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This research investigated the impacts of the diverse framings of corporate and activist NGOs website communications of a proposed Canadian oil-sands pipeline on participants' perceptions of a) the tripartite sustainability values of environmental safety, economic benefits and community social relations and b) the willingness to join the corporate and activist NGOs online networks. Given the importance of sustainability issues in business education curricula and research, the participants were drawn from a population of undergraduate students. They were exposed online to either neutral information (control group), or randomly exposed initially to either the Corporate or Activist NGOs website communications. These exposures were subsequently reversed creating a combined group exposed to both agenda framings. Results demonstrated the persuasive power of both communication framings. The Corporate communication created positive perceptions of tripartite sustainability values, whereas the Activist NGOs' created negative perceptions. After exposures to the opposite communications, the Corporate group's perceptions changed from positive to negative, whereas the Activist NGOs perceptions only became somewhat less negative. Also there was a stronger willingness to join an Activist NGO rather than the corporate online action network. The empirical findings reflect the powerful diverse impacts of agenda framing on a highly controversial societal issue. Concerned citizens, researchers, politicians and academics should not restrict their website consultation to just one framing of such complex wicked issues. The present findings also have important implications for developing a more balanced and ethical business curriculum in the area of sustainability and common good.

Nonprofit organizations are increasingly dependent on the involvement of Millennial constituencies. Three studies investigated their motivations to support charity-linked events: emotional identification with a cause, self-determination theory (SDT) regulations, and context-related Facebook promotions. This article addresses the recent call to expand SDT research from a simple analysis of autonomous versus controlled motivation, to studying the effects of all the regulations in the SDT continuum, in particular, the inclusion of the tripartite dimensions of intrinsic motivation and integrated motivation. Results demonstrated that the greater the emotional identification with the cause, the stronger was the tendency to support the charity-linked event. Also, the results in these social media contexts revealed that specific intrinsic dimensions (e.g., experience stimulation) are motivators of online and offline support, as is the personal value nature of integrated regulation. Whereas only autonomous motivational regulations predicted support for the two events organized specifically a for charitable causes, both autonomous and controlled regulations predicted support of a for-profit event organized with a charitable cause as an adjunct. These findings can assist practitioners in designing more effective social media communications in support of charity-linked events.

Purpose – The purpose of this paper is to study micro-level research into the social dimensions of entrepreneurial partnerships assessed by the influences of: the degree of interpersonal attraction, the strength of relational norms and the level of partner trustworthiness on value co-creations in an emerging biotechnology network. Design/methodology/approach – Financial and scientific partnerships were investigated by structured interviews with entrepreneurs. Financial partnerships were also studied using interviews with lead investors. Research design and analyses were based on a Conditional Process Model. Findings – Partner trustworthiness was found to be critical for the co-creation of value in both types of partnerships. In financial partnerships, the level of interpersonal attraction and relational norms strength acted independently as antecedents of partner trustworthiness. Only the entrepreneur linked interpersonal attraction directly to value co-creation. Both entrepreneurs and lead investors perceived the association between interpersonal attraction and co-created value to be mediated through partner trustworthiness. Only the lead investor perceived this mediation to be moderated by relational norms strength. However, in scientific partnerships, relational norms strength, but not interpersonal attraction, contributed to partner trustworthiness that subsequently effected value co-creation. The entrepreneur’s trustworthiness perception in both types of partnerships was mainly due to a partner’s reputation, whereas for lead investors it was primarily the perceived reliability of the entrepreneur. Originality/value – This research points out the challenges of measurement and interpretation of network research. Theoretical conclusions based on only one partner’s perspective and in one context would not be sufficient to describe the complexity of value co-creations in entrepreneurial networks. Also, the cooperative social, rather than competitive opportunistic nature of entrepreneurial knowledge-intensive networks was confirmed.

The present research was designed to examine the effects of Millennial women’s past fashion experiences and gender identity on both online and offline support of a luxury fashion show from a cause-related social media perspective, while investigating the specific relative effects of manipulating the promotion of the fashion products and of the charitable cause. A Conditional Process Model proposed a direct effect of Millennial women’s history of fashion experiences on their online and offline support of a fashion show. Female gender identity was proposed as a mediator of this direct effect and the Facebook event page appeal (augmented cause versus augmented fashion) as the moderator. The participants were (N = 218) female Millennials at a Canadian university business school. Data collection was conducted online in two phases using Qualtrics. Gender identity was found to be an important predictor of online and offline support of a fashion show promoted on Facebook. It also significantly mediated an...

Using the framework of the self-determination theory continuum, we investigated the influence of the distinct autonomous and controlled motivational regulations for engaging participants in online and offline support of charitable events for the causes of breast cancer and homeless youth. Participants were exposed online to Facebook event pages appealing to helping others. When the often omitted integrated autonomous regulation was included in the model, it was the strongest predictor of supportive intentions. Without integrated regulation in the model, we would have overestimated the relatively minor influence of controlled introjected regulation. Furthermore, rather than one overall measure of autonomous intrinsic regulation, we assessed the differential influences of three separate dimensions (to experience stimulation, to learn and to accomplish). Intrinsic motivation to experience stimulation had a unique influence on online and offline supportive intentions. Such was not the case for the dimensions of to learn or to accomplish. Follow-up meditation analyses of self-reported behaviours confirmed that autonomous integrated and intrinsic to experience stimulation regulations led to stronger intentions to support online behaviours, which, in turn, increased the likelihood of actual online engagement. The findings in a social media context highlight the importance of analysing distinct regulatory styles within the self-determination theory continuum. Copyright © 2015 John Wiley & Sons, Ltd.

This research investigated gender differences of Millennials’ online and offline prosocial intentions to support charitable events for the causes of breast cancer and homeless youth after exposure to Facebook appeals to self-benefit and others-benefit, as well as with respect to their empathy identification with the cause and their social-oriented moral identity. In general, the results agree with the literature indicating that women tend to be more altruistic, empathetic, and moral than men. Paradoxically, the findings indicate that, within a social media context, emotions related to altruism, empathy toward the cause, and socially oriented moral identity are factors more closely predictive of males’ inclinations to engage in activities to support charitable events. Whereas women are already more predisposed to helping others, nonprofit marketers must emotionally prod men to help others through specific emotional hooks for prosocial behaviors.

