Rozprawy doktorskie na temat „Intermal medicine”

Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2015. In conjunction with the Leaders for Global Operations Program at MIT.
Thesis: S.M., Massachusetts Institute of Technology, Engineering Systems Division, 2015. In conjunction with the Leaders for Global Operations Program at MIT.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 105-107).
Internal Medicine Associates (IMA) is the largest primary care practice at Massachusetts General Hospital (MGH) with over 40 attending physicians, 60 residents, and 80 support staff that deliver care to more than 30,000 patients. The IMA is structured into seven pods that act independently to serve patients. Each pod consists of patient care providers and support staff that work collaboratively in a team structure. In particular, providers and medical assistants work closely together during the clinical session to meet patient needs. A lack of standardization in the practice's operations has contributed to inefficiencies that add to a sense of overload and burnout with the medical assistant staff A detailed study of providers' clinical schedules revealed that individual clinical sessions are highly variable in terms of the number of concurrent clinical sessions per pod, session length, and number of patient appointments booked during this time. Providers in the IMA are part-time and create their clinical schedules based on personal preference and coordination with their other MGH related commitments. Variability in the schedule arises from many systematic, predictable, and unpredictable sources. Additionally, as part of a teaching hospital, IMA supports the educational training of over 60 Internal Medicine residents who hold a varying number of clinical sessions per week, depending on specific requirements of their residency program. Coordinating and supporting provider presence consumes many resources, impacts medical assistant workload, and adds to variability within the practice. The project develops an optimization model to level-load the expected workload on medical assistants and other members of the medical care team by determining the clinic schedules of providers. The expected workload is measured by the number of concurrent sessions and expected number of patient visits per hour. The project has developed an optimization model to suggest changes to the clinic schedule. Specifically in Pod 2/3, by strategically shifting 19.5% of provider sessions, we can achieve an 83% improvement in variability, as measured by the difference between maximum and minimum expected workload. Similar results are modeled for all pods in the IMA. The team has identified a pilot pod to test the model and is
by Vaishal J. Patel.
M.B.A.
S.M.

An acceptable agreement permits interchangeability of the instruments. For this purpose, we have investigated the agreement of several clinical instruments frequently used in clinical practice with their laboratory counterpart. We have estimated the agreement between a point-of-care blood gas analyzer (i-Stat, Abaxis) and a bench-top blood gas analyzer (Nova, Biomedical) in venous samples from Hermann’s tortoises. We have estimated the agreement between a point-of-care chemistry analyzer (VetScan VS2, Abaxis) and a laboratory analyzer (Olympus AU400, Olympus Co.) in venous samples from Hermann’s tortoises. We have estimated the agreement between portable blood glucose meters (Accu-Chek, Aviva; AlphaTrak 2, Abbott) and a laboratory analyzer (Dimension EXL, Siemens) in venous samples from client-owned rabbits. We have estimated the agreement between point-of-care bench-top glucose measurement (VetScan VS2, Abaxis) and a laboratory analyzer (Dimension EXL, Siemens) in venous samples from client-owned rabbits. Beyond method comparison and validation, reference interval determination for common laboratory testing is required to allow the clinician to discriminate individuals that are different from the remaining population for a certain parameter. We have calculated reference intervals for blood gas in Hermann’s tortoises. We have calculated reference intervals for protein electrophoresis in Hermann’s tortoises. We have described normal hematology in Hermann’s tortoises. We have calculated reference intervals for clinical chemistry in Hermann’s tortoises. We have calculated reference intervals for aldosterone in ferrets. Based on our results, animal species requires individual validation of laboratory methods and reference intervals. Lack of consideration of these findings may result in clinical misdiagnosis and improper treatment of animals.

An acceptable agreement permits interchangeability of the instruments. For this purpose, we have investigated the agreement of several clinical instruments frequently used in clinical practice with their laboratory counterpart. We have estimated the agreement between a point-of-care blood gas analyzer (i-Stat, Abaxis) and a bench-top blood gas analyzer (Nova, Biomedical) in venous samples from Hermann’s tortoises. We have estimated the agreement between a point-of-care chemistry analyzer (VetScan VS2, Abaxis) and a laboratory analyzer (Olympus AU400, Olympus Co.) in venous samples from Hermann’s tortoises. We have estimated the agreement between portable blood glucose meters (Accu-Chek, Aviva; AlphaTrak 2, Abbott) and a laboratory analyzer (Dimension EXL, Siemens) in venous samples from client-owned rabbits. We have estimated the agreement between point-of-care bench-top glucose measurement (VetScan VS2, Abaxis) and a laboratory analyzer (Dimension EXL, Siemens) in venous samples from client-owned rabbits. Beyond method comparison and validation, reference interval determination for common laboratory testing is required to allow the clinician to discriminate individuals that are different from the remaining population for a certain parameter. We have calculated reference intervals for blood gas in Hermann’s tortoises. We have calculated reference intervals for protein electrophoresis in Hermann’s tortoises. We have described normal hematology in Hermann’s tortoises. We have calculated reference intervals for clinical chemistry in Hermann’s tortoises. We have calculated reference intervals for aldosterone in ferrets. Based on our results, animal species requires individual validation of laboratory methods and reference intervals. Lack of consideration of these findings may result in clinical misdiagnosis and improper treatment of animals.

This thesis investigates the application of classical and contemporary statistical methods in medical research attempting to bridge the gap between statistics and clinical medicine. The importance of using simple and advanced statistical methods in constructing and assessing risk models in medicine will be demonstrated by empirical studies related to vascular complications: namely abdominal aortic aneurysm and diabetic retinopathy. First, data preprocessing and preliminary statistical analysis are examined and their application is investigated using data on abdominal aortic aneurysm. We illustrate that when dealing with missing data, the co-operation between statisticians and clinicians is necessary. Also, we show advantages and disadvantages of exploratory analysis. Second, we describe and compare classification models for AAA selective screening. Tow logistic regression models are proposed. We also show that it is important to assess the performance of classifiers by cross-validation and bootstrapping. We also examine models that include other definitions of abnormality, weighted classification and multiple class models. Third, we consider the application of graphical models. We look at different types of graphical models that can be used for classification and for identifying the underlying data structure. The use of Naïve Bayes classifier (NBC) is shown and subsequently we illustrate the Occam’s window model selection in a statistical package for Mixed Interactions Modelling (MIM). The EM-algorithm and multiple imputation method are used to deal with inconsistent entries in the dataset. Finally, modelling mixture of Normal components is investigated by graphical modelling and compared with an alternative minimisation procedure. Finally, we examine risk factors of diabetic sight threating retinopathy (STR). We show the complexity of data preparation and preliminary analysis as well as the importance of using the clinicians’ opinion on selecting appropriate variables. Blood pressure measurements have been examined as predictors of STR. The fundamental role of imputation and its influence on the conclusions of the study are demonstrated. From this study, we conclude that the application of statistics in medicine is an optimisation procedure where both the statistical and the clinical validity need to be taken into account. Also, the combination of simple and advanced methods should be used as it provides additional information. Data, software and time limitations should be considered before and during statistical analysis and appropriate modifications might be implemented to avoid compromising the quality of the study. Finally, medical research should be regarded for statisticians and clinicians as part of a learning process.

Mestrado em Tradução Especializada
No âmbito do Mestrado em Tradução Especializada, vertente Saúde e Ciências da Vida, este projeto procura explorar a metodologia e a problemática associada à atividade tradutológica, através da realização de uma tradução de um capítulo da obra Harrison’s Principles of Internal Medicine, subordinado ao tema da Aterosclerose, explorando a patogenia, prevenção e tratamento daquela que é uma das principais causas de mortalidade nos países ocidentais. Além da tradução, este projeto consiste também na análise de todos os processos ultrapassados antes de se iniciar a tradução, durante e após a sua completação.
In the context of Specialised Translation, this project seeks to explore the methodology and problems associated with the translational activity, through the translation of a chapter from Harrison’s Principles of Internal Medicine, under the subject of Atherosclerosis, exploring the patogeny, prevention and treatment of one of the leading causes of death in western countries. Additionally to the translation, this project also includes the analysis of all processes undergone before, during and after the translation was completed.

The purpose of the present study was to assess: a) perceived stress, burnout, depression, and empathy at three time points in internal medicine residents, b) the role of gender and trait mindfulness in stress response during residency and c) to evaluate the impact these variables have on performance evaluations. Additionally, specific tasks of the residency that may contribute to the experience of stress and burnout were evaluated to test a model of job strain. Stress predicted subsequent burnout and depression. Burnout predicted subsequent depression, and stress mediated this relationship. Women reported higher mean levels of empathy and burnout than men. The exploratory measure of job strain was not significantly related to stress outcomes. The acting with awareness facet of mindfulness was negatively related to burnout and depression. Performance was both negatively and positively related to stress outcomes. The results are discussed within the context of the current literature.

