| 11. |
- Koppel, Lina, 1988-
(författare)
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Pain, Touch, and Decision Making : Behavioral and Brain Responses to Affective Somatosensory Stimulation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stimulation of sensory nerves can give rise to powerful affective experiences. Noxious stimuli can give rise to pain, an unpleasant experience which, in turn, causes suffering and constitutes a major societal burden. Touch, on the other hand, can feel pleasant and plays an important role in social relationships and well-being. Slow, gentle stroking of the skin in particular has been shown to activate C-tactile (CT) afferents, which are thought to signal affective and socially relevant aspects of touch. However, little is known about how pain and affective touch influence everyday decision making.In Paper I, we investigated the effect of acute physical pain on risk taking and intertemporal choice. Participants (n = 109) performed a series of economic decision-making tasks, once while experiencing acute thermal pain and once in a no-pain control condition. Results indicated that pain increased risk taking for monetary gains but not for equivalent losses, and increased impatience.In Paper II, we investigated the effect of affective touch on betrayal aversion, altruism, and risk taking. Participants (n = 120) performed a series of economic decision-making tasks, once while being stroked on the forearm at CT-optimal speed using a soft painter’s brush and once in a no-touch control condition. Results indicated no effect of affective touch on any of the outcome measures.In Paper III, we investigated how the ability to affect an upcoming painful event via voluntary action influences cortical processing of ongoing somatosensory stimulation. fMRI data was collected from 30 participants while they performed a task that involved pressing a response button to reduce the duration of upcoming thermal stimuli. Whole-brain analyses revealed no significant task-related effects in brain regions typically involved in pain, except activation in a cluster in anterior cingulate cortex (ACC) was greater when upcoming stimulation was painful than when it was nonpainful. However, region-of-interest analyses in anterior insula (AI) and midcingulate cortex (MCC) indicated that the noxious nature of the upcoming stimulation, as well as the ability to affect it, influenced processing of ongoing stimulation in both of these regions. Activation in MCC, but not AI, also correlated with response times.Taken together, these studies contribute to the broader understanding of everyday decision making, and of how affective experiences such as pain and touch shape everyday decisions and behaviors.
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| 12. |
- Larsson, Johan, 1990-
(författare)
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Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ion channels are membrane proteins that regulate the permeability of ions across the cell membrane. The sequential opening of different types of ion channels produces action potentials in excitable cells. Action potentials are a way for the body to, for example, transmit signals quickly over a long distance.The KV7 family is an important group of voltage-gated potassium channels. Mutations that cause dysfunction in members of the KV7 family are associated with several forms of disease. Compounds that can activate KV7 channels have previously been shown to work as medical treatments. However, the previously available antiepileptic drug retigabine, has been withdrawn due to adverse effects. Thus, there is a need for further development of compounds that target these channels. PUFA and PUFA analogs have previously been demonstrated to activate KV7.1 through an electrostatic mechanism. This thesis investigates new aspects of the interaction between KV7 channels and PUFA-related compounds.The data in this thesis are from human KV7 channels expressed in Xenopus laevis oocytes. The currents produced by the channels expressed in the oocytes have been studied using twoelectrode voltage clamp. Our aim was to study the mechanism for the activation of KV7 channels by PUFA and PUFA analogs. More specifically, we intended to study why the beta subunit KCNE1 abolishes the activating effect of PUFA on KV7.1 and how PUFAs activate KV7.2 and KV7.3. Additionally, we wanted to study aspects that may affect whether these compounds are viable as medical treatments. For instance, whether these compounds can activate channels containing disease-causing mutations and whether we can improve compound selectivity towards certain KV7 channels.In Paper I, we introduce disease-causing mutations found in patients into KV7.1 and KCNE1. The characterization showed that these channels had altered biophysical properties compared to wild type channels. A PUFA analog was found to activate and, to a large degree, restore wild type-like biophysical properties in the mutated channels regardless of the localization of the mutation in the channel.In Paper II, we demonstrate why PUFA is unable to activate KV7.1 co-expressed with beta subunit KCNE1. KCNE1 induces a conformational change of KV7.1 that moves the S5-Phelix loop closer to the PUFA binding site. This causes negative charges of the loop to attract protons that reduce local pH at the PUFA binding site. The decreased local pH leads to protonation of PUFA and the PUFAs therefore lose their negative charge. Thus, PUFA cannot activate KV7.1 when it is co-expressed with KCNE1.In Paper III, we study a group of PUFA-related substances, endocannabinoids, on KV7 channels. One endocannabinoid, Arachidonoyl-L-Serine (ARA-S), was identified as a potent activator of the neuronal M-channel, comprising KV7.2 and KV7.3 heteromers. We study the activating mechanism of ARA-S in KV7.2 and KV7.3, demonstrating how the activating effect is linked to two parts of the channel protein, one in the voltage sensor domain and the other in the pore domain. ARA-S was also found to activate KV7.1 and KV7.5 but not KV7.4, which instead was inhibited. Retigabine, a compound that activates the M-channel but has a different KV7 subtype selectivity compared to ARA-S, was used in combination with ARA-S to maintain a potent effect on the M-channel while limiting the activation of other KV7 channels.In conclusion, the activating effect of PUFA analogs on KV7 channels may be helpful in the development of future drug candidates for diseases such as arrhythmia and epilepsy.
