No description available.

In under a century, melioidosis, the infection due to Burkholderia pseudomallei, has emerged from Whitmore’s series of glanders-like infections amongst the morphia addicts in Burma to a major cause of mortality in northeastern Thailand and northern Australia. Also endemic in other parts of south-east Asia, melioidosis may have varied presentations ranging from severe, overwhelming infection to chronic, low grade disease. Observational evidence had suggested that granulocyte colony stimulating factor (G-CSF), a naturally occurring substance produced by the body in response to infection, may have been useful in reducing the high mortality associated with the more severe forms of this infection. Other observations linked the occurrence of this disease to various environmental factors, such as contamination of drinking water and the annual rainfall. This thesis explores and attempts to quantify these associations. There are three parts to this thesis. In the first part, I reviewed the epidemiology and management of patients with melioidosis. The use of G-CSF and meropenem was associated with a fall in mortality, although other factors may have at least partially contributed to this effect. In the second part, I progressed towards a clinical trial of G-CSF. There was no other evidence supporting the use of G-CSF in severe sepsis and ethical issues precluded a trial in Darwin. There was not evidence from laboratory models of G-CSF action in melioidosis to support the use of G-CSF in patients, although there remained some doubt regarding the applicability of such models to human disease. I examined clinical methods to identify patients at high risk of death from melioidosis. A simple scoring system based on clinical and laboratory parameters was developed and externally validated. However, clinical definitions of severe sepsis appeared to be better predictors of mortality. A clinical trial based on clinical definitions was commenced in Thailand. In the final part, I explored the question of whether different strains or B. pseudomallei or different environmental conditions caused different patterns of infection. There was no evidence that strain types of this bacterium determine the pattern or severity of disease, but weather conditions appeared to influence the distribution of disease in northern Australia.

Gastrointestinal symptoms have a prevalence of 20-40% in the general adult population in the Western world. These symptoms are generally considered to be poor predictors of organic findings [e.g. peptic ulcer disease (PUD) or malignancy]. Approximately 50% of patients seeking care for such symptoms have no organic explanation for these upon investigation. When other organic or other functional conditions are excluded [e.g. PUD, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS)] the remaining patients are labelled as having functional dyspepsia (persistent or recurrent pain and/or discomfort centred in the upper abdomen). Management of functional dyspepsia remains a challenge, reflecting the heterogeneity of the patients and the uncertain role of drug treatment. Also, prognostic factors for treatment success are largely unknown. I have therefore performed a series of studies to shed light on these issues: The first study (Paper I) was performed in a randomly selected adult population (n=1,001) assessing upper and lower gastrointestinal symptoms at two occasions with 1 to 6 month intervals. The results show that gastrointestinal symptoms are common (57%) and fluctuate to some extent in the shorter term. Troublesome dyspeptic symptoms remain in two out of three individuals. This proportion was similar whether or not organic findings were present. In the second study (Paper II) 799 patients with dyspeptic symptoms were evaluated with regard to whether gastrointestinal symptoms, identified by self-administered questionnaires, correlate with endoscopic diagnoses and discriminate organic from non-organic (functional) dyspepsia. The impact of dyspeptic symptoms on health-related well-being was also evaluated. Approximately 50% of these dyspeptic patients were found to have functional dyspepsia at upper endoscopy. A difference was discovered in the symptom profile between patients with organic and functional dyspepsia. Predicting factors for functional dyspepsia were found. This study shows that use of self-administered symptom questionnaires may aid in clinical decision making for patient management, e.g. by reducing the number of endoscopies, although probabilities of risks for organic dyspepsia are difficult to transfer to management of the individual patient. The results also indicate that the health-related well-being in patients with functional and organic dyspepsia is impaired to the same extent, illustrating the need for effective treatment of patients with functional dyspepsia, a group not well served by currently available treatment modalities. The aim of the third study (Paper III) was to develop and evaluate a selfadministered questionnaire focusing on upper abdominal and reflux complaints to allow for identification of patients with heartburn and factors that might predict symptom relief with omeprazole both in GERD and functional dyspepsia patients. The diagnostic validity of the questionnaire was tested against endoscopy and 24-hour pH monitoring. The questionnaire had a sensitivity of 92%, but a low specificity of 19%. Symptom relief by omeprazole was best predicted by the presence of predominant heartburn described as ‘a burning feeling rising from the stomach or lower chest up towards the neck’ and ‘relief from antacids’. These results indicate that this questionnaire which used descriptive language, appeared to be useful in identifying heartburn and predicting responses to omeprazole in patients with upper gastrointestinal symptoms. The fourth study (Paper IV) was a pilot study investigating the symptom response to omeprazole 20 mg twice daily or placebo for a duration of 14 days in 197 patients with functional dyspepsia. We concluded that a subset of patients with functional dyspepsia, with or without heartburn, would respond to therapy with omeprazole. In the final study (Paper V) the aim was to identify prognostic factors for the treatment success to a 4-week course of omeprazole 10 or 20 mg once daily in 826 patients with functional dyspepsia. The most highly discriminating predictor of treatment success was the number of days without dyspeptic symptoms during the first week of treatment. Fewer days with symptoms during the first week indicated higher response rates at four weeks. In addition, positive predictors of treatment response to omeprazole were identified as age >40 years, bothersome heartburn, low scores of bloating and diarrhoea, history of symptoms for <3 months and low impairment of vitality at baseline. The results indicate that early response during the first week to treatment with a proton pump inhibitor seems to predict treatment success after four weeks in patients with functional dyspepsia. Conclusion: These studies have shown that a large proportion of adult individuals in society, both those who seek and those who do not seek medical care, suffer from symptoms located in the upper part of the abdomen regardless of whether an organic cause is present. A subset of patients without organic findings and other functional conditions, i.e. functional dyspepsia, respond to therapy with omeprazole irrespective of the presence or absence of heartburn . An excellent way to predict the response to a full course of omeprazole in functional dyspepsia is to assess the early response (first week) to treatment. These findings allow for better and faster targeting of acid inhibitory therapy in functional dyspepsia, which potentially can result in more effective clinical management of these patients and savings of health care resources.

