• An unusual DNA sequence observed in the [gamma] globin gene loci of two members of a Chinese family

      Ryan, Qin Cao; Department of Cell and Molecular Biology (1989-05)
      There are two nonallelic human y globin genes located on the short arm of ~hromosome #11 in the order 5'-Gy-Ay-3'. Various modifications of the two y genes have been reported and include: deletion·s., triplications., quadruplications and recently a quintuplication. These are :.generally created by one or more unequal crossovers in the y globin ge~e- _regions on adjacent chromosomes. During the c~urse of looking for a y0 thala~semia,. which might be due to a_ crossover within the y genes., two cases were found in the family W. · Bgl II mapping studies showed a 5 kb deletion at the y gene loci in these individuals. The ·Bgl II fragment from th(= y gene loci of R .W. was cloned into the phage vector ·oRl. Phage mapping showed that two out o·f the three Pst I sites within the Bgl II fragment were missing which suggested that the crossover might· have occurred within the y gene., possibly within the yIVS II region. Sequence analysis of the cloned fragment revealed an unusual sequence which had no sequence homology with the r gene region except for a small 264 .bp region near the 3' end. The orientation of the 264 bp fragmen~ is inverted _relat~ve to homologous sequences in the Gr and A'Y IVS II. . The unus~al sequence was computer analyzed for homology with every DNA sequence file in the EMBL data base and GenBank and did not show ·any significant homologies to._ all the available DNA sequences except for the 264 ~p _yIVS II homology. Sine~ mor~ than 99% of the DNA sequences in. the whole of nature still remain unknown., ~he origin of this unusual sequence is a question which mu.st ~wait further investigation.
    • The Use of Sex Chromosomes as Markers to Determine The Fate of Allogenic Bone Implants

      Amin, Mohammed Assem Mahmoud; Department of Oral Biology (1979-08)
      ,This ·study investigated the survival of whole ·fresh hip marrow allografts in four genetically (DLA) mismatched mongrel dogs, paired on the basis of opposit~ sex. Allografts were placed into tooth extraction · s i'~,es: autographs and nongra fted sites served as contra 1 s. The graft material recovered from the experimental sites was grown ~vitro and chromosomal preparations made from these cells were examined for pre~ence of donor cells, at various tim~s up to 56 d~ys after transplantation. In addition, the survtval of allograft osteocytes was observed dsing histological techniques. The use of t i ssu~ cu-1 ture and chromosoma 1 prep~ rations indicated the survi va 1 of an uni denti fi ed. allogeneic cell type for up to .. 56 days. Thus, the morphologic ch~nges of t~e graft osteocytes did-correlate with the.su~viv~l .. ~·~ ' of those unidentified cells after the 20 d~j survival limit of the osteoc}t~s, indicating that allogeneic bone· cells can survive this ·long in bone grafts and may contribute to he a 1 i ng ·of the defects. ·
    • Use of Sigma Receptor Ligands to Prevent Retinal Ganglion Cell Apoptosis Characteristic of Diabetic Retinopathy

      Martin, Pamela M; Department of Cellular Biology and Anatomy (2003-04)
      (First Paragraph)Diabetic retinopathy is a major sight-threatening disease and is the leading cause of blindness among working-aged Americans, affecting approximately 10 to 12 million persons (Wu, 1995). Although retinal vasculature is particularly vulnerable to damage in diabetes, other retinal cells are at risk. Very recently, Barber et al. (1998) documented increased apoptosis of neural retinal cells in experimental diabetes in rats and diabetes mellitus in humans. Notably, retinal ganglion cells (RGCs) were found to be at particular risk. Ganglion cell death in diabetic retinopathy is thought to be mediated via overstimulation o f N-methyl-D-aspartate (NMDA) receptors by glutamate. oRl is a nonopiate and nonphencyclidine-binding site that has numerous pharmacological and physiological functions. In some studies, agonists for aR l have been shown to afford neuroprotection against overstimulation of the NMDA receptor. The purpose of these studies was to evaluate the potential use of aR ligands, particularly those that bind specifically to o R l, as neuroprotective agents in the treatment of RGC apoptosis characteristic of diabetic retinopathy. A detailed description of the retina, followed by information about diabetes and the mechanisms thought to be involved in the pathogenesis of diabetic retinopathy, particularly the apoptotic death of RGCs associated with diabetic retinopathy, is provided below.
    • Use of Stress Management to Decrease Nurse Burnout

