2017

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A Bioinformatics Approach to the Design and Engineering of Biomimetic Personalized Nanoparticle Therapy for Bone Metastatic Prostate Cancer
(2017-03-21) Ranjan, Amalendu; Lin, Victor; Lampe, Jana B.; Vishwanatha, Jamboor; Gdowski, Andrew
Purpose: Bone metastatic prostate cancer remains a challenge to treat clinically due to lack of therapies prolonging overall survival and off target side effects of current treatments. In this study, we employ a bioinformatics approach for target validation and design of biomimetic cancer-coated nanoparticles (CCNP) for treatment of bone metastatic prostate cancer. Our goal is to personalize this targeted therapy by utilizing a patient’s own cancer cells to coat the nanoparticles. We hypothesize that this approach will be an effective strategy to deliver drugs to the site of metastasis. Methods: A bone metastatic prostate cancer target was identified utilizing The Cancer Genome Atlas (TCGA) database from a study of 130 patients with metastatic prostate cancer who underwent next-generation sequencing of their tumors. We used this information and stimulated prostate cancer cells to increase expression of this targeted cell membrane protein. These membranes where purified and used to coat nanoparticles. Nanoparticles were characterized with TEM, DLS, and zeta potential. Membrane purification was validated with coommassie stain and western blot. Membrane orientation on nanoparticle surface was verified with an immuno-conjugation assay. Nanoparticle cancer cell uptake was quantified through immunofluorescence and flow cytometry. Cell viability was performed with MTT assay. Results: Nanoparticles were successfully coated with stimulated cancer cell membranes. Nanoparticle size and zeta potential both increased after coating with membrane. After membrane purification, only markers for cell membranes were identified. Immuno-conjugation assay demonstrated that the cell membrane coating was correctly oriented on the nanoparticle surface. Immunofluorescence results showed when nanoparticles were coated with the cell membrane, there was increased nanoparticle uptake. This was verified by flow cytometry. Stimulated nanoparticles showed decreased cell viability in MTT assay. Conclusions: We successfully engineered cancer coated nanoparticles and validated the manufacturing process. This novel approach to target identification and personalized coating of nanoparticles has tremendous potential as a strategy for treating bone metastasis in prostate cancer patients. Future experiments will study in vivo targeting of bone metastatic lesions with these biomimetic nanoparticles.
A Biotechnology Platform for Fighting Mosquito-Borne Disease Transmission
(2017-03-14) Dalwadi, Dhwanil; Schetz, John; Wang, Huanyu
Background: Zika, West Nile virus, dengue and malaria are infectious diseases transmitted by the bite of a mosquito. Thus, technologies that prevent biting will prevent infectious disease transmission. Octopamine is a biogenic amine that controls key physiological responses including those related to fine motor control. Since biting requires fine motor control, disruption of octopaminergic systems appears to be an attractive approach to prevent mosquito biting. Every year, over a billion mosquito-borne disease cases were reported and increasing resistance of mosquitoes to first-line control measures is a cause for growing concern. To address this concern we seek to discover and develop new chemical classes of arthropod octopamine receptor deterrents to prevent biting. Our hypothesis is that at mosquito octopamine receptor activators will prevent mosquito biting. Methodology: Cloned octopamine receptors from two species of mosquitoes Anopheles gambiae (AgOctR) and Aedes egypti (AeOctR) were functionally expressed in mammalian cells. The expression levels of these receptors were quantified using radioligand binding. The ability of octopamine and experimental compounds to active the Gq-PLC-IP3-Ca2+ signaling pathway was assessed by measuring changes in intracellular calcium. Results: Specific binding of a radioligand to cells transfected with mosquito OctR DNA confirmed the successful high expression of OctR protein from both genera of mosquitoes. Functional assays with the endogenous ligand octopamine showed the expressed receptors are truly octopamine receptors given the dose-response nature of the response and the ability of an OctR antagonist to block the response. High potency of octopamine at the receptors over tyramine confirmed these receptors as OctRs instead of closely related tyramine receptor. Robust Gq-PLC-IP3-Ca2+ signaling responses indicate these receptors are Gq-coupled consistent with their identity specifically as α-like OctRs. These systems were used to begin to characterize novel experimental compounds, some of which act as potent OctR agonists. Conclusions: In this study, we created cell lines stably expressing cloned mosquito OctRs and validated that the sequences code for bona fide α-like OctRs. Correlation of the agonistic effect of experimental compounds at these cloned mosquito OctR with protection against biting suggest that this molecular platform could serve as a useful biotechnology of discovering novel mosquito deterrents.
