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1.
  • Al-Alawi, Kamila, 1974- (författare)
  • Team-based approach in the management of diabetes at primary health care level in Muscat, Oman : challenges and opportunities
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: The growth of type 2 diabetes is considered an alarming epidemic in Oman. The efficient team-based approach to diabetes management in primary health care is an essential component for providing ideal diabetic care. This thesis aimed to explore the current situation related to team-based management of type 2 diabetes in public Primary Health Care Centres (PHCCs) under the Ministry of Health (MOH) in Oman, including the various challenges associated with diabetes management and the most preferable Human Resources for Health (HRH) management mechanism, and to examine how this could be optimized from provider and patient perspectives.Materials and methods: The entire project was conducted in Muscat Governorate and was based on one quantitative and three qualitative studies. In the quantitative study, 26 public PHCCs were approached through cross-sectional study. The core diabetes management team recommended by the MOH for PHCCs in Oman was explored in terms of their competencies, values, skills, and resources related to the team-based approach to diabetes management. For the qualitative studies, five public purposely-selected PHCCs were approached. The diabetes consultations conducted by the core members and other supportive members involved in diabetes management were observed and later the Primary Health Care Providers (PHCPs) were interviewed. The different approaches explored challenges related to diabetes management and the most preferable HRH mechanism by PHCPs. Seven type 2 diabetes patients with different gender, employment status, and education were consequently interviewed to explore their perceptions towards the current diabetes management service and their opinions towards nurse-led clinics.Results: The survey provided significant and diverse perceptions of PHCPs towards their competencies, values, skills, and resources related to diabetes management. Physicians considered themselves to have better competencies than nurses and dieticians. Physicians also scored higher on team-related skills and values compared with health educators. In terms of team-related skills, the difference between physicians and nurses was statistically significant and showed that physicians perceived themselves to have better skills than nurses. Confusion about the leadership concept among PHCPs with a lack of pharmacological, technical, and human resources was also reported. The observations and interviews with PHCPs disclosed three different models of service delivery at diabetes management clinics. The challenges explored involved PHCCs’ infrastructure, nurses’ knowledge, skills, and non-availability of technical and pharmaceutical support. Other challenges that evolved into the community were cultural beliefs, traditions, health awareness, and public transportation. Complete implementation of task-sharing mechanisms within the team-based approach was selected by all PHCPs as the most preferable HRH mechanism. The selection was discussed in the context of positive outcomes, worries, and future requirements. The physicians stated that nurses’ weak contribution to the team within the selected mechanism could be the most significant aspect. Other members supported the task-sharing mechanism between physicians and nurses. However, type 2 diabetes patients’ non-acceptance of a service provided by the nurses created worries for the nurses. The interviews with type 2 diabetes patients disclosed positive perceptions towards the current diabetes management visits; however, opinions towards nurse-led clinics varied among the patients.Conclusions and recommendations: The team-based approach at diabetes management clinics in public PHCCs in Oman requires thoughtful attention. Diverse presence of the team members can form challenges during service delivery. Clear roles for team members must be outlined through a solid HRH management mechanism in the context of a sharp leadership concept. Nurse-led clinics are an important concept within the team; however, their implementation requires further investigation. The concept must involve clear understandings of independence and interdependence by the team members, who must be educated to provide a strong gain for team-based service delivery.
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2.
