M.S. - Biomedical Sciences

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Anal dysplasia screening and human papillomavirus characterization by Raman-enhanced spectroscopy in individuals infected with human immunodeficiency virus
(University of Hawaii at Manoa, 2022) Nagata, Michelle; Lim, Eunjung; Agsalda-Garcia, Melissa; Biomedical Sciences
Background: People living with human immunodeficiency virus (PLHIV) are at increased risk for developing anal cancer and anal dysplasia due to persistent infection by high-risk human papillomavirus (HPV). It is recommended they undergo anal cancer screening with anal cytology and, if abnormal cytology is reported, a more invasive high-resolution anoscopy (HRA) to obtain biopsies for definitive diagnosis. However, HRA and biopsy are invasive, and variable sensitivity and specificity have been reported for both anal cytology and HRA with biopsy. Raman-enhanced spectroscopy (RESpect), a noninvasive laser-based technology that characterizes the chemical and molecular composition of cells and tissues, has demonstrated the potential to improve current standards of anal cancer screening. The feasibility of translating RESpect clinically relies on consistent Raman-based characterization of dysplastic anal tissues and a positive control for squamous epithelial carcinoma. By comparing the spectral profiles of anal tissues biopsied from PLHIV and cervical carcinoma cell lines acquired by RESpect microscope (micro-Raman) and portable RESpect probe instruments, this study evaluates the clinical potential for RESpect probe screening as a real-time, noninvasive supplemental tool in detecting anal dysplasia. Methods: Participants being evaluated for anal cancer screening at the Hawai‘i Center for AIDS clinic were recruited following guidelines approved by the University of Hawai‘i Institutional Review Board. Anal cytology was followed by HRA and biopsy to obtain two tissue samples from the same location: one specimen for RESpect analysis and one specimen for pathology assessment. The tissues for RESpect analysis were cut into two before mounting onto reflective aluminum slides for spectra acquisition by the micro-Raman and RESpect probe instruments. HeLa and SiHa cervical carcinoma cell lines were similarly mounted and analyzed by micro-Raman and RESpect probe. Following baseline correction and smoothing, spectra were averaged to produce a representative spectrum of each cell or tissue specimen and normalized. Averaged spectra representing negative, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) pathologies were visually inspected to identify significant differences in intensity, as determined by a two-sample t-test. To determine the feasibility of using HeLa and SiHa cell lines as positive controls of HPV-infected squamous epithelial carcinoma, peak differences identified by visual inspection of HeLa and SiHa spectra were compared to the peaks distinguished in anal tissues. Results: Forty-three participants were enrolled to date. Overall agreement between cytology and biopsy results was 71%, with Cohen’s kappa (κ) = 0.484 (95% CI: 0.266–0.741) indicating moderate agreement. Comparison across pathologies (26 negative, 12 LSIL, and 5 HSIL) revealed spectral differences. Based on visual observation, LSIL and HSIL tissues demonstrated averaged spectra closer to each other than to negative tissue. Significant peak differences (p < 0.2) between tissue pathologies were found at three regions in both the micro-Raman and RESpect probe spectra. Between cervical carcinoma cell lines, SiHa cells generally exhibited a higher intensity than HeLa cells, and peak differences were observed at six spectral regions, with a consistent peak difference at 1554 cm–1 corresponding to amide II distinguished in both cells and tissues. Conclusion: Peak differences elucidated from micro-Raman and RESpect probe spectral fingerprints of anal tissues and cervical carcinoma cell lines demonstrate the potential of RESpect to distinguish between pathology grades and support the integration of RESpect technology into the anal cancer screening paradigm. Previous studies have demonstrated similar differences between normal and dysplastic/cancerous cervical tissues at peaks associated with amide as well as similar agreement between cytology and biopsy results. These findings lay the foundation to consider RESpect as a real-time, noninvasive screening tool for further exploration.
The Impact Of Diet Quality On Microbial Diversity Throughout Pregnancy In An Ethnically Diverse Cohort In Hawai‘i
(University of Hawaii at Manoa, 2020) Miller, Corrie; Lee, Men-Jean; Biomedical Sciences
AbstractBackground: The gastrointestinal (GIT) microbiome influences metabolism and modulates inflammation during pregnancy, influencing energy regulation, gestational weight gain, and risk of adverse pregnancy outcomes. Manipulating the GIT microbiota has been an area of earnest research interest, with hopes that manipulating an aberrant microbial community may translate to improved pregnancy outcomes. While some dietary patterns have been associated with improved GIT microbial health, few studies have investigated the impact of comprehensive diet quality on this outcome. Our study aimed to associate Diet Quality as defined by the Healthy Eating Index (HEI) with alpha diversity metrics longitudinally across pregnancy in healthy, low risk pregnant women. Methods: Forty-one women were recruited, from the 4 largest ethnic groups in Hawaii. Participants completed Food Frequency Questionnaires (FFQs) during each trimester (12 weeks, 20 weeks and 34-36 weeks), to which HEI Diet Quality Score was assigned. Rectal swabs were collected concomitantly at each time point, from which DNA extraction and 16s rRNA sequencing were performed. Alpha and beta diversity profiles were assigned, and correlated in a linear fashion with HEI Score. Linear regression was also used to account for confounding demographic factors. Results: HEI score did not correlate with any alpha diversity metrics. Those with the highest HEI score had greater amounts of lactobacillaceae (not significant), and several species were associated with higher diet quality. Native Hawaiians had the highest HEI score compared to Filipina participants, and had higher amounts of Acidaminoaceae and lactobacillaceae, respectively. There were no differences observed with microbial diversity among the 4 ethnic groups. All alpha diversity indices decreased from the first to third trimester, as expected from published literature in other cohorts. Conclusion: Alpha diversity decreased throughout pregnancy in this cohort, commensurate with other studies. Hormonal changes of pregnancy had the largest influence in change over time of microbial composition in this cohort, greater than dietary intake, ethnicity, body mass index, or parity.