A Case Study of Deafness-Dystonia-Optic Neuropathy & Treatments
(2017-03-14) Hamby, Tyler; Marks, Warren; Reed, Mary-Ann; Aalbers, Brian; Honeycutt, John; Durand, Christopher
Purpose: DDON, also known as Mohr-Tranebjaerg syndrome is an inherited disorder of an Xp22 mutation of the mitochondrial transport protein TIMM8A. This mutation leads to progressive dystonia, otic neuropathy, and visual disturbances. Most patients will progress to dementia by early adulthood. Methods: We report on a teenage male with DDON and the treatments he received at Cook Children’s Medical Center (CCMC). Results: A 15-year-old patient with a prior diagnosis of DDON presented to CCMC for treatment of worsening dystonia. He communicated by gesture and sign language, and relied on a iPad. His increasing dystonia made him incapable of communicating effectively, particularly dystonia of the upper extremities. He was was previously treated with botulinum toxin chemodenervation, however, that treatment had lost efficacy as a relief of dystonia. He received Deep Brain Stimulation (DBS) of the globus pallidus internus (GPi). Since receiving DBS implants, several programming adjustments have been made and have led to a decrease in severity of symptoms. The patient was also started on a trial of baclofen to decrease muscle dystonia. Following a good response to trial, the patient was implanted with an intra-thecal baclofen pump (ITB) to decrease the dystonia of the trunk and lower extremities that had progressed. Over five years of treatment, scores on disability scales such as the Burke-Fahn-Marsden dystonia scale have slowly worsened as the disease has progressed. Concern was expressed about efficacy of the treatment, so a trial of observed time without DBS was performed. Marked worsening of disability was noted, showing that therapy has slowed the progression of this patient’s disease. Future care includes monitoring of DBS implants and transitioning care to another provider closer to the patient’s home. Conclusions: This is the fourth known case of DBS used in DDON treatment. This is also the first reported combination of ITB and DBS. Compared to other cases, this patient’s outcomes with DBS have not been as marked, due to some unique brain anatomy. ITB is a unique treatment for DDON and has shown some of the most efficacious results for this patient.
A comparison of varus and valgus slipped capital femoral epiphysis: a case series
(2017-03-14) Bowman, W.; Mayfield, Matthew; Meiling, James
Introduction: Slipped capital femoral epiphysis (SCFE) is an infrequent adolescent hip disorder. The most common presentation of SCFE is varus slip, a posterior and inferior displacement of the proximal femoral epiphysis on the femoral metaphysis; however, SCFE also presents less frequently as a valgus slip, a posterior and lateral displacement. SCFE is often first seen by a family physician before prompt referral to an orthopedist. The family physician’s immediate recognition and diagnosis of this emergent condition is crucial. Methods: These cases were identified and reviewed using electronic medical records and imaging. Results: Case 1 is an 11-year-old obese boy with pain for several months due to left unilateral varus SCFE. Surgical management consisted of situ pinning and prophylactic pinning in the contralateral right hip. Case 2 is a 12-year-old obese boy with acute traumatic pain who had right unilateral varus SCFE, was managed with in situ pinning, and has suspected pre-slippage of the contralateral left hip. Case 3 is an 11-year-old non-obese girl with acute pain who had simultaneous bilateral valgus SCFE, underwent in situ pinning twice because of hardware complications, and later required removal of previously placed hardware. Conclusions: Varus SCFE tends to occur more often in males and valgus slips tend to occur more in females. Body mass index (BMI) seems to show little indication on whether the slip will be varus or valgus. Varus slips commonly present unilaterally with the potential to progress to sequential bilateral slips, while valgus slips have a greater probability of presenting as simultaneous bilateral slips.
A High Throughput and Integrative Approach to Evaluating the Functional Significance of a Glycosidase NGLY1 in Human Brain Development
(2017-03-14) Shakhbazau, Antos; Zolekar, Ashwini; Wang, Jack; Lin, Victor
Background: Mutations of the NGLY1 gene, leading to NGLY1 deficiency and associated neurodysfunction in pediatric patients, have been identified as the cause of a previously undiagnosed congenital disorder of deglycosylation. Despite the identification of the causal mutations, how NGLY1 deficiency disturbs normal cerebral development and causes neurological abnormalities is unknown. Purpose: Our desire is to unravel the mystery behind this novel disease and how it influences the assembly and function of the human cerebral landscape. Further, our hope is to develop mid-to-high throughput platforms that can be applied to discover and test druggable targets for this disease and adapted for associated neurocognitive or neurodegenerative disorders. Methods: Using human induced pluripotent stem cells (hiPSCs) and the state-of-the-art gene editing technology, CRISPR-Cas9, NGLY1 deficient human pluripotent stem cells (hPSCs) were created and used to elucidate the disease pathophysiology. In succession, middle-to-high throughput platforms were applied to recapitulate the disease in 2D and 3D, used in tandem with systems biology and novel imaging capabilities to discover new understandings and the importance glycosylation states for cerebral development and function. Results: The CRISPR-Cas9 mediated knockout of NGLY1 was confirmed by DNA sequencing and a biochemical test. Our optimized two-dimensional and three-dimensional differentiation protocols for neurogenesis in the control and NGLY1-deficient hESCs and hiPSCs showed that the loss of NGLY1 appears to have a negligible impact on the viability and cellular pluripotency in undifferentiated hPSCs. Neuroepithelial differentiation can be successfully generated in both control and NGLY1-deficient hPSCs, suggesting that the commitment of hPSCs to the neural lineage is not profoundly hindered by the loss of NGLY1 activity. However, compared with the differentiated derivatives of control hPSCs, the derivatives from neural differentiation in NGLY1-deficient hPSCs showed noticeably increased apoptosis, suggesting that NGLY1 activity may play a critical role in the viability of neural progenitor cells, as well as, play a role in the success of their subsequent differentiation into neuronal or astroglial lineages. Conclusions: We have built a new and unique model that can recapitulate the early-stage neurodevelopment patterns associated with NGLY1 deficiency. Using systems biology and imaging approaches, we are uncovering unprecedented insights into this newly identified disease. With the hiPSC and CRISPR-Cas9 gene editing, we demonstrate how regenerative medicine and genetic engineering approaches can be applied to studying the pathogenesis of human hereditary disease, applied in like to understand other brain pathologies, and possibly assist in the discovery of new therapeutics.
