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  • 351.
    Homeyer, Andre
    et al.
    Fraunhofer MEVIS, Germany.
    Nasr, Patrik
    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 Gastroentorology.
    Engel, Christiane
    Fraunhofer MEVIS, Germany.
    Kechagias, Stergios
    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 Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ekstedt, Mattias
    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 Gastroentorology.
    Kost, Henning
    Fraunhofer MEVIS, Germany.
    Weiss, Nick
    Fraunhofer MEVIS, Germany.
    Palmer, Tim
    University of Leeds, England.
    Karl Hahn, Horst
    Fraunhofer MEVIS, Germany.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. University of Leeds, England; Leeds Teaching Hospital NHS Trust, England.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Automated quantification of steatosis: agreement with stereological point counting2017In: Diagnostic Pathology, ISSN 1746-1596, E-ISSN 1746-1596, Vol. 12, article id 80Article in journal (Refereed)
    Abstract [en]

    Background: Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist. Methods: The evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability. Results: The new method showed the strongest agreement with the expert. At 20x resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10x resolution, it was more accurate than and twice as fast as all other methods at 20x resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer. Conclusions: The results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers.

  • 352.
    Horner, Patrick J
    et al.
    School of Social and Community Medicine, University of Bristol, UK.
    Karla, Blee
    Bristol Sexual Health Centre, University Hospitals Bristol NHS Foundation Trust, UK.
    Falk, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    van der Meijden, W
    Department of Dermatology, New Cross Hospital, UK..
    Moi, H.
    Olafia Clinic, Oslo University Hospital, Institute of Medicine, University of Oslo, Norway.
    2016 European Guideline on the management of non-gonococcal urethritis2016In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 27, no 11, p. 928-937Article in journal (Refereed)
    Abstract [en]

    We present the updated International Union against Sexually Transmitted Infections guideline for the management of non-gonococcal urethritis in men. This guideline recommends confirmation of urethritis in symptomatic men before starting treatment. It does not recommend testing asymptomatic men for the presence of urethritis. All men with urethritis should be tested for Chlamydia trachomatis and Neisseria gonorrhoeae and ideally M. genitalium using a NAAT as this is highly likely to improve clinical outcomes. If a NAAT is positive for gonorrhoea, a culture should be performed before treatment. In view of the increasing evidence that azithromycin 1 g may result in the development of antimicrobial resistance in Mycoplasma genitalium azithromycin 1 g is no longer recommended as first line therapy, which should be doxycycline 100 mg bd for 7 days. If azithromycin is to be prescribed an extended of 500 mg, then 250 mg daily for 4 days is to be preferred over 1 g stat. In men with persistent NGU, M. genitalium NAAT testing is recommended if not previously undertaken, as is Trichomonas vaginalis NAAT testing in populations where T. vaginalis is detectable in >2% of symptomatic women.

  • 353.
    Huang-Link, Yu-Min
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Al-Hawasi, Abbas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lindehammar, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning.2015In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 36, no 4, p. 617-620Article in journal (Refereed)
    Abstract [en]

    Optic neuritis (ON) causes axonal loss as reflected by thinning of retinal nerve fiber layer (RNFL) and can be tracked by optical coherence tomography (OCT) about 6 months after ON onset, when swelling of optic nerve head (ONH) has vanished. Changes of macular ganglion cell layer (GCL) thickness provide another window to track the disease process in ON. GCL thinning over time in relation to RNFL change after ON remains elusive. Using OCT, we followed 4 patients with acute unilateral isolated ON for more than 9 months. A diagnosis of multiple sclerosis (MS) was established in all 4 patients. First follow-up was 2-3 weeks after ON onset, and thereafter every 2-3 months. RNFL swelling peaked during first month after acute ON, followed by rapidly reduced swelling (pseudoatrophy) during following 2 months, and thereafter successively vanished 6 months after ON onset. GCL thinning was observed 1-3 months after ON onset, i.e. already during optic disk swelling and before real RNFL thinning. The results imply that quantifying GCL thickness provides opportunities to monitor early axonal loss and ON-to-MS progression, and facilitates distinguishing real atrophy from pseudoatrophy of RNFL after acute ON.