Defining role of different virus sensing pathways in modulating ZIKV replication in human Sertoli cells
(University of Hawaii at Manoa, 2020) Jiyarom, Boonyanudh; Verma, Saguna; Biomedical Sciences
ZIKV is shown to establish persistence in the testes; however, the mechanisms remain undefined. We recently demonstrated that ZIKV was able to replicate and persist in human Sertoli cells (SC), an important cell type of seminiferous tubules. In addition, our host transcriptomic data predicted RIG-I and TLR3 as the top virus sensing pathways modulated in SC, however the specific role and efficiency of these pathways in controlling ZIKV is not yet determined. Here, we elucidate the impact of blocking these critical antiviral pathways on ZIKV replication. TLRs and RLRs were inhibited using siRNA or small molecule inhibitors in SC and infected with ZIKV PRVABC59. A549 cells were used as controls in some experiments. Data demonstrated that the independent inhibition of both RIG-I and MDA5, but not TLR3 nor TLR7 signaling increased ZIKV replication. Gene expression of IFNβ showed no change in both siMDA5 and siRIG-I SC, however, there was a reduction in the activation of IRF3 and MXA expression in these PRR deficient SC. Further, we observed that exogenous IFNβ treatment significantly reduced ZIKV titers in SC that was comparable to A549, thus indicating that IFN signaling is active in SC. To delineate the crosstalk of PRRs with other immunosuppressive pathways in the testes, SC were pretreated with TGFβ superfamily members molecules (TGFβ, Activin A, and BMP6) and virus titers measured. We first showed that ZIKV does not induce changes in TGFβ and Activin A mRNA expression. Additionally, there was no change in ZIKV titers in TGFβ and Activin A treated SC. However, ZIKV downregulated BMP6 at later time points of infection and the exogenous BMP6 treatment decreased ZIKV in these cells SC. Interestingly, treatment of BMP6 resulted in an increased in both RIG-I and MDA5 in ZIKV infected SC at 120hpi. Our data suggest that downregulation of BMP6 and downstream signaling by ZIKV at later stages of infection may modulate functioning of antiviral response and facilitate virus persistence. Collectively, these results fill in gaps in our understanding of the antiviral signaling mechanisms underlying ZIKV infection and persistence in human testes.
Developing a Predictive Model for Measuring Health Literacy in Hawaiʻi’s Adult Populations
(University of Hawaii at Manoa, 2017-08) Lubimir, Karen T.; Biomedical Sciences
Background: Adequate health literacy is necessary to effectively participate in one’s own health care, yet many American adults lack the health literacy skills to navigate the US health care system. Lower health literacy has been associated with poorer health status, higher health care utilization, and greater health disparities in studies conducted both nationally and in Hawai’i. Other factors associated with inadequate health literacy include older age, immigrant status, ethnic minority status, poverty and fewer years of education. Successful health interventions aimed at reducing disparities and improving health outcomes should be based on adequately identifying the unique characteristics of the population, including health literacy skills. Direct measurement of health literacy is labor intensive and controversial, hindering its study in population-based research. National health literacy predictive models have been developed to help address this problem. To date, the applicability of national health literacy predictive models in Hawai’i’s ethnically diverse population has not been studied. Objective: To identify demographic variables associated with low health literacy and develop a multivariable predictive model for low health literacy in Hawai’i’s adult population. Methods: We completed a cross-sectional analysis of a representative sample of Hawai’i’s adult population from the annual telephone based Hawai’i Health Survey (HHS) data, years 2008 and 2010. The sample included 11,941 respondents. Descriptive analysis was used to identify individual socio-demographic variables associated with low health literacy. Predictors included age, gender, marital status, educational attainment, race/ethnicity, insurance status, poverty status, rural residence and migration status. We used multivariable logistic regression models, Thesis: Developing a Predictive Model for Measuring Health Literacy in Hawai’i’s Adult Populations Karen T. Lubimir, Candidate for Masters in Clinical Research including sub-group analysis for age over 65 years and migration status, to predict the probability of inadequate health literacy. Results: In the descriptive results, 18% had low health literacy, which was significantly associated with extremes of age (<25 or >84 years old, compared to those ages 25-64 and 64-84 years old ), less than high school education (compared