Successful antiretroviral (ARV) treatment is associated with suppression of HIV viral load and the reduction of clinical disease progression. Despite marked improvements in ARV medication, side effects from long-term treatment, such as loss of muscle mass do occur. The mechanism by which ARVs affect muscle mass is unclear, however, published in vitro data suggests a negative effect on myoblast fusion during differentiation. The objective of this study was therefore to determine the effect of ARVs on processes required for successful myogenesis; these included proliferation, migration during wound repair, and differentiation. C2C12 mouse skeletal myoblasts and human primary culture skeletal (HSk) myoblasts were incubated with Zidovudine (nucleoside reverse transcriptase inhibitor-NRTI), Tenofovir (nucleotide reverse transcriptase inhibitor-NtRTI) or Ritonavir (protease inhibitor-PI) at a concentration range of 0.01 μM to 10 μM. Proliferation was determined using crystal violet and migration was analyzed using a 2D wound healing assay. The commitment of myoblasts into the myogenic lineage was assessed via the expression of the transcription factor Pax7. Differentiation was measured by assessing the fusion index of multinucleated myotubes. C2C12 myoblast proliferation was observed to increase significantly in response to Tenofovir (1 μM and 10 μM). In HSk cells however, proliferation was observed to decrease significantly in response to Tenofovir (1 μM). Zidovudine had no consistent effect on C2C12 proliferation at any dose tested, but caused a decrease in HSk myoblast proliferation (0.01 μM and 0.1 μM); however this was statistically non-significant. A small dose-dependent increase in C2C12 and HSk cell number, although not significant, was seen in response to Ritonavir. Wound closure results revealed both dose-dependent and time-dependent effects of Tenofovir and Zidovudine on human myoblast migration, with significant decreases in the rate of wound closure (4-7 hours) noted at 0.1 μM and 0.01 μM doses respectively. Zidovudine had no significant effect on migration while Ritonavir (0.01 μM) was observed to significantly increase percentage wound closure of human myoblasts, suggesting an increased ability to migrate during wound repair. Differentiation results indicated a decrease in myoblast fusion in response to all three ARVs. However only Ritonavir was shown to negatively affect myosin heavy chain expression. Further research into the exact mechanism of decreased fusion is required. To our knowledge, this study is the first to suggest that selected ARVs may significantly influence myoblast regeneration capabilities by modulating myoblast proliferation, migration, differentiation and fusion, and thereby decrease their myogenic capability. Extended human myoblast studies on differentiation could confirm this hypothesis. / Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2013.

Ketamine has shown promise as a novel treatment for depression and as a means to investigate the biology of depression. The drug effectively and rapidly treats depressed patients with the effects lasting approximately 1 week. However, concerns about ketamine’s efficacy do exist because of the inadequacy of blinding procedures used in existing trials. A dose of 0.5 mg/kg has been found to be most effective. Prolonged ketamine infusions have not extended the antidepressant effect beyond the timeframe of a regular infusion. Repeat infusions may be successful in extending ketamine’s effect, but definite conclusions cannot yet be made in this regard. Combination treatment with escitalopram and cognitive behavioral therapy (CBT) hold promise, as does the development of an intranasal formulation. Ketamine has shown additional efficacy as an acute anti-suicide treatment. Side effects from a single administration usually fade within a few hours and commonly include dissociation, elevations of blood pressure, nausea, and anxiety. Less data is available on the side effects caused by repeated ketamine infusions. Concerns exist regarding genitourinary, hepatic, and cognitive side effects after repeated infusions, as well as a risk of addiction. Research on ketamine’s mechanism of action has focused on the glutamate system in the brain. Ketamine may act by inhibiting release of γ–aminobutyric acid (GABA) from interneurons, activating intrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), increasing mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase (ERK) signaling, enhancing brain-derived neurotrophic factor (BDNF) production, inhibiting glycogen synthase kinase 3 (GSK3), blocking extrasynaptic N-Methyl-D-aspartate receptors (NMDARs), and promoting synaptogenesis and neuroplasticity. The two existing ketamine stereoisomers, (R)- versus (S)-ketamine, have different actions and potentially different efficacies and side effect profiles. Ketamine also produces regional changes in brain activity and connectivity. These include decreased burst firing in the lateral habenula (LHb), increased activity in the prefrontal cortex (PFC) and subgenual anterior cingulate cortex (ACC), and alterations in the amygdala’s response to angry and happy faces. Ketamine has the potential to be developed into a novel and useful clinical tool in the treatment of depression and to advance the understanding of the biology of depression.

