• Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.

      Machado, Livia S; Kozak, Anna; Ergul, Adviye; Hess, David C.; Borlongan, Cesar V; Fagan, Susan C.; Vascular Biology Center; Department of Neurology (2006-08-15)
      BACKGROUND: Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. RESULTS: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). CONCLUSION: Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.
    • Delivering Diagnostic Quality Video over Mobile Wireless Networks for Telemedicine.

      Rao, Sira P; Jayant, Nikil S; Stachura, Max E; Astapova, Elena; Pearson-Shaver, Anthony; Center for Telehealth; Department of Pediatrics (2009-05-07)
      In real-time remote diagnosis of emergency medical events, mobility can be enabled by wireless video communications. However, clinical use of this potential advance will depend on definitive and compelling demonstrations of the reliability of diagnostic quality video. Because the medical domain has its own fidelity criteria, it is important to incorporate diagnostic video quality criteria into any video compression system design. To this end, we used flexible algorithms for region-of-interest (ROI) video compression and obtained feedback from medical experts to develop criteria for diagnostically lossless (DL) quality. The design of the system occurred in three steps-measurement of bit rate at which DL quality is achieved through evaluation of videos by medical experts, incorporation of that information into a flexible video encoder through the notion of encoder states, and an encoder state update option based on a built-in quality criterion. Medical experts then evaluated our system for the diagnostic quality of the video, allowing us to verify that it is possible to realize DL quality in the ROI at practical communication data transfer rates, enabling mobile medical assessment over bit-rate limited wireless channels. This work lays the scientific foundation for additional validation through prototyped technology, field testing, and clinical trials.
    • Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide.

      Krishnamurthy, Kannan; Wang, Guanghu; Rokhfeld, Dmitriy; Bieberich, Erhard; Institute of Molecular Medicine and Genetics; Student Research and Training (STAR) Program, School of Graduate Studies (2009-02-23)
      INTRODUCTION: At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells. METHODS: Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis. RESULTS: We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 +/- 1%) of slowly dividing, CD44+ cells gave rise to rapidly dividing, CD44- cells. DC promoted survival of CD44+ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide. CONCLUSIONS: Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial growth factor receptor 2/Flk-1 antagonists may thus be a promising strategy to reduce breast cancer metastasis.
    • Design, Synthesis, and Initial Evaluation of D-Glyceraldehyde Crosslinked Gelatin-Hydroxyapatite as a Potential Bone Graft Substitute Material

      Florschutz, Anthony V; Institute of Molecular Medicine and Genetics (2012-07)
      Utilization of bone grafts for the treatment of skeletal pathology is a common practice in orthopaedic, craniomaxillofacial, dental, and plastic surgery. Autogenous bone graft is the established archetype but has disadvantages including donor site morbidity, limited supply, and prolonging operative time. In order to avoid these and other issues, bone graft substitute materials are becoming increasingly prevalent among surgeons for reconstructing skeletal defects and arthrodesis applications. Bone graft substitutes are biomaterials, biologies, and guided tissue/bone regenerative devices that can be used alone or in combinations as supplements or alternatives to autogenous bone graft. There is a growing interest and trend to specialize graft substitutes for specific indications and although there is good rationale for this indication-specific approach, the development and utility of a more universal bone graft substitute may provide a better answer for patients and surgeons. The aim of the present research focuses on the design, synthesis, and initial evaluation of D-glyceraldehyde crosslinked gelatin-hydroxyapatite composites for potential use as a bone graft substitutes. After initial establishment of rational material design, gelatinhydroxyapatite scaffolds were fabricated with different gelatin:hydroxyapatite ratios and crosslinking concentrations. The synthesized scaffolds were subsequently evaluated on the basis of their swelling behavior, porosity, density, percent composition, mechanical properties, and morphology and further assessed with respect to cell-biomaterial interaction and biomineralization in vitro. Although none of the materials achieved mechanical properties suitable for structural graft applications, a reproducible material design and synthesis was achieved with properties recognized to facilitate bone formation. Select scaffold formulations as well as a subset of scaffolds loaded with recombinant human bone morphogenetic protein-2 were implanted ectopically in a rodent animal model and histologically evaluated for biocompatibility, degradation, and bone formation in vivo. The gelatin-hydroxyapatite scaffolds retained dimensional structure over 28 days and did not elicit any undesirable systemic or local effects. Distinct areas of mineralization and osteoid/bone were noted in all the implanted scaffolds and quantitative differences were primarily dependent on the presence of hydroxyapatite.
    • Determinants of adherence to physical activity guidelines among adults with and without diabetes

