Tracing Hybrid Collectives of Illness, War, and Medicine in Twentieth- and Twenty-First Century Narratives of Illness

Thesis (Ph.D.)--University of Washington, 2016-06

Multifaceted roles of the lysosome in the establishment and expansion of tuberculous infection

Thesis (Ph.D.)--University of Washington, 2016-04

Validation and refinement of survival models for liver retransplantation

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P < .0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P = .004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model χ(2) = 105, P < .0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Doctors and their patients: A context for understanding the wish to hasten death

There is a paucity of research that has directly examined the role of the health professional in dealing with a terminally ill patient's wish to hasten death (WTHD) and the implications of this for the support and services needed in the care for a dying patient. Themes to emerge from a qualitative analysis of interviews conducted on doctors (n = 24) involved in the treatment and care of terminally ill patients were (i) the doctors' experiences in caring for their patients (including themes of emotional demands/expectations, the duration of illness, and the availability of palliative care services); (ii) the doctors' perception of the care provided to their respective patients (comprising themes concerning satisfaction with the care for physical symptoms, for emotional symptoms, or overall care); (iii) the doctors' attitudes to euthanasia and (iv) the doctors' perception of their patients' views/beliefs 'regarding euthanasia and hastened death. When responses were categorised according to the patients' level of a WTHD, the theme concerning the prolonged nature of the patients' illnesses was prominent in the doctor group who had patients with the highest WTHD, whereas there was only a minority of responses concerning support from palliative care services and satisfaction with the level of emotional care in this group. This exploratory study presents a set of descriptive findings identifying themes among a small group of doctors who have been involved in the care of terminally ill cancer patients, to investigate factors that may be associated with the WTHD among these patients. The pattern of findings suggest that research investigating the doctor-patient interaction in this setting may add to our understanding of the problems (for patients and their doctors) that underpins the wish to hasten death in the terminally ill. Copyright (C) 2003 John Wiley Sons, Ltd.

Medicalizing meaning: demoralization syndrome and the desire to die

Objective: To critically analyse the proposed new psychiatric condition, demoralization syndrome, and the implications drawn by its proponents for the clinical-ethical status of requests by terminally ill patients for assistance to die. Method: The diagnostic features of demoralization syndrome, a proposed new psychiatric disorder, recognizable particularly in palliative care settings, are summarized. The consequences of proposed therapeutic interventions are described, one of which is relief of the desperation which motivates some demoralized patients to consider ending their lives and to seek assistance in dying. The connections between the proposed condition and the desire to die are analysed in the context of the continuing tensions surrounding the ontological status and sociopolitical implications of psychiatric categories and the pervasive medicalization of modern life. Results: The analysis suggests that by medicalizing existential cognitions at the end of life, the proposed diagnostic category also normalizes a particular moral view concerning assistance in dying. Conclusions: While further research into the issues described in this provisional syndrome may benefit some patients, the categorization of demoralization as a medical diagnosis is a questionable extension of psychiatry's influence, which could serve particular social, political and cultural views concerning the end of life.

Rhizoctonia crown and root rot of the pasture legume, sulla (Hedysarum coronarium)

Rhizoctonia solani AG-2-2 was isolated from wilting and dying plants of sulla ( Hedysarum coronarium), which is currently being assessed in eastern and southern Australia for its potential as a pasture and forage legume. Infected plants in the field had extensive rotting of the taproot, lateral roots and crown. Koch's postulates were fulfilled using three inoculation methods. The disease may pose a considerable threat to the potential use of H. coronarium in the dryland, grazing farming systems of Australia, with resistance offering the most viable option for minimising its impact.

Physicians' attitudes towards end-of-life decisions: a comparison between seven countries

In the context of an European collaborative research project (EURELD), a study on attitudes towards medical end-of-life decisions was conducted among physicians in Belgium, Denmark, Italy, the Netherlands, Sweden and Switzerland. Australia also joined the consortium. A written questionnaire with structured questions was sent to practising physicians from specialties frequently involved in the care of dying patients. 10,139 questionnaires were studied. Response rate was equal to or larger than 50% in all countries except Italy (39%). Apart from general agreement with respect to the alleviation of pain and symptoms with possible life-shortening effect, there was large variation in support-between and within countries-for medical decision that may result in the hastening of death. A principal component factor analysis found that 58% of the variance of the responses is explained by four factors. 'Country' explained the largest part of the variation of the standardized factor scores. (c) 2004 Elsevier Ltd. All rights reserved.

