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Item BMP4 Induced ID Protein Protects TM From Glaucomatous Effects of TGFβ-2(2015-03) Mody, Avani A.; Wordinger, Robert J.; Clark, Abbot F.Purpose: Elevated levels of pro-fibrotic growth factor transforming growth factor b2 (TGFb2) are have been reported in the aqueous humor and trabecular meshwork (TM) of primary open angle glaucoma (POAG) patients. TGFb2 treatment results in accumulation of extracellular matrix (ECM) molecules in the TM, which are associated with increased outflow resistance. Expression of TGFb2 in rodent eyes and ex-vivo anterior segment perfusion models elevate intraocular pressure, suggesting that TGFb2 plays a role in the development and progression of glaucoma. Interestingly, bone morphogenetic protein 4 (BMP4) inhibits ECM proteins that are up-regulated in TM cells by TGFb2.The purpose of our study is to determine the mechanism by which BMP4 inhibits the TGFb2 induction of ECM proteins in the TM. Prominent downstream targets of the BMP4 pathway are inhibitor of DNA binding proteins (IDs). There are four family members of IDs (ID1-4). In this study, we determine the expression of IDs in TM cells and determine the role of BMP4 induced ID1 and ID3 in regulating TGFb2 induction of ECM proteins Methods: Time and dose dependent BMP4 induction of ID1 and ID3 were studied in cultured human TM cells by Q-PCR and western blot analysis. GTM3 cells were transfected with pCMV-ID1 and pCMV-ID3 plasmids to determine their effect on TGFb2 induced ECM proteins (Fibronectin, PAI-1) by western blot analysis. Results: BMP4 (10ng/ml) significantly induced ID1 and ID3 mRNA and protein expression, starting 30 minutes after treatment. Conclusions: BMP4 induced ID1 and ID3 expression in TM cells, and ID1/ID3 suppressed the profibrotic ECM effects of TGFb2. Therefore, the BMP4 suppression of TGFb2 effects in TM cells may be mediated by ID1 and ID3. Further this study suggests ID1 and ID3 to be potential therapeutic targets for POAG.Item Wnt induction of SMAD/TGFβ signaling in the Trabecular Meshwork(2015-03) Webber, Hannah C.; Clark, Abbot F.; Mao, WeimingPurpose: Primary Open Angle Glaucoma is a progressive, irreversibly blinding disease, the leading risk factor of which is increased intraocular pressure (IOP) thought to be due to an inherent pathological change in the trabecular meshwork (TM) tissue. Canonical Wnt signaling genes are expressed in the TM, the primary site for regulation of aqueous humor outflow and therefore IOP. Canonical Wnt signaling activation has been found to regulate IOP, but the mechanism behind this phenomenon remains unknown. Extracellular matrix deposition in the TM caused by increased activation of the TGF-β pathway by the TGF-β2 ligand has been associated with increased IOP and with primary open angle glaucoma. In other cell types and diseases, evidence exists for crosstalk between the TGF-β and Wnt signaling pathways. Our study aims to pinpoint the affect of Wnt signaling on the glaucoma-associated TGF-β pathway in the TM. Methods: Lentivirus-based luciferase assays were conducted in normal trabecular meshwork (NTM) and glaucomatous trabecular meshwork (GTM) cells by using TGF-β/SMAD or TCF/LEF (Wnt) signaling reporter vectors. Trabecular meshwork cells were all kind gifts from Novartis. Cell were treated with or without 100ng/ml Wnt3a or 5ng/ml TGF-β2. In some experiments, siRNAs were also used to knock down smads in NTM cells. Western immunoblotting was performed on nuclear and cytosolic fractions of NTM and GTM cells with corresponding primary as well as secondary antibodies. Results: In NTM cells, Wnt3a treatment increased TGFβ/SMAD pathway reporter activity (n=5 p less than 0.05) but TGF-β2 did not affect and even slightly decreased TCF/LEF (Wnt) signaling activity, although this decrease was not statistically significant (n=5, P greater than 0.05). SiRNA knockdown of SMAD pathway mediator smad3 decreased Wnt3a-induced SMAD/TGFβ signaling activity (n=6 p less than 0.05) in NTM cells. However, nuclear fractions of NTM and GTM cells showed translocation of smad4 (co-smad) into the nucleus upon Wnt3a treatment but not smad2 or smad3. Nuclear fractions also showed translocation of β-catenin by TGFβ2 treatment. Conclusions: The Wnt pathway ligand Wnt3a is able to activate SMAD/TGFβ transcriptional activity in TM cells, but not vice versa. This activation seems to involve translocation of only smad4. We hypothesize that a protein complex consisting of β-catenin and smad4 can form in the TM. By selectively recruiting other smad proteins into the complex during SMAD activation, the SMAD/TGFβ pathway can be differentially regulated. Defining how Wnt and SMAD signaling pathways crosstalk in the TM is imperative in defining the role of Wnt signaling in IOP regulation, and could lead to discovery of a therapeutic target for regulation of TGF-β pathway and therefore regulation of POAG.Item Relationship of Poor Oral Health to Depression in US Adults(2015-03) Rudraraju, Hemanth; Mandapati, Surendra R.; Vinjamuri, Gopi K.; Dhara, Prabodh K.; Homan, SharonPurpose: Oral health is a key