  • Alenius Dahlqvist, Jenny, 1972- (författare)
  • Heart rate variability and pacemaker treatment in children with Fontan circulation
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Fontan surgery is performed in children with univentricular heart defects. Arrhythmias are frequent complications, occasionally requiring pacemaker treatment. Previous data regarding indications and risk factors for pacemaker treatment in Fontan patients is limited and conflicting. Heart rate variability (HRV) reflects autonomous nervous activity controlling the sinus node and has been associated with tachyarrhythmias in both adults and children, as well as in adults with sinus node dysfunction (SND).Aim: To study HRV, arrhythmia and pacemaker treatment  in children with Fontan circulation— with the purpose of contributing to the reduction of long term complications in this patient group.Methods: We have retrospectively reviewed pacemaker therapy in all Swedish patients who underwent Fontan surgery from 1982 to 2017 (n=599). We have also analysed HRV from 24-hour Holter ECG recordings in 112 children with Fontan circulation and in children with univentricular heart defects before bidirectional Glenn (BDG) procedure (n=47), before and on completion of Fontan surgery (n=47 and 45 respectively). Analysis was performed by power spectral analysis and Poincaré method, and results compared with healthy controls. Furthermore, HRV was analysed in Fontan patients who later required a pacemaker due to severe SND. Results were compared with Fontan patients who had SND, without indication for pacemaker treatment, with patients with Fontan circulation without SND and healthy controls. In addition we evaluated the possibility to analyse arrhythmias and HRV in 27 Fontan children using intermittent ECG recordings with a handheld devices at home during a 14-day period.Results: After a mean follow-up of 12 years, 13% (78/599) of patients with Fontan circulation had received a pacemaker. Patients operated with the extracardiac conduit (EC) had a significantly lower prevalence of pacemaker implantation (6%) than patients with a lateral tunnel (LT) (17%). The most common pacemaker indication in patients with Fontan circulation was SND (64%). Children with Fontan circulation showed significant reductions in several HRV parameters, compared with controls. No significant differences were found between patients operated with LT versus EC (paper I). After BDG the RR interval and SD2 (representing changes in heart rate over 24-hours) significantly increased compared to pre-BDG. Compared with healthy controls, patients post-BDG, had significantly longer RR intervals and reduced overall HRV. PHF (reflecting parasympathetic control of the heart) was significantly reduced after TCPC as compared to before (paper II). Fontan patients with SND showed significantly elevated SD2 (representing changes in heart rate over 24-hours), somewhat reduced in patients that later required a pacemaker (Paper V). Handheld ECG analysis revealed frequent ventricular extra systoles in one patient and episodes of supraventricular tachycardia in another. Seven Fontan patients showed reduced HRV recorded with the handheld device over a 14-day period (paper III).Conclusions: Overall HRV was reduced in patients with univentricular heart defects during the different surgical stages of Fontan surgery, compared to healthy controls. HRV was reduced in both patients with LT and EC with no significant difference between them. After BDG heart rate was significantly reduced as compared to before. PHF, reflecting the parasympathetic innervation of the heart was reduced after as compared to before TCPC. Pacemaker treatment is commonly needed in patients with Fontan circulation, and SND was the most prevalent indication for implantation. The prevalence of Fontan patients requiring pacemaker treatment was significantly lower in patients with EC. HRV analysis can contribute to management when following-up patients with Fontan circulation.  
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3.
  • Asplund, Pär, 1974- (författare)
  • Percutaneous Balloon Compression for the Treatment of Trigeminal Neuralgia
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background. Trigeminal neuralgia (TN) is a paroxysmal unilateral facial pain condition. That it is rather rare is of little comfort to those who are affected, as TN is often described as one of the worst pains known to mankind. Advanced age and multiple sclerosis (MS) are risk factors for developing TN. The first line of treatment is medical, primarily with carbamazepine. When medical treatment fails, as it does in many patients, there are several surgical options. One of the minimally invasive options, suitable for patients with comorbidity, is percutaneous balloon compression (PBC). Despite its introduction in the early 1980s, PBC is arguably the least well studied of the minimally invasive procedures for the treatment of TN.Aims. The aim of this thesis was to evaluate the efficacy of PBC, both overall and in MS-TN patients specifically. Further, it intended to identify and evaluate pre- and intraoperative parameters associated with the efficacy of PBC. It also investigated changes in sensory function after PBC, and identified side effects and complications associated with PBC. Finally, it sought to evaluate how efficacy, side effects and complications differed between PBC and another minimally invasive technique; percutaneous retrogasserian glycerol rhizotomy (PRGR).Methods. Cohorts of patients treated with PBC in Umeå and Stockholm, and with PRGR in Umeå, were followed retrospectively. Data from an existing database was combined with data from medical records, radiographs and telephone interviews.Results. After PBC, 90 % of the patients were completely pain free without medication for TN. The median time to recurrence of pain was 28 months. In patients with concurrent MS, the initial success rate was 67 % and the median time to recurrence was 8 months. In patients without MS, who had not previously been treated surgically, the initial success rate was 91 % and the median time to recurrence was 48 months. The procedure could, however, be repeated with good results. A good compression, indicated by a pear-shaped balloon as seen on intraoperative lateral radiograph, was crucial to achieve good pain relief. Postoperative hypoesthesia was present in the majority of patients, but after 3-6 months, sensibility was partly or fully normalized in most patients. Severe complications were rare, but included transient cardiac arrest, meningitis and dysesthesia. The side effects profile was favorable to that of percutaneous retrogasserian glycerol rhizotomy, in that the latter produced more cases of dysesthesia and decreased corneal sensibility. The efficacy of the two treatments were, however, not significantly different.Conclusions. PBC is an effective and relatively safe treatment option for patients with TN refractory to medical treatment. It deserves its place among the standard treatments for TN, and could be considered for those patients eligible for surgery for which open surgery is a less suitable option. 
