<p>The ability to image ventilation and perfusion enables pulmonary researchers to study functional metrics of gas exchange on a regional basis. There is a huge interest in applying imaging methods to study the large number of genetic models of pulmonary diseases available in small animals. Existing techniques to image ventilation and perfusion are often associated with low spatial resolution and ionizing radiation. Magnetic Resonance Imaging (MRI) has been demonstrated successfully for ventilation and perfusion studies in humans. Translating these techniques in small animals remains challenging. This work addresses the ventilation and perfusion imaging in small animals using MRI. </p><p>Qualitative ventilation imaging in rats and mice is possible and has been demonstrated using MRI, however perfusion imaging remains a challenge. In humans and large animals perfusion can be assessed using dynamic contrast-enhanced (DCE) MRI with a single bolus injection of a gadolinium (Gd)-based contrast agent. But the method developed for the clinic cannot be translated directly to image the rat due to the combined requirements of higher spatial and temporal resolution. This work describes a novel image acquisition technique staggered over multiple, repeatable bolus injections of contrast agent using an automated microinjector, synchronized with image acquisition to achieve dynamic first-pass contrast enhancement in the rat lung. This allows dynamic first-pass imaging that can be used to quantify pulmonary perfusion. Further improvements are made in the spatial and temporal resolution by combining the multiple injection acquisition method with Interleaved Radial Imaging and 'Sliding window-keyhole' reconstruction (IRIS). The results demonstrate a simultaneous increase in spatial resolution (<200>um) and temporal resolution (<200>ms) over previous methods, with a limited loss in signal-to-noise-ratio. </p><p>While is it possible to create high resolution images of ventilation in rats using hyperpolarized ³He, extracting meaningful quantitative information indicative of changes in ventilation is difficult. In this work, we also present a signal calibration technique used to normalize the signal of ³He to volume of ³He which can then be used to extract quantitative information of changes in ventilation via normalized difference maps. Combining the techniques for quantitative ventilation and quantitative perfusion we perform studies of change in ventilation/perfusion (V/Q) before and after airway obstruction in rats. The technique is sensitive in detecting statistically significant differences in the heterogeneity of the distribution of V/Q ratio.</p> / Dissertation

Bakgrund: Kronisk obstruktiv lungsjukdom (KOL) är en världsomfattande sjukdom. År 2012 dog mer än tre miljoner människor världen över till följd av sjukdomen. Av de dödsfall som sker till följd av sjukdomen, sker 90 % i låg- och medelinkomstländer. Den huvudsakliga orsaken till att sjukdomen utvecklas är rökning. Sjukdomen kan leda till b.la. depression, utmattning, ångest och smärta. Sjuksköterskans arbete innefattar att tillgodose basala och specifika omvårdnadsbehov. KASAM (känslan av sammanhang) består av tre dimensioner begriplighet, hanterbarhet och meningsfullhet. Alla dessa bidrar till en känsla av sammanhang. Syfte: Att beskriva upplevelsen av att leva med kronisk obstruktiv lungsjukdom (KOL). Metod: Litteraturöversikten genomfördes med hjälp av 11 kvalitativa artiklar. Artiklarna analyserades med hjälp av Fribergs femstegsmodell. Resultat: Fem teman framkom, Upplevd andfåddhet, Upplevd påverkan av aktivitetsförmågan, Upplevd ensamhet och social isolering, Upplevd meningslöshet och suicidala tankar och Upplevd kontroll. KOL är en svår sjukdom som involverar många olika negativa känslor. Rädsla, panik, ångest och depression var förekommande. Slutsatser: KOL är en sjukdom som innefattar många negativa känslor och medför problem som påverkar hela livet i stor utsträckning. De som är drabbade av KOL kunde ha en låg känsla av sammanhang. Dessa fynd ger sjuksköterskan en viktig insikt i de upplevelser vårdtagarna upplever i sin sjukdom. / Background: COPD is a worldwide disease. Year 2012 more than three million people died as a result of the disease worldwide. Of the deaths that occur as a result of the disease, 90 % occur in low- and middle-wealth countries. The main cause of the illness is smoking. The disease can lead to for instance depression, fatigue, anxiety and pain. The nurse profession involves satisfying basic and specific nursing needs. SOC (sense of coherence) is comprised of three dimensions of comprehensibility, manageability and meaningfulness. All these contribute to a sense of coherence. Aim: To describe the experience of living with chronic obstructive pulmonary disease (COPD) Method: Literature review was conducted using 11 qualitative articles. The articles were analysed with Friberg´s five-stage model. Results: Five themes emerged, Perceived breathlessness, Perceived loneliness and social isolation, Perceived meaninglessness and suicidal thoughts and Perceived control. These themes indicate that COPD is a difficult disease involving many different negative emotions. Fear, panic, anxiety and depression were frequent. Conclusion: COPD is a disease involving many negative feelings and poses problems that effects the entire life extensively. Those who are afflicted with COPD could have a low sense of coherence. These findings give nurses an important insight into the experiences patients have in their illness.

