Ph.D. - Biomedical Sciences

Permanent URI for this collectionhttps://hdl.handle.net/10125/862

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Evaluation of Sepsis-Related Cytokines on Endothelial Cell Permeability
(University of Hawaii at Manoa, 2022) Campbell, Carmen Elaine; Rodriguez, Beatriz; Boisvert, William; Biomedical Sciences
Sepsis elicits a complex immune response in which endothelial cell function is affected by various critical inflammatory mediators and coagulation factors. The endothelial cell lining plays a central role in the pathogenesis of sepsis leading to Severe Inflammatory Response Syndrome (SIRS) and Multiple Organ Failure Syndrome (MOFS). Although diagnostic methods to assess endothelial cell function would be valuable for evaluating the effectiveness of therapeutic interventions designed to repair damaged endothelium in septic patients, no such tools exist at this time. Thus, the overall goal of this research was to characterize vascular endothelial cell monolayer integrity and barrier function changes that may be induced by inflammatory cytokines in vitro. To meet this objective, we recorded dynamic responses of endothelial cell monolayers treated with a selection of sepsis-related cytokines including TNF-, IL-1, IL-6, IL- 8, IL-10, IL-12, IFN-, and TGF- in-vitro using a novel method known as Electric Cell-substrate Impedance Sensing (ECIS). Our results demonstrate that Human Aortic Endothelial Cell (HAoEC) monolayer permeability is significantly increased when treated with TNF-α, IL-1β, IL-6, IL-10, or IFN-γ compared to untreated controls reflected by impedance changes of cell-covered electrodes. The data revealed a significant decrease in normalized impedance (ohm@16kHz) changes at early time-points (<2 hrs.) between untreated control cells compared to: IL1- (p<0.001), IL-6 (p=0.0019), IL-10 (p<0.0001), TNF- (p<0.001), or IFN- (p=0.0288) treatment groups. On the other hand, the response of cells treated with IL-8 (p<0.0001) resulted in a significant increase in the normalized impedance change compared to untreated controls. No significant difference in the normalized impedance at early time-points was observed for the TGF- or IL-12 treated cells. Using the ECIS modeling parameters, significant differences in permeability of cell monolayers treated with sepsis-related cytokines were revealed. A significant reduction in Rb resulting in increased permeability was observed for TNF- (p=0.0112), IL1- (p=0.0196), and IL-10 (p=0.0010) treatment groups. Conversely, the Rb values were significantly increased in the case of IL-6 (p=0.0007), IL-8 (p=0.0016), and TGF- (p<0.0001). No significant difference in Rb was observed for cells treated with IL-12. Significant reductions in Rb values were observed in monolayers treated with cytokines combined. IL-1β combined with TNF-α at ratios of 1:1, 5:1, and 10:1 resulted in significant reduction in Rb compared to mock-treated controls. In the case of IL-12 and IFN- combined, Rb is significantly increased when treated with IL-12:IFN- (10:1) and IL-12:IFN- (5:1) ratios but is significantly decreased when treated with IL-12:IFN- (1:1). Interestingly, Rb of HAoECs is significantly increased when treated with TGF-:TNF- (1:1) (p<0.0001), IL-10:TNF- (1:1) (p<0.0001), IL-10:TNF- (10:1) (p<0.0001), or IL-12:TNF- (5:1) (p<0.0001) compared to TNF- alone. Likewise, preincubation of the anti-TNF-α monoclonal antibody with TNF-α led to loss of cytokine effect and no significant reduction in barrier resistance (Rb) was observed compared to mock treated controls. Results from these in vitro studies provide further evidence to support the translation of new technological approaches from bench-top research tools to clinical applications. More research using the ECIS technology in a clinical setting, using plasma from patients with sepsis, would be of great value to extend these findings and identify early evidence of damage of the endothelial cell integrity of the vasculature and its barrier function. This could potentially lead to more timely treatments and improvement of outcomes in people with sepsis.
