ASSOCIATION OF AGE, GENDER AND RACE IN CHRONIC KIDNEY DISEASE PATIENTS WITH AND WITHOUT DIALYSIS 1Busayo Adeyemi Onatolu, 2Hemang Panchal, 3Edward Francis Leinaar, 1*Shimin Zheng, 2Timir K. Paul 1Department of Biostatistics and Epidemiology, College of Public Health, ETSU, Johnson City, TN 37614 2Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN, 37614 3Department of Health Services Management and Policy, CPH, ETSU, Johnson City, TN 37614 *Sponsoring faculty Introduction: Studies have shown that chronic kidney disease (CKD) is common among adults in the United States. The Centers for Disease Control and Prevention (CDC) states that 30 million people, or 15% of US adults, are estimated to have CKD. Forty-eight percent of those with severely reduced kidney function are not aware of having CKD, and therefore do not receive hemodialysis (HD). Methods: A nationwide inpatient sample database from 2012-2014 was used to identify all patients admitted to the hospital using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (n= 534,845). Patients with dialysis dependent CKD (n=8,100) and CKD without dialysis (n=51,285) were compared to non-CKD patients (n=475,460). Hierarchical logistic regression was performed and p Results: Of the 534,845 patients, 88.9% were without CKD and 9.59% had CKD without HD and 1.51% had CKD with HD. Among patients with CKD, 13.64% were on HD and 86.34% were non-HD patients. The result shows that a higher proportion of patients with CKD without HD in the ≥ 80 years age group (≥ 80 = 37.84%, 65-79 = 36.94%, 50-64 = 20.80%, 35-49 = 4.12% and 18-34 = 0.30%) and a higher proportion of patients with CKD with HD in the 65-79 years age (≥ 80 = 16.30%, 65-79 = 41.79%, 50-64 = 33.09%, 35-64 = 8.09% and 18-34 = 1.29%). The OR of age group 18-34 compared to ≥ 80 is 5.690, 95% CI: 4.202,7.705, OR 35-49 is 4.552, 95% CI: 4.552, 95% CI: 4.103, 5.050, OR of 50-64 is 3.693, 95% CI: 3.444, 3.961 and OR 65-79 is 2.626, 95% CI: 2.457, 2.807. Males had higher rates of CKD than females, without HD (Male= 63.12%, female= 36.88%, p Conclusion: From this study, males had higher rates of CKD with and without HD than females, the age group ≥ 80 years had higher proportion of CKD without HD and those between 65-79 years had higher number of CKD with HD. Whites had higher rates of CKD with and without HD than other races.

Evidence suggests that toxic stressors introduced early in development have prolonged effects on neuronal function due, in part, to the maturation of the hypothalamic- pituitary- adrenal (HPA) axis during adolescence. Early life stress has been implicated as a driver of mood and anxiety disorders, like depression and post-traumatic stress disorder - the extent to which appears to be sex dependent. While it is known that early life stress results in several consequences in adulthood, the mechanisms by which these changes manifest are unclear. Stress-induced changes in mood and behavior are often associated with alterations in inflammatory reactivity in both the brain and in the periphery. Previous work from our lab, and others, demonstrates that both male and female rats respond to chronic adolescent stress (CAS) but may differ in inflammatory markers within the brain and periphery and in the induction of negative affective-like behaviors. Inflammatory reactivity has been targeted as a means of identifying how these sex differences arise in studies of chronic stress in adults. Circulating concentrations of inflammatory cytokines have not been directly employed as predictors of behavioral outcomes of stress exposure in adolescence but may be a useful tool in uncovering mechanisms that protect or predispose an organism from the effects of chronic stress. To further assess immunological and behavior deficits following chronic stress in adolescence, the current work used a model of chronic adolescent stress where male and female adolescent mice were exposed to a predator stress for 15 consecutive days. In late adolescence, these mice were treated with an acute inflammatory challenge with lipopolysaccharide (LPS)to elicit an inflammatory response. We predicted that chronic, predatory stress experienced during adolescence would induce negative anxiety-like behaviors and alter circulating proinflammatory levels. Furthermore, we expected females to be more susceptible to the effects of adolescent stress than males. We observed that, chronic, predatory stress during adolescence increased anxiety-like behaviors in males and females, but did not alter social behaviors during late adolescence. Predatory stress also impacted circulating levels of TNFα, but no sex differences in LPS-induced cytokine concentrations were apparent.