A Matter of Balance Service Learning Activities Positively Impact both Physical Therapy Students and Seniors Confidence
(2017-03-14) Bugnariu, Nicoleta; Kinzler, Brenda
Purpose/Hypothesis: The purposes of this study were to investigate the impact of Service Learning (SL) activities consisting of A Matter of Balance (AMOB) classes on: 1) physical therapy (PT) students’ self-perceived confidence in working with older adults and 2) seniors’ attitude towards fear of falling. We hypothesized PT students will have an increase in confidence working with seniors after participating in SL activities. Secondly, we hypothesize seniors who participate in the fall prevention course will have a decreased fear of falling as well as an increase in physical activity levels. Materials/Methods: The PT department established a collaborative relationship with Senior Citizen Services (SCS), an organization which identified a community need for senior education regarding fall risk reduction. The SL activities consisted of 86 PT students from two consecutive cohorts of a first-year geriatrics course: 1) attending an 8-hour training class in AMOB: A Fall Prevention Course and 2) leading 8 classes of AMOB workshops at senior community centers in Tarrant County, TX. PT students completed a 25-question questionnaire rating self-perceived levels of competence at pre-training, post-training and post workshops. 490 older adults ranging from 62-96 years of age, whom voluntarily signed up for a fall prevention course through the Senior Citizens Service (SCS) completed a questionnaire addressing their fall concerns and fears; pre and post AMOB workshops. The questionnaires for the older adults were collected over the course of a two-year period by the SCS. Results: Both student cohorts had similar confidence levels at the beginning of SL activities. All students reported increased confidence in essential competencies for assessing and mediating the risk for falls in older adults post AMOB trainings. Conclusions: Integrating SL into a first-year geriatric course improved students’ confidence and competence when working with the older adult population. PT students will apply this confidence in the clinical setting and will be prepared to effectively evaluate and treat the growing older adult population. Providing education regarding fall reduction may improve the safety and wellness for older adults, possibly leading to injury reduction and hospitalization.
A multidisciplinary team-based approach to reduce non-alcoholic fatty liver disease-related fibrosis in patients with psoriasis
(2017-03-14) White, PharmD, MS, PhD, Annesha; Rungruangphol, Patra
Purpose: Psoriasis impacts approximately 7.5 million people in the United States and recent studies support the link between psoriasis and non-alcoholic fatty liver disease (NALFD). The majority of psoriasis patients are not being screened for NAFLD. All clinicians must be aware of this association so they can recognize and provide a proper follow-up and medication selection in psoriasis patients to prevent NAFLD. The aim of this review is to explore the current evidence within the last decade with respect to the association between the pathophysiological mechanisms of psoriasis and NAFLD. A secondary aim is to highlight the importance of utilizing a multidisciplinary patient care team to manage moderate-to-severe psoriasis. Methods: A systematic review was conducted using Pubmed, Scopus, and International Pharmaceutical Abstracts databases between 2006-2016. Key search terms included ‘Psoriasis,’ ‘Patient Care Team,’ ‘Multidisciplinary approach,’ ‘Metabolic Disease,’ ‘Obesity,’ ‘Psoriatic Arthritis,’ and ‘Mental disorders.’ Abstracts were screened against inclusion criteria and selected based upon relevance and quality. Randomized controlled trials, prospective and retrospective studies were excluded if they were not in English or lacked information on moderate and severe psoriasis. Once articles were retrieved, they were evaluated based on the Oxford Centre for Evidence-Based Medicine and summarized in a table structured by Title, Author, Research Question, Inclusion Criteria, Resources, Findings, and Quality. Results: The search yielded a total of 33 studies for review. The articles retrieved have shown a strong association between NAFLD and psoriasis. Psoriasis patients should be routinely screened for NAFLD and the presence of NAFLD should be taken into consideration when choosing pharmacological treatment to reduce the progression of liver disease. Multidisciplinary patient care team management (pharmacists, dermatologists, psychologists and dietitians) should include monitoring for metabolic disease, osteoporosis, and mental health assessment. Conclusions: Psoriasis patients who have multiple comorbidities can benefit from multidisciplinary team care. A unique opportunity exists to screen psoriasis patients with multiple comorbidities or not well managed on current therapy for NAFLD, which is predicted to be the leading cause of liver transplantation by 2020. Few studies have explored the supportive role of pharmacists for patients with psoriasis. Future research is warranted.