Health Care Needs Of Homeless Women With Children Living In Honolulu
(University of Hawaii at Manoa, 2021) Kissinger, Deborah; Rodriguez, Beatriz; Biomedical Sciences
Homeless individuals often experience significant physical, psychological, and social health problems associated with experiencing high level of social determinants of health deficits. This particularly vulnerable population requires specialized health care tailored to their needs. This study aimed to address a gap in the literature regarding self-reported health care needs and barriers to care experienced by homeless women with children. A mixed study using individual open-format and closed-format interview questions was conducted involving homeless women (n = 20) with children living in Honolulu, Hawaii. Qualitative data analysis revealed five main themes related to health care: 1) self-remedy; 2) personal criteria for pivoting to professional health care; 3) connection; 4) barriers to care; and surviving conditions of homelessness. Findings emphasize the gap between perceived and evaluated health care needs of homeless women with children and the strategies these women use to manage the disparity. This study provides a sketch of how the practice of these strategies may bridge the gap experienced by homeless individuals between self-perceived illness symptoms and illness symptoms evaluated and treated by a care provider. This mixed methods study addressed a gap in the literature and allowed a better understanding of the health, health care needs, barriers to health care, and health services use patterns of sheltered homeless women with children living in the City and County of Honolulu (Honolulu), on the Island of Oahʻu, Hawaiʻi. Therefore, it encourages health care providers to be more aware and inclusive of self-remedies in treatment plans as well as to regularly solicit information about patient’s self-remedy practices, to ensure safety. The findings are expected to be beneficial in efforts to improve tailoring health care approaches to the needs and health outcomes of homeless women with children.
Divergent Microbial Profiles in Tumor and Adjacent Normal Tissue across Cancer Types
(University of Hawaii at Manoa, 2019) Rodriguez, Rebecca Maria; Hernandez, Brenda Y.; Deng, Youping; Biomedical Sciences
Background: There is growing evidence that microbial variation can influence cancer development, progression, response to therapy, and outcomes. We wanted to examine the microbial composition of paired tumor and adjacent normal tissue across various cancer types in order to provide an improved understanding of microbial diversity and abundance patterns of the tumor microenvironment and their influence on clinical presentation and survival. Methods: Using raw whole exome sequencing data from 22 cancer types from the The Cancer Genome Atlas (TCGA) network, we examined differential relative abundance and diversity data in primary tumor and adjacent solid tissue normal (adjacent normal), nine of which are presented in this work. Data were processed through a bioinformatics pipeline designed to extract microbial profiles from human sequencing data based on PathoScope 2.0. Differential abundance and diversity metrics were calculated using R-package tools to compare primary tumor and adjacent normal within cancer types and across cancer cohorts correlating to clinical features including histologic and pathologic features and survival data. Analyses were controlled for demographic, exposures and batch effects. Findings were then validated by qPCR for selected cancer types with tissue from the Hawaii Tumor Registry RTR. Results: As part of a pilot project we have created microbial composition and diversity profiles for a subset of solid tumors within TCGA cancers building a platform for ongoing and future studies. We screened over 10,000 files encompassing a total of 1,838 paired cases from which 813 are discussed here. From those, 767 tumors and 753 adjacent normal samples had positive microbial (viral and bacterial) sequence reads detection. Microbial composition and diversity (richness, within sample alpha diversity, evenness and beta diversity) varied across cohorts with similar patterns at the phylum level in compositional structures. Bacterial shifts were evident in tumor compared to adjacent normal. Proteobacteria phyla was observed to be increased in tumors of all cohorts except for STAD, where Proteobacteria species were reduced and Firmicutes levels increased. Differences between patient samples were evident at the higher taxonomic levels. Differential abundance analyses revealed significant differences in stomach adenocarcinoma (STAD) and colon adenocarcinoma (COAD). Compared to adjacent normal, tumor samples were found to have lower number of species present overall and lower diversity indices. We found significant association between microbial relative abundance and diversity to clinicopathological presentation and survival dependent on race in some cancers, particularly those of infectious origin like STAD and LIHC. Conclusion. This project demonstrates the feasibility of the utilization of exome sequencing data to derive complex microbial data with easy to interpret results. This project facilitates the understanding of the role of bacteria play in cancer pathogenesis across different race groups as demonstrated in LIHC and STAD cancer cohorts. In these cancers, relative abundance was associated with tumor stage and overall survival days and within sample diversity was associated with race in fully adjusted models.
Assessment of Non-Pharmacologic Patient-Centered Pain Control Adjuncts on Pain Scores during First Trimester Abortion.
(University of Hawaii at Manoa, 2017-05) Tschann, Mary S.; Biomedical Sciences
Objectives: The objective of this study is to review the literature regarding non-pharmacologic pain management techniques during first trimester abortion and to determine if a patient-centered approach to non-pharmacologic pain management is associated with lower pain scores during a first-trimester surgical abortion. Study Design: Chapter one contains an integrative review of the literature regarding predictors of pain during first trimester abortion and of the efficacy of non-pharmacologic pain management techniques. Chapter two presents a randomized controlled trial of a patient-centered non-pharmacologic pain management approach during first trimester surgical abortion. Results: The integrative review found that pre-procedure anxiety and depression are associated with increased pain during first-trimester surgical abortion. The trials of non-pharmacologic pain management techniques found that none of the interventions had a significant impact on pain scores during the procedure. The randomized controlled trial presented in Chapter Two found no difference between the intervention (patient-centered non-pharmacologic pain management) and control (standard care) groups. Conclusions: Anxiety, depression and isolation have consistently been shown to be a good predictor of patient pain levels during first-trimester surgical abortion. The studies in the integrative review and the randomized controlled trial attempted to mitigate these impacts through non-pharmacologic pain management techniques. While none of the trials demonstrated an association between these techniques and reduced pain scores, patients were consistently positive about the use of these techniques. Adding these interventions to clinical practice could be a low-cost, low-risk quality improvement measure.