The current study aims to determine physical activity levels among people living with HIV treated with high active antiretroviral therapy in Kigali, Rwanda. A cross-sectional design using quantitative method was used. The participant’s levels of physical activity participation and their association with anthropometric profiles were measured, using a structured selfadministered questionnaire adapted from the Sub-Saharan Africa Activity Questionnaire. Based on a scientific calculation, 407 clients passing through the clinics were included in the study. A convenient sample of people attending the clinics approached to participate voluntarily in the study. The findings of the current study highlighted the lack of motivation, lack of time and fear of worsening the disease amongst the strong barriers to physical activity participation. The current study recommends education about the benefits of physical activity participation and encouragement of patient treated with high active antiretroviral therapy in Rwanda to be emphasized on to improve their lives.

Falls and their consequences are a major health problem in the older population, increasing their immobility, morbidity and mortality. This thesis focuses on older people living in geriatric care settings, frail older people who are most prone to suffer falls. The aim was to study predisposing and precipitating factors associated with falls in older people with or without cognitive impairment. In a cross-sectional study with a one-year prospective follow-up for falls 63% of the 83 residents suffered 163 falls and 65% of the fallers fell more than once. The antidepressants selective serotonine reuptake inhibitors (SSRIs), impaired vision and being unable to use stairs independently were the factors most strongly associated with sustaining falls. Acute diseases were judged to have precipitated 32 % of the falls and drug side effects 9%. In another cross-sectional study with a one-year follow-up for falls, including 199 residents, previous falls and treatment with antidepressants (mainly SSRIs) were found to be the most important predisposing factor for falls. Acute disease was judged to be the precipitating factor alone or in combination, in 39% of the falls, medical drugs in 8%, external factors such as obstacles in 8% and other conditions both related to the individual and the environment, such as misinterpretation, misuse of roller walkers or mistakes made by the staff were judged to have precipitated 17% of the falls. In a population-based cross-sectional study including 3604 residents in geriatric care settings more than 8% sustained a fall at least once during the preceding week. A history of falls, the ability to get up from a chair, the need for a helper when walking, pain, cognitive impairment, use of neuroleptics and use of antidepressants were all associated with falls in multivariate analyses. In the subgroup of people with cognitive impairment (2008 residents) more than 9% had sustained a fall at least once during the preceding week. As for the whole population, being able to get up from a chair, previous falls, needing a helper when walking with the addition of hyperactive symptoms were the factors independently associated with falls. In a study with a one-year prospective follow up for falls, including 439 residents in residential care facilities, 63% sustained 1354 falls, corresponding to an incidence rate of 3.5 falls / person year. Thirty-three percent of the falls and 37% of the injurious falls occurred during the night (9pm-6am). There were significantly higher fall rates in the evening and in January, April, May, November and December. There were no associations between fall rates and any of the weather parameters studied. In conclusion falls and fall-related injuries in older people in geriatric care settings are common. Both predisposing and precipitating factors contribute to the risk of falling. Addressing precipitating factors for falls seems to be important in an individualised preventive strategy among older people in geriatric care settings.