component of the overall health of individuals. In 2012, an estimated 16 million adults in the U.S had at least one major depressive episode in the past year which represented 6.9 percent of all the U.S adults2. The purpose of this study is to examine the relationship between poor dental health and depression in US adults, adjusting for demographic and health risk variables. Methods: We analyzed data from 4949 adults participating in the National Health and Nutrition Examination Surveys (NHANES 2011-2012)1. Decayed Missing Filled Surfaces (DMFS) Index was used as a measure of oral health. Depression was measured as a subjective score based on answers to the Patient Health Questionnaire 9 (PHQ-9) designed by the United States Preventive Services Task Force. Ordinal logistic regression was performed to examine if depression was associated with poor oral health. We used SAS© 9.3 for the analyses. We adjusted for confounding variables including age, race, gender, smoking status, marital status and diet. Results: Poor dental health as measured by DMFS, is only weakly associated with depression. We estimated the adjusted odds ratio for depression in people with poor oral health to be 1.01 (95% CI: 1.00, 1.03; p= 0.4). Conclusion: There is a weak positive association between poor oral health and depression that is independent of age, race, gender, smoking status, marital status and diet.Item Mechanical performance of dual and single locking plate constructs for fixation of humeral mid- diaphyseal fractures: a finite element study with Retrospective Case Series(2015-03) Luedke, ColtenPurpose: To compare the mechanical performance of four different locking plate constructs (three single and one dual plate) for mid-diaphyseal humeral fracture fixation and present our clinical case series Materials and Methods: Five humeral shaft finite element models (1 intact and 4 fixation) were loaded in torsion, compression, posterior-anterior (PA) bending, and lateral-medial (LM) bending. A comminuted fracture was simulated by a 1-cm fracture gap. Fracture fixation was consistsed of: (A) 4.5-mm 9-hole large fragment plate (wide), (B) 4.5-mm 9-hole large fragment plate (narrow), (C) 3.5- mm 9-hole small fragment plate, and (D) one 3.5-mm 9-hole small fragment plate and one 3.5-mm 7- hole small fragment plate. Outcome measures include construct stiffness, and hardware stresses. The clinical series of patients include 41 patients having undergone dual plating of humeral shaft fractures with primary outcomes of time to healing, nonunion and failures. Results: Model A showed the best outcomes in torsion and PA bending, whereas Model D outperformed the others in compression and LM bending. Stress concentrations were located near and around the unused screw holes for each of the single plate models and at the neck of the screws just below the plates for all the models studied. Of the 41 patients included in our clinical series, 26 were available at final follow up. All 26 patients showed clinical and radiographic healing. 2 complications were noted: 1 hardware failure due to infection, 1 infection at an olecranon plate. Conclusions: The results support using a dual small fragment locking plate construct as an alternative in cases where crutch weight-bearing (compression) tolerance may be important and where anatomy limits the size of the bone segment available for plate fixation. Our clinical series show the 26 patients available at final follow-up all demonstrate clinical and radiographic healing.Item Use of 1,3,5–Trimethylbenzene in Unconventional Shale Gas Hydraulic Fracturing Operations and Potential for Water and Soil Contamination(2015-03) Patel, Tarang Mukeshbhai; Patel, Maulikkumar Natubhai; Rich, AlisaIntroduction and Objective: Hydraulic fracturing (fracking) of unconventional shale gas formations allows for extraction of natural gas in tight geologic formations. Large quantities of water, proppants and chemical additives are required during hydraulic fracturing. These chemicals have the potential to contaminate water and soil if not properly used and contained. The chemical’s unique characteristics increase the potential for human exposure from contaminated water, soil and bioaccumulation in fish. The objective of this study is to examine the use of 1,3,5-Trimethyl benzene (TMB) as a chemical additive in fracking and the potential for human ingestion. Methodology: A meta-analysis was performed and articles related to 1,3,5-TMB evaluated. Databases searched included Science direct, PubMed, Scopus, Web of Science, ACS ChemWorx and TOXNET. Keywords searched include 1,3,5-Trimethyl benzene, Mesitylene, soil and water contamination, runoff, ground, surface and drinking water, fish kills, fracking fluids and petroleum industry. Published articles dates ranged from 1993-2012. Inclusion criteria were chemical properties of 1,3,5-TMB (Mesitylene), TMB water concentration, substantiality of TMB in water and soil, use of TMB in hydraulic fracturing. Exclusion criteria were health effects of TMB, air pollution, aerosolization of TMB, and toxicology studies on animals. All the relevant