| 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. |
- 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.
|
|
| 4. |
- Schagatay, Erika
(författare)
-
The human diving response : effects of temperature and training
- 1996
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim was to elucidate the cardiovascular response associated with breath-hold diving, especially the effects of temperature in its elicitation and the effects of different types of training on the human diving response (DR) and breath-holding time (BHT), and to evaluate the human DR in a mammalian perspective. A model for simulated diving by apnea and facial immersion in cold water was developed. Cardiovascular parameters were registred using non-invasive techniques. The bradycardia response to breath-holding and chilling of the forehead was found to be more pronounced than that obtained when other facial areas of the same size were chilled, indicating that the ophthalmic branch of the trigeminus nerve is the main sensory area for initiating bradycardia in humans. It was found that both water temperature and ambient air temperature had significant, but opposite, effects on the magnitude of bradycardia developed at apneic face immersion, and the results indicate that diving bradycardia is negatively correlated to wate temperature within a range that is determined by the ambient air temperature. Furthermore, it was found that there is an increase in BHT over five dives when diving is repeated with short intervals, due to a delay of the the physiologi- cal breaking point (PBP) up to dive three, while to an increased tolerance by the subject up to dive five. It was conclude that an increased diving response is not the cause of the prolonged BHT seen in repeated diving, as has been suggested. A positive correlation between individual BHT and maximum bradycardia at repeated diving was found. There was also a positive correlation between mean bradycardia, skin capillary blood flow reduction and BHT on the group level, with the trained divers showing the most pronounced DR and the longest BHT. In trained divers the increase in diving bradycardia seen during apnea with face immersion compared to during apnea in air was accompanied by an increase in diving time, which was not seen in untrained subjects. Physical training leading to increase in maximal oxygen uptake does not increase the time before the PBP or the diving bradycardia. However, the tolerance to IBM appears to be en- hanced after physical training, which prolongs the BHT. Apnea training leads to a delay of the PBP and an increased diving bradycardia and BHT, and may be an essential factor in dive training. It was concluded that a pronounced DR is not only genetically determined but appears as a result of training and disappears as a result of aging. Taken together, data suggest that the human DR may have an 02 conserving effect in trained divers. The mean DR of trained human divers is in the range of that of the beaver, a semiaquatic mammal, while that of untrained humans is in the range of the pig, a terrestrial species. It is hypothesized, based on the results concerning temperature dependence of the trigemi- nus cold-response in adults, that this response may be involved in the events leading to sudden infant death syndrome.
|
|
| 5. |
- Kim, Sea-Yong, 1987-
(författare)
-
The neurotoxin β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) : possible risk of human exposure, and the effect and function in diatoms
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The toxic secondary metabolites β-N-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB) produced by phytoplankton groups such as cyanobacteria, diatoms and dinoflagellates are known to cause neurotoxicity in vertebrates. BMAA has been linked to development of the neurodegenerative diseases amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) and Alzheimer's disease. Despite these risks, previous studies have focused mostly on food webs in aquatic ecosystems as a possible source of human exposure to BMAA and DAB. Moreover, most studies in regard to the producer of BMAA and DAB are biased towards cyanobacteria.The first aim of this thesis was to investigate the possible risk of human exposure to BMAA via the agro-aqua cycle that artificially interconnects agriculture and aquaculture. Two groups of commercial chickens, fed on either standard feed or standard feed mixed with blue mussel meat, were investigated. The results show that BMAA can be transferred to and accumulated in the chickens through the mixed fodder. It has been suggested that the consumption of chicken may cause a risk of human exposure to BMAA if the chickens are fed with the fodder mixed with mussel meat (Paper I).The second aim was to assess the effect of biotic stresses (i.e. predation, competition) as possible causative factors to regulate the production of BMAA and/or DAB in diatoms, and assess the toxic effect of BMAA and/or DAB on predator and competitor (if specific production patterns occur for either toxin). The production of DAB was specially regulated only in the diatom T. pseudonana as responses to the predation and the competition. The toxic effect of DAB was significant on the population growth of the copepod Tigriopus sp. as predator, and the growth of cell numbers in T. pseudonana as competitor. However, given the environmental relevance of the DAB effect, the results suggest that DAB may play an important role in the defense mechanisms of the diatom T. pseudonana (Paper II and III).The last aim was to study the effect and function of BMAA in the diatom Phaeodactylum tricornutum. P. tricornutum was exposed to different concentrations of BMAA. The results showed concentration dependent responses to BMAA. The following were observed when the growth (i.e. cell number) of P. tricornutum was arrested due to exogenous BMAA; oxidative stress, reduced carbon fixation, increase in intracellular Chl a, alterations in GS-GOGAT, and suppressed urea cycle. The results suggest that BMAA represents a toxic secondary metabolite capable of controlling the growth of P. tricornutum via oxidative stress and alterations in the activity of photosynthesis and nitrogen metabolism (Paper IV).