Evaluation of Tumor Localization in Respiration Motion-Corrected Stereotactic Body Radiotherapy Patients Treated with TomoTherapy.
(University of Hawaii at Manoa, 2017-05) Hirata, Emily Y.; Biomedical Sciences
Lung cancer is the second most common cancer in both men and women, estimated to account for 158,080 deaths in 2016 according to the American Cancer Society(1). Approximately 85% of all lung cancers are non-small cell lung cancer (NSCLC). While surgical resection remains the standard therapy for operable stage I lung cancer patients(2), stereotactic body radiation therapy (SBRT) is a noninvasive alternative for the inoperable population(2–4). SBRT is a technique that delivers high doses of radiation to tumors, generally in one to five treatments which are known as “fractions”. Since SBRT demands a high degree of confidence in tumor definition and localization, it requires the assessment and management of tumor motion (i.e. the respiratory excursion of the tumor)(3–7). Respiratory motion is of particular concern for TomoTherapy (Accuray, Inc, Sunnyvale, CA), which utilizes a continuously rotating gantry (maximum speed of 12 seconds per rotation) synchronized with a linearly moving couch to irradiate a target volume in a helical manner(8,9). The interplay between the motion of the radiation and the motion of the tumor can cause a discrepancy between the desired dose and the dose actually delivered. This is commonly referred to as the “interplay effect.” The goal of this work was to investigate the interplay effect using a cohort of patient respiratory waveforms and a motion phantom. Respiratory waveforms were characterized using principal component analysis of tumor displacement sampled via four-dimensional computed tomography (4DCT). These waveforms, programmed into the motion phantom were used to evaluate both the imaging and treatment accuracy of TomoTherapy. Ion chamber and film measurements were collected for the static condition, motion at the native breath frequency of the patient, and a modified motion averaging 5 breaths per minute (bpm). TomoTherapy megavoltage CT (MVCT) scans did not show marked interplay effect. Scanning in fine mode resulted in smaller positional errors, though larger imaging artifacts were visible. Lower breath frequencies were significantly associated with larger variance in dose, and larger amplitude of tumor displacement correlated with larger penumbral blurring. Banding of hot and cold were observed on film for several cases, although ion chamber measurements were mostly within the recommended 2% criteria. Strategies for minimizing the interplay effect involve maintaining an elevated breath frequency, improving regularity of the respiratory waveform, and avoiding the use of TomoTherapy plans with a fast gantry period of 12 seconds per rotation. The results of this dissertation provide a clinically based evaluation of the interplay effect on TomoTherapy for SBRT treatments.
Prophylactic Pregabalin to Decrease Pain during Medical Abortion: A Randomized Controlled Trial
(University of Hawaii at Manoa, 2017-05) Friedlander, EmmaKate B.; Biomedical Sciences
OBJECTIVE: To evaluate whether prophylactic pregabalin reduces the level of maximum pain experienced with mifepristone-misoprostol medical abortion. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of women initiating a medical abortion up to 70 days of gestation. After taking mifepristone, participants were randomized to a capsule of pregabalin 300 mg or a matched placebo to be taken at the time of buccal misoprostol. All participants were dispensed ibuprofen and oxycodone with acetaminophen as additional analgesia to be taken as needed. Electronic surveys were sent via text message link at six time points over 72 hours to assess the primary outcome of maximum pain, as well as secondary outcomes such as analgesic use and adverse effects. RESULTS: From June 2015 to October 2016, 110 women were randomized to receive 300 mg of pregabalin or a matched placebo. Demographic characteristics were similar between groups. The primary outcome of maximum pain score in the pregabalin group was 5.0 versus 5.5 in the placebo group (standard deviations 2.6 and 2.2, respectively; p=0.32). More participants in the pregabalin group did not need additional analgesia. No ibuprofen was taken by 27% of the pregabalin group versus 12% placebo (p=0.04). No oxycodone with acetaminophen was taken by 69% of the pregabalin group versus 50% placebo (p=0.04). Satisfaction scores for the abortion process were highest in the pregabalin group (very satisfied: 41% versus 22%; p=0.03), as were satisfaction scores for the analgesic regimen (very satisfied: 47% versus 22%; p=0.006). CONCLUSION: Maximum pain scores were not significantly different between the pregabalin and placebo groups, though women who received pregabalin were less likely to require any ibuprofen or oxycodone with acetaminophen, and were more likely to report higher satisfaction scores.