to high school graduates or post high school education), non-white ethnicity, being poor, lack of health insurance, rural residence, and being born outside the U.S. (p<0.01). In the multivariable logistic regression model with the full population, Chinese, Filipinos, Japanese and Pacific Islanders were significantly more likely to have low health literacy compared to whites, even after control for the socio-demographic factors of education, poverty, insurance and rural residence. In the models including migration status, controlling for socio-demographic factors, low health literacy was associated with non-U.S. born, rural residence, lacking health insurance and Hawaiian, Chinese, Filipino, Japanese and “Other” ethnicities (p<0.05). Within the age 65+ year models, only age 85+ years and Pacific Islander ethnicity had increased odds for low health literacy (p<0.05). Across all models, those with less than high school education had twice the odds of having lower health literacy compared to those who completed high school or post-secondary education (p<0.02). Predictive accuracy for all models achieved AUROC between 0.624-0.689. Conclusions: Several of Hawai’i’s Asian American and Pacific Islander ethnic groups have significantly lower health literacy compared to White residents. Based on comparison of Hawai’i and national models’ statistical results, this study found a lack of predictive accuracy for Hawai’i health literacy models, patterned after national models, when applied to Hawai’is’ adult Thesis: Developing a Predictive Model for Measuring Health Literacy in Hawai’i’s Adult Populations Karen T. Lubimir, Candidate for Masters in Clinical Research population. A locally derived multivariable model may lead to better detection of community specific information than using individual predictors of low health literacy, and could supply Hawai’i’s healthcare stakeholders with an additional tool to help focus health interventions.
Effects of the Accessory Infraorbital Nerve and Foramen on the Morphology of the Infraorbital Nerve and Foramen
(University of Hawaii at Manoa, 2016-12) Polo, Carolina
Title: Effects of the accessory infraorbital nerve on the morphology of the infraorbital nerve and foramen Problem: Anatomical variations of the infraorbital neurovascular bundle are frequently encountered during a host of oral surgical procedures involving the infraorbital region. The accessory infraorbital foramen (AIOF) and its nerve (AION) are variable, but clinical implications are common and include failure of loco-regional anesthesia, risk of neural damage, or hemorrhage following surgical interventions particularly involving the infraorbital nerve (ION) and foramen (IOF). Thus, morphological characterization of the AIOF and AION and relationships to the IOF and ION are essential for optimizing oral surgical procedures. Additionally, predictive features of the AION based on its relationship to ION morphology could facilitate predictive capabilities enabling the surgeon to anticipate its presence and proceed accordingly Purpose: The purpose of this study is to determine whether the presence of an AION affects the size, shape and composition of the infraorbital foramen and nerve. The specific hypothesis tested is that the topography and morphology of the ION and IOF differs between individuals possessing an AION and those lacking this anatomical variant. Data will serve to determine the potential field of innervation of the ION with and without the presence of AION and identify potential morphological correlates between ION and AION features. Procedure: Gross topographic features of IOF (84 hemifaces) were compared between specimens possessing (test) or lacking (control) an AIOF. Nerve fascicle features of ION (60 cadaveric sides) were examined histologically and compared morphometrically between specimen with or without an AION. Results: Occurrence of AIOF was determined as 47.6% of the skulls (20 crania), but only 32.1% of the sides (27 sides). A single AIOF was observed in 24 sides and double AIOF in 3 sides. AIOF occurred bilaterally in seven specimens (16.7%). The majority of AIOF (86.7%) were located superomedial to IOF, but overall a heterogeneous direction of the canal leading to AIOF was noted. A higher frequency of AION was found in left side compared to the right. The number and area of nerve fascicles were determined histologically. The size of the ION without an AION was not significantly different than the ION with AION (1.45x106/1.32x106, p < 0.35). However, the number of ION fascicles was greater in specimens without and AION compared to those with an AION (15.15/12.71, p <0.04) Conclusions: The data indicate that the area of the ION is not affected by an AION, suggesting that the field of innervation of this area will not be modified However the ION appears to divide more proxima in the cases when the AION is present.
