STUDIES OF THE MOLECULAR MECHANISMS OF CHROMOSOME ABERRATION FORMATION (DNA REPAIR, CROSSLINKS, MITOMYCIN C)

The objective of this research has been to study the molecular basis for chromosome aberration formation. Predicated on a variety of data, Mitomycin C (MMC)-induced DNA damage has been postulated to cause the formation of chromatid breaks (and gaps) by preventing the replication of regions of the genome prior to mitosis. The basic protocol for these experiments involved treating synchronized Hela cells in G(,1)-phase with a 1 (mu)g/ml dose of MMC for one hour. After removing the drug, cells were then allowed to progress to mitosis and were harvested for analysis by selective detachment. Utilizing the alkaline elution assay for DNA damage, evidence was obtained to support the conclusion that Hela cells can progress through S-phase into mitosis with intact DNA-DNA interstrand crosslinks. A higher level of crosslinking was observed in those cells remaining in interphase compared to those able to reach mitosis at the time of analysis. Dual radioisotope labeling experiments revealed that, at this dose, these crosslinks were associated to the same extent with both parental and newly replicated DNA. This finding was shown not to be the result of a two-step crosslink formation mechanism in which crosslink levels increase with time after drug treatment. It was also shown not to be an artefact of the double-labeling protocol. Using neutral CsCl density gradient ultracentrifugation of mitotic cells containing BrdU-labeled newly replicated DNA, control cells exhibited one major peak at a heavy/light density. However, MMC-treated cells had this same major peak at the heavy/light density, in addition to another minor peak at a density characteristic for light/light DNA. This was interpreted as indicating either: (1) that some parental DNA had not been replicated in the MMC treated sample or; (2) that a recombination repair mechanism was operational. To distinguish between these two possibilities, flow cytometric DNA fluorescence (i.e., DNA content) measurements of MMC-treated and control cells were made. These studies revealed that the mitotic cells that had been treated with MMC while in G(,1)-phase displayed a 10-20% lower DNA content than untreated control cells when measured under conditions that neutralize chromosome condensation effects (i.e., hypotonic treatment). These measurements were made under conditions in which the binding of the drug, MMC, was shown not to interfere with the stoichiometry of the ethidium bromide-mithramycin stain. At the chromosome level, differential staining techniques were used in an attempt to visualize unreplicated regions of the genome, but staining indicative of large unreplicated regions was not observed. These results are best explained by a recombinogenic mechanism. A model consistent with these results has been proposed.^

The emergence of the social determinants of health on the policy agenda in Britain: A case study, 1980--2003

Numerous theories have been advanced in the effort to explain how a given policy issue manages to take root in the public sphere and subsequently move forward on the public legislative agenda—or not. This study examined how the social determinants of health (SDOH) came to be part of the legislative policy agenda in Britain from 1980 to 2003. ^ The specific objectives of the research were: (1) to conduct a sociopolitical analysis grounded in alternative agenda-setting theories to identify the factors responsible for moving the social determinants health perspective onto the British policy agenda; and (2) to determine which of the theories and related dimensions best accounted for the emergence of this perspective. ^ A triangulated content and context analysis of British news articles, historical accounts, and research commentaries of the SDOH movement was conducted guided by relevant agenda-setting theories set within a social movement framework to chronicle the emergence of the SDOH as a significant policy issue in Britain. ^ The most influential social movement and agenda setting elements in the emergence of the SDOH in Britain were issue generation tactics, framing efforts, mobilizing structures, and political opportunities grounded in social movement and agenda setting theories. Policy content or the details of the policy had comparatively little impact on the successful emergence of the SDOH. Despite resistance by the government, from 1980 to 1996 interest groups created a political understanding of the SDOH utilizing a framing package encompassing notions of inequality, fairness, and justice. This frame transmitted a powerful idea connected to a core set of British values and beliefs. After 1996, a shift in political opportunities cemented the institutional arrangements needed to sustain an environment conducive to the development and implementation of SDOH policies and programs. ^ This research demonstrates that the U.S. emergence of the SDOH on the policy agenda will depend upon: (1) U.S. ideals and values regarding poverty, inequality, race, health, and health care that will determine issue framing; (2) political opportunities that will emerge—or not—to advance the SDOH policy agenda; and (3) the mobilizing structures that support or oppose the issue. ^

HEALTH MAINTENANCE ORGANIZATION ENVIRONMENT: AN EMPIRICAL STUDY OF THE RELATIONSHIP OF EXTERNAL CONTEXT AND PERFORMANCE

The research project is an extension of a series of administrative science and health care research projects evaluating the influence of external context, organizational strategy, and organizational structure upon organizational success or performance. The research will rely on the assumption that there is not one single best approach to the management of organizations (the contingency theory). As organizational effectiveness is dependent on an appropriate mix of factors, organizations may be equally effective based on differing combinations of factors. The external context of the organization is expected to influence internal organizational strategy and structure and in turn the internal measures affect performance (discriminant theory). The research considers the relationship of external context and organization performance.^ The unit of study for the research will be the health maintenance organization (HMO); an organization the accepts in exchange for a fixed, advance capitation payment, contractual responsibility to assure the delivery of a stated range of health sevices to a voluntary enrolled population. With the current Federal resurgence of interest in the Health Maintenance Organization (HMO) as a major component in the health care system, attention must be directed at maximizing development of HMOs from the limited resources available. Increased skills are needed in both Federal and private evaluation of HMO feasibility in order to prevent resource investment and in projects that will fail while concurrently identifying potentially successful projects that will not be considered using current standards.^ The research considers 192 factors measuring contextual milieu (social, educational, economic, legal, demographic, health and technological factors). Through intercorrelation and principle components data reduction techniques this was reduced to 12 variables. Two measures of HMO performance were identified, they are (1) HMO status (operational or defunct), and (2) a principle components factor score considering eight measures of performance. The relationship between HMO context and performance was analysed using correlation and stepwise multiple regression methods. In each case it has been concluded that the external contextual variables are not predictive of success or failure of study Health Maintenance Organizations. This suggests that performance of an HMO may rely on internal organizational factors. These findings have policy implications as contextual measures are used as a major determinant in HMO feasibility analysis, and as a factor in the allocation of limited Federal funds. ^