Purpose – It has been suggested that the future success of non-profit organizations lies in ensuring the sustainable involvement of the Millennial generation through social network sites. Facebook is a social media (SM) network that creates new research contexts and methodologies in service management. Organizations must now engage in learning how customer-with-customer interactions in SM could work best for them. The purpose of this paper is to better understand the factors influencing Millennials support for social causes through their autonomous engagement in the public environment of SM. Design/methodology/approach – The authors conducted two studies of events for social causes (breast cancer and youth homelessness). In each, two Facebook event pages appealing to others-benefits and self-benefits were designed. Participants were randomly assigned the task of examining the appeal pages online. The dependent variables were two sets of intentions in support of the cause (online and offline). The effectiveness of an others-benefit vs a self-benefit Facebook appeal, the influence of empathetic identification with these causes and the direct and mediating effects of autonomous motivation was studied. Findings – The studies provide consistent evidence that, to gain Millennial's support for social causes through SM, it is better to appeal mainly to the benefits others derive than to benefits to the self. Autonomous motivation is a strong predictor of supportive intentions and it also significantly mediates the positive influence of empathetic identification with a cause. Self-reported behavioral data following the youth homelessness event provided empirical evidence that the supportive intentions data were valid predictors of actual behaviors. Originality/value – The paper used innovative experimental and correlational research methodologies to address Millennial's social behaviors within a SM context. The paper also introduced self-determination theory of motivation to this literature. From a practical standpoint, Millennials readily engage in impression management. Therefore, their supportive activities should be publicly lauded. Managers should also identify those Millennials who already empathize with the cause and facilitate their ability to influence other members in their networks. SM are changing at a fast pace and managers should employ Millennials in developing pertinent strategies and practices to keep pace. Taking advantage of marketing “with” Millennials can facilitate the development of new approaches for creating and supporting cause events.

In brief: Echocardiographic studies permit direct, accurate measurements of the ventricular wall thickness and cavity diameter. The authors review several of these studies, which show that elite athletes' left ventricles are larger than those of sedentary persons. Left ventricular wall thickness is greater in athletes excelling in sports involving static exercise, whereas those in endurance sports have larger ventricular cavities. These differences in cardiac dimensions may be the result of genetic makeup, prolonged and strenuous training, or a combination of both. Studies of short-term training showed only minor or no changes in left ventricular morphology, although significant improvements in performance and aerobic capacity were reported.

Purpose: This article investigates the implication and importance of the service-dominant (S-D) logic to the increasingly relevant study and practice of Interorganizational relational exchange. It points out that relational exchange theory (norms) is an earlier reflection of the S-D logic. Recognizing a need for the transactional cost economics (TCE) framework to address bilateral or hybrid types of exchanges, marketing channel researchers have for over twenty years incorporated relational exchange theory (RET) and TCE to investigate problems of formal contract, environmental uncertainty, power/dependency, and opportunism. However, some theoreticians view relational modes of exchange to be broader in scope than that studied within TCE. We propose a conceptual framework that incorporates TCE constructs with S-D logic principles in order to provide a rich contemporary guide for future relational exchange research and practice. Methodology/Approach: We first expose the essential elements of the S-D logic and...

PurposeThe service‐dominant logic describes customer‐actualized value as being idiosyncratic, experiential, contextual, and meaning laden. Since positive word‐of‐mouth (WOM) is an expression of customer‐actualized value, the paper postulate that WOM is not only related to a holistic set of assessments of the service experience but also to the idiosyncratic nature of the individual customer. In particular, do socially oriented individuals have a greater propensity to engage in positive WOM? The purpose of this paper is to test hypotheses that socially oriented personality traits, and personal values as well as a set of dimensions of the total service experience, are antecedents of positive WOM. The context studied is a surgical operation involving considerable personal meaning and implication in the whole service process.Design/methodology/approachA cohort of 500 surgical patients are studied prior to, three‐days after and one‐month post‐surgery. Independent variables include the socially oriented personality traits of agreeableness and extraversion, social‐ vs self‐oriented personal values, as well as dimensions of the total service experience assessed by information adequacy, pain and discomfort, patient‐to‐patient interaction, patient‐to‐personnel interaction, and recovery outcomes. The dependent variable is the strength of positive WOM intentions.FindingsThe sociability of surgery patients as measured by both their personality traits and socially oriented values is significantly related to the strength of positive WOM intentions. Self‐oriented values are not associated with positive WOM intentions. Also, to varying degrees, all dimensions of the total service experience are associated with positive WOM intentions.Originality/valueThe paper is the first to illustrate that, in a given service context, the antecedents of customer loyalty may be complex, not only dependent on customer assessments of their interactions and experiences throughout the service process, but also relative to their dispositional characteristics such as sociability. The consistency of the results for positive WOM assessed at three‐days and one‐month post‐surgery adds to the robustness of the findings. This paper makes a significant contribution to the service‐dominant logic and the concept of value co‐creation.

Service employees are simultaneously concerned with their own and their customers' well-being. Managing these dual concerns is of strategic importance in a customer-oriented service firm. This research tests a model comparing overall and customer-linked antecedents and consequences of employee affective organizational commitment. The study determines (a) how service climate variables influence both overall and customer-linked job satisfaction, (b) the contribution of both job satisfaction measures to commitment, (c) the relationship between commitment and both overall citizenship behaviors and customer-linked behaviors, and (d) the influence of commitment with regard to employee intentions to recommend the organization to prospective employees and customers. Co-worker support and the perception of fair treatment are precursors of customer-linked job satisfaction (not overall job satisfaction). Customer-linked job satisfaction is more related to organizational commitment than is overall job satisfaction. Organizational commitment influences both overall citizenship behaviors and customer-linked behaviors as well as intentions to recommend the organization.

To determine if the likelihood of preterm delivery is more dependent on the specific organisms present in the vagina than on the presence of bacterial vaginosis.We evaluated the vaginal fluid of a prospective cohort of women at 23-32 weeks of gestation with signs and symptoms of preterm labor and intact membranes. Forward stepwise logistic regression models were used to evaluate the relationship between preterm delivery and the presence of anaerobic bacteria, Gardnerella, ureaplasmas and mycoplasmas, and sialidase.The cohort included 137 women, and complete delivery information was available for 134 of them. The rate of preterm delivery was 28% (37 of 134). Mycoplasma genitalium independently was associated with spontaneous preterm delivery (OR 3.48; 95% CI 1.41, 8.57). After controlling for this factor, none of the other variables were significantly prognostic for spontaneous preterm delivery (residual overall p = 0.19).The presence of Mycoplasma genitalium in the vagina of pregnant women is an independent risk factor for spontaneous preterm delivery.

