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Background: The purpose of this study was to examine the impact of a culturally sensitive, cognitive-behavioral family treatment (CBFT) for pediatric patients with Sickle Cell Disease (SCD) to improve pain symptoms, health-related quality of life, functionality, depression, and coping strategies. Individual cognitive-behavioral treatment has been shown previously to be effective at improving pain symptoms, functionality, adaptive coping, and health care utilization, but such benefits have not yet been shown for SCD patients. The present study aimed to address this limitation by modifying the intervention to both include the family and to utilize culturally sensitive practices, which may be particularly relevant for this population. Methods: A non-concurrent multiple baseline design was used to assess the effectiveness of the intervention. A sample of 4 children (ages 8 to 12) and 4 adolescents (ages 13 to 15) participated in the intervention. Manualized treatment consisted of five sessions (including child and parent) that targeted problem-solving skills, cognitive processes, coping strategies, goal setting, and family processes. Outcomes of interest including health-related quality of life, functionality, psychological adjustment, and coping strategies, were assessed by child and parent report at pre-treatment (baseline), post-treatment, and 2-, 4-, and 6-month follow-up. Participants completed daily diaries to quantify pain, anxiety, and functionality. Results: Repeated-measures general linear model analyses were run separately for all outcome variables. A significant main effect of time was found for youth-reported HRQoL, F(4, 20) = 4.6, p=.01, depressive symptomatology, F(4, 20) = 4.5, p=.01, and parent-reported Internalizing, F(4, 16) = 3.4, p=.03, Externalizing, F(4, 16) = 7.2, p=.00, and Total Behavior Problems, F(4, 16) = 7.7, p=.00 from baseline to 6-month post-treatment. The mean frequency of pain symptoms also decreased for five of the eight participants (i.e., visual inspection of the daily diaries from baseline to treatment). Conclusions: These results suggest the potential for clinical gains through the incorporation of culturally sensitive and family-based practices into existing cognitive-behavioral interventions for SCD. The symptomatic improvements observed in the present study indicate gains in both specific domains (i.e., pain), as well as general psychological outcomes (i.e., improvements in depression, health-related quality of life, internalizing and externalizing behaviors). / Ph. D.

Multiple contributors to neurocognitive impairment in individuals with sickle cell disease have been identified. Research indicates that a history of cerebrovascular accidents, such as silent infarcts and strokes are associated with greater cognitive decline among children with sickle cell disease. Additionally, disease effects such as hemoglobin and hematocrit levels significantly effect cognitive performance among this population and should be taken into consideration when examining neurocognitive impairment. Further, previous studies show a significant relationship between child behavior problems, family functioning, and cognitive performance in children with sickle cell, marking those as important targets for intervention among this population. While cognitive decline with increased age is not typically examined in healthy child populations, some research indicates the presence of age effects in those with SCD. A majority of the literature addresses cognitive impairment from a broad perspective, while a limited number of studies have begun to address effects among specific cognitive domains. Using archival data from the National Institutes of Health's Cooperative Study of Sickle Cell Disease, results revealed that disease severity was negatively correlated with some aspects of cognitive functioning, including visual-spatial domains. Additionally, some measures of cognitive performance were inversely correlated with age. Consistent with hypothesized outcomes, family functioning was strongly associated with measures of cognitive functioning. Implications are discussed.

