University of Texas Medical Branch

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    2D layout of bead based thioaptamer/aptamer selection platform for therapeutics and diagnostics
    (2007-07-20) Xu Zhao; Bruce A. Luxon; William D. Willis; L.Lilian Chan
    Nucleic acid research has expanded the way we can intervene with biological systems. Especially, oligonucleotide agents (ODN or aptamers) are believed to affect cell function via complementary recognition or binding to specific proteins by forming tertiary structure. This opens new ways in therapeutics and diagnostics. The phosphoro- mono-/di- thioate substitutions in the backbone (termed “thioaptamer”) grants ODN nuclease resistance and higher binding affinity. \r\nA bead-based combinatorial library, in which every bead contains a unique species of aptamers, provides a promising platform for selection of aptamers and thioaptamers. To successfully screen the bead-based library, 2D layout of beads in gel and on bead screening model is proposed. To develop the 2D layout of beads and its corresponding functional assays, a model system is first established: NF-kappa B proteins were expressed, purified and characterized. Thioaptamer XBY6, which specifically targets NF-kappa B protein, and its natural origin, I-kappa B were synthesized and verified. Thioaptamer purification using FPLC and HPLC was also investigated, and several 5’-funtionalized thioaptamers were successfully purified. Electrophoretic mobility shifting assay (EMSA) has been used to verify XBY6 binding, and ELISA assay has been used to verify I-kappa B binding towards human recombinant NF-kappa B protein. Preliminary study of bead in 2D gel showed applicability of bead-based selection and thus on bead functional assays were developed. Both double strand one species library with I-kappa B sequence and a 212=4096 different species beads library were constructed and verified. The library was then tested using on-bead EMSA like assay and ELISA assay. Both assays showed encouraging results for 2D layout selection and further enhancement of visualization (signal/noise improvement) is discussed. \r\nThe project suggested that 2D layout of beads in gel (PAGE) is well suited for parallel high-throughput selection of thioaptamers and aptamers, thus paving a new way for drug discovery and future therapeutics and diagnostics.\r\n
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    A 4-month randomized controlled clinical trial of adjuvant exenatide or pramlintide versus insulin alone in pediatric type 1 diabetes mellitus: Effect on glycemic control
    (2010-07-29) Sarah Elizabeth Withycombe; Elena Volpi; Melinda Sheffield-Moore; Antonella Casola
    This study investigates the effects of 16 weeks of treatment with adjuvant Exenatide or Pramlintide versus insulin alone on glycemic control, as measured by glycated hemoglobin (HbA1C) and 1,5-Anhydroglucitol (1,5-AG), or GlycoMark, in pediatric Type 1 Diabetes Mellitus (T1DM). We present here the preliminary results (n=24) of a Phase III randomized clinical trial designed to compare the glycemic effects of using adjuvant Pramlintide or Exenatide versus insulin alone in pediatric T1DM. Sample size calculations estimated 21 patients per treatment arm (63 total) are needed. So far, 24 patients have been recruited from Texas Children’s Hospital’s main Diabetes Care Center or its outlying clinics in the Houston, TX area. Recruited patients were randomized to one of 3 treatment arms (Pramlintide + insulin, Exenatide + insulin, or insulin alone) and completed 16 weeks of treatment. HbA1C and 1,5-AG levels were the primary endpoints analyzed as measures of glycemic control. All statistical analyses were\r\ndone using two-sample t-tests assuming equal variance and paired two-sample t-tests performed in Excel. No statistical differences in ΔHbA1C or Δ1,5-AG were observed between each treatment arm and the insulin control arm. Similarly, no statistical differences in HbA1C or 1,5-AG were reported within each group from baseline to 16 weeks. These preliminary data suggest that addition of Pramlintide or Exenatide to insulin regimen of pediatric T1DM does not improve glycemic control. However, reevaluation of the results upon study completion is warranted.
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    Acculturation and disability in Mexican American older adults
    (2008-11-19) Mary Ellen E. Kuhlmann; Kenneth Ottenbacher, Ph.D.; Ronald Angel, Ph.D.; M. Kristen Peek, Ph.D.; Laura Ray, M.P.A.; Judith Drew, Ph.D., R.N.; Gayle Weaver, Ph.D.; Elbert Whorton, M.S., Ph.D.