Morphological Study of the Human Hyoid Bone in Cleft Lip and Palate Patients
(University of Hawaii at Manoa, 2016-08) Abdelkarim, Ahmed
Qualitative assessment of 3-D reconstructions derived from MRI and CT imaging technologies is critical for the diagnosis and treatment of patients with cleft lip and palate (CLP). However, rapid and reliable quantitative assessment remains elusive. This is particularly true for the analysis of regional deficiencies in morphology of CLP patients. Recent interest has focused on the morphology of the hyoid region of CLP patients since this area is derived from pharyngeal arch 2 and may be indirectly affected by the deficiency in the primary palate derived from pharyngeal arch 1. The objective of this study is to develop and apply novel morphometric methodology to quantitatively assess hyoidal morphology in CLP patients. The hypothesis to be tested is that CLP patients display hyoidal regions that differ quantitatively from patients lacking CLP. Five geometric models with known parameters were designed to simulate size and shape descriptors and used to test the precision and accuracy of ER3D. Cone beam computed tomography (CBCT) images derived from CLP patients as well as patients lacking CLP and these were utilized to generate 3D reconstructions of the hyoidal region in corresponding individuals and compared utilizing affine and non-affine methodologies.. Anatomical landmarks were determined and digitized on the model. Results showed significant accuracy of ER3D morphometric analysis with respect to volumetric and linear measurements and proved the ability of the software to quantitatively record changes in size and shape. For the hyoid models, CLP individuals mostly displayed affine hyoidal changes relative to controls since the defect likely causes size reductions in affected individuals. Non-affine changes were consistent among CLP subjects and were characterized as changes in position with respect to controls rather than shape change. Interestingly, female controls revealed a high degree of diversity compared to both male controls and all CLP groups. These data suggest that the hyoidal region is affected as a result of CLP, but the difference is dominated by size rather than shape change.
Hospitalization Predicts Functional Decline in Nursing Home Patients
(University of Hawaii at Manoa, 2016-05) Takenaka, Cody
Objectives: According to CMS data, a higher percentage of nursing home (NH) patients in Hawaii demonstrated functional decline than the national average. We examined the effects of hospitalization on functional and cognitive decline in elderly NH patients. Design: Longitudinal observational study. Setting: A 170-bed hospital-affiliated NH in Honolulu, Hawaii. Participants: All patients admitted to the study NH between January 2003 and December 2006 (n=238) and followed from admission until discharge or death through 6/30/2011, using Minimum Data Set (MDS) assessments, NH and hospital medical records. We excluded patients with total Activities of Daily Living (ADL) dependence or severe cognitive impairment (Cognitive Performance Scale CPS=6) at baseline. Measurements: Our primary outcome was change in function, measured by the MDS-ADL scale (range 1-28, higher=more disability) from admission and quarterly assessments. Our secondary outcome was change in cognition, measured with the MDS-CPS (range 0-6, higher=more cognitive impairment). For all patients, functional and cognitive decline over time was analyzed using multivariable linear regression analyses. Subgroup analysis examined those with at least one hospitalization and MDS data before and after hospitalization for within-person pre/post-hospitalization changes in ADL and CPS scores without covariate adjustment. Results: After exclusions, our analytic sample included 147 patients. Mean age was 82.9 years, 36.1% were male and 91.5% were Asian. Mean baseline ADL score was 18.2 (SD 5.4) and mean baseline CPS score was 2.9 (SD 1.4). Mean follow-up time was 1.5 years (SD 1.2). Linear regression adjusting for Charlson Comorbidity Index showed increased ADL disability (2.9 points, 95%CI(2.13, 3.78), p<0.001) after hospitalization, with slight decreased disability by the 2nd MDS after NH readmission (-2.01, 95%CI(-1.35, -2.67), p<0.001). CPS score worsened by 0.47 (95%CI(0.28, 0.65), p<0.001). On within-person comparisons, ADL disability increased by 4.5 points (95%CI(4.3,5.8), p<0.001) after hospitalization, with slight decreased disability by the 2nd MDS assessment after NH readmission (-1.6, 95%CI(-3.2,-0.1), p=0.04). CPS score worsened by 0.7 points (95%CI(0.4,1.1), p<0.0001). Conclusion: Hospitalization was significantly associated with increased functional decline among elderly NH patients, with slight improvement after readmission to the NH. Treatment of acute illness in the NH should be included as an option during goals of care discussions.
Association between Oxytocin Use during Dilation and Evacuation and Estimated Blood Loss
(University of Hawaii at Manoa, 2015-08) Whitehouse, Katherine
Objectives: Many providers use oxytocin during dilation and evacuation (D&E) to prevent or treat hemorrhage. Evidence to support this practice is scarce. We sought to describe the association between oxytocin use, estimated blood loss (EBL), and surgical outcomes during D&E. Study Design: Women undergoing D&E (≥14 weeks) between 2010 and 2014 were included in this retrospective cohort study to assess the association between oxytocin use and EBL. We also determined whether sociodemographic and health-related factors were associated with higher EBL and whether oxytocin use was associated with a lower complication rate. Mean EBL was compared with a t-test. Excessive blood loss, defined as EBL at or above 250 ml, demographics, and complications were compared with a chi-square and Fisher's Exact tests. Logistic regression was performed. Our database, which included 649 women undergoing D&E, had the ability to detect a 7.5% difference in excessive blood loss. Results: Oxytocin was used in 68.3% of the procedures. Asian (p= 0.02) and Native Hawaiian/Pacific Islander (p=0.03) race, abortion indication (p=0.008) and higher gestational age (p<0.001) were associated with osytocin use. Mean EBL [133.1 (sd=133.9) ml versus 105 ml (73.8), p<0.001] and excessive blood loss (11.1% vs. 4.9%, p=0.01) were higher in the oxytocin group. No significant difference in complication rates emerged (4.7% with oxytocin vs. 4.4% without, p=0.579). The adjusted OR for excessive blood loss was 1.61 (95% Cl 0.77, 3.77) when women received oxytocin. Conclusions: Oxytocin use during D&E did not have a significant association with surgical outcomes including EBL and complications in our population. Implications: Routine use of interventions for bleeding, such as intravenous oxytocin, should be based on scientific evidence or not performed. Findings from our study provide information on how oxytocin use is associated with blood loss during D&E.
