Master of Science / Biomedical Sciences / Gregory F. Grauer / Chronic kidney disease (CKD) is a potentially life-threatening disease that reportedly affects 10% of dogs and 30% of cats over the age of 15. There is no cure available for CKD, but medical management is available for patients with this disease. Research has focused on earlier detection of CKD with the goal of instituting medical management and monitoring as early in the disease course as possible. Symmetric dimethylarginine (SDMA) has recently emerged as a novel renal excretory biomarker that may aid in early detection of CKD in cats and dogs. SDMA is non-protein bound and is freely filtered by the glomerulus, is not secreted or reabsorbed, and has greater than 90% excretion by the kidneys, making it a potential target for measurement of glomerular filtration rate (GFR). Previous studies have demonstrated a close parallel between SDMA and serum creatinine (sCr), which is the currently favored serum biomarker for assessment of GFR. Research has also demonstrated a correlation between SDMA and GFR. Serum concentrations of SDMA increase above normal when GFR is decreased by 25-40%; much earlier than the 75% decrease in GFR typically required for sCr to increase above its reference interval. The studies reported here demonstrate a potential use for the SDMA:sCr ratio as a predictor of volume responsive azotemia. Furthermore, longitudinal assessment of older dogs and cats for early detection of CKD showed that SDMA was a more sensitive indicator of CKD than sCr. The evaluation of SDMA reported in this thesis presents a novel perspective on SDMA and its use clinically.

Psychological and contextual factors play an important role in the development and maintenance of chronic spine-related pain, and effective treatment of pain-related conditions requires an understanding of how these factors contribute to pain and disability. The present study examined the relative contributions of spine pathology, psychological complications, and demographic factors to perceived pain intensity and disability in patients with chronic spine-related pain. Because most patients were assessed in the context of a compensable injury, exaggeration of symptoms and disability was systematically controlled for using multiple validity indicators. A high prevalence of psychological complications was observed in the present sample. Analysis indicated that psychological factors were not significantly related to pain intensity, but were significantly related to reported pain-related disability. Further, psychological factors were found to predict pain-related disability beyond demographics, medical findings, and pain intensity. Clinical implications of these findings are discussed.

The increased influence of digitalizing in the Swedish healthcare is a change that some people find it hard to adapt to. For most youths and people from the younger generations this is not considered a problem, since they have been exposed to different aspects of digitalization throughout their lives. However, how do older people and especially older people with chronic diseases feel about the digitalization and the changes it brings? The purpose of this study is to explore how people with chronic diseases experience this progresses in the society that has contributed to the digitalization within healthcare and the increased utilization of digital platforms. Previous studies indicate that both the change in the doctor-patient relationship and the increased possibilities for patient to access health information from their homes, is an effect of the digitalization. In this study, which is conducted with a qualitative method, we come to understand that older people with chronic diseases find it difficult to adapt to the digitalization. None of the participants are opposing it, rather they experience the changes as complicated. Furthermore, the participants stress the prerequisite of the physical contact with a doctor to enable a correct medical assessment. Whether or not this means that health centers will be dismantled is still unknown. However, our study shows that there is no resistance to digitalization among the participants, provided it is executed in a correct and trustworthy manner.

