University of Texas Medical Branch

Permanent URI for this collectionhttps://hdl.handle.net/2249.1/9401

Browse

Recent Submissions

Now showing 1 - 20 of 285
  • No Thumbnail Available
    Item
    Understanding the assembly of simple ssRNA virus nucleocapsids
    (2010-08-28) Lamb, Kristen; Werner Braun, Ph.D.; Wlodzimierz Bujalowski, Ph.D.; Stanley Watowich, Ph.D.; Stanley Lemon, MD; Bidadi V. Prasad, Ph.D.; Andres Oberhauser, Ph.D.
    The assembly of simple ssRNA viruses from the initial interactions critical for nucleocapsid formation until the morphogenesis which occurs at each maturation stage of the virus’s “life” can entail a wide range of possibilities at every given stage. By whatever seeding event initiates the nucleocapsid formation, the nucleocapsid, encasing the nucleic acid, then undergoes changes associated with the virus maturation process, which can involve, becoming enveloped, interacting with additional virus/host proteins, becoming subsequently stripped of its envelope, and/or exposure to changes in ion concentration or pH change. My studies focused on two viruses, Hepatitis C Virus (HCV), focusing on the physical characteristics of core protein and in vitro nucleocapsid assembly; and Venezuelan Equine Encephalitis Virus (VEEV), focusing on in vivo formation of pre-viral nucleocapsid structures and briefly the subsequent post-entry nucleocapsid stage. Experimentally, it was found that H124 expressed better in E. coli expression systems than H158 and H36-169, which was attached to MBP. Purified H158 was found to be largely unstructured and exist as a multimer, even at a concentration of 1 mg/mL, making crystallization attempts with it a vain and unprofitable goal. The nucleocapsid-like-particles produced with H158 or H124 both showed size heterogeneity within the reactions, and given the scale of the reactions, projected purification yields would make cryo-EM reconstructions of these impractical. Therefore, focus shifted to VEE nucleocapasids, formed in vivo, enabling the experimental scale and biological relevance to increase substantially. VEE pre-viral nucleocapsid cryo-EM reconstructions were successfully achieved, but at low resolution. Given, again, the heterogeneity of the system at this maturation stage, it is more an insight into one, maybe two, structures,which exist within the population. Thus, more questions are formed for the formation of ssRNA virus nucleocapsid formation.
  • No Thumbnail Available
    Item
    The Role of Sacsin as a Molecular Chaperone
    (2013-06-03) Anderson, John; Barral, Jose M; Boehning, Darren F; Epstein, Henry F; Fox, Robert O; Jackson, George R; Oberhauser, Andres F
    The central pathological finding in neurodegenerative disease is loss of neurons. In many disorders, this loss of neurons appears to be related to protein misfolding, comprising a large public health burden. For example, the two most common neurodegenerative diseases, Alzheimer’s and Parkinson’s diseases, possess protein misfolding as a core component of their pathology. In order to properly fold, many proteins require the assistance of molecular chaperones. While substantial gains in our knowledge of the function of general chaperones have been made in the last two decades, the role of molecular chaperones in brain-specific processes is not clearly defined. In this study, we examined the function of the protein sacsin, mutated in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Pathologically, these patients demonstrate loss of neurons in the cerebellum and cervical spinal cord along with inclusions reminiscent of misfolded proteins in the remaining neurons. Sacsin contains regions of similarity to both molecular chaperones and co-chaperones. Thus, this disease may represent a useful model to study the role of molecular chaperones in neurodegenerative disease. We performed bioinformatics and biochemical investigations to determine the function of sacsin. We found that this protein contains a novel supra-domain present three times. We show that this domain is both ATPase active and contains molecular chaperone activity. Additionally, we determined that a region of sacsin possesses co-chaperone activity. Thus, sacsin is a novel molecular chaperone, with built-in co-chaperone modules, directly involved in a neurodegenerative disease.