Polymorphisms in Kynurenine Pathway Genes and Psychological Distress in HIV Patients
(University of Hawaii at Manoa, 2015-08) Tanizaki, Naomi
Background: HIV infection, neuroinflammation and psychopathology are each associated with imbalances in the kynurenic pathway (KP), which includes kynurenine-3-monooxygenase (KMO) and kynurenine aminotransferase II (KATII). Both KMO and KATII enzymes mediate levels of kynurenic acid (KYNA), which increases with HIV infection, and may decrease with psychopathological symptoms such as depression. Since people with HIV are more vulnerable to neuroinflammation and comorbid depression, variations in the genes of these enzymes may influence psychopathological symptoms in HIV. Methods: 72 HIV seronegative (SN) and 72 HIV positive participants were evaluated using the Center for Epidemiologic Studies Depression and Symptom Checklist-90-Revised scales, and were genotyped at KATII rs1480544 at KMO rs1053230. Cerebrospinal fluid kynurenic acid concentration [KYNA] was measured in 51 SN and 49 HIV participants. T-test, and one-way and two-way AN(C)OVA were used to compare effects of genetic variation and HIV status on psychological symptoms or KYNA levels. Pearson or Spearman analyses was used to find correlation between psychopathological symptom scores and KYNA levels. Results: For psychopathological symptoms, overall, HIV participants had higher scores than SN, and SN KATII C-carriers tended to have lower scores than SN TT homozygotes. Older age correlated with higher CSF [KYNA] in KATII C-carriers and KMO CC-homozygotes independently of serostatus. HIV participant psychopathological scores did not differ between KMO genotypes. Conclusions: KATII genotypes and HIV serostatus were associated with psychopathological symptoms. Furthermore, CSF [KYNA] varies with age depending on both KMO and KATII genotypes. Together, this supports a functional role of these variations in the dysregulation of the KP that may moderate psychopathological symptoms in HIV and SN individuals. Understanding the KP mechanisms in HIV may lead to novel treatments for psychopathological symptoms.
Family History of Substance Use Problems on Cortical Morphometry in Healthy Children
(University of Hawaii at Manoa, 2015-08) Lee, Kristin
Background Common structural brain abnormalities reported in substance use related (SUD) related regions were found in children with family history (FH) of SUD. However, the effect of FH-degree of SUD is not well examined. Therefore, the influence of degree of FH of substance use problems (SUP) on cortical morphometry was investigated. Methods 921 typically developing children (ages 3-20 years old; 470 boys/451 girls) had structural MRI and executive functions measures. The influence of first and/or second-degree FH (Any-FH) and the separate effects of first-degree (First-FH) and second-degree FH of SUP (Second-FH) on cortical structures were investigated using FreeSurfer. The relationships between FH related cortical alterations and executive functioning were examined. Sex interactions with FH-degree on cortical morphometry were also investigated. Results Any-FH children had volume alterations mediated by changes in surface areas. FH children have larger left prefrontal and right superior areas and volumes when compared to No-FH children. First-FH and Second-FH show a variable effect on cortical volumes particularly for regions in the posterior frontal and anterior parietal regions as well as the right fusiform gyrus. Sex differences for cortical morphometry between First-FH and Second-FH children were widespread, but strongest in the left frontal regions. The left supramarginal and right fusiform gyri, regions specifically reduced for First-FH children, were also related to differential executive functioning and this same association was found in First-FH girls. Importantly, the majority of results remained even when controlling for confounders such as ADHD. Conclusion The children with FH of SUP have overall differences in prefrontal regions. First-FH and Second-FH children showed different morphometric alterations in parietal and temporal regions, which may contribute to deficits in executive function. Further studies are need to explore the sex-specific influences in cortical morphometry of children with FH of SUP, and the possible consequences on cognition.