A Novel Cooling Wheelchair Design as a Proof-Of-Concept Study
(2017-03-14) Liao, En-Szu; Foster, Veronica; Hankins, Christopher; Martin, Sloane; Adams, Linda; Richardson, Mike; Yavuz, Metin; Ersen, Ali
Background: For many wheelchair users, the combination of reduced mobility and impaired sensation, including but not limited to neurological insults, vascular issues, decreased cognition, and morbid obesity, results in a life-time risk of pressure ulcer development. Pressure ulcers are a type of wound that results from a breakdown of tissue over bony prominences due to localized ischemia caused by constant pressure. The compromised blood circulation along with reduced airflow results in an accumulation of heat in the tissue over the bony prominence which accelerates the tissue breakdown. In recent years, wheelchair cushions employed thick foam type materials, which provided a higher quality of pressure distribution but poorer heat dissipation. Purpose: In this study, we designed a custom-built cushion that circulated chilled water. We measured buttocks surface temperatures and peak pressures around the ischial tuberosity, with a targeted maximum temperature and pressure of 28°C and 60mmHg, respectively. Methods: In this ongoing study, we recruited one subject so far. The subject was asked to sit and actively propel the wheelchair with the aforementioned cushion for 30 minutes. Thermal images of the participant’s buttocks were collected before and after wheelchair use and temperatures were collected in 10 minute intervals while seated, using thermocouples (K-type). Pressure distribution was captured at the end of the wheelchair use using a Tekscan ConforMat, which was placed on top of the cooling cushion. All study procedures were approved by the institutional review board (IRB) prior to recruitment and testing, and informed consent was obtained from subjects prior to testing. Results: The results indicated that the cooling wheelchair cushion was capable of cooling the tissue from 28.1°C to 24.9°C. The chilled water temperature ranged from 21.5-21.8°C during wheelchair use. Peak pressure occurred at the right ischial tuberosity and was quantified as 115mmHg. Conclusions: The custom-built cooling wheelchair cushion maintained temperatures of the buttocks below 28°C but failed to lower the peak pressure to below 60 mmHg. Further modification and testing of the cushion design are warranted to achieve the pressure reduction goal. Another improvement will be adding a closed-loop control system to prevent overcooling of the tissue.
A Retrospective Analysis and Curricular Mapping Assessment of Student Engagement in Research Design in Classes Offered by the College of Pharmacy at University of North Texas Health Science Center at Fort Worth
(2017-03-14) Mukasa, Kevin; Torres, Oscar; Clay, Patrick
Purpose: Currently, UNTSCP does not have a process or a methodology developed to identify classes within its curriculum that offer the opportunity to learn, understand, and/or develop research design as outlined by the ACPE in 2016 Standards document. The aim of this study is to create a methodology and physical repository necessary to identify and classify core and elective classes offered by UNTSCP, which have provided opportunities in “research design”. This study is being submitted to receive feedback from students and faculty on classes, where at least one of the four key components of research design is presented, discussed, tested and actively practiced as outlined in the 2016 Standards document created by ACPE. Significance: The tool developed in our research will potentially allow pharmacy students to search for and identify classes offered at UNTSCP that have provided exposure to research design and identify which of the four key components of research design each class has covered. Faculty may even use the results of this study to elicit changes to the class curriculum. In addition, the administration of UNTSCP has its first full accreditation review in May 2017. To prepare for this, the administration of UNTSCP may use the results of this quality assurance project to show its compliance/adherence to the 2016 standards in the section detailing “Research Design.” Materials and Methods: Three stages will be undertaken in order to achieve the specific aims outlined. These stages include a curricular mapping assessment looking at course syllabus objectives and then verifying the results obtained with students through surveys and faculty via personal interviews. Conclusions: The results of this quality assurance project may lead to increased reproducible and meaningful research conducted by students and faculty at UNTSCP as a result of improved or increased research design experiences in the offered curriculum. This project could also lead to assessments done in other schools within UNTHSC such as School of Public Health, School of Health Professionals, and Texas College of Osteopathic Medicine (TCOM).
