Thesis (Ph.D.)--University of California, San Francisco with the University of California, Santa Barbara, 2009. / Source: Dissertation Abstracts International, Volume: 70-04, Section: A, page: 1333. Adviser: Sharon Kaufman.

<p> Pressure ulcers are a hospital-acquired condition with reported incidence of up to 27% in acutely ill infants and children, who are particularly vulnerable during long periods of immobilization. Pressure is a key risk factor for pressure ulcer formation and pressure-redistributing surfaces are used in the clinical setting to mitigate this risk. However, there is a lack of information on the most effective surfaces available to redistribute pressure in pediatric patients, especially because the occiput is the highest risk location for pediatric patients, while the sacrum and heels are at highest risk for adults. The aim of this research is to evaluate the pressure-redistributing properties of surfaces used to redistribute pressure under the bony prominence of the occiput of hospitalized pediatric patients through pressure mapping experiments on healthy children. </p><p> A commercially available pressure mapping system is validated for use in the pediatric population through studies on sensitivity, accuracy, creep and repeatability. Then, the capacitive pressure sensor is used to measure mean peak pressure and contact area between the occipital region of the skull of children under 6 years old and each of four pressure-redistributing surfaces: gel, foam, fluidized, and air cushion. Lastly, finite element analysis is performed to simulate the pressure generated on the occiput during contact with a foam surface for two loading conditions. Predictions from the finite element model are compared to experimental pressure mapping data. The results of this study provide clinical recommendations for pediatric pressure ulcer prevention protocols.</p>

The development and maintenance of a vascular network is critical to the growth and survival of a tissue and ultimately an organism. An understanding of the mechanisms which regulate angiogenesis within and surrounding currently used polymeric devices would contribute to the success of these implants by establishing methods to enhance tissue in-growth and new vessel development. Furthermore, tissue-engineering currently used polymers such as expanded polytetrafluoroethylene (ePTFE) may create an angiogenic material that can be used to induce new microvessel formation in infarcted myocardium. Myocardial infarcts represent a pathology that affects a large percentage of the patient population who suffer from coronary heart disease. Disease of the coronary vasculature can lead to narrowing of the coronary vasculature and result in regions of ischemia which can progress to infarction. Studies in this dissertation evaluate two different tissue-engineered polymer constructs for their ability to stimulate a new collateral network in infarcted myocardium. The results from these studies indicate that the tissue site of implantation is an important factor in influencing the healing response. Therefore, it is important to evaluate future polymer devices in tissues where the device will ultimately reside. Additionally, the physical and chemical characteristics of polymers were found to have a significant influence on the healing response. Furthermore, tissue-engineered polymer constructs stimulated a significant angiogenic response within infarcted myocardium. Tissue-engineered constructs that secreted soluble angiogenic agents were found to have the greatest depth of angiogenic effect into infarcted myocardium leading to the formation of arterioles, capillaries, and venules. Additionally, hearts treated with these devices demonstrated significantly greater left ventricular function in comparison to infarct-only hearts. Based on this work, it is apparent that tissue-engineered polymer constructs may have a future role as cardiac patches and thus provide the patient population with an additional therapy to revascularize infarcted cardiac tissues.