  • No Thumbnail Available
    Item
    ORGAN DONATION IN THE UNITED STATES
    (2013-06-03) Basraon, Jaswant; Arcari, Christine M; Eschbach, Karl; Rudkin, Laura
    Introduction: The demand for donor organs far exceeds the number of donors. Approximately 18 people in the United States die every day waiting for an organ transplant. The purpose of this capstone is to describe the demographic characteristics of organ donors, recipients and waitlist populations in the United States. This information is essential to guide the planning and implementation of focused interventions to improve organ donation participation rates and diminish inequities. Methods: We analyzed data from the Organ Procurement and Transplantation Network (OPTN) for the years Jan 1, 1988 – Aug 15, 2012. We describe characteristics of organ donors, transplant recipients and waiting list candidates by age, gender and race/ethnicity for the United States. Results: The rate of organ donation has steadily increased in the United States, from a rate of 2.10 per 100,000 in 1988 to 5.16 per 100,000 in 2010 (R2=0.963). In 2010, 14,503 individuals donated organs (7,943 (54.7%) deceased donors and 6,560 (45.3%) living donors) and 28,662 individuals received one or more organs. There are differences in organ donation and transplantation by gender, age and race/ethnicity. As of August 2012, 114,719 individuals are on the waiting list for an organ transplant. Conclusion: Increased awareness of the importance of organ donation and registering as an organ donor is needed among young adults and females. Males need to be encouraged to be living donors. Efforts to educate the Hispanic and Asian communities are needed to promote awareness and willingness to be an organ donor. ¬¬
  • No Thumbnail Available
    Item
    Molecular Pathogenesis of Spinocerebellar Ataxia type 10
    (2013-06-03) Lim, Jung gook 1971-; Sarkar, Partha S; Ashizawa, Tetsuo; Chung, Jin Mo; Jackson, George R; Barral, Jose M
    Spinocerebellar ataxia type 10 (SCA10) is a unique autosomal dominant cerebellar ataxia (ADCA) which habors non-coding ATTCT repeat expansion on the 9th intron of the ATXN10 gene. The presence of seizure in addition to pancerebellar ataxia is a characteristic clinical manifestation of SCA10. How this enlarged intronic ATTCT repeat leads to degeneration or dysfunction of the nervous system underlying SCA10 phenotype is not well known. The present study focused on elucidating a molecular pathogenesis of this unique inherited disease. In this study, we demonstrated normally transcribed ATTCT-repeats form a lengthy AUUCU pre-mRNA molecule in SCA10 cells, after being completely spliced out. We identified the specific interaction between this AUUCU RNA repeat and a RNA-binding protein, Nova, which leads to the aberrant splicing of Nova target transcripts, including major inhibitory neurotransmitter receptors, glycine and GABA. Our study also indicated that the sequestration of the RNA-binding proteins by toxic expanded repeats result in complex SCA10 phenotype. We clearly showed that aberrant splicing of GABAARγ2 and GlyRα2 causes disruption of inhibitory transmission in Purkinje cells in the SCA10 cerebellum. We demonstrated that abnormal electrophysiology in SCA10 occurs specifically through modulating GABA neurotransmission but not glycine. In our current study, we were able to define SCA10 as a toxic RNA disease, and presented one of the possible molecular and electrophysiological mechanisms of SCA10 pathophysiology.
  • No Thumbnail Available
    Item
    Molecular Pathogenesis of Spinocerebellar Ataxia type 10
    (2013-06-03) Lim, Jung gook; Sarkar, Partha S; Ashizawa, Tetsuo; Chung, Jin Mo; Jackson, George R; Barral, Jose M
    Microsatellite plays a major pathogenic role in repeat expansion disorder. This heterogeneous group of disease is caused by the expanded sequences of nucleotide repeat within a target gene. Spinocerebellar ataxia type 10 (SCA10) is a unique autosomal dominant cerebellar ataxia (ADCA). The presence of seizure in addition to pancerebellar ataxia is a characteristic clinical manifestation of SCA10. More interestingly, the genetic mutation to cause SCA10 is a non-coding ATTCT repeat expansion located on the 9th intron of the ATXN10 gene. How this enlarged intronic ATTCT repeat leads to degeneration or dysfunction of the nervous system underlying SCA10 phenotype is not well known. The present study is focusing on elucidating a molecular pathogenesis of this unique inherited disease. In this study, we demonstrate normally transcribed ATTCT-repeat forms a lengthy AUUCU pre-mRNA molecule in SCA10 cells, after being completely spliced out. We identify the specific interaction between this AUUCU RNA repeat and a RNA-binding protein, Nova, which leads to the aberrant splicing of Nova target transcripts, including major inhibitory neurotransmitter receptors, glycine and GABA. Our study also indicates that the sequestration of the RNA-binding proteins by toxic expanded repeat results in complex SCA10 phenotype. We clearly show that aberrant splicing of GABAARγ2 and GlyRα2 causes disruption of inhibitory transmission in Purkinje cells in SCA10 cerebellum. We demonstrate that abnormal electrophysiology in SCA10 occurs specifically through modulating GABA neurotransmission but not glycine. In our current study, we are able to define SCA10 as a toxic RNA disease, and present one of the possible molecular and electrophysiological mechanisms of SCA10 pathophysiology.  
