Previously a t(2;14)(p13;q32) translocation was characterized in four unusually aggressive cases of B cell chronic lymphocytic leukemia (B-CLL). A gene located near the 2p13 breakpoint, B cell lymphoma/leukemia 11A (BCL11A), was shown to overexpress 3 isoforms (BCL11A-XL, L and S). Bcl11a knockout mice are severely impaired in B cell development at the early (pro-B) stage. I have further characterized BCL11A, focusing on the most abundant and evolutionarily conserved isoform, BCL11A-XL (XL). I demonstrated that XL resides in the nuclear matrix, is modified by ubiquitination, and is destabilized by B cell antigen receptor ligation. I identified domains within XL required for its localization within nuclear paraspeckles and for its transcriptional repression. While BCL11A-XL represses model promoters in non-B cells, its biologically relevant targets in B lymphocytes were unknown. I have identified and confirmed a number of XL targets which are both up- and down-regulated by XL over-expression in B cell lines. A number of these genes have been implicated in B cell function, including the V(D)J recombination activating (RAG) genes. Both RAG1 and RAG2 transcripts were up-regulated by XL. XL binds to the RAG1 promoter and RAG enhancer (Erag) in vivo as well as in vitro. Unexpectedly, XL repressed RAG1 transcription in non-B cells, indicating that additional B cell-specific factors are required for activation. Overexpression of XL in a V(D)J recombination-competent pre-B cell line markedly induced RAG expression and VDJ recombination. IRF4 and IRF8, transcription factors previously shown to be required for early B cell development, were also induced by BCL11A-XL. I propose that the early B cell progenitor block in Bcl11a knockout mice is, at least in part, a direct result of BCL11A-XL regulation of V(D)J recombination. Further experiments are required to establish how other XL targets promote B cell lineage development and how malignant transformation such as in B-CLL may corrupt BCL11A function.

<p>Friendship has consistently been found to act as a buffer against psychological maladjustment for healthy youth and youth experiencing difficulties including parental divorce and natural disasters. Less known is the role of friendship may have for females coping with a chronic health problem. Therefore, the objective of the current study was to evaluate the health factors and friendship precursors that may influence friendship, and in turn, how those friendships may predict psychosocial adjustment. A sample of chronically ill females (N = 30) was compared to a control group of healthy females (N = 45) on measures of opportunities for social interaction, similarity to their best friend, social capability, friendship quality, and psychological adjustment. Results revealed that health condition and friendship precursors were not associated with friendship quality. However, higher friendship quality was predictive of fewer externalizing symptoms for healthy girls. Additionally, positive parent relationships predicted fewer internalizing symptoms for both groups of females. Notably, chronically ill girls noted their friendships were higher in punishment and lower in companionship than healthy girls. Further assessment, including objective measures, will elucidate the beneficial processes of friendships and parent-child relationships that buffer youth from maladjustment.</p> / Dissertation

Researchers and practitioners have developed new treatment options for chronic pain management based on biopsychosocial models of pain known as interdisciplinary pain management programs (IPMP), which involve interdisciplinary care that integrates physical treatment with emotional, environmental, behavioral, and cognitive interventions. Despite literature documenting the effectiveness of IPMPs, patients find it difficult to obtain authorization for these programs from third party insurance payers. The purpose of this quantitative causal comparative study was to explore whether a patient's perceived quality of life after injury but prior to treatment will affect his or her success in an IPMP. This study was based in the theoretical foundations of the biopsychosocial model of pain as well as positive psychology. Regression analysis and a test of mean differences were used to analyze the data to determine if there was a statistically significant difference in the perceived success in an IPMP program between patients who were part of a workers' compensation program (n = 77) and those who were not (n = 60). None of the null hypotheses could be rejected. Quality of Life Index (QOLI) scores were not predictive of success in an IPMP. None of the QOLI 16 subscales were predictive of success in an IPMP. Additionally, there was no significant difference between patients who were on workers' compensation and those who were not. This study contributes to the knowledge gap regarding appropriate screening tools for admittance into an IPMP. The results of this study can be used by practitioners who are trying to get patients approved for an IPMP and by third party insurance payer when determining which patients would most benefit from attending an IPMP.