Kūkulu Ola Hou. Rebuilding Native Hawaiian Health by Reconnecting Ancestral Practices of Traditional Medicine: An Inventory of Researched Customs, Rituals, and Practices Relating to Hawaiian Mai.
(University of Hawaii at Manoa, 2017-05) Fox, Leanne K.; Biomedical Sciences
This qualitative health study examined customs, rituals, and practices relating to Hawaiian maʻi, —kānaka ʻōiwi perceptions of imbalance, illness, sickness and disease—and produced a comprehensive inventory of findings. Maʻi shape biomedical classification of illness by Native Hawaiians from their Ka „Oihana Mauli Ola; recounted here from the nosology within their traditional Hawaiian health structure. A Hawaiian medical epistemological framework was developed to conduct this mixed method study across eight arms before interpreting both ancient and contemporary knowledge and beliefs. Primary data collection consisted of key informant interviews (N=25) and one focus group (N=25) sampling from experts and learners of traditional Hawaiian medicine. Secondary data collection, synthesis and analyses were conducted in English and ʻōlelo Hawaiʻi utilizing over 100,000 records in multiple archives (N=11). Study significance indicates the first comprehensive medical inventory documenting knowledge of Hawaiian maʻi across time periods and traditional practices, systematically referencing more than 7,000 Hawaiian maʻi terms and dozens of unique disease classes and categories. Findings suggest this integrative medical inventory and taxonomy can inform the diagnostic process and improve diagnosis procedures for health care and prevention. Further, it can create new quality standards for culturally and linguistically appropriate services for Native Hawaiian health.
Dietetics Practice and Culturally Safe Care in the Diverse Pacific Region
(University of Hawaii at Manoa, 2017-05) Endrizal, Cynthia L.; Biomedical Sciences
ntroduction. The prevalence of non-communicable disease (NCD) rates in the diverse Pacific region is deeply concerning. The impact of these diseases and associated complications is overwhelming to families and communities and are a common point of discussion in medical, political and social domains. While much research has been dedicated to the prevention and treatment of NCDs, less research is focused on interactions between health care practitioners and their patients with NCDs. With the Pacific region representing a very diverse community of Indigenous peoples, migrated groups and new-comers; this creates a consequential mix in cultural worldviews and values. Health care providers are challenged with recognizing and understanding these cultural values. Registered Dietitian Nutritionists (RDNs) are particularly challenged as their scope of practice includes having knowledge and expertise in the dietary and lifestyle values of the populations they serve. Cultural safety, a theory of practice in regions with similar demographics as the Pacific, will be used to guide and inform this research. Objectives. To examine the practice of dietetics in the Pacific region to understand specific needs and unique practices relevant to the culturally diverse populations served. To identify dimensions of dietetics practice that describe culturally safe care. Methods. Descriptive analysis will be conducted using data from a dietetics practitioner survey. Interpretative Phenomenological Analysis will be used to identity RDN experiences that reveal culturally safe care in the Pacific from key informant interviews. Findings. Survey results describe the practice of dietetics in the Pacific region (n=106), by demographics of RDNs and populations served, and RDN identified needs for culturally relevant and disease-specific nutrition resources, particularly resources for Pacific Islander and Asian populations and NCDs. Key informant interviews (n=18) of practicing dietitians in the Pacific reveal dimensions of cultural safety in the following themes: (i) self-awareness and self-reflection to one’s own historical and social culture and location; (ii) relationship building and creating an environment of respect, caring, trust, empathy, and acceptance between client/patient and RDN; (iii) working through a social justice lens, recognition of power imbalance or struggles, and potential for repressed cultural identities as described through their practice experiences. Conclusion. Understanding dietetics practice in the Pacific as unique with needs specific to the region is important to inform the identification and development of the necessary nutrition resources to enhance dietetics practice and patient care experiences. Identifying and describing practice experiences of culturally safe care could inform new practice guidelines in the dietetics profession. This has promising implications for improving health care services in the Pacific region, and to places where Pacific groups have migrated in other parts of the world.