Bakgrund: Patienter med kronisk obstruktiv sjukdom (KOL) som behandlas med Non-invasiv ventilation (NIV) har risk för trycksår och malnutrition. Observation och övervakning av patienterna är viktigt för att kunna följa behandlingsförloppet och tidigt upptäcka en eventuell försämring samt förebygga komplikationer. Dokumentation av given omvårdnad måste kunna följas för att utvärdera och säkerställa kraven på en god och säker vård. Syfte: Syftet med studien var att granska omvårdnadsdokumentationen för patienter med KOL som behandlats med NIV på en medicinsk akutvårdsavdelning. Metod: Studien genomfördes som en retrospektiv systematisk journalgranskning i 75 journaler med en granskningsmall. Resultat: Omvårdnadsprocessens steg fanns inte dokumenterad i sin fullständighet för trycksår eller nutrition i någon journal. Dokumentationen av omvårdnadsprocessen för trycksår var oberoende av antal vårddygn, kön och ålder men beroende av antal dygn med NIV.  För nutrition var dokumentationen av omvårdnadsprocessen beroende av antal NIV- och vårddygn men oberoende av kön och ålder. Dokumentationen för omvårdnad och behandling med NIV var utspridd i journalen under olika rubriker. Slutsats: Studiens resultat visade att det fanns brister i omvårdnadsdokumentationen.

The overall aim of this thesis was to describe how people with very severe obstructive pulmonary disease (COPD) experienced their every day lives and created meaning, with focus on end-of-life. A second aim was to describe how death and dying can be viewed from the perspective of relatives to people with COPD. In study I, eight patients were interviewed about how COPD affected their everyday lives. A phenomenological method was used. In study II, four people with COPD who lived alone were interviewed over time, to illuminate how the illness influenced their everyday life and their existential thoughts about life and death. In study III, four couples of whom one partner in each couple had COPD were interviewed several times to illuminate the affect the illness had on the spousal relationship, their self-expressed needs, and their existential thoughts, from the perspective of two people living together. A phenomenological-hermeneutic method was used for the analyses in studies IIand III. Study IV aimed at studying patients’ last six months of life with focuson dying and death, and in this study content analysis was used.The studies (I-IV) revealed that suffering from very severe COPD can be a daily struggle to survive as well as to maintain the self-image. The studies also explicate experiences of a shrinking life space, and questions of meaning were being challenged (I). Study II showed that living alone provided feelings of independency. However the bodily losses reminded the patients’ about death and raised fears about death of being painful, as they did not want to face death alone. For the couples in study III living with COPD meant living in a changed pace with uncertainty, changed intimate relationship and finding new ways of living together. Study IV outlined the trajectory of illness to be irregular and characterized by periods of sudden deterioration, making it difficult to plan for the future. Death was experienced as an unexpected experience and was described by all as peaceful. The results in this thesis have outlined important insight into the existential challenges of living with COPD as experienced by the ill persons themselves and their next of relatives. / Birgitta Andershed is also affiliated to Enheten för forskning i palliativ vård, Ersta Sköndal Högskola, Stockholm och Institutionen för omvårdnad, Gjøvik universitet, Norge.Eva Sahlberg-Blom is also affiliated to Enheten för forskning i palliativ vård, Ersta Sköndal Högskola, Stockholm