Introdução: A rinossinusite crônica (RSC) é uma doença prevalente, multifatorial, de fisiopatologia ainda muito pouco compreendida e que tem se apresentado como grande desafio na dificuldade de tratar a doença não controlada. Embora tenha sido aceito recentemente que a RSC precisa ser diferenciada em RSC com e sem pólipos nasais, tornou-se claro que essa distinção é insuficiente para definir claramente subgrupos com fisiopatologia e padrões de citocinas uniformes. Objetivos: Estudar o perfil inflamatório TH nos pacientes da região de Ribeirão Preto-SP, Brasil, e comparar com o perfil de outras populações. Casuística e Metodos: Foi realizado estudo transversal prospectivo para identificar o perfil inflamatório (Th1/Th2/Th17) pela concentração das seguintes citocinas: IFN-?1, IFN-?, TGF-?, IL-33, IL-10, IL- 17A, IL-1?, IL-2 e IL-5, em pacientes com RSC com pólipo nasal (RSCcPN), RSC sem pólipo nasal (RSCsPN) e controles. Foram colhidas amostras de tecido nasal (concha média, seio maxilar, seio etmoidal e pólipo nasal) e analisadas por PCR em tempo real. Resultados: Foram avaliados 117 pacientes, sendo que 67 com RSCcPN e 29 com RSCsPN e 21 controles. Pacientes com RSCcPN apresentaram aumento de todas citocinas em relação ao grupo controle, e os com RSCsPN demonstraram aumento de IFN-?1, IFN-?, IL-10, IL-17A, IL1?, IL-2 e IL-5. Na comparação entre RSCcPN e RSCsPN observou-se diferença nas IFN-?, TGF-?, IL- 2, IL-1? e IL-10. Em relação ao pólipo verificou-se padrão eosinofílico em 70% dos casos e relação com IL-5 e AERD (doença respiratória exacerbada por aspirina, do inglês Aspirin-exacerbated respiratory disease). Conclusões: Os resultados mostraram que não existe um perfil inflamatório padrão de RSCcPN e RSCsPN, confirmando que há uma diversidade ampla nas diferentes populações, podendo estar associado a diferentes fatores ainda a serem estudados. / Introduction: The chronic rhinosinusitis (CRS) is a prevalent, multifactorial disease of pathophysiology that is still poorly understood and has been presented as a major challenge in the difficulty of treating uncontrolled disease. Although it has now been accepted that chronic rhinosinusitis needs to be differentiated into CRS with and without nasal polyps, it has become clear that this distinction is insufficient to clearly define subgroups with uniform cytokine pathophysiology and patterns. Objectives: The objective was to study the inflammatory TH profile in region of the Ribeirão Preto-SP, Brazil, patients and compare it with the profile of other populations. Casuistic and Methods: A prospective cross-sectional study was conducted to identify the inflammatory profile (Th1 / Th2 / Th17) by concentration of the following cytokines: IFN-?1, IFN-?, TGF-?, IL-33, IL-10, IL-17A, IL-1?, IL-2 and IL-5 in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP) and controls. Samples of nasal tissue (medial turbinate, maxillary sinus, ethmoidal sinus and nasal polyp) were collected and analyzed by real-time PCR. Results: A total of 117 patients were studied, of which 67 had CRSwNP and 29 with CRSsNP and 21 controls. Patients with CRSwNP showed an increase in all cytokines compared to the control group, patients with CRSsNP showed an increased in IFN-?1, IFN-?, IL-10, IL-17A, IL-1b, IL-2 and IL-5. In the comparison between CRSwNP and CRSsNP we found difference in IFN-?, TGF-?, IL-2, IL-1? and IL-10. In relation to the polyp we found an eosinophilic endotypes (70%) and relation with IL-5 and AERD (Aspirin-exacerbated respiratory disease). Conclusions: Our results show that there is no standard inflammatory profile of CRSwNP and CRSsNP, confirming that there is a wide diversity in the different populations, and may be associated with different factors still to be studied.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury like those sustained in sport, military combat, and other activities with repetitive head impact exposure. Repetitive head impacts typically cause mild traumatic brain injury (mTBI) resulting in both concussive and subconcussive injury. Repeated mTBIs injuries appear to cause an abnormal accumulation of proteins, including hyperphosphorylated tau (p-tau) and TDP-43, progressive axonal failure with gradual structural degradation, microvascular disruption, breach of blood-brain barrier, neuroinflammation and microglial activation; each of these manifestations lead to axonal degeneration and neuronal death, which impairs neuronal pathways and are