The adverse interaction between smoking and chronic pain has been known for decades. A variety of chronic pain conditions – ranging from headache to low back pain to fibromyalgia – markedly exacerbate smoking prevalence and intensity in packs per day among multiple patient populations. In patients seeking pain treatment, the prevalence of smoking approaches 50%, compared to less than 20% in the general population. Perhaps not surprisingly, the relationship is bidirectional: not only does persistent pain increase rates and intensity of smoking, but smoking also appears to exacerbate both the intensity and associated impairment of chronic pain. In fact, smoking appears to place individuals at risk for developing a chronic pain condition and may also facilitate the transition from acute to chronic pain. The growing body of literature documenting these associations has led to the proposition of a positive feedback loop: individuals smoke in part to cope with their pain, but smoking actually worsens the pain. Despite the strong evidence for the existence of this adverse interaction, the mechanisms responsible for it remain poorly understood. A number of preclinical and clinical studies have documented that nicotinic acetylcholine receptor (nAChR) agonists, e.g., nicotine, have analgesic efficacy in the acute pain setting, such as that produced experimentally in the research laboratory or experienced by patients postoperatively. In contrast, the role of nAChR activation in modulating chronic pain is less well characterized. The experiments described in this thesis determine whether persistent pain diminishes the antinociceptive (analgesic) efficacy of an α4β2 nAChR agonist in the rostral ventromedial medulla (RVM), a key brainstem pain modulatory nucleus, and subsequently begin to elucidate the mechanisms by which persistent pain elicits this plasticity. The complete Freund’s adjuvant (CFA) model of chronic pain was employed to test the hypothesis that persistent inflammatory injury diminishes the antinociceptive efficacy of the selective and potent α4β2 nAChR agonist epibatidine in key brainstem pain modulatory nuclei. Paw withdrawal latency to a noxious heat stimulus was used to evaluate the anti-hyperalgesic and antinociceptive effects of epibatidine microinjected in the RVM or periaqueductal gray (PAG) of male rats. The effects of epibatidine were assessed both in uninjured animals and in animals at different times after intraplantar CFA injection. Interestingly, pretreatment with an α4β2-selective antagonist demonstrated that the antinociceptive effects of epibatidine in naïve rats were mediated by α4β2 nAChRs in the RVM but not in the PAG. While the antinociceptive effects of epibatidine in the RVM were abolished after two weeks of inflammatory pain, the anti-hyperalgesic effects remained unchanged. Surprisingly, epibatidine no longer appeared to be acting primarily at α4β2 nAChRs as early as four hours after injury. Persistent inflammation did not alter the anti-hyperalgesic or antinociceptive effects of epibatidine in the PAG. Radioligand binding studies were conducted to test the most parsimonious hypothesis that a global reduction in α4β2 nAChR number or binding affinity during persistent injury was in part responsible for the decreased efficacy of epibatidine in the RVM after intraplantar CFA. Saturation binding using [3H]-epibatidine in membrane homogenates prepared from RVM and PAG tissue revealed no differences in receptors between saline- and CFA-treated rats at any time after injury, suggesting that a whole-nucleus reduction in nAChRs could not explain the observed behavioral phenomena. To query functional changes with greater resolution, whole-cell patch clamp electrophysiology was employed to begin assessing the consequences of nAChR activation by nicotine at the level of the neuron. Initial studies performed in the locus coeruleus demonstrated that all neurons responded to nicotine with an inward current that desensitized with continued exposure to the drug. Neurons in the RVM exhibited significantly more heterogeneity in their response to nicotine: desensitizing inward currents were seen in some; sustained outward currents in others; inward currents followed by outward currents in a third population; and still others had no response to nicotine exposure. The sustained outward currents persisted in the presence of the sodium channel blocker tetrodotoxin, were not blocked by an α4β2 nAChR-selective antagonist, and appeared to be mediated by G protein-coupled receptors and potassium channels. Taken together, the present results demonstrate that persistent inflammatory injury produces adaptive changes in nicotinic signaling in the RVM such that the antinociceptive effects of epibatidine activation are abolished in a time-dependent manner. These changes cannot be attributed to a whole-nucleus reduction in α4β2 nAChRs. However, nicotinic signaling in the RVM is complex, and small alterations in the pre- or postsynaptic actions of nicotine may have significant ramifications for the overall nociceptive sensitivity of an animal. The data presented here suggest that plasticity in nicotinic signaling within the bulbospinal pain modulatory pathways may in part explain the adverse interaction between smoking and chronic pain observed in humans.

