| 1. |
- Khoshnood, Ardavan
(författare)
-
Prehospital Diagnosis and Oxygen Treatment in ST Elevation Myocardial Infarction
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionPaper I: An Artificial Neural Network (ANN) was constructed to identify ST Elevation Myocardial Infarction (STEMI) and predict the need for Percutaneous Coronary Intervention (PCI). Paper II, III and IV: Studies suggest that O2 therapy may be harmful in STEMI patients. We therefore conducted the SOCCER study to evaluate the effects of O2 therapy in STEMI patients.MethodsPaper I: 560 ambulance ECGs sent to the Cardiac Care Unit (CCU), was together with the CCU physicians interpretation and decision of conducting an acute PCI or not collected, and compared with the interpretation and PCI decision of the ANN. Paper II, III, IV: Normoxic (≥94%) STEMI patients accepted for acute PCI were in the ambulance randomized to standard care with 10 L/min O2 or room air. A subset of the patients underwent echocardiography for determination of the Left Ventricular Ejection Fraction (LVEF) and the Wall Motion Score Index (WMSI). All patients had a Cardiac Magnetic Resonance Imaging (CMRI) to evaluate Myocardial area at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI).ResultsPaper I: The area under the ANN’s receiver operating characteristics curve for STEMI detection as well as predicting the need of acute PCI were very good.Paper II, III, IV: No significant differences could be shown in discussing MaR, MSI or IS between the O2 group (n=46) and the air group (n=49). Neither could any differences be shown for LVEF and WMSI at the index visit as well after six months between the O2 group (n=46) and the air group (n=41)ConclusionsPaper I: The results indicate that the number of ECGs sent to the CCU could be reduced with 2/3 as the ANN would safely identify ECGs not being STEMI.Paper II, III, IV: The results suggest that it is safe to withhold O2 therapy in normoxic, stable STEMI patients.
|
|
| 2. |
- Nowak, Christoph, 1986-
(författare)
-
Insulin Resistance : Causes, biomarkers and consequences
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.
|
|
| 3. |
- Mottahedin, Amin
(författare)
-
Developing brain and systemic inflammation: a "Toll-like" link with consequences
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The developing brain is vulnerable to external insults, and perinatal brain injury (PBI) is a major cause of life-long neurological syndromes such as cerebral palsy. Currently, no pharmaceutical intervention is available. Hypoxia/ischemia (HI), infections and inflammation are implicated in the pathogenesis of PBI. However, the crosstalk between these etiologies is not fully understood. Toll-like receptors (TLR) 3 and TLR2 are responsible for sensing viral and bacterial infections and initiating the inflammatory response. The aim of this thesis was to investigate the effect of systemic inflammation induced by activation of these TLRs on neonatal HI brain injury. We demonstrate that intraperitoneal administration of TLR3 and TLR2 ligands (PolyI:C and P3C, respectively) prior to HI increases the brain injury in neonatal mice. PolyI:C and P3C induced neuroinflammation and altered microglial phenotype as assessed by RT-qPCR, multiplex cytokine assay or flow cytometry. PolyI:C also upregulated the pro-apoptotic gene, Fasl, expression and reduced activation of pro-survival signaling molecule Akt. On the other hand, P3C suppressed mitochondrial respiration, a major mechanism of cellular energy production. P3C, unlike other TLR agonists, induced marked infiltration of leukocytes to the cerebral spinal fluid and brain of neonatal mice and rats. Confocal microscopy, Cre recombinase-mediated gene targeting and in vitro cell transmigra-tion assay revealed the choroid plexus as a site of leukocyte entry. RNA sequencing of the choroid plexus followed by transcriptome cluster analysis and Ingenuity Pathway Analysis revealed potential mechanisms of leukocyte infiltration, including a specific chemotaxis signature and cytoskeleton-related pathways. Finally, we show that N-acetylcysteine treatment inhibits TLR2-mediated leukocyte trafficking in vivo and in vitro. To conclude, this thesis describe a TLR-mediated link between systemic inflammation and developing brain with detrimental consequences on HI brain injury, suggesting potential novel therapeutic strategies.