likely to give rise to CTE symptoms. CTE can be microscopically characterized mainly by p-tau accumulation in perivascular spaces and at the depths of the cortical sulci. Clinical presentation of CTE may include behavioral, mood, cognitive, or motor symptoms. Some of the common symptoms include impulsivity, aggression, anxiety, depression, memory impairment, dementia, and suicidality. The Locus Coeruleus (LC), a nucleus in the pons of the brainstem, is suspected to be involved in CTE. The LC provides the main source of norepinephrine to the entire brain and is critical for its control over arousal, behaviors, attention, and memory. Dysfunction of the locus coeruleus has shown to cause a wide array of symptoms, many of which are similar to those seen in CTE. Furthermore, the LC is affected in many other neurodegenerative diseases and is believed to be responsible for the progressive and widespread nature of the various diseases and their clinical symptoms. Although the LC has been implicated in CTE there have been no studies examining LC pathology in relation to the disease progression or its symptoms. We hypothesize LC CTE pathology should increase with the severity of CTE. Furthermore, increased CTE pathology in the LC should create disturbances to the LC and the LC-NE system and manifest clinically. Specifically, LC CTE pathology may be associated with age of onset of general behavioral and cognitive symptoms as well as individual symptoms and outcomes including impulsivity, depression, depressed mood and death by suicide. To determine this, a postmortem study was performed on 184 individuals with a history of RHI and no comorbid diseases examining the relationship between AT8-immunopositive tau density in the LC and various clinical variables. The study found that LC AT8 density showed a significant positive correlation with duration of repetitive head impact (RHI) exposure when controlled for age. There also was a significant increase in LC AT8-immunoreactive tau in cases with stage III and IV CTE compared to those with no CTE and stage I and II CTE, and AT8 density was predictive of CTE stage when controlled for age. There were no significant relationships found between density of LC AT8-immunoreactive tau and age of any CTE symptom onset or individual symptom (impulsivity, depressed mood, MDD, death by suicide) presence. Future studies should continue to evaluate CTE pathology in the LC and its effects on both the pathological and clinical characteristics of the disease.

Angiotensin II inhibitors or Angiotensin Receptor Blockers (ARB s) are the most recent addition to the suite of antihypertensives. They are also one of the most expensive of the drug classes. Since the introduction of the first ARB on the market, the merits of ARB s have been investigated. The mechanism of action and indications are similar to ACE inhibitors thus comparisons have been done between the two classes to ascertain if there are any added benefits in using ARB s. This study was an analysis of out of hospital chronic medication claims from a managed care organisation in South Africa to view the utilisation pattern of ARB s and to establish if there were any indications for the choice of this specific drug class for the conditions hypertension and heart failure.. A managed care organisation aims to provide clinically appropriate and cost effective medication to its members. It is therefore important to investigate if there are any reasons for a more expensive drug to be used if there is a more cost effective alternative available. The medication claims for ARB s were investigated, in relation to ACE inhibitors to try and establish if there were any specific reasons for the use of ARB s. From the results obtained, it was evident that ACE inhibitors and ARB s were widely used within the managed care organisation and made up a high percentage of the amount spent on antihypertensive drugs. The gender utilisation patterns showed that more males used ACE inhibitors and ARB s for both hypertension and heart failure, although there were more females registered for these conditions within the organisation. The incidence of hypertension and heart failure was more prevalent in the over 45 year old age group and the use of these antihypertensive medications mirrored this. ARB s were the most expensive class of drugs used for hypertension and heart failure, and there was no reason found to support the specific use of these agents.

