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  • 201.
    Ahlström, Christer
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Nonlinear phonocardiographic Signal Processing2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis work has been to develop signal analysis methods for a computerized cardiac auscultation system, the intelligent stethoscope. In particular, the work focuses on classification and interpretation of features derived from the phonocardiographic (PCG) signal by using advanced signal processing techniques.

    The PCG signal is traditionally analyzed and characterized by morphological properties in the time domain, by spectral properties in the frequency domain or by nonstationary properties in a joint time-frequency domain. The main contribution of this thesis has been to introduce nonlinear analysis techniques based on dynamical systems theory to extract more information from the PCG signal. Especially, Takens' delay embedding theorem has been used to reconstruct the underlying system's state space based on the measured PCG signal. This processing step provides a geometrical interpretation of the dynamics of the signal, whose structure can be utilized for both system characterization and classification as well as for signal processing tasks such as detection and prediction. In this thesis, the PCG signal's structure in state space has been exploited in several applications. Change detection based on recurrence time statistics was used in combination with nonlinear prediction to remove obscuring heart sounds from lung sound recordings in healthy test subjects. Sample entropy and mutual information were used to assess the severity of aortic stenosis (AS) as well as mitral insufficiency (MI) in dogs. A large number of, partly nonlinear, features was extracted and used for distinguishing innocent murmurs from murmurs caused by AS or MI in patients with probable valve disease. Finally, novel work related to very accurate localization of the first heart sound by means of ECG-gated ensemble averaging was conducted. In general, the presented nonlinear processing techniques have shown considerably improved results in comparison with other PCG based techniques.

    In modern health care, auscultation has found its main role in primary or in home health care, when deciding if special care and more extensive examinations are required. Making a decision based on auscultation is however difficult, why a simple tool able to screen and assess murmurs would be both time- and cost-saving while relieving many patients from needless anxiety. In the emerging field of telemedicine and home care, an intelligent stethoscope with decision support abilities would be of great value.

  • 202.
    Ahlström, Christer
    et al.
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Ask, Per
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Rask, Peter
    University Hospital, Örebro, Sweden .
    Karlsson, Jan-Erik
    County Hospital Ryhov, Jönköping, Sweden.
    Nylander, Eva
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Hult, Peter
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Assessment of Suspected Aortic Stenosis by Auto Mutual Information Analysis of Murmurs2007In: Engineering in Medicine and Biology Society, 2007. EMBS 2007, 2007, 1945-1948 p.Conference paper (Refereed)
    Abstract [en]

    Mild sclerotic thickening of the aortic valve affects 25% of the population, and the condition causes aortic valve stenosis (AS) in 2% of adults above 65 years. Echocardiography is today the clinical standard for assessing AS. However, a cost effective and uncomplicated technique that can be used for decision support in the primary health care would be of great value. In this study, recorded phonocardiographic signals were analyzed using the first local minimum of the auto mutual information (AMI) function. The AMI method measures the complexity in the sound signal, which is related to the amount of turbulence in the blood flow and thus to the severity of the stenosis. Two previously developed phonocardiographic methods for assessing AS severity were used for comparison, the murmur energy ratio and the sound spectral averaging technique. Twenty-nine patients with suspected AS were examined with Doppler echocardiography. The aortic jet velocity was used as a reference of AS severity, and it was found to correlate with the AMI method, the murmur energy ratio and the sound spectral averaging technique with the correlation coefficient R = 0.82, R = 0.73 and R = 0.76, respectively.

  • 203.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Hult, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Rask, P
    Karlsson, J-E
    Nylander, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Dahlström, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Using the intelligent stethoscope for extraction of features for systolic heart murmur classification2006In: World Congress on Medical Physics and Biomedical Engineering WC2006,2006, 2006Conference paper (Other academic)
  • 204.
    Ahlström, Christer
    et al.
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Hult, Peter
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Rask, Peter
    Örebro university.
    Karlsson, Jan-Erik
    Nylander, Eva
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Ask, Per
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Feature Extraction for Systolic Heart Murmur Classification2006In: Annals of Biomedical Engineering, ISSN 0090-6964, Vol. 34, no 11, 1666-1677 p.Article in journal (Refereed)
    Abstract [en]

    Heart murmurs are often the first signs of pathological changes of the heart valves, and they are usually found during auscultation in the primary health care. Distinguishing a pathological murmur from a physiological murmur is however difficult, why an “intelligent stethoscope” with decision support abilities would be of great value. Phonocardiographic signals were acquired from 36 patients with aortic valve stenosis, mitral insufficiency or physiological murmurs, and the data were analyzed with the aim to find a suitable feature subset for automatic classification of heart murmurs. Techniques such as Shannon energy, wavelets, fractal dimensions and recurrence quantification analysis were used to extract 207 features. 157 of these features have not previously been used in heart murmur classification. A multi-domain subset consisting of 14, both old and new, features was derived using Pudil’s sequential floating forward selection (SFFS) method. This subset was compared with several single domain feature sets. Using neural network classification, the selected multi-domain subset gave the best results; 86% correct classifications compared to 68% for the first runner-up. In conclusion, the derived feature set was superior to the comparative sets, and seems rather robust to noisy data.

  • 205.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Hult, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Schmekel, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Automatisk detektering av ronki med icke-linjära metoder2004In: Svenska Läkaresällskapets riksstämma,2004, 2004, 66-66 p.Conference paper (Other academic)
  • 206.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Hult, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Schmekel, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Wheeze detection with nonlinear statespace embedding2004In: International Lung Sound Association,2004, 2004, 38-39 p.Conference paper (Other academic)
  • 207.
    Ahlström, Christer
    et al.
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Höglund, Katja
    Hult, Peter
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Häggström, Jens
    Kvart, Clarence
    Ask, Per
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Assessing Aortic Stenosis using Sample Entropy of the Phonocardiographic Signal in Dogs2008In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, Vol. 55, no 8, 2107-2109 p.Article in journal (Refereed)
    Abstract [en]

    In aortic valve stenosis (AS), heart murmurs arise as an effect of turbulent blood flow distal to the obstructed valves. With increasing AS severity, the flow becomes more unstable, and the ensuing murmur becomes more complex. We hypothesize that these hemodynamic flow changes can be quantified based on the complexity of the phonocardiographic (PCG) signal. In this study, sample entropy (SampEn) was investigated as a measure of complexity using a dog model. Twenty-seven boxer dogs with various degrees of AS were examined with Doppler echocardiography, and the peak aortic flow velocity (Vmax) was used as a reference of AS severity. SampEn correlated to Vmax with R = 0.70 using logarithmic regression. In a separate analysis, significant differences were found between physiologic murmurs and murmurs caused by AS (p < 0.05), and the area under a receiver operating characteristic curve was calculated to 0.96. Comparison with previously presented PCG measures for AS assessment showed improved performance when using SampEn, especially for differentiation between physiological murmurs and murmurs caused by mild AS. Studies in patients will be needed to properly assess the technique in humans.

