only factor common to alcoholics who are able to achieve moderate drinking is their being mild cases (i.e., having fewer lifetime alcohol-related problems than other alcoholics). Factors pertinent in assessing discrepancies between the various studies are discussed.     

Respiratory symptoms associated with the use of azodicarbonamide foaming agent in a plastics injection molding facility

Respiratory health variables were studied cross-sectionally in 227 employees of a plastics molding facility where numerous complaints had been apparently associated with the use of azodicarbonamide foaming agent in injection molding. Pre- and postshift respiratory status measures and azodicarbonamide concentrations were also obtained for 17 employees. Cross-sectional pulmonary function differences by injection molding status were not observed. Modest decrements in pulmonary function measures were observed between start and end of shift but with no dose-effect relationship. A strong association was observed for injection molding workers for eye/nose/throat irritation, cough, and wheezing. Additionally, wheezing, chest tightness, and symptoms of chronic bronchitis were strongly associated with work in injection molding during periods in which azodicarbonamide was in use. These results suggest respiratory symptom causation by some combination of azodicarbonamide itself, reaction products of azodicarbonamide formed during injection molding, or other unidentified agents uniquely associated with the process of injection molding with azodicarbonamide foaming agent.     

Identifiability and exchangeability for direct and indirect effects.

We consider the problem of separating the direct effects of an exposure from effects relayed through an intermediate variable (indirect effects). We show that adjustment for the intermediate variable, which is the most common method of estimating direct effects, can be biased. We also show that even in a randomized crossover trial of exposure, direct and indirect effects cannot be separated without special assumptions; in other words, direct and indirect effects are not separately identifiable when only exposure is randomized. If the exposure and intermediate never interact to cause disease and if intermediate effects can be controlled, that is, blocked by a suitable intervention, then a trial randomizing both exposure and the intervention can separate direct from indirect effects. Nonetheless, the estimation must be carried out using the G-computation algorithm. Conventional adjustment methods remain biased. When exposure and the intermediate interact to cause disease, direct and indirect effects will not be separable even in a trial in which both the exposure and the intervention blocking intermediate effects are randomly assigned. Nonetheless, in such a trial, one can still estimate the fraction of exposure-induced disease that could be prevented by control of the intermediate. Even in the absence of an intervention blocking the intermediate effect, the fraction of exposure-induced disease that could be prevented by control of the intermediate can be estimated with the G-computation algorithm if data are obtained on additional confounding variables.     

Identifiability, exchangeability and confounding revisited

In 1986 the International Journal of Epidemiology published "Identifiability, Exchangeability and Epidemiological Confounding". We review the article from the perspective of a quarter century after it was first drafted and relate it to subsequent developments on confounding, ignorability, and collapsibility.     

Nucleoside peptides. 10. Synthesis and T-cell immunostimulatory properties of certain peptide derivatives of 6-azacadeguomycin

Several amino acid and peptide conjugates of 6-azacadeguomycin (6-amino-1-beta-D-ribofuranosyl-4,5-dihydro-4-oxopyrazolo[3,4-d]py rimidine- 3-carboxylic acid, 2) have been prepared in good yields, via a two-step procedure involving 1-hydroxybenzotriazole and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride mediated coupling of 2 with an appropriately protected amino acid or peptide, followed by ammonolysis. Thus, condensation of 2 with L-phenylalanine methyl ester, glycine ethyl ester, and L-glutamic acid diethyl ester gave the corresponding protected linear nucleoside peptides (3, 5 and 7, respectively). Subsequent ammonolysis of 3, 5 and 7 furnished L-phenylalanine amide (4), glycine amide (6) and L-glutamic acid diamide (8) conjugates of 6-azacadeguomycin, respectively. Saponification of 7 gave the corresponding L-glutamic acid derivative 9. A similar coupling of 2 with L-phenylalaninyl-N epsilon-nitro-L-arginine methyl ester trifluoroacetate and subsequent ammonolysis (after catalytic hydrogenation) gave L-phenylalaninyl-L-arginine amide conjugate (12) of 6-azacadeguomycin. Compounds 2, 4, 6, 8, 9, and 12 were evaluated for their ability to potentiate T-cell responses to plant mitogens, in comparison with cadeguomycin (1). Compounds 4, 6, and 9 exhibited an increase in the T-cell proliferation in a dose-dependent manner.     

Post-traumatic stress disorder in the general population. Findings of the epidemiologic catchment area survey

There have been numerous studies of post-traumatic stress disorder in trauma victims, war veterans, and residents of communities exposed to disaster. Epidemiologic studies of this syndrome in the general population are rare but add an important perspective to our understanding of it. We report findings on the epidemiology of post-traumatic stress disorder in 2493 participants examined as part of a nationwide general-population survey of psychiatric disorders. The prevalence of a history of post-traumatic stress disorder was 1 percent in the total population, about 3.5 percent in civilians exposed to physical attack and in Vietnam veterans who were not wounded, and 20 percent in veterans wounded in Vietnam. Post-traumatic stress disorder was associated with a variety of other adult psychiatric disorders. Behavioral problems before the age of 15 predicted adult exposure to physical attack and (among Vietnam veterans) to combat, as well as the development of post-traumatic stress disorder among those so exposed. Although some symptoms of post-traumatic stress disorder, such as hyperalertness and sleep disturbances, occurred commonly in the general population, the full syndrome as defined by the Diagnostic and Statistical Manual of Mental Disorders, third edition, was common only among veterans wounded in Vietnam.     

Difficult-to-recruit respondents and their effect on prevalence estimates in an epidemiologic survey

Generous contact efforts were used to recruit 3,004 respondents into the first wave of the St. Louis Epidemiologic Catchment Area (ECA) project, a psychiatric epidemiologic study of the general population, conducted from 1981-1982. These efforts were analyzed to establish which sociodemographic characteristics or current psychiatric disorders were determinants of difficulty in recruitment. Being young, male, black, a nonrural resident, educated, and full-time employed were the demographic characteristics associated with increased contact efforts. Persons currently meeting criteria for an alcohol disorder required almost 20% more contact attempts than those without the disorder; this difficulty lay both in their being less available for an initial contact and refusing at a higher rate once contacted. An optimal recruitment effort cutoff point is provided, and a method is suggested for detecting that optimal point in the course of ongoing studies.