Purpose – Emerging biotechnology firms rely on a network of socio‐economic partnerships that can be classified as “interimistic” or close, collaborative but relatively short‐lived. Few studies have assessed the importance of relational governance to the performance of these partnerships. The purposes of this research were to determine the effect of relational governance on the performance of financial partnerships and to compare biotechnology manager assessments of their financial and non‐financial partnerships.Design/methodology/approach – Interviews were conducted with managers of emerging biotechnology companies and lead investors in Canada, France and Germany. Relational governance was assessed by relational norms such as flexibility, information sharing, solidarity and fairness. Performance was assessed by overall effectiveness and partnership benefits. First, the contribution of relational governance to partnership effectiveness and benefits was examined. Second, for the financial partnerships, the ...

Academics and managers are confronted with reconciling the social and economic aspects of business-to-business exchanges. In a service context, the authors investigate the relative importance of contractual and relational governance on exchange performance and the influence of the boundary spanner on the implementation of these governance mechanisms and on exchange performance. They test a model of the governance of commercial banking exchanges using interview data with both parties to the exchange (the account manager as the bank’s boundary spanner and the business client). Relational governance is the predominant governance mechanism associated with exchange performance. Contractual governance is also positively associated to exchange performance, but to a much lesser extent. The closeness of the account manager to the client company in terms of information gathering is also positively associated to exchange performance. However, this is mediated through both contractual and relational governance mechanisms with relational governance being the stronger mechanism.

Paulin et al. (1998) previously reported that the higher Mexican business clients assessed the strength of the relationship with their banks (relational norms): the higher were their judgements of satisfaction and service quality, the more they were inclined to recommend the bank and the account manager to colleagues and, the less likely they were to switch banks. However, over 50 percent of the business clients of three commercial banks in Mexico City indicated that there was at least a 50–50 percent probability that they would change banks within the next year and that poor service was the principal reason given. Despite an expressed strategy to develop long-term relationships with business clients, commercial banks in Mexico and Canada (Paulin et al. 1997) do not have the most appropriate processes and organizational cultures for being client-oriented according to a service management perspective (Gummesson 1994; Gronroos 1992). However, this is only a one-sided view of this business-to-business relationship. Therefore, the purpose of this paper was to examine the possible link between the organizational cultures of the client companies and their assessments of the bank’s effectiveness and their likelihood of switching banks.

The service management perspective as described by Gummesson (1994) and Gronroos (1992) is based on the concepts of relationship marketing and service quality. This perspective is a client-centred approach dependent on managerial processes and a service culture which foster the development and maintenance of the firm-client relationship. Commercial banking is a professional services business characterized by the relationship between the account manager and the business client Although North American commercial banks seek long-term relationships with their business clients, these same clients gave bureaucratic inflexibility (Canada) and poor service (Mexico) as the principal reasons for terminating the relationships with their banks (Paulin et al. 1998). The purposes of the present research were to determine the type of organizational culture present in North American commercial banks and to relate these findings to a services management perspective.

The oral bacterium Streptococcus mutans is able to gain a selective advantage over other oral microbes by withstanding extreme fluctuations in plaque pH. In the plaque environment, resident bacteria metabolize dietary carbohydrate, which results in the production of organic acids and a decrease in plaque pH. Telemetric measurements of plaque pH indicate that the pH can drop from 7.0 to values ranging from 4.0 to 3.0 (23). The ability to adapt to moderate pH promotes the survival of S. mutans under lower-pH conditions that would otherwise be lethal (37). This adaptive response in S. mutans is called the acid tolerance response (ATR) (37, 42), and similar mechanisms have been identified in some enteric bacteria (11, 12). Acid adaptation in S. mutans requires de novo protein synthesis (37) of up to 36 acid-regulated proteins (19) presumably encoded by acid-inducible genes. Aside from the general features of the cellular response to acid pH, relatively little is known about the function of the numerous proteins encoded by the pH-inducible genes that constitute the S. mutans ATR. The genes for the protein repair chaperone, DnaK (22), and the 54-kDa subunit homologue of the eukaryotic signal recognition particle, Ffh (16), have been shown to be acid inducible in S. mutans, and ffh has been linked to the ATR, whereby ffh mutants revealed a lack of adaptive response to acid pH (16). To elucidate the molecular mechanisms of the ATR, we utilized the differential display PCR (dd-PCR) technique adapted from the method of Kwaik and Pederson (25). Here, isolation of total RNA from cells grown at pH 7.5 (unadapted state) and pH 5.0 (adaptive state) was followed by PCR amplification with arbitrary primers and separation by polyacrylamide gel electrophoresis (PAGE) for visualization of differential expression. Our goal was to identify up-regulated genes in S. mutans during acid adaptation. From this analysis, we have identified a gene with homology to the uvrA gene belonging to the nucleotide excision repair (NER) pathway involved in DNA repair in Bacillus subtilis. This pathway primarily consists of the protein complex UvrABC, which functions in locating and excising bulky DNA lesions (34). It has been proposed elsewhere that the ATR in bacteria can be divided into two main components (13). The first involves mechanisms that maintain internal pH homeostasis. In S. mutans, this primarily involves an increase in H+-ATPase activity and acid end product efflux (3, 9, 18) and a decrease in proton permeability (18) by changes in membrane fatty acid composition (31) and increased synthesis of the cell surface component d-alanyl-lipoteichoic acid (6). The second component of the ATR is thought to involve the repair of cellular components damaged by acidic pH. Previous studies of S. mutans have shown the repair of acid-induced cellular damage to consist of the protein repair chaperone DnaK (22), a DNA repair enzyme exhibiting alkaline phosphatase (AP) endonuclease activity (17), and the DNA damage regulatory-repair protein RecA (30). However, little more is known about other repair mechanisms in S. mutans, specifically those involved in DNA repair. Several known DNA repair mechanisms in bacteria could potentially be involved in the repair of acid-induced DNA damage, including direct damage reversal repair, recombinational repair (e.g., RecA), mismatch repair, base excision repair (e.g., AP endonuclease), and NER (e.g., UvrA) (2, 15). This picture is further complicated by the existence of specialized, regulated forms of repair such as those potentially found in the SOS, heat shock, and adaptive responses. The NER pathway, however, is thought to be the major system for repairing damaged DNA because of its capacity to repair essentially all types of DNA lesions (28). DNA repair (including NER) has been implicated in the resistance of bacteria to acidic pH (4, 17, 32, 33, 40). In Escherichia coli, mutants defective in the NER constituents uvrA and uvrB (32, 36) were shown previously to be more acid sensitive than the parent strain, suggesting that the NER pathway functions in the repair of acid-induced DNA damage. Whereas the internal pH of E. coli is maintained near neutral during acid challenge (29), S. mutans maintains a pH gradient that is only 0.5 to 1.0 pH units higher than the extracellular pH (9), indicating an increased likelihood of intracellular acidification in S. mutans during low-pH exposure. Therefore, the need for several DNA repair mechanisms in S. mutans, such as the NER pathway, would be paramount in ensuring the integrity of the genome during acid stress and ultimately the survival of the species in its natural habitat. In this study, we have demonstrated that the S. mutans uvrA gene is up-regulated in response to an acidic environmental pH. We also show that in several strains of S. mutans uvrA mutants were not as resilient as the wild type (WT) in surviving UV irradiation and challenges by pH as low as 3.0.