    Abstract: The purpose of this study is to examine acculturation and disability in Mexican American older adults living independently in the southwestern United States. Design: A prospective cohort study (1993-2005). Setting: Texas, New Mexico, Colorado, Arizona, and California. Participants: Participants in the Hispanic Established Population for Epidemiologic Studies of the Elderly (H-EPESE), a population-based sample of 3050 non-institutionalized Mexican-American men and women aged 65 and over. Measures: Variables included three measures of acculturation (English proficiency, English usage, and Mainstream contact), risk factors (age, gender, education, marital status, and BMI), disablement process factors (chronic pathology, cognitive status, and physical performance), and activities of daily living disability (ADLs), and instrumental activities of daily living disability (IADLs). Chi-Square, Chi-Square test for trends, ordinary least squares regression and discrete hazard analyses were used to identify associations of measures of acculturation with incidence of ADL and IADL disability. Results: There was a significant association between one measure of acculturation (English proficiency) and incidence of IADL disability, which remained after adding risk factors and Disablement process variables to the model. Conclusion: The findings support the importance of acculturation when examining ADL and IADL disability. Interventions that consider acculturation may be useful in reducing ADL and IADL disability in Mexican American older adults.
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    Acute febrile respiratory illness aboard ships in the US Navy
    (2009-08-01) Jonathan F. Stinson; Christine Arcari, Ph.D.; Miriam Alter, Ph.D.; Laura Rudkin, Ph.D.
    Acute Febrile Respiratory Illness (A/FRI) is a common but significant category of illness with world wide effect and impact on morbidity and mortality. In the shipboard environment the environmental, susceptibility and exposure factors that favor the spread of A/FRI are augmented. This paper assesses the risk of A/FRI aboard US Navy ships and compares that risk to preparations and policy already in place to reduce the risk of epidemics aboard ships. For ships to have the best chance at avoiding disabling epidemics, improvements are needed in the following five areas: 1) accurate and timely medical intelligence about A/FRI outbreaks worldwide, disseminated to all ships medical departments, as well as aggressive ship board surveillance programs with rapid testing Influenza kits and real time submission up the chain of command, 2) mandated education for all shipboard personnel about proper hygiene, the avoidance of disease, and self reporting of symptoms to facilitate early diagnosis and intervention if needed, 3) facilitation of early detection of outbreaks through the widespread availability and use of point of care rapid testing for influenza A & B with reflex testing to identify Avian Flu or novel strains, 4) early treatment with antiviral medications including keeping supplies aboard for ready use to avoid time delay in procurement, and 5) development of effective respiratory isolation methods and procedures standardized by ship class, established, in place and ready for immediate use. Improvements in these five critical areas are necessary to avoid the potential of an A/FRI epidemic aboard ship and its resultant impact on morbidity, mortality and operational readiness.
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    Adaptation of Chikungunya virus to Aedes albopictus mosquitoes: The role of mutations in the E1 AND E2 glycoproteins
    (2009-10-08) Konstantin Tsetsarkin; Stephen Higgs; Stanley J. Watowich; Scott C. Weaver; Robert B. Tesh; Margaret Kielian
    Chikungunya virus (CHIKV) is a positive sense single-stranded RNA virus in the family Togaviridae that between 2005 and 2007 caused its largest outbreak/epidemic in documented history, affecting parts of Africa, the Indian Ocean islands, India, and Europe. An unusual feature of this epidemic was the involvement of the previously unrecognized vector of CHIKV: Ae. (Stegomyia) albopictus mosquitoes. It was postulated that genetic changes in the virus might have contributed to the scale of these epidemics by facilitating CHIKV transmission by Ae. albopictus mosquitoes. In order to characterize genetic factors that might influence the ability of CHIKV to be transmitted by Ae. albopictus, I developed full-length infectious clone (i.c.) (pCHIKV-LR i.c.) and an i.c. that expressed enhanced green fluorescent protein (eGFP) from either a 3’ or 5’ additional sub-genomic promoters (pCHIKV-LR 3’GFP and pCHIKV-LR 5’GFP respectively) based on a CHIKV strain isolated during 2005-2006 epidemic on Reunion Island (LR2006 OPY1). The viruses produced from these i.c. were characterized in cell culture and in Ae. aegypti and Ae. albopictus mosquitoes. I concluded that, pCHIKV-LR i.c. and pCHIKV-LR 5’GFP infectious clones are suitable for investigation of the genetic factors influencing CHIKV fitness in the mosquito and vertebrate hosts. \r\nPrevious phylogenetic analysis had demonstrated that the 2005-2006 epidemic on Reunion Island was associated with a strain of CHIKV with a mutation in the E1 glycoprotein (E1-A226V). Using viral infectious clones of Reunion and West African strains of CHIKV, into which either the E1-226 A or V residues were engineered, I demonstrated that the E1-A226V mutation was directly responsible for a significant increase in CHIKV infectivity for Ae. albopictus, and led to more efficient viral dissemination into mosquito secondary organs and transmission to suckling mice. I also demonstrated that increased CHIKV infectivity of Ae. albopictus midgut cells associated with the E1-A226V mutation is directly responsible for more efficient virus replication in the mosquito, more rapid dissemination of the virus into salivary glands and more efficient transmission. Interestingly, this mutation caused a marginal decrease in the ability of CHIKV to infect the Ae. (Stegomyia) aegypti midgut, but had no effect on viral dissemination, and was associated with a slight increase in transmission by Ae. aegypti. These findings demonstrate that the E1-A226V mutation confers CHIKV adaptation to transmission by Ae. albopictus, and provide a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical vector.