Motor Development and Subcortical Brain Volumes in Children Prenatally Exposed to Methamphetamine and Tobacco
(University of Hawaii at Manoa, 2015-08) Fukaya, Erin
Introduction: Methamphetamine use is a significant health concern, and doubly so for pregnant women who expose their fetuses during the prenatal period. Such prenatal methamphetamine exposure (PME) is associated with neurological alterations with developmental deficits seen clinically. This study investigated subcortical brain volume and motor development in children who were prenatal tobacco exposed (PTE), and both prenatal tobacco and methamphetamine exposed (PTE+PME). As adults often abuse both drugs concurrently, this study explored the combined influence of prenatal methamphetamine and tobacco exposure. Method: The Movement Assessment Battery for Children-2 was used to assess motor skills in three domains: Manual Dexterity, Aiming and Catching, and Balance. These three domains were then combined to calculate an overall global score. Scores of 32 PME+PTE, 26 PTE, and 116 unexposed control (CON) children were compared. A subset of participants was also evaluated with brain MRI Scans. 27 PME+PTE, 11 PTE, and 19 CON were scanned on a Siemens 3.0 Tesla TIMTrio MR System. Brain images were analyzed using FreeSurfer 5.1. Results: PTE children scored poorer than CON on Manual Dexterity, especially on the trail making task. PME+PTE children scored poorer than CON on Balance domain, including two tasks, balance board and jumping. The three groups were not different on Aiming and Catching. On brain imaging, PME+PTE children had smaller caudates and tended to have smaller ventral diencephalon and right globus pallidus compared to CON. Smaller caudates and right globus pallidus were associated with lower balance scores. Conclusions: Findings suggest that PME+PTE may negatively impact gross motor skill development, while PTE alone may negatively influence fine motor skill development. Smaller subcortical volumes in children with PME+PTE compared to unexposed CON are consistent with prior reports. Correlations between smaller brain structures and lower MABC-2 scores suggest that brain morphometry may predict developmental outcome.
Role of Γ-H2AX in DNA damage response
(University of Hawaii at Manoa, 2011-12) Sil, Payel
Little is known about the molecular mechanism of γ-H2AX in DNA damage response in mammalian embryos when compared to the somatic cells. An integrative review of the literature on the molecular mechanism of γ-H2AX in DNA damage response in somatic cells and in mammalian embryos was performed. The objective of the study is to summarize and synthesize the published databased literature over the last 10 years on molecular mechanism of γ-H2AX in mouse pre-implantation embryos and somatic cells using the key words--"γ-H2AX", "DNA damage", "somatic cells", "mouse embryo". An initial medline search was performed using our inclusion and exclusion criteria and then expanded by snowballing. The articles were compiled in the form of a Review Matrix. The knowledge gap was investigated and the conceptual model was formulated to hypothesize the sequence of DNA damage responses occurring during the time of early mouse embryogenesis. Major themes drawn from the studies are-1). Periodic appearance and disappearance of γ-H2AX in early mouse pre-implantation embryos, 2) Development of γ-H2AX foci in the pronuclei without imposing any replicative stress on the mouse embryo, 3) Occurrence of γ-H2AX in the S-phase of somatic cells under replicative stress and normal embryos, 4) Prevalence of prominent γ-H2AX signal in male pronuclei compared to the female pronuclei during mouse embryogenesis. The study will also show scopes of future research to explore the arena in clinical context.
Prevalence and risk factors for pre-hypertension among adolescents exposed to volcanic air pollution on Hawaiʻi Island
(University of Hawaii at Manoa, 2011-12) Rudnick, Judith Renee
We tested the hypothesis that exposure to volcanic air pollution (vog) is associated with elevated blood pressure (BP) in a cohort of Hawaii Island school children. Between September, 2009 and May, 2010, we measured BP in 807 participants enrolled in the Hawaii Island Children's Lung Assessment Scientific Study (HICLASS). The initial cohort of 1,986 children had been recruited in 2002-2003 from 29 Hawaii Island schools in areas with different vog exposure. Data were analyzed by uni-and multivariate logistic regression models. The mean age was 17; 51% were boys; 62% were of more than 1 race; mean BMI was 24.3 (125 had BMI>30); 32% reported asthma; 56% reported exposure to environmental tobacco smoke (ETS). Vog exposure (n) was categorized as low (168), intermittent (263), SO2 (48), or acid (328). The mean BP was 119/70 and the prevalence of BP>120/80 was 8.9%. Univariate analysis showed an association with male gender (OR 3.5, p<0.005) and obesity (OR 4.7, p<0.05), but not with vog or ETS. Multivariate analyses run separately for boys and girls (adjusting for race, BMI, asthma, tobacco smoke exposure) showed no association between BP>120/80 and vog exposure, but a strong association with obesity in both boys and girls. This study was limited by a single measurement of BP in a cross-sectional design. Longitudinal follow up, addressing obesity and other risk factors will be important to understand the relative contribution of vog and other factors in developing hypertension.
Fractures and mortality among elderly Japanese-American men living in Hawaii: the Honolulu heart program
(University of Hawaii at Manoa, 2011-08) Murakami, Satona
The risk and cost of osteoporotic fractures is steadily rising. With longer life expectancies and population growth of older people, the situation will only get worse. Most osteoporosis and fractures studies have focused on postmenopausal women because of the higher incidence of fractures related to a significant decrease in bone density after menopause, combined with a longer life expectancy of women. This has resulted in limited data related to fractures and subsequent mortality among elderly men. The purpose of this study is to examine the relationship between hip, spine, and forearm fractures as predictors of total mortality among elderly Japanese-American men, participating in the Honolulu Heart Program. The data from the Honolulu Heart Program (HHP)/Honolulu Asia Aging Study (HAAS) Exam4 (1991-1993) was used as the baseline, with the death of subjects being tracked though the year 2000. The average age, among the 3,845 male participants, was 77.9 years at baseline. A history of previous hip fracture was a predictor of total mortality, the risk was comparable to the mortality rate associated with being a current smoker. Anthropometric measurements including taller height, lower weight, lower BMI, higher WHR and lower grip strength of participants in their 70s, were associated with a higher risk of mortality after a hip fracture. The study suggests that interventions to retain muscle strength in midlife and in the elderly, may be helpful in preventing fractures and related deaths.