Introduction: Several problems arise when HMEs are used while giving aerosolized medication including increased airway resistance (Raw) or the need to open the ventilator circuit. Recently, heat and moisture exchangers designed to allow aerosol delivery (HME-AD) have been developed to solve this problem, but no tests have been performed to confirm their effectiveness. The purpose of this study is to evaluate the effect of HME-ADs on aerosol deposition and Raw. Methods: An in-vitro lung model consisting of an 8.0 mm ID endotracheal tube (ETT) connected to a standard ventilator circuit and ventilator was connected to a rubber test lung via cascade humidifier set to deliver 37˚C and 100% relative humidity. The ventilator settings were as follows: Vt 450 ml, RR 20/min, PIF 50 L/min, PEEP 5 cm H2O, and I:E ratio 1:2. HME-ADs used in this study include Circuvent HME/HCH bypass (Smiths-Medical, Keene, NH), Gibeck Humid-Flo HME (Hudson RCI, Arlington Heights, IL), and Airlife BHME (Carefusion, San Diego, CA). As a control, albuterol sulfate (2.5 mg/3mL) was delivered with a vibrating mesh nebulizer (Aeroneb Solo, Aerogen Inc) placed at the wye without any HME-AD in the circuit. Then, the aerosol and HME configurations of each HME-AD were tested by measuring pre-post Raw and aerosol deposition at the end of each run. Each condition was repeated in triplicate (n=3). Aerosol deposition between the aerosol and HME configurations of each HME-AD was compared with a series of student t-tests. Then, differences both in aerosol deposition and in airway resistance among the HME-ADs were analyzed using one-way analysis of variance (ANOVA). Significance was determined as p<0.05. Results: Raw increased after each albuterol treatment with every HME-AD. In the aerosol configuration, the Circuvent and Humid-Flo delivered significantly less aerosol compared to the control (p=.004 and p=.002, respectively), while there was no significant difference on aerosol delivery between the Airlife and the control (p=.084). The Airlife gave the highest aerosol deposition which was not significantly different than control (p=.084). When aerosol delivery between the HME and aerosol configurations in each HME-AD was compared, aerosol deposition with the Humid-Flo was not significantly different (p=.078) but both the Airlife and the Circuvent showed a statistically significant reduction in aerosol deposition with the HME configuration (p=.002 and p=.005). Conclusions: Aerosol delivery and Raw with each HME-AD differ in simulated mechanically ventilated patients. Further studies are needed to determine the effectiveness of these devices over time and with different aerosol generating devices.

No description available.

The HIV/AIDS pandemic has implications at every level of social functioning. It affects individuals, families, communities and organisations. The burden of caring for those exposed, affected and infected is vast, but one of the most significant developments which have the potential to reduce disease burden is antiretroviral therapy. Antiretroviral therapy (ART) is complex and difficult to administer, and requires a learning process which is mediated through a number of means. Vygotskian theory was utilised to better understand the process of adherence through mediated learning, and as a framework for explaining compliance. In this study, mediated learning occurs both in the context of the clinic staff and the clinic attendees, and the caregivers and the child. Therefore Vygotsky‟s theory offers useful insight into this process. This qualitative study aimed to research the factors which contribute to ART adherence in a small sample of HIV positive children who are attending a local clinic. Eight child-caregiver dyads were interviewed, and drawings utilised to better understand child and caregiver factors which contribute to compliance. There were a number of psychosocial factors identified which contribute to compliance, or lack thereof, including social support, stigma, medication fatigue, disclosure, access difficulties, psychoeducation, and motivation. A number of qualitative differences were also identified between children who knew their HIV status and those who did not. These differences emerged primarily through the analysis of the child participants‟ drawings and there appeared to be a number of inter- and intrapersonal benefits to disclosure. The factors identified in this study, if better understood, can inform interventions to improve compliance on ART. / Thesis (M.Soc.Sci.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