PhD, Faculty of Health Sciences, University of the Witwatersrand / Background: Chronic diseases have increased worldwide. Despite the significant advances in medical science, the management of chronic diseases continues to be poor. To meet this challenge, we need to try to implement existing chronic illness models of prevention, early detection, and risk factor management. This is achievable in part by linking primary health care clinicians, such as primary health care nurses (PHCNs) and hospital-based medical specialists. This study evaluated a ‘real life’ chronic disease outreach program (CDOP), which assisted PHCNs with the early detection and management of chronic illnesses known to cause chronic kidney disease (CKD) and cardiovascular disease (CVD). PHCNs are critical in the management of chronic illnesses but they require ongoing support of and links with specialists. This will ensure that current guidelines reach the people receiving primary health care (PHC) and detection of those needing referrals. Aims: The study aimed to determine if CDOP was an effective method for the early detection and management of diabetic and hypertensive patients at high risk for complications like stroke, ischaemic heart disease and CKD. It also aimed to evaluate the PHCNs’ knowledge and motivation, and to elucidate the challenges facing the current health system in the management of patients with chronic conditions. Methods: Patients at risk for complications were enrolled for increased monitoring and clinical support and management, at 20 clinics in Soweto, South Africa (SA). CDOP used a paper-based support and patient care system, modelled on the Wagner Chronic Illness Care Model (CICM). The components for evaluation included: (i) Focus on monitoring functional and clinical outcomes (ii) Health system interventions, such as increased ‘decision support’ and the development of a ‘prepared motivated health care team’ and (iii) Enhancing PHCNs’ knowledge and motivation. The evaluation followed the various elements of the Wagner CICM, as well as drawing on the WHO Innovative Care for Chronic Conditions (ICCC) Framework. A cohort analysis of functional and clinical outcomes in enrolled patients was conducted. PHCN knowledge and motivation was assessed through self administered questionnaires. Health worker knowledge was evaluated through the use of case scenarios and multiple choice questions. On the theme of health worker motivation, Franco’s model, with Penn-Kekana’s adaptation, was used to develop the questions and analyse diary recordings. Diary recordings of PHCNs and meetings with regional and provincial health managers’ discussions were collected by CDOP staff during follow-up focus groups and feedback meetings. Diaries were analysed thematically. The CDOP evaluation is thus a triangulated analysis of clinical and functional outcomes, diary recordings, and the self-administered questionnaire. Results: The CDOP ran from 2003-2006, during which time 618 patients (61% females, 39% males) deemed at risk of CKD or CVD were enrolled; 55% had uncontrolled hypertension (HTN), 45% DM with HT and/or proteinuria. Patients were followed for 2 years. In total, 108 patients completed 2 years of follow up, most of whom were referred for specialist support (n=69, 11%), more intensive medication regimes or because were not available in the PHC system. Most did not require referral (515, 82%), 35 (6%) were referred but never arrived at the hospital and 6 (1%) died. Twelve percent had advanced CKD, 2% required dialysis, 6.9% required medications not available to primary care clinics, and 1% died. As a tool to detect those needing referral, the program was successful. The sensitivity and specificity for detecting those needing referral was 95% and 100%, respectively.. However, although PHCNs were able to detect high risk patients, not all those referred arrived at the hospital. Hypertension, blood glucose, cholesterol and proteinuria control significantly improved in those followed (p<0.01) over 2 years, but no improvement was noted with weight control. Importantly, proteinuria and kidney function, in patients with static stable renal function, measured by estimated GFR equations and urine dipstick or albumin creatinine ratio (ACR), did not worsen significantly. Of the remaining 510 patient enrolled but not followed up, 213 (35%) were reabsorbed into the routine clinics, and a further, 123 (20%) of patients enrolled were lost to follow up completely. The diary recording thematic analysis revealed the problem of poor patient follow up, attributed to the poor existing health system in the clinics, competing demands on PHCNs, staff shortages, high staff turnover, and the low motivation and morale of clinicians. The analysis of the health worker questionnaire showed improved motivation and statistically better knowledge in those PHCNs involved with CDOP compared to those who were not exposed to the program (p<0.0034). Conclusions: CDOP was successful in supporting PHCNs, detecting patients with advanced disease and ensuring their early referral. Such programs are able to correctly detect people with disease, but this is dependent on the health and program systems being intact. It also improved patient risk factor control in the sub-set of referred patients and impacted on PHCNs’ existing knowledge and motivation for caring for patients. Its weaknesses were related to the poor existing health systems and infrastructure, and the poor integration of chronic illness care in the region. The PHC clinics had poor follow up compared with that in the hospital setting. The study also revealed an overworked, poorly supported, and frustrated primary health care team. This was despite the fact that the PHCNs were willing and motivated to deliver a good service.