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4.
  • Bamyaci, Sarp, 1986- (författare)
  • Multiple functions of YopN in the Yersinia pseudotuberculosis type III secretion system : from regulation to in vivo infection
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The type 3 secretion systems (T3SSs) are virulence mechanisms used by various Gram-negative bacteria to overcome the host immunity. They are often target-cell contact induced and activated. Activation results in targeting of virulence effector substrates into host cells. One class of secreted substrates, translocators, are required for the intracellular targeting of the second class, the virulence effectors, into host target cells. T3SSs are mainly regulated at 2 levels; a shift from environmental to host temperature results in low level induction of the system whereas target cell contact further induces and activates the system. In the Yersinia T3SS, YopN, one of the secreted substrates, is involved in the latter level of activation. Under non-inducing conditions, YopN complexes with TyeA, SycN and YscB and this complex suppresses the T3SS via an unknown mechanism. When the system is induced, the complex is believed to dissociate and YopN is secreted resulting in the activation of the system. Earlier studies indicated that YopN is not only secreted but also translocated into target cells in a T3SS dependent manner. TyeA, SycN and YscB bind to the C-terminal and N-terminal YopN respectively but so far the central region (CR) of YopN has not been characterized. In this study we have focused on the function of the YopN central region.We therefore generated in-frame deletion mutants within the CR of YopN. One of these deletion mutants, aa 76-181, showed decreased early translocation of both YopE and YopH into infected host cells and also failed to efficiently block phagocytosis by macrophages. However, the YopNΔ76-181 protein was expressed at lower levels compared to wt YopN and also showed a slightly deregulated phenotype when expressed from its native promoter and were as a consequence not possible to use in in vivo infection studies.Therefore, we generated mutants that disrupted a putative coiled coil domain located at the very N-terminal of CR. Similar to YopNΔ76-181, these substitution mutants were affected in the early translocation of effector proteins. Importantly, they were as stable as wt YopN when expressed from the native promoter. One of these mutants was unable to cause systemic infection in mice indicating that YopN indeed also has a direct role in virulence and is required for establishment of systemic infection in vivo.
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5.