A Small Chemical Chaperone, Sodium 4 Phenylbutyrate Inhibits TGFβ2-Induced ECM Remodeling in Human TM Cells
(2017-03-14) Kasetti, Ramesh; Phan, Tien; Maddineni, Prabhavathi; Zode, Gulab; Patel, Pinkal
Purpose: The pathological mechanisms underlying increased outflow resistance at the trabecular meshwork (TM) that is responsible for elevating intraocular pressure (IOP) have not been fully delineated. We have previously shown that progressive accumulation of unfolded proteins and endoplasmic reticulum (ER) stress play an important role in the pathophysiology of glaucomatous TM damage in myocilin-associated POAG. However, it is not understood whether other glaucoma factors lead to similar pathological ER stress in the TM, leading to IOP elevation. Transforming growth factor β2 (TGFβ2) is known to induce abnormal extracellular matrix (ECM) deposition in the TM cells, which may be responsible for IOP elevation. Here, we examined whether TGFβ2 induces ER stress and whether reducing ER stress via a small chemical chaperone, sodium 4-phenylbutyrate (PBA) reduces TGFβ2–induced ECM remodeling. Methods: Human GTM-3 cells or primary TM cells (n=2) were treated with TGFβ2 (5ng/ml) with or without 5mM PBA for 48 hours. Total cellular lysates, conditioned medium, and fixed cells were examined for ECM and ER stress markers by Western blotting and immunostaining. We also used RT-PCR to demonstrate XBP1 splicing in response to TGFβ2 treatment. Results: TGFβ2 increased synthesis and deposition of ECM proteins in GTM-3 and primary TM cells. TGFβ2 induced ER stress as evident from increased ER chaperones and splicing of XBP-1. Treatment of TM cells with TGFβ2 and PBA demonstrated reduced synthesis and deposition of ECM and ER stress markers as evident from reduced fibronectin, GRP78, GRP94 and CHOP. Conclusions: Our studies suggest that TGFβ2 induces abnormal ECM accumulation and ER stress, and PBA may reduce TGFβ2-induced IOP elevation by decreasing abnormal ECM accumulation and reducing ER stress.
A Small Molecule Derivative as a Targeting Agent for Sp1 and Survivin Effectively Suppresses Pancreatic Cancer Cell Growth
(2017-03-14) Sankpal, Umesh; Mahammad, Shahela; Chhabra, Jaya; Brown, Deondra; Gurung, Raj; Holder, Alvin; Basha, Riyaz; Hurtado, Myrna Ms
Background: Pancreatic cancer has one of the most fatal malignancies due to its poor prognosis. It currently has a one-year survival rate of 20%. Current standard forms of treatment contain a high level of toxicity, thus preventing an increase in dosage or frequency. This issue poses the need for more effective, yet less toxic agents for treatment. Tolfenamic acid (TA) is most commonly used to treat migraines but has recently been demonstrated to contain anti-cancer properties. It is known to downregulate the Specificity Protein (Sp) transcription factor, Sp1. Sp1 regulates several genes involved in cell proliferation and apoptosis, including survivin, an inhibitor of apoptosis protein. Interestingly, a recent discovery proposed that a copper(II) complex with TA as a ligand can result in higher therapeutic response; however its efficacy was not tested in gastro-intestinal cancers. Purpose: In this study, we assessed the therapeutic efficacy of a Cu(II)- containing complex of TA (Cu-TA) using human pancreatic cancer cell lines. Methods: MIA PaCa-2 and Panc1 cells were treated with increasing concentrations of DMSO (vehicle), equimolar CuCl2 (negative control), TA or Cu-TA and the cell viability was measured at 24 and 48 h post-treatment using CellTiter-Glo kit. CuTA was further tested for its effect on Sp1 and survivin expression by Western blot and quantitative PCR. The activation of apoptosis was determined by measuring the activity of effector caspases using the Caspase 3/7-Glo kit and the apoptotic cell population through flow cytometric analysis using Annexin-V staining. Cell cycle arrest was assessed by flow cytometry with propidium iodide staining. Results: While both TA and Cu-TA inhibited pancreatic cancer cell growth in a dose/time-dependent manner. Cu-TA was highly effective in inhibiting Sp1 and survivin protein expression and showed similar trend for inducing apoptotic markers and causing cell cycle arrest in G2/M phase. The results of qPCR demonstrated that the expression of survivin mRNA was significantly lower following both Cu-TA and TA treatment; however, the mRNA expression of Sp1 remained unchanged. This indicates that TA and Cu-TA could be affecting Sp1 by a similar mechanism. Conclusions: These results demonstrate that Cu-TA is more effective than TA and potentially useful for pancreatic cancer treatment after clinical testing. Studies to understand precise underlying mechanisms are currently under investigation.
A STEP in the Right Direction: An Interdisciplinary Approach to Transitional Care (2017)
(2017-03-14) Connally, Patrica; Allen, John G.
Background: The Affordable Care Act, calls for more focus on finding innovative delivery systems that improve care, increase efficiency, and reduce costs. Purpose: Hospital readmissions, excessive falls, and poor quality of life are factors that unnecessarily increase healthcare costs. The Safe Transitions for the Elderly Patients (STEP) program is a hybrid transitional care model developed by the UNT Health Science Center (UNTHSC) as part of an 1115 Waiver to address these factors in a home care setting in Tarrant County. Objectives: The primary goals of STEP are to reduce all-cause 30 day hospital readmissions, improve quality of life, and decrease falls among Medicaid patients over 50 years through a collaborative and interdisciplinary approach to patient care. Methods: An interprofessional team that includes a physician/geriatrician, nurse practitioner, physician assistant, social workers, physical therapists and a dietician assess and treats the patient in the home for up to 90 days post hospital discharge based on the individual patient needs. Conclusions: Through this model, UNT Health Science Center has the opportunity to demonstrate a unique transitional care model that will improve health care delivery post-hospitalization.