The epithelial cytoarchitecture and function in the prostate gland are maintained in part by the E-cadherin/catenin complex. In human prostate adenocarcinoma, an association between the loss of E-cadherin, increased Gleason score, and extracapsular dissemination has been observed. Further characterizations of human prostate carcinoma cell lines show loss of E-cadherin and expression of N-cadherin in poorly differentiated prostate carcinoma cell lines. N-cadherin expression correlates with an invasive phenotype in cancer cells and mediates the interactions between malignant tumor cells and N-cadherin expressing cells, such as prostate stromal fibroblasts. Additionally, N-cadherin-mediated intercellular adhesions generate a compensatory mechanism that promotes anchorage-independent growth and suppresses apoptosis through a phosphatidylinositol 3-kinase/Akt/protein kinase B survival pathway. Activated Akt results in the phosphorylation of two downstream substrates, Bad and CREB, to regulate Bcl-2 protein stability and bcl-2 transcription, respectively. Under serum deprivation, N-cadherin intercellular adhesion stimulates a 4-fold increase in bcl-2 mRNA expression resulting in a 3.5-fold increase in Bcl-2 protein expression, while the cellular level of proapoptotic protein Bax remains constant. Following N-cadherin homophilic adhesion the phosphatidylinositol 3-kinase p85 subunit is found in immunoprecipitates of the N-cadherin/catenin complex. The recruitment of phosphatidylinositol 3-kinase is dependent on both N-cadherin homophilic adhesion and N-cadherin binding to an intact actin cytoskeleton. These results suggest that the association of the N-cadherin/catenin complex with the actin cytoskeleton acts as a scaffold to localize the activation of phosphatidylinositol 3-kinase/Akt signaling pathway at adherens junctions. The identification of outside-in signal transduction mediated by N-cadherin adhesion provides new information on anti-apoptotic cell-cell adhesion mechanisms enhancing the activity of the phosphatidylinositol 3-kinase/Akt cell survival pathway in metastatic prostate carcinoma. Collectively, these observations indicate that alterations in cadherin expression play a role in prostate cancer progression that may have a profound affect on metastatic cell survival.

Asthma represents the most common chronic disease in childhood. Children with asthma are at increased risk for developing long-term irreversible airway obstruction in adult life, the fourth leading cause of death in USA. Our aims were to: (1) Determine whether reduced IFNgamma production and plasma soluble CD14 (sCD14) levels in early life are significant risk factors for the development of wheezing in the first year of life; (2) Estimate rates of persistence and remission of childhood wheezing after puberty; (3) Study risk factors affecting persistence of childhood wheezing after puberty. We used data from the two large ongoing birth cohorts of the Tucson Infant Immune Study (IIS) and the Tucson Children's Respiratory Study (CRS). Among 238 children from IIS, we found the odds of developing recurrent wheezing in the first year of life to be 4.5 times higher for children in the lowest quartile of IFNgamma production at 3 months (p = .0005) and 3.2 times higher for children in the lowest quartile of sCD14 levels at birth (p = .004) as compared with children in the other 3 combined quartiles of IFNgamma and sCD14, respectively. We studied persistence and remission of wheezing after puberty among 732 children from the CRS cohort. We found that 29% of children with infrequent wheezing during childhood experienced persistent wheezing after contrast, the proportion of persistent wheezing was much higher (60%) among children meeting the for asthma during childhood. Frequency of wheezing during childhood, obesity, an early onset of puberty, bronchial hyperresponsiveness, and skin test sensitization were significant predictors of persistent asthma after puberty. By looking at genetic factors, we also found that the homozygous status for Gly in codon 16 of the beta2 Adrenoceptor doubled the risk for persistent wheezing after puberty among boys (RR 2.01, p = .0008) but not girls. Our findings from two population-based longitudinal cohorts provide the first evidence that altered immunological markers precede the onset of wheezing early in life, challenge the commonly held view that most asthma cases remit during adolescence, and provide a profile of risk.

For coronary artery disease (CAD) patients, who cannot be managed with risk factor modification and pharmacologic medical therapy, coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI), are the primary means of treatment. CABG has been considered the standard for patients who are 'high-risk,' because of anatomic or functional characteristics, but stents and modern pharmacologic adjuncts have made PCI much more competitive. Additionally, as the population ages and becomes more comorbid, some of the features of CABG that allowed 'control' of functionally high-risk patients (such as general anesthesia and heart lung bypass) become disadvantages, especially for hemodynamically unstable patients. This dissertation summarizes the only prospective, multicenter, randomized clinical trial (RCT), and prospective registry of CABG versus PCI, specific to high-risk patients: AWESOME. Previously unpublished 5-year survival data is analyzed in the context of the published AWESOME randomized trial, registry and pre-specified subset 3-year results. Qualitative summaries of all published RCTs comparing medical therapy with CABG or PCI and comparing PCI (with or without stents) with CABG are included (Appendix B). Taken together, these data allow the conclusion that PCI is not simply an alternative for high-risk patients, but that for specific patient groups, such as ST-elevation myocardial infarction (STEMI), hemodynamically compromised unstable angina/non-STEMI, and patients with major comorbidity, PCI is the preferred initial revascularization strategy in 2004.