Consistency of epidemiologic estimates

Background: The epidemiology of a disease describes numbers of people becoming incident, being prevalent, recovering, surviving, and dying from the disease or from other causes. As a matter of accounting principle, the inflow, stock, and outflows must be compatible, and if we could observe completely every person involved, the epidemiologic estimates describing the disease would be consistent. Lack of consistency is an indicator for possible measurement error. Methods: We examined the consistency of estimates of incidence, prevalence, and excess mortality of dementia from the Rotterdam Study. We used the incidence and excess mortality estimates to calculate with a mathematical disease model a predicted prevalence, and compared the predicted to the observed prevalence. Results: Predicted prevalence is in most age groups lower than observed, and the difference between them is significant for some age groups. Conclusions: The observed discrepancy could be due to overestimates of prevalence or excess mortality, or an underestimate of incidence, or a combination of all three. We conclude from an analysis of possible causes that it is not possible to say which contributes most to the discrepancy. Estimating dementia incidence in an aging cohort presents a dilemma: with a short follow-up border-line incident cases are easily missed, and with longer follow-up measurement problems increase due to the associated aging of the cohort. Checking for consistency is a useful strategy to signal possible measurement error, but some sources of error may be impossible to avoid.

Apoptotic cell removal in development and tissue homeostasis

Cell deletion is a physiological process for the development and maintenance of tissue homeostasis in metazoa. This is mainly achieved by the induction of various forms of programmed cell death followed by the recognition and removal of the targeted cells by phagocytes. In this review, we will discuss cell deletion in relation to the development and function of the innate immune system, particularly of the mononuclear phagocyte system (MPS), its ontogeny and potential role in tissue remodeling in the embryo and adult. Ongoing studies are addressing the roles of professional phagocytes of the MPS and neighboring tissue cells in dying cell removal, and candidate molecules that might attract mononuclear phagocytes to the dying cells. The potential phagocyte must discriminate between living and dying cells; current concepts for this discrimination derive from the observation of newly exposed ligands on the dying cells and new evidence for direct inhibition of uptake by viable cells.

Expression profiling correlates with treatment response in women with advanced serous epithelial ovarian cancer

The majority of epithelial ovarian carcinomas are of serous subtype, with most women presenting at an advanced stage. Approximately 70% respond to initial chemotherapy but eventually relapse. We aimed to find markers of treatment response that might be suitable for routine use, using the gene expression profile of tumor tissue. Thirty one women with histologically-confirmed late-stage serous ovarian cancer were classified into 3 groups based on response to treatment (nonresponders, responders with relapse less than 12 months and responders with no relapse within 12 months). Gene expression profiles of these specimens were analyzed with respect to treatment response and survival (minimum 36 months follow-up). Patients' clinical features did not correlate with prognosis, or with specific gene expression patterns of their tumors. However women who did not respond to treatment could be distinguished from those who responded with no relapse within 12 months based on 34 gene transcripts (p < 0.02). Poor prognosis was associated with high expression of inhibitor of differentiation-2 (ID2) (p = 0.001). High expression of decorin (DCN) and ID2 together was strongly associated with reduced survival (p = 0.003), with an estimated 7-fold increased risk of dying (95% CI 1.9-29.6; 14 months survival) compared with low expression (44 months). Immunohistochemical analysis revealed both nuclear and cytoplasmic distribution of ID2 in ovarian tumors. High percentage of nuclear staining vas associated with poor survival, although not statistically significantly. In conclusion, elevated expression of ID2 and DCN was significantly associated with poor prognosis in a homogeneous group of ovarian cancer patients for whom survival could not be predicted from clinical factors. (c) 2006 Wiley-Liss, Inc.