      Ansa, Benjamin E.; Covington, Katherine; Augusta University (2017-10)
    • Determinants of adherence to physical activity guidelines among overweight and obese African American breast cancer survivors: Implications for an intervention approach

      Smith, Selina A.; Whitehead, Mary S.; Yoo, Wonsuk; Ansa, Benjamin E.; Coughlin, Steven S.; Augusta University (2015)
    • Development and Implementation of a Blended Learning Environment on an Inpatient Internal Medicine Team: A Pilot Study

      Hatzigeorgiou, Christos; Carson, Thaddeus; Wyatt, Tasha; Beidas, Sary; Department of Medicine (2016-03)
      Development and Implementation of a Blended Learning Environment on an Inpatient Internal Medicine Team: A Pilot Study Hatzigeorgiou C, Carson T, Wyatt T, Beidas S. Background We have witnessed an increase in the use of web-based collaborative software in recent years in undergraduate & graduate education and corporate operations. The notion of “anytime, anyplace” communication is characteristic of the millennial population and has facilitated the growth and integration of a blended or hybrid learning platform. However, there are limited reports and use of this communication platform in medical education. We propose that the setting of a high demand, inpatient clinical rotation with limited face-to-face time are ideal for the use of collaborative software, and expect this integration to positively influence medical education. Methods We set out to explore the practical and novel use of a collaborative software application. We compared the usefulness and functionality of several software options which included standard file sharing on a department hard-drive, Share-Point, Desire2Learn, Cerner “social media” application, and Box. The selected software application was chosen based on ease of use (collaborative & interactive potential), portability (smart phone / tablet operational), alerts, and HIPPA compliance. A post-experience survey tool was developed by our research team to measure the following important areas in medical training: impact on Learning Environment, Communication of Goals, Feedback, and Promotion of Self-Directed Learning. Results Completed surveys by all levels of learners (3rd and 4th yr medical students and all three levels of internal medicine residents) are underway. We anticipate descriptive statistics based on the learners self-assessment and reflection on how a collaborative software application impacts usual operations during an inpatient clinical rotation and its influence on learner growth and development. Conclusion Ultimately we chose Box and have pending survey data based on this “social media” intervention in a busy, high demand clinical environment. We look forward to the results of this innovative use of collaborative software and anticipated positive impact on medical education.
    • The Development of an Education Discovery Institute (EDI) to Advance Awareness and Expertise in Health Sciences Education Research

      Stepleman, Lara M.; Thomas, Andria M.; Fincher, Ruth-Marie; Medical College of Georgia; Education Discovery Institute (Georgia Health Sciences University, 2011)
      A team of educators and educational researchers was charged with developing an EDI to parallel the institution’s translational science discovery institutes. The EDI consists of a Center of Research in Education (CORE) and a Center of Teaching Excellence (COTE).
    • DEVELOPMENT OF TRANSGENIC ZEBRAFISH MODEL FOR INVESTIGATION OF THE FUNCTION OF MICROGLIA

