Thesis equivalent (M.P.H.)--University of Michigan, 1947.

Thesis equivalent (M.P.H.)--University of Michigan, 1947.

This thesis set out to explore the neglected field of nurses’ occupational health. Evidence from the three case study hospitals confirms that attitudes toward nurses’ health changed between 1888 and 1948. The health of nurses was an issue that was always taken seriously but each institution approached the problem differently and responses showed much variation over time. There were good reasons for this but the failure to adopt a coherent and consistent policy worked to the detriment of nurse health. This difficulty helps explain the ambiguous treatment of occupational health within wider histories of nursing. This can lead to the erroneous conclusion that occupational health was somehow neglected by contemporary actors, thereby facilitating the omission of the subject from historical studies concentrating on professional projects and the wider politics of nursing. This study takes a different approach showing that occupational health issues were inexorably connected to these nursing debates. Occupational health cannot be understood without reference to professional projects. This is as true in debates where occupational health was obscured as it was in cases of overt concern. The history of the occupational health of nurses is also important because it offers a new perspective on two other themes central to nursing history, particularly class and gender. This focus helps understand why attitudes towards the care of sick nurses changed over time and varied between different types of institutions. By concentrating on individual nurses’ experiences we reveal something new about the way national conversations affected ordinary nurses’ lives. Recognition that nursing presents a serious occupational health risk is a relatively recent phenomenon; it was not until the 1990s that most nurses had access to occupational health units. This study not only sheds light on why nurses’ health attracted little attention before the Second World War but also explains why this situation began to change from the 1940s.

Background Integrated team working is increasingly being used as a model of care within NHS Services. Whilst the integration agenda has evolved over time with increasing recognition of the continuum integration can refer to, consistent use of language and terminology has remained a challenge. The factors influencing integrated team working could be perceived as aspects of team, organisational and professional culture but there is a lack of studies formally assessing culture within an integrated team. Case studies also seldom appeared to include Allied Health Professionals with the reasons for this unclear. Care Aims is also being increasingly used as a model of care within NHS services particularly by Allied Health Professions yet the evidence base appears sparse, particularly exploring the use of Care Aims in an integrated team. Aim The overall aim of this study was to explore the effect of culture and context on integrated team working for Allied Health Professions in community settings. Methodology This exploratory study took place in two parts. The first part of the study investigated the Care Aims approach and the effect of culture and context for integrated team working for Allied Health Professionals in primary care settings and comprises of four case studies. The second part of the study evaluated and compared the case studies with other relevant models for promoting integrated team working for Allied Health Professionals (AHPs) in community settings. Data collection was primarily qualitative using both questionnaires and semi-structured interviews based on the critical incident technique. The Team Climate Inventory (TCI) and Organisational Culture Assessment Instrument (OCAI) were used to explore culture and climate to provide supplementary contextual information. The individual case studies were analysed using thematic networks. Cross case analysis was employed to identify themes for comparison. Findings The cross case analysis identified ten categories that appeared to influence integrated team working. Some of these categories were similar to themes identified in the literature exploring facilitators and barriers to integrated team working, such as leadership, staff roles and responsibilities, vision and professional culture. However different categories also emerged e.g. service type, team climate and relationship with the patient. The interdependency between the categories is also apparent, with philosophy and approach to care influencing all. Where there was a less dominant biomedical approach to care teams appeared to work in a more integrated way. Similarly, Care Aims implementation appeared to be influenced by similar factors. The approach to care pre-Care Aims and how the introduction of Care Aims was managed appearing most significant. The findings also appeared consistent with the evidence base for managing change. This study also suggested parallels between extent of integrated team working and success of Care Aims implementation. The more integrated a team appeared to be, the more successful Care Aims implementation also was. Whether level of team integration or introduction of Care Aims was the more significant factor is unclear. One of the challenges of this study has been to identify other sufficiently detailed published case studies to enable comparative analysis. As a result of the comparative analysis in this thesis a framework for a minimum data set to enable cross case analysis of case studies exploring integrated team working is proposed. This will facilitate a better understanding of the evidence base. This study adds to the literature for integrated team working by exploring and comparing several integrated teams within the same organisation. Unlike previous studies, these case studies explicitly explored the role and impact for AHPs of working in an integrated team. This study has led to the development of a framework to support implementation of Care Aims by identifying the potential barriers and facilitators to implementing Care Aims. This could support teams to identify those areas which may benefit from greater attention and support during implementation. This study also adds to the limited evidence base for Care Aims by exploring the implementation and use of Care Aims in integrated teams and undertaking a comparative analysis of teams in the same organisation.

