Numerous methods exist by which we can follow exposure to tobacco smoke in experimental animals as well as in human populations. The simplest method to follow tobacco exposure is by assessing either urinary or serum cotinine levels. Although this provides an accurate assessment of short-term exposure to tobacco, it fails to provide a loan term assessment of exposure over several weeks and/or months. DNA adducts also provide effective means of monitoring exposure to tobacco smoke carcinogens. However, with the use of DNA adducts one deals with repair mechanisms, which may be altered as a result of the initial exposures. The ideal biomarker for use in assessing chemical exposures over a long-term basis is the use of the red cell protein hemoglobin. Formation of electrophilic metabolites of carcinogens has been shown to react with a variety of nucleophilic sites on hemoglobin, therefore forming covalent adducts which persists for the life of the red cell (120 days) and thus can be detected in used as a biomarker of exposure. Tobacco carcinogens must first be activated by a variety of enzymes prior to becoming electrophilic intermediates. Metabolic activation of these compounds proceeds by a number of steps, including the activation via cytochrome enzymes (CYP). Following activation of the carcinogens to a reactive electrophile, the reactive compound can form covalent adducts with DNA and protein. Following activation of the carcinogens, enzymes also are responsible for the detoxification of the reactive electrophilic metabolites. These enzymes help the body handle exposure to these compounds by facilitating detoxification and illumination of those reactive carcinogenic derivatives. The present study examined the relationship between polymorphism of CYP1A1 pharmacogenetics and hemoglobin adducts to metabolites of benzo(a)pyrene in maternal and fetal blood samples.

Both genetic and environmental factors are involved in the development of cancer. The capacity to metabolize certain drugs and carcinogens is known to be variable in humans and appears to be of critical importance in determining the risk an individual has of developing cancer when exposed to carcinogens. For many phase I and phase II enzyme systems involved in foreign compound metabolism it is now understood that germ-line genetic variation within the genes encoding these enzymes leads to altered phenotypic expression impacting the metabolic capacity of the individual. This genetic variation is referred to as genetic polymorphism and the study of the association between genetic polymorphism and the resulting phenotypic changes in drug or foreign compound metaboism is referred to as pharmacogenetics. This variation in metabolic capacity is linked to environment–gene interactions on carcinogenesis and has been well demonstrated by enzymes that are involved in the metabolism of carcinogens including several human cytochrome P450 enzymes as well as certain glutathione S-transferases and N-acetyltransferases. The genetic lesion may involve a single but critical base pair change or complete gene deletion. Screening assays based on PCR amplification coupled to restriction fragment length polymorphism (RFLP) analysis or allele specific PCR have been developed to correlate genetic polymorphism with phenotypic expression and susceptibility to genotoxicity or carcinogenesis. The phase II enzymes, including GSTs, N-acetyltransferases, as well as epoxide hydrolase, are all involved in the detoxification of activated metabolites of carcinogens, including those carcinogens found in tobacco smoke. The substrates of GSTs include benzo(a)pyrene as well as other carcinogens. In the present study, we investigated the relationship between polymorphism of glutathione S-transferase in maternal and fetal cord blood samples obtained at delivery and correlated genotype with presence of hemoglobin adducts to the tobacco carcinogen benzo(a)pyrene.

Previous studies on the metabolic activation of polycyclic aromatic hydrocarbons have shown conclusively that activation to reactive electrophilic intermediates occurs via metabolism of the unsubstituted aromatic hydrocarbon to electrophilic diol-epoxide intermediates. These reactive electrophilic derivatives undergo reaction with various biological nucleophilic centers to form covalent modifications, which can be assessed by a variety of analytical techniques. While the formation of these adducts with various cellular nucleophiles has been clearly established, the relationships between relative rates of formation of various adducts in biological systems has not been significantly investigated. In the present study, we investigated the pharmacokinetics of reaction of the ultimate carcinogenic metabolite of benzo(a)pyrene, (±)-anti-7,8-dihydroxy-9α,10α -epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), with both male C57BL/6 mouse red cell hemoglobin and human red cells, in vitro. Comparative pharmacokinetic studies using both mouse and human hemoglobin were carried out by incubation of the packed red cells together with solutions of (±)-anti-7,8-dihydroxy-9α,10α -epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Similar rate constants for the binding of the epoxide to hemoglobin in both mouse and human were found, suggesting a similarity of amino acids that were adducted in both species. Overall binding of (±)-anti-7,8-dihydroxy-9α,10α -epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene to mouse hemoglobin was found to be slightly higher than that found using human hemoglobin, suggesting the potential of a facilitation of the binding of the epoxide with mouse protein or an additional reactive amino acid to which the epoxide was bound. In parallel studies, mice were injected intraperitoneally with benzo(a)pyrene to compare the kinetics of binding of this carcinogen to hemoglobin, in vivo. Blood samples were obtained at specific intervals, and the kinetics of binding to hemoglobin characterized. These results suggested that the binding to hemoglobin in the in vivo studies was slightly lower than that compared to the in vitro assessments. However the differences in adduct levels strongly suggests that other metabolic pathways are involved in the metabolic activation of benzo(a)pyrene as well as other related carcinogenic compounds.