\r\nI also demonstrated that the E1-A226V mutation is associated with an increase in cholesterol-dependency of CHIKV for growth and entry into C6/36 cells, and is responsible for increase in the pH dependency of CHIKV fusion reaction. However, analysis of viruses with specific mutations at position E1-226, and at other CHIKV genomic regions that modulate cholesterol dependency of CHIKV, demonstrated that there is no clear mechanistic correlation between dependency for cholesterol and increased infectivity to Ae. albopictus mosquitoes. Also no correlation was observed between pH dependency of CHIKV fusion and infectivity to Ae. albopictus mosquitoes. Based on these data, I conclude that the E1-A226V mutation probably acts at different steps of the CHIKV life cycle, affecting multiple functions of the virus.\r\nUsing i.c. of Reunion and Ugandan strains of CHIKV, I demonsrated that mutations at positions 60 and 211 of the E2 glycoprotein of CHIKV are responsible for modulating the effect of the E1-A226V mutation on CHIKV infectivity for Ae. albopictus. Analysis of the effect of the mutations at E2-211 on CHIKV replication in cell culture and on CHIKV binding to the brush border membrane proteins of Ae.albopictus midgut cells, indicated that different residues at E2-211 might differentially affect the ability of CHIKV to interact with specific proteins expressed on the surface of midgut epithelial cells. I hypothesized, that after internalization by endocytosis, these interactions might determine the particular location within endosomal compartments where the CHIKV membrane fusion and release of virus nucleocapsid occur.\r\nThe information from the present study provides insight into the processes of CHIKV adaptation to a new vector species, which would determine the potential threat for spreading and establishment of CHIKV in tropical and temperate regions populated with Ae. albopictus mosquitoes.\r\n
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    Airsickness treatment and prevention: Recommendations regarding antiemetics and/or acustimulation
    (2007-03-30) Shean Eric Phelps; Dr. Billy U. Philips; Dr. Darlene A. Martin; Dr. Daniel H. Freeman
    Airsickness has been an important concern for aviation since before World War II. Airsickness is still a topic of serious discussion in the aviation community, despite recent advances in medical science, aircraft engineering and performance. Symptoms of motion sickness range from mild to incapacitating in nature and can cause degradation in performance measures of reaction time, postural stability and cognitive functioning. This can result in unacceptable work force losses, incur significant costs, and ultimately result in mission compromise and/or missing critical objectives. Current pharmacological interventions may produce side effects such as sedation and diminished cognition. \r\nAcustimulation at the median P6, or Neiguan, point has recently generated interest as a non-pharmacological means of preventing motion sickness. A recent study evaluating a popular acupressure wristband reported it to be effective in the suppression of the major symptoms (nausea and vomiting) of motion sickness. This study concluded that continuous vigorous stimulation of the P6 point was required to achieve a significant benefit. \r\nThe commercially available Reliefband® provides electrical acustimulation at the P6 point thereby reportedly countering symptoms of chemotherapy-induced nausea and vomiting. Its makers market it as “the only FDA-cleared device for motion sickness”. A literature search revealed that no published studies comparing currently available pharmacologic and non-pharmacologic (Reliefband®) motion sickness treatments in conjunction with rotary wing operations are available. \r\nThis capstone describes a randomized, double blind, cross over study comparing the effectiveness of four airsickness countermeasures to a placebo control and to each other on reaction time, postural stability, and cognition in relation to airsickness symptom severity and their ability to ameliorate performance declines following simulated rotary wing combat operations. The data suggest that only the combination of phenergan with caffeine was effective in achieving these measures. This study will help enable the aerospace medical community to make recommendations to military commanders and civilian policy makers concerning the ability of viable treatments to mitigate performance decrements seen because of rotary wing flight induced motion sickness. \r\n
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    Alcoholism treatment in native americans
    (2008-04-21) David W. Cole; Laura Rudkin, Ph.D.; Jean Freeman, Ph.D.; Bret Simon
    The detrimental effects of alcohol misuse and dependence are well documented across all ethnicities. In particular, it is an important public health issue among Native Americans with their rates of preventable deaths (in large part alcohol related) at 133% higher than their European American counterparts. One of the problems of current addiction models is that they historically have been developed based on a predominantly white American male sample. Programs approach Native Americans’ alcohol abuse as the same as other ethnic groups, forgetting important cultural and historical factors unique to this population. I examined the correlates of alcoholism in this targeted population and addressed whether there are relevant cultural factors specific to this population. I then located and described select existing programs currently used for treatment of alcohol abuse. I compared the current treatment strategies and identified characteristics of the programs that may be most effective.