The primary objective and public health relevance of this investigation was to develop a chemical-animal model with a toxicological and therapeutic approach. The results outlined here are developed from the latest techniques being employed in the chemical and biomedical fields. This research outlines a model building approach that progressed from a preliminary agent screening technique (quantitative structure-activity relationship/structure-activity relationship, QSAR/SAR) and in vivo testing using the Chernoff-Kavlock (CK) assay through to in vitro testing in transgenic adenocarcinoma of the mouse prostate (TRAMP) cell lines. The preliminary investigation involved development of a QSAR/SAR model to predict the teratogenicity of a series of related chemical agents (dopamine mimetics). This QSAR/SAR model was then validated using a complete leave one out cross-validation. The predictivity of a more general QSAR/SAR model of developmental toxicity was then tested experimentally in vivo using the chemical agent retinoic acid. The second model was based on in vivo animal screening using the CK assay. The CK assay involves the dosing of pregnant animals, either mice or rats, during the organogenesis period of fetal development. This assay quantitatively measures effects on fetal viability and growth, and allows for a more qualitative assessment of teratogenicity by recording obvious malformations. The third segment of this study was an in vitro evaluation of the effects of a series of microtubule perturbing agents on cell viability, cell death and gene expression of the TRAMP cell lines. This research could contribute to the development of drug treatments that would be more effective against human prostate cancer. In the first section of my thesis, a mathematical model was generated with experimental data from the literature on a congeneric series of twelve dopamine mimetics. Based on a single physicochemical parameter, the final model is 100% effective at predicting biological activity (teratogenicity) of dopamine mimetics. We also found inconsistencies in the original biological data that might influence the choice of final model. The second section of my thesis involves the experimental validation of a general QSAR/SAR model that predicted retinoic acid would be positive for developmental toxicity. Retinoic acid was therefore tested in a standard mouse CK assay (the same assay used to generate the data used to generate the model) to test the SAR model prediction. Significant increases in the incidence of both fetal death and intrauterine growth retardation were observed in the offspring of the treated mice. Statistical analysis revealed these effects were dose-dependent. These results demonstrated, in a quantitative manner, the developmental toxic effects of retinoic acid in the mouse, as were predicted by the SAR model and as expected from developmental literature. The final segment of my thesis dealt with the preliminary in vitro screening of four promising anticancer agents, Analog II, 4-methoxy Analog II, JR oxime I and TDH 169 on the clonal TRAMP cell lines C1A, C2H and C2N. 4-Methoxy Analog II displayed the most promising antiproliferative effects and apoptosis inducing effects. A microarray analysis of mRNA expression in response to 4-methoxy Analog II was conducted to determine agent-induced expression alterations in the C1A cell line. Upregulation of the apoptosis activating genes Bok and Siva-pending was observed, while the apoptosis inhibiting genes Birc 4, Dad1 and Atf5 were significantly downregulated.