abstracts were evaluated with 150 articles reviewed in full-text. Results: This study confirmed 1,3,5-TMB used as a chemical additive in hydraulic fracturing. Published studies showed high concentrations of 1,3,5-TMB present in produced water from oil and gas production discharge. Migration of 1,3,5-TMB from accidental spills, uncontained fluids on pad sites, and holding ponds was found to increase the potential for municipal water, surface and groundwater contamination. Migration of 1,3,5-TMB in ambient temperature water was found to be possible due to its high concentration being used at fracking site. Conclusion: The use of 1,3,5-TMB as a chemical additive in hydraulic fracturing was confirmed in this study. Published literature supports the ability of 1,3,5-TMB to contaminate surface and ground water used as municipal water reservoirs. Bioaccumulation of 1,3,5-TMB in fish was found to be possible due to its low partition coefficient.Item Helping students beat the odds: Large scale Freshman Research Initiative improves student performance and persistence in the sciences(2015-03) Simmons, Sarah; Rodenbusch, Stacia; Hartos, Jessica; Rankin, Mary AnnPurpose: The U.S. is not producing enough graduates in STEM (science-technology-engineering-math) fields to meet current and projected needs. The Freshmen Research Initiative (FRI) is a large-scale undergraduate research program that involves students at the University of Texas at Austin (UT) in authentic research in the areas of biology, chemistry, physics, computer science, astronomy, and math beginning early in their undergraduate career. The purpose of this study was to assess the efficacy of FRI in improving undergraduate student persistence and success in the sciences. Methods: Using data from 2006 to 2012, we assessed whether participation in FRI showed differences in passing gateway courses, accumulating credit, remaining in academic track, maintaining adequate GPAs, and obtaining a degree. Multiple logistic regression analyses with adjusted odds ratios (AORs) were conducted to determine any significant differences in outcomes between FRI participants and all other students in their CNS entering freshman cohort after adjusting for demographic characteristics, college preparedness, and participation in other college programs. Results: Differences in demographic characteristics, college preparedness, and participation in other college programs were found between FRI participants and non-FRI participants. However, after adjusting for all factors related to demographic characteristics, college preparedness, and participation in other college programs, FRI participants were significantly more likely to have desired outcomes such as having a GPA ≥ 3.0 and graduating with a science degree within four years and were significantly less likely to have undesired outcomes such as having a GPA < 2.0 and failing science classes. Conclusions: The results indicate that FRI participation was related to improved undergraduate student persistence and success in the sciences. Programs like FRI may help students overcome risk factors such as lack of college preparedness and underrepresented status, and, thus, address our national shortage of STEM graduates.Item Seniors Assisting in Geriatric Education (SAGE): Reynolds Program addresses the lack of training in geriatrics and provides a model for interprofessional education.(2015-03) Marquez-Hall, Sandra; Lane, Yolanda; Knebl, JaniceSeniors Assisting in Geriatric Education (SAGE) is a program that helps healthcare students develop competency with older adults and strengthen their clinical applications of medical education through an interprofessional team experience. Two objectives for this study: 1) To increase development of competency in attitudes, knowledge, and skills in the care of older adults; and, 2) To provide an Interprofessional experience where students learn about, with, and from collaborating as a team member in the context of working with an older adult. Senior volunteers 60 years and older are mentors in the program. Student teams meet with senior mentors in their homes for a series of home visits over the course of a two year period. SAGE curriculum guides program content and is delivered through an online learning system. Student teams conduct eight home visits which include conducting environmental home safety and nutritional assessments; medical history, physiology of aging, bio-psychosocial interviews; medication reconciliation, review of community resources, and end of life issues. A survey was administered to students to evaluate perceptions of learning after participating in the SAGE Program; this is a self-report model. A quantitative survey using a five-point Likert Scale evaluates student perceptions of learning. Findings (n=332) revealed modest levels of student confidence and attitudes toward geriatric patients (3.6), and comfort in performing physical examinations (3.5). Higher levels were found in recognizing unique medical and psycho-social issues (3.8); competency in interviewing, physical assessment and examination skills (3.8); and practice