This report is an effort to describe most of the clinical procedures that took place during the integrated externship of the Master’s degree in Veterinary Medicine at the University of Evora. The externship had a duration of sixteen weeks and was realized in the “A&A Veterinary Hospital” which has a substantial caseload of Retired Racing Greyhounds with Osteosarcoma. The first part, of the report, relates to the casuistics of Small Animal Internal Medicine and Surgery, divided per area of interest. The second part, is a current bibliographic review on canine Osteosarcoma, followed by three case-studies of Osteosarcoma in Retired Racing Greyhounds, with different survival times; Resumo: Medicina Interna e Cirurgia em Pequenos Animais Osteosarcoma em cães de raça Greyhound, ex- corredores O presente relatório é uma descrição da maioria dos procedimentos clínicos, que se realizaram durante o estágio curricular do Mestrado Integrado em Medicina Veterinária da Universidade de Évora. O estágio, teve a duração de dezasseis semanas e realizou-se em “A&A Veterinary Hospital” que apresenta na sua casuística muitos cães de raça Greyhound, Ex- corredores, com Osteosarcoma. A primeira secção relata a casuística, em Medicina Interna e Cirurgia de Pequenos Animais, dividida por área de interesse. A classificação dos casos foi realizada com base no sistema somático afetado ou no motivo da visita. A segunda secção é uma revisão bibliográfica sobre Osteosarcoma canino, acompanhada por três casos de Osteosarcoma em cães ex-corredores, de raça Greyhound, com diferentes tempos de sobrevivência.

Medication errors are among the most common causes of unintended harm to patients and have led to many deaths. Some categories of medication errors include; medications administered to the wrong person; medications administered at the wrong time, through the wrong route; administration of the wrong medication and/or dose; and the omission of medications. Guided by the logic model, the just culture model, and the Knowles theory of andragogy, the purpose of the project was to determine if providing information related to evidence-based strategies to reduce medication errors would result in safer medication administration practices and improved patient outcomes A survey was administered to 11 medical and nursing staff at an outpatient internal medical clinic to determine their knowledge about medications errors prior to providing evidence-based information on strategies to reduce medication errors. After the educational session, a survey was conducted to determine staff members' retention of knowledge. A significant increase in the percent of correct responses to the survey from 68% to 100% after the educational session (t = -3.9; p = 0.001)) shows that the educational in-service had a positive outcome in increasing staff members' knowledge about reducing medication errors in an out-patient internal medicine clinic. Improving clinic staff knowledge and behaviors regarding medication administration has the potential to bring about social change by decreasing medication errors, improving patient safety, and improving health outcomes.

Epstein-Barr virus (EBV), an oncogenic virus that ubiquitously establishes life-long persistence in humans, encodes viral miRNAs in two clusters, BHRF1 and BART. EBV also regulates expression of a large pool of cellular miRNAs, including miR-155, miR-146a, miR-21, miR-29, and miR-34a. These miRNAs targets both viral and cellular genes involved in the entire viral lifetime from lytic infection to oncogenesis, including viral replication, immune responses, cell cycle regulation, apoptosis, and cell proliferation, and are indispensable for persistent infection, latency establishment and maintenance, and cancer development. Among them, circulating miRNAs and unique miRNA profiles are promising diagnosis and prognosis biomarkers alone or with other traditional biomarkers. Elucidation of the precise mechanisms of action of these miRNAs in EBV latent infection will improve our knowlege of EBV persistence and oncogenesis, and may foster new strategies to target these miRNAs for treatments of EBV-associated cancers.

O presente relatório de conclusão do curso de Mestrado Integrado em Medicina Veterinária da Universidade de Évora, refere-se ao período de estágio curricular obrigatório que decorreu na Clínica Equifort, em Fortaleza, Brasil, na área Patologia e Clínica de Equinos. Numa primeira fase é feita uma descrição das atividades desenvolvidas onde se apresenta a casuística acompanhada durante o estágio, que inclui atividades em diversas áreas como medicina desportiva, clínica médica, clínica reprodutiva, clínica cirúrgica e clínica hospitalar. Numa segunda fase desenvolve-se uma monografia onde se caracterizam as lesões radiográficas de membros anteriores de cavalos de desporto, e por fim são apresentados cinco casos clínicos; ABSTRACT: EQUINE PATHOLOGY AND CLINICAL The present report refers to curricular internship, integrated on the master degree in veterinary medicine at the University of Évora, that took place at the Clinic Equifort in Fortaleza, Brazil, in the área of Equine Pathology and Clinical. Initially a description of the activities accompanied during the internship is given which includes activities in areas such as sports medicine, internal medicine, reprodution and surgery. In a second part a monograph is developd with the characterization of radiographic injuries in forelimbs of sport’s horses, and finally five clinical cases are presented.

The most common risk factors for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) include chronic alcohol abuse and infection with hepatitis B (HBV) or hepatitis C (HCV) virus. Growing evidence from human studies and experimental models suggests that pre-degenerative and premalignant abnormalities include disturbances in intracellular signaling and ongoing injury with oxidative stress, inflammation, and lipotoxicity. The major signal transduction pathways affected in both degenerative and neoplastic disease states in liver include: insulin/IGF, Wnt/β-catenin, and others.

Point-of-care detection of urine lipoarabinomannan (LAM) is a low-cost rapid TB diagnostic for use in HIV co-infected patients. However, its sensitivity in these patients is suboptimal. Strategies to improve its performance is a need. The hypothesis was that early morning urine (EMU), rather than random urine sampling, would improve LAM's sensitivity. Methods Recruitment process conducted between June 2012 and February 2014 for HIV-infected patients from four hospitals in Cape Town, South Africa presenting with possible TB (all patients initiated on TB treatment). Fresh random and early morning urine (EMU) samples (~10-30 ml) collected in sterile containers. Following the manufacturer's instructions, an Alere Determine® TB Lateral flow assay performed on each sample, using both grade 1 and 2 cut-points. A single sputum Xpert MTB/RIF and/or liquid TB culture was a reference standard. Those designated probable TB patients were sputum Xpert MTB/RIF and/ TB culture negative, but started on TB treatment.

Introduction: Stroke is the leading cause of death and disability amongst South Africans older than 60 years. The majority of stroke patients in South Africa are managed in general medical wards where little is known about the quality and cost of care. The aim of this study was to determine the cost of stroke care and to identify factors associated with increased expense , as well as to evaluate the quality of stroke care in general medical wards in order to identify areas where quality of care could be improved. Methods: We conducted a retrospective folder review of all acute stroke admissions to the general medical wards at Groote Schuur Hospital from 1 January to 31 December 2012. Patients younger than 45 years and those that received thrombolysis were excluded. The hospital's finance department provided the bed costs, as well as expenditure on consumables, pharmacy, laboratory and radiology for each subject. The quality of care was measured according to the South African Stroke Guidelines. Results: The inpatient care of 261 patients was evaluated. Although neuroradiology was performed on 95% of patients, carotid duplex Doppler ultrasonography and echocardiography were not often done. Although all patients with ischaemic stroke received inpatient antiplatelet or anti - coagulation therapy, not all risk factors were adequately addressed on discharge. The median cost of a stroke admission was R19,072.07 (IQR R10,899.85 to R27,789.43 ). The strongest correlation with cost 12 was with length of stay (LOS), r = 0.9977. The median LOS was 6 days (IQR 3 to 9 days). Using non -¬‐ parametric univariable analysis, clinical factors prolonging LOS were previous stroke ( P = 0.0 2 8) and inpatient complications: fever ( P < 0.0 0 1), urinary tract infections ( P < 0.0 0 1) and acute kidney injury ( P < 0.0 0 1) . The LOS increased as the number of inpatient complications increased (P = 0.059). Mortality was 20% and 68% of patients experienced at least one medical complication during admission. Fever and pneumonia were predict ors of death. Pneumonia was less prevalent amongst patients who were mobilised early (P = 0.002). Early nutritional support was beneficial in reducing the incidence of acute kidney injury (P < 0.001). The median LOS was significantly prolonged by delaying speech therapy (P < 0.001), nutritional support (P < 0.01), physiotherapy (P < 0.01) and occupational therapy (P < 0.001). Discharge to inpatient rehabilitation centres significantly prolonged LOS as compared with patients discharged home (P < 0.001). Conclusions: This is the first study evaluating the cost of acute stroke care in South Africa. Length of stay was the greatest determinant of cost. Improving the quality of care to reduce the number of complications, early referral to allied health professionals and effective discharge planning would result in shorter length of hospital stay and therefore cost saving. There is a need for increased access to stroke unit beds, albeit dedicated stroke beds in the general medical wards, to ensure specialised nursing care and early inpatient rehabilitation to reduce the number of inpatient complications, as well as implementation of protocols to allow for better adherence to national guidelines.

Includes abstract.
Includes bibliographical references.
Stroke is an important cause of death and disability in sub-Saharan Africa. Recombinant tissue plasminogen activator (tPA) thrombolysis is effective in treating acute ischaemic stroke, but may not be a viable option in developing countries. This prospective observational study was designed to assess the short-termoutcomes and safety of tPA for the treatment of stroke at Groote Schuur Hospital.Data was collected from January 2000 to February 2012, and included patients witha clinical diagnosis of acute stroke with onset of stroke symptoms within 4.5 hours ofreceiving thrombolysis. Exclusion criteria were based on the National Institute ofNeurological Disorders and Stroke (NINDS) rt-PA trial protocol (upper age limit was 75 years). Primary outcomes were the proportion of patients achieving significant early neurological recovery defined as an improvement of 4 or more points on the National Institutes of Health stroke scale (NIHSS) score and functional independence defined as a modified Rankin score of 2 or less at discharge. The primary safety measures were the rates of symptomatic intracranial haemorrhage (SICH) and death. From January 2000 to February 2011 42 patients were thrombolysed, with a mean time to tPA infusion of 160 minutes (standard deviation (SD) 50; range 60 - 270). By discharge the median NIHSS score fell from 14 (interquartile range (IQR) 10.5 - 17) to 7.5 (IQR 1 - 15); 28 (66.7%) achieved significant neurological improvement, and 17 (40.5%) were functionally independent. Two patients (4.8%) suffered SICH and there were 3 (7.1%) deaths. Thrombolysis in routine clinical practice in a South African setting has similar safety and early efficacy outcomes to controlled trials and open-label studies in developing and developed countries.