  • Bendix, Marie, 1971- (författare)
  • Neuroendocrine studies in patients with affective disorders
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Affective disorders are common and a major cause for increased disability and mortality worldwide. Exogenous stressors and biological variables, including neuroendocrine factors, are assumed to contribute to an increased vulnerability to mood dysregulation. Affective disorders are highly heterogeneous and different neuroendocrine systems may play differential roles in the phenotypic expression of affective disorders in men and women.Aims: The overall aim of this thesis was to study three neuroendocrine systems in relation to underlying behavioral endophenotypes (personality traits, self-directed and interpersonal violence, and psychiatric symptoms) in patients with affective disorders.Methods: In Study I oxytocin plasma levels were assessed in 101 general psychiatric outpatients and followed-up in 36 patients after one month. Patients underwent diagnostic, symptomatic, and personality trait assessments.In Study II insulin and glucagon levels in plasma and cerebrospinal fluid (CSF) were assessed in 28 patients hospitalized after a recent suicide attempt and 19 healthy controls. Study persons were assessed regarding lifetime violence expression, psychiatric diagnoses and symptoms.In Study III serum levels of allopregnanolone, progesterone and estradiol were assessed in 14 women with severe postpartum depression and psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. Hormonal and symptomatic assessment were performed before and after 4 weeks of estradiol treatment. 28 healthy postpartum controls were included for baseline comparison.Results: I) Plasma oxytocin levels were positively associated with personality traits of impulsiveness (monotony avoidance) and negative emotionality (psychic anxiety) with potential gender differences.II) Patients after suicide attempt had higher insulin (plasma and CSF) and lower glucagon levels (CSF) than healthy controls. Insulin levels (plasma and CSF) were higher and glucagon levels (plasma) were lower in patients and controls with higher levels of prior violence expression.III) Serum allopregnanolone decreased in women with postpartum depression and psychosis during estradiol treatment. The ratio between allopregnanolone and progesterone was significantly lower in patients than in healthy controls at baseline and it remained unchanged after symptom remission.Conclusion: Behavioral endophenotypes, rather than categorical diagnoses, of affective disorders were associated with neuroendocrine variation in three different cohorts of patients with affective disorder. Hormonal variation pointed towards an association with trait, rather than state like facets of affective behavior, constituting potential vulnerability markers for affective dysregulation.
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6.
  • Berginström, Nils, 1984- (författare)
  • Fatigue after traumatic brain injury : exploring novel methods for diagnosis and treatment
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Traumatic brain injury (TBI) is one of the most common causes of disability and mortality. While some patients recover quickly, especially at the mild side of the injury severity continuum, many will experience symptoms for years to come. In this chronic phase, patients report a wide array of symptoms, where fatigue is one the most common. This fatigue makes huge impact in several areas of these patients’ lives. Despite the prevalence of fatigue after TBI, the underlying mechanisms are unclear. Further, there are no standardized way for assessment and diagnosis, and there are no treatments with satisfying empirical support. The aim of this thesis was to examine the effects of the novel compound OSU6162 on fatigue in patients with TBI, and to explore functional and structural brain imaging correlates of fatigue after TBI.Methods: Studies I and III were based on a placebo-controlled, double-blinded clinical trial examining the effects of the monoaminergic stabilizer OSU6162 on fatigue in patients in the chronic phase of traumatic brain injury. In study I, self-assessment scales of fatigue and neuropsychological tests were used as outcomes, while functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) signal was the primary outcome in study III. Studies II and IV used cross-sectional designs, comparing patients with TBI with age- and gender matched healthy controls. Study II examined whether fMRI BOLD signal could be used to detect and diagnose fatigue in patients with TBI, and study IV whether white matter hyperintensities (WMH) contribute to lower cognitive functioning and presence of fatigue after TBI.Results: Study I revealed no effects of OSU6162 during 28 days of treatment at maximum doses of 15 mg twice daily on measures of fatigue or any other outcome. The results from study II indicated that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and suggested that fMRI could be a promising technique to use in the diagnosis of fatigue after TBI. In study III the results revealed effects of treatment in the right occipitotemporal and orbitofrontal cortex. In these areas, the BOLD response was normalized in the OSU6162 group as compared to healthy controls, while the placebo group showed a steady low activity in these areas. The regional effects were located outside the network shown to be linked to fatigue in study II, which might explain why there were no effects on fatigue after treatment with OSU6162 in study I. Study IV showed that WMH lesions increased with increased TBI severity, but the presence and extent of lesions did not explain lower neuropsychological functioning or fatigue in subjects with previous TBI.Conclusions: In summary, although no effects on fatigue after treatment with OSU6162 were seen, the results provide support to the theory that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and on how fatigue after TBI could be assessed or diagnosed using fMRI. Structural damage within white matter was however not related to fatigue.
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7.