using ADLs and IADLs (3.8). Highest overall scores were found in environmental home safety and falls risk (3.9); use of Mini-Mental Status Exam (3.9); and real world experience (4.0). The SAGE experiential learning program provides insight into medical student perceptions toward older adults using a senior mentoring and home visit model. Medical education in geriatrics combined with experiential learning in student teams resulted in modest improvement in student perceptions of confidence and patient interaction.Item Selection of an Ancestry-Informative Marker (AIM) Panel of INDELs(2015-03) Thompson, Lindsey M.; Zeng, Xiangpei; Sage, Kelly; Sturm, Sarah; LaRue, BobbyPurpose (a): In forensics, there are two main concerns with the marker systems currently used for human identification. First, the identification of the source of a biological sample found at a crime scene requires a comparison to a known reference sample. When no suspect is available for comparison, these genetic markers cannot provide any additional phenotypic information. In such cases, Ancestry-Informative Markers (AIMs) can be used as an investigative lead to law enforcement. A second issue commonly encountered is caused by sample degradation. When DNA is exposed to the elements, it can degrade to fragments of less than 200 base pairs (bps). The genetic markers currently used in forensic settings are called Short Tandem Repeats (STRs). The commercially available STR amplification kits generally yield amplified products that are 200-600 bps in length. Marker systems that yield short fragments. Methods (b): INDELs, insertions and deletions in the genetic sequence as compared to a consensus reference sequence, are a bi-allelic marker system that can be easily multiplexed and analyzed using the instrumentation currently available in forensic laboratories. In this project, publically available genome data was used to select a panel of INDELs that can distinguish between three major global population groups; Caucasian, African, and East Asian. The markers were selected based on specific criteria; length of INDEL, allele frequency divergence, population substructure, and genetic location. Results (c): "All INDELs were tested for departure from Hardy-Weinberg Equilibrium (HWE) and evidence of linkage disequilibrium (LD). Principal Component Analysis (PCA) of the markers indicate the AIMs ability to completely separate the three population groups. Additionally, analysis in STRUCTURE v2.3.4 gives statistical support for the presence of three separate population clusters. Conclusions (d): A robust panel of AIMs was chosen to distinguish between three major global population groups. By multiplexing these markers into a single reaction, the panel will provide a quick, reliable method for determining the ancestry origin of an unknown sample, which may provide significant benefits to forensic investigations.Item Evaluation of the UNTHSC Campus as a Mother-Friendly Worksite(2015-03) Miller, Jennifer M.; Beyer, Molly; Barnes, Shelly; Hanich, Kristen; Sam, Justena; Adeniyi, Quadir; Pramanik, Priyanka; Chinyanta, Nellie; Lee, Parker; Paul, MarcyObjective Mothers face numerous barriers with breastfeeding specifically returning to work. Lack of privacy and storage to breastfeed or pump, and accepted break times are reasons to cease. Texas created the Mother-Friendly Worksite Initiative in 1995 which offers certification for worksites that meet certain criteria including “Flexible work schedules with breaks and work patterns providing time milk expression, access to a private location(s), not a bathroom and clean and safe water source for washing hands and cleaning equipment, and access to hygienic refrigeration to safely store breastmilk." This pilot research project evaluated breastfeeding-friendliness on the UNTHSC campus and sought to assess steps to become a mother-friendly worksite. Materials and Methods Fifteen MPH students and one DrPH student were assigned UNTHSC buildings and asked to evaluate the assets and barriers to breastfeeding on campus. The assessment, conducted with photographs and journaling ascertained whether there were already designated places to breastfeed, pump, and/or store milk. Results The results found three lactation-designated areas on campus and surrounding buildings. Two lactation rooms were private with locked doors but neither were labeled as such. The third lactation area was located in a restroom with a curtain and chair. None of the three lactation areas had refrigeration to store expressed breastmilk. Conclusions To become a certified mother-friendly worksite, UNTHSC needs to 1) increase lactation spaces on campus; 2) generate policy that facilitates faculty, staff, and students to take breaks to pump or breastfeed, and 3) create designated spaces for patients and guests to breastfeed and pump.Item Student Perceptions of a Flipped Classroom in Physical Therapy Education(2015-03) Canifax, April J.; Thomas, Brent A.; Papa, EvanPurpose In recent years, colleges and universities in the United States have faced considerable scrutiny for their apparent failure to adequately educate