Previous studies of the metabolic activation of chemical carcinogens including benzo(a)pyrene have demonstrated that selected aromatic hydrocarbons can undergo a series of biological substitution reactions in tissue cytosol preparations when in the presence of the methyl donor S-adenosyl-L-methionine. Although identification of the methylated metabolites of carcinogens had been tentatively established using liquid chromatographic techniques, confirmation of the identity of these methylated derivatives has remained elusive. In the present study, the carcinogen benzo(a)pyrene was found to undergo methylation reactions in the presence of rat liver cytosol preparations to yield products that were identified as methylated, formyl and hydroxyalkyl derivatives of the parent carcinogen. Identification and confirmation of the identity of the 6-methylbenzo(a)pyrene metabolite was confirmed by both UV detection, gas chromatographic and mass spectral identification, and NMR analysis of metabolic fractions obtained from incubations of benzo(a)pyrene. The results conclusively demonstrate that the carcinogen benzo(a)pyrene undergoes biological substitution reactions to yield 6-methylbenzo(a)pyrene in the presence of cytosolic enzymes. The presence of 6-methylbenzo(a)pyrene as a metabolite of benzo(a) pyrene illustrates and confirms the presence of centers of reactivity in unsubstituted aromatic hydrocarbons. These centers of reactivity serve as sites for biochemical substitution reactions, yielding methyl substituted hydrocarbons. Furthermore, these methylated metabolites of polycyclic aromatic hydrocarbons are further metabolically activated to hydroxyalkyl and formyl derivatives which can be subsequently activated to electrophilic esters leading to DNA and protein reactive species.

Proc Amer Assoc Cancer Res, Volume 45, 2004 3191 In the following experiments we investigated the binding of selected PAH epoxides (benzo(a)pyrene, benzo(b)fluoranthene, dibenz(a,hanthracene, fluoranthene, benzo(ghi)perylene, and benz(a)anthracene) to hemoglobin in order to determine the kinetics of binding of the PAH epoxide to hemoglobin. The following experiments were carried out using mouse (C57BL/6 male mice) hemoglobin in vitro . Through a series of binding studies as well as known carcinogenicity of the parent PAHs, we correlated extent of reaction of various epoxides with known carcinogenicity of the parent PAH. PAH epoxides arise via metabolism of the parent PAH to epoxides, followed by the addition of water to generate a diol. These reactions are catalyzd by microsomal enzymes as well as epoxide hydrolase. A second epoxidation reaction occurs at an adjacent double bond to yield a diol-epoxide of the parent PAH. Packed red cells (mouse) were resuspended in isotonic saline (2 mls). 100 μl aliquots of RBC suspension were used in reactions (volume brought to 500 μl with saline). PAH epoxide stock solutions were dissolved in tetrahydrofuran (1 mg/ml). 10 μl epoxide PAH stock was added to reactions. Reactions were carried out at 37° for 0,1,2,4,8,10,15,20,45,and 60 minutes. Reactions were stopped by addition of 500 μl water to hydrolyze unreacted PAH epoxide. Red cells were precipitated by centrifugation at 3,000 rpm for 10 minutes. The packed red cells were lyzed using 1 volume cold water and globin precipitated by addition of hemoglobin to acidified (0.1% HCl) acetone. Globin was collected, rinsed with acetone (100%), dried under nitrogen and stored at -20° until analysis. Control reactions were performed by preincubation of the PAH epoxides in saline for 15 minutes prior to addition of the red cell suspension. PAH epoxides were released from the globin by incubation (1 ml) with pronase for 24 hours at 37°. After reaction, released PAH tetrols were extracted using combinations of liquid and solid phase extraction and the tetrols taken to dryness under vacuum. The resulting PAH tetrols were analyzed spectrophotometrically by HPLC using both UV and fluorescence detection. Results from the study indicated that PAH epoxides bound covalently to the protein hemoglobin. The extent of PAH binding to the protein was similar with all epoxides, however there appears to be a correlation between the extent of binding and the overall carcinogenicity of the PAH with the stronger carcinogens having a faster rate of protein adduction than weaker carcinogens. These results suggest that the formation of hemoglobin adducts to PAH carcinogens may serve as reliable biomarkers of exposure as well as carcinogenicity. The limit of sensitivity of the assay by fluorometric detection of the released PAH tetrols is <10 pmols PAH epoxide/ mg protein. This limit of sensitivity suggests that the methods developed may be useful in routine monitoring of PAHs in population studies.