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| 13. |
- Lindau, Robert, 1989-
(författare)
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Immune regulation at the foetal-maternal interface; implications for healthy and complicated pregnancies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- For a successful pregnancy, the maternal immune system must acquire tolerance towards the paternal antigens present in the semi-allogeneic foetus. This tolerance is mainly established locally at the foetal-maternal interface, where foetally-derived trophoblasts invade the maternal endometrium (called decidua during pregnancy) and come in close proximity to maternal immune cells. The decidua is populated by maternal immune cells of a unique composition, characterised by their suppressive phenotypes that are essential for maintaining tissue homeostasis. Accordingly, failure of immune tolerance can lead to pregnancy complications. Macrophages and regulatory T-cells are enriched in the decidua and are believed to play important roles in the establishment of tolerance. However, there is limited information regarding the factors that regulate their functions and if their function is compromised in pregnancy complications.The aim of this thesis was to further elucidate which factors are responsible for induction of the regulatory phenotypes of macrophages and T-cells found in the decidua, how tissue resident cells in the decidua contribute to this and if this system is compromised during pregnancy complications, such as preeclampsia and recurrent pregnancy loss.Decidual stromal cells (DSCs) constitute the largest population of tissue resident cells in the decidua. In an in vitro system of macrophage differentiation, we found that Isolated peripheral blood monocytes cultured in conditioned medium (CM) from DSCs acquired a high expression of the regulatory M2 markers CD163, CD209 and CD14, and a low expression of CD86, characteristics of decidual macrophages. This induction was in part mediated by macrophage-colony stimulating factor (M-CSF), as neutralising its effects reduced the expression of CD163. However, since only a partial reduction was reached, other factors are involved. Another likely candidate for this polarisation is interleukin (IL)-34, a second ligand for the M-CSF receptor. We showed that IL-34 is expressed by both DSCs and the foetal placenta. Further, in vitro, IL-34 was able to induce macrophages with similar properties as that of M-CSF-induced macrophages, with high expression of CD163, CD209 and CD14. This was also coupled to a cytokine secretion profile similar to M-CSF-induced macrophages, with high production of IL-10, low production of tumour necrosis factor (TNF) and no production of IL-12. We found no evidence of IL-34 being aberrantly expressed in placentas from preeclamptic women.In addition to promoting induction of macrophages with a regulatory phenotype, CM from DSCs promoted expansion of Foxp3+CD25bright regulatory T (Treg) cells in an in vitro polarisation system, in a SMAD3 dependent manner. Protein profiling of DSCs revealed limited production of the Th2 related IL-13, IL-4, IL-33 and thymic stromal lymphopoietin (TSLP), as well as no production of the Th17 related IL-17A and chemokine (C-C motif) ligand (CCL) 20. Instead we found that DSCs were more prone to production of regulatory factors, such as M-CSF, leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)-β, albeit with addition of the more pro-inflammatory IL-6, chemokine (C-X-C motif) ligand (CXCL) 8 and the Th1-related CXCL10.We also investigated if the placenta´s ability to induce Treg cells and regulatory M2 macrophages is compromised in women with a history of unexplained recurrent pregnancy loss (uRPL) and if the placental secreted protein profile is skewed to a pro-inflammatory response in uRPL. Using surplus materials from chorionic villous sampling (CVS), we generated CM from placental tissue taken from healthy and uRPL pregnancies and used this to polarise macrophages and T-cells in vitro. We found no difference in the ability to induce Treg cells and regulatory M2 macrophages between the healthy group and the uRPL group. Likewise, no differences in the protein profile was observed between the two groups.Taken together, our findings imply that DSCs produce a variety of factors promoting foetal tolerance by induction of Treg cells and regulatory M2 macrophages. Furthermore, we also showed that the placenta retained its ability to induce Treg cells and regulatory M2 macrophages in women with a history of uRPL.