  • 354.
    Huang-Link, Yu-Min
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Al-Hawasi, Abbas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Oberwahrenbrock, Timm
    Charite University of Medical Berlin, Germany.
    Jin, Ya-Ping
    University of Toronto, Canada.
    OCT measurements of optic nerve head changes in idiopathic intracranial hypertension2015In: Clinical neurology and neurosurgery (Dutch-Flemish ed. Print), ISSN 0303-8467, E-ISSN 1872-6968, Vol. 130, p. 122-127Article in journal (Refereed)
    Abstract [en]

    Objective: Severity of papilledema and vision loss constitute a basis for therapeutic intervention in idiopathic intracranial hypertension (IIH), but both are often subjective and insensitive in guiding clinical management. The aim of this study was to identify reliable and sensitive measurements of optic nerve head (ONH) and macula, to provide objective guidance for prognostic evaluation and treatment in IIH. We analyzed potential of spectral domain optical coherence tomography (SD-OCT), to measure neuro-retinal rim thickness and area, optic cup-to-disc ratio (C/D) and cup volume of ONH which have not previously been reported in IIH. In parallel, thickness of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL) together with inner plexiform layer (IPL) (GCL-IPL) were examined. Results: All 7 enrolled IIH patients had increased neuro-retinal rim thickness (p less than 0.01 for both eyes) and rim area (p less than 0.05), decreased C/D (p less than 0.01) and optic cup volume (p less than 0.01) when compared to findings in 18 sex- and age-matched healthy controls (HC). In a longitudinal study, two IIH patients were followed repetitively by SD-OCT before and after measurement of intracranial pressure (ICP) and removal of cerebrospinal fluid (CSF) by lumbar puncture. Rim thickness and area, C/D and optic cup volume remained altered. RNFL thickness may change with very high ICP, but not immediately after CSF removal. GCL-IPL thickness was unchanged irrespective of ICP change or CSF removal. Conclusion: SD-OCT allows detection of ONH changes even in subtle IIH without papilledema and has potential for routine use in IIH.

  • 355.
    Huang-Link, YuMin
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    Eleftheriou, Andreas
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Yang, G.
    Southern Med Univ, Peoples R China.
    Johansson, J. M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Apostolou, Alexandros
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Link, H.
    Karolinska Inst, Sweden.
    Jin, Y-P
    Univ Toronto, Canada.
    Optical coherence tomography represents a sensitive and reliable tool for routine monitoring of idiopathic intracranial hypertension with and without papilledema2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no 5, p. 808-+Article in journal (Refereed)
    Abstract [en]

    Background and purpose We previously reported that certain optical coherence tomography (OCT) measures were sensitive and reliable in identifying idiopathic intracranial hypertension (IIH). This prospective study aimed to define OCT measures that allow differentiation of IIH with and without papilledema, thereby helping clinical decision-making. Methods Eight patients with IIH with papilledema, nine without papilledema and 19 with other neurological diseases were included. OCT measures were obtained before lumbar puncture and within 2 h, 1, 3 and 6 months after lumbar puncture with cerebrospinal fluid (CSF) removal. Results All patients with papilledema had increased retinal nerve fiber layer (RNFL) thickness and elevated CSF pressure. All patients without papilledema had normal RNFL but elevated CSF pressure. After CSF removal, reduced RNFL thickness was registered in all eight patients with IIH with papilledema. No significant change in RNFL thickness after CSF removal was observed in IIH without papilledema or in patients with other neurological diseases, although reduced CSF pressure was documented. RNFL thickness tended to be normal in patients with IIH with papilledema at 3-6 months after CSF removal. All patients with IIH showed increased rim area and rim thickness, but reduced optic cup volume regardless of RNFL thickness or papilledema. Conclusions Retinal nerve fiber layer thickness is sensitive for monitoring acute IIH and evaluating treatment effect. Increased rim area and rim thickness and decreased optic cup volume are reliable parameters that indicate persistently increased CSF pressure and risk of relapse. OCT measures are sensitive and reliable for diagnosing subtle IIH even in the absence of papilledema.

  • 356.
    Huang-Link, Yu-Min
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Link, Hans
    Karolinska Institute, Sweden.
    Benign Multiple Sclerosis is Associated with Reduced Thinning of the Retinal Nerve Fiber and Ganglion Cell Layers in Non-Optic-Neuritis Eyes2015In: JOURNAL OF CLINICAL NEUROLOGY, ISSN 1738-6586, Vol. 11, no 3, p. 241-247Article in journal (Refereed)
    Abstract [en]