|
|
| 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. |
- Nilsson, Linnéa
(författare)
-
Studies on the Role of Apoptosis in Kidney Diseases
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis is one of the most common types of cell death. Under physiological conditions, it plays an essential role in removal of damaged and potentially harmful cells. Excessive apoptosis has however been linked to a number of diseases including proteinuric kidney disease and DKD, and is believed to enhance the disease progression. Albuminuria and hyperglycemia are common symptoms of these diseases and albumin and high glucose have been seen to trigger intrinsic apoptosis in renal cells. Ouabain, a cardiotonic steroid, has previously been identified as an antiapoptotic agent that in subsaturating concentrations protect from intrinsic apoptosis. The mechanism of the protective effect of ouabain is still not fully understood and it remains to be concluded whether ouabain can protect from albumin and/or glucotoxic-triggered apoptosis.In study I we investigated the protective effects of ouabain in albumin-exposed primary rat PTC and podocytes and in the proteinuric kidney disease animal model passive Heymann nephritis. By reestablishing the balance between the proapoptotic protein BAX and the antiapoptotic protein BCL-XL, ouabain averted the albumin-triggered apoptosis in vitro and in vivo and protected from podocytes loss and glomerular-tubular disconnection.In study II we investigated the relationship between the glucose transporters renal cells express and their susceptibility of glucotoxic-triggered apoptosis. We identified the SGLT expressing cells, PTC and MC, to be more susceptible to high glucose-induced apoptosis than cells without SGLT. The apoptosis was mediated by BAX and BCL-XL imbalance and mitochondrial dysfunction, and was abolished when treated with ouabain or SGLT inhibitors. Podocytes, which lack SGLT, did not respond to short-term high glucose exposure.In study III we used super-resolution microscopy to investigate at which stage of the apoptotic process ouabain start to intervene. Ouabain interfered early in the apoptotic process, where it prevented activation of the sensitizer protein BAD. This allowed BCL-XL to avert BAX activation and translocation to mitochondria and thereby protected from mitochondrial dysfunction and apoptosis.In study IV we investigated differentially expressed genes between renal cortex and primary short-term PTC cultures and between PTC exposed to control and high glucose. The mRNA expression level of most genes was significantly up- or downregulated in PTC compared to renal cortex, with the biggest differences in mitochondria and metabolism related genes. Early state glucotoxicity did not significantly alter mRNA expression levels in PTC.
|
|
| 9. |
- Lindberg, Frida A.
(författare)
-
The Biological Importance of the Amino Acid Transporter SLC38A10 : Characterization of a Knockout Mouse
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The biggest group of transporters, the solute carriers (SLCs), has more than 400 members, and about 30% of these are still orphan. In order to decipher their biological function and possible role in disease, there is a need for characterization of these. Around 25% of SLCs are estimated to have amino acids as substrates, including transporters belonging to the SLC38 family. The SLC38 members are sometimes referred to their alternative name: sodium-coupled neutral amino acid transporters (SNATs). One of these transporters, SNAT10 (or SLC38A10), has been characterized as a bidirectional transporter of glutamate, glutamine, alanine and aspartate, as well as having an efflux of serine, and is ubiquitously expressed in the body. However, its biological importance is not yet understood. The aim with this thesis was to characterize a mouse model deficient in SNAT10 protein in order to find the biological importance of this transporter. In paper I, this is done by using a series of behavioral tests, including the open field test, elevated plus maze, rotarod and Y-maze, among others. The SNAT10 knockout mouse was found to have an increased risk-taking behavior, but no motor or spatial working memory impairments. Furthermore, the knockout mouse was found to have a decreased body weight. In paper II, an additional behavioral characterization was performed by using the multivariate concentric square field™ (MCSF) test. The MCSF test is an arena with different zones associated to different behavioral traits, which generates a behavioral profile depending on where the mouse spends its time. The result from this test implies that the SNAT10 deficient mouse has a lower explorative behavior than its wild type littermates. In paper III, gene expression was studied in whole brain and some genes related to cell cycle regulation and p53 expression were found to be differentially expressed in the knockout brain. Additional gene expression was studied in kidney, liver, lung and muscle, but no changes were found. Plasma levels of histidine and threonine were altered in males, but no altered amino acid levels were found in knockout females, suggesting a possible sex-specific effect. These studies together imply that SNAT10 might be involved in processes related to risk-taking and explorative behavior in the open field and MCSF tests. SNAT10 deficiency also affected amino acid levels in plasma, indicating a disrupted amino acid homeostasis.
|
|
| 10. |
|
|
