Preparation and enzymatic hydrolysis of dinucleoside monophosphates and DNA modified with aromatic residues.

The following procedures have been used to prepare fifteen modified dinucleoside monophosphates: (a) bisulfite-catalyzed transamination with aniline to give an N4-phenylcytidine (CPh), (b) bisulfite-catalyzed transamination with beta-naphthylamine to give an N4-beta-naphthylcytidine (CbetaN), (c) alkylation with 7-bromomethylbenz[a] anthracene to afford a 7(benz[a]anthryl-7-methyl)guanosine (GMBA), and (d) reaction with N-acetoxy-2-acetylaminofluorene to give an 8-(N-2-fluorenylacetamido)guanosine (GAAF). The compounds prepared were A-CPh, CPh-A, CPh-G, U-CPh, CPh-U, A-CbetaN, CbetaN-A, G-CbetaN, CbetaN-G, U-CbetaN, CbetaN-U, GMBA-U, U-GMBA, GAAF-U, and U-GAAF. All of the modified compounds were hydrolyzed to the expected monomers with venom and spleen exonucleases. Hydrolysis by micrococcal nuclease was inhibited in the following cases: A-CPh, A-CbetaN, U-GMBA, and U-GAAF. The first three reactions above were applied to denatured calf thymus DNA to prepare modified DNA samples containing from 0.3 to 2.0% bound aromatic residues. The modified nucleic acids were completely hydrolyzed to nucleosides by the combination of venom exonuclease, deoxyribonuclease I and alkaline phosphatase. The same results were obtained with a combination of spleen exonuclease, deoxyribonuclease II, and alkaline phosphatase. Hydrolysis of the modified nucleic acids by micrococcal nuclease and alkaline phosphatase afforded primarily nucleosides, with some dinucleoside monophosphates. The amount of the latter did not exceed that found in the hydrolysis of control DNA, however. Other workers have observed inhibition of enzymatic hydrolysis of nucleic acids modified by aromatic carcinogens. We postulated that their results may have been caused by cross-links, which were avoided in our studies.

Potential anticoagulant drug interactions in ambulatory patients.

Computer-generated prescription drug purchase records for ambulatory patients receiving oral anticoagulants (OAC) were studied for concomitant use of other drugs which have been reported to induce clinically significant interactions. One third of 479 patients taking OAC were exposed to a potentially interacting drug at some time during this 6-month period. The percentage of patients with drug interaction exposure correlated directly with total drug use (p less than 0.0005). There were no significant differences when interaction exposure rates were compared in the cases of single : multiple pharmacy and single : multiple physician-patient groups. Warfarin was the most common anticoagulant (greater than 95%) and barbiturates the most common interacting drug.

Prednisone-induced worsening of neuromuscular function in myasthenia gravis.

In patients with myasthenia gravis who received single doses of prednisone orally (40 to 100 mg), we found acute inhibition of neuromuscular function as manifest by increased decremental responses to repetitive nerve stimulation, reduced twitch tension, and lowered maximum voluntary contraction strength. The time course of these changes correlated with plasma methylprednisolone levels, implying direct drug effects on neuromuscular function.

Quantitative correlation between plasma pyridostigmine levels and neuromuscular function in myasthenia gravis.

In 10 patients with myasthenia gravis, we studied the relationship between plasma pyridostigmine levels and five measures of neuromuscular function (NMF) following single oral doses of 60 to 120 mg. The NMF measures were percent decrement of the evoked muscle compound potential, maximum force, force-time integral, vital capacity, and outstretched-arm time. The combined mean improvement was most significant 2 hours after pyridostigmine ingestion and coincided with the peak plasma pyridostigmine levels in eight patients. In seven patients, there was a positive correlation between plasma pyridostigmine levels and the mean percent improvement.

Social and environmental factors in lung cancer mortality in post-war Poland.