    Background and Purpose It is exceedingly difficult to differentiate benign multiple sclerosis (BMS) from relapsing-remitting multiple sclerosis (RRMS) based on clinical characteristics, neuroimaging, and cerebrospinal fluid tests. Optical coherence tomography (OCT) allows quantification of retinal structures, such as the retinal nerve fiber layer (RNFL) thickness, at the optic disc and the ganglion cell layer (GCL) at the macula, on a micrometer scale. It can also be used to trace minor alterations and the progression of neurodegeneration, help predict BMS, and influence the choice of therapy. To utilize OCT to detect the extent of changes of the optic disk and macular microstructure in patients with BMS and RRMS compared to healthy controls (HCs), with special focus on changes related to the presence/absence of optic neuritis (ON). Methods Spectral-domain OCT was applied to examine eyes from 36 patients with multiple sclerosis (MS), comprising 11 with BMS and 25 with RRMS, and 34 HCs. Results The RNFL and GCL were significantly thinner in eyes previously affected by ON, irrespective of the type of MS (i.e., BMS or RRMS), than in HCs. Significant thinning of the GCL was also observed in non-ON RRMS (and not non-ON BMS) compared to HCs. Correspondingly, a significant association between disease duration and thinning rates of the RNFL and GCL was observed only in non-ON RRMS (-0.54 +/- 0.24 and -0.43 +/- 0.21 mu m/year, mean SE; pless than0.05 for both), and not in non-ON BMS (-0.11 +/- 0.27 and -0.24 +/- 0.24 mu m/year). Conclusions The RNFL and GCL were thinner in both ON- and non-ON MS, but the change was more pronounced in ON MS, irrespective of the MS subtype studied herein. GCL thinning and the thinning rate of both the GCL and RNFL were less pronounced in non-ON BMS than in non-ON RRMS. These findings may help to predict the course of BMS.

  • 357.
    Hultcrantz, Elisabeth
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Nosrati Zare Noe, Ramesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Corticosteroid treatment of idiopathic sudden sensorineural hearing loss: analysis of an RCT and material drawn from the Swedish national database2015In: European Archives of Oto-Rhino-Laryngology, ISSN 0937-4477, E-ISSN 1434-4726, Vol. 272, no 11, p. 3169-3175Article in journal (Refereed)
    Abstract [en]

    A randomized placebo-controlled study has demonstrated no effect of prednisolone in customary dosage on idiopathic sudden sensorineural hearing loss (ISSNHL). The aim of the present paper is to analyse a larger patient group by meta-analysis of data from the RCT together with a corresponding material drawn from the Swedish national database for ISSNHL. Data from 192 patients, 18-80 years with ISSNHL, were available. All had an acute hearing loss of at least 30 dB measured as PTA in the three most affected contiguous frequencies. All patients had been enrolled within one week after onset and evaluated by audiograms after 3 months. 45/99 (RCT) and 54/99 (the database) had been treated with prednisolone in tapering doses from 60 mg daily and 42/93 with placebo (RCT) or 51/93 with no treatment (the database). Primary outcome was the mean hearing improvement on day 90 for the different groups. A mean difference of greater than 10 dB improvement was required to demonstrate a treatment effect for prednisolone compared to placebo/no treatment. No significant difference was seen between the prednisolone group and placebo/no treatment (p = 0.06). Total recovery was 38 % in prednisolone group, 40 % in the placebo and 14 % in the no treatment group. Vertigo at the onset of hearing loss and age at onset had an equal negative prognostic value in all groups and signs of inflammation had a positive effect. Prednisolone in customary dosage does not influence recovery after ISSNHL.

  • 358.
    Hägg, Mary K. D.
    et al.
    Hudiksvall Hospital, Sweden; Uppsala University, Sweden.
    Tibbling, Lita I. E.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Effects on facial dysfunction and swallowing capacity of intraoral stimulation early and late after stroke2015In: NeuroRehabilitation (Reading, MA), ISSN 1053-8135, E-ISSN 1878-6448, Vol. 36, no 1, p. 101-106Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Most patients with post-stroke dysphagia are also affected by facial dysfunction in all four facial quadrants. Intraoral stimulation can successfully treat post-stroke dysphagia, but its effect on post-stroke facial dysfunction remains unknown. OBJECTIVE: This study aimed to investigate whether intraoral stimulation after stroke has simultaneous effects on facial dysfunction in the contralateral lower facial quadrant and in the other three facial quadrants, on lip force, and on dysphagia. METHODS: Thirty-one stroke patients were treated with intraoral stimulation and assessed with a facial activity test, lip force test, and swallowing capacity test at three time-points: before treatment, at the end of treatment, and at late follow-up (over one year after the end of treatment). RESULTS: Facial activity, lip force, and swallowing capacity scores were all improved between baseline and the end of treatment (P less than 0.001 for each), with these improvements remaining at late follow-up. Baseline and treatment data did not significantly differ between patients treated short and late after stroke. CONCLUSIONS: Treatment with intraoral stimulation significantly improved post-stroke dysfunction in all four facial quadrants, swallowing capacity, and lip force even in cases of long-standing post-stroke dysfunction. Furthermore, such improvement remained for over one year after the end of treatment.