Background The burden of dyslipidaemia in Africa remains inadequately characterised. We aimed to estimate the prevalence of dyslipidaemia in African adults from hospital-based and community-based studies. Methods In this systematic review and meta-analysis, we searched MEDLINE via PubMed, EMBASE, African Journals Online, and African Index Medicus for studies published between Jan 1, 1980, and July 31, 2017, without language restriction. We assessed methodological quality of all crosssectional studies reporting on the prevalence of elevated concentrations of total cholesterol, LDL cholesterol, or triglycerides, or low concentrations of HDL cholesterol in adults residing in African countries. We excluded reports on Africans living outside Africa, studies of individuals selected on the basis of existing dyslipidaemia or those including children and adolescents, and case series with a small sample size. The most frequently used cutoffs in the included studies were chosen for the subgroup analysis. We used random-effect model meta-analysis to derive the pooled prevalence of elevated total cholesterol, low HDL cholesterol, elevated LDL cholesterol, and elevated triglyceride concentrations. This study is registered with PROSPERO, number CRD42014015376. Findings 177 studies (294063 participants) were included in the meta-analysis. The pooled prevalence of dyslipidaemia in the general population from population-based studies was 25·5% (95% CI 20·0– 31·4) for elevated concentrations of total cholesterol with a cutoff of at least 5·2 mmol/L, 37·4% (29·4–45·7) for low concentrations of HDL cholesterol with a cutoff of less than 1·0 mmol/L, 28·6% (15·8–43·5) for elevated concentrations of LDL cholesterol with a cutoff of at least 3·3 mmol/L, and 17·0% (11·9–22·7) for elevated concentrations of triglycerides with a cutoff of at least 1·7 mmol/L. Interpretation The prevalence of dyslipidaemia is high in the general adult population in Africa. Ongoing efforts to reduce cardiovascular diseases in Africa should integrate effective detection and treatment of dyslipidaemia.

Structured reflection has been shown to improve the diagnostic competence of undergraduate and postgraduate trainees in a range of experimental settings using written case scenarios. Evidence supporting the use of this strategy during real patient encounters is lacking. This paper reports on a study conducted to determine the effects of structured reflection on the diagnostic accuracy of postgraduate medical trainees during bedside tutorials using real patient encounters. Method Fifty-five postgraduate trainees in Internal Medicine at the University of Cape Town, South Africa, were prospectively studied during 18 beside tutorials using real patient encounters. Each patient encounter was conducted as a 4-stage diagnostic process and a diagnostic accuracy score (DAS) was calculated for all participants at each stage: • DAS 1: immediately upon arrival at the patient's bedside (visual cues only); • DAS 2: after an oral presentation of the interview and physical examination findings (pre-reflection); • DAS 3: after review of the clinical data using a process of structured reflection (post-reflection); • DAS 4: after discussion of the patient facilitated by the attending physician (facilitated reflection). Memory structure and flexibility in thinking of participants were evaluated using the Diagnostic Thinking Inventory (DTI) and compared to their post-reflection diagnostic accuracy scores. Results A total of 212 diagnostic events were studied. Friedman's test demonstrated a significant difference when comparing the median diagnostic accuracy scores (DAS) of the respective stages of the diagnostic process (χ² (3) = 406.34, p value < 0.001). The Wilcoxon signed-rank test confirmed that there was a significant difference between the immediate DAS (DAS 1) and the pre-reflection DAS (DAS 2) (Z = 8.66, p value < 0.001), the pre-reflection DAS (DAS 2) and the post reflection DAS (DAS 3) (Z = 4.98, p value < 0.001). Linear regression identified a significant relationship between DTI scores and DAS 3 (p value = 0.035), however this explains only a small portion of the variation in the data (r² = 0.093). Conclusion Structured reflection improved the diagnostic accuracy of postgraduate trainees during real patient encounters at the bedside. These data provide support for the suggestion that clinical teachers should consider adding structured reflection to their toolbox of bedside teaching strategies. In addition, DTI scores may help clinical teachers identify trainees struggling with the development of diagnostic expertise.

We studied the implementation of JAK2 mutation analysis in conjunction with the World Health Organisation (WHO) guidelines in the pathway to MPN diagnosis in 279 patients presenting with one of three clinical scenarios: erythrocytosis, OR leukocytosis and/or thrombocytosis and/or splenomegaly; OR patients with thrombosis without cytoses. Patients were investigated for MPN and managed in the haematology clinic of Groote Schuur Hospital. We studied the association of clinical and laboratory variables with clonal vs non-clonal diagnoses. In 120/297 patients MPN was confirmed: Polycythemia vera (PV), (n=51, 100% JAK2 mutated); essential thrombocytosis, (n=41, 42% JAK2 mutated); primary myelofibrosis (n=28, 57% JAK2 mutated). The 2016 WHO haemoglobin/haematocrit thresholds in PV were validated. Idiopathic erythrocytosis (IE) found in 44 patients. Bone marrow histology, but not serum EPO level, was essential to differentiate between clonal and non-clonal erythrocytosis. Both PV and IE patients complied with the criteria of absolute erythrocytosis on peripheral blood, yet nuclear red cell mass identified critical differences between clonal and non-clonal erythrocytosis. No patient venesected for nonclonal erythropoiesis developed thrombocytosis. JAK2 mutation analysis applied with the WHO diagnostic algorithm efficiently differentiated true clonal myeloproliferation from reactive cytoses. Lifestyle and metabolic factors such as smoking and thrombosis were not associated with either clonal or non-clonal erythrocytosis, and were equally present in mutated and unmutated essential thrombocytosis.

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The objective of this study was to identify and analyze the abundance of dipteran family Calliphoridae present along the decomposing carcass of pigs in the Cariri, Paraiba State, Brazil, in two periods: rainy and dry. The study was conducted in Reserva Particular do Patrimônio Natural (RPPN) Fazenda Almas, in São José dos Cordeiros-PB. We used two pig carcasses (Sus scrofa) by period, protected from scavengers by a metal cage inside trap like "Shannon". Samples were collected daily, twice a day, for eleven days in both periods. The meteorological data of precipitation were obtained at the Centro de Previsão e Estudos Climáticos do INMET and temperature and relative humidity were obtained in situ using a digital hygrometer. The insects collected were placed in the laboratory of entomology of UFPB and identified as well. We collected 8.811 individuals of the family Calliphoridae, belonging to six species (Chrysomya albiceps (Wiedemann, 1819), Cochliomyia macellaria (Fabricius, 1775), Chrysomya putoria (Wiedemann, 1818), Chloroprocta idioidea (Robineau-Devoidy, 1830), Chrysomya megacephala (Fabricius, 1794) e Lucilia eximia (Wiedemann, 1818)), which were presented the in both the periods, although a relative abundance of species was higher in the rainy period (4.706). We measured the abundance of species per period, where C. albiceps was the most abundant in the dry period (3.244/36, 81%) and C. idioidea in the rainy period (2.860/32, 45%). There were five stages of decomposition: fresh, chromatic, emphysematous, coliquative and skeletonization stage. The emphysematous was the stage where we most collected Calliphoridae (3.923/44, 52%), followed by skeletonization (3.458/39, 25%), chromatic (726 / 8.24%), coliquative (627/7, 12%) and fresh (77/0, 87%). It was also found that the highest abundance of C. idioidea occurred on the highest elevation of relative humidity and rainfall. This study is the first survey of the region of Caatinga in Paraiba state using active collecting, these results will serve to enrich the data to local forensic entomology and will contribute to the understanding the fauna of the region carrion flies.
Objetivou-se com este estudo inventariar e analisar a abundancia de dípteros da família Calliphoridae presentes ao longo da decomposição da carcaça de suínos na região do Cariri, estado da Paraíba, Brasil, em dois períodos: chuvoso e seco. O estudo foi desenvolvido na Reserva Particular do Patrimônio Natural (RPPN) na Fazenda Almas, no município de São José dos Cordeiros-PB. Foram utilizadas duas carcaças de suíno (Sus scrofa) por período, protegidas de animais carniceiros por uma gaiola metálica no interior de armadilha do tipo “Shannon”. As coletas foram realizadas diariamente, duas vezes ao dia, durante onze dias em ambos os períodos. Os dados meteorológicos de precipitação foram obtidos no Centro de Previsão de Tempo e de Estudos Climáticos do INMET e a temperatura e umidade relativa do ar foram obtidas in loco utilizando-se um termohigrômetro digital. Os insetos coletados foram encaminhados mediante autorização ao laboratório de entomologia da UFPB e posteriormente identificados e parte deles depositada na coleção de referencia. Foram coletados 8.811 indivíduos da família Calliphoridae, pertencentes a seis espécies: Chrysomya albiceps (Wiedemann, 1819), Cochliomyia macellaria (Fabricius, 1775), Chrysomya putoria (Wiedemann, 1818), Chloroprocta idioidea (Robineau-Devoidy, 1830), Chrysomya megacephala (Fabricius, 1794) e Lucilia eximia (Wiedemann, 1818), as quais estiveram presentes em ambos os períodos, porém a abundância relativa de espécies foi maior no período chuvoso (4.706/53,4%). Verificou-se a abundância de algumas espécies por período, onde a C. albiceps foi a espécie mais abundante no período seco (3.244/36,81%) e C. idioidea no período chuvoso (2.860/32,45%). Observaram-se cinco fases de decomposição: fresca, cromática, enfisematosa, coliquativa e esqueletização. A enfisematosa foi a fase onde mais se coletou Calliphoridae (3.923/44,52%), seguida pela esqueletização (3.458/39,25%), cromática (726/8,24%), coliquativa (627/7,12%) e fresca (77/0,87%). Constatou-se também que a maior abundancia de C. idioidea ocorreu no dia de maior elevação da umidade relativa e precipitação. Este é o primeiro estudo de levantamento realizado com coleta ativa em região de Caatinga paraibana, cujos resultados permitirão enriquecer os dados da entomologia forense local e contribuirão para o entendimento da fauna de dípteros necrófagos da região.