  • No Thumbnail Available
    Item
    Novel Insights Into Normal Aryl Hydrocarbon Receptor Biology Through the Regulation of Stanniocalcin 2
    (2013-06-03) Harper, Tod 1982-; Elferink, Cornelis J; Boldogh, Istvan; Bratton, Shawn B; Cheng, Xiaodong; Laezza, Fernanda
    Proper hepatocyte function is vital for survival; hence unrepaired destruction of the parenchymal tissue leading to liver decompensation is devastating. Therefore, understanding the homeostatic process regulating liver regeneration is clinically important, and evidence that the Aryl hydrocarbon Receptor (AhR) can promote cell survival following intrinsic apoptotic stimuli is integral to the regenerative process. Recent evidence suggests that the AhR promotes cell survival through the PI3K-Akt/PKB axis in the absence of an exogenous ligand. However this study was performed using a cancer cell line that does not accurately represent normal liver biology. Therefore, I hypothesize that the AhR mechanistically contributes to liver homeostasis through the regulation of genes hitherto not associated with AhR functions in the absence of an exogenous ligand. To test this hypothesis the current studies utilize primary hepatocytes to identify survival mechanisms consistent with normal AhR biology. Taking advantage of the Cre-lox system to manipulate AhR status, I report here that primary hepatocyte apoptosis is preferentially suppressed in cells expressing the AhR. Studies revealed that Akt/PKB activation previously linked to AhR dependent cell survival was not involved. Likewise, expression profiling of 84 key genes involved in apoptosis failed to account for the differential apoptotic susceptibility associated with AhR status. However, a comprehensive microarray analysis designed to identify immediate and direct changes in the transcriptome concomitant with AhR loss identified Stanniocalcin 2 (Stc2) as a novel receptor target gene previously reported to have a cytoprotective role in endoplasmic reticulum stress. The Stc2 promoter contains multiple xenobiotic response elements (XRE) clustered in a 250 bp region that was shown to recruit the AhR by chromatin immunoprecipitation. Interestingly, Stc2 gene expression is refractory to classic exogenous AhR agonists, but responds to cellular stress in an AhR-dependent mechanism consistent with a process promoting cell survival. In conclusion, AhR mediated transcriptional control of Stc2 represents a novel target gene associated with normal AhR biology that contributes mechanistically to liver homeostasis.
  • No Thumbnail Available
    Item
    Studies on Fortilin-Prohibitin Interaction
    (2013-06-03) Doan, Hung 1982-; Barral, Jose M; Fujise, Kenichi; Nesic-Taylor, Olivera; Wiktorowicz, John E; Goka, Thomas J
    Abstract: Apoptosis, programmed cell death, is a tightly regulated process that occurs in development, in tissue maintenance and turnover, and in regulating the immune system. Alterations in apoptosis regulation is known to be involved in various diseases including cancer, autoimmune diseases, and cardiovascular diseases including atherosclerosis initiation and maintenance. Fortilin is an antiapoptotic protein with a wide tissue distribution and a wide range of functions. fortilin has no sequence homology to other regulators of apoptosis, such as the Bcl-2 Proteins or the Inhibitors of Apoptosis proteins. In elucidating the mechanism of Fortilin-mediated cellular protection, fortilin protein interactions have been previously shown to modulate the cellular response to apoptotic stimuli. The goal of this dissertation is to investigate novel fortilin protein interactions in order to further shed light on the mechanism of fortilin mediated protection. In a proteomic screen fortilin was shown to interact with the anti-proliferative protein, prohibitin. I demonstrate that fortilin specifically interacts with this protein through in vitro studies. fortilin co-localizes with prohibitin in a perinuclear distribution and subcellular studies showed that fortilin and prohibitin are found in the nucleus, cytosol, and to a lesser degree in the endoplasmic reticulum. Fortilin was shown to mutually stabilize prohibitin. Finally, cells overexpressing fortilin and prohibitin attenuate the apoptosis response of cells compared to cells overexpressing either protein alone. In summary, these findings demonstrate a novel protein interaction between fortilin and prohibitin and shows a functional significance in modulating apoptosis after inducing cell stress.
  • No Thumbnail Available
    Item
    Behaving Collaboratively and Getting Along: A Classical Grounded Theory of Certified Nurse Midwives Collaborating With Physicians in U.S. Hospitals
    (2013-06-03) Nilsen, Susan 1958-; Phillips, Carolyn A; Mendias, Elnora (Nonnie) P.; Rahr, Richard R; Rath, Linda L; Camune, Barbara
    This dissertation is a classical grounded theory study that examines how certified nurse midwives perceive their collaborative role as they work with physicians in U.S. hospitals. The most common reason for hospitalization in the U.S. is birth and care of the newborn (Levit, Wier, Stranges, Ryan, & Elixhauser, 2009). Although the majority of women and their newborns are healthy, maternity care costs in the U.S. are staggering (Johantgen, Fountain, Zangaro, Newhouse, Hutt, & White, 2012). Collaboration within maternity healthcare teams may positively impact healthcare economics (Downe, Finlayson, & Fleming, 2010). Classical grounded theory methodology was used in the current study; it is a rigorous method suitable for exploring the processes of human social phenomenon (Glaser & Strauss, 1967). Classical grounded theory methodology is focused on the data which reveals the participants’ main concern. The participants’ main concern is discovered using Glaser’s (1978) constant comparative method. How participants resolve their main concern forms the basis for the basic social process/core category and subcategories. The links between the subcategories form the basis for the generation of substantive grounded theory. The most important finding of the current study is the discovery of the behaving collaboratively basic social process. This basic social process with its subcategories of holding, adjusting, and releasing fits the real life experiences of certified nurse midwives who work with physicians in U.S. hospitals. Certified nurse midwives in the current study perceived behaving collaboratively as a problematic experience and their main concern as getting along with their physician colleagues. The certified nurse midwives were able to resolve the problematic experience of behaving collaboratively through the phases of the subcategories which ultimately resulted in the generation of a substantive theory of getting along. Substantive theories explain the main concern of a specific group, in a specific setting, and predict the consequences of the modifiable conditions. Although the substantive theory of getting along described in this dissertation relates only to the certified nurse midwives who participated in the study, getting along has potential for the generation of formal grounded theory.