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| 14. |
- Lindgren, Anna, 1981-
(författare)
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Incontinence, physical activity, and pelvic floor muscle training in female pelvic cancer survivors after radiotherapy
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cancer treatment continues to improve, contributing to an ever-growing population of cancer survivors. Pelvic cancer survivors (PCS) constitute the second largest group of female cancer survivors after breast cancer. Many female PCS have been treated with radiotherapy as a part of their cancer treatment. Unfortunately, like all effective cancer treatments, pelvic radiotherapy is associated with a risk of subsequent, unwanted side effects. Some side effects remain or persist long after the end of treatment and some are even lifelong. A common and burdensome side effect after pelvic radiotherapy is urinary and/or fecal incontinence. Incontinence is known to negatively affect quality of life (QoL) and physical activity levels. Physical activity contributes to several positive health effects. In cancer survivors, it may reduce the risk of recurrence and even the mortality risk. Cancer survivors in general, and female PCS in particular, tend to be less physically active after cancer treatment than before treatment. When suffering from urinary and even fecal incontinence, pelvic floor muscle training (PFMT) is recommended as a first-line treatment for the general population. In addition to decreased incontinence levels, PFMT may contribute to increased physical activity and better QoL. However, little attention is given to PFMT as a potential treatment for incontinence in the Swedish national care program for pelvic cancer rehabilitation. Furthermore, there is as yet no evidence that PFMT is as effective in female PCS as in female non-cancer survivors. The effectiveness of PFMT cannot be taken for granted because female PCS survivors often have treatmentinduced damage to structures in the pelvic floor that might affect its applicability. However, the problem of incontinence among female PCS remains, along with the fact that they tend to be less physically active than other cancer survivors. Indeed, this is an important research area and a necessary problem for health-care providers to resolve, not least for physiotherapists.Aim: The overall aim of this thesis is to improve the understanding of female PCS’ experiences of incontinence in relation to physical activity, QoL, and rehabilitative efforts, including PFMT. This includes gaining increased knowledge about the relation between incontinence and physical activity in the form of exercise and QoL, and whether PCS experience that physiotherapy contributes in a valuable way to reducing their incontinence. This could enable the development of meaningful physiotherapeutic interventions, that PCS can and are willing to engage in, to achieve a potential reduction in incontinence, as well as increased QoL and activity levels.Methods: The thesis includes four different studies, using three different methods, all conducted with female PCS. Studies I (n=13) and IV (n=11) are qualitative individual interview studies, using semi-structured interview guides. Study II is a cohort-based cross-sectional observational study (n=578) and Study III is a prospective cohort-based observational study (n=260).Results: Female PCS reported an absence of information regarding incontinence as a potential side effect of radiotherapy treatment. They experienced that incontinence prevented them from being as physically active as before treatment, and that incontinence of urine and feces impaired several aspects of QoL, including sexual health. They lacked potential rehabilitative options beyond conventional pelvic cancer rehabilitation. After practicing PFMT for three months, they found it a valuable rehabilitative measure for incontinence. They also experienced the physiotherapeutic support and guidance as valuable in teaching them how to contract the pelvic floor muscles correctly and providing individual guidance regarding dose, frequency, and progression of the training. In Study II, 67% of female PCS exercised at least once a week, while 33% exercised less than once a week. Women who reported leakage of large or all volume of feces (multivariable analysis) were statistically significantly more likely to exercise less than once a week. A similar co-variation was seen among women who reported leakage of moderate to large volumes of urine (univariate analysis). This, however, was not statistically significant in a multivariable analysis. When exercising on a weekly basis, they reported less frequently depressed mood and better QoL, compared to those who exercised less than once a week. Three months after an individually designed intervention program, in line with the conventional pelvic cancer rehabilitation