The recent interest in hormonally active environmental contaminants has sparked a drive to find sensitive methods to measure their effects on wildlife. A molecular-based assay has been developed to measure the induction of gene expression in sheepshead minnows ( Cyprinodon variegatus ) exposed in vivo to the natural and pharmaceutical estrogens 17β-estradiol, ethinylestradiol, and diethylstilbestrol. This method used differential display reverse transcriptase polymerase chain reaction assays to compare the expression of individual mRNAs from control and estrogen-exposed fish. Forty-eight differentially expressed cDNAs were isolated by this method, including cDNAs for vitelline envelope proteins and vitellogenin. The mRNA expression patterns for fish injected with a pharmacological dose of estradiol (5 mg/kg) were identical to those obtained in fish receiving constant aqueous exposure to 212 ng estradiol/liter. Further, the cDNA “fingerprint” pattern observed in the estradiol-treated fish also matched that obtained in fish receiving continuous-flow aqueous exposures to 192 ng ethinyl estradiol/liter and a nominal concentration of 200 ng diethylstilbestrol/liter. The results demonstrate a characteristic expression pattern for genes upregulated by exposure to a variety of natural and anthropogenic estrogens and suggest this approach may be valuable to examine the potential effects of environmental contaminants on other endocrine-mediated pathways of reproduction, growth, and development.

This empirical study of commercial banking relationships in France demonstrates that, despite the current emphasis on new technology, contact personnel remain important for the success of professional business‐to‐business services. When account managers are changed, the business clients feel that their relationship with the bank is weaker and they judge the bank to be less client oriented. More important for the bank’s future profitability is the finding that changing account managers is negatively associated with the bank’s external effectiveness, as measured by the client’s judgement of satisfaction and service quality, by their purchase intentions and by their willingness to recommend the bank. Also, the business clients who change account managers express a greater likelihood of switching banks. In addition, the study points out the divergence between the transactional sales approach of the bank and the relational perspective of the business client. Commercial banks tend to overestimate both the degree to which they are client oriented and the benefits of technology as a substitute for human interactions with their business clients.

The purpose of the present study was to determine, across three distinct national contexts, to what extent the creation of customer‐perceived value, as determined by the measure of the firm’s external effectiveness, was deemed important and implemented within a professional business‐to‐business service industry (commercial banking). External effectiveness is a measure of business performance reflecting the client’s judgement of satisfaction, service quality, future purchase intentions and willingness to recommend the service firm to others. It was postulated that strong relationships would contribute to external effectiveness and that, in order to be effective, a service firm needs to be client‐oriented and develop managerial processes and an organizational culture compatible with the creation of client‐perceived value, the driver of longer‐term profitability. In all three countries, the higher the business client rated the strength of the relationship with their bank, the higher was their assessment of external effectiveness. However, the banks’ service management processes supporting the work of the account manager and the dominant organizational culture were not congruent with the bankers’ perception that their organizations were client‐oriented. Important differences were found in the banking relationships and managerial processes in Mexico as compared to Canada and the USA.

This study assessed the technical (tangible) and functional (human interaction) quality of services in a first‐class international health resort and related these to service management effectiveness. Service management is effective when customers judge the overall service quality to be good, they are highly satisfied, they are willing to recommend the firm to others and they intend to re‐purchase or are predisposed to purchase additional services from the firm. The technical and functional aspects of services quality and their relation to service management effectiveness, were found to be different between the core and supplementary services, between customers and service personnel and between customers with and without experience. The results support the statement that competitive advantage in this industry can be obtained by improving the functional aspects of services management, by better performance of supplementary services and by reducing the gap in perceptions between customers and contact personnel.

This study was designed to assess the theoretical and managerial implications of relational norms in two distinct business contexts within the same service industry. The relationship between commercial banks and client‐companies was studied using matched pairs of account managers and company representatives in Canada and Mexico. This research indicates that: relational as well as short‐term economic variables are important for successful commercial banking; front‐line personnel may not accurately assess the client’s reality; contextual differences are important with regard to both the theory and practice of management in banking.

We sought to determine if autologous umbilical cord blood (UCB) infusion followed by 1 year of supplementation with vitamin D and docosahexaenoic acid (DHA) can preserve C-peptide in children with type 1 diabetes. We conducted an open-label, 2:1 randomized study in which 15 type 1 diabetes subjects with stimulated C-peptide > .2 pmol/mL received either (1) autologous UCB infusion, 1 year of daily oral vitamin D (2000 IU), and DHA (38 mg/kg) and intensive diabetes management or (2) intensive diabetes management alone. Primary analyses were performed 1 year after UCB infusion. Treated (N = 10) and control (N = 5) subjects had median ages of 7.2 and 6.6 years, respectively. No severe adverse events were observed. Although the absolute rate of C-peptide decline was slower in treated versus control subjects, intergroup comparisons failed to reach significance (P = .29). Area under the curve C-peptide declined and insulin use increased in both groups (P < .01). Vitamin D levels remained stable in treated subjects but declined in control subjects (P = .01). DHA levels rose in treated subjects versus control subjects (P = .003). CD4/CD8 ratio remained stable in treated subjects but declined in control subjects (P = .03). No changes were seen in regulatory T cell frequency, total CD4 counts, or autoantibody titers. Autologous UCB infusion followed by daily supplementation with vitamin D and DHA was safe but failed to preserve C-peptide. Lack of significance may reflect small sample size. Future efforts will require expansion of specific immunoregulatory cell subsets, optimization of combined immunoregulatory and anti-inflammatory agents, and larger study cohorts.