  • No Thumbnail Available
    Item
    MOLECULAR INSIGHTS AND PHYSIOLOGICAL CONSEQUENCES OF ARYL HYDROCARBON RECEPTOR REGULATED PLASMINOGEN ACTIVATOR INHIBITOR-1 EXPRESSION
    (2013-06-03) Wilson, Shelly; Elferink, Cornelis; Barton, Michelle; Cicalese, Luca; Boor, Paul; Papaconstantinou, John
    The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, attenuates liver regeneration in vivo when activated by its prototypical agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) following 70% partial hepatectomy (PH). One reported target of the AhR that may account for suppression of the regenerative response is plasminogen activator inhibitor-1 (PAI-1), which negatively regulates the cleavage and activation of hepatocyte growth factor (HGF) from its latent form in the extracellular matrix. Once activated, HGF signalling through its receptor cMet is a crucial component early in regeneration. Recent studies identified a sequence distinct from the canonical AhR binding site, the ncXRE, which confers TCDD-inducible expression to the PAI-1 promoter. Since the ncXRE shares partial sequence homology with the Kruppel-like factor 6 (KLF6) consensus binding site; I hypothesize that the AhR interacts with KLF6 at the ncXRE, inducing transcription of PAI-1, suppressing HGF processing and its activation of cMet, inhibiting liver regeneration. To test this hypothesis, coimmunoprecipitation on liver nuclear extracts and recombinant proteins confirmed that KLF6 and the AhR interact, likely dependent on the C-terminus transactivating domain of AhR and the DNA binding domain of KLF6. Both proteins bind the ncXRE in vitro and deletion analyses revealed that the N-terminal 27 amino acids of hKLF6 were required for complex formation. Chromatin immunoprecipitation studies demonstrated that the AhR and KLF6 bind to the PAI-1 promoter in vivo. To assess the effects of AhR activation in vivo, C57BL/6 and PAI-1-/- mice were pretreated with TCDD, underwent PH, and liver samples and serum were collected at multiple time points post-PH to monitor PAI-1 expression, HGF processing, and cMet phosphorylation (activation) and DNA synthesis in the liver. I found that PAI-1 transcript and corresponding serum PAI-1 protein levels were markedly increased in TCDD-pretreated C57BL/6 mice, and this rise in PAI-1 levels inversely correlated to HGF processing and cMet phosphorylation. Hepatocytes in the periportal region of PAI-1-/- mice were able to overcome TCDD-mediated suppression of regeneration. The AhR-KLF6 interaction at the PAI-1 promoter, resulting in increased PAI-1 expression and decreased HGF processing and cMet activation, reveals a novel mechanism by which the AhR may contribute to liver homeostasis.
  • No Thumbnail Available
    Item
    Discovering the Current Wound Management Practices of Rural Africans: a Pilot Study
    (2013-06-03) Benskin, Linda 1959-; Bishop, Sheryl L; Hill, Alice; Melby, Peter C; Bolton, Laura L
    Unrelenting heat, poor sanitation, lack of knowledge, and poverty contribute to a disabling wound prevalence that often exceeds 20% in rural areas of tropical developing countries. Wounds in this environment are usually poorly managed at very high cost. Traditional health practitioners and village health workers, rather than health professionals, provide health care in most villages. Wound management education for these nonprofessional health providers should include only sustainable practices which prove to be safe and effective in tropical villages. However, usual practice data, needed for comparison studies, is absent from the published literature. This pilot study introduced an innovative data collection method to overcome cultural obstacles which have prevented researchers from obtaining meaningful quantitative data in this challenging setting. Between August and October of 2012, seventy-five participants from 25 diverse villages in Ghana provided detailed descriptions of their current usual topical wound management methods by completing the stories of patients representing each of seven wound types commonly found in this setting. Responses were tabulated and categorized as congruent or not congruent with modern topical wound management principles within three domains and six subcategories (two for each domain). Four research questions organized the data analysis. The wound management practices of nonprofessional health care providers were identified and described in detail for the first time. These results are foundational to the process of developing culturally and environmentally appropriate wound management protocols for indigenous wound care providers in rural areas of tropical developing countries. In addition, several significant differences in the wound management of the three nonprofessional provider groups were found. The unique data collection method introduced in this study can easily be adapted to rural areas of other tropical developing countries. When sufficient data have been accumulated, the information can be utilized to design comparison studies so that the ecological validity of the wound management protocols in planned educational programs can be ensured.