      Gramling, Lou; School of Nursing (1983-11)
      The impact of stress man~gement education'on the amount of reported nurse burnout was studied. A quasi-experimental two-group (control and experimental) pretest-posttest design was used. The Maslach Burnout Inventory (Maslacfi and Jackson, 1981) and a Demographic Data Form were used to study eight registered nurses who·registered to attend a J two-hour inservice program entitled "Reducing Your Stress Thr6ugh Self-Management.'' The results of the study indicated ' an increase (although not statistically significant) in reported burnout from the group that attended the workshop. Possibly in the allotted one month time frame, participants gained insight into their burnout, but did not have time to implement ne~ coping skills. A relationship was ·found be- ~tween burnout reported.and the nurse's practice setting, with nurses working in the medical-surgical area report~ng higher burnout than those working ,in the other areas represented. Additiohal study of the variables influencing burnout in nursing and interventions to prevent burnout is recommended.
    • The use of the mouse APRT gene in cultured human cells to study point mutations

      Jarrett, Robert A; Department of Cell and Molecular Biology (1988-08)
      Site-specific mutagenesis, gene transfer, and somatic cell selection have been used to develop a method for the identification of site- and sequence-specific point mutationsinduced in a mammalian cell transgenic system. This method utilizes a mouse adenine phosphoribosyltransferase [APRT] gene containing a specific point mutation in an intronjexon splice recognition sequence, which disrupts mRNA processing and destroys a diagnostic Pst I restriction site. This construct was introduced by cotransfection,with the bacterial n&Qr gene into HTD-114, a non-spontaneously-reverting, Aprt- human fibrosarcoma-derived cell line. The construct s·tudied contains I an A to G transition which is revertible with ethyl methanesulfonate [EMS], a mutagen known to produce G to A transitions in eukaryotes and prokaryotes. Exposing two independently derived cell lines containing the construct to EMS concentrations ranging from 0 to 200 ugjml (corresponding-to 100 to 0.8 percent survival) produced a frequency of reversion to the Aprt+ phenotype of 10-7 to 10-2 .
    • Use-dependent Antagonism of Nicotinic Acetylcholine Receptors as a Novel Treatment for Drug Addiction

      Hall, Brandon J; Department of Pharmacology and Toxicology (2011-11)
      The contributions of nicotinic acetylcholine receptors (nAChRs) to the onset and maintenance of drug addiction are well known, but these receptors are too often overlooked as potential targets for addiction treatment. The goal of this study was to demonstrate that use-dependent antagonism of nAChRs by the compound bis (2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (BTMPS) offers a novel approach to treatment for drug addiction, and that positive outcomes of this treatment can be demonstrated across different classes of abusive drugs, nicotine or morphine in all three phases of an animal model of what is known as the drug abuse cycle: 1) binge-intoxication, 2) withdrawal-negative affect, and 3) preoccupation-anticipation. Different groups of rats were allowed to self-administer drugs of abuse (nicotine or morphine) on a 24 hr basis for a period of 14 days to establish binge-intoxication. Upon completion of self-administration, each rat was evaluated for withdrawal-negative affect. Subsequent to acute withdrawal the rats were placed in standard housing cages for a period of six weeks. At the end of the six week period, each rat was examined for unrewarded drug seeking responses, or preoccupation-anticipation, for another 14 day period preoccupation-anticipation. Injections of vehicle or BTMPS were administered to the animals during each behavioral phase of the study. Treatment with BTMPS significantly reduced the self-administration of both nicotine and morphine compared to vehicle treated animals. BTMPS treated animals also displayed reduced acute withdrawal symptoms when compared to their vehicle treated counterparts. When intervention occurred during self-administration or acute withdrawal, BTMPS treatment resulted in a significant reduction in drug-seeking responses after a protracted period of abstinence from drug. However, delaying treatment with the compound until the drug seeking phase of the study was ineffective against reducing drug seeking behavior. Administration of BTMPS alone did not appear to elicit adverse side effects in the animals, neither affecting their motivation to obtain food nor compromising the animals' performance during the behavioral procedures in the study. Thus, the resultsof this study support the hypothesis that use-dependent antagonism of nAChRs offers the potential for an alternative approach to treatment of substance abuse and drug addiction.
    • Using peptide-based vaccines to enhance adoptive cell therapy with genetically engineered T cells