  • Boles, Usama, 1974- (författare)
  • Insight into coronary artery ectasia
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background:Coronary artery ectasia (CAE) is defined as a diffuse dilatation of the epicardial coronary arteries exceeding 1.5 folds the diameter of the normal adjacent arterial segment and/ or the remaining non-dilated part of the same artery. (1) The incidence of CAE has been variably reported between different nations and ranges between 1.4 -10 % (2-5). This wide range of variability is related to many factors including diverse definition of CAE, geographical distribution, association with other conditions (i.e. inflammatory, congenital or atherosclerosis) hence the existent uncertainty about disease burden and prevalence. (6) The main pathophysiology of CAE is initially understood to be part of atherosclerosis, (3) yet others reported the non-atherosclerotic nature of the disease. (2,7) The exact disease pathophysiology, prognosis and clinical outcome are not well studied; particularly the isolated, non-atherosclerotic, form of the disease has not been fully determined nor well identified. Methods:In paper 1, we examined the clinical presentation, prevalence and cardiovascular risk profile of the CAE patients in acute myocardial infarction (MI). We investigated the inflammatory response and short-term outcome in CAE patients of 3,321 acute consecutive MI patients who underwent primary PCI in two different centres in the UK (Royal Free Hospital, London and Norfolk, and Norwich University Hospital) between January 2009 and August 2012.In paper 2, we studied the personalised lipid profile and immune-inflammatory response in CAE patients from two different destinations (16 patients, mean age 64.9 ± 7.3 years, 6 female)  Umea, Sweden and Letterkenny, Ireland. The lipidomic profile was compared with 26 control group (mean age 59.2 ± 6.6, 7 female) with normal coronary arteries.In paper 3, the plasma levels of 16 CAE (mean age 64.9 ± 7.3 years, 6 female) were compared with 69 age and gender matched (mean age 64.5 ± 8.7 years, 41 female) subjects with evidence of coronary artery disease and 140 controls with normal coronary arteries (mean age 58.6 ± 4.1 years, 81 female) in order to determine differences in inflammatory markers and cytokines, specific for CAE.In paper 4, we investigated long term follow up data of CAE patients without atherosclerotic burden. This represents follow up data of 66 patients with CAE, among 16,464 patients, who underwent diagnostic coronary angiography in Umea, Sweden and Letterkenny university Hospital, Ireland between 2003 and 2009. Of the 66 patients, long-term follow up (mean 11.3 ± 1.6 years) data was complete in 41 patients (age 66 ± 9 years), 12 Female. All hospital readmissions with Major Acute Cardiac Events (MACE) including mortality and morbidity and hospital readmissions for acute coronary syndrome (ACS) were compared with gender matched 41 controls. No subject had >20% coronary stenosis in any coronary branch. Results:Paper 1:  The prevalence of CAE with acute MI was 2.7%. Apart from diabetes mellitus (DM) that was significantly less common in the CAE group (p=0.02), the other conventional cardiovascular risk factors were similar between ectatic and non-ectatic coronary arteries. The RCA and LCx were predominantly involved in patients with CAE (p=0.001 and 0.0001, respectively). CRP was higher (p=0.006) in CAE, but both WCC, neutrophil and neutrophil/lymphocyte ratio (N/L ratio) was lower (p = 0.002, 0.002 and 0.032). The short-term follow-up of 2 years showed no relationship between the inflammatory markers and MACE [(8/28, 28.6%) CAE vs. (13/60, 21.7%) without CAE, (p = 0.42)].Paper 2: We identified 65 different metabolites between CAE group and controls, 27 of them were identifiable using metabolomics library software (15 were fully identified and 12 were identified through the size of the side chains). Sixteen species of phosphatidylcholines (PC); and 11 sphyngomyelins (SM) species had significantly lower intensities in patients with CAE.Paper 3: Systemic levels of IFN-γ, TNF-α, IL-1β, IL-6 and IL-8 were significantly higher in the CAE group compared to the CAD group (p = 0.006, 0.001, 0.001, 0.046 and 0.009, respectively) and the control group (p = 0.032, 0.002, 0.001, 0.049 and 0.007 in the same order), while the levels of IL-2 and IL-4 were lower (P < 0.001 for both) compared to the CAD and the control group. No differences were detected