  • No Thumbnail Available
    Item
    Inpatient Rehabilitation Outcomes for Patients with Debility
    (2013-06-03) Galloway, Rebecca 1977-; Ottenbacher, Kenneth J; Granger, Carl V; Raji, Mukaila; Tan, Alai; Graham, James E
    Background: Inpatient rehabilitation facility (IRF) goals are to optimize functional independence and discharge patients to community living. Debility, or deconditioning associated with hospitalization, is the fourth most common impairment group, accounting for about 10% of IRF cases. Objectives were to provide benchmark data for patients with debility, consider trends with respect to health care policy changes, identify risk factors for discharge to acute or subacute care, and examine readmission to acute care after discharge to community. Aim 1: National benchmark data for years 2000 – 2010 were retrospectively analyzed for 260,373 patients from 830 IRFs contributing to the Uniform Data System for Medical Rehabilitation. Trends from 2000 to 2010 included decrease in mean (SD) FIM® instrument (“FIM”) total admission ratings from 73.9 (16.2) to 62.5 (15.8). FIM total discharge ratings decreased from 95.0 (19.7) in 2000 to 88.2 (19.8) in 2010. Mean length of stay decreased from 14.3 (9.1) in 2000 to 12.1 (6.2) days in 2010. FIM efficiency increased from 1.9 (1.7) in 2000 to 2.4 (1.9) in 2010. Discharge to community decreased from 80% in 2000 to 75% in 2010. Health policy changes may have influenced trends. Aims 2 & 3: Centers for Medicare and Medicaid Services data (years 2006 to 2009) were analyzed for factors associated with discharge to acute or subacute care (N = 67,626) and readmissions for 90 days following discharge (N = 45,424). Discharge setting was 76% community, 13% subacute, and 11% acute care. Significant risk factors for both acute and subacute discharge settings were lower FIM motor subscale, male gender, living alone, comorbidity tier, weight loss, and fluid/electrolyte disorders. Rehospitalization rates were 19% at 30 days and 34% at 90 days. Congestive heart failure, renal failure, and chronic pulmonary disease were common causes of hospital readmission and independent risk factors for reshospitalization. Conclusions: National data indicate the number of debility cases is increasing with diverse etiologic diagnoses. A high proportion of patients discharged to acute or subacute care. One-third of patients who discharged to the community experienced acute hospital readmission within 90 days. Functional independence is an important indicator for discharge setting and rehospitalization.
  • No Thumbnail Available
    Item
    Impact of Diabetes Comorbidity on Health Outcomes in Patients Undergoing Medical Rehabilitation after Lower Extremity Joint Arthroplasty
    (2013-06-03) Karmarkar, Amol; Ottenbacher, Kenneth J; Arcari, Christine M; Graham, James E
    Introduction: Diabetes is one of the rapidly increasing chronic conditions that can impact the health and well-being of individuals. Objectives: To determine the prevalence of diabetes in patients receiving medical rehabilitation after lower extremity joint replacement and to examine the associations between diabetes as comorbidity and outcomes including functional status, likelihood of discharge to acute care, and 90-day hospital readmission. Methods: Secondary analysis of Medicare data. We selected patients who underwent a primary hip/knee joint replacement procedure during 2007-2008. We identified diabetes-related ICD-9CM codes in the Medicare Provider Analysis and Review and Inpatient Rehabilitation Facilities Patient Assessment Instrument data files, and created a three-level diabetes status: no diabetes, non-tier diabetes (controlled diabetes), and tier diabetes (uncontrolled diabetes). The effect of diabetes status on functional status gain was estimated using multivariate regression models. Discharge to acute care (yes/no) after inpatient rehabilitation was compared against discharge to community using multinomial logistic regression. Hospital readmission (yes/no) rates were estimated using Cox regression hazard models. Results: The prevalence of controlled diabetes in the knee and hip joint replacement cohorts was 21% and 17%, respectively; uncontrolled diabetes was identified in 4% and 3% of patients, respectively. The adjusted effect of diabetes status on functional status gain was minimal. The likelihood of discharge to acute care was explained by marital status and discharge functional scores, as compared to diabetes status, in both knee and hip cohorts. Using no diabetes as the reference group, the risk of hospital readmission in the hip cohort was 19% higher for those with controlled diabetes (HR=1.19, 95% CI=1.08-1.30) and 31% higher for those with uncontrolled diabetes (HR=1.31, 95% CI=1.08-1.59). In the knee cohort the risk was 22% higher for those with controlled diabetes (HR=1.22, 95% CI=1.14-1.30) and 43% higher for those with uncontrolled diabetes (HR=1.43, 95% CI=1.26-1.61). Conclusion and Implications: Our findings indicate diabetes is an important comorbid condition across the continuum of care. Strategies to better manage diabetes, both prior to elective procedures such as joint replacement, and throughout the following rehabilitation stay and recovery phases, could improve the overall efficiency and quality of care in this population.