Thyroid cancer in Hawaii: concern for ethnic disparity in the Filipino population
(University of Hawaii at Manoa, 2011-05) Morita, Shane Y.
Background: Thyroid cancer is the most common endocrine malignancy. It is noteworthy that thyroid cancer is more common in particular geographic regions such as Hawaii. Additionally, there appears to be an ethnic predilection of thyroid cancer within particular groups such as the Filipino population in Hawaii. Outside the confines of ethnicity, other potential putative biologic determinants of aggression include genetic and protein alterations. Objective: Due to the higher preponderance of thyroid cancer within distinct populations, our principal goal was to comprehensively assess if there was an ethnic disparity of survival in Hawaii. Methods: This was a retrospective review of 622 patients with thyroid cancer treated at a tertiary care facility in Honolulu, HI from January 1, 1990 through December 2008. In addition, tissue biospecimens of 10 Filipino patients with papillary thyroid carcinoma from within the study cohort were subjected to DNA as well as protein characterization. A log-rank test was implemented to determine survival between the Filipino and non-Filipino cohorts. In order to model the survival of Filipinos vs. non-Filipinos adjusted for by age, gender, extra-thyroidal extension, and AJCC stage, regression analysis via the Cox proportional hazards model was utilized; hazard ratios with confidence intervals were computed.
Characterization of circulating tumor DNA in advanced prostate cancer
(University of Hawaii at Manoa, 2011-05) Kwee, Sandi Alexander
Background: Cell-free DNA (cfDNA) from tumors can be found in the blood of cancer patients. The clinical significance of these circulating nucleic acids is uncertain. The effects of chemotherapy on cfDNA is also not well understood, although tumor lysis may cause significant alterations in the cfDNA profile that could eventually translate into genomics-based blood tests for predicting treatment responses in cancer. Based on this premise, a pilot study was conducted testing the hypothesis that an increase in plasma cfDNA levels accompanies chemotherapy exposure. To explore the use of cfDNA profiling as a potential diagnostic complement to in-vivo molecular imaging, this pilot study was incorporated into a clinical trial of 18F-fluorocholine positron emission tomography (FCH PET) for assessing chemotherapeutic response in hormone refractory prostate cancer (HRPC). Results: Mean cfDNA levels increased significantly from a pre-chemotherapy level of 13.3 ng/ml to 46.8 ng/ml after the first chemotherapy cycle and 50.9 ng/ml after the 3rd chemotherapy cycle (ANOVA p=0.001). Plasma cfDNA fragments at baseline ranged in size from 160-180bp, consistent with DNA from apoptosis. Samples collected after chemotherapy showed additional cfDNA fragments ranging in size from 200bp-7kbs, suggesting DNA contributed by necrotic cells. All baseline samples demonstrated hypermethylation at GSTP1 or RARB2 suggesting that at least some DNA was of tumor origin. Treatment was associated with loss of GSTP1 or RARB2 methylation in 4/8 patients. Normalized plasma cfDNA level and mean tumor SUVmax were significantly correlated (r=-0.50, p=0.01) and lower cfDNA levels at baseline were associated with significant tumor metabolic responses on FCH PET after the 3rd chemotherapy cycle (8.0 ng/ml of cfDNA in PET responders vs. 16.4 ng/ml in PET non-responders, p=0.03). Conclusions: Exposure to docetaxel appears associated with quantitative and epigenetic changes in the plasma cfDNA of patients with HRPC. Preliminary findings support a relationship between cfDNA levels and tumor activity on FCH PET encouraging further exploration of these molecular markers as potential complementary measures of chemotherapeutic response.
Diffusion tensor imaging reveals micro-structural alterations in brain white matter of adult chronic active marijuana users
(University of Hawaii at Manoa, 2011-12) Gonzales, Rachael May K.
Since CB1 receptors are expressed within adult brain white matter (Molina-Holgado, Vela et al. 2002) and influence brain white matter development (Armstrong, Schleicher et al. 1995; Berrendero, Garcia-Gil et al. 1998), we hypothesized that longterm, daily MJ use in adults would result in lower FA and AD and higher Trace and RD in regions that continue to myelinate into adulthood such as the superior longitudinal fasciculus (Sowell, Thompson et al. 1999; Ashtari, Cervellione et al. 2007), temporal white matter (Ashtari, Cervellione et al. 2007), and frontal white matter (Ashtari, Cervellione et al. 2007). Conversely, we did not expect to see alterations in the corpus callosum or internal capsule as these structures complete myelination within the first year of life (Brubaker, Schmithorst et al. 2009). Additionally, we hypothesized that there would be a correlation between microstructural changes and age of MJ initiation.