Magister Scientiae (Physiotherapy) - MSc(Physio) / Evidence indicates that the current physiotherapy management of patients with chronic non-specific LBP only offers moderate benefit. Combined treatment programmes, addressing body as well as the mind, shows promising results in developed countries with adequate resources but low evidence in poorly-resourced countries and contexts. This is another gap in the existing knowledge. The study aimed to evaluate the effectiveness of a combined physiotherapy and cognitive-behavioral therapy treatment, compared to physiotherapy alone, in reducing pain, disability, mental health and fear-avoidance behavior, in adults with non-specific low back pain. The systematic review included articles published, in English only, between 1985-2018 (July) in the following databases available at the University of The Western Cape: EbscoHost, BioMedCentral, Cambridge Journals Online, CINAHL, Cochrane Library, Medline (EbscoHost), Medline (Pubmed), Sabinet Reference, SAGE Journals Online, ScienceDirect,SciFinder Scholar, SCOPUS, Wiley Online Library, Springerlink and PubMed.Two reviewers independently evaluated the methodological quality of full text articles, using a critical appraisal tool. Fourteen (14) articles were included based on methodological rigour. Five (5) articles were included in the narrative synthesis and nine (9) articles were included in the meta-analyses. Statistically significant improvements in pain, disability and mental health, in favour of combination therapy for patients with chronic lower back pain were found. A small but statistically significant cumulative effect size for mental health (g = -0.26, Z = -4.49, p <.01) , physical disability (g = -0.27, Z = -5.09, p <.01) and pain (g = -.27, Z = -5.05, p <.01) , in favour of a combination of cognitive behavioural therapy and physiotherapy in patients with chronic lower back pain was found. In addition, a medium but statistically significant cumulative effect size (g = -0.50, Z = -6.95, p <.01), in terms of fear avoidance, was found in favour of the combination therapy. In conclusion, physiotherapy in combination with cognitivebehavioral therapy was more effective than physiotherapy alone, in reducing pain, disability, mental health and fear-avoidance behaviour, in adults with non-specific low back pain. Ethics: Permission for the study was obtained from the university’s Biomedical Research Ethics Committee.