  • 208.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Johansson, Anders
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    A respiration monitor based on electrocardiographic and photoplethysmographic sensor fusion2004In: IEEE Engineering in Medical and Biological Society,2004, Piscataway, N.J. USA: IEEEEMBS , 2004, 2311- p.Conference paper (Refereed)
  • 209.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Johansson, Anders
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Monitorering av andning and blodtrycksförändringar baserat på EKG och hjärtljud2007In: Medicinteknik dagarna,2007, 2007Conference paper (Other academic)
  • 210.
    Ahlström, Christer
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Johansson, Anders
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Uhlin, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology.
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Ask, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Physiological Measurements.
    Noninvasive investigation of blood pressure changes using the pulse wave transit time: A novel approach in the monitoring of hemodialysis patients2005In: Journal of Artificial Organs, ISSN 1434-7229, Vol. 8, no 3, 192-197 p.Article in journal (Refereed)
    Abstract [en]

    Severe blood pressure changes are well known in hemodialysis. Detection and prediction of these are important for the well-being of the patient and for optimizing treatment. New noninvasive methods for this purpose are required. The pulse wave transit time technique is an indirect estimation of blood pressure, and our intention is to investigate whether this technique is applicable for hemodialysis treatment. A measurement setup utilizing lower body negative pressure and isometric contraction was used to simulate dialysis-related blood pressure changes in normal test subjects. Systolic blood pressure levels were compared to different pulse wave transit times, including and excluding the cardiac preejection period. Based on the results of these investigations, a pulse wave transit time technique adapted for dialysis treatment was developed and tried out on patients. To determine systolic blood pressure in the normal group, the total pulse wave transit time was found most suitable (including the cardiac preejection period). Correlation coefficients were r = 0.80 ± 0.06 (mean ± SD) overall and r = 0.81 ± 0.16 and r = 0.09 ± 0.62 for the hypotension and hypertension phases, respectively. When applying the adapted technique in dialysis patients, large blood pressure variations could easily be detected when present. Pulse wave transit time is correlated to systolic blood pressure within the acceptable range for a trend-indicating system. The method's applicability for dialysis treatment requires further studies. The results indicate that large sudden pressure drops, like those seen in sudden hypovolemia, can be detected. © The Japanese Society for Artificial Organs 2005.

  • 211.
    Ahlström, Christer
    et al.
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Länne, Toste
    Linköping University, Department of Medicine and Health Sciences, Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Ask, Per
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    Johansson, Anders
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Health Sciences.
    A method for accurate localization of the first heart sound and possible applications2008In: Physiological Measurement, ISSN 0967-3334, Vol. 29, no 3, 417-428 p.Article in journal (Refereed)
    Abstract [en]

    We have previously developed a method for localization of the first heart sound (S1) using wavelet denoising and ECG-gated peak-picking. In this study, an additional enhancement step based on cross-correlation and ECG-gated ensemble averaging (EA) is presented. The main objective of the improved method was to localize S1 with very high temporal accuracy in (pseudo-) real time. The performance of S1 detection and localization, with and without EA enhancement, was evaluated on simulated as well as experimental data. The simulation study showed that EA enhancement reduced the localization error considerably and that S1 could be accurately localized at much lower signal-to-noise ratios. The experimental data were taken from ten healthy subjects at rest and during invoked hyper- and hypotension. For this material, the number of correct S1 detections increased from 91% to 98% when using EA enhancement. Improved performance was also demonstrated when EA enhancement was used for continuous tracking of blood pressure changes and for respiration monitoring via the electromechanical activation time. These are two typical applications where accurate localization of S1 is essential for the results.

  • 212.
    Ahlström, Gerd
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Carlsson, C
    Att visa upp sin värld: Hur personer med stora varaktiga funktionshinder uppfattar sin livssituation relaterat till de etiska principerna i LSS2002Report (Other academic)
  • 213.
    Ahlström, Gerd
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science.
    Wennberg, S
    Coping with illness-related problems in persons with progressive muscular diseases: the Swedish version of the Ways of Coping Questionnaire2002In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, Vol. 16, 368-375 p.Article in journal (Refereed)
  • 214.
    Ahmad, Faiyaz
    et al.
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Lindh, Rebecka
    Lund University, Department Expt Med Science, S-22184 Lund, Sweden .
    Tang, Yan
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Ruishalme, Iida
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sahachartsiri, Bobby
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Degerman, Eva
    Lund University, Department Expt Med Science, S-22184 Lund, Sweden .
    C Manganiello, Vincent
    NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA .
    Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta(3)-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes2009In: BIOCHEMICAL JOURNAL, ISSN 0264-6021, Vol. 424, no 3, 399-410 p.Article in journal (Refereed)
    Abstract [en]

    In adipocytes, PDE3B (phosphodiesterase 3B) is an important regulatory effector in signalling pathways controlled by insulin and cAMP-increasing hormones. Stimulation of 3T3-L1 adipocytes with insulin or the beta(3)-adrenergic receptor agonist CL316243 (termed CL) indicated that insulin preferentially phosphorylated/activated PDE3B associated with internal membranes (endoplasmic reticulum/Golgi), whereas CL preferentially phosphorylated/activated PDE3B associated with caveolae. siRNA (small interfering RNA)-mediated KD (knockdown) of CAV-1 (caveolin-1) in 3T3-L1 adipocytes resulted in down-regulation of expression of membrane-associated PDE3B. Insulin-induced activation of PDE3B was reduced, whereas CL-mediated activation was almost totally abolished. Similar results were obtained in adipocytes from Cav-1-deficient mice. siRNA-mediated KID of CAV-1 in 3T3-L1 adipocytes also resulted in inhibition of CL-stimulated phosphorylation of HSL (hormone-sensitive lipase) and perilipin A, and of lipolysis. Superose 6 gel-filtration chromatography of solubilized membrane proteins from adipocytes stimulated with insulin or CL demonstrated the reversible assembly of distinct macromolecular complexes that contained P-32-phosphorylated PDE3B and signalling molecules thought to be involved in its activation. Insulin- and CL-induced macromolecular complexes were enriched in cholesterol, and contained certain common signalling proteins [14-3-3, PP2A (protein phosphatase 2A) and cav-1]. The complexes present in insulin-stimulated cells contained tyrosine-phosphorylated IRS-1 (insulin receptor substrate 1) and its downstream signalling proteins, whereas CL-activated complexes contained beta(3)-adrenergic receptor, PKA-RII [PKA (cAMP-dependent protein kinase)-regulatory subunit] and HSL. Insulin- and CL-mediated macromolecular complex formation was significantly inhibited by CAV-1 KID. These results suggest that cav-1 acts as a molecular chaperone or scaffolding molecule in cholesterol-rich lipid rafts that may be necessary for the proper stabilization and activation of PDE3B in response to CL and insulin.