Whereas first line therapy for chronic obstructive pulmonary disease (COPD) usually includes a short-acting bronchodilator, there are suggestions that these agents may increase the risk of cardiac arrhythmias. In this thesis, we first assessed the risks associated with short-acting beta-agonists (SABA), long-acting beta-agonists (LABA), ipratropium bromide (IB), and methyl xanthines (MX) within a cohort of COPD patients using the health databases of Saskatchewan. In order to confirm these findings and to address some methodological issues we then replicated this analysis within a larger cohort of patients using the health databases of Quebec. / Our first study cohort consisted of 6,018 adults aged 55 and older, newly treated with bronchodilator medications. We found that new users of both IB and LABA increased the risk of arrhythmia (RR 2.39 [95% CI 1.42-4.05] and (RR 4.55 [95% CI 1.43-14.45] respectively). When the cohort was restricted by excluding subjects who had recently either been hospitalised or experienced an exacerbation, the elevated risk associated with the new use of IB persisted (RR 3.65 [95% CI 1.72-7.74]), an effect was detected with new use of MX (RR 5.17 [95% CI 1.38-19.30]), but there was insufficient power to detect an effect associated with the new use of LABA. / Due to both power issues and the limited availability of LABA within the Saskatchewan data, we replicated the analysis in a larger new-user cohort of 76,661 Quebec adults aged 67 and over. This study confirmed our earlier results, with an elevated risk of arrhythmia associated with the new use of both IB and LABA (RR 1.43 [95% CI 1.08-1.88]) and (RR 1.54 [95% CI 1.00-2.36]) respectively, as well as with new use of SABA (RR 1.28 [95% CI 1.02-1.61]). Finally, using marginal structural models, we demonstrated that both exacerbations of COPD as well as minor non-event arrhythmias were moderate time-dependent confounders within this setting. / In conclusion, we found that new use of bronchodilators in COPD, particularly IB and LABA, was associated with an increase in the risk of cardiac arrhythmias. We also demonstrated the method by which the time-dependent confounder status of specific model covariates may be evaluated.

Cystic fibrosis (CF) is a single gene Mendelian disorder characterized by pulmonary disease and pancreatic insufficiency. Pulmonary disease is the major cause of death in CF patients. Although some cystic fibrosis transmembrane conductance regulator (CFTR) genotypes are associated with less severe disease, patients possessing the same genotype show great variation in pulmonary disease severity and progression. Genes involved in modulating the inflammatory response and genes increasing susceptibility to infection are proposed as modifiers of pulmonary disease severity. Polymorphisms selected for based on evidence that they affect the function of the gene and prevalence of the putative risk allele: 1) antiprotease gene alpha-1-antitrypsin (alpha-1-AT), 2) innate immunity genes: mannose binding lectin (MBL2) (promoter [G→C] at -221 and codon 52 (Arg52Cys, D allele), 54 (Gly54Asp, B allele), and 57 (Gly57Glu, C allele), and pulmonary surfactant genes SPA-1 (Arg219Trp), SPA-2 (Thr9Asn, Lys223Gln) and SPD (Thr11Met), 3) antioxidant genes GSTM1 and T1 (gene deletion polymorphisms), GSTP1 (Ile105Val) and GCLC repeats, 4) mucin genes (MUC2 and MUC5B). Pulmonary disease progression and survival in patients with chronic Burkholderia cepacia complex (BCC) infection were also investigated controlling for genomovar and RAPD type of the organism. BCC infection was associated with more severe pulmonary disease progression and worse survival. Alpha-1-AT genotype was not a major contributor to variability of pulmonary disease severity, but the results suggest that alpha-1-AT plasma levels during pulmonary infections may be affected by poor nutritional status. We showed similar pulmonary disease progression and MBL2 genotype. Contrary to the previous literature, wild-type MBL2 genotype was associated with steeper decline in pulmonary disease over time following chronic infection with BCC, but genotype was not associated with increased susceptibility to BCC infection. We showed inconsistant results for the pulmonary surfactant gene polymorphisms, GSTM1, T1 and GSTP1 polymorphisms, and number of repeats for GCLC and MUC5B depending on the phenotype investigated. We conclude that some of the variability in pulmonary disease severity and progression in CF is explained by polymorphisms in secondary genes.