in the systemic levels of cytokines IL-10, IL-12P “subunits IL-12 and IL-23”, and IL-13 between the two patient groupsPaper 4: While CAE patients were slightly older, they had longer follow up period (p<0.001) than controls. The overall mortality in the CAE group was higher (p<0.001) and similarly was CV mortality (p<0.03) compared with controls. MACE was similar in both groups (p=0.18). More patients smoked (p<0.001) and have family history for CAD (p<0.02) than controls but these variables were not different between survivals (36 patients) and non-survivors (5 patients). Females had more MACE than males (p<0.03). Finally, all non-survivors and 12/36 survivors had smoked and had dyslipidemia. Conclusion:Coronary artery ectasia, despite of common association with atherosclerosis, had a lower disease prevalence and dysregulated lipid metabolic profile than atherosclerosis. The pro-systemic inflammatory response in CAE is also different from atherosclerosis with different Cytokines milieu. In the context of CAE with acute coronary syndrome with obstructive atherosclerotic CAD, the management options should follow the standard guidelines for revascularization. CAE may lead to exaggerated inflammatory response in acute settings but the short-term outcome is similar to non-ectatic obstructive CAD. However, long term follow up data showed higher mortalities and hospital readmissions, yet no difference in MACE.
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8.
  • Bäckström, David C, M.D. 1978- (författare)
  • The biology of cognitive decline and reduced survival in Parkinson disease : prognostic factors in a population-based cohort
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Parkinson disease (PD) is a progressive neurodegenerative disease that affects about 1% of the population over 60 years. The cardinal symptoms are motor disabilities but cognitive decline is also common. About 50% of all persons with PD develop dementia within 10 years after disease onset. Dementia in PD account for high social costs and has large, negative effects on quality of life. Aims. The aim of the study was to investigate clinical, neurobiological and genetic factors of importance for progression and for the prognosis in PD and parkinsonism. First, we aimed to describe mortality and risk factors for death, including possible associations with cognitive dysfunction, in patients with idiopathic parkinsonism. Second, we aimed to study if biomarkers in the cerebrospinal fluid (CSF) are useful for the diagnosis of different forms of idiopathic parkinsonism and prediction of cognitive decline in PD. Methods. A population-based cohort consisting of patients with new-onset, idiopathic parkinsonism was studied prospectively. After screening in a catchment area of ~142 000 inhabitants in Sweden, 182 patients with parkinsonism were included. The patients were investigated comprehensively, including neuropsychological testing, multimodal neuroimaging and genetic and biosample analyses. During follow up, 143 patients were diagnosed with PD, 13 with multiple system atrophy (MSA), and 18 with progressive supranuclear palsy (PSP). A total of 109 patients died. Results. Patients with MSA and PSP had the shortest life expectancy. PD patients who presented with normal cognitive function had a largely normal life expectancy. In contrast, the mortality was increased in PD patients with cognitive impairment, freezing of gait, hyposmia, and mildly elevated leukocytes in the CSF. Of importance for the prognosis, patients with PD with an early CSF pattern of high Neurofilament light protein, low β-amyloid, and high heart fatty acid binding protein had an 11.8 times increased risk of developing PD dementia (95% CI 3.3-42.1, p <0.001), compared with PD patients with a more ”normal” CSF pattern. Variation in genes associated with dopamine function was also associated with some effects on cognitive functions in PD. Conclusions. PD subtypes, for instance the subtype characterized by cognitive decline, have distinguishing clinical, neurochemical and neurobiological traits, which are of importance for the prognosis and the survival. An early CSF analysis is useful for predicting cognitive decline. The finding of a low-grade immune reaction in the CSF of patients with PD may have clinical implications. In clinical practice, CSF biomarkers could be useful for improving diagnosis and prognostication.
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9.