It has been estimated that by the year 2014 there will be a 12 per cent increase in the number of adults with at least one chronic illness condition (Carrier, 2009). The turn to caring for those with a chronic illness at home has resulted in carers having an increased risk of developing health problems (Ohman & Soderberg, 2004). As such there is a need to understand how families manage and cope with illness at home. This study has examined the effect chronic illness had on not only the woman with illness, but also the immediate family closely involved with her care. Additionally the study has sought to address the effect chronic illness had on the 'self' and 'identity' of these three women and to determine what extent and impact the illness process had on the relationships within this family. The study used open-ended biographic narrative interviews to elicit data. The research revealed that each woman experienced change and loss to both 'self' and 'identity' albeit in different ways. Interestingly and of significance is the way these women in their narrative accounts revisited their past lives in implicating and accounting for the present and the future (Freeman 2010). It was discovered that the past history and past relationships of these women affected how they each responded to illness and each other in their present circumstances.

Hyperbaric oxygen (HBO) therapy is the intermittent inhalation of 100% oxygen at a pressure greater than one atmosphere absolute. It is an effective treatment for various inflammatory conditions, including chronic wounds which are characterized by an excessive influx of neutrophils and their prolonged persistence at the wound site. Neutrophil apoptosis and clearance have been shown to be required for resolution of inflammation. The mechanisms by which HBO aids wound healing are well documented, but its effects on cellular inflammatory response are not well understood particularly with respect to neutrophils. The hypothesis presented in this thesis is that increased oxygenation via HBO assists chronic wound healing by enhancing non-inflammatory neutrophil defences and cell death through apoptosis. An investigation was carried out into the effects of HBO on neutrophil antimicrobial function and apoptosis using differentiated HL-60 cells as an in vitro neutrophil model. The data clearly showed that a single HBO treatment for 90 min caused an increase in the oxidative burst activity of neutrophil-like cells as shown by increased NBT staining, superoxide (cytochrome c reduction) and H2O2 production (Kruskal-Wallis, P < 0.05), and phagocytosis of Staphylococcus aureus. HBO treatment displayed a pro-apoptotic effect, enhancing caspase 3/7 activity both in the presence and absence of a TNF-α stimulus (Kruskal-Wallis, P < 0.05) and causing morphological changes (observed using Giemsa and SYBR® Safe staining) associated with apoptosis. Although no consistent pattern was observed, both hyperoxia and pressure alone seemed to contribute to both the increase in antimicrobial activity and the increase in apoptosis induced by HBO in these neutrophil-like cells (Chapters 4 and 5). HBO-enhanced neutrophil clearance by macrophages was investigated using bovine neutrophils and monocyte-derived macrophages (MDMФ). A single 90 min HBO exposure significantly increased the clearance of fresh and 22 h-aged neutrophils by MDMФ (two-way ANOVA, P < 0.05), suggesting an increase in phosphatidylserine (PS) exposure in apoptotic neutrophils after HBO treatment (Chapter 6). Importantly, a long-term repetitive exposure to HBO in patients with chronic wounds caused a significant decrease in the antioxidant enzyme defence system (one-way repeated measures ANOVA, P < 0.05), plasma TNF-α and IL-1β after 30 HBO sessions, with down regulation of expression of the anti-apoptotic factors, NF-B and Bcl-2 (Chapter 7). These findings may go some way towards explaining the effectiveness of HBO treatment not only for chronic wounds but also for other inflammatory conditions that may be affected by this treatment.

To identify those with kidney disease early and thus facilitate earlier instigation of disease-progression slowing treatments, new definitions of chronic kidney disease (CKD) were introduced in 2002 (KDOQI). After this, the worldwide introduction of estimated glomerular filtration rate (eGFR) reporting (2006 onwards), also facilitated more widespread identification of those with CKD. Prognosis in those with CKD identified in this way was not known and the numbers with CKD appeared higher than originally expected. This thesis aimed to improve understanding of outcomes in those who met the definition of chronic kidney disease and facilitate better directed care. Data-linkage of several healthcare datasets including to laboratory, morbidity and mortality healthcare data for individuals in the Grampian region with measures of renal function in 2003 allowed those aims to be addressed. Patterns in the testing of kidney function over time were also described. Mortality and RRT initiation during the GLOMMS-I cohort's 6.5 years of follow-up were described, as were variables that were associated with these outcomes. Other measures of decline of kidney function over time (progression), were explored and compared to the ultimate measure of progression - the initiation of RRT. Various models to predict outcomes (RRT initiation, mortality and survival) were explored. Measures of model performance including discrimination, calibration, goodness of model fit and predictive performance were described. Overall the aim of this thesis was met - to improve the understanding of the prognosis of those currently labelled with chronic kidney disease. The work in this thesis has also provided the necessary information to plan and start a much wider population based study of outcome in those both with and without CKD (GLOMMS-II).