  • 215.
    Ahmadi, Ahmad
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Genetic predisposition and risk factors for neurodegenerative diseases2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The inter-individual variability in biotransformation, may lead to differences in activation and detoxification of both endogenous and exogenous compounds. Polymorphism studies in such genes were applied for Parkinson's disease (PD) and Chronic toxic encephalopathy (CTE), two diseases influenced by both genetic and enviromnental factors.

    An elevated median age for the onset of PD was found among GS1M1 gene carriers compared to PD patients being GS1M1 null genotypes (68 years versus 57 years). No similar difference was found for GSTT1. mEPHX (113HH) isoform, which has been suggested as a low activity variant, is over represented in PD patients (OR=3.8, CI 95%, 1.2-11.8).

    Monoamine oxidases (MAO-A and -B) are important in the dopamine metabolism and in the detoxification of neurotoxins and genetic variants in these genes have earlier been assigned to PD. However, no difference was revealed between any of the polymorphisms studied in the MAO-A and -B genes and PD. Smoking displayed an enviromnental exposure with a strong decreased risk for PD in this study (OR=0.40 for men and OR=0.48 for women) but no obvious interaction with the MAO genotypes could be observed.

    Mitochondrial dysfunction and oxidative stress have been hypothesized to contribute to the pathogenesis of PD. The superoxide dismutases (SOD) potentially play an important role in PD by detoxifying superoxide radicals in mitochondria. Polymorphisms neither in superoxide dismutase 2 (SOD2) nor mitochondrial complex I subunit, NDUFV2, were associated with PD.

    An increased risk ratio for CTE was found in smokers with the GSTM1 null genotype (RR=2.5, Cl 95%, 1.4-4.2) or the GSTT1 null genotype (RR=1.4, Ci 95%, 1.02-2.0). In non-smokers GS1M1 null genotype did not confer any risk for CTE. Polymorphisms in mEPHX were not associated with an increased risk for CTE.

    Thus, various genetic and enviromnental factors most likely influence both PD and solvent-induced CTE. Detoxification pathways may represent important protective mechanisms against reactive intermediates, thus genetic predisposition in these pathways could modify the susceptibility and onset of PD and solvent-induced CTE.

  • 216.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Bivik, Cecilia
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Monoamine oxidase A and B genes polymorphisms in Parkinson's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized by degeneration of nig:rostriatal dopaminergic neurons including the loss of cell bodies in the pars compacta of substantia nigra (SN). The mechanism for neurodegeneration is unknown, but the pathogenesis is considered to be multifactorial involving exposure for toxins, genetic inheritance, age, oxidative stress and mitochondrial electron transport chain defects. This study has been focused on polymorphisms in the genes for the enzymes monoamine oxidase A and B (MAO-A, MAO-B) and relation to smoking for the development of idiopathic Parkinson's disease. MAO enzymes are important in the dopamine metabolism and in the detoxification of neurotoxins. During metabolism of dopamine, MAO generates large amounts of free radicals and hydrogen peroxide, and may damage the neurons in substantia nigra, which has been suggested as a pathologic mechanism for PD.

    Blood samples were collected from 256 PD patients, age 30-80 years, and 582 unrelated control individuals, age 31 - 78 years, from southeastern Sweden.

    Two polymorphisms (exon 8 and exon 14) located in the MAO-A gene and one polymorphism located in the MA O-B gene were examined, with denatming HPLC, PCR-RFLP or DNA sequencing. Genotype and allele frequencies were determined for patients and controls. No statistical significant difference was revealed between any of the polymorphisms in the MAO-A and MAO-B genes and Parkinson's disease. Smoking displayed an enviromnental exposure with a strong decreased risk for both male (OR=0.40, 95% CI 0.25 - 0.63) and female (OR=0.48, 95% CI 0.25-0.89) PD without any interaction with MAO genotype.

    The polymorphisms in MAO genes might therefore not be acting as modifiers of risk for developing of PD either by itself or by interacting with smoking. With respect to the size of the study (256 PD patients and 582 controls) MAO polymorphisms do not represent any predisposing factor or a weak PD susceptibility factor.

  • 217.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Fredriksson, Mats
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Jerregård, H.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Åkerbäck, Anita
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Fall, Per-Arne
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Rannug, A.
    National Institute for Working Life, Solna and Inst. of Environ. Medicine, Karolinska Institutet, Stockholm, Sweden.
    Axelson, Olav
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset2000In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 269, no 3, 676-680 p.Article in journal (Refereed)
    Abstract [en]

    Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1.2–11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1–3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.

  • 218.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Johansson, Sofia
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Manganese superoxide dismutase and NDUFV2 polymorphisms and susceptibility to Parkinson's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Mitochondrial dysfunction has been hypothesized to contribute to the pathogenesis of Parkinson's disease (PD). Oxidative stress and production of oxygen radicals is produced in mitochondria. The superoxide dismutases (SOD) potentially play an important role in PD by detoxifying superoxide radicals. Oxidative stress has also an important role to decrease Complex I activity in the mitochondria. In addition, Complex I contains several subunits, where one, NDUFV2, plays a major role in the electron transport pathway of Complex I in substantia nigra.

    The aim of this project was to study polymorphisms in MTS-SOD2 and the Complex I subunit, NDUFV2 as predisposing factors for the development of idiopathic PD.

    Blood samples from 200 PD and 404 population controls were collected from the Southeastern part of Sweden. DNA was isolated and the polymorphisms were analyzed by pyrosequencing and direct dideoxy termination sequencing.

    Genotypes and allele frequencies were compared for the patient and control groups with Χ2 statistics. No statistical significant difference was evident for any of the polymorphisms neither in MTS-SOD2 (OR=0<85, 95% CI, 0<52-1.38) nor NDUFV2 (OR=0.64, 95% CI, 0.24-1.64) genes and PD.

    These results indicate that the MTS-SOD2 and NDUFV2 gene variants do not contribute to PD pathogenesis.