Social inequalities in male mortality, and in male mortality from smoking: indirect estimation from national death rates in England and Wales, Poland, and North America

Background There are substantial social inequalities in adult male mortality in many countries. Smoking is often more prevalent among men of lower social class, education, or income. The contribution of smoking to these social inequalities in mortality remains uncertain. Methods The contribution of smoking to adult mortality in a population can be estimated indirectly from disease-specific death rates in that population (using absolute lung cancer rates to indicate proportions due to smoking of mortality from certain other diseases). We applied these methods to 1996 death rates at ages 35-69 years in men in three different social strata in four countries, based on a total of 0.6 million deaths. The highest and lowest social strata were based on social class (professional vs unskilled manual) in England and Wales, neighbourhood income (top vs bottom quintile) in urban Canada, and completed years of education (more than vs less than 12 years) in the USA and Poland. Results In each country, there was about a two-fold difference between the highest and the lowest social strata in overall risks of dying among men aged 35-69 years (England and Wales 21% vs 43%, USA 20% vs 37%, Canada 21% vs 34%, Poland 26% vs 50%: four-country mean 22% vs 41%, four-country mean absolute difference 19%). More than half of this difference in mortality between the top and bottom social strata involved differences in risks of being killed at age 35-69 years by smoking (England and Wales 4% vs 19%, USA 4% vs 15%, Canada 6% vs 13%, Poland 5% vs 22%: four-country mean 5% vs 17%, four-country mean absolute difference 12%). Smoking-attributed mortality accounted for nearly half of total male mortality in the lowest social stratum of each country. Conclusion In these populations, most, but not all, of the substantial social inequalities in adult male mortality during the 1990s were due to the effects of smoking. Widespread cessation of smoking could eventually halve the absolute differences between these social strata in the risk of premature death.

Corpos mortos e vivos: as cerimônias mortuárias e as representações da morte entre católicos brasileiros

Esta pesquisa procurou descrever, analisar e comparar as cerimônias mortuárias e as representações coletivas de católicos brasileiros da morte e do luto. Tivemos por objetivo estudar os sistemas simbólicos desenvolvidos em várias sociedades, começando com as culturas tribais, passando depois para o cristianismo dos primeiros séculos, antes da instauração do processo de institucionalização que originou o cristianismo católico e durante ele. Analisamos as práticas e representações católicas relacionadas com a morte e o morrer, na Idade Média, Idade Moderna e Contemporânea, tanto na Europa como no Brasil. O objetivo também foi apresentar os ritos mortuários como formas de dar sentido à vida, de reforçar e manter a coesão social, em que indivíduos vivem constantemente os desarranjos gerados pela presença da morte que arrebata um dos seus semelhantes provocando um desequilíbrio social. Ao realizar tal pesquisa sobre os rituais mortuários católicos, a meta consistiu em avançar um pouco mais no conhecimento sobre um fenômeno social religioso nem sempre abordado pelos pesquisadores: a morte do crente, as práticas mortuárias dos grupos católicos, seus hábitos e discurso quanto ao morto, dentro de um cenário brasileiro que se torna cada vez mais urbano e secularizado.(AU)

Corpos Enlutados: Por um cuidado espiritual terapêutico em situações de luto

Esta tese tem como objetivo compreender o fenômeno do luto por morte a partir da fenomenologia, por meio das experiências de membros da Igreja Metodista no Grande ABC. Para alcançar o objetivo geral, tem como objetivos específicos: dialogar com teóricos do luto nas áreas da teologia e da psicologia; conhecer a fenomenologia do corpo existencial de Maurice Merleau-Ponty como parâmetro para a compreensão do estudo do luto por morte; contribuir para as pesquisas de Cuidado Espiritual em situações de luto por morte. A trajetória teórico-metodológica tem como lócus da pesquisa o relato oral de dez pessoas, que trazem sua vivência do luto a partir da pergunta norteadora: como você viveu a sua experiência do luto? Depois de transcritos e literalizados, esses relatos permitiram levantar as unidades de significado e estabelecer as categorias analíticas: dor, tipo de perda, desorganização do ser, corpo existencial, cuidado, fé, luto por morte como ordem natural, processo relacional, racionalização, saudade, luto antecipatório, dimensão material do viver, culpa, memória e serenidade. A partir dessas categorias, fenomenologicamente interpretadas, a construção de uma tabela nomotética tornou possível a identificação das convergências e divergências entre os relatos, bem como das idiossincrasias. No percurso em direção à compreensão da experiência do luto, os relatos foram submetidos à análise ideográfica, que é a tentativa de alcançar a psicologia individual dos sujeitos da pesquisa. A síntese de um pensar, como a expressão da fenomenologia do luto, desvela nuanças da práxis pastoral. Resultantes da construção desse novo saber em torno da vivência do luto por morte, foram significativas algumas percepções: o processo do luto no contexto religioso institucionalizado é similar ao de um contexto não-religioso; a teologia cristã tem espaço para a ressignificação da morte, por meio da criação de uma espiritualidade para o processo do morrer e, para que isso seja possível, destaca-se a necessidade, no interior das comunidades religiosas, de uma teologia da perda, que possibilite uma educação cristã voltada para o enfrentamento do luto, ou seja, de uma teologia de valorização da vida em meio às perdas; o corpo foi a linguagem mais presente na vivência do luto e, no entanto, o corpo enlutado é um paradoxo na igreja cristã, na medida em que esta se tem debruçado sobre o tema da corpo de forma tímida, no que se refere à educação da fé. Ficou patente a percepção da necessidade de fomentar um cuidado espiritual terapêutico abrangente e continuado em situações de luto, de forma a alcançar não apenas o indivíduo em situação de enlutamento, mas também de alcance comunitário, como parte do conjunto de ações públicas que acolham essa questão.(AU)