Two separate sets (Bio. 1.5/H and Bio. 82.73/H) of Syrian hamster lines congenic at the NAT2 gene locus were constructed. In both sets, N-acetylation capacity was NAT2-dependent in vivo and in vitro, with highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators and lowest levels in homozygous slow acetylators. NAT1 and NAT2 acetyltransferase isozymes from liver and colon cytosols activated N-hydroxy-2-aminofluorene (N-OH-AF) to DNA adducts. NAT2-catalyzed metabolic activation of N-OH-AF was acetylator genotype-dependent. NAT1-catalyzed metabolic activation of N-OH-AF was independent of acetylator genotype. Hamster NAT1 and NAT2 were cloned, sequenced, and expressed. Recombinant NAT1 from rapid and slow acetylators activated N-OH-AF at equivalent rates, but rapid acetylator recombinant NAT2 activated N-OH-AF at rates over 750-fold higher than slow acetylator recombinant NAT2. These results provide clear evidence for metabolic activation of arylamine carcinoge...

N-acetyltransferases have an important role in the metabolism of arylamine and hydrazine drugs and carcinogens. Human N-acetylation phenotype may predispose individuals toward a variety of drug and xenobiotic-induced toxicities and carcinogenesis. Syrian hamsters express two N-acetyltransferase isozymes; one varies with acetylator genotype (polymorphic) and has been termed NAT2; the other does not (monomorphic) and has been termed NAT1. The intronless NAT1 coding region was cloned via the polymerase chain reaction from homozygous rapid acetylator and homozygous slow acetylator congenic and inbred hamster genomic DNA templates and sequenced. The NAT1 alleles from the homozygous rapid (NAT1) and homozygous slow (NAT1s) acetylator hamsters differed in one nucleotide, but the mutation is silent with no change in deduced amino acid sequence. To characterize the enzyme products of the NAT1 alleles, we developed a prokaryotic-expression system. The NAT1r and NAT1s alleles were amplified by expression-cassette polymerase chain reaction and subcloned into the tac promoter-based plasmid vector pKK223-3 for over-production of recombinant NAT1 in E. coli strain JM105. Induced cultures from selected NAT1-inserted transformants yielded high levels of soluble protein capable of N-acetylation, O-acetylation, and N,O-acetylation. The recombinant NAT1r and NAT1s proteins did not differ in substrate specificity, specific activity, Michaelis-Menten kinetic properties, intrinsic stability, and electrophoretic mobility. Also, the over-expressed NAT1 proteins displayed substrate-specificity and electrophoretic mobilities characteristic of NAT1 isolated from Syrian hamster liver and colon cytosols.

Recombinant human NAT1 and polymorphic NAT2 wild-type and mutant N-acetyltransferases (encoded by NAT2 alleles with mutations at 282/857, 191, 282/590, 341/803, 341/481/803, and 341/481) were expressed in Escherichia coli strains XA90 and/or JM105, and tested for their capacity to catalyze the metabolic activation (via O-acetylation) of the N-hydroxy (N-OH) derivatives of 2-aminofluorene (AF), and the heterocyclic arylamine mutagens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Both NAT1 and NAT2 (including all mutant human NAT2s tested) catalyzed the metabolic activation of each of the N-hydroxyarylamines to products that bound to DNA. Metabolic activation of N-OH-AF was greater than that of the heterocyclic N-hydroxyarylamines. The relative capacity of NAT1 versus NAT2 to catalyze activation varied with N-hydroxyarylamine substrate. N-OH-MeIQx and N-OH-PhIP exhibited a relative specificity for NAT2. These results provide mechanistic support for a role of the genetic acetylation polymorphism in the metabolic activation of heterocyclic amine mutagens and carcinogens.

Congenic Bio. l.5/H-NAT2 Syrian hamster lines were constructed by introducing the NAT2r gene from MHA/SsLak inbred hamsters into a background BIO 1.5 Syrian inbred hamster line. Genetic identity of the Bio. 1.5/H-NAT2 congenic lines and nonidentity with the previously constructed Bio. 82.73/H-Pat congenic lines were determined by "DNA fingerprints" of genomic DNA derived from the different hamster lines. The N-acetylation capacity of the Bio. 1.5/H-NAT2 congenic hamster lines was clearly NAT2-dependent both in vivo and in vitro, with highest levels expressed in Bio. 1.5/H-NAT2r homozygous rapid acetylators, intermediate levels in Bio. l.5/H-NAT2r/ NAT2s heterozygous acetylators, and lowest levels in Bio. 1.5/ H-NAT2s homozygous slow acetylators. The NAT2-dependent expression of N-acetyltransferase activity was evident toward p-aminobenzoic acid, 4-aminophenol, 2-aminofluorene, 4-aminobiphenyl, β-naphthylamine, and 3,2′-dimethyl-4-amino-biphenyl in liver, kidney, colon, lung, and urinary bladder cytosols. The polymorphic acetyltransferase (NAT2) and the monomorphic acetyltransferase (NAT1) were isolated from hepatic cytosols and tested separately for their ability to catalyze arylamine N-acetyltransferase and N-hydroxyarylamine O-acetyltransferase activities. Both arylamine N-acetylation and N-hydroxyarylamine O-acetylation were clearly acetylator genotype-dependent when catalyzed by NAT2, and both were clearly acetylator genotype-independent when catalyzed by NAT1. NAT2/NAT1 activity ratios varied with the particular arylamine substrate acetylated. These studies show an important role for NAT2 acetylator genotype in Syrian hamster carcinogenic arylamine metabolism and confirm its role in the metabolic activation of N-hydroxyarylamines. The Bio. 1.5/H-NAT2 congenic lines provide a new model for investigating the preciserole of the NAT2 gene locus in arylamine metabolism and toxicity.