      Fan, Aaron; Department of Neuroscience and Regenerative Medicine (6/27/2018)
      Adoptive cell therapy (ACT) of retrovirally transduced (RV) CD8 T cells is a powerful technique that has shown promise in tumor eradication in cancer patients. However, some major barriers to current methods are that ACT is expensive, time consuming, and requires harmful and toxic adjunct procedures. The Celis laboratory has demonstrated the use of TriVax, a potent peptide vaccination strategy that dramatically expands ACT cell populations and bypasses the necessity for adjunct procedures. The purpose of my thesis project was to enhance current methods of ACT+TriVax by testing an antigen-specific antitumor response of RV CD8 T cells and if it could be improved with constitutively active STAT5 (CA-STAT5) expression, a protein activated downstream several cytokine pathways that have been shown to play a role in increasing CD8 T cell persistence and resistance to apoptosis. Here, I aimed to test the hypothesis that CA-STAT5 in CD8 T cells enhances an antitumor effect by increasing T cell persistence and efficacy. My results show that TriVax administration selectively expanded frequencies of the ACT cell population expressing gp100-TCR in both blood and spleen. When co-transduced with CA-STAT5, an even higher fold expansion of antigen-specific cells was observed. +CA-STAT5 T cells were able to expand more robustly than -CA-STAT5 T cells upon repeated antigen stimulation (vaccine boost), demonstrating nearly 4000-fold increases in antigen-specific CD8 T cells. +CA-STAT5 T cells also seemed to persist longer in vivo over time, and they expressed lower levels of surface PD-1. Using B16F10 melanoma, ACT+TriVax of these cell populations into tumor-bearing mice demonstrated a powerful antitumor effect, leading to tumor regression in treated groups. CA-STAT5 seemed to recapitulate similar antitumor effects our laboratory observed previously with combinatorial anti-PD-L1 treatment or IL2/anti-IL2 mAb complexes (IL2Cx), suggesting a potential role for STAT5 in resisting the PD-1/PD-L1 inhibitory pathway. Altogether, these results demonstrate that RV CD8 T cells expressing gp100-TCR and CA-STAT5 are capable of antigen-dependent expansion in response to TriVax. CA-STAT5 plays a role in increasing T cell proliferation and persistence, as well as increasing efficacy through resistance to PD-1/PD-L1 inhibition.
    • Value orientation and activity interests in two cultural groups

      Jih, Guey-Fang; Department of Occupational Therapy (1987-04)
      A study of value· orientation in Ufe goals and activity interests was conducted to explore how culture influences thes_e two variables. The relationship between value· orientation and activity interests was also investigated to explore the theoretical framework of human occupation. The human occupation model borrowed the general system theory and assumed that t Man as an open system, interacted with the environment through a process of input, throughput , output and feedback. The environment is physical, social and cultural phenomena. Output information results in purposeful occupation or human occupation. A descriptive survey was designed using two questionnaires to measure the value orientation and activity interests in two cultural g~oups, American occupational therapy students at the Medical College of Georgia, Augusta, GA, U. S. A. and Chinese occupational therapy students at the National Taiwan University, Taipei, Taiwan,· R. 0. C .. The questionnaires were translated into Chinese for the Chinese subjects. The California Life Goals Evaluation Schedules was administered to measure the value orientation in life goals. It included 150 statements categorized into 10 categories: esteem, profit, power, fame, leadership, security, social service, interesting experiences, self expression and independence. Matsutsuyu's Neuropsychiatric Institution Interest Checklist was used to measure activity interests which were categorized with the assistance of occupational therapy faculty at the Medical College of Georgia. The 80 activity items were categorized as active, passive, cooperative, competitive, creative, structured, solitary and group activities. A total.of 35 questionnaires was sent out for the Chinese subjects. All of them were returned , but one of them was not completed. A total of 50 questionnaires was distributed for the American subjects. Thirty·questionnaires were returned, 20 of them were completed. ·Data were analyzed using "STATGRAPHICS" computer package. The statistical tests utilized were_ Student's t-test and Pearson product moment Correlations. Findings indicated that the value orientation in these two groups had .statistically significant differences in fame, power, leadership, security, interesting experiences, and independence. But, there were no significant differences in the activity interests except-in the category of structured activities. A further finding was that the American group in this study tended to prefer passive, cooperative, creative and group activities. The Chinese group tended to prefer passive, and cooperative activities and had no significant preferences in creative versus structured and solitary versus group activities. Considering the correlation of value and activity interests in each cultural group, the results showed that there existed some correlations of value and activity interests. These findings did not supp·ort all the hypotheses, but did provide clues of relationship in value and activity interests.
    • A Variable Prenatal Stress Paradigm as a Valid Drug Discovery Platform for Cognitive Deficits Associated with Neuropsychiatric Disorders