offered within Swedish healthcare today, female PCS reported statistically significantly lower levels of urinary and fecal incontinence. However, no statistically significant changes in frequency of exercise were seen.Conclusion: Incontinence was a barrier to physical activity and exercise, and it reduced QoL and impaired sexual health in female PCS. When experiencing incontinence, and in particular fecal incontinence, female PCS were less likely to exercise on a weekly basis. Female PCS who exercise at least once a week experienced better QoL and less frequently depressed mood than PCS who were not exercising every week. Female PCS did not exercise more often after conventional pelvic cancer rehabilitation, not even after incontinence levels were reduced. Female PCS had a positive attitude towards PFMT. After at least three months’ experience of practicing PFMT, they found it a valuable rehabilitative effort for incontinence. They also found physiotherapeutic support and guidance to be of great importance. Female PCS expressed a need for better information routines regarding side effects, such as incontinence, after cancer treatment. They also expressed a need for better information routines, including accessibility of additional rehabilitative efforts, beyond the conventional pelvic cancer rehabilitation offered today, when suffering from incontinence of urine and/or feces.
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| 15. |
- Lundqvist, Martina, 1986-
(författare)
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Health Technology Assessment of Assistance Dogs and Dog-Assisted Interventions
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dogs as an assistive aid for people with disabilities date as far back in time as the first century CE. Today, dogs are used in various settings to help and assist humans. ‘Assistance dogs’ is an umbrella term for guide dogs, hearing dogs and service dogs. They are custom trained to help and support their owners in their everyday life and thereby give them greater independence. Dogs who perform dog-assisted interventions are another type of working dog, where the dog and the owner work together as a team visiting people with various needs in different settings such as hospitals and nursing homes. These visits aim to strengthen people’s inner motivation, using the dog as an external motivator. There is a lack of evaluations of working dogs in the health technology assessment context, and in the health economic evaluation context. Hence, there is a need for structured analyses that include both the short and long-term effects and the costs of assistance dogs and dog-assisted interventions.The overall aim of this thesis is to explore and assess the use of assistance dogs and dog-assisted interventions.The research questions were investigated using a variety of methods. In paper I, inferential statistical analysis was used to analyse patient-reported outcomes measures. In paper II, a thematic content analysis was employed to explore the experiences of service and hearing dogs. To study the long-term cost-effectiveness of physical service dogs and diabetes alert dogs, a decision analytic model was used in paper III. The input data in studies I, II, and III was obtained from the Service and Hearing Dog Project. In paper III, the data was also supplemented with information from published literature and expert opinions. Paper IV investigated the effects and cost-effectiveness of dog-assisted interventions, and takes the form of a systematic review.Paper I showed that a service or hearing dog may have positive impact on its owner’s health-related quality of life, well-being and activity level. Paper II showed that owners of service or hearing dogs experienced both positive physical and psychosocial effects from their dog. Negative experiences were also identified, for example being denied access to public places and negative attitudes from other people. Paper III showed that physical service dogs and diabetes alert dogs are cost-effective in comparison with regular companion dogs, resulting in both lower costs and a gain in QALYs. The one-way sensitivity analysis did not change the results, but the probabilistic sensitivity analysis showed that the results were uncertain. Synthesizing the results from the review in paper IV showed that dog-assisted interventions for therapeutic purposes led to minor to moderate effects in psychiatric conditions. Dog-assisted interventions as an activity had minor to moderate effects on cognitive disorders, and dog-assisted interventions for support purposes were beneficial in different types of medical interventions. Studies of cost-effectiveness were lacking. To conclude, assistance dogs are valuable and may be cost-effective for use as assistive aids and dog-assisted interventions render minor to moderate effects in certain situations in healthcare settings.