An understanding of pain presupposes that the sufferer is able to use a language which is understood by all. Pain is always described in the language of experience and this experience, encountered by all, is nevertheless lived alone. The interpretive process provides the framework for this study which explores the experiences of five persistent pain sufferers. They have not had their pain validated by diagnosis and persistent pain has become the centrepiece of their existence. The use of epiphany moments illuminates an understanding of the essence of persistent pain experiences, and sufferers are provided with a voice to tell their own stories as their experiences unfold through events in time. These stories are then deconstructed and analysed in order to bring meaning to the lives described. This study found that the communal folklore of pain remains underpinned by dominant ideological forces and discursive practices which sustain the powerlessness of persistent pain sufferers. The sufferer is rendered powerless through medical technologies including the medical interview. Through language the perception of pain is understood and translated in such a way as to cause the sufferer to question the validity of their experience while accepting blame for the persistence of their pain and the need to have it stop. It was postulated that resistance to this process provides the mechanism through which persistent pain sufferers are able to surrender previously held notions of self to alternate identities, which encapsulate the embodied experience of pain. The sufferer can then move to a position where their persistent pain experience is validated. / Doctor of Philosophy (PhD)

The current research was a randomised two group (control and treatment) study that evaluated the effectiveness of an ACT-based self-help book for people with chronic pain. Over a 6-week period, 6 participants read the book and completed exercises from it with weekly telephone support while 8 others waited. Five of these others began the intervention after a 6-week control period. Participants completed pre- and post-intervention questionnaires for acceptance, values illness, quality of life, satisfaction with life, depression, anxiety and pain. Initial outcome data were collected for 8 control participants and 6 intervention participants. A total of 11 participants completed pre- and post-intervention measures. Participants' who read the book, rated the content of the book each week according to reading level and usefulness, and their comprehension of the content was also assessed. Original group data showed statistically significant improvement in acceptance and quality of life for those who completed the intervention. Once the data were pooled, statistically significant improvements in acceptance, quality of life, satisfaction with life, and values illness were found. In general, using the self-help book did not result in reduced pain, depression or anxiety, although for some individuals gains were made in these areas. Individual perceptions of the book components were varied but findings suggest that cognitive defusion and mindfulness were parts of the book that participants found hard. The current findings support the hypothesis that using the self-help book would add value to the lives of people who experience chronic pain. Thus, the book may be a useful tool for people who experience chronic pain.

B cell chronic lymphocytic leukemia (B-CLL) is a hematologic neoplasm characterised by the proliferation and accumulation of sIgM+/D+ B cells that fail to progress to the final stages of B cell development. The malignant cells in B-CLL also express the pan-T cell antigen CD5, suggesting that CLL is a malignancy of the CD5+ subset of B cells. Additional characteristics of the malignant clone include a low proliferative index, enhanced in vivo survival and constitutive expression of the anti-apoptosis oncoprotein bcl-2. The behaviour of leukemic CD5 B cells in vitro contrasts their arrested in vivo state. That is, despite the majority of cells being arrested in the G0 phase of the cell cycle, the leukemic B cells are not irreversibly frozen as they can be induced to differentiate to Ig-secreting cells under appropriate in vitro conditions. Furthermore, leukemic CD5 B cells rapidly undergo death by apoptosis following in vitro culture. This thesis describes the requirements for in vitro activation of leukemic CD5+ B cells, the characterisation of the events involved in apoptosis of these cells as well as the identification of various growth factors capable of modulating these events. Stimulation of unfractionated peripheral blood lymphocytes (PBLs) from three patients with B-CLL with the phorbol ester PMA and the mitogens PHA and PWM resulted in significant increases in cell proliferation, RNA synthesis and 1gM secretion when compared to unstimulated cell populations. PMA was the most potent inducer of 1gM secretion and this occurred irrespective of the presence of residual T cells. PMA-induced proliferation and RNA synthesis were also independent of T