students. Studies suggest that a significant portion of students are not learning the critical thinking, written communication, and complex reasoning skills thought to be at the core of higher education.1 A growing body of literature consistently points to the need to rethink what is taking place in the classroom.2-4 To that end, a novel pedagogical approach has been proposed: the flipped classroom. This instructional model uses instructor’s prerecord lectures posted online for students to watch at home. This allows class time to be dedicated to student-centered learning activities, like problem-based learning and inquiry oriented strategies.5-7 Student and instructor satisfaction regarding this model has been reported in nursing, pharmacy, and medical school curricula8-10, however no research exists regarding student perceptions of the model in a Doctor of Physical Therapy (DPT) curriculum. The purpose of this study was to identify student perceptions of a flipped classroom in physical therapy education. Methods A five-point Likert scale survey was administered to 2nd year DPT students on the first day of the Evidence-Based Practice III course at the University of North Texas Health Science Center (UNTHSC), Fort Worth, Texas. Qualtrics.com hosted the survey and links were provided to all students attending the class. All participants were provided with electronic informed consent. This study was approved by the Institutional Review Board at UNTHSC. Results 41 students ages 21-35, representing diverse ethnic and educational backgrounds agreed to participate. Approximately ⅔ of respondents were female. The majority of student responses indicated a positive impression of the flipped-classroom. Means of responses to detailed questions were high (3.83-3.95) covering student perceptions of communication skills, personal initiative in the learning process, and interaction with topics expected in a flipped-classroom. The lowest mean response (3.56) was to the survey item “My overall perception of a flipped-classroom is positive.” Conclusion The results of this seminal survey on the efficacy of the flipped classroom in a DPT curriculum suggest that second year DPT students believe that a flipped classroom can enhance skills at the core of higher education. Paradoxically however, participants in this study rated lower on their overall perception of a flipped classroom. Given an increased need for PT education to evolve as team-based healthcare becomes more prevalent,4 shifting to a flipped classroom model could serve to enhance future student’s abilities to thrive in a more collaborative work environment.Item The use of virtual reality and a sub-threshold vibratory noise as a tool to enhance sensory reintegration and postural control among patients with diabetic peripheral neuropathy.(2015-03) Pair, Brad; Bugnariu, NicoletaPurpose: Peripheral neuropathy frequently occurs among patients with diabetes and can result in many complications, including plantar sensory loss. Diminished sensation alters the sensory weighting mechanism, causing individuals to become increasingly reliant on visual stimuli to maintain adequate balance and postural control. The purpose of this study was to evaluate the clinical usefulness of a virtual reality- (VR) based sensory reweighting and balance training program that incorporates principles of the stochastic resonance theory in subjects with diabetic peripheral neuropathy. Methods: Seven subjects, ages 63 to 69 years old, with peripheral neuropathy due to type II diabetes have completed the study; enrollment is ongoing. This study was conducted using a V-Gait CAREN system. Subjects were fitted with vibratory devices placed around both ankles and underwent increasingly challenging postural stability activities over the course of 6 one-hour sessions. Visual dependency was reduced by manipulating the lighting conditions and applying visual distractions from the VR. Subjects received an acute application of a sub-threshold vibration throughout the duration of each session. Pre- and post- measurements of fall risk and standing balance were assessed at visits 1 and 8 using the Activity Balance Confidence (ABC), Falls Efficacy, and Clinical Test of Sensory Interaction for Balance (CTSIB). Data was analyzed using paired t-tests. Results: Post training analysis showed a significant improvement in ABC score (p=0.02) but not with Fall Efficacy score (p Conclusions: Subjects improved overall balance and sensory selection strategy as indicated by an improved ability to control both the amplitude and velocity of their sway during conditions of altered visual and somatosensory information. Preliminary results support the use of a sub-threshold background noise as an adjunct to a VR- based balance and sensory re-integration training program for individuals at risk for falls due to diabetic peripheral neuropathy.Item A comparison of photophysical characteristics of rHDL encapsulated anti-cancer drug valrubicin and free valrubicin.