The socioeconomic constraints generated by patients with cardiovascular disease necessitates the development of novel treatment strategies for the pathologies associated with disease progression. One promising field of active research and development is Cardiovascular Tissue Engineering. It is believed this discipline will ultimately provide alternative strategies for the development of vascular bypass conduit, bioprosthetic valves, functional microvascular networks, and solid organ replacement tissue. The primary goal of this project was to test the hypothesis that, following implantation, tissue engineered microvascular grafts are capable of inosculation with host coronary vasculature and attenuating the loss of ventricular function following acute myocardial infarction. To test this hypothesis, microvascular grafts were constructed of adipose-derived microvascular fragments suspended in a 3-dimensional matrix. These tissue engineered grafts were transplanted and evaluated in a number of in vivo research scenarios. Research protocols were designed to critically evaluate the potential of microvascular network grafting in multiple tissue sites, and in differing pathophysiologic conditions. Microvascular grafts were initially implanted and studied in a subcutaneous position in recipient animals. Following implantation, the microvessel network within the grafted construct established spontaneous anastomotic connections with the host. Inosculation of the grafted microvessles and host circulation occurred rapidly following surgical placement, with evidence of significant vascular remodeling within the graft. The experimental grafts were also evaluated in the cardiac position following acute cardiac injury. Perfusion was realized through the grafted microvascular tissue. The resulting microvasculature was complete with well-formed arterioles, venules, and capillaries. It was established that development of left ventricular dysfunction following experimental coronary artery occlusion was abated in animals treated with epicardial placement of microvascular grafts. Interestingly, while there was overwhelming evidence of microvascular remodeling in both the subcutaneous and cardiac position, there was a noted tissue-specific adaptation that occurred. Grafts in the cardiac position had a higher vascular density than those in the subcutaneous position, and developed a vessel-type distribution that was approximate to that observed in native epicardium. The results described in this dissertation project support the utility of tissue engineered microvascular grafts for the treatment of pathophysiologic tissue within the cardiovascular system proper, as well as in peripheral systems.

Research suggests that the fighting spirit (FS) of patients coping with serious illness correlates with their physical health and psychological adjustment, but studies to date have operationalized FS primarily through questionnaires and have neglected the possibility that close relationships influence (or are influenced by) an individual patient's FS. This study examines the reliability and validity of an observational measure of FS, developed by the author, and its relationship to patient, spouse, and marital variables. The measure is based on an expanded definition consisting of eight dimensions: optimism, control, self-efficacy, sense of purpose, self-esteem, persistence, active participation, and adaptability. Participants were 88 couples in which one of the partners (63 men and 25 women) had congestive heart failure (CHF). As part of the Michigan Family Heart Project (Coyne, 1993), both partners participated in individual home interviews and completed questionnaires related to physical health, psychological functioning, approaches to coping with the illness, and the partners' marital relationship. Biomedical measures of illness severity were recorded concurrently from the patient's chart, and a telephone interview 9 months later provided follow-up measures of patient life satisfaction and distress. Judges reliably rated FS dimensions from audiotaped interview segments of the patient describing how he or she had coped with a recent health problem, and the composite FS measure demonstrated good internal consistency and fair convergent and discriminant validity. Although FS did not predict four-year survival, it did relate to health, psychological functioning, and the marital context, though in different ways for male and female patients. For female patients, FS appeared to be a problem-focused, spouse-involving approach associated with initial distress that improved over time; whereas for male patients, FS appeared to represent a private self-efficacy in illness management independent of problem-solving efforts and associated with initial well-being that deteriorated over time. Though preliminary, these results suggest that FS coping may have different correlates and consequences for men and women, and highlight the importance of dose relationships in managing serious illness.