|
|
| 4. |
- Ghorbani, Ramin, 1981-
(författare)
-
Real-time breath gas analysis of carbon monoxide : laser-based detection and pulmonary gas exchange modeling
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breath gas analysis is a promising approach for non-invasive medical diagnostics and physiological monitoring. Real-time, breath-cycle resolved biomarker detection facilitates data interpretation and has the potential to improve the diagnostic value of breath tests as exhalation profiles carry spatiotemporal information about biomarker origin and gas exchange in the respiratory tract. This thesis presents and scrutinizes a novel methodology for the analysis of real-time breath data, where single-exhalation profiles are simulated using a pulmonary gas exchange model and least-squares fitted to measured expirograms to extract airway and alveolar contributions and diffusing capacities. The methodology is demonstrated on exhaled breath carbon monoxide (eCO), a candidate biomarker for oxidative stress and respiratory diseases. The thesis mainly covers (1) the construction of a compact optical sensor based on tunable diode laser absorption spectroscopy (TDLAS) in the mid-infrared region (4.7 μm) for selective and precise real-time detection of CO in breath and ambient air (detection limit 9 ± 5 ppb at 0.1 s), (2) the design of an advanced online breath sampling system, (3) the implementation of a trumpet model with axial diffusion (TMAD) to simulate the CO gas exchange, and (4) the application of extended eCO analysis in clinical studies to establish the healthy non-smoker baseline of the eCO parameters and to study the response to CO and wood smoke exposure. It is shown that the TMAD adequately describes the gas exchange during systemic CO elimination for different breathing patterns, and that there is no difference between eCO parameters from mouth- and nose exhalations. Expirogram shape and eCO parameters exhibit a dependence on the exhalation flow rate, but for a given breathing maneuverer, the parameters lie in a narrow range. Airway CO is close to and correlates with ambient air CO, indicating negligible airway production in the healthy population. The alveolar diffusing capacity is independent of endogenous CO, even after exposure to elevated exogenous CO, and could be used to assess lung diffusion abnormalities. Compared to CO exposure, no clear additional effect of exposure to wood smoke particles on eCO is observed. The discrimination between endogenous and exogenous CO sources remains a challenge.
|
|
| 5. |
- Pellegrini, Mariangela
(författare)
-
Regional Lung Mechanics and Influence of an Active Diaphragm in Experimental Lung Injury
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite being an essential life-support strategy in severe respiratory failure, mechanical ventilation can, if not optimally set and monitored, lead to injury of the lung parenchyma and diaphragm. These conditions are called ventilator-induced lung injury and ventilator-induced diaphragmatic dysfunction (VIDD), respectively. Although substantial progress has been made in the ventilator management of severely lung-injured patients, we are still far from a fully protective mechanical ventilation. In consideration of this gap of knowledge, this doctoral thesis aimed at investigating regional lung mechanics during both inspiration and expiration, in both controlled and assisted ventilation. Particular emphasis was placed on the expiratory phase, which is involved in expiratory flow limitation, airway closure and atelectasis formation, although commonly considered non-harmful.A novel methodological approach has been the fundamental basis for this research project. The combination of respiratory mechanics, diaphragmatic electromyographic activity and lung imaging enabled a breath-by-breath analysis at high temporal and spatial resolution.In Study I, the gravitational field affected the distribution of gas and transpulmonary pressures, as previously shown. This effect differed between healthy and injured lungs. Moreover, lung injury induced a heterogeneous distribution of gas within the lungs, as well as an increased gravitational gradient in transpulmonary pressure. Study I was mainly aimed at testing the new methodological approach centred on the investigation of regional lung mechanics.In Study II, the focus was on assisted ventilation and the phenomenon of gas redistribution within the lungs. Large pendelluft events had been demonstrated in disproportionate inspiratory efforts. In Study II, we showed that large pendelluft resulting from pathological respiratory drive could be attenuated by high positive end expiratory pressure (PEEP). Moreover, we showed that transient and widespread small gas redistribution events occur at all times during inspiration. Assisted ventilation and high PEEP reduced the size of gas redistribution as compared with controlled ventilation and low PEEP.In Study III, we demonstrated a diaphragmatic expiratory contraction in lungs prone to collapse, serving to brake the expiratory flow. It preserved end expiratory lung volume (EELV) and counteracted tidal atelectasis. However, the expiratory brake induced by diaphragmatic contraction is a known cause of VIDD.In Study IV, we tested the effects of external expiratory resistances (ExpR). We showed that, by applying ExpR, an expiratory brake was induced. The beneficial effects on EELV were retained, while the diaphragm could quickly relax during the expiration, thus reducing the risk of VIDD.
|
|
| 6. |
- Bhandage, Amol K., 1988-
(författare)
-
Glutamate and GABA signalling components in the human brain and in immune cells
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.