The Association between Occupational Exposure to Pesticides and Cardiovascular Disease Incidence: The Kuakini Honolulu Heart Program
(University of Hawaii at Manoa, 2017-05) Berg, Zara K.; Biomedical Sciences
Previously, Kuakini Honolulu Heart Program researchers reported that occupational exposure to pesticides is significantly associated with total mortality. Objective: The current study examines occupational exposure to pesticides on the job in relation to incident cardiovascular diseases (CVD), that is, coronary heart disease (CHD) incidence and cerebrovascular accident (CVA) incidence, combined. Methods: Using the OSHA exposure scale as an estimate of exposure, statistical analyses were performed using a cohort of 7,557 Japanese-American men from The Kuakini Honolulu Heart Program. Results: In the first 10 years of follow-up of the cohort, a positive correlation was observed between age-adjusted CVD incidence and pesticide exposure with a p-value of 0.021. This relationship remained significant after adjustment for other CVD risk factors. No significant association for coronary heart disease or stroke incidence and pesticide exposure was observed when examined separately, possibly due to a smaller number of events. The biochemical mechanisms leading to CVD and associated risk factors will be discussed. Conclusion: These results are novel, as the association between occupational exposure to pesticides and cardiovascular disease incidence has not been examined previously in this cohort. These findings may contribute to our understanding of the role of occupational exposure to pesticides plays in the development of cardiovascular diseases.
The Ebola Virus and West Africa: Medical and Sociocultural Aspects
(University of Hawaii at Manoa, 2015-12) Ikuomola, Felix
Problem: Little attention has been given to the undeniable impact of the socio-cultural factors on communicable disease, especially Ebola. We have failed at managing Ebola outbreaks in Africa. Most of the preparatory and intensive training of health personnel attending to the needs of those societies where culture is at the center of life have given only lip service to the importance of integrating this culture into the medical training curriculum and practice. Purpose: To itemize and emphasize the role of sociocultural factors in Ebola virus disease acquisition, transmission, containment, prevention, surveillance, screening, and control. To propose cultural modification of the aspects of the West African cultural practices that enhanced the Ebola virus disease spread through constructive community engagement. To recommend integration, collaboration, and cooperation between traditional medicinal practitioners and medical practitioners. Procedure: Gathered data on Ebola virus disease and West Africa and sociocultural factors through Pubmed, government websites, organizations, media, and personal stories. The data were synthesized into comparative, descriptive, and exploratory analyses. Conclusion: This cognitive and literature review paper will generate data to support the impact of cultural practices on Ebola spread and containment. Recommendations from this paper will not only contribute greatly to preventing any further Ebola spread but also be useful in surveillance, screening, patient tracing, and disease control.
The role of 5-aminolevulinic acid (5-ALA) and sleep
(University of Hawaii at Manoa, 2013-05) Perez, Michael Helio
Objective: To determine if there is a relationship between the administration of the dietary supplement containing 5-Aminolevulinic Acid (5-ALA) and sleep. Methods: A double-blind, randomized parallel-group study was conducted. It was a 4 month study of 40 participants between the ages of 40 and 70. Males and females were recruited equally. There were 20 in each group who had existing sleep disorders, excluding sleep apnea and Restless Leg Syndrome (RLS). The tools used to measure participant sleep improvement included: the Body Mass Index (BMI-a measure of body fat based on height and weight), a daily diary and the Pittsburgh Insomnia Rating Scale--20 Question (PIRS-20). The PIRS-20 design suggests improved sleep when the total score is lower. Results: Improvement in sleep in the group taking 50 mg 5-ALA, compared to controls, was significant. The mean change, from baseline through week 6, was-5.67 units less on the sleep scale than the control group with a p value of .001. The mean change from week 6 to week 10 when the participant was no longer taking the supplement was 4.55 units higher than the control with a p value of .062, which is of borderline significance. Conclusion: There appears to be a relationship between the administration of dietary supplements containing 5-ALA and sleep. The results of this study suggest that 5-ALA does in fact improve sleep. The mechanism for sleep improvement needs to be explored.
Transwarmer® mattress project (temp) at delivery: a prospective, randomized control trial of the transwarmer mattress to reduce admission hypothermia of low birth weight infants
(University of Hawaii at Manoa, 2013-12) Almeida, Pamela Gertrude
Background/Significance Low birth weight infants are at particularly high risk for altered thermoregulation. Factors such as the absence or low amounts of brown fat in the preterm infant do not allow for non-shivering thermogenesis. Despite research of hypothermia in low birth weight infants it remains a common problem today. (1-3) Hypothesis Standardized use of the TransWarmer® mattress will reduce the incidence of admission hypothermia. Sample Low birth weight infants, between 30-35 weeks gestation, born at Kapi'olani Medical Center for Women and Children, Honolulu, HI, admitted to the neonatal intensive care unit. Research Design Prospective, experimental randomized control trial. Instrument TransWarmer® mattress, CooperSurgical, Trumbull, CT Procedure Patients were randomized into a control group or an experimental group. Infants in the control group underwent routine care provided by the medical team attending the delivery. Participants in the experimental group followed a scripted protocol of the use of the TransWarmer® mattress with the infant through delivery and admission into the NICU for a total time period of two hours. Data 53 infants recruited into the study. Thirteen participants were removed from the study due to delivery after 35 weeks gestation. Data was obtained from a sample of 40 infants. Results The results revealed that the occurrence of hypothermia on admission was significantly lower in the TransWarmer® mattress group.