O presente trabalho constitui uma avaliação prospectiva da utilização do método de esterilização feminina não-cirúrgica com quinacrina. O grupo em estudo é formado por dez mulheres, atendidas no período de abril a setembro de 1990, no Ambulatório de Planejamento Familiar do Hospital Sotero del Rio, Santiago, Chile. O perfil reprodutivo das mulheres, revela que o inicio da vida fértil foi, em media, aos 12.1 anos e aproximadamente quatro anos depois (16.4 anos), iniciaram a atividade sexual sem uso de métodos anticoncepcionais. Em consequência, verifica-se que a primeira gravidez ocorreu, em média, aos 19.1 anos, ou seja, ainda dentro do período que compreende a adolescência. Após este evento obstétrico - gravidez - a maioria iniciou o uso de métodos de planejamento familiar por volta dos 21 anos, tendo como resultado, uma variada e não muito bem sucedida história anticoncepcional. A decisão de encerrar a vida reprodutiva com medidas definitivas foi tomada pelo casal, baseado em informações fornecidas pelos profissionais de saúde e referindo razões de planejamento familiar, história anticoncepcional e obstétrica negativa. No momento de concretizar esta decisão, as mulheres faziam em média, 34.8 anos e parte de uma família legalmente constituída com 3.2 filhos vivos. Destas mulheres, 40 por cento ainda tinham a opção de utilizar métodos reversíveis modernos, no momento de submeter-se a este método definitivo. O seguimento prospectivo do método não-cirúrgico mostra que os efeitos colaterais, como os maiores níveis de quinacrina plasmática e urinária apresentam-se no período das primeiras 48 horas, após inserção intrauterina da primeira e segunda doses de \"pellets\" de quinacrina. / This paper consists of an evaluation on the use of quinacrine as a non-surgical irreversible method for female sterilization. The study group is made up of ten women, seen at the Sotero del Rio Hospital outpatient clinic in Santiago, Chile, from april to september 1990. This study reveals that the women\'s reproductive life began on average at the age of 12.1 years and approximately four years later they began their sexual activity without the use of contraceptive methods. Consequently their first pregnancy occurred at the age of 19.1 years, during late adolescent years. Two years after pregnancy many of these women began to use contraceptive methods (at the age of 21, on average). As a result their obstetric history shows a non well succeeded and varied response to anticonceptional methods. The decision to close reprodutive life taking permanent steps was made by the couples based on information furnished by health professionals. The reasons given were related to family planning, anticonceptional and negative obstetric history. On implementing their decision, the group averaged 34.8 years and averaged 3.2 a lived children per subject. A total of 40 per cent of these women could still use other modern reversible methods before being submited to this permanent one. The follow-up of this non-surgical procedure shows that side effects such as higher levels of quinacrine in the blood and urine ocurred in the first 48 hours after the first and second intrauterine insertion of quinacrine pellets.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

O presente trabalho constitui uma avaliação prospectiva da utilização do método de esterilização feminina não-cirúrgica com quinacrina. O grupo em estudo é formado por dez mulheres, atendidas no período de abril a setembro de 1990, no Ambulatório de Planejamento Familiar do Hospital Sotero del Rio, Santiago, Chile. O perfil reprodutivo das mulheres, revela que o inicio da vida fértil foi, em media, aos 12.1 anos e aproximadamente quatro anos depois (16.4 anos), iniciaram a atividade sexual sem uso de métodos anticoncepcionais. Em consequência, verifica-se que a primeira gravidez ocorreu, em média, aos 19.1 anos, ou seja, ainda dentro do período que compreende a adolescência. Após este evento obstétrico - gravidez - a maioria iniciou o uso de métodos de planejamento familiar por volta dos 21 anos, tendo como resultado, uma variada e não muito bem sucedida história anticoncepcional. A decisão de encerrar a vida reprodutiva com medidas definitivas foi tomada pelo casal, baseado em informações fornecidas pelos profissionais de saúde e referindo razões de planejamento familiar, história anticoncepcional e obstétrica negativa. No momento de concretizar esta decisão, as mulheres faziam em média, 34.8 anos e parte de uma família legalmente constituída com 3.2 filhos vivos. Destas mulheres, 40 por cento ainda tinham a opção de utilizar métodos reversíveis modernos, no momento de submeter-se a este método definitivo. O seguimento prospectivo do método não-cirúrgico mostra que os efeitos colaterais, como os maiores níveis de quinacrina plasmática e urinária apresentam-se no período das primeiras 48 horas, após inserção intrauterina da primeira e segunda doses de \"pellets\" de quinacrina. / This paper consists of an evaluation on the use of quinacrine as a non-surgical irreversible method for female sterilization. The study group is made up of ten women, seen at the Sotero del Rio Hospital outpatient clinic in Santiago, Chile, from april to september 1990. This study reveals that the women\'s reproductive life began on average at the age of 12.1 years and approximately four years later they began their sexual activity without the use of contraceptive methods. Consequently their first pregnancy occurred at the age of 19.1 years, during late adolescent years. Two years after pregnancy many of these women began to use contraceptive methods (at the age of 21, on average). As a result their obstetric history shows a non well succeeded and varied response to anticonceptional methods. The decision to close reprodutive life taking permanent steps was made by the couples based on information furnished by health professionals. The reasons given were related to family planning, anticonceptional and negative obstetric history. On implementing their decision, the group averaged 34.8 years and averaged 3.2 a lived children per subject. A total of 40 per cent of these women could still use other modern reversible methods before being submited to this permanent one. The follow-up of this non-surgical procedure shows that side effects such as higher levels of quinacrine in the blood and urine ocurred in the first 48 hours after the first and second intrauterine insertion of quinacrine pellets.