      Wilson, Christina Ann; Department of Pharmacology and Toxicology (2012-10)
      Cognitive dysfunction is now recognized to be central to the functional disability of several neuropsychiatric disorders. However, treatment options for the management of cognitive symptoms are limited and the development of novel therapeutics has been made difficult by the lack of appropriate animal models. It has been suggested that variable prenatal stress (PNS) in rodents might be an etiologically appropriate model for some components of schizophrenia. Thus, the overall goal of this dissertation project was to conduct a comprehensive behavioral study of the model to assess face validity, and to make a preliminary assessment of its construct and predictive validity. Our results indicate that exposure to PNS results in elevated corticosterone levels following exposure to acute stress, increased aggressive behaviors, as well as increased locomotor activity and stereotypic behaviors. Further, PNS rats had altered innate fear responses to predator odor as well as impaired fear extinction. Additionally, PNS in rats was associated with impairments of sustained attention, inhibitory response control, and recognition memory all of which could be attenuated by the norepinephrine reuptake inhibitor, atomoxetine. Collectivity, these data support the premise that PNS in rodents is a valid model system for studying some behavioral components of neuropsychiatric disorders as well as their treatment.
    • A Variable prenatal stress paradigm as a valid drug discovery platform for cognitive deficits associatied with neuropsychiatric disorders

      Wilson, Christina Ann; Medical College of Georgia (Augusta University, 2012-10)
      Cognitive dysfunction is now recognized to be central to the functional disability of several neuropsychiatric disorders. However, treatment options for the management of cognitive symptoms are limited and the development of novel therapeutics has been made difficult by the lack of appropriate animal models. It has been suggested that variable prenatal stress (PNS) in rodents might be an etiologically appropriate model for some components of schizophrenia. Thus, the overall goal of this dissertation project was to conduct a comprehensive behavioral study of the model to assess face validity, and to make a preliminary assessment of its construct and predictive validity. Our results indicate that exposure to PNS results in elevated corticosterone levels following exposure to acute stress, increased aggressive behaviors, as well as increased locomotor activity and stereotypic behaviors. Further, PNS rats had altered innate fear responses to predator odor as well as impaired fear extinction. Additionally, PNS in rats was associated with impairments of sustained attention, inhibitory response control, and recognition memory all of which could be attenuated by the norepinephrine reuptake inhibitor, atomoxetine. Collectivity, these data ,support the premise that PNS in rodents is a valid model system for studying some behavioral components of neuropsychiatric disorders as well as their treatment.
    • Variables That Affect Adaptation In Post-Mastectomy Women

      Pritzker, Joanie K; School of Nursing (1982-05)
    • Vascular alterations in the sprague-dawley rat mandible during intravenous bisphosphonate therap

      Guevarra, Chestine S.; Department of Oral Biology (Augusta University, 2012-02)
    • Vascular Effects of β-Amyloid in Alzheimer's Disease

      Ozcan, Ozan; Medical College of Georgia (Augusta University, 2006-08)
    • Vascular neuroeffector mechanisms in experimental diabetes mellitus

      White, Richard E.; Department of Pharmacology & Toxicology (1987-05)
    • Venous contraction to endothelin-1 in congestive heart failure.