Cancer imaging based on tissue biomarkers of phosphocholine synthesis
(University of Hawaii at Manoa, 2012-05) Kwee, Sandi Alexander
Phosphocholine synthesis is upregulated in a variety of cancers as a means of supplying phosphatidylcholine for cell membrane proliferation and alternatively as a source of phospholipid second messengers for mitogenic and apoptosis-related signal transduction. This has made phosphocholine synthesis an attractive molecular target for cancer therapeutics and diagnostics. Flurorine-18 fluorocholine (FC) is an investigational derivative of choline designed as an imaging tracer for positron emission tomography (PET). Tissue uptake of FC has been shown to parallel phosphocholine synthesis since, like choline, FC is transported by membrane choline transporters and phosphorylated by choline kinase (CK). Hepatocellular carcinoma (HCC) is a primary tumor of the liver and one of the most common cancers worldwide. Hepatocarcinogenesis is known to involve abnormal signaling in multiple molecular pathways, including those that rely on phosphocholine as a second-messenger. This dissertation advances the concept of phosphocholine synthesis as an imaging biomarker of HCC by testing the feasibility of clinically detecting HCC by FC PET. A 2-tissue compartment model for describing the tissue pharmacokinetics of FC was proposed and tested by fitting this model to liver PET imaging data from patients with HCC. Various methodological aspects of dynamic PET image feature extraction were tested, including partial-volume effect, temporal resolution, and image-derived arterial input function reliability. The results of parametric modeling indicated that HCC could be distinguished from non-neoplastic hepatic tissue by the blood-to-tissue influx constant (k1) reflecting the activity of the membrane choline transporter. To determine if over-expression of choline transporter could be the mechanistic basis for the increase in this PET-imaging kinetic parameter in HCC, an independent study using tissue micro-arrays examined CK and choline transporter protein expression in HCC tumors. An immunohistochemical comparison between archival liver tumor specimens and corresponding non-neoplastic hepatic tissues revealed over-expression of the choline transporter, and to a lesser extent CK, in HCC. Translocation of the choline transporter to the nuclei of neoplastic cells was also discovered in this analysis. Altogether, the results of this dissertation provide a mechanistic basis for the upregulation of phosphocholine synthesis as a novel imaging and tissue biomarker for HCC.
What is the prevalence of chronic pelvic pain amongst the various ethnicities in Hawaiʻi?
(University of Hawaii at Manoa, 2014-05) Kim, David Seil
Objective: The primary objective of this study was to examine the prevalence of chronic pelvic pain (CPP) amongst various ethnic groups in the state of Hawaiʻi. A second objective was a secondary analysis of the data to identify any factors that may increase the risk of chronic pelvic pain. Methods: From 2005-2006, the annual Hawaiʻi Health Survey was administered to residents of the state of Hawaiʻi, by a third party vendor contracted with the Hawaiʻi Department of Health, to households with landline phones. Survey data were gathered on 24,642 people in 8503 households statewide. Questions about pelvic pain were added to the annual Hawaii Health Survey. Non-pregnant women household responders, over the ages of 18, were surveyed to assess the 3 month cross-sectional prevalence of chronic pelvic pain. Chronic pelvic pain is defined as pain below the belly button or in the female organs for more than 6 months. Those who reported chronic pelvic pain were surveyed on severity, frequency, diagnosis, and treatment. The data were weighted to account for age, gender, island location, and ethnicity. Results: All data is reported weighted to represent the general population. The survey data were weighted to represent 957,540 household members, reflecting the general population of Hawaiʻi. Forty-nine percent were male and 51.1% were female. The mean age of non-pregnant female adult respondents was 49.7 years old (SD 18.0). Of the 488,833 adult women, 10,404 (2.1%) were pregnant and 477,996 (97.8%) were not pregnant. In the last 3 months, 34,210 (7.2%) of the non-pregnant adult women surveyed responded yes to having pelvic pain. Of these, 13,449 of women responded yes to having the pain for more than 6 months. The prevalence of chronic pelvic pain was 2.8%. The mean pain score was 5.95 out of 10 (SD 2.50). Most women were not given a diagnosis, but the most common pathological diagnosis cited was endometriosis (11.3%). Though most women 10,553 (79.9%) did not miss any work, 9.1% missed less than 5 days of work, and 10.7% missed from 5 days to more than 15 days of work due to pelvic pain the previous 3 months. Twenty percent (2,580) rated themselves as fully productive, but 21% rated themselves with very low productivity, when having pelvic pain. African-American/Black (10.4%), Hawaiian (5.0%), and Caucasian/white (3.4%) were the ethnicities with the highest prevalence of chronic pelvic pain. And Chinese (1.7%), Japanese (1.1%), Other (1.3%), Asian (0.6%), and Samoan (0.4%) were below the mean