The present study was designed to test the hypothesis that hormone replacement therapy (HRT) and exercise training would be related to differences in resting hormone levels in association with soft tissue composition changes in postmenopausal women. Estrone (E₁), estradiol (E₂), androstenedione (A-4), cortisol, growth hormone (GH) and insulin-like growth factor I (IGF-I) were determined along with estimates of lean soft tissue (LST) and fat mass in total and regional body by dual-energy x-ray absorptiometry in a cross-sectional sample of women on HRT (n = 38) and not on HRT (no HRT, n = 46) and in a 12 month longitudinal data of the effects of exercise training on these variables. Postmenopausal women aged 40-65 years who were on HRT and no HRT were randomized to exercise [HRT (EX+HRT) and no HRT (EX))] and no exercise [HRT (HRT) and no HRT (CONTROL)]. Subjects were further classified in non-obese and obese (>40% fat) resulting in the following groups: no EX (non-obese and obese) and EX (non-obese and obese). Obese HRT had significant higher E₁, E₂, and lower GH than non-obese HRT. IGF-I was lower in obese HRT compared to both non-obese HRT and no HRT. Non-obese HRT had higher cortisol than non-obese no HRT. Exercise training decreased E₁ and E₂ with no effect on GH, IGF-I, A-4 and cortisol. Exercise training without HRT increased total body, arms and legs LST and decreased % fat. Arm LST increased in EX+HRT and in both non-obese EX and obese EX. Leg LST and % fat increased and decreased, respectively, in non-obese EX. The following was concluded from the study: there were no HRT effect on LST: HRT resulted in high E₁, E₂, GH, and cortisol, and low IGF-I; obesity was positively related to E₂ and negatively related to GH and IGF-I; obesity in addition to HRT was associated with a greater decrease in IGF-I; HRT had no beneficial effect on LST gains and fat mass losses resulting from exercise training; our exercise training effectively increased arm LST but not leg LST in the obese; exercise training did not modify E₁, E₂, A-4, cortisol, GH and IGF-I.

The Chung peripheral nerve injury model shows consistent allodynia and thermal hyperalgesia, which represent the most common clinical neuropathic pain symptoms. Also clinically relevant, in the Chung model spinal morphine was inactive against tactile allodynia and diminished in potency in acute nociception without spinal/supraspinal antinociceptive synergy. Further, there are increased levels of dynorphin in multiple segmental regions of the spinal cord. This loss of spinal/supraspinal synergy and the spinal antiallodynic effect of morphine is restored by spinal MK-801 or antiserum to dynorphin. It is shown here that spinal transection blocks tactile allodynia, but not thermal hyperalgesia in Chung model rats, suggesting that thermal hyperalgesia involves both spinal and supraspinal circuits, whereas tactile allodynia depends on a supraspinal loop. The c-fiber specific neurotoxin resiniferatoxin before or after Chung surgery abolishes thermal nociception in Chung and sham-operated rats, but not allodynia in Chung model rats. These data suggest that tactile allodynia may be mediated by Aβ-fibers rather than c-fibers, offering a mechanistic basis for the observed insensitivity of allodynia to spinal morphine in Chung model rats. The data also show that PN3 sodium channel protein expression is increased in medium to large diameter neurons in the L4 ipsilateral DRG of Chung rats, and that selective knockdown of PN3 protein in the DRG with specific antisense prevents and reverses allodynia and hyperalgesia in Chung model rats without affecting normal nociceptive functions. Meanwhile, the increased dynorphin level in the spinal cord of Chung model rats returns to normal following spinal PN3 antisense. This suggests that increased PN3 protein in the DRG of Chung model rats may underlie an important mechanism for central sensitization and peripheral ectopic firing after nerve injury. Increased expression of PN3 is also found in the DRGs of diabetic and CFA model rats; knockdown of PN3 reverses allodynia and thermal hyperalgesia in these models. Together, these data suggest that relief from peripheral nerve injury, chronic inflammation, or diabetic neuropathy might be achieved by selective blockade of PN3. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.