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    Analysis of aspects of health care delivery and safety for space tourism and space passengers
    (2008-03-13) Joseph Paul Dervay; Clarence Jernigan, MD; Richard Jennings, MD; Clarence Peters, MD
    Non-career space travelers from around the world will be venturing into space as commercial programs develop and mature. There are multiple forces promoting human suborbital and orbital flight, including; public interest and desire, market and financial drivers, technological advances, and a paradigm shift from governmental to privately funded space enterprises. This Capstone project seeks to evaluate factors of health and safety related to the space traveling general public. These elements involve: (1) pre-mission medical standards and evaluation, (2) medical risk mitigation, (3) physiological impacts of acceleration, microgravity, and radiation exposure, (4) in-flight medical monitoring and health care delivery, (5) pre-flight training, and (6) regulatory issues. Space tourism has indeed started, and the coming decades will see this dream of flight come true for a sizeable number of participants.
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    Analysis of nuclear transport signals of the human apurinic/apurimidinic endonuclease (APE1/REF1)
    (2005-04-22) Elias Bernard Jackson Jr.; Sankar Mitra; John Papaconstantinou; Istvan Boldogh; Guillermo Altenberg; Ben Van Houten
    The nuclear localization signal (NLS) in human apurinic/apyrimidinic endonuclease (APE1), a key protein in both DNA base excision repair and transcriptional regulation, has not been analyzed in detail. We examined the role of specific residues in nuclear translocation of APE1, using green fluorescent protein (EGFP) fused to APE1 as a reporter. Nuclear localization (NL) of ectopic APE1 was abrogated for the mutant lacking 20 N-terminal aa residues (ND20). Fusion of these 20 residues directed nuclear localization of EGFP. While an APE1 mutant lacking N-terminal 7 residues (ND7 APE1) showed normal nuclear localization, ND7 APE1 with E12A/D13A double mutation resulted in drastic decrease of nuclear localization, indicating that E12 and D13 are critical components of the NLS. \r\n On the other hand, nuclear localization of the full-length APE1 containing the E12A/D13A mutations suggests that the putative NLS and residues 8-13 contribute independently to nuclear import. Nuclear accumulation of the ND7 APE1(E12A/D13A), but not EGFP alone, after treatment with leptomycin B or after oxidative stress suggests the presence of a previously unidentified nuclear export signal in APE1. Together, these results indicate that the mechanism of nuclear localization of APE1 is complex and regulated via import and export.\r\n In addition increase DNA damage occurs in astronauts during space flight. Humans in space are exposed both to radiation and microgravity. It is clear that the increased exposure to radiation influences DNA damage however it is not clear as to the role that microgravity plays in this increase in damage. \r\n Our investigation on the effects of microgravity on the nuclear translocation of DNA repair enzyme APE1 has revealed that microgravity interferes with the normal trafficking of APE1. \r\n
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    Analysis of the thermodynamic determinants of protein fold specificity in the denatured state ensemble
    (2008-05-27) Suwei Wang; Robert O. Fox; Vincent Hilser; R. Bryan Sutton; Bernard M. Pettitt; Andres F. Oberhauser
    Although the thermodynamic control of protein folding has been known for decades, a complete understanding of the thermodynamic determinants that defining protein folds is still elusive. In this regard, it is becoming clear that focusing only on the native states of protein folds will be insufficient for deciphering the protein folding problem. Knowledge of the thermodynamics of the denatured state is also necessary. In this project, the thermodynamic determinants of the native fold, present in the denatured ensemble, were investigated and the critical role of the denatured state ensemble in controlling protein folding is discussed. In this work, the COREX algorithm, used until now to model the native state ensemble, was for the first time used to model the denatured state ensembles and investigate the relationship between denatured ensemble energetics and sequences, as well as between denatured ensemble energetics and secondary structures. Substantial thermodynamic differences were found between the denatured and the native states ensembles. The generality and robustness of our results were validated by performing fold-recognition experiments that matched sequences with their respective folds using only energetic information. The success of our study and the unique energetic information found in denatured states suggest a wide range of strategies for developing novel algorithms for protein prediction and classification. \r\nIn addition, this work has particular medical relevance. Understanding the chemical and physical processes underlying thermodynamic determinants of protein folding specificity will enable the rational design of drugs to combat the rapidly expanding family of misfolding diseases. Some misfolding diseases are known to be related to non-specific beta sheet formation. The value of this project lies in the detailed analysis between denatured ensemble energetics and sequences, as well as between energetics and secondary structures. Correlation analysis between structure and energetic information revealed that denatured states have evolutionarily evolved to avoid early beta sheet formation, suggesting that the therapeutic strategies to combat misfolding diseases (especially for diseases related to non beta sheet formations) could be found in the energetics information of the denatured states rather than the native states. \r\n