cells. However, in the presence of T cells, these parameters of cellular activation were enhanced during in vitro culture. Thus, the inductive ability of PMA on leukemic CD5 B cells was independent of T cells. In contrast, activation and differentiation of the leukemic CD5 B cells into 1gM-secreting cells following culture with mitogens did not occur in the absence of T cells. Interestingly, co-stimulation of leukemic CD5+ B cells with PMA and anti-Ig induced cellular responses that exceeded those induced by either activator alone. Thus, leukemic CD5+ B cells from patients with B-CLL can be activated in vitro and differentiate in response to stimulation via both T cell-dependent and T cell-independent mechanisms. Apoptotic cell death was characterised in purified leukemic CD5 B cells obtained from six B-CLL patients. All leukemic CD5 B cell populations entered an apoptotic pathway in vitro as evidenced by a reduction in cell size, loss of cell viability and fragmentation of DNA into multimers of -180 base pairs. Following 24 hours of in vitro culture 24.0±16% of DNA was fragmented. After 8 days, the majority of DNA was fragmented, and fewer than 10% of cultured cells were viable. Examination of bcl-2 expression in the malignant B cells by flow cytometry revealed a unimodal pattern of expression in greater than 85% of cells from each B-CLL patient prior to culture. During in vitro culture, bcl-2 expression became bimodal such that the B cells displayed a bcl-2hjgh and bcl-2iow phenotype. The level of expression by the bCl2hjgh cells was similar to that observed prior to in vitro culture, indicating that bcl-2 is down-regulated in apoptosing cells. Interestingly, despite this downregulation, the overall number of cells positive for bcl-2 remained constant. This suggests that the enhanced survival of leukemic CD5+ B cells in vivo is mediated by the sustained expression of bcl-2 and that additional mechanisms exist capable of overriding the protective effect of bcl-2 when bcl-2 is present at reduced levels. Leukemic B cell apoptosis has previously been reported to be delayed or prevented by IL-4, IFN-y and IFN-a. These results were confirmed in this study where it was found that culture of leukemic CD5 B cells with IL-4 or IFN-y enhanced cell viability and delayed apoptosis in 6/6 and 5/6 populations of leukemic B cells, respectively. This function was also found to be shared by IL-2, IL-6, IL-13 and TNF-a as these cytokines enhanced cell viability and delayed apoptosis in some of the cell populations examined at a level similar to that observed for IL-4 and IFN-y. These cytokines may mediate their effect via the expression of bcl2 as culture in the presence of IL-2, IL-4, IL-6, IL-13, IFN-y or TNF-a resulted in a higher percentage of cells displaying the bcl-2high phenotype, compared to unstimulated cells. Taken together, these results suggest that autocrine and/or paracrine growth loops may play a role in the pathogenesis of B-CLL and that cytokines that prevent apoptosis in vitro may be targets for treatment of this B cell malignancy.

Masters of Science in Medicine / The relationship between COPD and laryngopharyngeal sensitivity has not been previously determined. Limited research into the relationship between COPD and swallow function suggests that patients with COPD are at increased risk of aspiration. One possible mechanism for this is a reduction in laryngopharyngeal sensitivity (LPS). Reduced laryngopharyngeal sensitivity (LPS) has been associated with an increased risk of aspiration in pathologies such as stroke, however impaired LPS has not been examined with respect to aspiration risk in COPD. The Aims of this study were to investigate the effect of COPD on laryngopharyngeal sensation using Laryngopharyngeal Sensory Discrimination Testing (LPSDT) and to determine whether a relationship between LPS and swallow function in patients with proven COPD exists. Method: 20 patients with proven COPD and 11 control subjects underwent LPSDT utilising an air-pulse stimulator (Pentax AP4000) via a nasendoscope (Pentax FNL10AP). The threshold of laryngopharyngeal sensation was measured by the air pressure required to elicit the laryngeal adductor reflex (LAR). A number of further examinations were also completed for COPD subjects. These included respiratory function testing, self-reporting questionnaire on swallowing ability (SSQ), bedside clinical examination of swallowing (MASA) and endoscopic assessment of swallowing (EAS). Results: subjects with COPD had a significantly higher LAR threshold when compared to their normal healthy counterparts (p<0.001). Positive correlations were identified for the relationships between MASA score and EAS results for presence of laryngeal penetration / aspiration (p<0.04), vallecular residue (p<0.01) and piriform residue (p<0.01). Conclusion: Patients with COPD have significantly reduced mechanosensitivity in the laryngopharynx. Patients with COPD also have impaired swallow function characterised primarily by pharyngeal stasis. These changes may place patients with COPD at increased risk of aspiration.