Introduction: Chronic diseases tend to increase with old age. Older people with chronic disease are commonly suffering from conditions which produce a multiplicity of symptoms and a decreased health-related quality of life. Nurses have a responsibility to prevent, ease or delay a negative outcome through symptom management, or assist in achieving an acceptable level of symptom relief. Aim: The overall aim of the thesis was to describe different aspects of symptom burden from the perspective of community-dwelling people with chronic disease. Methods: This thesis is based upon four papers that used both quantitative and qualitative data to describe different aspects of symptom burden, experienced by people with chronic diseases. Paper (I) is a cross-sectional study with 91 participants diagnosed with chronic obstructive pulmonary disease. Papers (II and IV) are based upon secondary outcome data from a randomized controlled trial with 382 community-dwelling older people with multimorbidity. Paper (II) is a cross-sectional study and Paper (IV) has a descriptive and an explorative design reporting on the trajectory of symptom prevalence and symptom burden. Paper (III) is a qualitative study with participants from the AGe-FIT. Results: Among people diagnosed with COPD the most prevalent symptoms with the highest symptom burden scores were shortness of breath, dry mouth, cough, sleep problems, and lack of energy, with just a few differences between participants with moderate and severe airflow limitation (I). For older people with multimorbidity, pain was the symptom with the highest prevalence and burden. Other highly prevalent symptoms were lack of energy and a dry mouth. Poor vision, likelihood of depression, and diagnoses of the digestive system were independently related to the total symptom burden score (II). The symptoms experienced by the older people were persistent and the symptom burden remained high over time (IV). The experience of living with a high symptom burden was described as an endless struggle. The analysis revealed an overall theme, “To adjust and endure” and three sub-themes, “to feel inadequate and limited”, “to feel dependent”, and “to feel dejected” (III). Conclusions: The results of this thesis indicate the importance of early symptom identification. People with chronic diseases have an unmet need for optimized treatment that focuses on the total symptom burden, and not only disease specific symptoms. A large proportion of older people with multimorbidity suffer a high and persistent symptom burden, and the prevalence and trajectory of pain are high. Older people sometimes think their high age is the reason they experience a diversity of symptoms, and they do not always communicate these to their health-care provider.

Childhood obesity has been prevalent for a number of years despite programs designed to educate children and families on healthy diets and activities. Multiple disciplines have reported chronic stress can interfere with normal neuroendocrine functions in the body which include energy balance. Research into alternate mechanisms contributing to childhood obesity is just beginning to include psychosocial factors’ and their influence on biology. Healthy coping strategies can reduce the effects of stress and influence perceptions of what is stressful. Warm, secure relationships with parents, family connectedness, and a secure stable environment all contribute to the buffering of chronic stress as well as promote the ability to cope with stress. Through the years, changes in the family environment through divorce, single parenthood, and cohabitation may play a role in the child’s ability to cope with stress. Therefore, the purpose of this study was to explore relationships between the child’s perceptions of chronic stress, coping strategies, family connectedness, family characteristics, and weight in 4th and 5th grade children. This study used a cross sectional and correlational design. The conceptual framework guiding this study was the Bio-Psycho-Social Model for Health integrating the three dimensions (biological, psychological, and sociological) as they relate to obesity in children. Well established instruments were used to measure chronic stress, coping, family connectedness, and weight. Results did not reveal a relationship between chronic stress and children’s weights. The ‘frequency the family sat down to eat dinner together’ was significantly related to weight: the more dinners together the lower the body mass indices and accounted for 14.7% variance in children’s body mass indices. Frequency of family meals was also correlated with the frequency of cooking dinner and negative trending of both ‘frequency’ and ‘helpfulness’ of coping strategies: possibly suggesting less need for the coping strategies. Parents’ education was positively correlated with more sleep on school nights for children. The findings suggest the importance of family time together is related to lower body mass indices in children. / text