Arylamine-hemoglobin adducts are a valuable dosimeter for assessing arylamine exposures and carcinogenic risk. The effects of age, sex, time-course, dose, and acetylator genotype on levels of 2-aminofluorene-hemoglobin adducts were investigated in homozygous rapid (Bio. 82.73/H-Patr) and slow (Bio. 82.73/H-Pats) acetylator hamsters congenic at the polymorphic (NAT2) acetylator locus. Following administration of a single ip dose of [3H]2-aminofluorene, peak 2-aminofluorene-hemoglobin adduct levels were achieved at 12-18 hr and retained a plateau up to 72 hr postinjection in both rapid and slow acetylator congenic hamsters. 2-Aminofluorene-hemoglobin adduct levels did not differ significantly between young (5-6 weeks) and old (32-49 weeks) hamsters or between male and female hamsters within either acetylator genotype. 2-Aminofluorene-hemoglobin adduct levels increased in a dose-dependent manner (r = 0.95, p = 0.0001) and were consistently higher in slow versus rapid acetylator congenic hamsters in studies of both time-course and dose-effect. The magnitude of the acetylator genotype-dependent difference was a function of dose; 2-aminofluorene-hemoglobin adduct levels were 1.5-fold higher in slow acetylator congenic hamsters following a 60 mg/kg 2-amino-fluorene dose (p = 0.0013) but 2-fold higher following a 100 mg/kg 2-aminofluorene dose (p < 0.0001). These results show a specific and significant role for NAT2 acetylator genotype in formation of arylamine-hemoglobin adducts, which may reflect the relationship between acetylator genotype and the incidence of different cancers from arylamine exposures.

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences inNAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences inNAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i.e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, β-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated byNAT2 acetylator genotype. The ability to determine acetylator genotype from DNA derived from human surgical samples should facilitate further epidemiological studies to assess the role of acetylator genotype in various cancers.

A genetic polymorphism at the NAT2 gene locus, encoding for polymorphic N-acetyltransferase (NAT2), segregates individuals into rapid, intermediate or slow acetylator phenotypes. Both rapid and slow acetylator phenotypes have been associated with increased incidence of cancer in certain target organs related to arylamine exposure, suggesting a role for acetylation in both the activation and deactivation of arylamine carcinogens. A second gene (NAT1) encodes for a different acetyltransferase isozyme (NAT1) that is not subject to the classical acetylation polymorphism. In order to assess the relative ability of NAT1 and NAT2 to activate and deactivate arylamine carcinogens, we tested the capacity of recombinant human NAT1 and NAT2, expressed in Escherichia coli XA90 strains DMG100 and DMG200 respectively, to catalyze the N-acetylation (deactivation) and O-acetylation (activation) of a variety of carbocyclic and heterocyclic arylamine carcinogens. Both NAT1 and NAT2 catalyzed the N-acetylation of each of the 17 arylamines tested. Rates of N-acetylation by NAT1 and NAT2 were considerably lower for heterocyclic arylamines such as 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), particularly those (e.g. IQ) with steric hindrance to the exocyclic amino group. For carbocyclic arylamines such as 4-aminobiphenyl and beta-naphthylamine, the apparent affinity was significantly (P < 0.05) higher for NAT2 than NAT1. NAT1/NAT2 activity ratios and clearance calculations suggest a significant role for the polymorphic NAT2 in the N-acetylation of carbocyclic arylamine carcinogens. Both NAT1 and NAT2 catalyzed acetyl coenzyme A-dependent O-acetylation of N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl to yield DNA adducts. NAT1 catalyzed paraoxon-resistant, intramolecular N,O-acetyltransferase-mediated activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl at low rates; catalysis by NAT2 was not readily detectable in the presence of paraoxon. In summary these studies strongly suggest that the human acetylation polymorphism influences both the metabolic activation (O-acetylation) and deactivation (N-acetylation) of arylamine carcinogens via polymorphic expression of NAT2. These findings lend mechanistic support for human epidemiological studies suggesting associations between both rapid and slow acetylator phenotype and cancers related to arylamine exposure.

Arylamine chemicals inflict a number of toxicities including cancer. Metabolic activation (i.e., oxidation) is required in order to elicit the toxic actions. Acetylation is an important step in the metabolic activation and deactivation of arylamines. N-acetylation forms the amide derivative which is often nontoxic. However, O-acetylation of the N-hydroxyarylamine (following oxidation) yields an acetoxy arylamine derivative which breaks down spontaneously to a highly reactive arylnitrenium ion, the ultimate metabolite responsible for mutagenic and carcinogenic lesions. Human capacity to acetylate arylamine chemicals is subject to a genetic polymorphism. Individuals segregate into rapid, intermediate, or slow acetylator phenotypes by Mendelian inheritance regulated by a single gene encoding for a polymorphic acetyltransferase isozyme (NAT2). Individuals homozygous for mutant alleles are deficient in the polymorphic acetyltransferase and are slow acetylators. A second acetyltransferase isozyme (NAT1) is monomorphic and is not regulated by the acetylator genotype. Several human epidemiological studies suggest an association between slow acetylator phenotype and urinary bladder cancer. In contrast, a few studies suggest a relationship between rapid acetylator phenotype and colorectal cancer The basis for this paradox may relate to the relative importance of N- versus O-acetylation in the etiology of these cancers. Conclusions drawn from human epidemiological data are often compromised by uncontrolled environmental and other genetic factors. Our laboratory recently completed construction of homozygous rapid, heterozygous intermediate, and homozygous slow acetylator congenic Syrian hamsters to be homologous in greater than 99.975% of their genomes. The availability of these acetylator congenic lines should eliminate genetic variability in virtually all aspects of arylamine carcinogenesis except at the acetylator gene locus. Ongoing studies in these congenic hamster lines should provide unequivocal information regarding the role of genetic acetylator phenotype in susceptibility to arylamine-related cancers.