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| 16. |
- Mirrasekhian, Elahe, 1978-
(författare)
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Immune-to-Brain Signaling in Fever : The Brain Endothelium as Interface
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever is a brain-regulated elevation of body temperature that occurs in response to infectious and non-infectious stimuli. During inflammatory episodes, circulating cytokines that are released by activated immune cells, trigger the induction of cyclooxygenase (COX)-2 in the ventromedial preoptic area of the hypothalamus (the thermoregulation center). COX-2-dependent-prostaglandin (PG)E2 synthesis is essential for the generation of fever and upon an immune challenge, it is induced in several cells within the brain including the brain endothelial cells and perivascular macrophages. However, due to lack of experimental models with cell type-specific modulation of PGE2 synthesizing enzymes, the cellular source of pyrogenic PGE2 and its induction mechanism(s) remained obscure. Using such technology, we showed that the brain endothelium is the cellular source of pyrogenic PGE2 and that activation of brain endothelial IL-6 receptors by circulating IL-6 is critical for the PGE2 induction.Inhibition of PGE2 synthesis is assumed to be the mode of action of many antipyretic drugs, possibly including paracetamol. Given that paracetamol at a high dose has been shown to induce hypothermia by activation of the transient receptor potential ankyrin 1 (TRPA1) ion channel, we examined whether the antipyretic effect of paracetamol is also TRPA1 dependent. Our findings revealed that the antipyretic effect of paracetamol is independent of TRPA1 and associated with inhibition of the PGE2 synthesis in the brain.This thesis provides new insight into the molecular mechanism behind the febrile response in which the peripheral circulating IL-6 communicates with the brain by induction of pyrogenic PGE2 in the brain endothelium. It also demonstrates that the antipyretic effect of paracetamol is exerted by inhibition of the PGE2 synthesis in the brain.
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| 17. |
- Moberg, Anna, 1976-
(författare)
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Diagnosing pneumonia in primary care : Aspects of the value of clinical and laboratory findings and the use of chest X-ray
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is important to identify patients with pneumonia because it is potentially a serious disease, often of bacterial origin, that should be treated with antibiotics. It is equally important to identify those with acute bronchitis, a self-limiting disease, that should not be treated with antibiotics. Because bacterial resistance is increasing, over-prescribing of antibiotics should be avoided. However, it is sometimes difficult to differentiate between the two diagnoses, and guidelines concerning the assessment do not conform. The general aim of this thesis was to investigate if diagnostics of pneumonia in primary care can be improved and whether this could contribute to reduced prescription of antibiotics. As a first step, different anamnestic, clinical and laboratory findings and the doctor’s degree of suspicion of pneumonia in primary care were compared with chest X-ray (CXR) findings. The doctor’s degree of suspicion of pneumonia was shown to be a good predictor. When the physician was sure of the diagnosis, the likelihood for radiographic pneumonia was high and when quite sure, CXR was positive in less than half of the cases. To further improve the diagnostics of pneumonia, and thus reduce antibiotic prescriptions, patients were referred for CXR when the physician was unsure or quite sure of a pneumonia diagnosis. The intervention did not result in any decrease in antibiotic prescriptions compared with a control group. However, it emerged that the physicians did not fully trust the CXR outcome, but prescribed antibiotics even when the results were negative. To gain insight into the contribution of C-reactive protein (CRP) levels to the degree of suspicion, physicians were asked to estimate their degree of suspicion of pneumonia before and after CRP testing. CRP affected the degree of suspicion to a great extent, and most often resulted in a lowered degree of suspicion and thereby in the clinical decision of dismissing the diagnosis of pneumonia. The use of different diagnostic tests and prescription of antibiotics in the assessment of acute bronchitis and pneumonia over time was evaluated in a register-based study. The study showed that the use of diagnostic tests for both diagnoses has increased, and that there has been a reduction in antibiotic prescriptions for acute bronchitis. In conclusion, the doctor’s degree of suspicion of pneumonia seems to be a good predictor of the condition. When the physician is sure of the diagnosis, no further investigation is needed, and antibiotics can be prescribed on reliable grounds. CRP testing affects the degree of suspicion and is most valuable when unsure of the diagnosis where it can be helpful to exclude pneumonia. In contrast, more extensive use of CXR does not contribute to a decrease in antibiotic prescriptions in the diagnostics of pneumonia.