  • 219.
    Ahmadi, Ahmad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Pia
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Flodin, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy2002In: Toxicology and industrial health, ISSN 0748-2337, E-ISSN 1477-0393, Vol. 18, no 6, 289-296 p.Article in journal (Refereed)
    Abstract [en]

    Exposure to organic solvents is still common in industrial and other work environments, and increases the risk of chronic toxic encephalopathy (CTE). Genetic variation in metabolic enzymes for solvents and other xenobiotics may modify the risk of developing toxic effects. Therefore, we investigated the presence of null genotypes for glutathione S-transferases M1 and T1 (GSTM1, GSTT1) and two genetic polymorphisms of microsomal epoxide hydrolase (mEPHX) in relation to the risk for chronic toxic encephalopathy (CTE) when exposed to solvents and smoking. We genotyped 115 patients who were classified into three categories: CTE (n = 56), incipient CTE (n = 27) and non-CTE (n = 32) patients. DNA was isolated from leucocytes and the GSTM 1 and GSTT1 null genotypes were determined by multiplex-polymerase chain reaction. The two polymorphisms of mEPHX were analysed by PCR-RFLP (restriction fragment length polymorphism) based assays. All analyses were performed blindly with regard to both exposure and disease status. An increased binomial regression risk ratio = 2.5, 95% confidence interval (CI) 1.5-4.2, of the GSTM1 null genotype for CTE was found in smokers and for the GSTT1 null genotype (binomial regression risk ratio 1.5, 95% CI 1.0-2.0). In nonsmokers, the GSTM1 null genotype did not confer any risk for CTE. None of the studied mEPHX polymorphisms were associated with an increased risk for CTE. We suggest that the GSTM1 null genotype in smokers is a possible risk for solvent-induced CTE.

  • 220.
    Ahn, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Baranowski, Jacek
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Dahlin, Lars-Göran
    Linköping University, Department of Medical and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Nielsen, Niels-Erik
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Nylander, Eva
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Wallby, Lars
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    TAVI without concomitant balloon dilatation2012Conference paper (Other academic)
  • 221.
    Ahn, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Baranowski, Jacek
    Myasnikova, Irina
    Rahgozar, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine.
    Delshad, Baz
    First in man: wireless pressure sensors in left heart rooms'2014Conference paper (Refereed)
  • 222.
    Ahn, Henrik Casimir
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Mitral valve surgery - current results and future development to catheter based approaches2006In: International Society of Extracorporeal Circulation - Cardiac Surgery beyond 2006,2006, 2006Conference paper (Other academic)
  • 223.
    Ahn, Henrik Casimir
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    The Impella temporary assist device, the Swedish experience2006In: International Society of Extracorporeal Circulation - Cardiac Surgery beyond 2006,2006, 2006Conference paper (Other academic)
  • 224.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Baranowski, J
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Nielsen, Nils Erik
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Nylander, Eva
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Tamas, Eva
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Wallby, Lars
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Transcatheter aortic valve implantation in high-risk surgical candidates with low risk-scores1984Conference paper (Other academic)
  • 225.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Jodal, M.
    Lindhagen, J
    Lundgren, O.
    Nilsson, Gert
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Bestämning av tunntarmsblodflödet med laser Doppler teknik1984In: Läkarsällskapets Riksstämma,1984, 1984Conference paper (Other academic)
  • 226.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Johansson, K.
    Lindhagen, J.
    Nilsson, Gert
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Förändringar av blodflödet i ventrikeln i samband med mätt med laser Dopplerteknik1984In: Läkarsällskapets Riksstämma,1984, 1984Conference paper (Other academic)
  • 227.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Johansson, K.
    Lindhagen, J.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Laser Doppler flowmetry in the assessment of gastric blood flow1984In: man. Scand J of Gastroenterology,1984, 1984, 98:33-98:33 p.Conference paper (Other academic)
  • 228.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Lindhagen, J.
    Nilsson, Gert
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Jodal, M.
    Lundgren, O.
    Evaluation of Laser Doppler Flowmetry in the assessment of blood flow in the small intestine1984In: Third World Congress of Microcirculation,1984, 1984Conference paper (Other academic)
  • 229.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Lindhagen, J
    Nilsson, Gert
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Salerud, Göran
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Jodal, M
    Lundgren, O
    Evaluation of Laser Doppler Flowmetry in the assessment of intestinal blood flow1985In: Gastroenterology, ISSN 0016-5085, Vol. 4, no 88, 951-957 p.Article in journal (Refereed)
    Abstract [en]

      

  • 230.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Lönn, Urban
    IMV/Thoraxkirurgi/Hjärtcentrum LiU/HU.
    Peterzén, Bengt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Alternatives to circulatory support during coronary artery surgery1999In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, Vol. 16 suppl 2, 143-150 p.Article in journal (Refereed)
  • 231.
    Ahn, Henrik Casimir
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Nielsen, Niels Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Baranowski, Jacek
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Can predilatation in transcatheter aortic valve implantation be omitted? - a prospective randomized study2016In: Journal of Cardiothoracic Surgery, ISSN 1749-8090, E-ISSN 1749-8090, Vol. 11, no 124Article in journal (Refereed)
    Abstract [en]

    Background: The use of a balloon expandable stent valve includes balloon predilatation of the aortic stenosis before valve deployment. The aim of the study was to see whether or not balloon predilatation is necessary in transcatheter aortic valve replacement (TAVI). Methods: Sixty consecutive TAVI patients were randomized to the standard procedure or to a protocol where balloon predilatation was omitted. Results: There were no significant differences between the groups regarding early hemodynamic results or complication rates. Conclusions: TAVI can be performed safely without balloon predilatation and with the same early results as achieved with the standard procedure including balloon predilatation. The reduction in the number of pacing periods required may be beneficial for the patient.

