| 1621. |
- Stålhammar, Maria
(författare)
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Neutrophil Chemotaxis and Respiratory Burst in Term and Preterm Newborn Infants
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neutrophil activation is the most important initial immune defense against invading microbes in newborn infants. The reduced neutrophil migration and uncontrolled regulation of reactive oxygen species (ROS) production observed in neonates, could result in a diminished infectious response or in tissue damage. The aims were to study neutrophil chemotactic response towards IL-8 and fMLP in term neonates; to examine neutrophil receptor expression involved in adhesion, migration, phagocytosis and complement after stimulation with IL-8 and fMLP in term neonates; and to investigate neutrophil production of ROS, induced by PMA and E.coli, after preincubation with IL-8 and fMLP in term and preterm newborn infants. Comparisons were made to neutrophils from healthy adults.Chemotaxis was distinguished from randomly migrating neutrophils, and the neutrophil migration distance and the number of migrating neutrophils per distance was evaluated. Neutrophils were labeled with antibodies to cell surface antigens (CD11b, CD18, CD65, CD15S, CD162, CD44, CD35, CD88, CD181, CD182 and CD64) after stimulation with IL-8 and fMLP. After preincubation of neutrophils with fMLP or IL-8 and stimulation with PMA or E.coli, respiratory burst was detected. The same analyses were also made in preterm infants (median 25+3weeks GA; range 23+0–29+2) within 3 days postnatal age.Neutrophils from neonates exhibited different migratory and receptor responses to IL-8 and fMLP, with a diminished response towards IL-8 in term newborn infants in terms of reduced chemotaxis and modulation of receptors involved in adhesion, chemotaxis, complement and phagocytosis as compared to adults. fMLP reduced PMA- and E.coli-induced respiratory burst in neutrophils from term neonates and adults. The reduced respiratory burst by fMLP may be a mechanism for reducing the detrimental effects of uncontrolled inflammation. Although a similar burst reduction was observed in preterm infants born >25 weeks GA with fMLP, a diminished neutrophil respiratory burst modulation in very preterm infants cannot be excluded and requires further studies at different gestational and postnatal ages.
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| 1622. |
- Ställberg, Björn, 1951-
(författare)
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Asthma in Primary Care : Severity, Treatment and Level of Control
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims. The overall aim was to examine the severity, treatment and level of control in patients with asthma in primary care in Sweden. The specific aims were to assess what matters to asthma patients, evaluate symptoms, medication and identify factors related to asthma severity, compare the extent of asthma control in 2001 and 2005, and investigate the development of asthma and degree of asthma control in adolescents and young adults who had reported asthma six years earlier. Methods. The first study was a telephone interview of a representative sample of Swedish asthmatics. In the second study a random sample of 1,136 patients answered two questionnaires. A classification of the asthma severity similar to that in the GINA guidelines was made. In the third study two surveys were performed, in 2001 and in 2005, with a random sample of 1,012 and 224 asthma patients, respectively, and a classification of asthma control similar to the recent GINA guidelines was made. In the fourth study 71 individuals who reported physician-diagnosed asthma in a population-based survey in 1997 and were defined as current asthmatics, were reinvestigated in 2003 with a skin prick test, methacholine challenge test, eucapnic voluntary hyperventilation test and measurement of exhaled nitric oxide. Results. Common situations causing symptoms of asthma were physical exertion and contact with pets. Nocturnal symptoms were frequent. In primary care 35% of the women and 24% of the men were classified as having severe asthma. Female sex, increasing age, not filling the asthma prescription owing to cost, daily smoking, and pollen allergy increased the odds of having severe asthma. In 2001, 37% had achieved asthma control, as compared with 40% in 2005. Uncontrolled asthma was more common in women and smokers. In the 2003 study of adolescents and young adults with asthma six years earlier, the definition of current asthma was fulfilled by 50 of the 71 subjects and one third had achieved asthma control. Conclusions. The majority of the asthmatics reported a large number of symptoms and limitations in their daily living. Many asthma patients in primary care have insufficient asthma control. One reason for lack of control might be undertreatment with inhaled corticosteroids.