Dissertation submitted to the Faculty of Health Sciences, University of Witwatersrand in fulfillment of the Master of Science in Medicine in the School of Physiology / Introduction: The changing socio-economic landscape in Africa has brought with it unique health challenges previously uncommon in people of African ancestry. Noncommunicable diseases such as coronary artery disease and stroke have emerged as pressing public health concern highlighting the need to find more on-target diagnostic tools as well as therapeutic interventions. Although ambulatory blood pressure (AMBP) has in many studies conducted in the western world proved to be an independent predictor of carotid intima-media thickness (C-IMT), such results cannot outright be imputed to people of African ancestry living in Africa. That is because people of African ancestry living in Africa are not only of a different ethnicity but are still in the early phases of an epidemiological transition while people in the western countries who are mostly Caucasians, are believed to be in the middle to late phases of an epidemiological transition. Methods: The relationship between the intima-media thickness of the common carotid artery (SonoCalcTM IMT version 3.4) and AMBP (Space labs model 90207) was determined in 320 randomly selected participants of African descent living in an urban developing community in South Africa. Relationships were determined after adjustment for (clinic blood pressure) BPc, age, gender, alcohol and tobacco use, the presence or absence of diabetes mellitus or inappropriate blood glucose control measured by glycated hemoglobin (ghb), antihypertensive therapy and menopausal status. III Results: Mean age for the study population was 43.7± 16.0 years. Both BPc and AMBP parameters were strongly associated with C-IMT (p<0.001) in univariate analysis. In multivariate analysis with BPc. and AMBP entered into separate models and after adjusting for cofounders, BPc. and AMBP maintained significant associations with CIMT. [BPc (partial r=0.0648, p< 0.1612), systolic blood pressure 24 (SBP24) (partial r= 0.236, p< 0.001), systolic blood pressure day (SBPd) (partial r= 0.302, p<0.05), systolic blood pressure night (SBPn) (partial r= 0.0983, p<0.05)]. When adjustments were made with BPc. and SBP24 entered into the same model, BPc lost its association with C-IMT, [SBP24 (partial r=0.236, p<0.001) SBPd (partial r=0.149, p<0.05), SBPn (partial r=0.172, p<0.05)]. Importantly the relationship between SBP24 and C-IMT persisted independent of body mass index (BMI), BPc and age. SBP24 had the highest significant association with C-IMT. Conclusion: SBP24 independently predicts C-IMT even in a model that includes conventional systolic blood pressure (SBPc) leading to the conclusion that AMBP is a more effective tool at diagnosing C-IMT alterations while BPcdoes not have an independent relationship C-IMT.

BACKGROUND: Patients receiving haemodialysis (HD) treatment experience a significant symptom burden and their needs are multifaceted. In HD unit, patients receive treatment in a diverse cultural and open ward setting. However, patients‟ experiences of receiving HD treatment in an open ward setting are not known. OBJECTIVES: The central aim of this study was to explore and describe the experiences of patients receiving HD treatment in an open setting environment at an academic hospital in Johannesburg. DESIGN: A qualitative, exploratory and descriptive study was conducted at a public, tertiary level academic hospital in Johannesburg after obtaining ethical approval from Wits University and relevant authorities. SETTING: The research setting for this study was an adult Chronic Renal Dialysis Unit. POPULATION: Sixteen adult (age 18 and above) patients receiving chronic HD treatment were recruited purposively in this study. INTERVENTIONS: An in-depth semi-structured interview was conducted either before or after receiving HD treatment, which was audio-recorded, transcribed then analysed by using Giorgi Phenomenological method. FINDINGS: A mood enhancer appeared a major theme as participants positively valued the open setting environment for their overall and psychological well-being. Participants expressed by being with others and sharing experiences, a sense of community likened to a family developed. Common to all participants‟ language was the use of the “we” in relation to being in the open setting environment. This expression of the “we” by participants was interpreted as a community concept. The use of “we” associated with the concept of community described as a space to which every patient receiving HD belonged. They described their experiences in a collective manner. This was evident in repetitive reference to their common space, being together, sharing experiences, and finding identity from one another, being understood and a sense of being protected with personal