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BACKGROUND AND PURPOSE: The cost of medication overuse headache (MOH) is underestimated. Our aim was to address the cost-effectiveness of a structured treatment protocol and to present annual cost estimates. METHODS: Patients were enrolled on the occasion of a structured treatment protocol, were administered a research protocol addressing direct and indirect costs and were followed up for 3 months. RESULTS: Of 176 enrolled patients, 138 completed the study. The 3-month cost per patient fell from €2989 to €1160: the difference was €696 per month for patients treated in the ward and €466 for those treated in day-hospital; thus it takes 2-3 months to compensate for the protocol's cost. The per-person annual costs of MOH were €10 533 (95% confidence interval €8700-12 406): direct healthcare costs accounted for 44.8% and indirect costs for 51.5% of the total MOH cost. The annual MOH cost for Italy is estimated at €13.5 billion (95% confidence interval €11.1-15.9 billion). CONCLUSION: The cost of MOH around the period of a structured treatment protocol is much higher compared to previous estimates. Our protocol is cost-effective for reducing the economic burden of MOH.

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We evaluated 44 old patients (mean age 84 years) in order to study the frequency of headaches. The frequency found in our sample is higher in comparison to other studies. Further studies including a larger number of patients are needed to obtain more incisive results.

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A model for a population-game with multiple asymmetry is studied, in which the participants are assumed to be different from one another both in size and in status as owners or non-owners of a territory. Only owners can reproduce, hence natural selection is assumed to operate in favor of the increase of ownership-time. Conditions for the evolutionary stability of the Bourgeois Principle of owner-priority, despite difference in body size, are characterized. It is shown that ownership-priority tends to be at least partially replaced by strength-priority as the availability of habitats, the expected longevity of potential intruders and the harm inflicted on the loser of an aggressive confrontation decrease, and as the expected longevity of the owner increases. It is further established that the combined effect of all these parameters can be characterized by a single parameter, referred to as the concord coefficient of the population. Finally, when this parameter reaches a certain critical level, only strength-priority can prevail. If the concord coefficient decreases below this critical level, no priority-rule can remain stable in the population, in which case aggressive confrontations cannot be avoided, at least in certain situations. In this case, it is shown that aggression emerges first among low-rank individuals.

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A stochastic process of long-term evolution due to mutation and selection is defined over an asexually reproducing population, with selection according to a population game with a one-dimensional continuity of pure strategies. Limiting the analysis to mutations of small effect, it is shown that long-term dynamic stability in such a process is equivalent to continuous stability in the relevant population game. In the case of a one-dimensional strategy set (but not necessarily if the strategy set is multi-dimensional), this result is virtually independent of the distribution of mutations.

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OBJECTIVE: The polymorphism of erythrocyte thiopurine methyltransferase (TPMT) is genetically regulated as an autosomal codominant trait, and so should be congenital. RESULTS: We tested this hypothesis by measuring TPMT activity in erythrocyte preparations from adults and newborns and observed polymorphic distribution of TPMT activity in the adult and newborn erythrocytes. The activity of TPMT was higher in red cells from the newborns than adults. The frequency distribution of TPMT activity was also investigated in the liver and kidney. In the kidney, TPMT activity fell into two subgroups, whereas in the liver the distribution pattern was more complex. The activity of TPMT in erythrocytes and liver from the same subject was correlated, but the values of only half the cases fell within the 95% confidence limits, suggesting that the control of hepatic and/or erythrocyte TPMT is multifactorial.

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Diisopropyl fluorophosphate (DFP), a volatile highly toxic enzyme inhibitor, in buffer (pH 3, pH 5, pH 7, pH 9, pH 11, Hank's, Dulbecco's, PBS, TBE, and HEPES) or water (10 mM), in DMF solution (200 mM), and bulk quantities can be degraded by adding 1M NaOH. The DFP was completely degraded, as determined by enzymatic assay, and the final reaction mixtures were not mutagenic.