Thesis (MFamMed)--Stellenbosch University, 2015.
ENGLISH ABSTRACT: Introduction: Diabetes is the most prevalent endocrinology problem encountered in primary care practice. If recent trends showing a dramatic increase in prevalence (believed to be a consequence of a decline in physical activity and excessive caloric intake) continue, then the condition will soon affect nearly 20 million people in the U.S a reflection of the global trend. Effective management requires care that is thoughtful and meticulous, incorporating intensive patient education. Euglycemic control, with the level of glycosylated haemoglobin (HbA1c) kept below 7.0mmol/L, has emerged as a major treatment objective because of its association with a marked reduction in the risk for micro vascular complications. The primary physician is in the unique position to provide comprehensive care to the diabetic patient. Setting: The aim of this study is to evaluate the profile of complications arising due to diabetes mellitus among adult diabetics attending internal medicine outpatient department and family medicine/primary care outpatient department in the Dora Nginza hospital, PE hospital complex. Method: The study is a descriptive retrospective study in which names of patients were collated from clinic records of both clinics, files sought at the records department covering the period between Jan 2007 and Jan 2008 inclusive. Prevalence of statistical variables was generated using frequency tables, bar graphs, cross tabulations and chi square test. Results: Hyperglycemia was the major complication which predominantly was associated with high haemoglobin A1c (HbA1c) levels. However, some hyperglycaemic cases were also found to be associated with normal HbA1c. Complications were found to be more in type 2 diabetics. Patients with hypertension, obesity, smoking and alcohol use were observed to have a higher risk of developing diabetic complications. The findings on retinopathy in this study was inconclusive in view of the fact that patients sent for fundoscopy did not return with documented results from the sister hospital PE provincial hospital. Family Medicine outpatient department overall did better in patient care compared to the Internal Medicine outpatient department. Conclusion: The challenge for the primary care physician is to design a therapeutic program that is safe practical and acceptable to the patient. The ultimate goal of therapy is the prevention of micro vascular and macro vascular complications, consequence of diabetes that makes the condition a major risk factor for cardiovascular disease, stroke, visual impairment, renal failure, impotence, peripheral neuropathy, limb loss and ultimately death. These can be averted through appropriate education of both hospital staff, patients and their care givers. The recommendations made are based on the findings of the study.
AFRIKAANSE OPSOMMING: Nie beskikbaar.

The purpose of the study was to:

• Study the effect of vascular gas bubbles on the brain and lung

• Study changes in the endothelial function caused by gas bubbles

• Study the preventive effects of monoclonal anti-C5a antibody on functional changes caused by gas bubbles

It is important to reveal any changes in the function of the endothelium caused by gas bubbles, as the endothelium probably plays an important role in the development of decompression sickness (DCS). Furthermore, we followed up previous studies using monoclonal anti-C5a antibody trying to prevent damages caused by gas bubbles. In order to prevent damages causes by gas bubbles and maybe prevent DCS, the mechanisms behind have to be revealed. This thesis is part of an ongoing project that for several years has tried to bring to light the “secrets” of DCS.

Pressemelding:

Behandling av type 2 diabetes har trolig best effekt i en tidlig fase av sykdommen. Dette skriver assistentlege Elisabeth Qvigstad (36) fra Grimstad i doktoravhandlingen sin ved Norges teknisk-naturvitenskapelige universitet NTNU. Arbeidet kan bidra til at det utvikles nye medisiner mot diabetes.

Avhandlingen tar utgangspunkt i type 2 diabetes, som rammer 105-120 000 nordmenn. Tidligere forskning i form av celle- og dyreforsøk har vist at vedvarende høye nivåer av fettsyrer i blodet og langvarig stimulering av insulinfrigjøring kan svekke funksjonen til de insulinproduserende beta-cellene i bukspyttkjertelen. Avhandlingen ville teste om lignende forhold er til stede hos mennesker og om korrigerende tiltak ville bedre insulinfrigjøringen ved type 2 diabetes.

Nivået av frie fettsyrer hos personer med type 2 diabetes er oftest forhøyet. Langvarig faste hos friske gir også forhøyet fettsyrenivå og kan ses på som en modellsituasjon for type 2 diabetes. Qvigstad fant redusert insulinfrigjøring hos friske forsøkspersoner etter 58 timer faste.

Fettsyrenivået i blod under testing ble senket ved hjelp av et nikotinsyrederivat hos friske personer og personer med type 2 diabetes. Hos friske påvirket ikke medikamentet insulinfrigjøring eller -følsomhet. Imidlertid virket behandlingen positivt på insulinfrigjøring hos de diabetikerne som hadde best blodsukker-kontroll. Derimot, når type 2 diabetikere reduserte fett i kosten, ga dette ingen utslag på insulinfrigjøringen, men noe nedsatt insulinfølsomhet. Nivået av fettvevshormoner (leptin, adiponectin) ble redusert. Den egne insulinfrigjøringen ble hemmet med medikamentet diazoxid, og insulininjeksjoner ble brukt som erstatning. Insulinfrigjøringen økte uten å endre insulinbehov eller blodsukkerkontroll sammenliknet med placebo. Disse resultatene tyder på at "betacelle-hvile" er gunstig ved type-2 diabetes.

Qvigstads doktorgradsarbeid bidrar til økt forståelse av betydningen av fettsyrer for insulinfrigjøring og insulinfølsomhet hos friske og ved type 2 diabetes. I tillegg støtter funnene betydningen av "betacelle-hvile», som kan bidra til utvikling av nye medisiner mot diabetes.

http://www.ntnu.no/doktorgrader/dr.med/02.03/qvigstad.htm

The main purpose of the present work was to evaluate the efforts taken by the Norwegian surgical community in order to promote and enhance the standards of rectal cancer treatment on a national level, in particular:

- to examine the outcome of rectal cancer surgery following implementation of total mesorectal excision as the standard rectal resection technique

- to explore the prognostic impact of the circumferential resection margin on local recurrence, distant metastases and overall survival following mesorectal excision

- to evaluate the oncological outcomes following mesorectal excision of cancer of the lower rectum, particularly the rates of local recurrence and overall survival for patients with tumours in this areas

- to illustrate the influence of a rectal cancer registry as a quality control instrument on outcome of rectal treatment, and furthermore, to investigate the rates of postoperative mortality, anastomic leakage, local recurrence (LR) and overall survival related to hospital caseload among Norwegian hospitals during implementation of mesorectal excision.

The aim of this thesis is to explore why parents bring their children to homeopaths and to investigate the effect of homeopathic treatment for prevention of upper respiratory tract infections (URTI) in children. The reason for doing studies on this is that there has been a nearly threefold increase in the proportion of children among patients visiting Norwegian homeopaths. This raised the question of why it is so. Furthermore, recurrent respiratory complaints are a main reason why child patients consult homeopaths. This raised the question of the effect of homeopathic treatment in this patient group, because there is very little research on this. The thesis builds on four different studies conducted between August 2002 and June 2004.

Parents of nine children that recently had been to a homeopath for the first time were interviewed to explore why parents take their children to homeopaths. All parents had been to a medical doctor before consulting the homeopath. It was the experiences with conventional medical treatment that led the parents to look for alternatives. The reasons were that 1) the parents did not want to give the medication prescribed by the doctor, 2) they wanted treatment while waiting for a problem to be assessed, 3) they did not want to continue to use the prescribed medication, 4) they stopped taking conventional medication due to side effects or 5) they were not offered any treatment by the medical doctor. The parents would consult a medical doctor if they felt insecure about the health conditions of the child and would visit a homeopath when they felt that the situation was clarified. There are parents who take their child to homeopaths despite not understanding or having belief in whether ultramolecular homeopathic medicines can have effects.

One hundred and sixty-one children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of treatment by homeopaths for prevention of URTI in children. The children were randomly allocated to two groups. One group received an appointment immediately with one of five homeopaths who treated the patients as they do in their everyday practice. The other group (control) got such treatment after three months. The occurrence of URTI judged by the parents were significantly lower among those treated immediately by homeopaths (median 8 days in three months) compared to the control group who used self-selected conventional health care (median 13 days) (p=0.006).

Homeopathic medicines are frequently used for self-treatment (over the counter-OTC). It is not known if the choice of the patient is the same, as a homeopath would have prescribed. A study was therefore conducted to explore if there can be developed indications for homeopathic medicines that facilitate that parents can chose the same medicine as a homeopath would prescribe for children with URTI. Firstly, data from a survey was used to find three medicines Calcarea carb, Pulsatilla and Sulphur that accounted for 60% of all prescription made by Norwegian homeopaths for children with URTI. Simplified constitutional indications for these medicines were developed and tested by comparing the choices of 70 parents with the prescription of eleven homeopaths. The parents were able to choose the same homeopathic medicine as homeopaths prescribed for 55% of the children.

Two hundred and fifty-nine children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of one of three self-selected ultramolecular homeopathic medicines for prevention of URTI in children. The indications developed were used. The children was randomly allocated to receive either ultramolecular homeopathic medicine (C-30) or placebo. There was no difference in the occurrence of URTI judged by the parents among getting ultramolecular homeopathic medicine compared to those getting placebo (median 9 days in three months for both groups) (p=0.531).

Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004.

Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet).

Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004. Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet).

Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI var signifikant lavere hos de som fikk behandling hos homøopat med én gang (median 8 dager på tre måneder) sammenlignet med den andre gruppen som brukte standard behandling ved behov mens de ventet (median 13 dager) (p=0,006).

Homøopatisk medisin brukes internasjonalt i stor grad til selvbehandling. Man vet ikke om pasientens eget valg av homøopatisk

medisin er lik det en homøopat ville foreskrevet. Det ble derfor gjennomført en undersøkelse av om det kan utvikles beskrivelser for indikasjoner for homøopatiske medisiner som gjør at foreldre kan velge samme medisin som en homøopat foreskriver for barn med ØLI. Først ble det funnet fram til tre medisiner, Calcarea carb, Pulsatilla og Sulphur som homøopater i Norge foreskriver til 60% av barn med ØLI. Så ble det utviklet indikasjoner for disse tre medisinene som ble testet ut ved at valgene til 70 foreldre ble sammenlignet med foreskrivingen til 11 homøopater. Foreldrene valgte samme medisin som homøopaten for 55% av barna.

To hundre og femtien barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av en av tre selvvalgte homøopatiske medisiner i forebyggingen av ØLI hos barn. Indikasjonene som ble utviklet ble brukt. Barna ble tilfeldig fordelt til enten å få homøopatisk medisin eller placebo. Det var ingen signifikant forskjell i forekomsten av ØLI mellom de som fikk homøopatisk medisin sammenlignet med de som fikk placebo (median 9 dager på tre måneder i begge grupper) (p=0,531).

The aims of this dissertation were to investigate alcohol-related seizures in clinical neurological practice. We wanted to assess the extent of this problem, to classify the seizures, and to investigate methods to improve the clinical diagnosis of such seizures. We propose an arbitrary but simple and reproducible way of diagnosing alcohol-related seizures and alcohol withdrawal seizures. Papers I and II relate to seizure classification and the extent of the problem in relation to the level and weekly pattern of alcohol use. Paper III investigates the performance of various biological markers as aids in the diagnosis of alcohol-related seizures. Paper IV explores pitfalls in the result interpretation for two methods for detection of CDT in patients with neurological disorders. Paper V investigates the utility of standard EEG for the identification of alcohol-related seizures.

Even though the general alcohol consumption in our region is low, every third patient with an epileptic seizure leading to hospitalisation had hazardous alcohol consumption.

Evidence of focal lesions or focal seizure start was found in a high proportion of alcohol-related seizures. All such seizures were secondarily generalized and thus, we challenge the establishment impression that the vast majority of alcohol-related seizures are primarily generalized. Binge drinking (more than six drinks for men or four drinks for women, in a single drinking occasion) was common, but had little influence on seizure susceptibility or timing of seizures. In contrast to prior knowledge, we found that in some patients there was no time lag from cessation of drinking to the occurrence of a seizure, but falling intake levels prior to withdrawal seizures were demonstrated. This indicates that a state of relative withdrawal while still drinking may be sufficient to induce a seizure. Carbohydrate-deficient transferring (CDT) is the most accurate biomarker for alcohol use and good adjunct to the diagnosis of alcohol-related seizures, but its accuracy does not compete with a good clinical investigation. Generally poor accuracy should be expected for fertile women. Women on enzyme-inducing antiepileptic drugs who drink no or little alcohol seem to be at risk of having false positive CDT. Other variables associated with increased CDT were low body mass index, or having total transferring levels outside normal range. A definitely abnormal EEG suggests epilepsy or symptomatic seizures unrelated to alcohol use. The predictive value of a normal EEG is limited, but the typical post-ictal finding in alcohol-related seizures is nevertheless a normal low-amplitude EEG record.

The best method for identification of alcohol-related seizures is a clinical work-up based on a thorough medical history. The Alcohol Use Disorders Identification Test (AUDIT) provides a reliable measure of drinking habits. CDT is a good supplement to the clinical diagnosis when there is doubt, if factors associated with false-positive values are appreciated. The diagnostic value of EEG is limited.

The main purpose of the theses is to explore the significance of anxiety and depression in patterns of pain, fatigue, quality of life. Lifestyle, functional disability, co-morbidity and gender among individuals given the diagnosis of fibromyalgia by their doctor.

Diabetic nephropathy (DN) is associated with morbidity and mortality due to cardiovascular disease and renal failure. This study focused on the impact of glycemic control on the development of DN and the metabolic consequences of DN. The euglycemic hyperinsulinemic clamp technique was used to assess insulin sensitivity and insulin clearance. Two different registries, the Diabetes Incidence Study in Sweden (DISS) and the Swedish Childhood Diabetes Registry, as well as questionnaires and data from medical records were used to study diabetic complications in population-based cohorts.

Microalbuminuria is an early marker of DN and may also be associated with impaired insulin sensitiv-ity in diabetic and non-diabetic subjects. We studied the relationship between insulin sensitivity and the degree of albuminuria in patients with type 1 diabetes and micro- or macroalbuminuria but normal glomerular filtration rate (GFR). We did not find a direct quantitative association between the degree of albuminuria and insulin resistance, arguing against a cause-effect relationship.

With progression of DN, a decline in GFR is seen. Patients with severe renal failure have both im-paired insulin sensitivity and insulin clearance. We studied insulin sensitivity and insulin clearance in type 1 diabetes patients with three different degrees of renal involvement (none, only albuminuria, and slightly reduced GFR, ~40-70 ml/min/1.73 m2, respectively). A clear reduction in insulin sensitivity in vivo, but not in insulin clearance, was seen in the group with reduced GFR, and concomitant changes in the levels of PTH, IGF-1, IL-6 and TNF-α were found. In parallel, cellular insulin sensitivity and insulin degradation were examined in vitro, in subcutaneous fat cells but no differences were found between the three groups of patients.

To study the occurrence of renal involvement in patients with modern diabetes treatment we moni-tored a cohort of young adults from the DISS-registry with onset of diabetes in 1987-88 at age 15-34 years. We found that ~7% of the patients had signs of renal involvement, i.e. incipient nephropathy (5%) and overt nephropathy (2%), after a median follow-up of ~9 years and the strongest risk markers were poor glycemic control (HbA1c) and high blood pressure. Patients with type 2 diabetes were most prone to have renal involvement in this age group.

Retrospectively, we studied 94 patients diagnosed with type 1 diabetes in 1981-1992 at age 0-14 years at the Umeå University Hospital. Incipient nephropathy and background retinopathy occurred in 18 and 45%, respectively, of the patients, during ~12 years of follow-up. Glycemic control, also during the first five years of diabetes, was a strong risk marker. Young age at onset of diabetes prolonged the time to development of microvascular complications.

Conclusion: Despite modern diabetes treatment some patients with diabetes develop renal involvement within the first ten years. Inadequate glycemic control, also early in the disease, is a risk marker as well as type 2 diabetes and high blood pressure. In patients with type 1 diabetes and diabetic neph-ropathy a slightly reduced GFR, but not albuminuria, is associated with insulin resistance. Concomi-tant changes in insulin-antagonistic hormones and cytokines may be involved.

Thesis (Msc.(Med.)(Pharmacy))--University of Limpopo, 2010
Background Information regarding disease epidemiology, treatment options and emerging infections and resistance constantly challenge the knowledge of the health care practitioner. Antibiotic prescribing patterns was identified by the Dr George Mukhari hospital antibiotics committee as an area of concern. Due to this concern it was decided to investigate the prescribing patterns in adult patients with meningitis admitted to the internal medicine wards at Dr George Mukhari hospital. Objectives To determine the current antimicrobial prescribing patterns in adult patients diagnosed with meningitis, to record the causative organisms and sensitivity patterns, to record the outcom e, cost and length of treatment. Method Patient and prescriptions data were recorded prospectively on specially designed data sheets from five internal medicine wards for four months (May to August 2008). Patients were followed until discharged. Results Sixty-six patients were enrolled; 41 recovered, 22 died, 2 refused treatment and 1 absconded. Ceftriaxone was prescribed the most frequently and was administered to 58 patients; four patients with confirmed cryptococcal meningitis received amphotericin B IVI, three patients were started on iv Rifafour® for suspected tuberculosis meningitis and one was started on cefuroxime. Specimens from only 22 patients were sent for culture and sensitivity tests; ten were positive for yeast-like organisms, three for S pneumoniae and one for N meningitides and tuberculosis respectively. The average duration of treatment of patients with meningitis was 9.2days. The total cost of antiinfectives used for treatment of meningitis amounted to R111, 292.53 and the average cost per patient was R1 686.25. The cost of all medicines prescribed for the 66 patients amounted to R116, 490.43. Conclusion Ceftriaxone was used frequently as empiric therapy. Specimens for culture and sensitivity were not sent routinely. Therefore it was difficult to monitor and observe any resistance patterns and to contain cost of treatment.

Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by different cellular pathogen recognition receptors (PRRs), which are expressed on cell membrane or in the cytoplasm of cells of the innate immune system. Nucleic acids derived from pathogens or from certain cellular conditions represent a large category of PAMPs/DAMPs that trigger production of type I interferons (IFN-I) in addition to pro-inflammatory cytokines, by specifically binding to intracellular Toll-like receptors or cytosolic receptors. These cytosolic receptors, which are not related to TLRs and we call them "Toll-free" receptors, include the RNA-sensing RIG-I like receptors (RLRs), the DNA-sensing HIN200 family, and cGAS, amongst others. Viruses have evolved myriad strategies to evoke both host cellular and viral factors to evade IFN-I-mediated innate immune responses, to facilitate their infection, replication, and establishment of latency. This review outlines these "Toll-free" innate immune pathways and recent updates on their regulation, with focus on cellular and viral factors with enzyme activities.