The respiratory tract is the target of multiple infectious agents. Because the lungs are continually exposed to infectious pathogens in inspired air, natural defense mechanisms have devolved to prevent infection. These defense mechanisms coordinate with each other to provide efficient protection against infection. As a result, pulmonary infections can be viewed not just as a consequence of exposure to a virulent pathogen but as a result of a breakdown of natural host defenses. SPLUNC1 or SPURT (secretory protein in upper respiratory tracts) is small, secreted protein that is expressed in epithelial areas of the nose, mouth, pharynx and lungs. It may be involved in host defense because it is highly homologous to bactericidal/permeability-increasing protein (BPI); a protein that mediates LPS related bacteria killing. In this study, we established a constitutively overexpress CCSP-spurt transgenic mouse model to examine the biological function of spurt. We compared mRNA expression of CCSP-spurt in transgenic mice and their transgenic negative litermates. We determined that mRNA expression of CCSP-spurt was elevated in transgenic mice. The tissue distribution of overexpressed spurt in CCSP-spurt mice was confirmed to be only at trachea and lung and exist in no other tissues. Bronchoalveolar lavage (BAL) fluid from unchallenged CCSP-spurt mice had higher spurt concentration as was determined by ELISA and western blot. BAL from unchallenged CCSP-spurt mice also exhibited antibacterial activity. Furthermore, CCSP-spurt mice display enhanced bacterial clearance than wild-type mice after both groups of mice were challenged with aerosolized gram negative microorganisms Pseudomonas aeruginosa (PAO1) infection. BAL of CCSP-spurt mice had lower levels of proinflammatory cytokines than BAL of their wild-type littermates after the challenge with aerosolized P. aeruginosa. Results from our studies suggest that spurt is a novel BPI-like antibacterial protein that may play a critical role in airway specific innate immunity. Further studies of this protein might have potential public health significance in providing better understanding of natural defense processes in respiratory tract.

Cytochrome c (cyt c) binds with high affinity with anionic phospholipids such as phosphatidylserine (PS) and cardiolipin (CL) to form a complex with peroxidase activity capable of oxidizing polyunsaturated phospholipids, including CL. Release of cyt c from mitochondria plays a pivotal role in cytosolic triggering of apoptotic caspase cascades whereby CL oxidation is involved in mitochondrial membrane permeabilization. Thus control of CL oxidation is critical to regulation of early stages of apoptosis. Given the lipid antioxidant potency of etoposide as well as its ability to induce apoptosis, we hypothesized that cyt c catalyzed CL oxidation during apoptosis can be sensitive to etoposide, hence affect execution of the apoptotic program. We analyzed how the apparent inability of etoposide to prevent apoptosis is related to the mechanism of mitochondrial cardiolipin oxidation by hydrogen peroxide catalyzed by cyt c molecules which has public health relevance since etoposide is a commonly used anti-tumor drug. In a model biochemical system, we showed that 160 pmol lipid hydroperoxides / nmol CL were generated when 100µM liposomes containing a mixture tetralinoleoyl-CL (TLCL) with dioleoyl phosphatidylcholine (DOPC) [1:1] were incubated with 4µM cyt c and 100µM H2O2 or 250µM AMVN. Etoposide inhibited CL hydroperoxide production in a concentration dependent manner but with different sensitivity to the different oxidizing systems. Etoposide was more effective in AMVN system (I50=3µM) compared to cyt c/H2O2 system (I50=15µM), suggesting CL is not oxidized randomly but via a definite pathway. Next we tried to outline the pathway of cardiolipin oxidation using EPR techniques and PAGE studies. Characterizing the protein derived (tyrosyl) radical and etoposide-phenoxyl radical we noted that cardiolipin oxidation occurs via the heme of the cyt c peroxidase and also partly by the protein derived (tyrosyl) radical generated as result of cyt c peroxidase reaction. Etoposide, in the model system inhibits cardiolipin oxidation by preventing formation of protein derived (tyrosyl) radical. However, in HL-60 cells, etoposide enhanced CL oxidation while suppressing AMVN-induced oxidation of other phospholipids. Thus etoposide-dependent inhibition of CL oxidation is not likely to interfere with the execution of apoptotic program via prevention of mitochondrial membrane permeabilization.

The purpose of this study was to investigate the prevalence of smoking among workers at a major academic medical center including hospitals and other medical and health care facilities. It also was designed to investigate the prevalence of smoking among employees while at the workplace and the amount of time spent doing so. Finally, this study investigates the possible connection between the level of addiction to nicotine and the amount of time spent smoking while at work. The findings in this study may help employers target employees who smoke and assist them in efforts to quit. This study has public health significance because it may improve the health of the employees and those around them, as well as decrease costs and increase productivity. An internet-based survey questionnaire addressing the issues of smoking, demographics, the prevalence of smoking at the workplace, second-hand smoke, and level of dependence to nicotine was distributed via e-mail to employees of a major academic medical center and its affiliated university. The results of this study revealed that 12% of those that responded to the survey are current smokers and half of these individuals smoke at work. Those individuals who have been smoking for a longer period of time seem to be more likely to smoke at work and take more breaks to smoke. Those individuals who have a higher level of dependency to nicotine, according to their score on the Fagerstrom score of nicotine dependency, appear to be more likely to smoke at work, take more breaks to smoke, and have more difficulty refraining from smoking at work for one day than those with lower levels of dependency.

