Tissue eosinophilia is a prominent feature of allergic inflammatory diseases that may be in part mediated through the regulation of eosinophil survival at inflammatory site. T helper 2 type cytokines, such as interleukin (IL)-5, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), are the important mediators of allergic inflammation leading to prolonged survival of eosinophils. Due to the proposed central role of eosinophils in asthma and other allergic airway diseases, there is considerable interest, to determine the mechanisms that regulate eosinophil functions and accumulation. IL-12 and IL-18 attract considerable attention for their immunomodulatory roles on T helper cell subsets, and their potential to affect on eosinophil function. / The general aim of this study was to determine the effect of IL-12 and IL-18 on eosinophil functions. Results from this thesis demonstrate that eosinophils express functional receptors for IL-12 and IL-18. Acting alone or in synergy, IL-12 and IL-18 induced eosinophil apoptosis, in vitro. The apoptotic effect of IL-12 was reversed by IL-5, suggesting that IL-5 and IL-12 have counter-regulatory effects on eosinophil survival. Our regulation studies demonstrated that Phorbol-Myristate-Acetate (PMA) induced optimal expression of IL-18 and IL-12 receptors by eosinophils. IL-18 receptor expression by eosinophils was markedly increased following stimulation with interferon (IFN)-gamma, Tumor Necrosis Factor (TNF), or IL-12. Up-regulation of IL-18 receptor upon IL-12 stimulation was particularly important, which may explain IL-12 and IL-18 synergy on eosinophil apoptosis. We also investigated IL-12 and IL-18 expression by eosinophils. Eosinophils did not express IL-18. However, there was constitutive IL-12 expression by eosinophils. Release of IL-12 was also confirmed in eosinophil supernatants, which suggested an autocrine mechanism of IL-12 action on eosinophils. / Extending our understanding of the role of IL-12 and IL-18 in allergic inflammation, we have defined a novel pathway by which IL-12 and/or IL-18 may actually regulate eosinophils functions, and exert an inhibitory effect on eosinophil survival. Our findings provide critical new insights into mechanisms regulating eosinophil survival. To gain an even more detailed understanding of regulatory signals mediating eosinophil survival, we need to define the mechanisms involved in IL-12 and IL-18 signalling. We have just begun to identify the molecules involved, and these include IL-12 and IL-18 receptors. Activation via IL-12 and/or IL-18 receptor-mediated mechanisms may provide a novel strategy for reducing the numbers or inhibiting the function of these cells in allergic diseases or other diseases characterized by increased numbers of, or mediators from, eosinophils.

<p> Introduction: Melanoma, a malignancy of melanocytes, is the most deadly and aggressive form of skin cancer. Although science has led to much advancement in melanoma treatment, significant disparities and practice variation exist in the United States. The objective of this study are to: examine National Comprehensive Cancer Network (NCCN) guidelines adherence rates in the state of California, determine what patient and provider level characteristics predict receiving NCCN adherent care, and to measure the association between guideline directed treatment and improved patient outcomes.</p><p> Methods: This is a retrospective, population-based study of invasive melanoma diagnosed between 2000 and 2006, using the California Cancer Registry (CCR). Patients were classified as having received NCCN adherent or non-adherent treatment. Multivariate analysis was used to identify patient and provider characteristics associated with non-adherence. Finally, melanoma specific and overall survival was analyzed. Results: A total of 29,533 patient cases were analyzed. NCCN recommended treatment for both surgical margins and lymph procedures was achieved in 73.2% of patient cases. Adherence to surgical margins was observed in 84.8% of all patient cases and lymph node adherence was 61%. NCCN Surgical guidelines were correlated with improved survival.</p><p> Conclusion: Compliance with NCCN guidelines is suboptimal in California, especially regarding lymph node procedures. Patients with more advanced stage, difficult tumor location, treated by less experienced physicians, of non-white race, with non-private insurance and advanced age had a higher risk of non-adherent treatment. NCCN guidelines are correlated with improved survival and represent a valid measure of quality for patients diagnosed with melanoma.</p>