(2015-03) Shah, Sunil Ajit; Chib, Rahul; Raut, Sangram; Bermudez, Jaclyn Y.; Sabnis, Nirupama; Duggal, Divya; Kimball, Joseph; Lacko, Andras G.; Borejdo, Julian; Gryczynski, Zygmunt; Gryczynski, IgnacyNanotechnology as a channel for drug delivery is one of the rapidly developing fields in cancer therapeutics. Targeted drug delivery has the advantage of having minimal interaction with healthy tissue, thereby reducing the toxicity of the drug to the rest of the body. rHDL nanoparticles have been found to be an efficient delivery system for highly lipophilic anti-cancer drugs. This is achieved through the interaction of scavenger receptors class B type I (SR-BI), which are highly expressed on cancer cells interact with rHDL nanoparticles for effective drug delivery to the cancer cell and tumor. The drug under investigation is Valrubicin, which, apart from being an effective anti-cancer drug, also has intrinsic fluorescence. This allowed for the comparison of photophysical properties of free Valrubicin and rHDL Valrubicin via steady state and time resolved fluorescence measurements. The steady-state anisotropy of rHDL Valrubicin is higher as compared to free Valrubicin, suggesting its encapsulation in rHDL nanoparticles. A longer rotational correlation time was observed for rHDL Valrubicin in time resolved anisotropy measurements compared to free Valrubicin, further supporting steady state anisotropy data.. We also studied the cellular internalization of free Valrubicin and rHDL Valrubicin using confocal microscopy. This could help track the movement of rHDL nanoparticles within the cancer cells.Item Anatomical observation of the dorsal scapular nerve- A series of cadaver study.(2015-03) Nguyen, Vuvi H.; Liu, Howe; Rosales, Armando; Reeves, RustinPurpose: The impingement of the dorsal scapular nerve (DSN) often leads to shoulder weakness and scapular pain radiating to the upper limb. This nerve originates from a branch of the root of C5 in the brachial plexus and typically pierces the middle scalene muscle to innervate the levator scapulae, rhomboid minor, and rhomboid major muscles. Due to its anatomical location, the DSN is difficult to dissect and thus, is not often shown to medical students in lab. The purpose of this study is to show and educate medical students on the variable anatomy of the DSN. Materials and Methods: Studies were conducted on 3 embalmed adult Caucasian cadavers in which the origin, anatomical route, and muscular innervations of the DSN were dissected and documented. Results: It was found that the DSN originated from C5 spinal nerve root in two cadavers whereas in one cadaver, the DSN branches from C4. The route of the DSN varies either by passing anteriorly to the scalene muscles or piercing through the middle scalene muscle in order to travel posteroinferiorly to its targeted muscles. The DSN innervated only the rhomboid muscles in one cadaver and in the other two cadavers, this nerve innervated the rhomboid muscles as well as the levator scapulae muscle. Conclusions: The variations of the DSN spinal contribution, route, and muscle innervations are identified in this study. Such variations will help clinicians become better aware of its anatomy in order to make the appropriate diagnosis and treatment plan to patients with pain related to DSN impingement.Item A Case Presentation of Acute CHF Exacerbation in the Presence of Several Co-mobordities(2015-03) Wong, Long; Amlani, Farah M.; Colmenero, EvanPurpose: To highlight clinical features and management of congestive heart failure (CHF) exacerbation in a patient with several co-morbidities such as chronic kidney disease (CKD), hypertension (HTN), and diabetes (DM). Methods: A 66 year old African American male with a history of systolic CHF, CKD with anemia, DM, HTN, hyperlipidemia, and tobacco abuse presented to his primary care physician with complaints of fatigue, a cough productive of pink sputum, and intermittent chest pain. For 9 months, he had worsening dyspnea with exertion, cough with chest pain, and orthopnea. On physical exam, lung auscultation revealed 50% rales with diminished breath sounds. 2+ edema was present on the lower extremities bilaterally. An EKG in clinic showed left ventricular hypertrophy. The patient was sent to Plaza Medical for evaluation of CHF exacerbation due to fluid overload while on high dose Lasix and a history of CKD. Results: Labs showed an elevated BUN, creatinine, and BNP. He was anemic with a Hgb of 10.3. Troponins were negative. Initial CXR showed interstitial edema with cardiomegaly and pleural effusions. IV Lasix was started. During his hospital stay, his Hgb dropped to 8.3 and he was started on procrit. Cardiology and nephrology consults were ordered. An echocardiogram showed a dilated left ventricle with an ejection fraction of 25-30% with diffuse hypokinesis. The cardiologist began him on nitrates and digoxin. The nephrologist diagnosed end stage renal disease. A permcath was placed for dialysis. He received 3 treatments of inpatient dialysis. After 6 days, the patient was discharged home and put on outpatient dialysis. Procrit, isosorbide mononitrate, digoxin, hydralazine, and lisinopril were prescribed. The doses of furosemide and simvastatin were