Poland and other Eastern European countries have undergone heavy industrial development with marked increases in air pollution and occupational exposure in the nearly 50 years since World War II. These countries have also experienced substantial increases in chronic disease mortality in the past three decades. While it is tempting to assume a direct association between these phenomena, more detailed analyses are called for. Poland offers a potentially rich opportunity for comparing geographical patterns of disease incidence and of industrial change. In this paper we 1) elucidate the prospects for attributing lung cancer mortality to industrial emissions in Poland, using an ecological approach based on the hitherto unaddressed geographic differences, and accounting for regional differences in cigarette consumption; 2) propose explanatory hypotheses for the observed geographic heterogeneity of lung cancer; 3) begin systematic testing of the widely accepted but not well-scrutinized notion that pollution in Poland is a major contributor to declining life expectancy. Regions with the highest fraction of cancer that cannot be explained by smoking appear to be highly urbanized, have high population exposure to occupational carcinogens, experience the highest rates of alcoholism and crime, and are associated with the post- World War II population resettlement. Although the analysis does not rule out pollution as a significant contributor to lung cancer mortality, it indicates that other factors such as occupational exposures and various social factors are of at least comparable importance.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual effects of pilocarpine in glaucoma comparative study of administration by eyedrops or by ocular therapeutic systems.

Eighteen glaucoma patients each received four pilocarpine regimens in random sequence: 1% and 4% eyedrops and 20mug/hr and 40mug/hr ocular therapeutic systems. Unimportant changes in refraction, near vision, and distance vision occurred during the use of either ocular therapeutic system. Miosis with ocular therapeutic systems was almost always less intense and variable than with eyedrops. Refractive changes occurred in 12 patients following 1% pilocarpine and in 16 patients following 4% pilocarpine drops; decreased distance vision occurred in nine patients after 1% drops and in 12 patients after 4% drops. Fewer patients showed decreases in near vision. In all cases, visual effects peaked one half hour after eyedrop instillations and returned gradually toward normal in the next two to three hours. Intraocular pressure levels were within comparable ranges during all four treatments, but the ocular therapeutic systems maintained pressure at a more constant level.

Time course of improved neuromuscular function following plasma exchange alone and plasma exchange with prednisone/azathioprine in myasthenia gravis.

Ten patients with myasthenia gravis (MG) were treated with weekly plasma exchange (PE) in combination with prednisone and azathioprine; 4 of the patients were treated with 3-6 PE alone, before instituting prednisone/azathioprine. Four clinico-physiological parameters of neuromuscular function as well as the anti-acetylcholine receptor antibody (anti-AChRAb) titers were measured 1-3 times per week. Evidence of improved neuromuscular function (NMF) was based on: (1) reduced % decrement of the maximum muscle compound potential following 2/s supramaximal nerve stimulation; (2) increased maximum force; (3) increased outstretched arm time, and (4) increased vital capacity. An early improvement in NMF occurred within the first 2 weeks (sometimes as early as 1-2 days), which was quantitatively comparable in patients treated with PE alone and PE plus prednisone/azathioprine. This early improvement reached a plateau, and was subsequently maintained for 3-4 weeks, followed by a later substantial improvement after 8-12 weeks of combined PE plus prednisone/azathioprine.

Physician demand for leisure: implications for cesarean section rates.

Logistic regression models test whether physician demand for leisure affects both total and unplanned cesarean section rates, after controlling for relevant clinical variables. Although nature distributes births and associated problems uniformly, time-dependent dummy variables related to leisure are significant predictors of both total and unplanned c-sections.

Exposure to tetrachloroethylene via contaminated drinking water pipes in Massachusetts: a predictive model.

A computer model was developed to estimate exposure to tetrachloroethylene leaching from drinking-water pipes in Massachusetts between 1968 and 1979. The model was to be used for an epidemiologic study of cancer in five communities in Massachusetts. This model assigned a relative cumulative exposure score to each individual participant in the study, based on the geometry, size, age, and water flow through the water pipe that supplied a particular household and on the individual's duration of residence in that household. The results of modeling showed a wide range of exposure levels among the study participants. The epidemiologic study is described in the accompanying paper by Aschengrau et al.

Income, location, and the demand for health care from public, nonprofit, and for-profit hospitals.

Although, empirically, for-profit hospitals serve few poor and indigent patients, they may be able to shift capital more quickly than hospitals of other ownership types, thereby spatially avoiding poor patients. However, in a market with a relatively high proportion of for-profit hospitals, spatial avoidance of poor patients is not possible because spatial competition will exist in non-poor areas. The study examines hospital choice for maternity care in a market with many for-profits using a gravity model or conditional logit. The analysis shows that poor and Medicaid populations choose for-profit hospitals overall. Income, along with distance, is an important factor in hospital choice.

Pharmacokinetics of the dermal route of exposure to volatile organic chemicals in water: a computer simulation model.