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    Anthrax toxin effects on B lymphocyte function
    (2010-01-11) Bryan Thomas Gnade; Johnny Peterson; Rolf Konig; Gustavo Valbuena; David Craft
    Bacillus anthracis is a gram-positive spore-forming rod capable of causing cutaneous, gastrointestinal and inhalational anthrax. It has a number of virulence factors of which, the two toxins are of great importance. Lethal toxin is a zinc metaloprotease that cleaves the N terminus of the mitogen-activated protein kinase (MAPK) kinase family 1-7, with the exception of MEK5. This kinase family is responsible for activating the mitogen-activated protein kinase (MAPK) cascade. This cascade includes extracellular signal-regulated protein kinases (ERK), c-Jun NH2-terminal kinases (JNK) and p38 kinases. The disruption of these signaling pathways has a number of deleterious downstream effects that vary by cell type. Edema factor is a powerful calmodulin-dependent adenylyl cyclase that forms 3’,5’-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). This enzymatic reaction causes an increase in intracellular cyclic AMP (cAMP) in host cells. As cAMP is a prominent second messenger in cellular signaling, edema toxin has a wide array of effects on numerous cell types and functions. \r\nTo determine the effects of the anthrax toxins on the adaptive immune response, B lymphocytes were exposed to LeTx or EdTx in vitro. LeTx and EdTx both inhibit B cell activation in different manners. LeTx inhibited B cell proliferation but not migration, while EdTx inhibited B cell migration but not proliferation. LeTx and EdTx altered expression patterns of B cell activation markers. EdTx inhibited MIP-1α and MIP-1β while enhancing IL-6 production. Previously unseen in any cell type EdTx was demonstrated to be cytotoxic to naïve B cells.\r\nThe research presented in this report illustrates the inhibitory effects of LeTx and EdTx on B lymphocytes, providing valuable insight into the immunoevasion tactics of B. anthracis.\r\n
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    Applications for human neural stem cell-derived motor neurons in amyotrophic lateral sclerosis: Cell replacement therapy and disease modeling
    (2010-04-19) Jason Robert Thonhoff; Ping Wu, M.D., Ph.D.; Steven A. Weinman, M.D., Ph.D.; Stanley H. Appel, M.D.; Jin Mo Chung, Ph.D.; Darren F. Boehning, Ph.D.
    Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease characterized by the selective degeneration of spinal and upper motor neurons. One approach in the development of therapies for ALS is to explore the potential of human fetal neural stem cells (hNSCs) to replace lost motor neurons. The therapeutic efficacy of stem cell transplantation would depend greatly on the survival of grafted stem cell-derived motor neurons in the microenvironment of the spinal cord in ALS. Previously, we reported that hNSCs could be instructed to differentiate into motor neurons both in vitro and in vivo. Here, we report that the transplantation of primed hNSCs into the spinal cords of transgenic ALS rats only slightly delayed disease progression. Morphological analyses of the transplantation sites revealed that the grafted hNSCs differentiated into motor neurons, but were degenerated and showed signs of nitroxidative damage at the disease end-stage. Using an in vitro coculture system, we provided evidence that human mutant SOD1(G93A)-expressing primary microglia, isolated after disease onset, were directly toxic to hNSC-derived motor neurons. Additionally, normal astrocytes not only lost their protective capacity toward hNSC-derived motor neuron survival in vitro, but also exhibited toxic features, when cocultured with mutant SOD1(G93A) microglia. Using inhibitors of inducible nitric oxide synthase and NADPH oxidase as well as scavengers for reactive oxygen and nitrogen species (ROS/RNS), we showed that microglia-generated nitric oxide, superoxide and peroxynitrite, at least, partially contributed to motor neuron loss and astrocyte dysfunction in this coculture paradigm. In summary, ROS/RNS released from overactivated microglia directly damage motor neurons and reduce the neuroprotective capacity of astrocytes, collectively dooming motor neuron survival in ALS. These data provide evidence that treating ALS with motor neuron cell-replacement therapies will not be efficacious unless the toxic milieu created by endogenous overactivated microglia in the spinal cord of ALS is dramatically altered. Outcomes from these studies should aid in the development of novel combined therapies using stem cells to treat patients with ALS.\r\n
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    Arthritis impact on the physical function, disability, and health-related quality of life among older Mexican-Americans
    (2009-03-02) Saad M. Bindawas; Elizabeth J. Protas, P.T., Ph.D.; Yong-fang Kuo, Ph.D.; Soham Al Snih, M.D., Ph.D.; Kenneth J. Ottenbacher, O.T.R., Ph.D.; Dennis L. Hart, P.T., Ph.D.; Anita C. Mercado, M.D.