  • Chandra, Naresh, 1987- (författare)
  • The glycobiology of human adenovirus infections : implications for tropism and treatment
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Human adenoviruses (HAdVs) are common human pathogens, causing gastrointestinal, ocular, and respiratory infections on a regular basis. Epidemic keratoconjunctivitis (EKC) is a severe ocular infection for which no approved antivirals are available. HAdV-D37 is one of the causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. HAdV-D37 interacts with SA via the knob domain of the trimeric virus fiber protein, containing three SA-binding sites. HAdV-D37 also bind to glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, using biochemical and cell-based assays, the impact of GAGs on HAdV-D37 infection (paper I) was investigated. We found that HAdV-D37 interacts with both soluble and cell-surface sulfated GAGs via the knob domain of the viral fiber protein. Remarkably, removal of heparan sulfate (HS; a type of GAG) from human corneal epithelial (HCE) cells by heparinase III enhanced HAdV-D37 infection. We propose that sulfated GAGs in bodily secretions and on plasma membranes function as decoy receptors that prevent the virus from binding to SA-containing receptors and inhibit subsequent virus infection. We also found abundant HS in the basement membrane of the human corneal epithelium. We suggest that this layer of HS functions as a barrier to sub-epithelial infection of HAdV-D37. Based on this finding, we hypothesized that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Here, the antiviral effect of suramin (a known GAG-mimetic) and its analogs against HAdV-D37 (paper II) was evaluated. Interestingly, all compounds displayed antiviral effects by inhibiting the binding of HAdV-D37 to HCE cells. The antiviral effect of suramin was HAdV species-specific. We report for the first time that virus binding to cell-surface decoy receptor constitutes a potential target for antiviral drug development.HAdVs are the major cause of infectious conjunctivitis, constituting up to 75% of all conjunctivitis cases worldwide. Species B HAdV type 3 (HAdV-B3) causes pharyngoconjunctival fever (PCF), whereas HAdV-D8, -D37, and -D64 cause EKC. Recently, HAdV-D53, -D54, and -D56 have emerged as new EKC-causing agents. HAdV-E4 causes both PCF and EKC. SA-containing glycans have been established as cellular receptors for HAdV-D37. By means of cell-based assays, we investigated if ocular HAdVs other than HAdV-D37 also use SA-containing glycans as receptors on HCE cells (paper III). It was found that SA-containing glycans function as cellular receptors for five (HAdV-D8, -D37, -D53, -D54, and -D64) out of six EKC-causing species D HAdVs. We showed that these viruses interact with SAs via the knob domain of the viral fiber protein. HAdV-E4 and -D56 infection of cells was independent of SAs. Surprisingly, HCE cells were completely refractory to HAdV-B3 infection. A trivalent sialic acid (TSA) derivative ME0462 (compound 17a in paper II), designed to bind to SA-binding sites on HAdV-D37 fiber knob, also showed potent antiviral activity against several EKC-causing HAdVs. This suggests that ME0462 can be used as a broad-spectrum antiviral against known and emerging EKC-causing HAdVs. Surface plasmon resonance (SPR) analysis confirmed a direct interaction between ME0462 and fiber knobs of EKC-causing HAdVs.Recently, a TSA derivative (ME0322; designed to bind to SA-binding sites on HAdV-D37 fiber knob) was shown potent antiviral against HAdV-D37 in vitro. To improve the antiviral potency of this compound, six new TSA derivatives were synthesized and their inhibitory effects were evaluated against HAdV-D37 (paper IV). Interestingly, the best compound 17a was found approximately three orders of magnitude more potent (IC50 (binding) = 1.4 nM, IC50 (infection) = 2.9 nM) than ME0322 (IC50 in µM range). SPR data showed that HAdV-D37 fiber knob binds to TSA compounds with high affinities. Structural data revealed the trivalent binding mode of all newly synthesized TSA compounds to HAdV-D37 fiber knob. Ophthalmic toxicity of compound 17a (best compound) was also investigated in rabbits without any sign of toxicity.HAdV-D36 is a member of species D HAdV and has the ability to infect a broad range of animals, which is unusual for HAdVs. Another remarkable feature of HAdV-D36 is that this virus induces obesity in experimental animals. Several epidemiological studies highlighted a link between HAdV-D36 and human obesity. There is no information about the cellular receptor usage by HAdV-D36. Using structural biology and cell-based approaches, we investigated the cellular receptor(s) for HAdV-D36 (paper V).  