ceils is abolished by anti-TNF.Ceils are protected against EtOH-induced apoptosis by pre-tream~ent with anti-TNF and CAPls In early stage of apoptosis was al rupture of the outer mitochondrial membrane.The cells may be "true" apoptotic with condensed chmmatin and high enzyme activity (10%), pre-apoptonc, without chromatin condensation but high enzyme activity (35%), and neither condensed chromatin nor a remarkable reaction product of cytochrome oxidase activity(55%).Fas molecules on the plasma membrane of hepatocytes increased in cells ~thout chromatin condensation.The NHPHSC present nsany SC with huge amount of lipids, that transfbrms in myofibroblast and some apo-necrotic cells are seen.In conclusion NHPHSC are more susceptible to EtOH-induced apoptosis than NHPH Both anti-TNF and CAPIs might inhibit hepatic apoptosis but their signature differs with the ty?e of cell:s.Mitochondria play a pivotal role in pre-apoptotic stages. Apoptoelsand repair .... EtOH+anti-TNFA § 'E tOT t § EtOH + Cells Contrd EtOH TNFA TNFA TNFA CAPI9 ChPI 3 12,3 10 NHPH 60.5 26q c 53,5c 164b,d 14~4b,d b,d lb,d NHPHSC 50,5 462 661c 36~8 a,b,c 26~5 a, b,c 25~ 144 a,c a,b,c b,d a-p0,05 higher apoptosis than the same treatment in NHPH; in the same type of cetls apoplosis is significantly: b-p0.05lower than the EtOH; c-p0.001 and d-p0.05 higher than the controL_<.~.

In 1999, an organization contributed a large group of enhancement projects to the International Software Benchmarking Standards Group's Data Repository. The contributing organization received an individual benchmark report for each project, comparing it to the most relevant projects in the repository. The ISBSG also performed an organizational benchmarking exercise that compared the organization's set of 60 projects as a whole to the repository as a whole. The benchmarking exercise aimed to provide valuable information to the organization and to measure the exercise's effectiveness given the repository's anonymous-nature.

A method is presented for estimation of wideband sound power levels produced by low-pressure axial-flow fans, The method stems from prior work in the literature and is intended to be used in selection tradeoff studies, or in the preliminary design layout process, for such fans, The resulting algorithms may be used to relate fan-performance specifications (i.e., airflow rate and static or total pressure rise) to fan diameter, fan rotational speed, and fluid density, with constraint information on fan configuration, total fan efficiency, and sound power level, A modified form of the classical concept of specific sound power level is related to the concepts of nondimensional specific rotational speed and specific diameter of an axial-flow fan, Fan data from the open literature were used to establish a quantitative dependence of specific wideband fan sound power level on specific fan diameter through a simple curve-fitted algorithm, Examples for selection or preliminary design layout of a low-pressure axial-flow fan were developed and discussed to illustrate the usefulness of the method. (C) 1995 Institute of Noise Control Engineering.

The health care system in the United States is suffering from a severe shortage of registered nurses. Burn treatment facilities are no exception to this phenomenon. As a result of this shortage, institutions have begun hiring less trained personnel such as licensed practical/vocational nurses (LPNs/LVNs), nursing assistants, burn technicians, and nursing students to fill the void. This shortage is so significant that the American Medical Association (AMA) has proposed a new category of bedside care provider, a "Registered Care Technologist" (RCT). The purpose of this paper is to determine the magnitude of the registered nurse shortage in burn care facilities. A second purpose is to identify factors associated with high turnover rates and to document the reasons why registered burn nurses are leaving their positions.