The ability to attract and retain loyal customers depends on the successful implementation of a customer-centric strategy. Customer loyalty is an attitude about an organization and its' services that is manifested by intentions and behaviors of re-patronization and recommendation. In the context of many medical services, loyalty through repeat patronization is not pertinent, whereas loyalty through positive word-of mouth (WOM) recommendation can be a powerful marketing tool. The Shouldice Hospital, a well-known institution for the surgical correction of hernias, instituted a marketing plan to develop a stable base of patients by creating positive WOM advocacy. This study focused on the consequences of both hernia patient overall satisfaction (and overall service quality) and hospital personnel satisfaction on the level of positive WOM advocacy. Using a commitment ladder of positive WOM advocacy, respondents were divided into three categories described as passive supporters, active advocates and ambassador advocates. Patient assessments of overall satisfaction and service quality were significantly related to these progressive levels of WOM for recommending the hospital to potential patients. Similarly, the satisfaction of the hospital employees was also significantly related to these progressive levels of positive WOM about recommending the hospital to potential patients and to potential employees. High levels of satisfaction are required to create true ambassadors of a service organization.

The genetic constitution of mammalian enzymes involved in the metabolism of xenobiotics is one of the important factors responsible for large inter-individual differences in the rate of biotransformation and consequently the magnitude of genotoxic effects exerted in target tissues. The present study examines the mutagenic activation of 2-aminofluorene (AF) with hepatic post-mitochondrial (S9) preparations derived from homozygous rapid (Patr/Patr) acetylator and homozygous slow (Pats/Pats) acetylator Syrian inbred hamsters and its relationship to acetylator genotype. These hamster strains differ in their capacities for acetyl coenzyme A (AcCoA)-dependent, N-acetylation and O-acetylation of carcinogenic arylamines and their N-hydroxyarylamine metabolites. AF N-acetyltransferase activities determined in hepatic S9 fractions were 72.2 +/- 4.2 nmol/min/mg in rapid acetylator hamsters and 6.65 +/- 0.37 nmol/min/mg in slow acetylators, and were unaffected by the presence of 0.1 mM paraoxon. Mutagenic activation of AF was measured by reversion to histidine prototrophy in Salmonella typhimurium strain TA98. The metabolic activation of AF utilizing standard hepatic S9 preparations exhibited typical saturation kinetics that did not differ between acetylator genotypes. However, the addition of AcCoA to the standard S9 mix resulted in a dose-dependent reduction in the number of histidine revertants. In dose-response studies in which the concentrations of AF, AcCoA or S9 protein were varied, higher numbers of revertants were consistently generated with hepatic S9 derived from the slow acetylator compared to the rapid acetylator hamsters. These results indicate an acetylator genotype-dependent modulation of arylamine genotoxicity was reflected as a reduction in the levels of mutagenic metabolites generated in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

PROBLEM To determine the associations between preterm delivery

Objective The purpose of this study was to determine the associations between preterm delivery (PTD), cervical fluid interleukin-6 (IL-6) concentration, and the single nucleotide polymorphism at position −174 in the IL-6 gene. Study design Cervical fluid samples were obtained from women 23 to 32 weeks' gestation with symptoms of preterm labor. Concentrations of IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). IL-6 genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results One hundred thirty-seven women were enrolled, and complete information was available for 126. Cervical fluid IL-6 concentrations were not elevated in women destined to have a spontaneous PTD (P = .86). IL-6 −174 genotype was not associated with PTD (P = .62) or cervical fluid IL-6 concentration (P = .36). Neonatal IL-6-174 genotype was not associated with PTD or IL-6 concentration. Conclusion Cervical fluid concentrations of IL-6 were not elevated in symptomatic women destined to have a spontaneous PTD. The presence of maternal IL-6 −174C was not associated with cervical fluid concentration of IL-6 or risk of PTD.

Objective The purpose of this study was to determine if cervical fluid antibody concentrations can enhance the value of cervical length in predicting risk of preterm delivery. Study design We obtained cervical fluid samples with preweighed cellulose wicks from a prospective cohort of women 23 to 32 weeks' gestation with signs and symptoms of preterm labor and intact membranes. Total immunoglobulin A and G (IgA and IgG) concentrations were determined by enzyme-linked immunosorbent assay. Bacterial vaginosis was diagnosed by Gram stain, and cervical length was measured with endovaginal ultrasound. Results For subjects with term (n = 77) and preterm (n = 24) deliveries, median IgA and IgG concentrations were 736 vs 643 μg/mL (P = .33) and 1528 vs 1769 μg/mL (P = .85). For subjects with normal flora (n = 71), intermediate flora (n = 14), and bacterial vaginosis (n = 16), median IgA and IgG concentrations were 717, 624, and 774 μg/mL (P = .90) and 1383, 1553, and 2731 μg/mL (P = .02). In a forward stepwise logistic regression model, cervical length was the only factor associated with preterm delivery (P Conclusion Measuring the concentrations of IgA and IgG in cervical fluid does not enhance the value of cervical length in predicting risk of preterm delivery.

Anyone who undertakes the task of enlightening the public on blindness faces the challenge of only “seeing through a glass darkly.” Examining blindness is a complex undertaking as it requires the r...

This paper has four purposes. First, it points out and explains why the Market‐type culture, is not the culture type most conducive to business performance. This Market‐type culture reflects mainly a Transactional approach to the market rather than a longer term Relational approach to clients. Second, a modification of the CVM is presented which forces the respondents to weigh the value their firm places on the client or customer compared with the other competing values in the model. This modified version can be used to describe organizational cultures which are more Relational or Transactional in nature. Third, an empirical study of commercial banking relationships in France indicated that business effectiveness was greater when both parties in the exchange (account manager and business client) perceived their respective organizations to be Relational‐type cultures. Conversely, the worst business performance was found when both organizations had Transactional‐type cultures. Fourth, the managerial implications of the paper are discussed in the context of commercial banking.

This research investigated how the Millennial generation’s intentions to support charitable causes within a social media context is influences by (i) the type of Facebook appeals they are exposed t...