  • 232.
    Ahn, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Granfeldt, Hans
    Linköping University, Department of Medical and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Hübbert, Laila
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Peterzén, Bengt
    Linköping University, Department of Medical and Health Sciences, Cardiothoracic Anaesthesia and Intensive care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Long-term mechanical circulatory support in patients with a prosthetic aortic valve2012Conference paper (Other academic)
  • 233.
    Ahn, Jae-Il
    et al.
    Ottawa Hospital, Canada .
    Kuffova, Lucia
    University of Aberdeen, Scotland .
    Merrett, Kimberley
    Ottawa Hospital, Canada .
    Mitra, Debbie
    Ottawa Hospital, Canada .
    Forrester, John V.
    University of Aberdeen, Scotland .
    Li, Fengfu
    Ottawa Hospital, Canada .
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Ottawa Hospital, Canada .
    Crosslinked collagen hydrogels as corneal implants: Effects of sterically bulky vs. non-bulky carbodiimides as crosslinkers2013In: Acta Biomaterialia, ISSN 1742-7061, Vol. 9, no 8, 7796-7805 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that recombinant human collagen can be crosslinked with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) to fabricate transparent hydrogels possessing the shape and dimensions of the human cornea. These corneal implants have been tested in a Phase I human clinical study. Although these hydrogels successfully promoted corneal tissue and nerve regeneration, the gelling kinetics were difficult to control during the manufacture of the implants. An alternative carbodiimide capable of producing hydrogels of similar characteristics as EDC in terms of strength and biocompatibility, but with a longer gelation time would be a desirable alternative. Here, we compared the crosslinking kinetics and properties of hydrogels crosslinked with a sterically bulky carbodiimide, N-Cyclohexyl-N-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC), with that of EDC. CMC crosslinking was possible at ambient temperature whereas the EDC reaction was too rapid to control and had to be carried out at low temperatures. The highest tensile strength obtained using optimized formulations were equivalent, although CMC crosslinked hydrogels were found to be stiffer. The collagenase resistance of CMC crosslinked hydrogels was superior to that of EDC crosslinked hydrogels while biocompatibility was similar. We are also able to substitute porcine collagen with recombinant human collagen and show that the in vivo performance of both resulting hydrogels as full-thickness corneal implants is comparable in a mouse model of an orthotopic corneal graft. In conclusion, CMC is a viable alternative to EDC as a crosslinker for collagen-based biomaterials for use as corneal implants, and potentially for use in other tissue engineering applications.

  • 234.
    Ahn, Song Ee
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Education and Adult Learning. Linköping University, Faculty of Educational Sciences.
    Rimpilainen, Sanna
    University of Stirling, UK.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Fenwick, Tara
    University of Stirling, UK.
    Interprofessional training in technology-enhanced medical simulation: Locations and knowings2013In: Conference Programme Book: 8th International Conference on Researching Work and Learning 2013, 2013, 15-16 p.Conference paper (Other academic)
    Abstract [en]

    This paper take an actor-network theory perspective on the use of medical simulators in professional education as a means of training students in medical education and nursing in handling acute emergency situations in health care.  The main aim of the study is to investigate what activities are performed in what material arrangements in a full cycle of simulation, i.e  the briefing, the simulation in the emergency room, the observations in the control room and the debriefing and what knowing is produced as an effect of these arrangements.

     The use of simulators has become a common teaching strategy in medical education. An ageing population, declining financial resources and lack of trained health care personnel are global trends that call for changing the system of health care practice as well as for professional education in the sector.  To build more effective health services, professionals are required to work more collaboratively and in partnership with health care consumers (WHO 2008; 2010). Recently, leading medical experts have also criticised the training of health personnel for not adequately preparing for cooperation and inter-professional communication (Frenk et al, 2010). In health care, this concern situations demanding effective communication for making prompt decisions that are of critical importance in emergency situations. Training of students and professionals by means of full-scale simulators is a response to accommodate for these needs.  Education in simulation-based environments is seen to offer opportunities to address the needs for training interprofessional collaboration by focusing on communication, situation awareness, decision making and coping with stress (Arafeh et al 2010; Östergaard et al,2011). Cook et al has shown in a meta analysis of more than 600 research articles, that in comparison with no intervention, technology-enhanced simulation is consistently associated with large effects for outcomes of knowledge, skills, and behaviors but moderate effects for patient-related outcomes (Cook et al 2011). A majority of the studies are effect studies with quantitative designs. The authors argue that there is a need for rigorous, theory based qualitative studies in order to clarify how and when to effectively use technology enhanced simulations in the training of health care professionals.

     The present study draws upon Actor-network theory (Latour, 2005).  This perspective which situates materiality as a part of the social practices, provides theoretical tools for observation and discussion of the relation between the material assemblages and human actors. Observations of full-scale simulations of acute trauma handling in the emergency room with ten groups of medical and nursing students make up the data for analysis. Preliminary findings indicate that the different locations and material arrangements of the simulation cycle produce different kinds of knowing and learning than the intended curriculum objectives. The findings can contribute to the theoretical knowledge of how to design simulation-based medical education.

     

     

     

     

     

  • 235.
    Ahn, Song Ee
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Education and Adult Learning. Linköping University, Faculty of Educational Sciences.
    Rimpiläinen, Sanna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Three locations of technology enhanced medical simulation training and their effect on learning and knowing2014In: Professional Matters: Materialities and virtualities of professional learning, 2014Conference paper (Refereed)
    Abstract [en]

    This qualitative study aims to address the identified gap in literature concerning  the lack of rigorous, theory-based, qualitative studies to clarify how and when to effectively use simulations to train health care professionals (Cook, et al, 2011). By drawing upon actor-network theory (ANT) (Latour, 2005) an approach that situates materiality as a part of the social practices, and provides theoretical tools for observation and discussion of the relation between the material assemblages and human actors, we have investigated how learning takes place during a simulation-based medical training. Knowing and learning, according to ANT, are not simply cognitive or social phenomena, but are seen as emerging as effects of the socio-material networks gathered together and being performed into being in particular locations (Law, 2004; Rimpiläinen, 2011).  In this study we have focussed on observing the socio-material arrangements that emerged in three locations involved in the simulation – the simulation room, the observation room and the reflection room - and analysing what kinds of knowing and learning they have produced through which socio-material arrangements. Data for analysis consists of observations of full-scale simulations of acute trauma handling in the emergency room with ten groups of medical and nursing students.  Preliminary findings indicate that the different locations and material arrangements of the simulation cycle produce different kinds of knowing and learning from the intended curriculum objectives. The findings can contribute to the theoretical knowledge of how to design simulation-based medical education.