  • 359.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
    Biomarkers and Disease Activity in Multiple Sclerosis: A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors.

    Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without.

    Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3).

    Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p≤0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters.

    Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.

    List of papers
    1. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
    Open this publication in new window or tab >>Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
    Show others...
    2017 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, no 5, p. 703-712Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

    Place, publisher, year, edition, pages
    WILEY, 2017
    Keywords
    biomarker; clinically isolated syndrome; disease activity; multiple sclerosis; neurofilament light chain
    National Category
    Neurology
    Identifiers
    urn:nbn:se:liu:diva-137379 (URN)10.1111/ene.13274 (DOI)000399704400010 ()28261960 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University, Sweden; University Hospital Linkoping, Sweden; Novartis; Torsten Soderberg foundation; Royal Academy of Sciences, Sweden

    Available from: 2017-05-18 Created: 2017-05-18 Last updated: 2019-10-07
    2. Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
    Open this publication in new window or tab >>Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
    Show others...
    2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 209Article in journal (Refereed) Published
    Abstract [en]

    Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI (R)) were recorded during 4 years of follow-up. Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p amp;lt; 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.

    Place, publisher, year, edition, pages
    BMC, 2018
    Keywords
    Multiple sclerosis; Clinically isolated syndrome; Disease activity; Neurofilament light chain; CHI3L1; CXCL10; Brain volume
    National Category
    Neurology
    Identifiers
    urn:nbn:se:liu:diva-150263 (URN)10.1186/s12974-018-1249-7 (DOI)000439133500001 ()30021640 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University; University Hospital of Linkoping, Sweden; Novartis; Torsten Soderberg Foundation; Royal Academy of Sciences, Sweden

    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-10-07
  • 360.
    Håkansson, Irene
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Gouveia-Figueira, Sandra
    Umea Univ, Sweden.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ghafouri, Nazdar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Nording, Malin
    Umea Univ, Sweden; Univ Calif Davis, CA 95616 USA.
    Oxylipins in cerebrospinal fluid in clinically isolated syndrome and relapsing remitting multiple sclerosis2018In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 138, p. 41-47Article in journal (Refereed)
    Abstract [en]

    Although oxylipins are involved in inflammation, data on these lipid mediators in multiple sclerosis are sparse. In this study, a panel of oxylipins were analysed swith liquid chromatography tandem mass spectrometry in cerebrospinal fluid (CSF) from 41 treatment naive patients with clinically isolated syndrome (CIS) or relapsing remitting MS (RRMS) and 22 healthy controls. CSF levels of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE) were significantly higher in patients than in healthy controls (9-HODE median 380 nM (interquartile range 330-450 nM) in patients and 290 nM (interquartile range 250-340 nM) in controls, 13-HODE median 930 nM (interquartile range 810-1080 nM) in patients and 690 nM (interquartile range 570-760 nM) in controls, p amp;lt; 0.001 in Mann-Whitney U tests). 9-HODE and 13-HODE performed well for separation of patients and healthy controls (AUC 0.85 and 0.88, respectively, in ROC curve analysis). However, baseline CSF levels of the oxylipins did not differ between patients with signs of disease activity during one, two and four years of follow-up and patients without. In conclusion, this study indicates that 9-HODE and 13-HODE levels are increased in CSF from CIS and RRMS patients compared with healthy controls, but does not support 9-HODE or 13-HODE as prognostic biomarkers of disease activity in patients during follow-up.

  • 361.
    Håkansson, Irene
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lundin, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Askmark, Håkan
    University of Uppsala Hospital, Sweden.
    Pirskanen, Ritva
    Karolinska Institute, Sweden.
    Carlson, Kristina
    University Hospital, Sweden.
    Piehl, Fredrik
    Karolinska Institute, Sweden.
    Hägglund, Hans
    University Hospital, Sweden.
    Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis - a case report2017In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 27, no 1, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Myasthenia gravis (MG) is an autoimmune disease, with immune reactivity against the post-synaptic endplate of the neuromuscular junction. Apart from symptomatic treatment with choline esterase blockers, many patients also require immunomodulatory treatment. Despite existing treatment options, some patients are treatment refractory. We describe a patient with severe MG refractory to corticosteroids, four oral immunosuppressants, cyclophosphamide, rituximab and bortezomib who was treated with autologous haematopoietic stem cell transplantation. Two years after this, the patient has significantly improved in objective tests and in quality of life and leads an active life. Diplopia is her only remaining symptom and she is completely free of medication for MG. We believe that autologous haematopoietic stem cell transplantation can be an effective therapeutic option for carefully selected cases of severe, treatment refractory MG. (c) 2016 Elsevier B.V. All rights reserved.