The role of the innate immune system in the clearance of apoptotic cells

Rapid clearance of dying cells is a vital feature of apoptosis throughout development, tissue homeostasis and resolution of inflammation. The phagocytic removal of apoptotic cells is mediated by both professional and amateur phagocytes, armed with a series of pattern recognition receptors that participate in host defence and apoptotic cell clearance. CD14 is one such molecule. It is involved in apoptotic cell clearance (known to be immunosuppressive and anti-inflammatory) and binding of the pathogen-associated molecular pattern, lipopolysaccharides (a pro-inflammatory event). Thus CD14 is involved in the assembly of two distinct ligand-dependent macrophage responses. This project sought to characterise the involvement of the innate immune system, particularly CD14, in the removal of apoptotic cells. The role of non-myeloid CD14 was also considered and the data suggests that the expression of CD14 by phagocytes may define their professional status as phagocytes. To assess if differential CD14 ligation causes the ligand-dependent divergence in macrophage responses, a series of CD14 point mutants were used to map the binding of apoptotic cells and lipopolysaccharides. Monoclonal antibodies, 61D3 and MEM18, known to interfere with ligand-binding and responses, were also mapped. Data suggests that residue 11 of CD14, is key for the binding of 61D3 (but not MEM18), LPS and apoptotic cells, indicating lipopolysaccharides and apoptotic cells bind to similar residues. Furthermore using an NF-kB reporter, results show lipopolysaccharides but not apoptotic cells stimulate NF-kB. Taken together these data suggests ligand-dependent CD14 responses occur via a mechanism that occurs downstream of CD14 ligation but upstream of NF-?B activation. Alternatively apoptotic cell ligation of CD14 may not result in any signalling event, possibly by exclusion of TLR-4, suggesting that engulfment receptors, (e.g. TIM-4, BAI1 and Stablin-2) are required to mediate the uptake of apoptotic cells and the associated anti-inflammatory response.

Modelling Apoptotic cell clearance within the atherosclerotic plaque

The aged population have an increased susceptibility to infection, therefore function of the innate immune system may be impaired as we age. Macrophages, and their precursors monocytes, play an important role in host defence in the form of phagocytosis, and also link the innate and adaptive immune system via antigen presentation. Classically-activated 'M1' macrophages are pro-inflammatory, which can be induced by encountering pathogenic material or pro-inflammatory mediators. Alternatively activated 'M2' macrophages have a largely reparative role, including clearance of apoptotic bodies and debris from tissues. Despite some innate immune receptors being implicated in the clearance of apoptotic cells, the process has been observed to have a dominant anti-inflammatory phenotype with cytokines such as IL-10 and TGF-ß being implicated. The atherosclerotic plaque contains recruited monocytes and macrophages, and is a highly inflammatory environment despite high levels of apoptosis. At these sites, monocytes differentiate into macrophages and gorge on lipoproteins, resulting in formation of 'foam cells' which then undergo apoptosis, recruiting further monocytes. This project seeks to understand why, given high levels of apoptosis, the plaque is a pro-inflammatory environment. This phenomenon may be the result of the aged environment or an inability of foam cells to elicit an anti-inflammatory effect in response to dying cells. Here we demonstrate that lipoprotein treatment of macrophages in culture results in reduced capacity to clear apoptotic cells. The effect of lipoprotein treatment on apoptotic cell-mediated immune modulation of macrophage function is currently under study.