  • 236.
    Ahnström, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Karolinska University Hospital.
    Skoog, Lambert
    Karolinska University Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, 441-448 p.Article in journal (Refereed)
    Abstract [en]

    Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

  • 237.
    Ahnström Waltersson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Cell cycle alterations and 11q13 amplification in breast cancer: prediction of adjuvant treatment response2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The growth and development of the breast is to a large extent regulated by oestrogens through the oestrogen receptor (ER). Activation of the ERα triggers transcription of genes that are important for cell proliferation and stimulates entry into the G1 phase of the cell cycle. In breast cancer the ERα is often upregulated and is therefore a suitable target for adjuvant therapies such as tamoxifen. Although tamoxifen is an effective treatment in most cases, tumours sometimes acquire resistance to the drug. The aim of this thesis was to investigate the impact of G1 phase proteins and 11q13 amplification on prognosis and treatment response in breast cancer. The material used was from a clinical trial in which postmenopausal breast cancer patients were randomised to chemotherapy or radiotherapy and tamoxifen or no adjuvant treatment. We studied the expression of cyclin D1, cyclin E and Rb with immunohisochemistry and amplification of CCND1 and PAK1 with real time PCR. We found that among patients with high tumour expression of cyclin D1, overexpression of ErbB2 was associated with reduced recurrence-free survival. Both cyclin D1 and cyclin E overexpression were associated with reduced tamoxifen response. High expression of cyclin D1 has been found to induce ligand independent activation of ERα in breast cancer cells and might also switch tamoxifen from acting as an antagonist to an agonist. Overexpression of cyclin E has been shown to be associated with expression of low molecular weight isoforms of the protein that possess an increased kinase activity and are insensitive to p21 and p27 inhibition. Furthermore, amplification of 11q13, and in particular the gene PAK1, was a strong predictor of tamoxifen resistance. The pak1 protein is involved in phosphorylation and ligand independent activation of the ERα. We also found that lost expression of either p53 or Rb reduced the patients benefit from radiotherapy compared with patients with normal expression of both proteins. Normally, ionizing radiation upregulates p53 resulting in G1 arrest or apoptosis. If either functional p53 or Rb is missing the cells can proceed from G1 to the S phase despite damaged DNA. The expression of the microRNA, miR-206, was analysed with real time PCR, and the results showed that high expression of miR-206 correlated to low expression of ERα and 11q13 amplification. In vitro studies have shown that miR-206 negatively regulates the expression of ERα. Taken together the G1 regulators and amplification of 11q13 seem to have an important role in predicting the patient’s response to adjuvant therapy.

  • 238.
    Ahnström Waltersson, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Department of Cytology, Karolinska University Hospital, SE-104 01 Stockholm, Sweden.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-104 01 Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    miR-206 expression is downregulated in cyclin D1 amplified breast tumoursManuscript (preprint) (Other academic)
    Abstract [en]

    Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrencefree survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and - 19 genes. The FGF-4 protein has been shown to inhibit the expression of the ERα regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using real-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ERα than tumours with intermediate and high expression (P=0.043). We conclude that miR-206 might be an important regulator of the ERα. Our finding that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon.

  • 239.
    Ahnström Waltersson, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Rutqvist, Lars Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Skoog, Lambert
    Department of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.2005In: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 91, no 2, 145-151 p.Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.

  • 240.
    Aho, Anna Carin
    et al.
    Linnaeus Univ, Dept Hlth & Caring Sci, Vaxjo, Sweden.
    Hultsjö, Sally
    Cty Hosp, Psychiat Clin, Jonkoping, Sweden.
    Hjelm, Katarina
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences.
    Young adults' experiences of living with recessive limb-girdle muscular dystrophy from a salutogenic orientation: an interview study.2015In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 37, no 22, 2083-2091 p.Article in journal (Refereed)
    Abstract [en]

    To describe young adults' experiences of living with recessive limb-girdle muscular dystrophy (LGMD2) from a salutogenic orientation. Methods: A qualitative explorative interview study, including 14 participants aged 20-30 years, was performed focusing on comprehensibility, manageability and meaningfulness in daily life. Content analysis was used for data analysis. Result: Living with LGMD2 not only implies learning to live with the disease and the variations between good and bad periods but also means trying to make sense of a progressive disease that brings uncertainty about future health, by striving to make the best of the situation. Disease progression involves practical and mental struggle, trying to maintain control over one's life despite vanished physical functions that require continual adjustments to the body. Restrictions in a double sense were described, not only due to the disease but also due to poor comprehension of the disease in society. Lack of knowledge about LGMD2 among professionals often results in having to fight for the support needed. Conclusion: In order to manage daily life, it is important to be seen and understood as an individual in contacts with professionals and in society in general, to have informal social support and meaningful activities as well as access to personal assistance if necessary. Implications for Rehabilitation Recessive limb-girdle muscular dystrophy (LGMD2) is a group of progressive disorders, which manifest in physical and psychological consequences for the individual. According to the salutogenic orientation, people need to find life comprehensible, manageable and meaningful, i.e. to achieve a sense of coherence (SOC), but living with LGMD2 may recurrently challenge the individual's SOC. Through the holistic view of the individual's situation that the salutogenic orientation provides, professionals may support the individual to strengthen SOC and thereby facilitate the movement towards health.

  • 241.
    Ahrén, Maria
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Olsson, Petter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Söderlind, Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Klasson, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Petoral, Rodrigo Jr
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Center for Medical Image Science and Visualization, CMIV.
    Käll, Per-Olov
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry .
    Uvdal, Kajsa
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Rare earth nanoparticles as contrast agent in MRI: Nanomaterial design and biofunctionalization2007In: IVC-17/ICSS-13 ICNT,2007, 2007Conference paper (Other academic)
  • 242.
    Ahrén, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Selegård, Linnéa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Klasson, Anna
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 8, 5753-5762 p.Article in journal (Refereed)
    Abstract [en]

    Recently, much attention has been given to the development of biofunctionalized nanoparticles with magnetic properties for novel biomedical imaging. Guided, smart, targeting nanoparticulate magnetic resonance imaging (MRI) contrast agents inducing high MRI signal will be valuable tools for future tissue specific imaging and investigation of molecular and cellular events. In this study, we report a new design of functionalized ultrasmall rare earth based nanoparticles to be used as a positive contrast agent in MRI. The relaxivity is compared to commercially available Gd based chelates. The synthesis, PEGylation, and dialysis of small (3−5 nm) gadolinium oxide (DEG-Gd2O3) nanoparticles are presented. The chemical and physical properties of the nanomaterial were investigated with Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, and dynamic light scattering. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. The proton relaxation times as a function of dialysis time and functionalization were measured at 1.5 T. A capping procedure introducing stabilizing properties was designed and verified, and the dialysis effects were evaluated. A higher proton relaxivity was obtained for as-synthesized diethylene glycol (DEG)-Gd2O3 nanoparticles compared to commercial Gd-DTPA. A slight decrease of the relaxivity for as-synthesized DEG-Gd2O3 nanoparticles as a function of dialysis time was observed. The results for functionalized nanoparticles showed a considerable relaxivity increase for particles dialyzed extensively with r1 and r2 values approximately 4 times the corresponding values for Gd-DTPA. The microscopy study showed that PEGylated nanoparticles do not activate neutrophils in contrast to uncapped Gd2O3. Finally, the nanoparticles are equipped with Rhodamine to show that our PEGylated nanoparticles are available for further coupling chemistry, and thus prepared for targeting purposes. The long term goal is to design a powerful, directed contrast agent for MRI examinations with specific targeting possibilities and with properties inducing local contrast, that is, an extremely high MR signal at the cellular and molecular level.