Acanthosis Nigricans - A reliable diagnostic indicator of insulin resistance and type 2 Diabetes Mellitus in obese youth and adolescents
(2017-03-14) Shah, Taksh; Kolluru, Samyuktha; Rich, Alisa; Barve, Amruta
Background: Over the last few decades, there has been an increasing prevalence of Type 2 diabetes mellitus (DM) in youth with obesity. Acanthosis Nigricans (AN) is frequently associated with obesity and is a reliable risk indicator for developing type 2 diabetes. Although the risk for obesity is elevated in African American populations in general, there is a 2-fold increased risk in African Americans having AN to develop non-insulin dependent diabetes mellitus (NIDDM). AN once considered a rare dermatological condition is now frequently observed among obese youths and adolescents across ethnicities. Objective: The aim of this study is to evaluate AN as a diagnostic indicator; and its correlation to insulin resistance, obesity, and increased risk for development of diabetes in obese youth and adolescents. Methods: A systematic review of databases (Pubmed, Scopus, and Medline) resulted in 1743 publications related to AN, and Type 2 DM. Cross referencing AN, and Type 2 DM with obesity resulted in 679 publications since 2000. Search was narrowed using keywords AN, type 2 DM, insulin resistance, obesity, risk, youth and screening which resulted in 27 referenced papers. Abstracts of the papers were retrieved and reviewed for relevance resulting in 22 papers retrieved in full and evaluated. Studies, where AN presents with drug induced, autoimmune (systemic lupus erythematosus) or syndromic (hyperandrogenism) conditions, were excluded. Results: Results of the study confirm AN is associated with insulin resistance in obese youth and adolescents. Reports indicate a strong association of AN with insulin resistance, hyperinsulinemia, and risk for developing diabetes. Hyperpigmentation of the skin in AN is generally symmetrically distributed in the neck area, but can also be present in the forehead and folds of the skin (groin, armpits, and bends of the arms and knees). Research confirmed a positive and independent association between ethnicity, family history of diabetes, high body mass index (BMI), obesity, hyperinsulinemia, insulin resistance and AN. Conclusions: AN is strongly associated with obesity, hyperinsulinemia, insulin resistance and type 2 DM, which can be used as a reliable index for insulin resistance and to identify diabetes risk. It provides a valuable tool to primary care providers for prediabetes identification and secondary prevention. Screening programs for AN can be conducted in schools to identify children at the highest risk of developing type 2 DM associated with obesity. Intervention programs should incorporate AN screening, an easily performed and noninvasive technique along with other important risk factors for identifying obese adolescents at risk for type 2 diabetes. Adopting lifestyle changes along with early detection of AN and other risk markers may reduce the prevalence, incidence, and burden of type 2 DM in obese youth and adolescents.
Actual Versus Perceived Use of Pharmacokinetic (Primarily Absorption) Influential OTC Agents and ART Tolerability in a Nationwide Matched Cohort of HIV Patients and Their Healthcare Providers
(2017-03-14) Clay, Patrick; Perry, Richard; Hadfield, Anna; Liu, Jialiang; Suzuki, Sumihiro; Gehrig, Mark
Background: Antiretroviral therapy (ART) for HIV patients is lifelong. ART efficacy is clear, adverse effects (AE) severity has decreased yet still impact outcomes. This study obtained ‘real world’ data comparing healthcare providers' (HCP) perceptions and clinic records to their patients' perceptions of ART tolerability and self-management. Methods: Study utilized Adelphi's HIV Disease Specific Programme, a cross-sectional survey including provider interviews (n = 131) and matched HCP and patient self-completed surveys (n = 485), conducted among HIV patients and their HCPs. Similar questionnaires focused on disease symptoms, ART AEs, other AEs, compliance, impact and reasons for switching or discontinuing therapy. Results: A total of 131 HCPs were interviewed (n = 80 ID physicians) at 18 metro areas across the US. “Efficacy” was stated by 58% of HCPs as the most important attribute when selecting ART yet the top 5 attributes for ART selection in patient charts revealed criteria of “well tolerated by patients.” ID specialists perceived 32% of all patients are experiencing ART side effects and this increases with subsequent regimens. HCPs interviewed revealed diarrhea as one of the most common symptoms seen with 66% stating diarrhea was the most “most troublesome” AE. This agrees with patients, who recorded diarrhea as equal second “most problematic symptom.” ART changes are most frequently for lack of virologic control (36%) but secondarily (28%) due to GI AEs. HCPs and patients agree on proportion experiencing diarrhea and being treated for it, yet only about 1/3 of patients receive therapy. Finally, our results also reported a concerning discrepancy between prevalence of OTC drugs used by patients versus perceived use by HCPs. Conclusions: HIV patients experience and self-medicate GI symptoms disparate with HCPs knowledge, representing a potential major detrimental influence on outcomes.