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| 1623. |
- Suarez Sipmann, Fernando, 1966-
(författare)
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Titrating Open Lung PEEP in Acute Lung Injury : A clinical method based on changes in dynamic compliance
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The recognition that supportive mechanical ventilation can also damage the lung, the so called ventilation induced lung injury (VILI), has revived the more than 40 year long debate on the optimal level of PEEP to be used. It is established that the prevention of VILI improves patient outcome and that PEEP exerts protective effects by preventing unstable diseased alveoli from collapsing. Therefore, the term “open lung PEEP” (OL-PEEP) has been introduced as the end-expiratory pressure that keeps the lung open after its collapse has been eliminated by an active lung recruitment manoeuvre. The determination of such an optimal level of PEEP under clinical circumstances is difficult and remains to be investigated.The aim of this study was to investigate the usefulness of breath by breath monitoring of dynamic compliance (Cdyn) as a clinical means to identify OL-PEEP at the bedside and to demonstrate the improvement in lung function resulting from its application.In a porcine lung lavage model of acute lung injury PEEP at maximum Cdyn during a decremental PEEP trial after full lung recruitment was related to the onset of lung collapse and OL-PEEP could be found 2 cmH2O above this level Ventilation at OL-PEEP was associated with improved gas exchange, efficiency of ventilation, lung mechanics and less than 5% collapse on CT scans. In addition, dead space, especially its portion related to alveolar gas changed characteristically during recruitment, PEEP titration and collapse thereby helping to identify OL-PEEP.The beneficial effects of OL-PEEP on lung function and mechanics was demonstrated in a porcine model of VILI. OL-PEEP improved lung function and mechanics when compared to lower or higher levels prior to or after lung recruitment. By using electrical impedance tomography it could be shown that PEEPs within the range of 14 to 22 cmH2O resulted in a similar redistribution of both ventilation and perfusion to the dorsal regions of the lung. OL-PEEP resulted in the best regional and global matching of ventilation and perfusion explaining the drastic improvements in gas exchange. Also regional compliance was greatly improved in the lower half of the lung as compared to all other situations.In ARDS patients OL-PEEP could be identified applying the same protocol. The physiological changes described could now be reproduced and maintained during a four hours study ventilation period in real patients at four study centres.In conclusion, the usefulness of dynamic compliance for identifying open lung PEEP during a decremental PEEP trial was demonstrated under experimental and clinical conditions. This PEEP should then be used as an essential part of any lung protective ventilation strategy. The impact of ventilating ARDS patients according to the principles described in these studies on outcome are currently being evaluated in an international randomized controlled trial.
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| 1624. |
- Sun, Song, 1982-
(författare)
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Dynamics and Mechanisms of Adaptive Evolution in Bacteria
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Determining the properties of mutations is fundamental to understanding the mechanisms of adaptive evolution. The major goal of this thesis is to investigate the mechanisms of bacterial adaptation to new environments using experimental evolution. Different types of mutations were under investigations with a particular focus on genome rearrangements. Adaptive evolution experiments were focused on the development of bacterial resistance to antibiotics.In paper I, we performed stochastic simulations to examine the role of gene amplification in promoting the establishment of new gene functions. The results show that gene amplification can contribute to creation of new gene functions in nature. In paper II, the evolution of β-lactam resistance was studied by evolving S. typhimurium carrying a β-lactamase gene towards increased resistance against cephalosporins. Our results suggest that gene amplification is likely to provide an immediate solution at the early stage of adaptive evolution and subsequently facilitate further stable adaptation. In paper III, we isolated spontaneous deletion mutants with increased competitive fitness, which indicated that genome reduction could be driven by selection. To test this hypothesis, independent lineages of wild type S. typhimurium were serially passaged for 1000 generations and we observed fixation of deletions that significantly increased bacterial fitness when reconstructed in wild type genetic background. In paper IV, we developed a new strategy combining 454 pyrosequencing technology and a ‘split mapping’ computational method to identify unique junction sequences formed by spontaneous genome rearrangements. A high steady-state frequency of rearrangements in unselected bacterial populations was suggested from our results. In paper V, the rates, mechanisms and fitness effects of colistin resistance in S. typhimurium were determined. The high mutation rate and low fitness costs suggest that colistin resistance could develop in clinical settings. In paper VI, a novel Metallo-β-lactamase (MBL) with low resistance against β-lactam antibiotics was employed as the ancestral protein in a directed evolution experiment to examine how an enzyme evolves towards increased resistance. For most isolated mutants, in spite of their significantly increased resistance, both mRNA and protein levels were decreased as compared with the parental protein, suggesting that the catalytic activity had increased.
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| 1625. |
- Sun, Wei, 1981-
(författare)
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A New Look into Protein C Inhibitor : Posttranslational Modifications and their Functions
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The influences of posttranslational modifications on the functions of the versatile serpin protein C inhibitor (PCI) were studied. PCI is a serine protease inhibitor that is expressed in many tissues and secreted to various fluids in human, including blood plasma, seminal plasma, and urine. PCI in blood can act both as an anticoagulant and a procoagulant and is believed to play a role in pathogen defence. PCI in reproductive tissues is believed to regulate human reproduction at several steps, including the fertilization process. Due to the broad protease specificity and the contradictory activities, the physiological role of PCI is elusive. In this work the inhibitor was purified from blood and seminal plasma by immunoaffinity chromatography. Blood-derived PCI was found to be highly heterogeneous, due to variations in posttranslational modifications. The occupancy and structures of N- and O-glycans attached to blood plasma PCI and N-glycans of seminal plasma PCI were determined by mass spectrometry. An O-glycosylation site at Thr 20 was identified in PCI derived from blood. N-glycan structures of PCI isolated from blood and seminal plasma differed markedly, demonstrating that they are expressed in a tissue-specific manner. Proteolytic processing also appeared to be tissue-specific, since N-terminally cleaved PCI was found in PCI isolated both from blood and seminal plasma, but the length of the lacking segment differed. The effects of the N-linked glycans and the N-terminus of PCI on protease inhibition were determined using enzymatic measurements with chromogenic substrates. The N-glycans and the N-terminus had different effects on the inhibition of thrombin, factor Xa and prostate specific antigen, demonstrating that posttranslational modifications of PCI affect its functional specificity. These findings enhance the understanding of the regulation of the various functions of PCI and may potentially be used for the production of specialized PCI variants for medical purposes.