Dissertação de Mestrado Integrado em Medicina Veterinária
O impacto das mastites na eficiência reprodutiva dos bovinos leiteiros, tem sido estudado ao longo dos últimos anos, por diversos autores. O objetivo do presente estudo, foi analisar a possível associação causal entre a ocorrência de mastites subclínicas e a alteração do desempenho reprodutivo. Recorrendo a uma base de dados de contraste leiteiro, na qual existiam registos provenientes de 9 explorações nacionais, introduzidos entre 1996 e 2016, procedeu-se à análise da relação da contagem de células somáticas, com o intervalo parto-conceção. Os resultados obtidos demonstraram que, à medida que aumenta a contagem de células somáticas, aumenta o intervalo parto-conceção. Tais resultados foram estatisticamente significativos e mais pronunciados para os dados relativos à segunda lactação. Observou-se ainda que, para cada aumento do número de eventos, cuja contagem de células somáticas se encontra acima do limiar de distinção entre infetado e saudável, o intervalo parto-conceção aumenta 28,7 dias para a primeira lactação e 27,9 dias para a segunda. Tais resultados, sugerem a hipótese de haver uma relação da cronicidade da infeção, com a fertilidade. Assim, à semelhança do reportado por autores anteriores, os resultados obtidos apontam a existência de uma relação entre as mastites subclínicas e o desempenho reprodutivo dos bovinos leiteiros.
ABSTRACT - Dairy Production Medicine: studies of the relationship between reproductive performance and mastitis - The impact of mastitis on reproductive performance of dairy cattle has been studied throughout the last years, by several authors. The objective of this study was to evaluate the possible causal association between the occurrence of subclinical mastitis and altered reproductive performance. Through the analysis of a database, in which there was access to milk recording data from 9 national dairy farms, introduced from 1996 to 2016, the relationship between the somatic cell count and the calving-to-conception interval was analyzed. The obtained results showed that, as the somatic cell count increases, the calving-to-conception interval increases. These results were statistically significant and more pronounced on the second lactation. Furthermore, it was observed that, with increases in the number of mastitis episodes, in which somatic cell counts were above the considered threshold between infected and healthy, the calving-to-conception interval progressively increased 28,7 days for the first lactation and 27,9 days for the second. These results support the existence of a relationship between the chronicity of the episodes and fertility. As such, similarly to results presented by previous authors, this study supports the existence of a direct relationship between mastitis and the reproductive performance of dairy cattle.
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Chronic hypoxia, in animals and man, results in remodelling of the pulmonary vasculature with consequent pulmonary hypertension. The pulmonary artery fibroblast (PAF) has been shown to play an early and important role in hypoxia-induced pulmonary vascular remodelling. In acute and chronic hypoxia there is excess proliferation of PAFs. Morevoer, it is likely that cell-cell interactions between hypoxia-stimulated PAFs and other vascular cells – particularly smooth muscle cells - initiates and progresses the changes that occur in pulmonary vascular remodelling in the other vessel compartments. Although hypoxic proliferation of PAFs has been shown to be circulation specific and dependant on phosphorylation of p38 mitogen-activated protein (MAP) kinase, the cell signalling pathway(s)underlying this are incompletely characterised. Hypoxic activation of PAFs is a potential therapeutic target but, as p38 MAP kinase inhibitors are not established for clinical use, work was proposed to better characterise this pathway and identify agent(s) which may inhibit p38 MAPK indirectly. The HMG-CoA reductase inhibitor simvastatin was recently shown to inhibit hypoxic pulmonary vascular remodelling in rats, but the applicability of this finding to clinical practice is incompletely established and the mechanism of action of the statin is unclear. Statins have been shown to influence MAP kinase pathways in other cell types and, as their modes of action are well established, they can be used to interrogate uncharacterised upstream cell signalling pathways. On this basis, the aims of this study were firstly to determine whether statins had a therapeutically useful inhibitory effect on hypoxia-induced, p38 MAP kinase-mediated PAF proliferation. A second aim was to exploit the known effects of statins to better characterise hypoxic cell signalling upstream of p38 MAP kinase in PAFs. Lastly, comparison of the effects of statins with established pulmonary hypertension therapeutics and a preliminary assessment – also using statins as an experimental tool - of cell-cell interactions between PAFs and pulmonary artery smooth muscle cells (PASMCs) was proposed. 1μM of fluvastatin was found to selectively inhibit acute and chronic hypoxia-induced p38 MAP kinase phosphorylation and proliferation in rat PAFs. At this dose, fluvastatin had no effect on serum-induced proliferation in PAFs, no effect on systemic adventitial fibroblast proliferation, and no effect on the phosphorylation status of other MAP kinases. Selective use of mediators and inhibitors related to the HMG-CoA pathway indicated that a geranylgeranylated protein, probably Rac1, had an obligatory role upstream of p38 MAPK, in this signalling pathway. Co-culture and conditioned media experiments with bovine PAFs and PASMCs demonstrated the release of PASMC mitogens from hypoxic PAFs. 1μM fluvastatin and the p38 MAP kinase inhibitor SB203580 selectively blocked the hypoxic PAF-PASMC interaction. Results with hypoxic PAF proliferation with the prostacyclin analogue treprostinil, the phosphodiesterase-5 inhibitor sildenafil and the endothelin-1 antagonist bosentan were negative. Bosentan, however, inhibited the hypoxic PAF-PASMC interaction, suggesting endothelin-1 release by hypoxic PAFs, with proproliferative effects on PASMCs. The results reported in this thesis provide new information on hypoxic signalling,PAF proliferation and PAF cell-cell interactions in hypoxic states. A circulation and stimulus specific anti-proliferative effect of fluvastatin on PAFs was identified and this may be of clinical relevance in hypoxia-associated pulmonary hypertension.

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world, mainly through cerebrovascular and coronary artery related events. Cardiovascular disease is a chronic progressive disease with different stages. These stages can be assessed by a variety of biomarkers. Biomarker quantification can be used for different purposes: screening, prediction of disease recurrence, therapeutic monitoring, diagnosis and prognostication. Noninvasive, inexpensive diagnostic tests currently applied in clinical practice have a relative high rate of false positive and false negative results. Therefore further refinement of the diagnostic process could improve clinical care. Regarding prognostication the need for improvement also remains as current risk models only predict a small quantity of occurring cardiovascular events. The concept of the cardiovascular continuum postulates that cardiovascular disease consists of a chain of events, is initiated by numerous cardiovascular risk factors and subsequently progresses through pathophysiological processes, ultimately leading to end-stage heart failure. For that reason cardiovascular diseases are chronic progressive conditions and can be divided into different stages, such as early tissue dysfunction or subclinical atherosclerosis prior to development of clinically overt disease. Biomarkers suitable for prognostication and diagnosis can differ at each stage. The general aim of this thesis was therefore the investigation of a variety of biomarkers in diagnosis and prediction of cardiovascular disease at different stages of the cardiovascular continuum, as covered by three different study cohorts contributing to this thesis. This included several approaches: the comparison of central and peripheral pulse pressure in middle aged hypertensive patients in regards of their prognostic potential; the application of established circulating, functional and structural biomarkers to the diagnostic process of coronary artery disease in stable angina patients; the development/refinement of a urinary proteomic biomarker for coronary artery disease and the examination of its diagnostic potential in stable angina patients. Biomarkers successful in the diagnosis of coronary artery disease were included in multiple biomarker models. Aside from biomarker development for the general population, investigations of specific cohorts, such as patients with certain diseases and belonging to certain age groups or sharing specific biochemical features provided advances in the past. To estimate the potential of a biomarker in risk prediction association studies with surrogate biomarkers are applicable. We collected a cohort of middle-aged hypertensive patients to assess if central pulse pressure, derived from non-invasive assessment of arterial stiffness, could improve risk prediction. Central pulse pressure has been previously shown to have prognostic value in populations with end-stage renal failure, coronary artery disease and high prevalence of diabetes mellitus. Considering the prognostic information of peripheral pulse pressure in the elderly, the hypothesis that central pulse pressure could improve risk prediction is comprehensive and was investigated as part of this thesis. This was accomplished by comparing the strength of correlation between central or peripheral pulse pressure and these surrogate biomarkers. When compared to peripheral pulse pressure, central pulse pressure had stronger associations with aortic pulse wave velocity, carotid intima-media thickness, and left ventricular mass index, but equal association with the albumin:creatinine ratio. In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between central and peripheral pulse pressure for prediction of listed surrogate biomarkers in multivariate analysis. These results suggested that central pulse pressure is unlikely to provide more prognostic information than peripheral pulse pressure in middle-aged hypertensive patients. The diagnosis of coronary artery disease is clinically relevant in symptomatic patients, either acute or stable. The diagnosis of stable flow limiting coronary artery disease is especially challenging as non-cardiac as well as other cardiac conditions can mimic symptoms. Non-invasive diagnostic tools have either moderate sensitivities or specificities, or are not widely available. Therefore new biomarkers for the diagnosis of flow limiting coronary artery disease have the potential to improve current diagnostic strategies. This could be accomplished adjacent to existing biomarkers or by replacement of such, due to cost effectiveness, better discriminatory etc. As part of this thesis, a biomarker identification and validation study was conducted into urinary proteomics of coronary artery disease. First we tried to replicate a study conducted by our research group in the past. Therein, an established coronary artery disease specific polypeptide pattern was unable to differentiate between patients with severe coronary artery disease and healthy controls despite strong cohort similarities to the original study. We therefore recalibrated the urinary polypeptide pattern using an enlarged biomarker discovery cohort and adjusted the pattern for lipid lowering and angiotensin converting enzyme inhibitor treatment effects. We calculated a score from the resulting polypeptide pattern, which identified coronary artery disease patients with a sensitivity of 79% and a specificity of 88% in a biomarker validation cohort. As the next step of biomarker development we performed a diagnostic validation study. The investigated clinical cohort consisted of stable angina patients with or without coronary artery disease. The new polypeptide pattern score was unable to differentiate between these two groups. The score however correlated strongly with coronary artery disease extent as measured by the Gensini score, implying that urinary proteomics in the diagnosis of coronary artery disease is promising, yet requires further effort before clinical employment. In addition to the urinary proteomic biomarker development second diagnostic approach was selected. As coronary artery disease is a complex chronic disease, the combination of different biomarkers should result in a better discrimination between stable angina patients with or without coronary artery disease. This approach attempts to position the individual as precisely as possible on the cardiovascular continuum including serologic, functional vascular and imaging biomarkers of subclinical atherosclerosis. Serologic markers thereby present a plasma proteomic approach covering pathophysiological processes with known correlation or causative for coronary artery disease. Functional and structural changes of the peripheral vasculature resemble the coronary artery system. We investigated circulating biomarkers and vascular biomarkers separately. A variety of circulating biomarkers differentiated patients with severe coronary artery disease from healthy control subjects. When patients with stable angina and with or without coronary artery disease as diagnosed by coronary angiography were investigated no statistically significant differences could be detected for circulating biomarkers. In the same study a microvascular biomarker, the reactive hyperaemia index, and a macrovascular biomarker, the carotide plaque score, were able to differentiated between cases and controls. Both markers either added separately or together improved the risk classification of exercise treadmill test results. This suggests that a multiple biomarker approach in the diagnosis of coronary artery disease in stable angina patients could be successful. Different aspects of the cardiovascular continuum can be applied to diagnosis and prognostication of cardiovascular disease.