  • No Thumbnail Available
    Item
    Inpatient Rehabilitation Outcomes for Patients with Debility
    (2013-06-03) Galloway, Rebecca 1977-; Ottenbacher, Kenneth J; Granger, Carl V; Raji, Mukaila; Tan, Alai; Graham, James E
    Background: Inpatient rehabilitation facility (IRF) goals are to optimize functional independence and discharge patients to community living. Debility, or deconditioning associated with hospitalization, is the fourth most common impairment group, accounting for about 10% of IRF cases. Objectives were to provide benchmark data for patients with debility, consider trends with respect to health care policy changes, identify risk factors for discharge to acute or subacute care, and examine readmission to acute care after discharge to community. Aim 1: National benchmark data for years 2000 – 2010 were retrospectively analyzed for 260,373 patients from 830 IRFs contributing to the Uniform Data System for Medical Rehabilitation. Trends from 2000 to 2010 included decrease in mean (SD) FIM® instrument (“FIM”) total admission ratings from 73.9 (16.2) to 62.5 (15.8). FIM total discharge ratings decreased from 95.0 (19.7) in 2000 to 88.2 (19.8) in 2010. Mean length of stay decreased from 14.3 (9.1) in 2000 to 12.1 (6.2) days in 2010. FIM efficiency increased from 1.9 (1.7) in 2000 to 2.4 (1.9) in 2010. Discharge to community decreased from 80% in 2000 to 75% in 2010. Health policy changes may have influenced trends. Aims 2 & 3: Centers for Medicare and Medicaid Services data (years 2006 to 2009) were analyzed for factors associated with discharge to acute or subacute care (N = 67,626) and readmissions for 90 days following discharge (N = 45,424). Discharge setting was 76% community, 13% subacute, and 11% acute care. Significant risk factors for both acute and subacute discharge settings were lower FIM motor subscale, male gender, living alone, comorbidity tier, weight loss, and fluid/electrolyte disorders. Rehospitalization rates were 19% at 30 days and 34% at 90 days. Congestive heart failure, renal failure, and chronic pulmonary disease were common causes of hospital readmission and independent risk factors for reshospitalization. Conclusions: National data indicate the number of debility cases is increasing with diverse etiologic diagnoses. A high proportion of patients discharged to acute or subacute care. One-third of patients who discharged to the community experienced acute hospital readmission within 90 days. Functional independence is an important indicator for discharge setting and rehospitalization.
  • No Thumbnail Available
    Item
    Post Traumatic Story Disorder: Using the Power of Narrative to Heal the Invisible Wounds of War
    (2013-06-03) Genovese, Jacqueline 1964-; Hudson-Jones, Dr. Anne; Clark, Dr. Mark; Rhoads, Dr. Jacqueline
    Abstract Soldiers traumatized by war often experience debilitating effects of invisible wounds such as post-traumatic stress disorder (PTSD). An obstacle to recovery from PTSD for male soldiers can be an inability to share their stories. This obstacle is exacerbated by the construct of American masculinity in the military and society. The purpose of this thesis is to explore the efficacy of the use of narrative to overcome male soldiers’ inability to share their stories. Using psychiatrist Jonathan Shay’s concepts of moral injury, the shrinking of the social and moral horizon, and the berserk state, this work illuminates the moral injury that can lead to PTSD and explores the brain injury associated with PTSD― two factors that can contribute to post-traumatic story disorder. The research methods used for this thesis included a literature review exploring the timelessness of war trauma, the experience of trauma and its effect on the physiology of the brain, and the effectiveness of narrative intervention. This review covered historical and contemporary narratives from wars in Ancient Greece, Renaissance Europe, the American Civil War, World War I, World War II, the Vietnam War, and the wars in Iraq and Afghanistan. I conducted interviews with service members and veterans with and without PTSD, health-care professionals treating soldiers with PTSD, and veterans currently using writing as a form of healing for themselves and others. I also participated in a conference employing the arts as a mode of expression for service members with PTSD. My research, interviews, and observations resulted in an understanding of the power of narrative to facilitate storytelling and listening, particularly for male soldiers. As an indirect form of communication, narrative can help soldiers tell their stories through the words and experiences of others, and provide tools to give shape and meaning to their own experiences. Narrative also offers a window to the world of war and war trauma that can facilitate understanding for civilian personnel caring for soldiers with PTSD. In conclusion, I propose the utilization of narrative interventions by military, medical and civilian communities in an effort to help soldiers recover from the invisible wounds of war.
  • No Thumbnail Available
    Item
    Tuberculosis: Epidemiology, Diagnosis, Treatment, Prevention and Control in the United States and Worldwide
    (2013-06-03) Calderon, Veronica Elena; Mayhall, C. Glen; Arcari, Christine; de Boer, Melanie
    TB is one of the most common infectious diseases worldwide. Approximately one-third of the world’s population is infected with TB. In 2011, there are about 9 million new infections and almost 1.4 million deaths. Furthermore, TB is the leading cause of death in HIV-positive individuals. With the global HIV pandemic and the emergence of MDR- and XDR-TB, new diagnostics and treatments are urgently needed for the control and prevention of TB. Ultimately, the coordinated efforts of international and national government agencies, non-government agencies, healthcare professionals, and the public is needed to ensure the implementation and adherence of control strategies that will lead to the eradication of TB. This capstone will focus on the epidemiological and clinical aspects of TB, and the TB prevention and control measures as recommended by national and international organizations. The objectives of this project were accomplished through the direct observation of TB control and prevention measures in the hospital (UTMB) and public health (Galveston County Health District) settings. In addition, an extensive literature review was performed to gain a complete understanding of TB epidemiology, diagnostics, treatments, and prevention and control strategies.