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| 1626. |
- Sund, Fredrik, 1969-
(författare)
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Cytomegalovirus Infection in Immunocompetent and Renal Transplant Patients : Clinical Aspects and T-cell Specific Immunity
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytomegalovirus (CMV) is a β-herpesvirus that, after primary infection, establishes a life-long persistence in the human host. Up to 90% of humans are infected with CMV, that is kept under control by CMV-specific CD8+ and CD4+ T cells. In patients with an impaired cellular immunity, however, CMV infections can be life-threatening. Thus, it is vital to identify risk factors and target high-risk patients. In this thesis we have evaluated low-dose valacyclovir prophylaxis in renal transplant patients and studied CMV-specific T cell immunity in healthy and renal transplant patients. In renal transplant patients, the CMV serostatus of both the recipient (R) and the donor (D) has a major impact on the risk of developing CMV disease. In the high-risk D+/R- population, >50% are likely to develop CMV disease in the absence of prophylaxis and/or pre-emptive therapy. We have used low-dose valacyclovir prophylaxis for high-risk renal transplant patients, and graft and patient survival up to 5 years after transplantation was comparable to data reported for other prophylactic protocols. The incidence of CMV disease and graft rejection during the first year after transplantation was also comparable to that achieved with other protocols, and without the adverse effects reported for other therapies. In the D+/R+ population, with a 15-35% risk of developing CMV disease, it is important to identify those individuals that are subject to a higher risk because of risk factors other than CMV serostatus. We therefore measured several immunologic parameters in renal transplant patients and in immunocompetent individuals with latent and primary CMV infection. In patients with a primary symptomatic CMV infection, CMV-specific CD8+ T cells peaked within a month after onset of symptoms but declined rapidly. In renal transplant patients, we found that the reduction in IFNγ-producing CMV-specific CD4+ T cells at 2 months post-transplantation may predict high-grade CMV DNAemia.
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| 1627. |
- Sundberg, Isak
(författare)
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Exploring Links between Melatonin, Inflammation and Depression
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Major depressive disorder (MDD) is one of the leading global causes of disease burden. Worse yet, about one third of the patients with MDD do not experience a remission with current treatments. The symptoms of MDD likely represent a variety of underlying pathologic processes and more knowledge about these processes is needed to optimize treatment for MDD. The focus of this thesis was to study the relationship between inflammation, melatonin and symptoms of depression. In papers I-III a population of young adults seeking psychiatric care was examined for depressive symptoms, melatonin levels in saliva, gastrointestinal (GI) symptoms and inflammatory markers in blood. In paper IV a cohort of patients with hepatitis C receiving treatment with new direct-acting agents (DAAs) were prospectively followed during treatment for depressive symptoms and sleep.All patients were diagnosed by means of structured or semi-structured interviews and depressive symptoms were assessed with the self-rating version of the Montgomery Åsberg Depression Rating Scale. Sleep quality was measured by the Pittsburgh Sleep Quality Index, and GI symptoms were assessed with the Gastrointestinal Symptom Rating Scale-IBS. Melatonin in saliva was measured using enzyme-linked immunosorbent assay, and inflammatory markers in blood were analysed by proximity extension assay.In young adults seeking psychiatric care melatonin levels at bedtime were inversely correlated with depressive symptoms. In those patients with a current depressive episode low melatonin values at bedtime were a negative prognostic factor for response after 6 months (paper I). Postprandial melatonin levels were positively associated with GI symptoms of bloating and pain (paper II). Postprandial melatonin levels were also associated with the inflammatory markers vascular endothelial growth factor A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1α (MIP-1α). Evening levels of melatonin did not correlate with the inflammatory markers. VEGF-A and MCP-1 as well as postprandial levels of melatonin correlated with a diagnosis of anxiety disorder, whereas MIP-1α correlated with MDD (paper III). Patients with hepatitis C underwent treatment with DAAs without experiencing pronounced psychiatric side effects in terms of depressive symptoms or sleep disturbances (paper IV).In summary, the findings confirm a relationship between bedtime melatonin levels and depressive symptoms. The findings also show a connection between daytime melatonin and GI-symptoms. In addition, the findings indicate an association between inflammation and daytime melatonin. Together these results demonstrate links between melatonin, inflammation and depression. Lastly, interferon-free treatment against hepatitis C did not induce depressive symptoms.