Polymorphic aromatic amine N-acetyltransferase (NAT2) catalyzes the N-acetylation of aromatic amines and the metabolic activation of N-hydroxyarylamines (via O-acetylation) and N-hydroxy-N-acetylarylamines (via N,O-acetylation) to electrophilic intermediates that mutate DNA. Acetylation capacity in humans and other mammalian species such as Syrian hamsters is subject to a genetic polymorphism. NAT2 is regulated by a single gene (NAT2) containing a single coding exon of 870 bp. Syrian hamster slow acetylator differs from the rapid acetylator NAT2 coding region by three nucleotide substitutions at T36C, A633G, and C727T. We measured expression of immunoreactive NAT2 protein and aromatic amine N-acetylation, N-hydroxyarylamine O-acetylation and N-hydroxy-N-acetylarylamine N,O-acetylation by recombinant NAT2 proteins expressed from alleles containing all combinations of the T36C, A633G, and C727T substitutions. The C727T substitution, which creates an opal stop codon in slow acetylator NAT2, was the sole mutation responsible for substantial reduction in expression of a truncated NAT2 protein with reduced capacity for the deactivation of aromatic amines (N-acetylation) and the metabolic activation of N-hydroxyarylamines (O-acetylation) and N-hydroxy-N-acetylarylamines (N,O-acetylation). The reductions in aromatic amine N-acetylation correlated very highly with the reductions in metabolic activation of the corresponding N-hydroxyarylamines and N-hydroxy-N-acetylarylamines.

Syrian hamster acetylation capacity is catalysed by two N-acetyltransferase isozymes (NAT1 and NAT2). Hamster NAT2 (polymorphic) displays acetylator-genotype dependent activity resulting in high, intermediate, and low activity levels in homozygous rapid, heterozygous and homozygous slow acetylators, respectively. A lambda gt10 size-selected genomic library was constructed from Eco RI-digested homozygous slow acetylator Bio. 82.73/H-Pats congenic hamster DNA and screened with a hamster NAT1 probe. A 4.2 kb Eco RI insert from a positive clone was subcloned into pUC18 and the intron-free NAT2 coding region was sequenced. The NAT2 coding regions from genomic templates of other homozygous rapid and slow acetylator congenic and inbred hamster lines were amplified by the polymerase chain reaction, cloned, and sequenced. Two NAT2 alleles were found, one (NAT2*15) from each homozygous rapid acetylator line and one (NAT2*16A) from each homozygous slow acetylator line. NAT2*15 contained an 870 bp open reading frame encoding a 290 amino acid protein. NAT2*16A was similar except for two silent (T36C and A633G) and one nonsense (C727T) substitutions yielding a 242 amino acid open reading frame. The NAT2*15 and NAT2*16A alleles were expressed in Escherichia coli JM105 and the recombinant proteins were characterized. Electrophoretic mobilities of the NAT2 15 and NAT2 16A recombinant hamster proteins differed and correlated with the theoretical molecular weights calculated from their respective open reading frames. NAT2 16A exhibited 500-to 1000-fold lower maximum velocities compared to NAT2 15 for N-acetylation of all arylamine and hydrazine substrates tested. NAT2 16A also catalysed the metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides at rates 33- and 23-fold lower than NAT2 15. Intrinsic clearance (Vmax/Km) calculations suggest that N-acetylation of p-aminobenzoic acid and 2-aminofluorene in Syrian hamsters is catalysed primarily by NAT2 (NAT2 15) in rapid acetylators but by NAT1 (NAT1 9) in slow acetylators. These results provide a molecular basis for rapid and slow acetylator phenotype in the Syrian hamster.

To obtain scarce human and financial resources, non-profit organizations and their corporate partners must identify and work closely with the most promising constituencies of potential supporters. ...

Development of new leads for drug design and structure/function relationship studies were revolutionized by the introduction of combinatorial or “library” techniques (for review see e.g. (Moos et al., 1993; Gallop et al., 1994; Gordon et al., 1994)). These techniques allow for the generation and screening of millions of potentially active structures. Due to the well developed and finely tuned synthetic methodology, peptides were the first group of compounds evaluated by this new approach. However, the next logical challenge is to synthesize libraries of nonpeptidic structures. The combinatorial library approach applied at Selectide consists of three basic steps: (i) chemical synthesis based on the split synthesis method yielding a library with one test compound structure per one bead; (ii) screening of the library either using an on-bead binding assay or a multiple step release assay; and (iii) recovery of positive beads and determination of the structure of the test compound (Lam et al., 1991).

Human polymorphic N-acetyltransferase (NAT2) catalyzes the N-acetylation of arylamine drugs and carcinogens. Human acetylator phenotype is regulated at the NAT2 locus and has been associated with differential risk to certain drug toxicities or cancer. We examined arylamine substrate and acetyl coenzyme A cofactor affinities, and the N-acetyltransferase catalytic activities of the wild-type and 14 different mutant or chimeric human NAT2 alleles expressed in an Escherichia coli JM105 expression system. NAT2 alleles contained nucleic acid substitutions at positions 191(G-->A; Arg64-->Gln), 282(C-->T; silent), 341(T-->C; Ile114-->Thr), 481(C-->T; silent), 590(G-->A; Arg197-->Gln), 803(A-->G; Lys268-->Arg), 857(G-->A; Gly286-->Glu) and various combinations (282/590; 282/803; 282/857; 341/481; 341/803; 341/481/803; 481/803) of the 870 base pair NAT2 coding region. Expression of all 15 NAT2 alleles produced immunoreactive NAT2 protein with N-acetylation activity. NAT2 proteins encoded by alleles with nucleic acid substitutions at positions 191, 341, 590, 282/590, 341/481, 341/803, and 341/481/803 exhibited arylamine N-acetyltransferase maximum velocities significantly (P < 0.001) lower than the wildtype NAT2. Thus, nucleic acid substitutions at positions 191, 341, and 590 either alone or in combination with other silent or conservative amino acid substitutions were sufficient to result in NAT2 proteins with significant reductions in N-acetylation activities. The recombinant NAT2 proteins also showed relative differences in intrinsic stability following incubation at 37 degrees C and 50 degrees C. NAT2 encoded by alleles with nucleotide substitutions at positions 191 and 857 were particularly unstable relative to the wild type.(ABSTRACT TRUNCATED AT 250 WORDS)

The nucleotide (nt) and deduced amino acid (aa) sequences were determined for polymorphic arylamine N -acetyl-transferase (NAT2) and its gene, NAT 2, from homozygous rapid and slow acetylator congenic Syrian hamsters. The slow acetylator ( NAT 2 s ) allele contained three point mutations which differed from the rapid acetylator allele ( NAT 2 r ); two mutations were silent, and the third mutation resulted in a premature stop codon. The NAT 2 r allele contained a truncated open reading frame of 726 nt encoding a 242-aa protein, which is 48-aa shorter than NAT2 r .