We show that HAdV-D36 attaches to host cells (via the fiber knob) using the coxsackie and adenovirus receptor (CAR), SA-containing glycans, and one or more unknown proteins or glycoproteins. Using glycan microarray, we found that HAdV-D36 displays binding preference to a rare SA-variant: 4-O,5-N-diacetylneuraminic acid (Neu4,5Ac2), over the more common SA (in humans) i.e. 5-N-acetylneuraminic acid (Neu5Ac). Structural analysis of HAdV-D36 fiber knob:Neu4,5Ac2 complex explained this preference. To date, Neu4,5Ac2 has not been detected in humans, although it is synthesized by many domestic and livestock animals. Our results indicate that HAdV-D36 has evolved to utilize a specialized set of cellular receptors that coincide with a unique host range and pathogenicity profile.These studies provide insights into multiple roles of glycans in HAdV infection cycle and highlight the therapeutic potential of glycans/glycan-mimetics in HAdV-D37 infection.
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10.
  • Dwibedi, Chinmay Kumar, 1987- (författare)
  • Francisella tularensis: persistence, dissemination and source attribution : a theoretical and computational approach
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The bacterium Francisella tularensis causing tularemia in humans and other mammals displays little genetic diversity among genomes across temporal and spatial scales. F. tularensis infects humans with an extremely low infectious dose and causes natural seasonal tularemia outbreaks. During the Cold War, this bacterium was developed as a biological weapon.In paper I, we aimed at investigating the genetic diversity of F. tularensis over space and time and were especially interested in the influence of spatial dispersal on the genetic diversity. By analyses of single-nucleotide polymorphisms (SNPs) among 205 F. tularensis genomes, we found that tularemia had moved from East to West over the European continent by dispersal patterns characterized by multiple long-range dispersal events. Evolutionary rate estimates based on the year of bacterial isolation from 1947 to 2012 indicated non-measurable rates. In outbreak areas with multiple recent outbreaks, however, there was a measurable rate of 0.4 SNPs/genome/year indicating that in areas with more intense disease activity, there is a detectable evolutionary rate. The findings suggest that long-range geographical dispersal events and mostly very low evolutionary rates are important factors contributing to a very low genetic diversity of F. tularensis populations.In paper II, we focused on a geographically restricted area with a history of frequent tularemia outbreaks to study F. tularensis persistence. By analyzing F. tularensis genomes from 138 individuals infected from 1994 to 2010 in Örebro County in Sweden and performing a long-term laboratory storage experiment, we explored the microbial population concept of a pathogen seed-bank. We found that eight indistinguishable genomes – each of them defined by no SNPs across 1.65 million whole-genome nucleotides – locally persisted over 2-9 years. We found unmeasurable SNP accumulation rates and overlapping bacterial generations among the outbreak genomes and that F. tularensis survived in saline for four years without nutrients. By these findings, and analyses of nucleotide substitution patterns, we suggest that a pathogen seed-bank effect is an important feature of F. tularensis ecology influencing genetic diversity.In paper III, we developed a new concept for source attribution of a F. tularensis sample. We aimed to identify genetic variation that is characteristic to laboratory culturing and we used culture amplification to identify genetic variation present at exceedingly low frequencies in a sample. Based on a biological enrichment scheme followed by high-throughput sequencing, we could track genetic variation back to a source sample. These results suggest that the concept has potential for linking a F. tularensis sample to its laboratory source sample.Taken together, the results presented in this thesis provide new understanding of the dissemination patterns and local persistence of tularemia. This is important for the interpretation of molecular epidemiology investigations of the disease. In a wider context, the results demonstrate how spatial dispersal and a microbial seed-bank effect may contribute to the diversity of a disease-causing agent. Finally, we have described a promising concept for source attribution of F. tularensis samples
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