Cardiovascular disease is multifactorial. The main risk factors for developing cardiovascular disease (age, sex, smoking, diabetes, hyperlipidaemia and hypertension) do not explain its development in everyone. New risk factors are continually being sought in order to better understand and treat the disease process. In recent years homocysteine has been proposed as a risk factor for the development of premature cardiovascular disease as a consequence of the accelerated arterial and venous thrombotic disease seen in homocystinuria as a result of a single gene defect. This theory has been difficult to test because patients with premature cardiovascular disease are thankfully rare and because of the difficulties in measuring homocysteine itself. We propose that, if homocysteine is a causative risk factor for atherothrombosis, it will be involved in the development of cardiovascular disease regardless of age and have therefore studied affected patients from routine hospital clinics. Homocysteine analysis has become easier over the past decade with the development of HPLC methods utilising fluorescent detection, but these methods involve toxic chemicals and suffer from high background fluoresence. I have developed an HPLC method more suited to a routine hospital laboratory utilising coulometric detection for measuring plasma total homocysteine and used it to investigate the relationship between homocysteine levels and both micro- and macro-vascular atherothrombotic disease.

Trichotillomania (TTM) is a body focussed repetitive behaviour (BFRB) characterised by the repetitive pulling out of one’s hair. It is a moderately new disorder having only been classified in 1987 and it is under-researched relative to other psychological disorders. This thesis investigates TTM by presenting a series of experiments designed to further understand attitudes towards, and attentional biases in, TTM. The experiments in this thesis address 3 central issues: stigmatising attitudes towards TTM; attentional bias pertaining to the experience of shame in TTM; and attentional bias towards hair-related stimuli in TTM. Experiment 1 investigated differences in ratings of stigma towards perceived controllable (TTM, compulsive skin-picking) and perceived uncontrollable (alopecia, psoriasis) hair-loss and skin-lesioning conditions in a TTM and control group. The main findings indicated that stigma ratings varied as a function of group: the public rated perceived controllable conditions with higher stigma than perceived uncontrollable conditions while TTM participants rated these conditions equally. Experiment 2 used a modified emotional Stroop task using shame-related words to investigate the affective correlate of shame in individuals with TTM and a control group. TTMs did not demonstrate different response latencies to shame-related words, relative to other word types or the control group, indicating no evidence of attentional bias towards shame-related linguistic stimuli. Experiments 3, 4 and 5 focussed specifically on disorder-stimuli (i.e., hair-related) linguistic stimuli in a series of lexical paradigms. Experiment 3 was a lexical decision task and Experiment 4 was a modified Stroop task: these paradigms investigated response latencies towards hair-related words in TTMs and a control group. The main findings for both experiments showed that TTMs do not demonstrate an attentional bias towards hair-related words, relative to other word types and the control group. Experiment 5 investigated higher-level judgements of hair-related words in a word rating task. The findings revealed a group-by-word-type interaction for arousal ratings: TTMs rated hair-related words higher in arousal than body image and neutral words, and these ratings were higher than those of the control group for hair-related words. No group-by-word-type interaction for valence ratings was found. This indicates that TTMs rate hair-related words as more arousing but not more positive or negative, than other word types, relative to individuals without TTM. Finally, Experiment 6 utilised a modified dot probe paradigm to investigate attentional bias towards hair-related images. Our findings showed that TTMs disengage more slowly from hair-related images at a longer stimulus duration compared to neutral images, relative to control participants. This evidence is consistent with an attentional bias characterised by maintained attention towards hair-related stimuli in individuals with TTM. In conclusion, this thesis has presented evidence indicating that TTM (and other BFRBs) are associated with higher public stigma ratings than comparable perceived uncontrollable conditions. Results have also shown an attentional bias towards hair-related images but not words. This represents an important contribution towards the understanding of the processing of disorder-related stimuli in TTM. This may have implications for the maintenance mechanisms potentially involved in the hair-pulling condition.

Poor sleep and high levels of anxiety have a detrimental effect on cognitive functioning. However, very little is known about what cognitive functions are affected by poor sleep or high levels of anxiety and if some are more affected than others. This thesis informs the understanding of poor sleep and anxiety with a focus on generalised anxiety disorder and how they affect specific cognitive functioning namely Attention and Working Memory. Chapter one is a systematic literature review of the qualitative research exploring how sleep deprivation impacts on the cognitive functioning of people with Autistic Spectrum Conditions (ASC) and the principal challenges associated with trying to study the impact of sleep deprivation in people with ASC. Following both database and manual searches, fifteen studies were included and reviewed. The review highlights the suggestions that poor sleep has a detrimental effect on the cognitive functioning of people with ASC. Also, the use of objective and subjective measures of sleep was discussed to help in the early detection of these problems and considerations of carers and families was reviewed. Future research/clinical implications are discussed. Chapter two is a quantitative research study that investigated the combined effects of GAD and poor sleep on Attention and Working Memory. Sleep quality and quantity were assessed using subjective and objective measures of sleep. Attention and Working Memory was measured using various neuropsychological measures. Groups were compared for differences in cognitive scores using a non-parametric test. Relationships between GAD-7 scores, sleep quality/quantity and cognition scores were investigated using correlation analyses. Implications for future research and clinical implications are discussed. Chapter three is a reflective account, exploring the role of reflexivity in personal and professional development during the research process.

Treating people living with severe health conditions has, and always will be, a fundamental part of the National Health Service. Given the complex nature of conditions such as Huntington's Disease and Cancer, research exploring the impact severe health conditions can have on those affected is of paramount importance. Chapter one is a systematic review utilising a meta-ethnographic approach to explore qualitative research portraying people's experiences of genetic testing for Huntington's Disease (HD). Electronic databases cataloguing relevant research were searched which, combined with manual searches, resulted in eleven studies suitable for inclusion. Three meta-themes were identified, highlighting the complex and individual nature of undergoing genetic testing, together with the potential emotional and behavioural consequences. The implications of such findings, together with clinical recommendations are considered. There is a dearth of research exploring what it is like to live with cancer as a young person in the United Kingdom. Chapter two is a qualitative research study that explored the lived experiences of young people (13-24 years) who had recently been diagnosed with cancer. Utilising an interpretative phenomenological approach, emergent findings related to the adversarial nature of being diagnosed with cancer, with young people speaking to the unjust nature of battling this disease at such a youthful age, questioning their identity and having to navigate a new, and at times, uncertain world. The clinical and service implications of these findings are discussed, alongside areas of future research. Chapter three represents the author's reflective account of conducting this research. From exploring initial motivations, to evaluating the role of "insider" and "outsider" perspectives, the author explores the reciprocal nature of conducting qualitative research, particularly in relation to the mutuality felt between himself and his participants.

Chronic liver disease is a highly prevalent condition associated with significant morbidity and mortality. There is need for clinicians to stratify chronic liver disease and for researchers to define meaningful study endpoints. Currently this is often reliant on liver biopsy histology, which is known to be a flawed gold standard. There is a need to develop novel, non-invasive techniques for the evaluation of chronic liver disease that are accurate and reliable. In this thesis I have demonstrated that multiparametric MRI can stage hepatic fibrosis in an unselected cohort with performance comparable to existing non-invasive fibrosis markers. The assessment of fibrosis is however confounded by inflammation. The sensitivity of multiparametric MRI to inflammation allows the differentiation of simple steatosis and NASH but in a non-alcoholic fatty liver disease (NAFLD) cohort, multiparametric MRI fails to predict fibrosis stage. Evaluating NAFLD with magnetic resonance spectroscopy has shown that this technique is feasible and that lipidomic differences can be demonstrated in patients with NAFLD. Exploring the role of multiparametric MRI in primary sclerosing cholangitis (PSC) has demonstrated a characteristic pattern in the distribution of corrected Tl in PSC suggesting that multiparametric MRI may have a role in its diagnosis and evaluation.