      Sura, Survasha; Department of Biological Sciences; Department of Biochemical and Molecular Biology; Georgia Cancer Center; Rajpurohit, Surendra K; Augusta University (2019-02-13)
      Zebrafish have emerged as a powerful model organism for elucidating the development and function of microglia. Generation of new transgenic reporter lines and imaging tools strengthen the zebrafish model in microglia study�in-vivo. The aim is to develop a novel compound transgenic line to study the inflammatory process mediated by NF-kB in microglia cells. This novel compound transgenic line will establish a new model for microglia study. To generate the novel compound zebrafish transgenic model for microglia, we are crossbreeding microglia transgenic line zebrafish (Tg(mpeg1:mCherry) with the NF-kB Tg(6xNFkB:EGFP) transgenic progeny. We first generate a heterozygous F1 progeny which will be bred to generate an F2 homozygous progeny. Once the F1 progeny of the Microglia-NfkB transgenic line is developed, they will be crossbred to develop the Homozygous compound transgenic line. Fluorescent Microscopy will be used to screen the larvae generated from the breeding events. By developing the compound transgenic line, we are optimizing microglia isolation and sorting methodology by using the related antibodies as the marker. The NF-kB microglia transgenic line will provide a unique platform for drug screening to address microglial based ailments, thus furthering the understanding and treatment of human disease.
    • Different Neuroplasticity for Task Targets and Distractors

      Spingath, Elsie Y.; Kang, Hyun Sug; Plummer, Thane; Blake, David T.; Brain & Behavior Discovery Institute; Graduate Program in Neuroscience; Department of Neurology (2011-01-31)
      Adult learning-induced sensory cortex plasticity results in enhanced action potential rates in neurons that have the most relevant information for the task, or those that respond strongly to one sensory stimulus but weakly to its comparison stimulus. Current theories suggest this plasticity is caused when target stimulus evoked activity is enhanced by reward signals from neuromodulatory nuclei. Prior work has found evidence suggestive of nonselective enhancement of neural responses, and suppression of responses to task distractors, but the differences in these effects between detection and discrimination have not been directly tested. Using cortical implants, we defined physiological responses in macaque somatosensory cortex during serial, matched, detection and discrimination tasks. Nonselective increases in neural responsiveness were observed during detection learning. Suppression of responses to task distractors was observed during discrimination learning, and this suppression was specific to cortical locations that sampled responses to the task distractor before learning. Changes in receptive field size were measured as the area of skin that had a significant response to a constant magnitude stimulus, and these areal changes paralleled changes in responsiveness. From before detection learning until after discrimination learning, the enduring changes were selective suppression of cortical locations responsive to task distractors, and nonselective enhancement of responsiveness at cortical locations selective for target and control skin sites. A comparison of observations in prior studies with the observed plasticity effects suggests that the non-selective response enhancement and selective suppression suffice to explain known plasticity phenomena in simple spatial tasks. This work suggests that differential responsiveness to task targets and distractors in primary sensory cortex for a simple spatial detection and discrimination task arise from nonselective increases in response over a broad cortical locus that includes the representation of the task target, and selective suppression of responses to the task distractor within this locus.
    • Differential Consolidation and Pattern Reverberations within Episodic

      Osan, Remus; Chen, Guifen; Feng, Ruiben; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2011-02-15)
      One hallmark feature of consolidation of episodic memory is that only a fraction
    • Differential gene expression in the salivary gland during development and onset of xerostomia in Sj??gren's syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse.