<p> This paper seeks to investigate how concerns regarding pregnant women have been resolved by state legislatures when drafting surrogacy and advance directive statues. It also examines two related questions: Have narrow concerns regarding a relatively rare phenomenon had a significant and potentially detrimental impact on overall state policy regarding end-of-life decision making? And what lessons can be drawn from these experiences for understanding future policy battles at the nexus of bioethics and public health?</p>

<p> <b>Background:</b> Whole genome sequencing (WGS) is increasingly used for research and clinical purposes. This study explored attitudes of parents of children with a suspected autism spectrum disorder (ASD) toward WGS. <b>Methods:</b> A topic guide informed by the Theory of Planned Behavior was developed covering perceived benefits, concerns, barriers, and facilitators regarding WGS. Participants also summarized likely major factors in their decision. Interviews were audio-recorded, transcribed and analyzed for themes using framework analysis. <i><b>Results:</b></i> Participants (n=10) were generally in favor of WGS. The most recurring themes were: helping their affected child; concerns that secondary findings could be emotionally overwhelming; facilitators relating to access, e.g. living near a major medical center. When summarizing, money/insurance issues were most raised; this was also the most recurring barrier. <b>Conclusion: </b> Parents of children with ASD were enthusiastic but also expressed concerns about WGS. These findings will be useful to future research with this and other populations.</p>

<p>Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully explained. Recent literature has focused on 1) inflammatory processes, 2) adipokines, and 3) estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of TNF-alpha, MCP-1, and IL-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, while leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although its role remains controversial; some studies have implicated estrogen as being protective, while others have suggested it to be a risk factor. We highlight the most important recent advances that have been made on the aforementioned mechanisms that are thought to link obesity to CRC.

<p> During procedures like venipuncture, Child Life Specialists are able to incorporate non-pharmacological measures when most medical staff focused on pharmacological measures. There is little research about what types of interventions Child Life Specialists believe are effective at minimizing children's pain and increasing coping skills during venipuncture. The purpose of the current study was to examine Child Life Specialists' perspectives on the different techniques available in the hospital setting. An online survey of 75 Certified Child Life Specialists asked about the types of techniques that Child Life Specialists use during venipuncture. Further, questions asked how Child Life Specialists felt about the efficacy of pharmacological and non-pharmacological techniques with a variety of different ages. Results revealed that Child Life Specialists felt that combining two techniques helps to minimize pain during venipuncture for pediatric patients more than the use of a single technique. These results applied to preschoolers, school-aged children and adolescents.</p><p> <i>Keywords:</i> child life specialist, venipuncture, pain, distress</p>

<p> Cancer is an ideal target for personal genomics-based medicine that uses high-throughput genome assays such as DNA sequencing, RNA sequencing, and expression analysis (collectively called <i>omics</i>); however, researchers and physicians are overwhelmed by the quantities of big data from these assays and cannot interpret this information accurately without specialized tools. To address this problem, I have created software methods and tools called <i>OCCAM</i> (OmiC&nbsp;data Cancer Analytic Model) and DIPSC (Differential Pathway Signature Correlation) for automatically extracting knowledge from this data and turning it into an actionable knowledge base called the <i>activitome.</i> An activitome signature measures a mutation's effect on the cellular molecular pathway. As well, activitome signatures can also be computed for clinical phenotypes. By comparing the vectors of activitome signatures of different mutations and clinical outcomes, intrinsic relationships between these events may be uncovered. OCCAM identifies activitome signatures that can be used to guide the development and application of therapies. DIPSC overcomes the confounding problem of correlating multiple activitome signatures from the same set of samples. In addition, to support the collection of this big data, I have developed <i>MedBook,</i> a federated distributed social network designed for a medical research and decision support system. OCCAM and DIPSC are two of the many apps that will operate inside of MedBook. MedBook extends the Galaxy system with a signature database, an end-user oriented application platform, a rich data medical knowledge-publishing model, and the Biomedical Evidence Graph (BMEG). The goal of MedBook is to improve the outcomes by learning from every patient.</p>