The infusion of intravenous immunoglobulin therapy in the home setting requires a critical nursing assessment and interventions aimed at managing and preventing the escalation of adverse events. Some patients experience side effects that necessitate a rapid response by field nurses, requiring standing orders for nursing administration and the availability of essential medications to alleviate symptoms in the patient's home. The clinical practice issue was that the home health agency did not have a uniform clinical practice nursing guideline to assist field nurses in providing rapid responses for managing infusion-related reactions. The purpose of this project was to develop an evidence-based clinical practice guideline using standing orders for the comprehensive management of immunoglobulin side effects in the patient's home. The practice-focused question centered on whether the use of a nursing practice guideline based on interprofessional collaboration could manage the side effects of patients in the home by decreasing the use of emergent care and improved quality of care for those patients susceptible to significant side effects. An interdisciplinary expert panel experience in IVIG l used Newman's system theory and the reach, effectiveness, adoption, implementation, maintenance framework for interprofessional collaboration in developing a clinical nursing guideline with a standing order for rating side effects. Panelists used the appraisal of guidelines, research, and evaluation II tool to appraise the evidence for the guideline. The use of clinical guideline with standing orders to address the needs of patients in the home setting may lead to positive social change by enabling more rapid management of symptoms, more effective care in the home, and improved patient outcomes

Bibliography: leaves 107-109.

Background. Medication-related patient injuries (adverse drug events, ADEs) are an important problem in all hospitalised populations; however, the potential for injury is reported to be greater in children than adults. Many ADEs are due to error and therefore could be prevented. Data regarding the risk factors (or predictors) for these events in paediatric inpatients is limited. It was hypothesised that "identification of risk factors for ADEs and medication errors in the paediatric inpatient setting will inform likely prevention strategies". Aims. To determine the frequency, nature and risk factors for ADEs and potential ADEs occurring in a paediatric inpatient population; to assess the vulnerable processes in the neonatal intensive care unit (NICU) medication use process; and to provide recommendations for the targeting of likely prevention strategies. Setting. A general paediatric ward (PW), postnatal ward (PNW) and NICU of a University- affiliated urban general hospital. Design. There were two study components: the medEVENT study which involved identification of actual ADEs and potential ADEs over a twelve week period, through prospective review of medical records, medication charts and administration records along with voluntary and solicited staff report and parent interview; and the FMEA study which used a proactive risk assessment technique, Failure Mode and Effect Analysis (FMEA), to rank all potential failures in the NICU medication use process according to risk. Results. In the MedEVENT study 3160 prescription episodes were reviewed (which represented 520 admissions, 3037 patient-days) and revealed a total of 67 ADEs and 77 potential ADEs. The greatest number of events occurred in NICU with very few events in the PNW. However, paediatric surgical admissions experienced the highest rate of ADEs per 1000 patient-days (80) as compared to medical (65) then NICU admissions (19). Over half of the ADEs were deemed preventable, 38 (57%), with the �more serious� ADEs more likely to be preventable than �not serious� ADEs. The impact on hospital resources was considerable with the cost attributed to extra bed days due to ADEs to be $NZD 50,000. Dosing errors were the most common type of error, particularly when prescribing and administering medications. Antibacterial and narcotic analgesics were commonly implicated, as was the intravenous route of administration. Few events were related to unlicensed use of medications. For ADEs, the major risk factors when analysed by admission, were greater medication exposure and increasing age; by prescription, were increasing age, oral route and narcotics and antibacterial agents; for paediatric ward admission, were increasing age and increased length of stay; and for NICU admission, no major risk factors emerged. For potential ADEs, the major risk factors when analysed by admission were greater medication exposure; by prescription, were junior prescriber, intravenous route, narcotics and antibacterials; for paediatric ward admission, were junior prescriber and narcotics; and for NICU admission were antibacterials, electrolytes and umbilical venous catheter administration. Neither ADEs nor potential ADEs were associated with unlicensed use of medicines or high alert status drugs. The FMEA study identified 72 potential failures in the NICU medication use process with 193 associated causes and effects. Multiple failures were possible in the process of �prescribing medication� and in the process of �preparation of medication for administration�. The highest ranking issues were found to occur at the administration stage. Common potential failures related to errors in the dose, timing of administration, infusion pump settings and route of administration. Conclusions. Analysis of the risk factors of ADEs and potential ADEs found that the most vulnerable processes were when prescribing and when preparing a medicine for administration; especially when involving narcotic and antibacterial agents and for children with greater medication exposure Strategies that selectively target these high risk areas are therefore likely to have the greatest impact on preventing drug-related injuries in hospitalised children.

Corrigenda inserted opposite title page. / Copies of author's previously published articles inserted inside back cover. / Bibliography: leaves 245-291. / xvii, 291 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / An improved HPLC method was developed to measure the concentration of the three compounds in plasma and urine. The stability of the compounds during storage in plasma was also established. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995?

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