Acute Necrotizing Encephalopathy: Case Report
(2017-03-14) Acosta, Fernando; Feezel, Ashlea
Background: Acute Necrotizing Encephalopathy (ANE) is a rare disease that follows viral infections, most commonly influenza. Patients present with altered mental status and rapidly progress into a comatose state. Characteristic bilateral thalamic and brainstem lesions are seen on magnetic resonance imaging scans. Most early cases were isolated to East Asian countries such as Japan and Taiwan, with very few cases reported in the United States and Europe. Results/Conclusions: Recent studies of sporadic and familial cases of ANE have found a missense mutation in the Ran Binding Protein 2 (RANBP2) gene. We describe the clinical and radiological findings and treatment of a 14 year old female with recurrent RANBP2 positive ANE.
Adherence Rates of Antibiotic Use During Antiretroviral Therapy in People Living with HIV/AIDS
(2017-03-14) Clay, Patrick; Elrod, Shara; Truong, Doris
Objective: To determine frequency of antibiotic use and medication adherence to antibiotics used for opportunistic infections (OI) in people living with HIV/AIDS (PLWHA) who are taking anti-retroviral therapy (ART). Methods: This retrospective review was conducted as a part of a larger study examining communication patterns between pharmacists and PLWHA using medication refill data obtained from community pharmacies between June 2014 to September 2015. Medication refill history, which included initial research participation date, prescription fill history, and day supply were collected. Patients were included in this study if they were aged 25 years or older, infected with HIV and received both ART and antibiotic therapy for 6 months or longer. To distinguish OI and non-OI antibiotic regimens, medications were classified according to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents from the U.S. Department of Health & Human Services. The adherence rates of ART and OI antibiotics was determined using standard metrics of proportion of days covered (PDC), or the number of days that a patient has had a medication for a specific period of time. Satisfactory PDC value for adherence is ≥ 95%. Results: A total of 155 patients were included in this study with a mean age of 48.8 years (range 25-73). The total proportion of males was 66.9% (n=101). Overall, 72 (46.5%) participants were taking antibiotics for OI, 106 (68.4%) subjects were taking antibiotics for non-OI infections, and 25 (16.1%) subjects were taking both therapies. More males were using OI antibiotics than females (p=0.021). There was no difference between genders with respect to non-OI antibiotic use (p=0.239). The most common antibiotic for OI was sulfamethoxazole/trimethoprim and the most common non-OI antibiotic was doxycycline. The mean PDC for ART and antibiotics for OI are 93.5% and 88.1%, respectively. Conclusions: Antibiotic use is common for opportunistic infections and short term infections in PLWHA. Adherence to both ART and antibiotics for opportunistic infections was good overall, but less than ideal. Future interventions should be targeted at increasing adherence to ART and OI antibiotic therapies.
Alcohol Influences HAND Via Astrocyte-TLR4 and cPLA2 Signaling
(2017-03-14) Ghorpade, Anuja Ph.D.; Pandey, Richa Ph.D.
Background and Objective: Over the past few decades, ~25 million people died with human immunodeficiency virus (HIV)-1 disease. About 70% of HIV patients suffer from HIV-associated neurocognitive disorders (HAND). The prevalence of alcohol abuse among HIV-1+ve individuals is estimated to be 2-3 times that of the general population in the USA. HIV patient brains harbor up to 20% HIV-infected astrocytes, thus making them critical players in HAND. Previously, we reported that HIV-1 and/or alcohol (EtOH) activated astrocytes induced inflammation via cytosolic phospholipase A2 (cPLA2) activation. How EtOH regulates HIV-1-mediated inflammatory episodes initiated at the cell surface level is still unclear. Toll-like receptor (TLR) signaling in immune cells, astrocytes, microglia and neurons may play roles in pathogenesis of multiple diseases including HIV-1. Hypothesis: We propose that TLR4 may serve as critical regulator of alcohol-mediated inflammatory responses in HAND directly or by controlling cPLA2 signaling. Materials and Methods: To investigate the temporal order of events, primary human astrocytes were cultured and treated with HIV-1 (10ng/ml) and/or EtOH (50mM). TLR4, COX2 and CCL2 mRNA levels were measured by RT2PCR at 8h whereas protein levels were analyzed by ELISA, western blot and immunocytochemistry on 24h. We also explored the phosphorylation studies of cPLA2 and TLR4 downstream molecules such as IRAK4 and NF-kB by western blot and immuno-staining analysis on 30 min. TLR4-RNAi and cPLA2-specific inhibitor AACOCF3 were employed to carried out TLR4 and cPLA2-specific responses. Results: We showed EtOH, HIV-1, IL-1b and anti-retroviral (ARV) drugs significantly upregulated TLR4 in human astrocytes. Our results established that EtOH+/- HIV-1 activated TLR4 signaling leads to IRAK4 phosphorylation followed by NF-kB activation, ultimately leading to excessive production of inflammatory mediators such as COX2 & CCL2. EtOH and/or HIV-1 increased inflammatory molecules in MyD88-dependent manner. TLR4-RNAi studies reversed EtOH and/or HIV-1-regulated effects. Moreover, on silencing TLR4, the increase in EtOH+/-HIV-1-induced cPLA2 phosphorylation was not observed. Conclusions: Our study demonstrated that TLR4 regulates inflammatory responses in primary human astrocytes directly or by controlling cPLA2 cascade in HAND. Hence, TLR4 could be the critical regulator of alcohol-induced astrocyte inflammation with HIV-1.