Bakgrund: Långvarig smärta är vanligt förekommande i Sveriges befolkning. Smärtupplevelsen är individuell och påverkas av många dimensioner i livet. Långvarig smärta är svår att bedöma och lindra, den kan skapa ett lidande. Att lindra lidande och främja hälsa hos dessa personer är en viktig men inte alla gånger lätt uppgift för sjuksköterskan. Därför är det nödvändigt med insikter i hur det är att leva med långvarig smärta. Syfte: Syftet med studien var att beskriva upplevelsen av att leva med långvarig smärta. Metod: En litteraturstudie har använts. Studien baseras på tio kvalitativa artiklar som granskats och analyserats med influens av Forsberg och Wengström (2013) samt Friberg (2012). Det vetenskapliga underlaget är hämtat ur databaserna CINAHL och PubMed och är publicerat år 2000-2013. Resultat: Tre huvudteman med subteman representerar resultatet. Första huvudtemat, Känsla av att livet är begränsat, beskriver de negativa förändringar som smärtan leder till, gällande fysiska, psykiska och sociala aspekter. Andra huvudtemat, Strävan efter att bemästra den långvariga smärtan, visar hur varierande strategier används för att bemästra den långvariga smärtan. I tredje huvudtemat, Kampen för att bli betrodd i sitt lidande, framträder smärtans osynlighet som problematisk, misstro i kontakt med närstående och vårdgivare förekommer. Diskussion: Resultatet knyts an till Erikssons omvårdnadsteori om lidande. Sjukdomslidande, livslidande och vårdlidande diskuteras. Försök att lindra, liksom anpassningen av livsmönster och förmågan till försoning belyses. Ensamhet och avskildhet diskuteras samt vikten av att få tid och rum att lida. Omgivningens roll i lidandet samt hur vårdlidande kan lindras berörs även. / Background: Chronic pain is common in the Swedish population. The pain experience is individual and influenced by the many dimensions of life. Chronic pain is difficult to cure and relieve, it causes suffering. To relieve suffering and promote health for these people is an important but not always easy task for the nurse. Therefore, it is necessary to have insight in the experiences related to living with chronic pain. Aim: The aim of this study was to describe the experience of living with chronic pain. Methods: A literature review was used. The study is based on ten qualitative articles that have been investigated and analyzed with influence by Forsberg and Wengström (2013) and Friberg (2012). The scientific evidence is from the databases CINAHL and PubMed and is published year 2000-2013. Results: Three main themes with subthemes represent the result. The first main theme, Feeling that life is limited, describes the negative changes that the pain creates concerning physical, psychological and social aspects. The second main theme, Efforts to overcome the chronic pain, shows that varying strategies are used to overcome the chronic pain. In the third main theme, The struggle to be trusted in their suffering, the invisible pain appears as problematic, suspicion in touch with both family and caregivers occur. Discussions: The result is related to Eriksson´s nursing theory of suffering. The suffering of illness, the suffering of life and the suffering of care is discussed. Attempts to relieve pain as well as adaptation of life patterns and the ability of reconciliation are illuminated. Loneliness and separation is discussed as well as the importance of having time and space to suffer. The role of the fellow people in the suffering, and how the suffering of care may be eased is mentioned as well.

The mechanisms that mediate the maintenance of chronic pain states are poorly understood, but elucidation of such could yield insight into how pain becomes chronic and how the process can potentially be reversed. This thesis investigated the role of ascending and descending spinal dorsal horn circuitry and interneurons in the plasticity that mediates a transition to pathological pain plasticity using hyperalgesic priming model. The results showed that, while dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons mediated IL-6- and carrageenan-induced acute mechanical hypersensitivity, they were not required for PGE₂-induced mechanical hypersensitivity. In stark contrast, ablation of dopaminergic neurons did interrupt the IL-6- and carrageenan-induced mechanical hypersensitivity, but the subsequent PGE₂ injection failed to cause mechanical hypersensitivity - thereby reflecting that primed state plasticity is driven by differential mechanisms. In addition, the pharmacological antagonism of spinal dopamine D1/D5 receptors reversed priming and its agonism induced mechanical hypersensitivity exclusively in primed mice, which suggests dopaminergic control of pathological pain plasticity in a D1/D5-dependent manner. Moreover, in a primed state, changes to spinal dorsal horn GABA pharmacology were accompanied by upregulation of neuroligin 2 mRNA and protein expression. These findings 1) indicate a novel role for descending dopaminergic neurons in the maintenance of pathological pain plasticity, and 2) point to the inhibitory synaptic expression of neuroligin-2 as the spinal determinants of this type of pain plasticity.