To determine the pK3 value of porphyrins, a simple spectrofluorometric titration method has been developed. The porphyrin solution is titrated with perchloric acid. After each addition of acid, the porphyrin solution is excited at one suitable wave length and the emission intensity is measured at another suitable wave length. The pK3 values of twelve porphyrins have been determined. Nitrobenzene, toluene and water have been used as solvents. The pK3 values have been compared with the literature values. Attempt has been made to correlate the Cu+2 insertion kinetics of six porphyrins and their pK3 values.

One way of overcoming the problem of Winchester backup, by using disc drive with closed loop air circulation and advanced servo techniques, is described. The system offers both backup and program load facilities for users who wish to remove their files onto hard disc.

: A single-rotation ducted fan of highest induced efficiency is characterized by an ultimate wake vortex system shed from the blade trailing edges whose apparent motion is that of rigid helical surfaces. In addition and concentric with this inner sheet system there is a cylindrical surface of helical vortex filaments shed from the duct trailing edge. For zero hub diameter and neglecting compressibility, viscosity, and tip clearance, a consistent mathematical model of the constant-diameter vortex wake is developed and the compatibility relationships to be satisfied are presented. It is shown that the wake vorticity and the velocity distribution in the wake, for all loadings from the lightly loaded limit to the heavily loaded static thrust condition may be extracted from the lightly loaded result through the use of a simple algebraic scale factor. The performance parameters, thrust, power and blade bound vortex strength, are thus expressed in terms of a lightly loaded solution for a given freestream velocity, blade tip speed, blade number and the loading parameter. The lightly loaded case is compared to existing theoretical and experimental results. Some sample results for heavily loaded performance parameters and design parameters are presented and compared to the exact results for a heavily loaded ducted fan with an infinite number of blades. Results for the heavily loaded system over a broad range of conditions are presented.

Like the free propeller in axial flight, a single-rotation ducted fan of highest induced efficiency is characterized by an ultimate wake vortex system shed from the blade trailing edges whose apparent motion is that of rigid helical surfaces. In addition and concentric with this inner sheet, there is a cylindrical surface of helical vortex filaments shed from the duct trailing edge. For zero hub diameter, and neglecting compressibility, viscosity, and tip clearance, a consistent mathematical model of the constant-diameter vortex wake is developed and the compatibility relationships to be satisfied are presented. Using the Biot-Savart equation, the vortex strength distribution in the wake may be determined by numerical methods and then related to the blade bound vortex strength. Some preliminary results of the analysis are presented for the lightly loaded case for comparison with existing methods.

The current size of the global industry developing custom built software is estimated to be in excess of $US200bn annually. The performance of the software industry in developing successful projects is poor with an estimated 32% of projects terminating before delivering anything to business and only 11% completing within budget. Of the remainder that do complete, the average budget overrun is 87% (2). A Recent survey of the International Software Benchmarking Group data repository has shown that the costs paid by business for comparable software can vary 7 fold (3). This litany of software failure makes the development of techniques to allow business to retain control of software acquisition compelling and ever more urgent. SouthernSCOPE is a framework strategy for software acquisition, which is designed to allow project business sponsors the ability to control and manage acquisition projects. The method allows the business sponsor to retain control of project scope and expenditure in terms that business can understand. The risk of budget overrun is considerably reduced as the sponsor is always in control of the scope; this ensures good value for money. The potential for bidding low and then loading the price of changes is largely eliminated. The State Government of Victoria, Australia introduced the initial ideas in 1996 and has since developed several projects refining the method in the light of experience. This has resulted in the development and introduction of the Southern SCOPE method as the standard purchasing policy of the state. This paper will explore the underlying ideas behind the method and the experience of the State government of Victoria in developing this unique approach to software acquisition. The paper will also review a case study of a software acquisition project. 1. Introduction The State Government of Victoria Australia has an annual software budget of around $50 Million (AUD), (29 Million Euro). The state government is a leader in the use of IT in the provision of services to its citizens. The UK government has based a large part of its e- government initiative on ideas originated by the state government. Yet despite a good record of achievement in the field of government on-line the state government was faced with the problem of acquiring software within budgets and of suitable quality. These are problems that any organisation faces when acquiring software. The difficulty is well categorised by a recent report. An estimated 32% of projects terminate before delivering anything to business and only 11% complete within budget. For projects that complete the average budget overspend is reported by the CHAOS report (2) as being some 87%. This report also stated that the situation was no better than the previous survey some years earlier. "There is no evidence that budget performance of software projects has changed"(2). These figures are depressingly familiar to IT managers and stand as an indictment of the global software industry. A survey