Structural brain changes associated with detectable HIV DNA
(University of Hawaii at Manoa, 2012-12) Tata, Kalpana Juliet K.
In the era of potent antiretroviral therapy, HIV-related neurocognitive dysfunction remains prevalent although its severest form, HIV dementia, has become less common. Patients with well-controlled infection often continue to experience neurologic and cognitive impairment. HIV neuropathogenesis is incompletely understood. The persistence of cognitive dysfunction in HIV may be secondary to HIV-infected peripheral blood mononuclear cells which cross the blood-brain barrier, eventually causing perivascular inflammation and neuronal injury. Optimal antiretroviral therapy can reduce HIV RNA in plasma to undetectable levels while failing to eradicate the virus from cellular reservoirs. Circulating proviral HIV DNA in peripheral blood cells is known to correlate with HIV-related cognitive deficits. Although altered brain structure has been linked to HIV-associated neurocognitive disorders, the relationship of HIV DNA to brain structure has not been previously examined. This thesis, in a study of antiretroviral-treated HIV-infected individuals with suppressed plasma HIV RNA, relates brain regional volumes and cortical thickness to HIV DNA in peripheral blood mononuclear cells. Identifying the association between this latent viral reservoir and structural brain changes may help to determine the neuropathogenesis of HIV infection, with possible implications for disease management and development of new therapies.
Impact of weight-based dosing on vancomycin dosing and trough levels
(University of Hawaii at Manoa, 2014-05) Bello, Erlaine F.
Background: In 2009, the American Society of Health System Pharmacists (ASHSP), Infectious Diseases Society of America (IDSA) and Society of the Infectious Diseases Pharmacists (SI DP) released a consensus statement on vancomycin dosing and monitoring. The appropriateness of these guidelines for a local population, particularly the subset of obese patients, has not been well-studied. Methods: A retrospective chart review was conducted on patients hospitalized at an acute care, university-affiliated, community hospital who received intravenous vancomycin for suspected/documented infections prior to and after implementation of the 2009 guidelines. Preguidelines, patient received vancomycin, 1 gram every 12 hours. After the guidelines were implemented, patients were dosed on actual body weight (ABW), lS-20mg/kg, or 2S-30mg/kg in seriously ill patients, every 8-12 hours. We compared the frequency of achieving therapeutic troughs, nephrotoxicity and trough group levels stratified by Body Mass Index (BMI). Results: There were no significant differences in achieving therapeutic troughs and nephrotoxicity. But when adjusted for BM I, was a significant difference in proportion of trough levels when between the two groups, p=0.0109. However, a large number of patients in the conventionally-dosed group were excluded due to inconsistent dosing. In the ABW-dosed group, there was a high number of supratherapeutic trough levels in 48% of patients with BMls >3S, p=O.OOS Conclusions: Obese patients may require an alternate dosing strategy as the ABW-dosing based on the 2009 national guidelines resulted in supra-therapeutic levels in patients with high BMls. Implementing guidelines-based monitoring resulted in more consistently and appropriately drawn trough levels.
Sex differences in impulsivity and brain volumes in methamphetamine users
(University of Hawaii at Manoa, 2014-12) Kogachi, Shannon Akiko
Methamphetamine (METH) is an addictive stimulant adversely affecting brain structure and function. The aim of this study was to investigate impulsivity and brain structures, and sex differences on these variables, between METH users and non-drug user controls (CON). Structural MRI was performed in 124 subjects: 62 METH (ages 41.2±1.4 years, 34 males, 28 females) and 62 CON (ages 43.3±2.3 years, 36 males, 26 females). FreeSurfer 5.1 automated morphometry was used to measure brain morphometry. Subjects completed the Barratt Impulsiveness Scale (BIS) questionnaire, which measures six factors. 2-way and repeated measures ANCOVA, co-varying for age, education, depressive symptoms, and intracranial volume, evaluated for independent and interactive effects of group status and sex. Relationships between METH usage characteristics, brain volumes, and impulsivity scores with significant group differences were examined with Pearson correlations. METH users had higher impulsivity scores in a majority of the factors (p<0.001-0.05). Male METH users had larger right superior frontal volumes compared to CON, while female METH users had smaller volumes compared to CON (p=0.02). Groupby-volume interactions were found in the right superior frontal (p=0.02) and right insula (p=0.02). In the male METH users, greater volumes in these regions were associated with less self-control. Female METH users had larger accumbens compared to female CON (p=0.03). METH users had consistently thinner left frontal cortical regions compared to CON (p=0.003). Consistent with prior reports, METH users were more impulsive and had thinner left frontal cortices than CON. Male METH users had larger superior frontal and insula volumes than CON, which was associated with less self-control (p=0.009-0.05). This was not seen in the female METH users, possibly due to a protective effect of estrogen from neuroinflammation in these regions. This suggests that men and women may be affected differently, and sex should be accounted for in brain morphometry studies.

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