  • No Thumbnail Available
    Item
    CHEMICAL MIXTURES OF XENOESTROGENS AND THEIR METABOLITES ALTER ESTRADIOL-INDUCED NON-GENOMIC SIGNALING
    (2013-06-03) Vinas, Rene; Watson, Cheryl S.; Cheng, Xiaodong; Laezza, Fernanda; Midoro-Horiuti, Terumi; Boonayaratanakornkit, Viroj
    BACKGROUND: Xenoestrogens (XEs) pose a threat to human health by disrupting natural responses of physiologic estrogens. Bisphenol-A (BPA), a plastics monomer, is potently estrogenic via non-genomic signaling; however, bisphenol-S (BPS), a BPA substitute, has unknown endocrine actions. Nonylphenol is a surfactant and a ubiquitous contaminant. Our goals were to use a well-characterized estrogen-responsive cell model, the GH3/B6/F10 pituitary line, to characterize the potentially potent nongenomic signaling and functional responses to these compounds alone, as mixtures, as metabolites and congeners, and in combination with estradiol (E2), while also automating these assays to facilitate future screening of a potentially large number of XEs. METHODOLOGY: Environmentally relevant concentrations of XEs (10-15-10-7M) were assessed individually and as mixtures by challenging 1nM E2-induced responses. We quantified phospho-activation of extracellular signal-regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs) by multi-well plate immunoassays. Cell proliferation was assessed by crystal violet assay, while apoptosis (caspase-8, -9) was assessed via the release of 7-amino-4-trifluoromethylcoumarin. Prolactin release was measured by radio-immunoassay after 1 min XE exposures. The BIOMEK FXP workstation was used to develop an automated screening system for changes in MAPKs activities due to XE exposures. RESULTS: XEs often activated MAPKs in a non-monotonic dose- and oscillating time-dependent (2.5-60 min) manner and attenuated 1nM E2 responses. While individual bisphenols did not activate JNK as NP did, the combination of all XEs with E2 generated an enhanced non-monotonic JNK dose-response. E2 and all XE compounds induced cell proliferation, while mixtures of these compounds with E2 suppressed proliferation. Caspase 8 activity was suppressed by E2, and elevated by BPS, while caspase 9 activity was inhibited by E2 and some XE combinations at later times. Mono- and di-chlorinated BPA activated, while tri-chlorinated BPA dephosphorylated ERK. Di- and tri-chlorinated BPAs caused JNK dephosphorylation. Phase II metabolites (sulfated and glucuronidated) were mostly unable to activate either kinase and in some cases severely inactivated them. CONCLUSIONS: Novel chemical analogues and conjugated forms of BPA individually or as mixtures with other known XEs had dramatic disrupting effects on physiologic estrogens, disrupting mechanisms of cell regulation and their downstream functional responses.
  • No Thumbnail Available
    Item
    Evaluation of granulysin and perforin as candidate biomarkers for protection following vaccination with Mycobacterium bovis BCG or M. bovis DeltaRD1
    (2008-09-18) Charles Fernando Capinos Scherer; D. Mark Estes; Slobodan Paessler; Janice J. Endsley; Gregg N. Milligan; Bernardo Villarreal-Ramos; Alfredo G. Torres
    The development of improved vaccines against tuberculosis (TB) is directly linked to the investigation of new and better correlates of protection after vaccination against TB. Cloning and characterization of bovine homologues of the antimicrobial protein granulysin (Bo-lysin) and perforin by our group could be used as potential biomarkers for TB vaccination efficacy. In the present study we examined the kinetics of granulysin, perforin, IFNgamma and Fas-L responses to Mycobacterium bovis purified protein derivative (PPD) stimulation by peripheral blood mononuclear cells from M. bovis DeltaRD1-, BCG- and non-vaccinated cattle. Gene expression profiles following PPD stimulation showed significant increases in transcripts for granulysin and IFNgamma in both CD4+ and CD8+ T cells in BCG-vaccinated as compared to non-vaccinated animals. Perforin and IFNgamma examined by flow cytometry, showed a difference of 1-2% more PPD-specific cells in BCG-vaccinated than non-vaccinated animals. In the vaccine trial, granulysin and perforin were significantly increased in both vaccine groups as compared to control after vaccination and challenge. IFNgamma expression was increased only after vaccination and secretion was higher in the control, as compared to both vaccine groups demonstrating no correlation with protection upon vaccination. In summary, results shown here provide evidence that granulysin and perforin are prospective candidates as biomarkers of protection after vaccination against TB.