While the molecular defect that cause sickle cell disease has well been established, the cause of vaso-occlusive crisis remains elusive and largely debated upon. Majority of studies have linked the painful episodes to polymerization of sickle hemoglobin following its deoxygenation. The variability of the disease symptoms among patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator of Hb F induction and a widely used treatment, has ameliorated the complication of SCD but it is only effective in 50% of the patients. Expression of Hb F lowers the content of Hb S in blood and hence reduces oxidative stress caused by Hb S denaturation. Sickle cell disease severity depends on several factors. Most importantly, the ability of red cell to sickle dominates all other determinants. While deoxygenation of sickle hemoglobin may be inevitable, the duration with which the red cell remains in the deoxygenated state can be manipulated. Deoxygenation is a transient process that when compared to the time taken to develop the long filaments of deoxyhemoglobin to causes severe sickling, the red cell would have been cycled back to the lungs and re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle cells would flow as fast as healthy erythrocytes, the detrimental impacts of sickling such as vaso-occlusive crisis, would not be a concern for this disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation through auto-oxidation, which imposes oxidative stress to the cells. The oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which subsequently impair their constitutive action against the tyrosine kinases. In the end, a net tyrosine phosphorylation state in the red cell membrane proteins, most notably the transmembrane protein band 3, succeeds. Band 3 tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage to the membrane thus engendering membrane destabilization. A destabilized erythrocyte sheds membrane fragments in form of microvesicles/microparticles and discharges free hemoglobin into the extra cellular matrix. In consequence, the microparticles power initiation of coagulation cascade through activation of thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is necessary for vasodilation and induces further oxidative stress within the microvasculature, and activates expression of adhesion receptors on the endothelium. Taken together, these events culminate in entrapment of red cells (not naming leucocytes and platelets) in the microvasculature, blockade of blood vessels and further damage of erythrocytes through prolonged deoxygenated state thus terminating in tissue injury, strokes, and organ damage, amid vaso-occlusive episodes which always require hospitalization and extensive medical care for survival. Band 3 tyrosine phosphorylation and membrane weakening is not unique just to SCD, but also a druggable target for malaria. Malaria, a disease that is touted as the evolutionary cause of sickle cell disease, surprisingly thrives through the same mechanism. Briefly, malaria parasite consumes hemoglobin for its DNA synthesis, and in the process generate reactive oxygen species from denatured hemoglobin that feeds into the oxidative stress which triggers band 3 tyrosine phosphorylation. In this case however, a destabilized membrane offers perfect conditions for merozoites’ (malaria daughter parasites) egress/exit out of the cell to begin infecting other red cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s death. Treatment of diseased cells with imatinib and other Syk inhibitors effectively reversed membrane weakening. A stabilized membrane not only survives longer in circulation to alleviate SCD symptoms but also traps and starves malaria parasite leading to termination of the parasitic infection. With band 3 tyrosine phosphorylation at center stage, this dissertation explores the above events in an effort to unveil a novel therapy for sickle cell and malaria diseases. First, the therapeutic strategy regarding SCD is discussed in detail beginning with non-transfused patients and ending in additional mechanistic study on inactivation of the principal erythrocyte’s protein tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial proof of concept on efficacy of imatinib in treatment of malaria as a monotherapy and its efficacy when used in a triple combination therapy with the standard of care treatment. Finally, I outline an alternative possible mechanism of action of quinine against malaria.

Doctor of Philosophy / Department of Family Studies and Human Services / Joyce A. Baptist / Sickle cell disease (SCD) is a prevalent, pervasive chronic illness. It is a hereditary condition that affects those of African, Mediterranean, Indian, Middle Eastern, and Hispanic/Latino descent. It causes extreme pain for patients and a myriad of other symptoms and complications. The medical issues associated with and the very nature of SCD has the potential to cause psychological distress and related problems for patients. Parents, caregivers, significant others, and family members are similarly affected by a family member with SCD. Applying the Vulnerability-Stress-Adaptation Model, this qualitative study used heterogeneous sampling and explored the experience of three families with SCD. Three main themes emerged from the data, analyzed using thematic analysis: Stress and Challenges, Adapting to and Coping with the Demands of SCD, and Individual and Family Strengths. The pervasiveness and unpredictability of SCD as well as the strengthening effects of having experienced SCD were shared across families, despite their heterogeneity. Clinical implications for families with SCD are discussed.

<p>Children with sickle cell disease (SCD) have a high risk of neurocognitive impairment. No known research, however, has examined the impact of neurocognitive functioning on quality of life in this pediatric population. In addition, limited research has examined neurocognitive interventions for these children. In light of these gaps, two studies were undertaken to (a) examine the relationship between cognitive functioning and quality of life in a sample of children with SCD and (b) investigate the feasibility and preliminary efficacy of a computerized working memory training program in this population. Forty-five youth (ages 8-16) with SCD and a caregiver were recruited for the first study. Participants completed measures of cognitive ability, quality of life, and psychosocial functioning. Results indicated that cognitive ability significantly predicted child- and parent-reported quality of life among youth with SCD. In turn, a randomized-controlled trial of a computerized working memory program was undertaken. Eighteen youth with SCD and a caregiver enrolled in this study, and were randomized to a waitlist control or the working memory training condition. Data pertaining to cognitive functioning, psychosocial functioning, and disease characteristics were obtained from participants. The results of this study indicated a high degree of acceptance for this intervention but poor feasibility in practice. Factors related to feasibility were identified. Implications and future directions are discussed.</p> / Dissertation