Asthma is a chronic disease of the airways and affects many people regardless of their age, gender, race and socioeconomic status. Since asthma is recognised as one of the major causes of morbidity and mortality in people and especially in South Africa, the prescribing patterns, prevalence and medication cost of asthma in South Africa are saliently important and need to be investigated. A non-experimental, quantitative retrospective drug utilisation review was conducted on medicine claims data of a pharmaceutical benefit management company in a section of the private health care sector of South Africa. The study period was divided into four annual time periods (1 January 2008 to 31 December 2008, 1 January 2009 to 31 December 2009, 1 January 2010 to 31 December 2010 and 1 January 2011 to 31 December 2011). The prescribing patterns and cost of asthma medication were investigated and stratified according to province, age and gender. Patients were included if the prescriptions which were provided by the health care practitioners matched the Chronic Disease List (CDL) of South Africa and the International Classification of Disease (ICD-10) coding for asthma and chronic obstructive pulmonary disease (COPD). Data analysis was conducted by means of the SAS 9.3® computer package. Asthma patients were divided according to different age groups (there were five different age groups for this study), gender and geographical areas of South Africa. The study indicated a steady increase in the prevalence of asthma patients from 0.82% (n = 7949) in 2008 to 1.18% (n = 15 423) in 2009 and reached a minimum of 0.79% (n = 8554) in 2011. Analysis of the prevalence regarding geographical areas in South Africa suggested that Gauteng had the highest number [n = 17 696, (0.85%)] of asthma patients throughout the study period, followed by KwaZulu Natal [n = 8 628, 1.16%)] and the Western Cape [(n = 8513, 0.97%) (p < 0.05)]. The prevalence of asthma in female patients [0.89% (n = 26 588)] was higher than in their male counterparts [0.79% (n = 19 244)] (p > 0.05). The results showed that asthma was not as common chronic disease in children. The total number of asthma patients younger than 7 years represented 0.64% (n = 2 909). It was found that patients over 65 years of age showed the highest prevalence of the five age groups [1.94% (n = 13 403) (p < 0.05)]. The average number of asthma prescriptions per patient per year was 8.28 (95% CI, 8.16- 8.40) and 5.15 (95% CI, 5.06-5.23) in 2008 and 2011, respectively. The number of asthma items per prescription varied from 1.55 (95% CI, 1.55-1.56) in 2008 to 1.40 (95% CI, 1.39- 1.40) in 2011. Medication from the MIMS® pharmacological group (anti-asthmatics and bronchodilators) was used to identify asthma medication. The top three asthma medication with the highest prevalence in the study period were the anti-inflammatory inhaler of fluticasone (n = 39 721) followed by the single item combination product of budesonide/ formoterol (n = 25 121) and salbutamol (n = 24 296). The influence of COPD on asthma treatment and the costimplication thereof were investigated. Medication from the MIMS® pharmacological group (anti-asthmatics and bronchodilators) was used to identify COPD medication. This study also showed that COPD had an influence in the economic burden of the South African asthma population. The cost of medication is responsible for the single largest direct cost involved in the economic burden of asthma. This study showed that asthma represented 0.88% of the direct medication cost in the study (excluding hospitalisation and indirect cost). The average cost per prescription and average cost per asthma item both increased throughout the study period. The prescribing patterns for the different medication used in the treatment of asthma were investigated and recommendations for further research in this field of study were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD is a slowly progressive, inflammatory disease in the airways and lungs, caused mainly by smoking. The inflammation leads to a narrowing of the small airways (airway obstruction) and a destruction of tissue in the lungs. This gives a decreased expiratory airflow which leads to dyspnea, the primary symptom of the disease. The chronic airflow limitation also is associated with the development of limb muscle dysfunction. Decreases in both limb muscle strength and endurance have been shown which, in turn, is associated with exercise intolerance, one of the key disabling factors of the disease. Pulmonary rehabilitation including exercise training is the cornerstone of treatment and is