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| 18. |
- Mofers, Arjan, 1990-
(författare)
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Proteasome Inhibitors against Cancer: Determining Biology and Finding Novel Compounds
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer continues to be a tremendous burden on society in terms of loss of quality of life and life-years. The ubiquitin proteasome system (UPS), responsible for the bulk of protein turnover in the cell, is considered an attractive target in cancer therapy. The proteolytic subunit of the UPS, the 20S, is targeted by three clinically approved anti-cancer drugs: Bortezomib, Carfilzomib, and Ixazomib. Proteins destined for degradation by the UPS are tagged with small protein ubiquitin. The 19S regulatory cap is responsible for recognition and processing of these ubiquitinated substrates, followed by proteolysis by the 20S. Deubiquitination by proteolytic enzymes of the 19S is an essential step in the progression of substrates to progress into the 20S. Our strategy is to pharmacologically inhibit the deubiquitinating enzymes associated with the 19S with the goal of disrupting the degradation of substrates. In Paper I of this thesis, we explore the occurrence of resistance to the 19S deubiquitinating enzyme inhibitor b-AP15. We find that minimal resistance to this compound occurs, and the small observed induction of resistance is likely mediated by glutathione. We also find that cells that are slow- or non-cycling are particularly insensitive to the treatment. In Paper II we employ screening methods based on the chemical properties of b-AP15 and find that a small subset of the screened compounds are relatively selective UPS inhibitors. In Paper III we employ a different screening methods, based on the gene expression profiles associated with disruption of the UPS. This screen finds several compounds with previously described UPS inhibitory effects but also compounds with different proposed mechanisms of action. In both Paper II and Paper III we reflect on the chemical structure of the compounds and challenges that come with chemical groups that are potentially promiscuously reactive. In Paper IV we explore the validity of b-AP15 as a treatment for acute lymphoblastic leukemia, a form of cancer for which the efficacy of b-AP15 has not been fully elucidated. This thesis contributes to the body of work supporting 19S inhibition in general, and 19S inhibition with b-AP15 in particular, as a promising modality for the treatment of cancer.
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| 19. |
- Norlin, Anna-Karin, 1977-
(författare)
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Exploring the Biopsychosocial Model in Irritable Bowel Syndrome : with emphasis on stress, comorbidities and fatigue
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIrritable bowel syndrome (IBS) is a common, chronic, relapsing, and sometimes disabling, symptombased disorder of gut brain interactions. It has got a female predominance and occurs in all ages, with a slight decrease among elderly. The IBS symptoms can affect everyday work and social life in addition to an increased use of health care resources. Most IBS patients are diagnosed and helped in primary health care (PHC). For many patients, available treatment is insufficient. It is known that both extraintestinal symptoms such as fatigue, as well as comorbidities such as mood disorders, chronic pain syndromes, and insomnia contribute to the illness burden, often to a larger extent than the gastrointestinal symptoms as such.Even though the pathophysiology of IBS is not completely known, it is now conceptualized as a disorder of altered brain-gut interactions, where a biopsychosocial model helps in understanding the symptoms. Exposure to stress is thought to play an important role overall in the pathology of IBS, as well as immune activation at least in a subgroup of patients.This thesis aimed to gain deeper understanding of the biopsychosocial mechanisms of IBS and its associations with stress, comorbidities, and fatigue.Methods Study I and II are based on the Twin cities IBS study population, which included IBS patients and a control group of other patients without gastrointestinal complaints from ten PHC centres in the county of Östergötland. Alongside demographics, psychosocial questionnaires and a GI symptom diary, it included analyses of hair cortisol concentrations (HCC) evaluated in study I, and data on self-rated health as well as diagnoses of comorbidities, and number of health care contacts from a regional registry, evaluated for study II.Study III of this thesis is based on the Brain-Gut study with a population of secondary care IBS patients, and healthy controls (HC). It included self-rated measures of fatigue impact on the daily life and early adverse life events, as well as measures of circulating TNF-α, and analyses of resting-state functional magnetic resonance imaging of brain areas