increased. Conclusions: Community based studies show that 30-40% of patients die within 1 year of diagnosis of CHF, 60-70% die within 5 years. NYHA class IV patients have a 30-70% annual mortality rate, while NYHA class II patients have an annual mortality rate of 5-10%. Thus, functional status is an important predictor of patient outcome. In our case, the functional status of the patient had deteriorated to the point of hospitalization. In addition, the patient had co-morbidities that affected the functionality of the heart. HTN, CKD, and DM can all play a role in the functional and morphological changes in the heart resulting in CHF. Management of all co-morbidities is imperative to improve patient outcomes.Item Alcohol Regulates HIV-1-Mediated Astrocyte Inflammatory Responses Via cPLA2 Signaling Pathway(2015-03) Pandey, Richa; Ghorpade, AnujaAlcohol (EtOH) abuse and HIV-1 remain significant public health problems. Globally, drinkers have approximately 70-77% higher risk of HIV-infection than non-drinkers. The prevalence of alcohol abuse among HIV-positive individuals has been estimated to be between 29-60% in the United States. Many studies showed that neurodegeneration in alcohol abusers include exacerbated neuroinflammation and oxidative damage. However, how EtOH regulates HIV-1-induced astrocyte neuroinflammation is unknown. Thus, we explored mechanism(s) involved in alcohol-mediated activation of human astrocytes with HIV-1 and subsquent alterations in their inflammatory functions. Alcohol exposure altered the morphology of astrocytes, proinflammatory responses and induced cytotoxicity in a dose-dependent manner. Time-depended changes were also evaluated. Alcohol and HIV-1 co-treatment decreased cell viability and proliferation, while increasing apoptosis and mitochondrial depolarization. Alcohol and HIV-1 together increased the levels of proinflammatory molecules, IL-1b, TNF-a, CXCL8, TIMP-1 and more importantly, arachidonic acid, known to be downstream of cPLA2. Consistent with this observation, phospho-cPLA2 levels were augmented in HIV-1 and EtOH co-treatment as compared to HIV-1 or EtOH alone. COX2 was upregulated as measured by real time PCR and western blot, whereas co-treatment of HIV-1 and EtOH decreased CYP2E1 levels as compared to EtOH alone. In summary, our results demonstrate that EtOH-mediated astrocyte inflammation and cytotoxicity in context of HAND occurs via cPLA2 signaling.Item Evaluation of the PowerSeq™ Auto System by Massively Parallel Sequencing(2015-03) Zeng, Xiangpei; King, Jonathan; Hermanson, Spencer; Patel, Jaynish; Storts, Doug; Budowle, BruceMassively parallel sequencing (MPS) is potential technology for STR typing by forensic laboratories and that some of the CE-based limitations may be overcome by MPS. In this study, the PowerSeq Auto System (Promega) containing 23 STR loci and Amelogenin, was evaluated by MPS. The PCR products were size selected using the MinElute PCR Purification Kit (Qiagen). DNA libraries were normalized, pooled and sequenced on the MiSeq (Illumina; 2 x 250 bp). This multiplex STR system was tested for sensitivity of detection based on input DNA. The result showed that a broad range of the quantity of PCR products could be used for library preparation. In mixture study, the partial profile of minor contributor could be detected up to 19:1 mixture. These studies indicate that PowerPlex Fusion STR system and the Illumina MiSeq system can generate reliable DNA profiles with the types of samples and amounts of input DNA that are relevant to forensic analyses.Item Post-Transcriptional Regulation of Astrocyte-Tissue Inhibitor Metalloproteinase-1 (TIMP-1) in HAND(2015-03) Thete, Mayuri V.; Ghorpade, AnujaPurpose (a): HIV-1 can lead to several central nervous system impairments together termed HIV-1-associated neurocognitive disorders (HAND). In acute versus chronic neuroinflammation, differential regulation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) is relevant to HAND neuropathogenesis. However, the underlying mechanisms are still being uncovered. In our study, we investigated the post-transcriptional regulation of TIMP-1 3’UTR via miRNAs. Method (b): Microarray analysis was used to analyze miRNA changes in IL-1β-activated astrocytes. To investigate miRNA-mediated TIMP-1 3’UTR post-transcriptional regulation, TIMP-1 3’UTR and specific miRNA overexpression constructs were used. Primary human astrocytes were nucleofected with TIMP-1 3’UTR and Pmir 146b/Pmir 155, and treated with IL-1b 24 h post-transfection. Firefly luciferase activity and astrocyte TIMP-1 levels were analyzed in parallel experiments 24 and 72 hours after IL-1β treatment. Result (c): Microarray analysis showed an increase in 12 miRNAs and decrease in 4 miRNAs. Seven of those were further confirmed by RT-PCR. The most consistent increase was observed in miRNA 155 and miRNA 146b. Overexpression of miRNA 155 and miRNA 146b in IL-1β-activated astrocytes decreased both luciferase activity and endogenous TIMP-1 levels. Conclusion (d): In summary, our preliminary studies suggest that astrocyte-TIMP-1 may be regulated post-transcriptionally by miRNAs (146b and 155) during HAND.Item N-Acetyl Cysteine Attenuates Hypoxia Induced Sympathoexcitation in Human Subjects(2015-03) Jouett, Noah; Moralez, Gilbert; Raven, Ph.D., Peter; Smith, Michael L.This investigation tested the hypothesis that central and peripheral reactive oxygen species (ROS) mediate hypoxia induced sympathoexcitation, which is a central feature of the Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS). 