strongly recommended. However, it is still unclear how to optimize exercise training for this group of patients. Also how to address the increase in dyspnea which limits the exercise stimulus, and how to assess muscular strength, need further study. Partitioning the exercising muscle mass, known as single limb exercises, is a novel exercise strategy aimed at reducing the negative consequences of chronic airflow limitation in patients with COPD. The aim of this thesis was to study the current evidence of single limb approaches in patients with COPD, to examine the feasibility and effects of a high-repetitive single limb exercise (HRSLE) regimen in patients with COPD and to examine whether elastic resistance could be used to evaluate muscular strength. This thesis is based on five papers. In order to study the evidence on single limb exercises, a systematic review of randomized controlled trials was performed. The review showed that single limb exercises, performed as one-legged cycling appeared to be more effective than two-legged cycling with regard to exercise capacity but not dyspnea, and might be included in exercise programs for patients with COPD (Paper I). Thirty healthy older women and men participated in a validation study comparing elastic resistance maximal strength with isokinetic dynamometry measurements. Excellent levels of agreement and no differences between the two pieces of equipment were found which indicates that elastic resistance could be used to evaluate muscular strength (Paper II). A study protocol was created for a randomized controlled trial designed to identify the effects of HRSLE in combination with COPD-specific patient training (experimental group) in comparison to patient information alone (control group) (Paper III). HRSLE was performed as resistance training, using a single limb at a time, elastic bands as resistance and a high number of repetitions (25 repetitions in 2 sets) with the aim of increasing limb muscle endurance. After eight weeks of exercise, the differences between the groups were in favor of the experimental group on lower- and upper-extremity functional capacity, upper-extremity endurance capacity and muscular function. No differences were seen between the groups on endurance-cycle capacity or health-related quality of life (Paper IV). In patients with COPD, the HRSLE regimen was considered feasible with a high attendance rate, excellent compliance and high relative exercise intensity. No severe adverse events occurred. The physiotherapists conducting the HRSLE in the clinical setting also found it to be feasible (Paper V). This thesis shows that single limb exercises performed as one-legged cycling may be useful and effective for patients with COPD. Eight weeks of HRSLE was feasible and effective with regard to exercise capacity but without effect with regard to health-related quality of life. Elastic resistance could be used as exercise equipment to improve limb muscle function in patients with COPD and to evaluate muscular strength in healthy older adults. / Kroniskt obstruktiv lungsjukdom (KOL) är idag ett stort globalt problem.  KOL är en långsamt fortskridande inflammatorisk sjukdom i luftvägar och lungor, i huvudsak orsakad av cigarrettrökning. Inflammationen leder till en förträngning i de små luftvägarna och förstör vävnaden i lungorna. Detta medför en luftvägsobstruktion där flödet av luft vid utandning är minskat, vilket bidrar till varierande grad av andnöd hos patienten. Luftvägsobstruktionen är relaterad till försämrad muskelfunktion hos patientgruppen. Både nedsatt muskulär styrka och uthållighet har påvisats vilket är relaterat till ett av huvudproblemen vid KOL; nedsatt förmåga till fysisk aktivitet och träning.  Lungrehabilitering inklusive fysisk träning är centralt i behandlingen och starkt rekommenderat. Det är dock inte fastställt hur patientgruppen skall träna för att optimera effekterna av träningen eller hur träningen bäst kan utvärderas. Det är också oklart hur man skall hantera den successivt ökande andfåddheten vid träning. Träning med en arm eller ett ben i taget, så kallad lokal muskelträning är en strategi som syftar till att minska andnöd under träning hos patienter med KOL Syftet med denna avhandling var att undersöka vilken evidens det finns för lokal muskelträning hos patienter med KOL, utvärdera genomförbarhet och effekter av lokal högrepetitiv muskelträning utfört med elastiska träningsband hos patienter med KOL samt att undersöka ifall elastiska träningsband kan användas för att utvärdera muskelstyrka. Avhandlingen består av fem delstudier. För att undersöka evidens för lokal muskelträning