prevalence of CPP. Vietnamese, Other Pacific Islander, Korean, and Asian Indian had no primary respondents who had CPP. When adjusting for age, marital status, weight, and menopausal status, African Americans (332% increased risk) and Hawaiians (27.5% increased risk) had the highest increased risk of CPP compared to Caucasians. Being in an unmarried relationship or divorced increased a woman's risk of having CPP by 8% and 10%, respectively. Being menopausal had a variable impact on risk of CPP depending on other confounding factors, and educational status was not significant for CPP. Conclusions: Chronic pelvic pain has a lower rate of prevalence at 2.8% than found nationally. African Americans and Hawaiians are at a greater risk of having CPP in the state of Hawaii. CPP results in missed days from work and adversely impacts work productivity. Hawaiians appear to be at greater risk of using more health care resources when having CPP. Additional investigations are needed to develop management approaches for this health disparity.
The relationship of 5-aminolevulinic acid on mood and coping ability in prediabetic adults
(University of Hawaii at Manoa, 2014-12) Gonzales, Rachael May K.
In the U.S., diabetes affects 25.8 million Americans (CDC 2011). The most effective diabetes prevention method in prediabetic individuals is lifestyle modification (Tabak, Herder et al. 2012). Despite the benefits of lifestyle change, diabetes prevalence continues to increase (CDC 2012). This may be because of the many emotional barriers that a prediabetic individual faces when it comes to starting an exercise routine and a healthy eating plan. A potential treatment for the emotional obstacles that prediabetic adults may face is a natural supplement called 5-aminolevulinic acid (5-ALA). In the current study, the group included 154 participants, both men and women, ranging between the ages of 41 to 71 years old. The study design was a double-blind, randomized parallel-group study. The Psychosocial Depression Symptoms Questionnaire (PDS) and the Perceived Stress Scale (PSS) were used to examine the relationship of two doses of 5-ALA (15mg and 50mg) with mood and coping ability. Using SAS software, an ordered logistic regression model was used to analyze the association between the dose groups (control, 15mg, and 50 mg) and responses to the two questionnaires. An integrative literature review, using the PubMed database, of the relationship between 5-ALA administrations and mood and coping ability was performed. First, our literature review resulted in zero published articles. Second, utilizing the two questionnaires, the intake of 5-ALA was found to be associated with significantly improve self-perception of effort spent (p = 0.002) and coping ability (p = 0.004). Finally, a significant dose-dependent relationship was found for the association of 5-ALA intake on measures of effort (p = 0.003), loneliness (p = 0.006), and coping ability (p = 0.003). The 50mg dose was more effective than the 15mg dose in improving these measures. In conclusion, we report that after 12 weeks of taking 5-ALA, self-perception of effort spent, loneliness, and coping ability were associated with improvements in a group of prediabetic adults. Improved mood and coping ability may enable prediabetic individuals to overcome the emotional obstacles preventing them from maintaining a healthy lifestyle and avoiding the development of diabetes.
Cortical atrophy and white matter hyperintensities in HIV infection
(University of Hawaii at Manoa, 2008) McMurtray, Aaron
Background: In normal elderly individuals (age greater than 65 years) presence of brain white matter hyperintensities is associated with cortical atrophy, particularly of the frontal lobes. As HIV-seropositive individuals experience increase longevity due to highly active antiretroviral therapy it is likely they will also develop typical aging related changes in brain structure such as white matter hyperintensities. The aim of this study was to determine the relationship between white matter hyperintensities and brain cortical gray matter volumes in human immunodeficiency virus, type 1 (HIV) seropositive individuals. Methods: Voxel-based-morphometry was used to compare cortical gray matter volumes between 62 HIV seropositive participants in the Hawaii Aging with HIV cohort study, 30 with moderate brain white matter hyperintensities and 32 with minimal or no white matter hyperintensities. The Hawaii Aging with HIV Cohort study included two groups of HIV seropositive individuals, an older group comprised of individuals with age greater than 50 years old, and a younger group comprised of individuals with age from 20-39 years old. Results: Presence of moderate brain white matter hyperintensities was associated with decreased cortical gray matter volumes in the frontal lobes bilaterally (p < 0.05) in HIV seropositive individuals. Conclusions: The findings of this study suggest that presence of moderate brain white matter hyperintensities is associated with frontal lobe cortical atrophy in HIV seropositive individuals. These results are supportive of the hypothesis iv that the frontal lobes have greater susceptibility to the effects of small vessel ischemic vascular disease than other brain regions.