|
|
| 7. |
- Mattsson, C. Mikael
(författare)
-
Physiology of Adventure Racing : with emphasis on circulatory response and cardiac fatigue
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aims of this thesis were to elucidate the circulatory responses to ultra-endurance exercise (Adventure Racing), and furthermore, to contribute to the clarification of the so called “exercise-induced cardiac fatigue” in relation to said exercise. An Adventure race (AR) varies in duration from six hours to over six days, in which the participants have to navigate through a number of check-points over a pre-set course, using a combination of three or more endurance/outdoor sports, e.g., cycling, running, and kayaking. This thesis is based on the results from four different protocols; 12- and 24-h (n = 8 and 9, respectively) in a controlled setting with fixed exercise intensity, and 53-h and 5-7-day (n = 15 in each) in field setting under race conditions. The subjects in all protocols were experienced adventure racing athletes, competitive at elite level. Study I and II address the circulatory responses and cardiovascular drift, using methods for monitoring heart rate (HR), oxygen uptake (VO2), cardiac output (non-invasive re-breathing) and blood pressure, during ergometer cycling at fixed steady state work rate at periods before, during and after the ultra-endurance exercise. In Study III and IV we examined the possible presence of exercise-induced cardiac fatigue after a 5-7-day AR, from two different perspectives. In Study III analyses were performed with biochemical methods to determine circulating levels of cardiac specific biomarkers (i.e., creatine kinase isoenzyme MB (CK-MB), troponin I, B-type natriuretic peptide (BNP) and N-terminal prohormonal B-type natriuretic peptide (NT-proBNP)). We also made an attempt to relate increases in biomarkers to rated relative performance. In Study IV we used tissue velocity imaging (TVI) (VIVID I, GE VingMed Ultrasound, Norway) to determine whether the high workload (extreme duration) would induce signs of functional cardiac fatigue similar to those that occur in skeletal muscle, i.e., decreased peak systolic velocities. Using conventional echocardiography we also evaluated whether the hearts of experienced ultra-endurance athletes are larger than the normal upper limit. The central circulation changed in several steps in response to ultra-endurance exercise. Compared to initial levels, VO2 was increased at every time-point measured. The increase was attributed to peripheral adaptations, confirmed by a close correlation between change in VO2 and change in arteriovenous oxygen difference. The first step of the circulatory response was typical of normal (early) cardiovascular drift, with increased HR and concomitantly decreased stroke volume (SV) and oxygen pulse (VO2/HR), occurring over the first 4-6 h. The second step, which continued until approximately 12h, included reversed HR-drift, with normalisation of SV and VO2/HR. When exercise continued for 50 h a late cardiovascular drift was noted, characterised by increased VO2/HR, (indicating more efficient energy distribution), decreased peripheral resistance, increased SV, and decreased work of the heart. Since cardiac output was maintained at all-time points we interpret the changes as physiologically appropriate adaptations. Our findings in Study III point towards a distinction between the clinical/pathological and the physiological/exercise-induced release of cardiac biomarkers. The results imply that troponin and CKMB lack relevance in the (healthy) exercise setting, but that BNP, or NT-proBNP adjusted for exercise duration, might be a relevant indicator for impairment of exercise performance. High levels of NTproBNP, up to 2500 ng · l -1 , can be present after ultra-endurance exercise in healthy athletes without any subjective signs or clinical symptoms of heart failure. However, these high levels of NT-proBNP seemed to be associated with decreased relative exercise performance, and might be an indicator of the cardiac fatigue that has previously been described after endurance exercise. Study IV revealed that the sizes of the hearts (left ventricle) of all of our ultra-endurance athletes were within normal limits. The measurements of peak systolic velocities showed (for group average) no signs of cardiac fatigue even after 6 days of continuous exercise. This discrepancy between ours and other studies, involving e.g., marathon or triathlon, might reflect the fact that this type of exercise is performed at relatively low average intensity, suggesting that the intensity, rather than the duration, of exercise is the primary determinant of cardiac fatigue.
|
|
| 8. |
- Farah, Idle Omar
(författare)
-
Immunopathogenesis of schistosomiasis mansoni : Immunity and pathology in a primary and a secondary infection following chemotherapy in the mouse and the baboo models
- 2000
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes a series of experiments aimed at elucidating the mechanisms ofimmunity and pathology elicited by both a primary infection and a reinfection exposure toSchistosoma mansoni following chemotherapy. The effects of a single large cercarial doseand a cumulatively equivalent dose, administered as multiple small doses are compared. Inaddition, the suitability of two animal models, a murine (BALB/c mice) and a non-humanprimate (Olive baboons, Papio cynocephalus anubis) for this purpose is evaluated. Duringthe primary infection, single-dose infected (SI) baboons developed more severe clinicaldisease than the multiple-dose infected (MI) group. Hepatic granulomata developed morerapidly and modulated more slowly in the SI group than in the MI group. Intestinal lesions inthe infected baboons included smooth muscle hypertrophy, villous atrophy and goblet cellhyperplasia, which were all less severe in baboons previously immunised with irradiatedcercariae. High tissue eosinophilia and recruitment of giant cells was observed in modulatingbaboon granulomata. By contrast, fibroblasts and collagen around the schistosome eggs werethe features of modulating mouse granulomata. In both animal models, reinfection followingchemotherapy resulted in reduced morbidity compared to a primary infection and a primaryMI dose elicited a T helper (Th) 2 cell associated immune response on reinfection. A primarySI dose in mice, however, led to a dominant Th1 response. Baboons exposed to multipleinfections, both prior to and following chemotherapy, developed peri-portal fibrosis. Insummary, i) variation in cercarial exposure contributes to the heterogeneity of the immuneresponse and morbidity ii) although the consequences of reinfection exposures are milder, they may be associated with increased risk for the development of hepatic fibrosis and iii)regarding the pathogenesis of natural schistosome infections, particularly repeated infections,the baboon is a better model than the mouse.