10 healthy human subjects were recruited. One hour prior to experimentation, each subject randomly ingested either 70 mg.kg-1 of N-Acetyl Cysteine (NAC, n=5) or vehicle placebo (n=5). ECG, BP, muscle sympathetic nerve activity (MSNA) and plasma ROS and catecholamines were measured. Subjects underwent a 20 minute intermittent hypoxia training (IHT) protocol consisting of cyclical end-expiratory apneas with 100% N2. Venous blood was analyzed pre/post IHT for ROS by electron paramagnetic spectroscopy and for catecholamines by ELISA. In the placebo group, MSNA was increased between pre vs. post IHT (P=0.01). In the NAC group, however, MSNA was unchanged (P=0.26). NAC reduced the percent change (% ∆) of ROS observed from pre- vs. post-IHT compared to placebo (P=0.02). The % ∆ of ROS was directly related to increasing MSNA (R2=0.83, p=0.01). The % ∆ of norepinephrine was lower in the NAC vs. placebo group after IHT (P=0.05), whereas the % ∆ of epinephrine was unchanged (P=0.40). These data indicate that NAC reduces central sympathetic outflow in response to IHT, and thereby could reduce cardiovascular risk in OSAS patients.Item Neutron-Activatable Holmium-Containing Nanoparticles for the Treatment of Non-small Cell Lung and Skin Cancers(2015-03) Shi, Yi; Munaweera, Imalka; Koneru, Bhuvaneswari; Levesque-Bishop, Daniel; Aliev, Ali; Coyle, Russell; Saez, Ruben; Balkus, Kenneth J.; Di Pasqua, Anthony J.Purpose: To improve therapeutic outcomes for patients with non-small cell lung and skin cancers using radiation therapy. Methods: Magnetic holmium-165 (Ho) nanoparticles (HoIG) and derivatives containing platinum-based chemotherapeutic drugs (HoIG-Pt) were prepared and then neutron-activated to radioactive holmium-166 (166Ho; Eβ-max = 1.84 MeV; t½ = 26.8 h) nanoparticles (166HoIG and 166HoIG-Pt, respectively). Cytotoxicities of 166HoIG and 166HoIG-Pt were tested against non-small cell lung cancer cells, and in vivo studies were performed. 165HoIG were also introduced into poly-acrylonitrile (PAN) polymer solutions; these solutions were electrospun to produce bandages that can be applied directly to tumor lesions after neutron-activation. Results: Ho materials were carefully characterized and successfully neutron-activated. HoIG contained approximately 56% w/w Ho. Two 166HoIG-Pt derivatives showed greater toxicity toward non-small cell lung cancer cells than blank 166HoIG and free platinum drug. The animal study data collected showed that the radiation and platinum drug act synergistically. HoIG was distributed homogenously throughout the radioactive bandages and the bandage was stable upon neutron-activation. Conclusion: Pt-based chemotherapeutic drugs and 166Ho have been incorporated together in a magnetic nanoparticle for the first time, and then used successfully in human cell culture and animal studies. A novel radiotherapeutic bandage was successfully prepared using PAN solutions and HoIG nanoparticles, and subsequently neutron-activated. The radiotherapeutic bandage is a more flexible strategy than that currently being used in the clinic for the treatment of skin cancer.Item Epigenetic alterations in Brain tissue and Alzheimer's Disease(2015-03) Shewale, Shantanu J.; Barber, Robert C.; Planz, JohnBackground: Epigenetic factors such as methylation of DNA have shown to impact the phenotype of a cell and irregular methylation of DNA has been correlated with numerous diseases. DNA methylation has been shown to impact the expression of certain genes associated with AD. Methods: A novel method, methylated DNA immunoprecipitation (MeDIP), is used to study genome wide methylation patterns via high throughput sequencing to assess DNA methylation patterns in brain tissue from individuals diagnosed with AD (N=12) and age matched controls (N=12). MeDIP isolation facilitates an unbiased methylation analysis of the entire human genome by enriching samples for methylated DNA fragments. The MethylMiner kit (Life Technologies) was utilized to precipitate methylated DNA, which was sequenced on the Illumina Hi-seq 2500. In addition, another aliquot will undergo MeDIP and bisulfite treatment. This will allow analysis of methylated cytosines at single base pair resolution across the entire genome. In addition, RNA and miRNA-seq was performed on the Illumina Hi-seq 2500. RNA-seq information obtained provides additional insight on epigenetic impacts on miRNA and RNA levels. Results: Sequence data reveal a genome wide methylation pattern profile, along with gene expression changes that differentiate case from control participants. Conclusions: These data provide insight and help explain a portion of the missing heritability that has yet to be characterized for AD.