relations that extend beyond 10 years for some. This open space contributed to shaping their perception of body image and illness. The nurse‟s role in timeously providing HD care was appreciated by many. However, being exposed to multiple situations of chronic illness and treatment a sense of fear developed. Any negative event experienced, watched, observed, or heard in the HD unit triggered fear in the patients. Two common fears were of HD complications and the constant threat of death. Complications such as clotting, muscle cramps and collapsing because of hypotension as well as watching somebody dying on the machine were all reported in this study and so psychological counselling was felt to be very important. CONCLUSION The recommendations proposed in this study hopefully will assist HD staff to intervene and make adjustments to support patients‟ holistic needs. Further studies into patients receiving HD in open settings and mixed-gender space are required for diversity of experiences and knowledge from different settings. Keywords: Haemodialysis, hospital environment, open setting, patient experiences

A Periodontite é uma doença de etiologia multifatorial que acomete os tecidos de suporte dentário resultando em perda progressiva de inserção e perda óssea. Este estudo clínico controlado, aleatorizado e duplo-cego avaliou a eficácia da Terapia Fotodinâmica antimicrobiana (TFDa), em aplicações múltiplas, como terapia adjuvante ao tratamento periodontal cirúrgico em pacientes com Periodontite Crônica Avançada (PCA). Dezesseis voluntários foram submetidos ao modelo de estudo do tipo boca dividida, recebendo tratamento de acesso cirúrgico associado a raspagem e alisamento radicular (RAR) adjunto à TFDa em protocolo de aplicação nos períodos de 0, 2, 7 e 14 dias pós-operatórios (Grupo Teste - GT), ou apenas tratamento de acesso cirúrgico associado a RAR (Grupo Controle - GC). Todos os pacientes receberam orientação de higiene oral e acompanhamento por 90 dias pós-cirúrgicos. Os seguintes parâmetros clínicos e microbiológicos foram avaliados: Nível clínico de inserção (NCI), Profundidade de sondagem (PS), Recessão gengival (RG), Sangramento à sondagem (SS), Índice de placa (IP) e contagem de 40 espécies microbianas subgengivais (checkerboard DNA-DNA hybridization). Os dados foram coletados nos períodos baseline (pré-terapia básica), 60 dias (30 dias após terapia não cirúrgica) e 150 dias (90 dias pós-cirurgia). Uma redução significativa na PS foi observada aos 150 dias para o GT, quando comparado ao GC no mesmo período (p &lt; 0,05). O ganho do NCI foi significativamente maior no GT entre os tempos de 60 e 150 dias (p &lt; 0,05). As mudanças da microbiota subgengival foram similares entre os grupos (p &gt; 0,05), mas o Grupo Teste apresentou quantidades mais elevadas de bactérias compatíveis com saúde periodontal no período final do experimento em relação ao GC (p &lt; 0,05). Concluiu-se que a utilização da TFDa em aplicações múltiplas, como terapia adjuvante ao tratamento cirúrgico periodontal, produziu melhoras significativas nos parâmetros clínicos no período de 90 dias de avaliação / Chronic Periodontitis is a multifactorial disease which results in tooth supporting tissues loss. This double-blind randomized controlled clinical trial assessed the efficacy of multiple sessions of antimicrobial photodynamic therapy (aPDT) as an adjunct to surgical periodontal treatment in patients with severe chronic periodontitis (SCP). Sixteen volunteers were selected into this Split-mouth study. They were subjected to scaling and root planning in open flaps (SRP) combined with aPDT at 0, 2, 7, and 14 postoperative days (Test Group - TG), or only SRP (Control Group CG). All patients were instructed about oral hygiene and were followed up for 90 days after surgery. The following clinical and microbiological parameters were assessed: clinical assessment level (CAL), probing depth (PD), gingival recession (GR), bleeding on probing (BOP), plaque index (PI). Levels of 40 subgingival species were measured by checkerboard DNA-DNA hybridization at baseline, 60 (30 days after non-surgical therapy) and 150 days (90 days post-surgery). Data were collected at baseline (pre-intervention), at 60 days (30 days after the end of nonsurgical therapy), and at 150 days (90 days after surgery). A significant reduction in PD was observed at 150 days for the TG, when compared to the CG (p &lt; 0.05). CAL gain was significantly higher in the TG at 60 and 150 days (p &lt; 0.05). Changes in the subgingival microbiota were similar between the groups (p &gt; 0.05), but the TG revealed a larger number of bacteria associated with periodontal disease at the end of the experiment compared to the CG (p &lt; 0.05). In conclusion, multiple sessions of aPDT as an adjunct to surgical periodontal treatment significantly improved clinical parameters at 90 postoperative days