Brugia malayi is one of the causative agents of the disabling and disfiguring disease known as Lymphatic Filariasis (LF). This infection is a well-established ailment in tropical and subtropical countries and recently the drug ivermectin has been introduced for the LF control programs. Ivermectin (IVM) is an excellent microfilaricide, but is not markedly macrofilaricidal. However, it causes a long-lasting reduction in the production of new larvae by female worms, suggesting that adult stages are affected. However, the mechanism by which IVM produces such effect in the adult worm is not well understood. One major reason is our incomplete understanding about the biological effect of IVM on adult stages. The present study was carried out to examine the in vitro effects of IVM on B. malayi adult worms using Brugia-gerbil animal model. And also to have some leads in understanding the drug-uptake and location of probable targets in the worm body by using fluorescent labeled IVM and confocal microscopy. / The antifilarial effects of IVM were examined using three parameters: mf release by female worms, and motility, and viability in both male and female worms. The results reported in this study demonstrate that although IVM did not kill the adult worm, but showed significant antifilarial effects on B. malayi adult stages when examined in an in vitro system. Confocal microscopy images of the worms incubated in bodipy FITC-IVM showed strong specific localization signal in the anterior cephalic region of both male and female worms. These observations suggest the early/initial interactions of the drug with its probable receptors that could be located specifically in the head region.

There are currently an estimated 33.2 million people living with human immunodeficiency virus (HIV) worldwide. For these individuals, long-term use of combination antiretroviral therapy (cART) is not feasible for a variety of reasons including major adverse complications, multi-drug resistance, poor adherence, and high cost. Hence, development of novel therapeutic strategies that can reduce the life-long dependency on cART is highly desired. In order to develop effective therapeutic strategies such as a therapeutic vaccine, we need to have a greater understanding of the immune correlates of viral control in chronic HIV infection. In this thesis, we used treatment interruption (TI) as a tool to test the efficacy of several therapeutic approaches and immune parameters for their association with effective control of viral replication. / In Chapter 2 we showed that cART intensification and Remune vaccination resulted in reduced viral load (VL) plateau during sequential TIs. Although HIV-specific immune responses measured by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) increased in the same time frame, neither their breadth nor magnitude correlated with the decrease in VL plateau. In Chapter 3 the effect of ALVAC-vCP1425 plus Remune vaccination on HIV proteome-wide HIV-specific responses was monitored using a dual color IFN-gamma/interleukin-2 (IL-2) ELISPOT assay. We observed an increase in the magnitude of HIV-specific IFN-gamma/IL-2 responses, as well as in the breadth of Gag-specific IFN-gamma responses in the vaccinated groups compared to placebo groups. A shift towards an increased contribution of Gag-specific responses to total HIV-specific vaccine induced immune response was associated with longer delay to viral rebound during TI. In Chapters 4 and 5, we examined baseline pre-TI immune parameters and their association with viral rebound and CD4 count change during TI in HIV-infected individuals in the chronic phase of infection experiencing virologic failure before TI (Chapter 4) or with different levels of VL control while on therapy prior to TI (Chapter 5). We saw that chronic antigen stimulation from persistent viremia as well as co-infections such as with cytomegalovirus are associated with T-cell senescence, which may result in less favourable clinical outcomes during TI. / Consequently, results from this thesis contribute to further understanding of immune correlates of viral control in chronic HIV infection. New therapeutic vaccines and interventions should induce polyfunctional HIV-specific immune responses, broad Gag-specific immune responses, as well as reducing chronic antigen stimulation to prevent irreversible T-cell exhaustion. Taken together, these insights could potentially lead to the development of novel treatment interventions that could effectively control viral replication off cART.