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| 1628. |
- Sundblom, Jimmy, 1981-
(författare)
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Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease : Translational Studies of Two Neurogenetic Diseases
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases: 1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood. 2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.
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| 1629. |
- Sundbom, Fredrik, 1982-
(författare)
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Asthma and Sleep Disturbances : Associations to Comorbidities and Asthma Control
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aimed to investigate the associations between asthma control, asthma-related comorbidity, and sleep. Insomnia symptoms with asthma are common, and have commonly been explained by poor asthma control and asthma symptoms during the night, which affect most asthmatics to some degree. The impact of asthma-related comorbidity, however, is not fully known. Further aims were to analyze the effects of asthma control and comorbidities on asthma-related quality of life, and to analyze the effects of co-existing asthma and obstructive sleep apnea on objective sleep quality. Four different populations were investigated: the two large community-based cohorts GA2LEN (n=25,610) and LifeGene (n=23,875), a cohort of 369 young asthma patients (MIDAS), and a polysomnography study of 384 women (SHE).The GA2LEN study confirmed that insomnia symptoms remain a common problem among asthmatics. Poor asthma control and nasal congestion were important risk factors for insomnia symptoms. Smoking and obesity were other risk factors for insomnia symptoms among asthmatics.Asthma control, as assessed using the Asthma Control Test (ACT), was identified as the most important predictor of asthma-related quality of life in the MIDAS study. Combining the ACT score with data on insomnia, anxiety, and depression showed considerable additive effects of the conditions. In the SHE study, co-existing asthma and OSA were associated with worse objective sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The group with both asthma and OSA had the highest levels of the markers of systemic inflammation CRP and IL-6. Uncontrolled asthma was a risk factor for all insomnia symptoms in the LifeGene study. Asthma-related comorbidity had a great impact on sleep quality; in particular, the combination of uncontrolled asthma and any comorbidity was unfavorable. Chronic rhinosinusitis was a risk factor for both insomnia symptoms and uncontrolled asthma. These findings have a high clinical relevance and underline the importance of structured evaluation of asthma control and attention to comorbidity in asthma care, as insomnia symptoms are common and affect quality of life. Optimizing asthma control is crucial for sleep quality, but treating asthma-related comorbidity must not be overlooked.
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| 1630. |
- Sundbom, Renée, 1981-
(författare)
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Surgical Stress in Rats : The Impact of Buprenorphine on Postoperative Recovery
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During surgery, both anesthesia and tissue damage cause physiological stress responses in the body. The hypothalamic-pituitary-adrenal (HPA) axis is activated with increased levels of glucocorticoids. After surgical procedures the stress response may be a cause of postoperative morbidity and pre-emptive analgesic treatment can attenuate the stress response during the postoperative period. In laboratory animals, buprenorphine is a commonly used analgesic. Subcutaneous (s.c.) administration of buprenorphine is most common, but oral administration would be preferable in many cases, enabling administration without any handling of the rat.In this thesis we studied the surgical stress response in laboratory rats during surgery and in the postoperative period, and its modulation by s.c. injection and oral voluntary ingestion (VI) of buprenorphine. Corticosterone levels and the clinical parameters body weight, water intake and behavior were observed. The concentration of buprenorphine in plasma was measured as well as stock-related differences in postoperative recovery.During surgery and anesthesia there was a higher corticosterone release during a more severe surgery and corticosterone levels were reduced more effectively after buprenorphine treatment than after lidocaine treatment.Buprenorphine treatment, independent of the route of administration, led to better postoperative recovery in body weight and water intake compared to local anesthetics. VI of buprenorphine resulted in a suppression of plasma corticosterone levels compared to s.c. buprenorphine treatment and treatment with local anesthetics during the first day after surgical catheterization. The corticosterone levels of all buprenorphine treated groups had, by the second postoperative day, reverted to the normal diurnal rhythm of corticosterone secretion. Buprenorphine treatment increased locomotor activity in non-operated rats only. The effect of buprenorphine in operated rats could not be detected via the monitoring of locomotor activity or the time spent resting in the present study.Treatment with buprenorphine by VI has similar effects on postoperative plasma corticosterone levels in both Wistar and Sprague-Dawley rats. VI of buprenorphine resulted in a buprenorphine concentration in plasma at least as high as by s.c. treatment.Thus, administration by VI of buprenorphine appears to be an effective stress-reducing method for administrating postoperative analgesia to laboratory rats.
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