A kinetic model of dermal absorption of nonpolar organic nonelectrolytes in dilute aqueous solutions is described. The model uses systems dynamics STELLA software and is designed for a Macintosh computer. The model assumes the outer stratum corneum layer of skin to be the rate-determining barrier to dermal absorption and assumes that both stratum corneum and viable epidermal layers have storage capacity for lipophilic solutes. The model predicts between 30 and 94% of experimental results with humans under the same conditions. The degree of departure between experimental and theoretical results is inversely related to the solute's octanol/water partition coefficient, which is consistent with the most recently hypothesized mechanisms of transport of molecules across the dermal barrier. The model has potentially useful applications for risk assessment if used within its defined limits.

Conformation of aromatic-substituted dinucleoside monophosphates: an extension of the base-displacement theory of carcinogenesis.

The conformations of 12 dinucleoside monophosphates containing N4-phenylcytidine (CPh) or N4(beta-naphthyl)cytidine (CbetaN) residues have been studied, using circular dichroic spectroscopy. The following compounds had aqueous spectra resembling their parent compounds, which lacked the modifying aromatic substituent: CPhpU, CbetaNpU, UpCPh, UpCbetaN, CPhpG, CbetaNpG, GpCPh, and CPhpA. The spectra of GpCbetaN and ApCbetaN were almost the reverse of the unmodified compounds, while CbetaNpA and ApCPh were intermediary in character. When the spectra were run in methanol, all major differences between the modified and unmodified compounds disappeared. This result suggested that the differences observed in aqueous solution were the result of stacking interactions between the aromatic ring and a neighboring purine. When the aromatic ring was naphthalene, the modified cytidine occupied the 3'-terminal position, and, when the purine was adenine, the effect was enhanced. These conclusions were supported by a consideration of chemical shifts in the 1H NMR spectra of ApCbetaN, and GpCbetaN, as compared to those of the unmodified compounds and CbetaNpG. A study of molecular models of ApCbetaN and GpCbetaN revealed a unique conformation in which the purine rotates to a syn position, in order to allow a close stacking interaction with the naphthalene ring. No such conformation is available for CbetaNpA and CbetaNpG, and the best partial stacking interaction occurs in a conformation with the purine in the anti conformation. The base-displacement theory of carcinogenesis (Levine, A. F., Fink, L. M., Weinstein, I. B., and Grunberger, D. (1974), Cancer Res. 34, 319) describes the conformational change resulting from the attachment of a bulky aromatic residue at the 8 position of guanine in RNA or DNA, and attributes biological importance to the event. The changes that occur upon substitution of the amino group of cytosine differ in detail from the above, but would be expected to produce similar biological results. Base-displacement effects need not be limited, therefore, to a particular substitution position in a nucleic acid.

The role of skin absorption as a route of exposure for volatile organic compounds (VOCs) in drinking water.

Assessments of drinking water safety rely on the assumption that ingestion represents the principal route of exposure. A review of the experimental literature revealed that skin penetration rates for solvents are remarkably high, and that the stratum corneum is a less effective barrier to penetration than traditionally assumed. Based on published skin absorption rates, we used Fick's law (Jos = Kop delta Cos) to determine permeability constants for selected compounds. We then calculated dose per kilogram for nine different exposure situations and compared this to the oral dose per kilogram. We found that skin absorption contributed from 29-91 per cent of the total dose, averaging 64 per cent. Dose per kilogram body weight ranged from .0002 mg/kg-.18 mg/kg, with an average of .03 mg/kg. In weak aqueous solutions, flux of the solute is directly proportional to concentration. Laboratory approaches differ markedly from environmental exposures and can underestimate absorption. We conclude that skin absorption of contaminants in drinking water has been underestimated and that ingestion may not constitute the sole or even primary route of exposure.

Chemical Health Effects Assessment Methodology for airborne contaminants.

Chemical Health Effects Assessment Methodology (CHEM) is a new procedure for assessing hazardous properties of airborne toxic contaminants. CHEM evaluates substances for four major health effect categories: carcinogenicity, mutagenicity, reproductive/developmental toxicity, and toxic effects other than the first three. Three elements are considered in the assessment: weight of evidence, potency, and severity of effect. This approach produces a profile of toxic properties of chemicals which preserves their unique multidimensional character and highlights data gaps.