  • No Thumbnail Available
    Item
    Sylvatic dengue: evolution, emergence, and impact on human health
    (2007-10-24) Nikolaos Vasilakis; Scott C. Weaver; Stanley J. Watowich; Robert B. Tesh; Peter W. Mason; Kathryn A. Hanley; D. Mark Estes
    Dengue viruses (DENV) are the most important arboviral pathogens in tropical and subtropical regions throughout the world. Transmission includes a sylvatic, enzootic cycle between nonhuman primates and arboreal mosquitoes of the genus Aedes, and an urban, endemic/epidemic cycle between Aedes aegypti, a mosquito with larval development in peridomestic water containers, and human reservoir hosts. All 4 serotypes of endemic DENV evolved independently from ancestral sylvatic viruses and have become both ecologically and evolutionarily distinct. The independent evolutionary events that resulted in the emergence of DENV were facilitated by the expansion of DENV progenitors’ host range in Asia to new vectors and hosts that occurred gradually over a period of several hundred years. Emerging viral pathogens often become human pathogens by changing their host range from another vertebrate organism. This study assessed the likelihood of current sylvatic DENV-2 strains to emerge into the human transmission cycle by investigating the factors that facilitate their emergence. My analysis of sylvatic and endemic DENV-2 strains’ ability to replicate in two surrogate human model hosts, determined that adaptation to humans is probably not a necessary component of sylvatic dengue emergence. Then, through an analysis of several sylvatic DENV-2, I demonstrated that both endemic and sylvatic DENV-2 share similar rates of evolutionary change and patterns of natural selection. These findings imply that the potential of future DENV re-emergence from the sylvatic cycle is high. Subsequently, phylogenetic analysis of virus genomes isolated from febrile patients in Nigeria during DENV-2 activity, demonstrated that unrecognized outbreaks of sylvatic DENV-2 in humans are possible. However, their re-emergence into the endemic cycle would be limited by homotypic immunity mediated by virus neutralizing antibodies.
  • No Thumbnail Available
    Item
    PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy
    (2008-11-25) Lindsey Nicole Jackson; B. Mark Evers, M.D.; Sundararajah Thevananther, Ph.D.; Kathleen O'Connor, Ph.D.; Frank C. Schmalstieg, M.D., Ph.D.; Cornelis Elferink, Ph.D.
    Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85Ą regulatory and a p110Ą catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In these studies, I used the potent PI3K inhibitor, wortmannin, and small-interfering RNA (siRNA) targeting the p85Ą and p110Ą subunits to determine if total or selective PI3K inhibition would abrogate the proliferative response of the liver following resection. After partial hepatectomy in mice, there is an increase in PI3K activity; total PI3K blockade with wortmannin, and selective inhibition of p85Ą or p110Ą with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest timepoints (ie, 48h and 72h). Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85Ą or p110Ą, as reflected by a paucity of F4/80+ cells present by immunohistochemistry (IHC). Additionally, PI3K inhibition led to an aberrant hepatocyte architecture characterized by vacuolization, lipid deposition, and glycogen accumulation. My data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, perhaps by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication.
  • No Thumbnail Available
    Item
    The role of ionotropic glutamate receptors in chronic central pain after spinal cord injury
    (2005-12-12) Huaiyu Tan; Claire Hulsebosch, Ph.D.; William D. Willis, M.D./Ph.D.; Volker E. Neugebauer, M.D./Ph.D.; Martin Grabois, M.D.; B. Mark Evers, M.D.
    Spinal cord injury (SCI) results in both loss of function and chronic central pain syndromes. In the clinical population, pain is characterized based on anatomical location: 1) Below-level pain – located at dermatomes corresponding to spinal segments caudal to the injury site, 2) At-level pain – located at dermatomes corresponding to spinal segments immediately adjacent to the injury site, 3) Above-level pain – located at segments rostral to the injury site (in area of sensory preservation). \r\n A contusion model of SCI was first characterized behaviorally and electrophysiologically. A contusion at spinal segment T10 at 150 kdynes of force and a 1 second dwell time resulted in the pain like behavior in the hindlimbs, thoracic region, and forelimbs 35 days post-injury. These contused animals exhibited spinal hyperexcitability during extracellular single-unit electrophysiological spinal recordings from the dorsal horn of the lumbar enlargement (below-level), thoracic cord (at-level; immediately rostral to injury site), and brachial enlargement (above level). \r\n In models of peripheral injury, increased ionotropic glutamate receptor mediated activity results in spinal central sensitization. Extracellular single-unit recordings from all three regions of the spinal cord (lumbar enlargement, thoracic cord, and brachial enlargement) were made on both contused and non-contused animals during ionotropic glutamate antagonist treatment (D-AP5 or NBQX). The thoracic cord, which is nearest to the site of injury, showed the greatest increase in ionotropic glutamate receptor mediated activity. \r\n Calcium-calmodulin protein kinase II (CaMKII) has been shown to be responsible for enhancing ionotropic glutamate receptor mediated activity. CaMKII also has been shown to be a molecular intermediate in both long-term potentiation (LTP) and peripherally induced central sensitization. After contusive SCI, the segments immediately rostral to the injury site show an increase in activated CaMKII. Application of CaMKII inhibitor, KN-93, during recording 35 days post injury, reduces spinal hyperexcitability induced by SCI. \r\n