    Background and Purpose: Arthritis is a major cause of disability with a sizable impact on health-related quality of life (HRQoL) in older adults, especially among older non-Hispanic white subjects. The purpose of this study is to examine the relation between arthritis and its effects on the physical function, disability, and health-related quality of life, over time, among older Mexican-Americans, the fastest growing subset of the older population. \r\nDesign: A six-year prospective cohort study (2000 to 2006). Setting: Five Southwestern states: Texas, New Mexico, Colorado, Arizona, and California. \r\nParticipants: A population-based sample of 621 non-institutionalized Mexican-Americans aged 65 or older from wave four of the Hispanic Established Population for Epidemiologic Studies of the Elderly (Hispanic EPESE). \r\nMeasurements: Included sociodemographic variables, self-reported of: arthritis, pain on weight-bearing, activities of daily living (ADL), instrumental activities of daily living (IADL), physical and mental HRQoL, medical conditions, cognitive function and depressive symptoms. Lower and upper extremity muscles strength, lower body function test and body mass index (BMI) were also obtained. General linear mixed models and generalized estimating equations (GEE) were used to examine the time effect on: 1) each stage of the disablement process and 2) physical and mental HRQoL over three points of time (2000-2001, 2001-2002, and 2006). This study conforms to STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines for cohort studies. \r\nResults: The results indicate 1) a significant association between arthritis and greater impairment (pain and poor muscle strength), functional limitation, disability (ADL and IADL), and physical HRQoL across time; and 2) a significant association between impairment, functional limitation, and IADL limitation with physical and mental HRQoL across time. Conclusions: In older Mexican-Americans, arthritis is a highly prevalent medical condition which significantly impacts physical function, daily activities, and physical HRQoL over time. In this cohort, impairment, functional limitation, and disability were associated with poorer physical and mental HRQoL. These findings could guide efforts in reaching the goals of the National Arthritis Action Plan, as well as the Healthy People 2010 initiative goals of increasing quality of life and eliminating health disparities in this segment of the older U.S. population.
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    An assessment of kilocalories and protein in the diets of HIV-infected adults in Kenya
    (2011-05-15) Elizabeth Mary Vaughan; Victor Cardenas, MD; Harvey Bunce, PhD; Christine Arcari, PhD
    INTRODUCTION: The detrimental effects of HIV are well known throughout the world. This public health burden is particularly evident in Kenya, Africa, where 6.7% of adults are infected with HIV. One problem of those living with HIV in this resource-poor country is the concurrent existence of malnutrition. Previous investigators undertook many studies to bridge the link between HIV and malnutrition. However, they were unable to gather individual diet information to allow accurate estimation of kilocalorie and protein needs. These deficits hinder accurate dietary interventions for these patients. \r\nMETHODS: Over the period of April 2009 to August 2009, we designed and implemented a dietary instrument (3-day recall survey) to assess the kilocalorie and protein consumption for HIV-infected adults in Kijabe, Kenya. We used this data to compare subject consumption to predicted nutrient needs. We used Harris-Benedict (HB) and Mifflin formulas for kilocalorie need predictions and World Health Organization (WHO) equation for protein need predictions. We then characterized the relationship between dietary intake, BMI and CD4 levels.\r\nRESULTS: A total of 201 patients were surveyed, 122 (60.7% [27% males, 73% females]) met inclusion criteria. There was no statistical difference between HB and Mifflin equations for kilocalories. Males averaged 68.8% (SD 23.3) of estimated kilocalorie requirements (HB) and 100.5% (SD 45.3) of protein. Women averaged 74.4% (SD 24.4) of kilocalorie needs (HB) and 100.5% (SD 42.5) of protein. Differences between genders were not statistically significant (p=0.247 [kilocalorie], p=0.936 [protein]). There was a significant correlation between protein intake and CD4 for males (r=0.7035, p=0.0004) but not for females (r=-0.1911, p=0.1546). There was no statistical significance found between kilocalories (male r=0.104, p=0.654; female r=0.0420, p=0.765) and CD4. No relationship was found between nutrient intake and BMI (male p=0.690; female p=0.477).\r\nCONCLUSIONS: A 3-day recall dietary assessment appears to be an adequate method to obtain dietary information for adult HIV patients in East Africa. Further, we conclude that current predictive formulas for protein underestimate needs in the male HIV population. \r\n
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    Bacterial and host dynamics of Mycoplasma genitalium infection of the human female reporductive tract
    (2009-03-02) Christopher L McGowin; Richard B. Pyles; Vsevolod Popov; Nigel Bourne; Joan Nichols; David H. Martin
    Mycoplasma genitalium (MG) is an emerging sexually transmitted pathogen that is associated with several inflammatory syndromes including cervicitis and pelvic inflammatory disease. Despite the clinical associations of MG with inflammatory sequeale, no experimental evidence was available for the capacity to establish infection of the female reproductive tract and activate host immune responses. This considered, we undertook a multifaceted approach to understanding the capacity and mechanisms of MG to cause inflammatory reproductive tract disease using cell culture models of human epithelia and a novel murine model. In our studies, MG established a long-term intracellular infection of cultured human vaginal, ecto- and endocervical epithelial cells that resulted in pro-inflammatory cytokine secretion. We determined that a significant proportion of the inflammation was activated through ligation of highly expressed Toll-like receptors (TLR) including TLR2/6 heterodimers and TLR9. Based on the responses elicited by exposure of MG to reproductive tract epithelial