genomfördes en systematisk litteraturgranskning av randomiserade kontrollerade studier. Granskningen visade att lokal muskelträning, i form av cykling med ett ben i taget kan vara effektivt, avseende fysisk förmåga, men utan effekt avseende andfåddhet för patienter med KOL (delstudie 1). Trettio friska kvinnor och män, deltog i en valideringsstudie där jämförelser gjordes mellan maximal kraftutveckling utfört med elastiska träningsband och en isokinetisk dynamometer. Ett högt samband mellan de två metoderna och ingen skillnad i maximal kraft, indikerade att elastiska band kan användas för att utvärdera muskelstyrka (delstudie 2). Ett studieprotokoll skapades för en randomiserad kontrollerad studie, som syftade till att undersöka effekterna av lokal högrepetitiv muskelträning i kombination med KOL-specifik patientutbildning (interventionsgrupp) jämfört med enbart KOL-specifik patientutbildning (kontrollgrupp) (delstudie 3). Lokal högrepetitiv muskelträning utfördes i grupp med elastiska träningsband som redskap. Övningarna genomfördes med en arm eller ett ben i taget med 25 repetitioner i 2 set med syfte att påverka muskulaturens uthållighet. Efter åtta veckors träning hade interventionsgruppen bättre muskelfunktion i både övre och nedre extremitet samt en bättre funktionell förmåga jämfört med kontrollgruppen. Inga skillnader i effekt sågs mellan grupperna avseende uthållighet vid test på ergometercykel eller avseende hälsorelaterade utfallsmått, såsom livskvalitet och tilltro till sin egen förmåga (delstudie 4). För patienter med KOL, visade sig lokal högrepetitiv muskelträning vara en genomförbar metod avseende följsamhet och närvaro i träningen. De fysioterapeuter som ledde träningen i klinisk verksamhet ansåg att den var möjlig att genomföra med hög relativ intensitet och utan allvarliga biverkningar (delstudie 5). Sammanfattningsvis visar denna avhandling att lokal muskelträning kan vara en användbar och effektiv metod för patienter med KOL. Åtta veckor med lokal högrepetitiv muskelträning är genomförbart och effektivt avseende fysisk förmåga hos dessa patienter. Elastiska träningsband kan användas som träningsredskap för att förbättra muskelfunktion hos patienter med KOL samt för att utvärdera muskelstyrka hos friska vuxna.

Cystic fibrosis (CF) is a single gene Mendelian disorder characterized by pulmonary disease and pancreatic insufficiency. Pulmonary disease is the major cause of death in CF patients. Although some cystic fibrosis transmembrane conductance regulator (CFTR) genotypes are associated with less severe disease, patients possessing the same genotype show great variation in pulmonary disease severity and progression. Genes involved in modulating the inflammatory response and genes increasing susceptibility to infection are proposed as modifiers of pulmonary disease severity. Polymorphisms selected for based on evidence that they affect the function of the gene and prevalence of the putative risk allele: 1) antiprotease gene alpha-1-antitrypsin (alpha-1-AT), 2) innate immunity genes: mannose binding lectin (MBL2) (promoter [G→C] at -221 and codon 52 (Arg52Cys, D allele), 54 (Gly54Asp, B allele), and 57 (Gly57Glu, C allele), and pulmonary surfactant genes SPA-1 (Arg219Trp), SPA-2 (Thr9Asn, Lys223Gln) and SPD (Thr11Met), 3) antioxidant genes GSTM1 and T1 (gene deletion polymorphisms), GSTP1 (Ile105Val) and GCLC repeats, 4) mucin genes (MUC2 and MUC5B). Pulmonary disease progression and survival in patients with chronic Burkholderia cepacia complex (BCC) infection were also investigated controlling for genomovar and RAPD type of the organism. BCC infection was associated with more severe pulmonary disease progression and worse survival. Alpha-1-AT genotype was not a major contributor to variability of pulmonary disease severity, but the results suggest that alpha-1-AT plasma levels during pulmonary infections may be affected by poor nutritional status. We showed similar pulmonary disease progression and MBL2 genotype. Contrary to the previous literature, wild-type MBL2 genotype was associated with steeper decline in pulmonary disease over time following chronic infection with BCC, but genotype was not associated with increased susceptibility to BCC infection. We showed inconsistant results for the pulmonary surfactant gene polymorphisms, GSTM1, T1 and GSTP1 polymorphisms, and number of repeats for GCLC and MUC5B depending on the phenotype investigated. We conclude that some of the variability in pulmonary disease severity and progression in CF is explained by polymorphisms in secondary genes.

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