      Reddy, Vikram; School of Graduate Studies (2003-04)
      Endothelin-1 (ET-1) is produced by endothelial cells and can stimulate either the ET A or the ET 8 receptors. The role of ET-1 and the identity of the endothelin receptors involved in mediating tone in the mesenteric small veins of the -Golden Syrian hamster are not known. ET-1. induces venoconstriction, thereby increasing the preload to the heart in congestive heart failure. However, mechanisms mediating contraction to ET-1 in the mesenteric small veins of the cardiomyopathic hamsters in the early and late stages of CHF are not known. Therefore, mechanisms mediating ET-1 induced contraction were determined in the mesenteric small veins of the Golden Syrian and cardiomyopathic hamsters in the early and late sta~es of CHF. Baseline intraluminal diameter of small veins was measured before anci after treatment with either ET A or ET 8 receptor antagonists. .ET-1 induced contraction was higher in the · early stage of CHF, while it was· decreased in the late stage of CHF. Blockade of the ET A receptor decreased ET-1 induced contraction in the mesenteric small veins from the control and cardiomyopathic hamsters in both the early and late stage of CHF. ET 8 receptor blockade decreased the ET-1 induced contraction in the control and cardiomyopathic hamsters in the early, but not late, stage of CHF. Therefore, ET-1 induced contraction in the mesenteric small veins is mediated by the ET A receptors alone in the late stage of CHF, while both the ET A and ET 8 receptors mediate vasoconstriction in the controls and in the early stage of CHF. Stimulation of ET-1 receptors is associated with an increase in calcium levels within the vascular smooth muscle cells. It is not known whether the increase in reactivity to ET-1 in the early stage of CHF or the decrease in reactivity to ET-1 in the late stage of CHF is due to problems with mobilization of the intracellular calcium levels within the vascular smooth muscle cell. Following ET-1, calcium levels within the vascular smooth muscle cell were increased to a larger extent in the early stage of CHF, than in the late stage _of CHF, in agreement with the vascular reactivity data. Calcium levels were also measured before and after treatment with either ET A or ET B receptor antagonists. Blockade of the ETA receptor inhibited the ET-1. ·induced increase in calcium levels in the mesenteric small veins from the control and cardiomyopathic hamsters in both the early and late stage of CHF. However, ETa_ receptor blockade inhibited the ET-1 induced increase in calcium levels in only the control and cardiomyopathic hamsters in the early stage of CHF. These results indicate the absence of a functional responses mediated by the ET a receptor in the late stage of CHF. Studies have shown that NO can modulate the contraction to ET-1 in the vasculature. Baseline intraluminal diameter of small veins were measured before and after treatment with N-nitro-L-arginine (LNA), a specific inhibitor of nitric oxide · synthase. LNA decreased the contraction to ET-1 in the early stage of CHF, but increased contraction to ET-1 in the late stage of CHF. This indicates thatNOS mediates a vasodilatory effect that counteracts contraction to ET-1 in the late stage, but contributes to the vasoconstrictor effect of ET-1 in the late stage of CHF. NOS activity was. measured to identify the NOS isoforms contributing to the modulation of ET-1 induced vascular reactivity. Total NOS activity was significantly increased in the cytosolic fraction of small veins from hamsters in the late stage of CHF and in the particulate fraction in hamsters in the early stage of CHF. In the late stage, the increase in NOS activity was inhibitable by 1400W, an iNOS selective inhibitor, suggesting that an increase in iNOS decreases the contraction to ET-1. In summary, in the early stage of CHF, there is an increase in the vascular reactivity to ET-1 associated with an increase in intracellular calcium levels and partially mediated by NOS. This may-increase preload and impair myocardial function in CHF. There is an absence of ET 8 receptor-mediated responses in the late stage of CHF, associated with very high plasma ET -1 levels and imp•aired intracellular calcium · signaling. NOS activity is significantly enhance4 in the mesenteric small veins from the cardiomyopathic hamsters in the late phase of CHF, and this increase in NOS activity is at least partially dependent on iNOS and may contribute to impaired venous contraction to ET-1 in cardiomyopathic hamsters. This may serve as a compensatory mechanism to decrease the preload to the failing heart.