cells, we next tested and determined that MG was susceptible to killing by human and murine macrophages. Importantly, we then showed that intracellular localization within epithelial cells provided MG a survival niche against macrophage-mediated killing thereby providing a mechanism for evasion of the host immune response. Considering the ability of MG to exploit long-term intracellular survival within epithelial cells, we next developed a murine model of reproductive tract infection to investigate how MG establishes infection and how intact mucosa respond to MG exposure. Similar to cultured human epithelial cells, vaginal lavages of MG-inoculated mice showed significant pro-inflammatory cytokine responses. Concomitantly, we observed intermittent vaginal shedding for up 77d PI indicating that MG is capable of long-term reproductive tract infection. Most importantly, we also determined that MG rapidly ascended to the upper reproductive tract tissues and disseminated to the knee joints following vaginal exposure. These findings were the first experimental evidence for dissemination of MG to the upper reproductive tract and provided excellent rationale for continued investigation into the capacity of MG to cause reproductive tract disease. Collectively, our results indicate that MG has the capacity to elicit reproductive tract inflammation and should heighten awareness for this emerging pathogen.
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    Bacterial pneumonia hospitalization and pneumonia inpatient mortality in Texas, 1999-2007
    (2010-05-01) Chuan Hong; Alai Tan; Daniel H. Freeman; Christine P. Baker
    Bacterial pneumonia has a disproportionate impact on the elderly. It is considered as an ambulatory care-sensitive condition by the Agency for Healthcare and Research (AHRQ), for which good outpatient care can potentially prevent the need for hospitalization or for which early intervention can prevent complications or more severe disease that lead to death. This project evaluated the trends in bacterial Pneumonia hospitalization and pneumonia inpatient mortality rates of older Texans during 1999-2007, and identifies the associated individual and contextual factors. \r\nThe data were from the Texas Hospital Discharge data during 1999-2007, linked with US Census data and Area Resource File. Observed and adjusted rates were calculated for Texas counties. Poisson regression and logistic regression models were used to evaluate the individual and contextual factors associated with bacterial pneumonia hospitalization and pneumonia inpatient mortality rates, respectively.\r\nThe study found that both bacterial pneumonia hospitalizations and pneumonia inpatient mortality rates were decreasing during 1999-2007. Population aged 75 years or above and Hispanics had the highest hospitalization and inpatient mortality rates. Increasing percent of Hispanics at the county-level was associated with a significant decrease of hospitalization rate and inpatient mortality rate. More number of non-Federal MDs per capita was associated with lower hospitalization rate and inpatient mortality rate. More hospital beds was associated with lower pneumonia inpatient mortality rates.\r\nThis study suggests interventions at county-level have great potential to improve the quality of pneumonia preventive and inpatient care for older population. \r\n
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    Bax-mediated coordination of cognate organelle cell death signaling cascades determines cell death phenotype after trauma in the neonatal rat cortex
    (2007-08-07) Martin Gill; Regino Perez-Polo; Jose Barral; John Papaconstantinou; Donna Ferriero; David Rassin
    Bax translocation to the mitochondria has been well-characterized to induce apoptotic cell death in multiple injury paradigms. However, pro-cell death actions for Bax outside of the mitochondria remain understudied. Bax’s pro-cell death role at other non-mitochondrial locales in response to oxidative stress and energy depletion injury paradigms were investigated in in vitro and in vivo neonatal cortical models.\r\n\r\nIn vivo, hypoxia-ischemia (HI) induces a distinct subcellular time course for Bax in the neonatal cortex, localizing first to the nucleus, then to mitochondria and, finally, to the ER with Bax localization coordinating with the activation of each organelle’s cognate cell death cascade, suggesting a new role for Bax in coordinating the cell death signaling at multiple subcellular organelles.\r\n\r\nIn vitro, using necrotic-like and apoptotic stimuli, we observed both treatments induced early nuclear Bax localization, the apoptotic stimulus increasing mitochondrial Bax localization and caspase-mediated cleavage of á-fodrin, and the necrotic-like stimulus increasing ER Bax localization and calpain-mediated cleavage of á-fodrin. Based on these findings, we concluded apoptotic and necrotic-like stimuli promote differential Bax localization and subsequent differential activation of cognate cell death signaling cascades to induce expression of their characteristic phenotypic cell morphologies.\r\n\r\nFinally, we provide novel mechanistic in vitro and in vivo evidence for Bax coordination of multiple cognate organelle cell death signaling cascades. In vitro, we found 1h pretreatment with immunosuppressive and neuroprotective FK506 inhibited high and low dose rotenone-mediated Bax relocalization and cell death signaling, in toto. In vivo, using 100% O2 as an intervention, we showed 100% O2 increases T2-weighted MRI lesion volumes, via increased inflammatory and necrotic signaling, with no amelioration of cortical apoptotic signaling when compared to HI alone. Furthermore, 100% O2 increased ER calpain activation and increased ER Bax protein levels, suggesting that 100% O2 increases HI-induced Bax-mediated activation of ER cell death signaling to increase inflammation and injury by increasing necrotic-like cell death. Taken together, these findings are the first to show Bax-mediated coordination of multi-organelle cell death signaling, demonstrate a link between ER Bax, ER cell death signaling and necrotic-like cell death, and provide evidence for a general trauma-induced Bax relocalization mechanism.\r\n
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    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.