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The degradation of 1,1-dimethylhydrazine (UDMH), a component of some rocket fuels, was investigated using atmospheric oxygen and hydrogen peroxide. The reactions were carried out in the presence and absence of copper catalysis and at varying pH. Reactions were also carried out in the presence of hydrazine, a constituent, along with UDMH, of the rocket fuel Aerozine-50. In the presence of copper, UDMH was degraded by air passed through the solution; the efficiency of degradation increased as the pH increased but the carcinogen N-nitrosodimethylamine (NDMA) was formed at neutral and alkaline pH. Oxidation was not seen in the absence of copper. Production of NDMA occurred even at copper concentrations of < 1 ppm. Oxidation of UDMH with hydrogen peroxide also gave rise to NDMA. When copper was absent degradation of UDMH did not occur at acid pH but when copper was present some degradation occurred at all pH levels investigated. The production of NDMA occurred mostly at neutral and alkaline pH. In general, higher concentrations of hydrogen peroxide and copper favored the production of NDMA. Dimethylamine, methanol, formaldehyde dimethylhydrazone, formaldehyde hydrazone, and tetramethyltetrazene were also produced. The last three compounds were tested and found to be mutagenic.

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Amoxicillin, ampicillin, bleomycin, carmustine, cephalothin, dacarbazine, lomustine, metronidazole, norethindrone, streptozocin, sulfamethoxazole, and verapamil were completely degraded in solution, without the production of mutagenic residues, by photolysis using a medium-pressure mercury lamp in an all-quartz apparatus. A stream of air was passed through the solution and for amoxicillin, ampicillin, bleomycin, lomustine, metronidazole, and norethindrone it was necessary to add hydrogen peroxide. Dilute aqueous solutions of ampicillin, bleomycin, carmustine, cephalothin, lomustine, norethindrone, streptozocin, trimethoprim, and verapamil can be decontaminated using polymeric Amberlite resins.

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Five enzyme inhibitors (phenylmethylsulfonyl fluoride, 4-amidinophenylmethanesulfonyl fluoride, 4-(2-aminoethyl)benzenesulfonyl fluoride, N alpha-p-tosyl-L-lysine chloromethyl ketone, and N-tosyl-L-phenylalanine chloromethyl ketone) in buffer, DMSO, or stock solutions were completely degraded by adding 1M NaOH and the final reaction mixtures were not mutagenic. The stability of these compounds decreased as the pH increased.

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Solutions of potassium permanganate in 3 M sulfuric acid, 1 M sodium hydroxide solution, and water can be used to degrade hazardous compounds. Excess oxidant can be removed by using sodium metabisulfite. Manganese, a carcinogen and mutagen, can be removed from the final reaction mixtures by making these mixtures strongly basic. Aqueous dilution causes the soluble potassium sulfate to dissolve while still allowing the insoluble manganese compounds to be removed by filtration and so reduces the weight of precipitate. In all cases the amount of manganese left in the filtrates was less than 2 ppm and the reaction mixtures were nonmutagenic. When ethanol was used as a test compound, degradation was much more rapid when the solvent was 3 M sulfuric acid or 1 M sodium hydroxide solution than when the solvent was water. However, the variation of the rate of reaction with pH depends on the nature of the substrate. Thus the effectiveness of the various methods may vary for other substrates. Potassium permanganate in sulfuric acid was used to degrade four polycyclic heterocyclic hydrocarbons. Destruction was greater than 99.9% and the final reaction mixtures contained no more than 0.5 ppm manganese and were not mutagenic. By modifying the work-up procedures to remove manganese from the final reaction mixture, procedures previously developed for degrading hazardous compounds can still be employed.

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Chromatography columns filled with Amberlite XAD-16 were used to decontaminate, using a continuous flow-through procedure, aqueous solutions of the following biological stains: acridine orange, alcian blue 8GX, alizarin red S, azure A, azure B, brilliant blue G, brilliant blue R, Congo red, cresyl violet acetate, crystal violet, eosin B, eosin Y, erythrosin B, ethidium bromide, Giemsa stain, Janus green B, methylene blue, neutral red, nigrosin, orcein, propidium iodide, rose Bengal, safranine O, toluidine blue O, and trypan blue. Adsorption was most efficient for stains of lower molecular weight (< 600). Adsorption of stain increased as the flow rate decreased; column diameter had little effect on adsorption. Adsorption of stain was greatest when finely ground resin was used, but if the resin particles were too small, column clogging occurred. Limited grinding of the resin gave increased adsorption while retaining good flow characteristics. Amberlite XAD-16 saturated with methylene blue was regenerated to its initial adsorption capacity by passing methanol through the column. The technique described provides an economical, rapid means of removing stains from aqueous solution.