Activated macrophages: implications in HIV-associated disease pathogenesis
(University of Hawaii at Manoa, 2005) Killebrew, Deirdre Anne
Cloning of the pmb gene encoding a basic amino acid transport protein in Neurospora crassa
(University of Hawaii at Manoa, 1993) Han, Hyo-Young
Neurospora crassa is known to possess at least six genetically and biochemically distinct amino acid transport systems; three constitutive amino acid permeases and three specialized amino acid permeases. The constitutive permeases include a neutral amino acid-specific system (N system), a basic amino acid-specific system (B system), and a general system (G system) that can transport neutral, basic, and acidic amino acids. We have cloned the pmb gene which codes for a component of the B system. A Neurospora crassa triple mutant (pmn:pmb:his-2 ) was constructed from previously described mutants. This strain is suitable for use as a host strain in a transformation procedure for selecting DNA from the wild type pmb locus. Protoplasts of the pmn:pmb:his-2 strain were prepared and transformed by sib selection with DNA fragments from cosmid library pools of wild type Neurospora crassa. One cosmid (pMOcosX-X7:5E) complemented the pmb mutant allele and was confirmed to be tightly linked to RFLP (Restriction Fragment Length Polymorphism) markers flanking the pmb locus on linkage group IV. A subclone of the pMOcosX-X7:5E cosmid, pB22-22 (3.2Kb), complemented the pmb mutant allele and was mapped with restriction enzymes. The subclone hybridizes to RNA transcripts 3.5Kb in size on Northern blot experiments. The subclone pB22-22 has been sequenced and the pmb portion of the sequence containing a promoter initiation site has been analyzed; it has two CAAT motifs at -166 and -155 when positions are given in base pairs (bp) from the A(+1) of the proposed translational start: a TATA motif is located at -123. There are two CT-rich regions; one is from -117 to -106 (l2bp length) and the other is from -50 to -23 (28bp length) containing 83% of and 75% of pyrimidine bases each. The promoter site of the pmb locus contains sequences for binding motifs of CPC-l (cross-pathway control protein) at upstream and downstream of the translation start point. This suggests that the pmb gene is regulated by the cpc-1 gene.
Structure-function relationship of the sodium channel rat brain IIA
(University of Hawaii at Manoa, 1993) Fleig, Andrea
Sodium channels are voltage-gated transmembrane proteins propagating electrical signals in neurons, heart and skeletal muscle cells. Cloning and subsequent expression in heterologous systems has yielded structure-function information about wildtype and mutant Na channels. The protein's a. subunit has four homologous and highly conserved domains (I-IV), each consisting of six transmembrane segments. The fourth segment (54) of each domain carries evenly spaced and positively charged amino adds and has been proposed to function as voltage sensor. The patch clamp technique was used to investigate Na channel mutations that substitute or screen a IIS4 charge in excised membrane patches from Xenopus oocytes expressing channels encoded by wildtype rat brain TIA (RBIIA) or single-point mutation cDNAs (K859Q or L860F). Since Na channels were expressed from singular mRNA, they are presumed to represent a single, homogeneous population. However, the initial characterization of wildtype Na currents revealed an unexpected behavior: After excision of membrane patches from the cytosolic environment, there was a unidirectional and time-dependent transition in channel inactivation from slow to fast kinetics, paralleled by alterations in voltage dependence. This suggests that a single sodium Na channel can adopt at least two distinguishable gating modes, whose equilibrium may be modified by biochemical processes. Moreover, Na channel characteristics were affected by modification of the molecular structure in the point mutations K859Q and L860F. Both mutants induce similar shifts in the current-voltage relationship and L860F affects the valence of activation. In addition, steady-state inactivation curves and kinetic rates of activation and inactivation differ considerably. These results challenge the notion that 54 segments exclusively control the activation of Na channels. Rather, it seems that specific locations within the protein may affect multiple features of Na channel function.

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