An Antiapoptotic Peptide for Neuroprotection in Glaucoma
(2017-03-14) Krishnamoorthy, Raghu R.; Sampathkumar, Sruthi; Nagaraj, Ram; Stankowska, Dorota L.
Purpose: Axonal degeneration and death of retinal ganglion cells (RGC) are primary contributors to vision loss in glaucoma. The purpose of this study was to determine if intraperitoneal administration of the core peptide derived from small heat shock protein αB-crystallin (ABCP) could inhibit RGC death in animal models of glaucoma. Materials and Methods: Brown Norway rats were retrogradely labeled (to detect RGCs) using Fluoro-gold and IOP was elevated (150 mmHg/days) in one eye using the Morrison’s method, while the contralateral eye served as control. The rats were intraperitoneally injected with 10μg of ABCP (n=3 animals per group) three times per week for five weeks. Surviving RGCs were counted in retinal flat mounts. In another model of ischemia reperfusion (I/R) injury, C57BL/6 mice were subjected to IOP elevation of 120 mmHg for 30 min, followed by rapid reperfusion. Intraperitoneal ABCP injections were given 3h before and immediately after the procedure and then once daily post I/R injury for 14 days. RGC apoptosis was assessed using a TUNEL assay (n=2 animals per group). Results: Intraperitoneal injections of ABCP significantly (p Conclusions: Intraperitoneally administered ABCP peptide was able to significantly attenuate RGC death in two animal models of glaucoma. These findings suggest that ABCP has the potential to be developed as a neuroprotective agent in glaucoma.
An Evaluation of Attitudes and Understanding of Vaccinations in Rural Populations
(2017-03-14) Mamun, Md Abdullah; Handoyo, Anthony; Pulvino, John; Abraham, Stacy; Kaushal, Deepika
Background: Recently in the media, there has been a movement to abstain from childhood immunizations. At the same time, a rise in the rate of preventable childhood diseases for which there are available immunizations has also been witnessed. It is known that the attitude towards vaccination of both the parents and providers and the knowledge about vaccines all influence vaccination compliance. Methods: My colleagues and I surveyed rural communities in Texas to assess parental knowledge and how that affected vaccination compliance. Clifton, Texas is located in Bosque County. As of the census of 2000, there were 3,542 people. Plainview, Texas is located in Hale County. The current census data reports a population of 22,194. Bilingual versions of surveys developed by Zingg et al were distributed to participants with children up to 10 years of age who live in or near the rural towns of Clifton or Plainview between the fall of 2015 and the spring of 2016. Results: When analyzing survey results, correct knowledge was estimated by summing over the number of correct answers for the 11 items in the survey. Using a multiple linear regression model our study revealed that here is statistically significant difference in knowledge on vaccination for parents who has a Bachelor degree or more in comparison to parents who are high school graduate or less after adjusting for the effects of race and number of children. However, there is no statistically significant difference in knowledge on vaccination for parents who has some college degree in comparison to parents who are high school graduate or less after adjusting for the effects of race and number of children. Conclusions: On an average, parent’s knowledge on vaccination increases as their number of children increases after adjusting for the effects of educational status and race. There is no statistical difference on vaccination knowledge in White versus Hispanic and White versus Other racial groups after adjusting for the effects of parent’s education and number of children.
An Evaluation of Socioeconomic Factors and Health Status on Health-Related Quality Of Life (HRQoL) in Rural Texas
(2017-03-14) Sanchez, Roberto; Abraham, Stacy; Mamun, Md Abdullah; Gibson, John Dr.; Urbanczyk, Rachel
Purpose: HRQoL allows us to focus on how the individual perceives his or her own impairments of health. HRQoL in rural areas is rarely examined, yet its measurements can help identify significant health disparity issues and community burdens that will further highlight the needs in communities. We hypothesized that demographic factors and mental illness would have a significant impact on HRQoL in rural Texas communities. Methods: A cross-sectional survey in the form of a questionnaire was completed by 191 patients in 2 different rural Texas communities. Survey questions were taken from the CDC Health Related Quality of Life-14 “Healthy Days Measure” system and from the Behavioral Risk Factor Surveillance System questionnaire. Relationship of socioeconomic factors and health status with HRQoL were assessed using univariate and multiple variable analysis. Wilcoxon signed rank test was used to examine the mean number of unhealthy days in Texas versus the two rural communities in the study. Results: After adjusting for age and gender, we found that on average Hispanics reported a significantly less number of physical or mental unhealthy days in comparison to Whites (p-value = 0.0167). We also found that people with high income reported significantly less number of physical and mental unhealthy days on average (p-value for Conclusions: The results suggest that HRQoL can be influenced by many factors, including income level, race, and location. Our results identified that mental health factors are an important component affecting HRQoL and should be studied further in rural Texas communities. Focus on mental health programs and economic development could be beneficial for these communities.

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