  • 243.
    Aifa, Sami
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Aydin, J
    Nordvall, G
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Svensson, Samuel
    Hermanson, O
    A basic peptide within the juxtamembrane region is required for EGF receptor dimerization2005In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 302, no 1, 108-114 p.Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is fundamental for normal cell growth and organ development, but has also been implicated in various pathologies, notably tumors of epithelial origin. We have previously shown that the initial 13 amino acids (P13) within the intracellular juxtamembrane region (R645-R657) are involved in the interaction with calmodulin, thus indicating an important role for this region in EGFR function. Here we show that P13 is required for proper dimerization of the receptor. We expressed either the intracellular domain of EGFR (TKJM) or the intracellular domain lacking P13 (ΔTKJM) in COS-7 cells that express endogenous EGFR. Only TKJM was immunoprecipitated with an antibody directed against the extracellular part of EGFR, and only TKJM was tyrosine phosphorylated by endogenous EGFR. Using SK-N-MC cells, which do not express endogenous EGFR, that were stably transfected with either wild-type EGFR or recombinant full-length EGFR lacking P13 demonstrated that P13 is required for appropriate receptor dimerization. Furthermore, mutant EGFR lacking P13 failed to be autophosphorylated. P13 is rich in basic amino acids and in silico modeling of the EGFR in conjunction with our results suggests a novel role for the juxtamembrane domain (JM) of EGFR in mediating intracellular dimerization and thus receptor kinase activation and function. © 2004 Elsevier Inc. All rights reserved.

  • 244. Aifa, Sami
    et al.
    Johansen, Knut
    Nilsson, Ulrica K
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Svensson, Samuel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Interactions between the juxtamembrane domain of the EGFR and calmodulin measured by surface plasmon resonance2002In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 14, no 12, 1005-1013 p.Article in journal (Refereed)
    Abstract [en]

    One early response to epidermal growth factor receptor (EGFR) activation is an increase in intracellular calcium. We have used surface plasmon resonance (SPR) to study real-time interactions between the intracellular juxtamembrane (JM) region of EGFR and calmodulin. The EGFR-JM (Met644-Phe688) was expressed as a GST fusion protein and immobilised on a sensor chip surface. Calmodulin specifically interacts with EGFR-JM in a calcium-dependent manner with a high on and high off rate. Chemical modification of EGFR-JM by using arginine-selective phenylglyoxal or deletion of the basic segment Arg645-Arg657 inhibits the interaction. Phosphorylation of EGFR-JM by protein kinase C (PKC) or glutamate substitution of Thr654 inhibits the interaction, suggesting that PKC phosphorylation electrostatically interferes with calmodulin binding to basic arginine residues. Calmodulin binding was also inhibited by suramin. Our results suggest that EGFR-JM is essential for epidermal growth factor (EGF)-mediated calcium-calmodulin signalling and for signal integration between other signalling pathways.

  • 245.
    Aifa, Sami
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Miled, N
    Frikha, F
    Aniba, MR
    Svensson, Samuel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Rebai, A
    Electrostatic interactions of peptides flanking the tyrosine kinase domain in the epidermal growth factor receptor provides a model for intracellular dimerization and autophosphorylation2006In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, Vol. 62, no 4, 1036-1043 p.Article in journal (Refereed)
    Abstract [en]

    The mechanism by which ligand-activated EGFR induces autophosphorylation via dimerization is not fully understood. Structural studies have revealed an extracellular loop mediated receptor dimerization. We have previously presented experimental data showing the involvement of a positive 13 amino acid peptide (R645-R657, P13+) from the intracellular juxtamembrane domain (JM) of EGFR important for intracellular dimerization and autophosphorylation. A model was presented that suggest that P13+ interacts with a negative peptide (D979-E991, P13-) positioned distal to the tyrosine kinase domain in the opposite EGFR monomer. The present work shows additional data strengthening this model. In fact, by analyzing protein sequences of 21 annotated ErbB proteins from 9 vertebrate genomes, we reveal the high conservation of peptides P13+ and P13- with regard to their sequence as well as their position relative to the tyrosine kinase (TK) domain. Moreover in silico structure modeling of these ErbB intracellular domains supports a general electrostatic P13+/P13- interaction, implying that the C-terminal of one receptor monomer is facing the TK domain of the other monomer in the receptor dimer and vice versa. This model provides new insights into the molecular mechanism of ErbB receptor activation and suggests a new strategy to pharmacologically interfering with ErbB receptor activity. © 2005 Wiley-Liss, Inc.

  • 246.
    Aili Fagerholm, Siri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Increasing numbers of people world-wide develops the disease type 2 diabetes. Development of type 2 diabetes is characterized by a shift from an insulin sensitive state to an insulin resistant state in peripheral insulin responding organs, which originates from the development of insulin resistance in the adipose tissue. Insulin resistance in combination with reduced pancreatic insulin secretion lead to overt type 2 diabetes.

    In this thesis, the insulin signaling network in primary adipocytes was analyzed. Key proteins and mechanisms were studied to gain deeper knowledge of signaling both in the insulin sensitive state and in the insulin resistant state produced by rapid weight gain as well as in type 2 diabetes.

    The surface of the adipocyte is dotted with invaginations in the cell membrane called caveolae that act as important metabolic and signaling platforms in adipocytes, and also harbor the insulin receptor. In paper I we show that insulin stimulation of primary adipocytes results in a rapid phosphorylation of the insulin receptor and caveolin-1, and that internalization of the proteins is mediated by endocytosis of caveolae.

    Weight gain due to overfeeding and obesity has been associated with the development of insulin resistance in insulin sensitive tissues such as the adipose tissue. In paper II we show that short-term overfeeding for one month of lean subjects results in an insulin resistant state. At the end of the study, the subjects had developed a mild systemic insulin resistance. Moreover, in isolated subcutaneous adipocytes we found several alterations of the insulin signaling pathway that mimicked alterations found in isolated subcutaneous adipocytes from subjects with type 2 diabetes.

    In paper III we present a first dynamic mathematical model of the insulin signaling network in human adipocytes that are based on experimental data acquired in a consistent fashion. The model takes account of insulin signaling in both the healthy, insulin sensitive state and in the insulin resistant state of type 2 diabetes. We show that attenuated mTORC1-mediated positive feedback to control of phosphorylation of IRS1 at Ser307 is an essential component of the insulin resistant state of type 2 diabetes. A future application of the model is the identification and evaluation of drug targets for the treatment of insulin resistance and type 2 diabetes.