The innate immune response is the first barrier against external stimuli arising from disease-causing pathogens. The primary membrane associated Toll-Like receptors (TLRs) play an important role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs). Recently nucleotide-binding oligomerization domain (NOD) proteins have been shown to serve as intracellular receptors that are also involved in the innate immune response. Caveolae are small plasma membrane invaginations that exist in a wide range of cell types. The overall goals of this proposal are to examine the molecular determinants of the interaction of the intracellular pathway (NOD2) with plasma membrane (TLR2) mediated events in the response of epithelial cells to bacterial pathogens and to identify the role of caveolae in the signaling events that may underlie this association. Revealing the mechanisms of interaction between NOD2 and pathogens has significant importance to control or prevent Crohn's disease and benefits the public health issues. Accordingly, the specific aims are: Aim 1: To reveal the molecular mechanism for the interaction between NOD2 and MDP. We hypothesize that a cognitive sequence in the LRR of NOD2 recognizes MDP and the cognitive sequence accounts for the interaction of PGN from Gram-positive microorganism in polarized epithelial cells. Aim 2: to determine the requisite role of NOD2/MDP pathway in response to Gram-positive infection. We hypothesize that constitutive levels of NOD2 are low in polarized epithelial cells. Gram-positive infection results in synthesis of TNFa that increases NOD2 expression and TNFa in an autocrine fashion and enables the cells to participate in host defense via synthesis of IL-8. Aim 3: to identify an interaction between NOD2 and TLR2 pathways in mediating Gram-positive bacterium Staphylococcus aureus activation (IL-8 synthesis) in polarized MDCK cells. IL-8 synthesis in response to gram-positive infection will be contrasted in wildtype MDCK cells vs. cells in which NOD2, TLR2 or both have been silenced by siRNA. We also hypothesize that cross talk between NOD2 and TLR2 pathways occurs at a MAP kinase step and accordingly, experiments will be repeated in the presence of pharmacological (or genetic, e.g. dominant negative) inihibitors of p38, JNK and MAPK.

The adverse health consequences of air pollution are well recognized and range from minor upper respiratory system irritation to severe chronic lung disease. The identity and mechanisms of these pollutants, as well as how toxicity is influenced by additional risk factors are unclear. This study elucidates the relationship between air pollution and microbial agents and explores the mechanisms by which the two stimuli interact to cause adverse health effects with important public health relevance. Mycoplasma fermentans is a species of atypical bacteria with immune-regulatory properties and potential to establish chronic latent infections. Particulate matter (PM) is a complex and diverse component of air pollution associated with adverse health effects. The hypothesis of this study is that M. fermentans infection modulates the cellular responses induced by exposure to residual oil fly ash (ROFA), a type of PM particularly rich in metals. Using human lung fibroblasts (HLF) as an in vitro model I measured the release of the immune-modulating cytokine interleukin-6 (IL-6) as a biomarker of stress-induced cell activation after exposure to various chemical and microbial challenges alone or together. The synergistic interaction between live M. fermentans and ROFA to stimulate IL-6 release and gene expression in HLF was demonstrated. This effect was specific for PM that contains high amounts of water-soluble metal and was recapitulated when NiSO4 was substituted for ROFA. The potentiating effect of live infection was mimicked by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2 agonist. Experiments with consecutive singular exposures to MALP-2 and NiSO4 revealed that pre-treatment of cells with NiSO4 facilitated MALP-2-induced IL-6 production, while pre-exposure to MALP-2 failed to influence the response to Ni. Facilitation of MALP-2 response by NiSO4 depended, in part, upon Ni-induced activation of the ERK1/2 MAP kinase. These interactive effects were studied at the level of gene transcription using a series of IL-6 promoter-luciferase reporter constructs and mutants.