      Nguyen, Cuong Q; Sharma, Ashok; Lee, Byung Ha; She, Jin-Xiong; McIndoe, Richard A; Peck, Ammon B; Center for Biotechnology and Genomic Medicine (2009-05-28)
      INTRODUCTION: Recently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sj??gren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying the onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study using genomic microarray technology. METHODS: By means of oligonucleotide microarrays, gene expression profiles of salivary glands at 4, 8, 12, 16, and 20 weeks of age were generated for C57BL/6.NOD-Aec1Aec2 male mice. Using Linear Models for Microarray Analysis and B-statistics software, 480 genes were identified as being differentially expressed (P < 0.01 and Q < 0.0001) during the development of SjS-like disease in the salivary glands. RESULTS: The 480 genes could be arranged into four clusters, with each cluster defining a unique pattern of temporal expression, while the individual genes within each cluster could be grouped according to related biological functions. By means of pair-wise analysis, temporal changes in transcript expressions provided profiles indicating that many additional genes are differentially expressed at specific time points during the development of disease. Multiple genes reportedly showing an association with autoimmunity and/or SjS, in either humans or mouse models, were found to exhibit differential expressions, both quantitatively and temporally. Selecting various families of genes associated with specific functions (for example, antibody production, complement, and chemokines), we noted that only a limited number of family members showed differential expressions and these correlated with specific phases of disease. CONCLUSIONS: Taking advantage of known functions of these genes, investigators can construct interactive gene pathways, leading to modeling of possible underlying events inducing salivary gland dysfunction. Thus, these different approaches to analyzing microarray data permit the identification of multiple sets of genes of interest whose expressions and expression profiles may correlate with molecular mechanisms, signaling pathways, and/or immunological processes involved in the development and onset of SjS.
    • Differential Impact of Stress Reduction Programs upon Ambulatory Blood Pressure among African American Adolescents: Influences of Endothelin-1 Gene and Chronic Stress Exposure

      Gregoski, Mathew J.; Barnes, Vernon A.; Tingen, Martha S.; Dong, Yanbin; Zhu, Haidong; Treiber, Frank A.; Georgia Institute for Prevention of Human Diseases and Accidents; Department of Pediatrics (2011-11-24)
      Stress-activated gene * environment interactions may contribute to individual variability in blood pressure reductions from behavioral interventions. We investigated effects of endothelin-1 (ET-1) LYS198ASN SNP and discriminatory stress exposure upon impact of 12-week behavioral interventions upon ambulatory BP (ABP) among 162 prehypertensive African American adolescents. Following genotyping, completion of questionnaire battery, and 24-hour ABP monitoring, participants were randomized to health education control (HEC), life skills training (LST), or breathing awareness meditation (BAM). Postintervention ABP was obtained. Significant three-way interactions on ABP changes indicated that among ET-1 SNP carriers, the only group to show reductions was BAM from low chronic stress environments. Among ET-1 SNP noncarriers, under low chronic stress exposure, all approaches worked, especially BAM. Among high stress exposure noncarriers, only BAM resulted in reductions. If these preliminary findings are replicated via ancillary analyses of archival databases and then via efficacy trials, selection of behavioral prescriptions for prehypertensives will be edging closer to being guided by individual's underlying genetic and environmental factors incorporating the healthcare model of personalized preventive medicine.
    • Directed neuronal differentiation of human embryonic stem cells.

      Schulz, Thomas C; Palmarini, Gail M; Noggle, Scott A; Weiler, Deborah A; Mitalipova, Maisam M; Condie, Brian G.; Institute of Molecular Medicine and Genetics (2004-05-10)
      BACKGROUND: We have developed a culture system for the efficient and directed differentiation of human embryonic stem cells (HESCs) to neural precursors and neurons.HESC were maintained by manual passaging and were differentiated to a morphologically distinct OCT-4+/SSEA-4- monolayer cell type prior to the derivation of embryoid bodies. Embryoid bodies were grown in suspension in serum free conditions, in the presence of 50% conditioned medium from the human hepatocarcinoma cell line HepG2 (MedII). RESULTS: A neural precursor population was observed within HESC derived serum free embryoid bodies cultured in MedII conditioned medium, around 7-10 days after derivation. The neural precursors were organized into rosettes comprised of a central cavity surrounded by ring of cells, 4 to 8 cells in width. The central cells within rosettes were proliferating, as indicated by the presence of condensed mitotic chromosomes and by phosphoHistone H3 immunostaining. When plated and maintained in adherent culture, the rosettes of neural precursors were surrounded by large interwoven networks of neurites. Immunostaining demonstrated the expression of nestin in rosettes and associated non-neuronal cell types, and a radial expression of Map-2 in rosettes. Differentiated neurons expressed the markers Map-2 and Neurofilament H, and a subpopulation of the neurons expressed tyrosine hydroxylase, a marker for dopaminergic neurons. CONCLUSION: This novel directed differentiation approach led to the efficient derivation of neuronal cultures from HESCs, including the differentiation of tyrosine hydroxylase expressing neurons. HESC were morphologically differentiated to a monolayer OCT-4+ cell type, which was used to derive embryoid bodies directly into serum free conditions. Exposure to the MedII conditioned medium enhanced the derivation of neural precursors, the first example of the effect of this conditioned medium on HESC.
    • Disparities of cervical cancer incidence and mortality rates in US between 2000 and 2012