|
|
| 9. |
- Guhad, Faisal Abdi
(författare)
-
Development and validation of a localized murine candidiasis model : The pathogenesis, chemotheraphy and defense mechanisms to Candida mastitis in the lactating mouse
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A murine model of localized candidiasis (mastitis) was developed. The model was analyzed withrespect to its discriminative abilities through investigation of the virulence properties of C.albicans mutant strains compared with the wild-type parental strain. Further validation of themodel was undertaken by assessment of pathogenesis, chemotherapy (amphotericin B andfluconazole) and complement activation using immunocompetent BALB/c mice, SCID andathymic nude mice. Six to eight week old mice were time mated. The pups were allowed to suckleup to day five post partum, at which time the lactating glands were inoculated with between 104 to109 cells of Candida. The animals were euthanized after 1-6 days of infection. The mammaryglands and several other organs were evaluated histopathologically. In the chemotherapy studies,the mammary glands were homogenized and fungal burden determined through culture of differentdilutions of the homogenate. Except in the very high inocula dose, the fungi were confined to themammary gland tissues. The infection remained localized and was most severe in SCID, followedby immunocompetent and athymic nude mice, in that order. The severity of pathological changes,which consisted of infiltration with neutrophils, necrosis and abscess formation, was exacerbatedby increasing the number of cells and/or the duration of infection in the untreated control animals.Animals infected with virulence factor knock-out strains showed reduced or no lesions while themajority of the animals infected with the wild-type strains showed severe lesions. In theamphotericin B treated animals, only mild pathological changes were seen compared to theinfected controls. Fluconazole treatment was ineffective in the treatment of mastitis. Complementfactor C3c levels were elevated and correlated to the severity of inflammation in all theexperiments and were significantly reduced by amphotericin B but not by fluconazole treatment.Conclusions: i) the murine mycotic mastitis is a discriminative model of localized candidiasis ii)severity of infection is dose- and duration-dependent iii) antifungal drugs can significantly reducefungal burden in the mammary gland and iv) there are other immune mechanisms that protect miceagainst dissemination of infection than T and B cell immunity.
|
|
| 10. |
- Gutiérrez, Antonio M.
(författare)
-
Studies of nucleotide receptors-induced calcium response in glomerular mesangial cells and afferent arterioles
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is known that intracellular calcium concentration ([Ca2+]i) changes in rat glomerular mesangial cells (GMC) and rabbit afferent arterioles (AA) in response to extracellular nucleotides. We studied the nucleotide-induced calcium response in cultured GMC and AA. We characterized the response of GMC to extracellular nucleotides at the single cell level and in first passage cells. GMC basal [Ca2+]i was always between 70-90 nM. The cells responded to 0.1 mM ATP or UTP with a biphasic [Ca2+]i increase. The order of efficacy of nucleotide agonists was UTP = ATP > ATPγS > ADP = 2MeS-ATP, Adenosine, AMP and β,γ-Me-ATP had no effect. Consecutive ATP challenges induced receptor desensitization. Stimulation of PKC (PMA) abolished responses to ATP or UTP. Inhibition of PKC (chelerythrine) in contrast prevented desensitization. The desensitization was reversed by 4-min incubation with PDGF-BB or insulin. Theinfluence of protein phosphatases (PP) on receptor desensitization and on insulin-induce resensitization was studied using the PP inhibitors okadaic acid and cypermethrin. Internalization of nucleotides receptors was blocked with hyperosmotic sucrose solution. The calcium response of freshly dissected AA to adenosine, ATP and UTP was characterized in defined proximal and distal AA regions.The results show that: (i) GMC express P2Y2 receptor subtype. (ii) Desensitization is mediated by PKC and resensitization is modulated by growth factors. (iii) PP2B antagonizes desensitization. PP1 is involved in the insulin-induced resensitization. Internalization is a prerequisite for resensitization. (iv) P1 and P2X receptors are present along AA and both, mediate calcium mobilization with no difference in distribution in the proximal and distal AA segments.
|
|