Antibiotic resistance is a major problem estimated to cost $100 trillion and cause 10 million deaths per year by 2050. Despite novel molecules targeting Gram-positive bacteria, there are no new antibiotics active against Gram-negatives. To prolong use of current drugs, we need to understand mechanisms of resistance to inform prescribing practices and drug discovery. Quinolone resistance is primarily conferred by mutations in the target loci: DNA gyrase (gyrA) and topoisomerase IV. Quinolone resistance arising from gyrA mutations has also been shown to confer a low level of protection against a range of non-quinolone drugs. This thesis investigated the hypotheses that altered supercoiling levels, resulting from gyrA mutations, alter expression of stress response genes and confer a generic protective effect against other antibiotics and chemicals. The effects of equivalent gyrA mutations in Salmonella and E. coli upon supercoiling were analysed. Both GyrA Ser83Phe and GyrA Asp87Gly substitutions resulted in altered topoisomer profiles, although these were different between the species. When exposed to stresses, Salmonella gyrA mutants maintain supercoiling in a relatively fixed manner, providing a degree of antimicrobial protection but possibly limiting flexibility in response to environmental change. Fluorescent reporter assays showed a modest elevation of stress responses in Salmonella GyrA Asp87Gly cells, but highly upregulated stress responses in E. coli GyrA Asp87Gly cells. This correlated with a competitive fitness benefit of E. coli GyrA Asp87Gly cells vs the parent in the presence of low levels of triclosan. The elevated stress responses likely result from supercoiling-induced changes in promoter accessibility, and are probably responsible for the generic protective effect gyrA mutation confers against other chemicals and antibiotics. Non-quinolone antimicrobials can provide a selective pressure that favours gyrA mutants, although this is highly dependent on condition and species.

Advancements in burn care have improved immediate outcome, however, the prevalence of sepsis and multiple organ failure (MOF) remain significant. Although well characterised the mechanisms responsible for the pathogenesis of MOF and increased propensity to infection are poorly understood. Neutrophil extracellular traps (NETs) provide protection against invading pathogens but also contribute to thrombosis. Sepsis is required for NET generation following severe thermal injury. Quantification of circulating NET biomarkers shows good discriminatory power for diagnosis of sepsis. Interestingly, neutrophils isolated from 24 patients with severe thermal injuries, ≥ 15% total body surface area, had a significantly reduced ability to form NETs ex vivo, potentially mediated by phenotypical changes of neutrophils and inhibitory effects of formyl peptides. This thesis identified a major biological mechanism driving MOF after severe thermal injury, namely the compromise to the actin scavenging system which leads to reduced DNAse activity and a build-up of circulating DNA. Preliminary analysis suggests that DNAse activity can be restored by prehospital use of fresh frozen plasma following major trauma. Thus, administration of blood products or manipulation of the actin scavenging system is a potential therapeutic target. This thesis has identified a number of novel mechanisms responsible for the regulation of NETs following severe thermal injuries and their implications for sepsis and MOF.

Mesenchymal stromal cells (MSC) suppress the inflammatory infiltrate through crosstalk with neighbouring endothelium. However, this response is lost at chronic inflammatory sites where stromal cells instead support leukocyte recruitment and upregulate expression of podoplanin. The mechanism and function by which this inflammatory phenotype is established is unknown. We hypothesise that MSC modulation of endothelium is also altered by exposure to inflammatory cytokines, and that expression of podoplanin confers an invasive phenotype, enabling the interaction of these perivascular MSC with circulating platelets. MSC resisted functional transformation during acute or prolonged exposure to tumour necrosis factor alpha, instead maintaining their ability to suppress neutrophil recruitment in a flow-based assay. Expression of podoplanin promoted MSC migration through Ras-related C3 botulinum toxin substrate dependent signalling, enabling perivascular MSC to interact with cells confined to the circulation. Indeed, podoplanin induced the activation of platelets from flow through MSC protrusions in the endothelial lining. The retention of MSC suppressive function under inflammatory conditions supports their use in equivalent environments for therapy. However, the implications of platelet CLEC-2 activation by its ligand, podoplanin on inflamed stroma have yet to be elucidated and warrant further investigation, with specific focus drawn to the pathophysiology of thromboinflammation and associated disorders.

The induction of specific-antibody that targets the surface of a pathogen or its secreted components is the basis of immunological memory to natural infection and vaccination. This antibody, induced after natural infection or vaccination, saves millions of lives every year. The few vaccines against Gram-negative bacteria either target one antigen, the surface capsular polysaccharides, or are complex vaccines involving the whole organism or complex mixtures of multiple antigens. In this project, we studied how antibody binds to the Salmonella outer membrane porin D (STm-OmpD) on the bacterial surface and why it is protective. Immunisation with STmOmpD provides serovar-specific protection because: 1) lgG can access a single epitope, which is under selective pressure; 2) lgG can access the bacterial surface in the "footprint" made by the OmpD trimer; and 3) Lipopolysaccharide (LPS) 0-antigen (0-Ag) influences the access of lgG to epitopes. Further, protection after immunisation with STm-OmpD is detectable by 4 hours after infection and requires GR1+ cells, IFNg, and Th1 responses for optimal protection, but not lgG2a/c. These data provide insights into how antibody to the Gramnegative bacterial surface can help protect against infection and will aid in the optimisation of subunit vaccines targeting Salmonella.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In around 85% of cases, the disease progresses through two distinct stages: relapsing-remitting MS (RRMS) is driven by repeated bouts of demyelination caused by autoimmune inflammation; and progressive MS, in which inflammation gives way to neurodegenerative processes that lead to axonal loss and the steady accumulation of disability. There is no cure for MS and the majority of disease-slowing treatments target the immune response in RRMS. These interventions are ineffective in progressive MS and other treatment options are extremely limited. Understanding the mechanisms underlying neurodegeneration in MS is critically important to developing therapeutics for progressive disease. Fibroblast growth factor 9 (FGF9) has recently been implicated in the pathogenesis of MS. FGF9 inhibits myelination and promotes the production of inflammatory chemokines. This led to the hypothesis that FGF9 is involved in remyelination failure and may promote neurodegeneration via tissue remodelling and inflammatory pathways. FGF signaling is complex and the findings in MS raised many questions: what cells respond to FGF9 in MS? Why is FGF9 expression induced in the first place? Can FGF9 cause demyelination as well as inhibit myelination? This thesis has focused on the roles of FGF9 in MS and tried to answer these questions. Through in vitro models, astrocytes, oligodendrocytes, and macrophages were shown to express feedback inhibitors of FGF signaling when treated with FGF9. Astrocytes produced FGF9 in response to hypoxic stress, macrophages expressed FGF9 when polarized towards an anti-inflammatory phenotype, suggesting hypoxia, and repair processes may drive FGF9 expression in the CNS. FGF9 did not cause demyelination in vitro but over-expression in vivo induced severe demyelination over the course of several months. Oligodendrocytes exposed to FGF9 failed to differentiate properly when the factor was removed which led to aberrant myelination. Long-term treatment with FGF9 induced axonal pathology, potentially via deficits in axon-transport. Over-expression of FGF9 in rat cortex also produced an axonal pathology, which suggests chronic exposure is detrimental to neurons. Together, these findings indicate that increased levels of FGF9 are detrimental to myelination and neurons in the CNS. Demyelination, and axonal pathology are hallmarks of MS and these studies provide evidence that FGF9 can mediate these processes in in vitro and in vivo models.

Ischaemia reperfusion injury and nephrotoxicity are the common insults of acute kidney injury. Drug induced nephrotoxicity can also lead to an ischaemic phenomenon. The key mediator to both insults is oxidative injury caused by reactive oxygen species, and prolonged injury can result in irreversible kidney fibrosis and chronic kidney disease. This thesis developed a simulated ischaemia reperfusion injury in an in-vitro model to investigate whether amino acid supplementation may facilitate human proximal tubule cell recovery and protect from H2O2 damage following starvation and whether this was mediated by pH. The findings showed that resupply of amino acids at pH 7.5 under H2O2 injury after starvation exacerbated cell death. The mammalian target of rapamycin was also activated in response to amino acids in a concentration dependent manner even if under H2O2 damage, but the link between mammalian target of rapamycin activation and endoplasmic reticulum stress leading to cell death was not yet identified in this thesis. The constant expression of chaperone protein Grp78 may suggest the persistent cellular stress caused by starvation. While amino acids at pH 6.4 failed to activate the mammalian target of rapamycin and potentially reduced protein synthesis, it still exacerbated cell death under H2O2 damage. It also inhibited Grp78 expression, but the link between Grp78 inhibition and cell death was unclear. Moreover, this thesis established an aristolochic acid induced nephrotoxicity in mice and investigated whether another putative nutrient, sodium nitrite, could be renoprotective. However, the therapeutic effects of sodium nitrite remain to be confirmed, as aristolochic acid did not induce any injury in this animal model. Overall, this thesis implicated that the return of circulating amino acids may be detrimental for ischaemia reperfusion injury and that antioxidant therapy may be the priority for acute kidney injury.