within a mesocorticolimbic circuitry of known relevance for fatigue.Results Study I: Perceived stress was higher in the IBS group while a considerable portion of IBS patients had low levels of HCC. No association between perceived stress and HCC was seen in either group.Study II: IBS patients had lower self-rated health and more PHC utilization than the non-IBS patients. Good self-rated health was independently associated with younger age, higher sense of coherence and less gastrointestinal pain in both groups. In IBS, PHC utilization was associated with comorbidities in general, and sleep disorders in particular.Study III: Fatigue impact on daily life, and TNF- α were higher in IBS patients than in HC. In IBS, further an association was seen between fatigue impact on the one hand, and TNF- α, emotional abuse in childhood, as well as altered mesocorticolimbic connectivity on the other.Conclusion In conclusion this thesis firstly emphasizes that IBS patients in many ways, including health outcomes, consists a vulnerable group of PHC patients. We add evidence for a possible suppression of the stress response system in a substantial portion of IBS patients.Further, comorbid sleep disorders seem to be particularly associated with excess PHC utilization in IBS and could possibly be a target for treatment interventions. Moreover, alongside treating gastrointestinal pain, efforts to improve the individuals’ sense of coherence could be one way to achieve better self-rated health in both IBS and non-IBS patients.Finally, we suggest that fatigue in IBS is associated with immune activation, central alterations and to some extend also previous childhood trauma.
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| 20. |
- Pupkaite, Justina, 1988-
(författare)
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Collagen Hydrogels for Regenerative Medicine
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The need for regenerative therapies to repair damaged or deteriorated organs and tissues, such as heart, skin, and cornea, is rising due to donor shortage and aging of the world’s population. Many proposed regenerative therapeutic approaches include a combination of cells, bioactive compounds, and hydrogels. Although collagen hydrogels have shown a lot of promise in regenerative medicine research, there are still challenges in their design and application strategies. Therefore, this thesis describes the development of novel collagen hydrogel designs for improved use in tissue bonding, cell delivery, and myocardial infarction therapy applications.Firstly, a visible-light crosslinked collagen hydrogel for tissue photobonding was developed. Methacrylated collagen hydrogel was crosslinked using the photoinitiator rose Bengal and visible light. The properties of the resulting hydrogel were tunable by changing the hydrogel composition. Biomimetic and ex vivo skin models were used to demonstrate the ability of the hydrogel to bond tissues whose edges are separated. Additionally, using the hydrogel led to less scarring compared to traditional sutures in a mouse skin incision model.Secondly, collagen was modified with thiol groups to design a hydrogel crosslinked using the thiol-Michael addition click reaction for cell encapsulation and delivery. The hydrogels demonstrated excellent shear-thinning and self-healing properties, allowing for injection after the crosslinking was complete. Additionally, the hydrogels showed minimal swelling and maintained their shape in an aqueous buffer for a prolonged period. Cell encapsulation and delivery using the hydrogels was demonstrated in vitro with mesenchymal stromal cells and endothelial cells.Thirdly, recombinant human collagen III hydrogels were prepared by crosslinking the collagen with EDC and NHS. The hydrogels contained either 1% or 2% collagen. Therapeutic strategies for these hydrogels were investigated, including the timing and dosage of the treatment, in a mouse MI model. Comparing 1% hydrogel injection at a single early time point (3 h) and three time points (3 h, 7 and 14 days) post-MI revealed improved cardiac function, reduced scar size and inflammation, and increased vascularization in the single injection group. Additionally, increasing the collagen III dose to 2% in the hydrogel at a single early time point (3 h) injection did not confer any additional functional improvement compared to 1% and resulted in scar size and vascular density comparable to control (PBS injection). In summary, this work contributes to the development of collagen hydrogel therapies for regenerative medicine by presenting a visible-light crosslinked collagen hydrogel for tissue bonding, a novel click-crosslinked collagen hydrogel with excellent shear-thinning properties for cell delivery, and the use of a recombinant human collagen III hydrogel in post-MI therapy, highlighting the importance of optimizing the timing and dosage of biomaterial therapies.
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