The past generation's revolution in medical ethics has had a tremendous impact on the definition of the therapeutic relationship. Where the traditional virtuous physician motivated by philanthropy once practiced "therapeutic deception", today health care practitioners in a variety of disciplines are held to a professional standard which demands that the therapeutic relationship be based in good communication between patient and caregiver. Medical ethics now looks to the images of contractual negotiation and covenantal compassionate presence to overcome the clash of values which may occur when patient and caregiver meet as strangers. In the U.S., a significant number of hospital patients are not only strangers to their caregivers and American medicine, they are strangers to the very language in which differences could be explained and strong therapeutic relationships established. Non-English speaking patients pose a complex problem for the ethical dedication to informed consent, as they are unable to take an active part in treatment without translation. In a study of 226 Hispanic hospital patients, non-English speaking patients were shown to have limited understanding of their conditions and treatment, and almost no meaningful interaction with their caregivers. Ironically, where patient satisfaction with medical care has been shown repeatedly to be based in factors of communication, non-English speaking patients placed almost no importance on their communication with the staff. Overall they had little interest in the active role that contemporary ethics assigns to patients. Non-English speaking patients' limited role in their own care also poses legal questions about the validity of their consent to treatment. Few non-English speaking patients are provided with translation, even for official consent documents. There is some indication, moreover, that an inability to speak English contributes to longer hospital stays. Providing the professional medical translation which would afford non-English speaking patients the ethical hospital care that they deserve might not only ensure against litigation, it may also save money for hospitals, insurers, and public health funds.

This study examines arguments for and against the sale of human organs for transplantation by exploring the ways in which one can conceptualize the ownership of organs. The conclusions I offer lead to bringing into question current prohibitions against the selling of human organs. Despite the considerable disparity between the number of patients who could significantly benefit from organ transplantation and the number of organs available for transplant, as well as the apparent potential of a market in human organs to increase the efficiency and effectiveness of organ procurement and the number of organs available for transplantation, an emerging consensus holds such a market to be morally impermissible and promotes global prohibition. This study critically assesses the grounds for such proscription. I examine the moral, ontological, and political theoretical concerns at issue in a human organ market. The various advantages and disadvantages of such a market are explored. In each chapter, I mark out the grounds for holding that the global consensus to proscribe organ sales does not have the force usually assumed; indeed, how it may be misguided. First, it fails adequately to appreciate the phenomenological and physiological distinctions among different body parts, the relative strength of ownership rights, as well as the general significance of forbearance and privacy rights. Second, the global consensus fails as well to take adequate account of the closeness of the analogy between dominion/possession/ownership of one's body and dominion/possession/ownership of other types of things, or of the ground and e0xtent of moral political authority. Moreover, third, maximizing health care benefits, promoting equality, liberty, altruism, and social solidarity, protecting persons from exploitation, and preserving regard for human dignity are more successfully supported through permitting a market rather than through its prohibition. Finally, I consider foundational arguments from the history of philosophy, including the positions of Aquinas, Locke, and Kant, which would usually be held to prohibit the sale of organs. In each case the arguments on closer examination do not unequivocally preclude the selling of redundant internal organs or those from cadaveric sources. On balance the analysis supports a market in human organs, rather than its prohibition. Indeed, such prohibition likely causes more harm than benefit.

This dissertation is a treatise on the merging of biomedical experimentation with modern data acquisition and analysis as an integrated teaching and research platform. Virtual (i.e. computer-based) instrumentation forms the foundation for this platform development. Original virtual instruments (V1s) have been developed as a standardized means of acquiring, analyzing, and displaying data relevant to two significant areas of biological research, namely cardiovascular hemodynamics and pulmonary mechanics. Combination of these areas leads to investigations of interactive cardiopulmonary dynamics. The VIs depicted herein incorporate the development of advanced mathematical models as a tool for increasing our comprehension of normal and abnormal function of the cardiovascular and pulmonary systems. The use of parameter estimation schemes makes the results of these studies relevant to individual subjects being tested. These innovative applications create a robust, user-friendly environment that enables the models developed to be used as instructional tools or as a basis for the pursuit of other significant research objectives. Additionally, these VIs are all modular in nature, enabling them to be used in a variety of settings with only minor modifications.