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    Belief systems and patient care: An examination of the relationship between nurse religiosity and end-of-life care
    (2007-07-23) Dana Bjarnason; Alice T. Hill; Suzanne S. Prevost; Regina P. Lederman; Michele A. Carter; Carolyn A. Phillips
    Much has been written about nurses’ responsibility to support patients’ spiritual needs. A plethora of literature explores patient religiosity and its effect on their approach and/or response to health care issues. Interestingly, there is little literature that explores the influence that healthcare providers’ religiosity has on the care they deliver to patients. This dissertation examines the relationship between nurses’ religiosity, their perceived self-efficacy, and the importance they place on aspects of care provided to patients at the end of life. This research was intended to provide a foundation for the future exploration of the importance of understanding the relationship of healthcare providers’ religiosity on other aspects of patient-centered care. This study further supports the body of literature that suggests that end-of-life care is complex and multidimensional. It presents findings that show significant relationships between religiosity, self-efficacy, and the importance that nurses’ report regarding end-of-life care and raises questions about the relationships between religiosity and perceived self-efficacy, and importance that nurses' report regarding end-of-life care. The study has shown that there are differences in nurses’ self-efficacy and the importance they place on aspects of end-of-life care that are based on years of nursing experience and belief systems. Finally, it shows the need for ongoing research that investigates aspects of nursing and end-of-life care.
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    Beneficial hispanic stroke mortality: An exploration of potential explanatory factors
    (2009-06-11) Bret Howrey; James S. Goodwin; Mukaila Raji; Ken Ottenbacher; Karl Eschbach; Jean Freeman; David Espino; Daniel Freeman
    Stroke mortality rates are reported to be lower for Hispanics than non-Hispanic Whites. This project investigates factors that contribute to this lower rate in three ways: 1) examine the role of immigrant status in stroke incidence and mortality, 2) investigate the impact of cause of death ambiguity, and 3) examine the role of misreport of ethnicity on death certificates. \r\nIn examining the effect of immigrant status I used the Hispanic Established Populations for the Epidemiologic Study of the Elderly (EPESE) and the East Boston EPESE. This research compares baseline health characteristics of immigrants with native-born respondents. Additionally, I examine differences in stroke mortality, as well as the risk of stroke between waves. In both EPESE samples significant differences in demographics and co-morbidities existed at baseline between immigrants and the US born. However, the odds of stroke mortality or having a stroke during follow-up were not significantly different for immigrants and the US born in either the East Boston or Hispanic data. \r\n To examine the impact of cause of death coding and misreport of ethnicity on death certificates, I used national vital registration data for the years 1989-1991 and 1999-2002, including foreign and US born Hispanics and non-Hispanic Whites. Hispanic deaths were adjusted for misclassification of ethnicity on the death certificate. These data were linked to census estimates and 5% census samples for the corresponding time periods, allowing for estimates of the foreign born population. Adjustment for nativity and death certificate misclassification removed the stroke mortality advantage for US born Hispanic men, but not women. After adjustment, US born Hispanic men and women have higher rates of mortality from subarachnoid stroke than Whites (RR 1.27 and 1.27 respectively), but lower rates of mortality from Ischemic (RR 0.85 and 0.79 respectively) and chronic effects of stroke (RR 0.95 and 0.79 respectively). \r\n These results suggest that health benefits immigrants receive do not continue in older age with regards to stroke. Additionally, after adjustment for misclassification, the lower stroke mortality advantage for Hispanic men disappears, while an advantage still remains for Hispanic women. Part of the previously reported advantage is a combination of imprecise measurement and data quality.\r\n