Secondary lymphoedema and venous oedema of the limb are the consequence of an imbalance between tissue fluid infiltrate and drainage, which leads to interstitial fluid accumulation, tissue changes, limb discomfort and morbidity. Numerous conservative therapies have been developed to address some of these negative outcomes, with a proportion of these being labour and cost intensive. This makes the investigation of cost effective and easy to implement home based regimes very important. One such therapy is limb exercise, which can be beneficial for limb oedemas through changes in both interstitial pressure and calf muscle activation. Therefore, this thesis explored the benefits of different exercise regimes for limb oedema of both lymphatic and vascular origin. This was achieved through a systematic review of existing conservative therapies for limb oedemas and four clinical trials investigating the benefits of home based exercise regimes. Results demonstrated that various positive and significant outcomes could be gained from the implementation of such regimes, including improvements in both subjective and objective parameters. These results reveal how these chronic and disabling conditions can be maintained by the patient in the home environment in between health care visits. It also demonstrates how self maintenance may alleviate the burden on the health care system.

Objectives: Electro-acupuncture (EA) has been demonstrated to be effective in reducing post-operative acute consumption of opioid-like medications (OLM) by previous studies. This effect has not been examined in patients with chronic pain. In this thesis, a randomised, double-blind, sham acupuncture-controlled study was reported. The trial aimed to evaluate the effect of EA in reducing OLM consumption in patients with chronic non-malignant pain. Methods: Thirty-five patients were recruited from a multidisciplinary pain management clinic in Melbourne. After a two-week baseline assessment, participants were randomly assigned to one of the two groups by a computer generated randomisation sequence: real EA (REA, n = 17) or sham EA (SEA, n = 18). The REA group received 2/100 Hz EA stimulation on two pairs of acupoints (Zusanli ST36 and Fenglong ST40 on one leg and Hegu LI4 and Quchi LI11 on one arm) and manual acupuncture on an additional five chosen acupoints for 30 minutes. The SEA group received superficial needling on non-acupoints without Deqi sensation or electrical stimulation. Both groups received treatment twice a week for six weeks. Participants were followed up for 12 weeks at intervals of four weeks. During the trial, participants were given clear instructions on how to reduce their OLM usage. A researcher telephoned the participants three times during the trial to encourage them to reduce OLM intake. The assessor, researcher and participants were blinded to treatment allocation. Outcome measures: The primary outcome measures included OLM consumption, related side effects, dosage of non-opioid analgesics and the intensity and unpleasantness of pain. These measures were recorded daily for two weeks before the intervention, six weeks during the treatment period and three times during the follow up period. Secondary outcome measures were depression and quality of life as assessed by the Beck Depression Inventory-II (BDI-II) and the Medical Outcome Study 36-Item Short Form (SF-36), respectively. Data were analysed with independent t-tests or analysis of variance (ANOVA) where appropriate and per protocol analysis was employed. Results: Nine participants withdrew from the study. At baseline, the two groups were comparable on all demographic characteristics and major outcome variables except for the average intensity of pain. During the treatment period, the reduction of OLM consumption was more rapid in the REA group (64%) than in the SEA (46%) (ANOVA, p less than 0.05). The effect was maintained for four weeks in the REA group. There were no differences in the improvement of all other measures between the two groups. The incidence of EA-related adverse events (AEs) per treatment was 21% and 10% in the REA and SEA groups, respectively. All AEs were minor. Over 90% of the participants were satisfied with the treatments given and would recommend EA to others. The blinding was successful. Conclusions: EA could be an effective and safe treatment for reducing OLM consumption for patients with chronic pain, and may be used as an adjunct therapy in chronic pain management. Further studies with larger sample sizes are warranted.