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Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.

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Two techniques were investigated for degrading a number of halogenated compounds of commercial and research importance. Reductive dehalogenation with nickel-aluminum alloy in potassium hydroxide solution was used to degrade iodomethane, chloroacetic acid, trichloroacetic acid, 2-chloroethanol, 2-bromoethanol, 2-chloroethylamine, 2-bromoethylamine, 1-bromobutane, 1-iodobutane, 2-bromobutane, 2-iodobutane, 2-bromo-2-methylpropane, 2-iodo-2-methylpropane, 3-chloropyridine, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, 4-fluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 4-fluoronitrobenzene, 2-chloronitrobenzene, 3-chloronitrobenzene, 4-chloronitrobenzene, benzyl chloride, benzyl bromide, alpha,alpha-dichlorotoluene, and 3-aminobenzotrifluoride. The products were generally those obtained by replacing the halogen with hydrogen although concomitant reduction of the other groups was also observed. Bibenzyl was produced during the reduction of benzyl chloride, benzyl bromide, and alpha,alpha-dichlorotoluene. Refluxing with ethanolic potassium hydroxide was used to degrade iodomethane, chloroacetic acid, 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, 1-chlorobutane, 1-bromobutane, 1-iodobutane, 2-bromobutane, 2-iodobutane, 2-bromo-2-methylpropane, 2-iodo-2-methylpropane, benzyl chloride, benzyl bromide, 1-bromononane, 1-chlorodecane, and 1-bromodecane. The products were the corresponding ethyl ethers. 2-Methylaziridine was cleaved with nickel-aluminum alloy in potassium hydroxide solution to a mixture of isopropylamine and n-propylamine. In all cases, the compounds were completely degraded and only nonmutagenic reaction mixtures were produced.

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In order to assess the exposure of workers administering N-nitrosodiethylamine (NDEA) parenterally to Macaca mulatta, air samples were drawn through Thermosorb/N cartridges. Samples were analysed by gas chromatography-thermal energy analysis; the limit of detection was 0.02 micrograms/m3. Significant amounts of NDEA were found in those samples taken in the animal holding room. The NDEA recovered may be accounted for by its expiration by the animals (the contribution from excreta and leakage from the injection site is probably minor). On the basis of the total amount of NDEA administered (840 mg during the first experiment and 250 mg in the second) and the rate at which the animal holding room was ventilated, and assuming that the samples were representative, we estimate that 0.9% of the NDEA administered was released to the atmosphere in 5 h in the first experiment and that 2.7% and 0.8% were released in the first and second 24-h periods, respectively, in the second experiment. It should be noted that this potential source of exposure may be significant not only for workers but also for control or other experimental animals housed in the same room.

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Aqueous solutions of a number of biological stains were completely decontaminated to the limit of detection using Amberlite resins. Amberlite XAD-16 was the most generally applicable resin but Amberlite XAD-2, Amberlite XAD-4, and Amberlite XAD-7 could be used to decontaminate some solutions. Solutions of acridine orange, alcian blue 8GX, alizarin red S, azure A, azure B, Congo red, cresyl violet acetate, crystal violet, eosin B, erythrosin B, ethidium bromide, Janus green B, methylene blue, neutral red, nigrosin, orcein, propidium iodide, rose Bengal, safranine O, toluidine blue O, and trypan blue could be completely decontaminated to the limit of detection and solutions of eosin Y and Giemsa stain were decontaminated to very low levels (less than 0.02 ppm) using Amberlite XAD-16. Reaction times varied from 10 min to 18 hr. Up to 500 ml of a 100 micrograms/ml solution could be decontaminated per gram of Amberlite XAD-16. Fourteen of the 23 stains tested were found to be mutagenic to Salmonella typhimurium. None of the completely decontaminated solutions were found to be mutagenic.

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