    In paper IV we examine the protein kinase that catalyzes the insulin stimulated mTORC1- mediated feedback to IRS1. We find that the phosphorylation of IRS1 at Ser307 is not likely to be catalyzed by the kinases S6K1, mTOR or PKB. However, a catalyzing protein kinase for the in vitro phosphorylation of IRS1 at Ser307 was found to be associated with the complex mTORC1.

    In conclusion, this thesis provide new insights and characterize mechanisms of the intrinsically complex insulin signaling network of primary adipocytes, both in insulin sensitive and insulin resistant states.

  • 247.
    Aittomaki, K.
    et al.
    Aittomäki, K., Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland, Department of Clinical Genetics, Helsinki University Central Hospital, POB 140, FI-00029 HUS Helsinki, Finland.
    Bergh, C.
    Department of Obstetrics, Institute of Women and Children's Health, Sahlgrenska University Hospital, Göteborg, Sweden.
    Hazekamp, J.
    Department of Reproductive Medicine, Volvat Medical Center, Oslo, Norway.
    Nygren, K.-G.
    IVF Clinic, Sophiahemmet, Stockholm, Sweden.
    Selbing, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Soderstrom-Anttila, V.
    Söderström-Anttila, V., Infertility Clinic, Family Federation of Finland, Helsinki, Finland.
    Wennerholm, U.-B.
    Department of Obstetrics, Institute of Women and Children's Health, Sahlgrenska University Hospital, Göteborg, Sweden.
    Genetics and assisted reproduction technology2005In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, Vol. 84, no 5, 463-473 p.Article, review/survey (Refereed)
    Abstract [en]

    In the past 20 years, a significant improvement has been shown in the treatment for infertility in both women and men through the development of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Only donated sperm could be previously used for treatment, now oocytes can also be donated. Furthermore, the combination of IVF and ICSI with advanced genetic methods has made preimplantation genetic diagnosis possible for many genetic conditions. These methods enable genetic testing of the early human embryo by using only a single cell, one blastomere biopsied from the embryo, as the sample from which the diagnosis of many chromosome rearrangements and other inherited diseases can be made. It has also been established that a considerable proportion of infertility is caused by genetic defects, which have several implications for infertility treatment. The purpose of this review is to give a concise introduction on how genetics is involved in assisted reproduction technology to specialists who may not be working in this particular field of gynecology, but who would need some knowledge of this for proper care of their patients. © Acta Obstet Gynecol Scand (2005).

  • 248. Aittomäki, K
    et al.
    Wennerholm, U-B
    Bergh, C
    Selbing, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Hazekamp, J
    Nygren, K-G
    Safety issues in assisted reproduction technology. Should ICSI patients have genetic testing before treatment? A practical proposition to help patient information2004In: Human Reproduction, ISSN 0268-1161, Vol. 19, no 3, 472-476 p.Article in journal (Refereed)
    Abstract [en]

    ICSI is a highly efficient treatment of male factor infertility and therefore increasingly used to treat infertile men successfully. However, when used to treat patients with a genetic cause for their infertility, there may be an increased risk for the offspring. Chromosome aberrations, Y chromosome microdeletions and CFTR (cystic fibrosis transmembrane conductance regulator) mutations alone may explain up to 25% of azoospermia and severe oligozoospermia. These genetic defects could be identified before treatment, in which case informed decisions could be made by the couple to be treated concerning the treatment, prenatal testing or preimplantation genetic diagnosis. Therefore, we propose that men with very low sperm counts (<5 × 106/ml) considering ICSI should always be informed of the possibility of genetic testing. The information should include a precise statement of the implications of the results for the patient, his family and his offspring, and reassurance that a decision to test or not to test, or the subsequent test results will not be used as a reason for withholding treatment. Testing should always remain voluntary, and the couples themselves should decide whether or not they choose to be tested. If an abnormality is identified, patients should be referred to specialist genetic counselling.

  • 249.
    Aittoniemi, J
    et al.
    Klin mikro Tampere, Finland.
    Turpeinen, H
    Virologen Turku, Finland.
    Tiitanen, M
    National Public Health Institute Helsinki, Finland.
    Knip, M
    Hospital for Children and Adolescents Helsinki, Finland.
    Simell, O
    Paediatrics Turku, Finland.
    Ilonen, J
    Virologen Turku, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Relation among mannose-binding lectin 2 genotype, β-cell autoantibodies, and risk for type 1 diabetes in Finnish children2008In: Human Immunology, ISSN 0198-8859, Vol. 69, no 2, 108-111 p.Article in journal (Refereed)
    Abstract [en]

    Mannose-binding lectin (MBL) is a key mediator of innate immunity, the insufficiency of which is caused by point mutations in the MBL2 gene. MBL insufficiency is associated with increased susceptibility to infections and certain autoimmune diseases, but its impact in the pathogenesis and risk of type 1 diabetes (T1D) is controversial. We investigated the significance of the MBL2 genotype on the risk of T1D in a Finnish study population comprising 470 diabetic children and 501 controls. Furthermore, the effect of MBL2 gene polymorphism on the emergence of β-cell autoantibodies in 289 unaffected children with human leukocyte antigen-conferred susceptibility to T1D was assessed. MBL genotype had no significant effect on the risk or onset age of T1D. However, children with the biallelic variant genotype reflecting total MBL deficiency tested positive more frequently for ≥3 autoantibodies compared with children with another genotype (odds ratio = 6.0, 95% confidence interval 1.3-28, p = 0.013). In conclusion, the MBL2 genotype did not affect susceptibility to T1D in children, and this finding does not support previous reports implicating a role of the MBL2 genotype as a factor predisposing to T1D. The association of the biallelic variant genotype with positivity for multiple autoantibodies suggests that intermolecular epitope spreading may be linked with impaired clearance of autoantigens as a result of MBL deficiency. © 2008 American Society for Histocompatibility and Immunogenetics.

  • 250.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Fuellhase, Claudius
    University of Munich, Germany.
    Ito, Hiroki
    University of Tokyo, Japan.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan .
    Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 3, 956-963 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Materials and Methods: Female Sprague Dawley (R) rats were anesthetized. Single unit afferent activity of A delta or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. Results: A total of 102 single afferent fibers (48 A delta and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean +/- SEM of 78% +/- 9% and of A delta-fibers to a mean of 67% +/- 7% while increasing bladder compliance to a mean of 116% +/- 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only A delta-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. Conclusions: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Ad and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

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