      Yoo, Wonsuk; Kim, Sangmi; Coughlin, Steven S.; Bae, Sejong; Augusta University; UAB Comprehensive Cancer Center (2016-10)
    • Disruption-induced mucus secretion: repair and protection.

      Miyake, Katsuya; Tanaka, Tomoaki; McNeil, Paul L.; Institute of Molecular Medicine and Genetics; Department of Cellular Biology and Anatomy (2006-08-28)
      When a cell suffers a plasma membrane disruption, extracellular Ca(2+) rapidly diffuses into its cytosol, triggering there local homotypic and exocytotic membrane fusion events. One role of this emergency exocytotic response is to promote cell survival: the internal membrane thus added to the plasma membrane acts as a reparative "patch." Another, unexplored consequence of disruption-induced exocytosis is secretion. Many of the cells lining the gastrointestinal tract secrete mucus via a compound exocytotic mechanism, and these and other epithelial cell types lining the digestive tract are normally subject to plasma membrane disruption injury in vivo. Here we show that plasma membrane disruption triggers a potent mucus secretory response from stomach mucous cells wounded in vitro by shear stress or by laser irradiation. This disruption-induced secretory response is Ca(2+) dependent, and coupled to cell resealing: disruption in the absence of Ca(2+) does not trigger mucus release, but results instead in cell death due to failure to reseal. Ca(2+)-dependent, disruption-induced mucus secretion and resealing were also demonstrable in segments of intact rat large intestine. We propose that, in addition to promoting cell survival of membrane disruptions, disruption-induced exocytosis serves also the important protective function of liberating lubricating mucus at sites of mechanical wear and tear. This mode of mechanotransduction can, we propose, explain how lubrication in the gastrointestinal tract is rapidly and precisely adjusted to widely fluctuating, diet-dependent levels of mechanical stress.
    • Dissecting the Roles of Reactive Oxygen Species in Cardiovascular Disease

      Wang, Yusi; Vascular Biology Center (2015-09)
      Cardiovascular disease remains the leading cause of death in the USA. While much has been learned about the root causes, the underlying mechanisms remain incompletely understood. In particular, elevated levels of reactive oxygen species (ROS) have been observed in the vasculature of blood vessels from animal models and humans with hypertension, atherosclerosis and diabetes. The importance of ROS to cardiovascular disease and the mechanisms by which it alters the function of cells of the cardiovascular system are the goals of this dissertation.
    • Dopamine Regulation of Fear Processing and Social Motivation: Implication for Common Psychiatric Comorbidities

      Lee, Jason ChiaTse; Brain and Behavior Discovery Institute (8/3/2017)
      Psychiatric disorders such as post-traumatic disorders and schizophrenia often present with common comorbidities such as increased depression, anxiety, and decreased social motivations. However, the underlying neural circuit that may account for occurrence of multiple psychiatric comorbidities remained unidentified. The dopamine system has been known to play prominent roles regulating emotional states and motivations. We therefore hypothesized that alteration in the dopamine system may lead to comorbidities such as negative mood and social isolation commonly observed in many psychiatric disorders. In this thesis work, we first examined how the dopamine system processes known triggers of psychiatric disorders, such as fear-charged stimuli. We then examined how the dopamine system regulates normal social interactions as well as how an altered dopamine system affects social interactions
    • Dorsal parietal area 5 only encodes the immediate reach in sequential arm movement

      Li, Yuhui; Cui, He; Brain & Behavior Discovery Institute; Department of Psychiatry and Health Behavior (2012-07-16)