  • 362.
    Håkansson, Irene
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tisell, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cassel, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Blennow, K.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Zetterberg, H.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden; UCL Institute Neurol, England.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis2017In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, no 5, p. 703-712Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

  • 363.
    Håkansson, Irene
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Tisell, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Cassel, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Blennow, Kaj
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; UCL Inst Neurol, England; UCL, England.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis2018In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 209Article in journal (Refereed)
    Abstract [en]

    Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI (R)) were recorded during 4 years of follow-up. Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p amp;lt; 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.

  • 364.
    Icenhour, Adriane
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Witt, Suzanne
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Elsenbruch, Sigrid
    University of Duisburg Essen, Germany.
    Lowén, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Tillisch, Kirsten
    University of Calif Los Angeles, CA USA.
    Mayer, Emeran A.
    University of Calif Los Angeles, CA USA.
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome2017In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 15, p. 449-457Article in journal (Refereed)
    Abstract [en]

    Increased perception of visceral stimuli is a key feature of Irritable Bowel Syndrome (IBS). While altered resting-state functional connectivity (rsFC) has been also reported in IBS, the relationship between visceral hypersensitivity and aberrant rsFC is unknown. We therefore assessed rsFC within the salience, sensorimotor and default mode networks in patients with and without visceral hypersensitivity and in healthy controls (HCs). An exploratory resting-state functional magnetic resonance imaging study was performed in 41 women with IBS and 20 HCs. Group independent component analysis was used to derive intrinsic brain networks. Rectal thresholds were determined and patients were subdivided into groups with increased (hypersensitive IBS, N = 21) or normal (normosensitive IBS, N= 20) visceral sensitivity. Between-group comparisons of rsFC were carried-out using region-of-interest analyses and peak rsFC values were extracted for correlational analyses. Relative to normosensitive IBS, hypersensitive patients showed increased positive rsFC of pregenual anterior cingulate cortex and thalamus within the salience network and of posterior insula within the sensorimotor network. When compared to both hypersensitive IBS and HCs, normosensitive IBS showed decreased positive rsFC of amygdala and decreased negative rsFC in dorsal anterior insula within the DMN. DMN and sensorimotor network rsFC were associated with rectal perception thresholds, and rsFC in posterior insula was correlated with reported symptom severity in IBS. Our exploratory findings suggest that visceral sensitivity in IBS is related to changes in FC within resting-state networks associated with interoception, salience and sensory processing. These alterations may play an important role in hypervigilance and hyperalgesia in IBS.

  • 365.
    Idh, Jonna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Blanka
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Woksepp, Hanna
    Linneaus University, Sweden; Kalmar County Hospital, Sweden.
    Werngren, Jim
    Public Health Agency Sweden, Sweden.
    Mansjo, Mikael
    Public Health Agency Sweden, Sweden.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linneaus University, Sweden; Kalmar County Hospital, Sweden.
    Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0181221Article in journal (Refereed)
    Abstract [en]

    Background Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis. Method Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry. NO-dependent intracellular killing in a selection of strains was assessed in interferon gamma/lipopolysaccharide-activated murine macrophages using the NO inhibitor L-NMMA. Results When M. tuberculosis H37Rv was compared to six clinical isolates and CDC1551, three isolates with inhA mediated INH resistance showed significantly reduced NO-susceptibility in broth culture. All strains showed a variable but dose-dependent susceptibility to RNS donors. Two clinical isolates with increased susceptibility to NO exposure in broth compared to H37Rv were significantly inhibited by activated macrophages whereas there was no effect on growth inhibition when activated macrophages were infected by clinical strains with higher survival to NO exposure in broth. Furthermore, the most NO-tolerant clinical isolate showed increased resistance to PRT both in broth culture and the macrophage model compared to H37Rv in the absence of mutational resistance in genes associated to reduced susceptibility against PRT or NO. Conclusion In a limited number of clinical M. tuberculosis isolates we found a significant difference in susceptibility to NO between clinical isolates, both in broth cultures and in macrophages. Our results indicate that mycobacterial susceptibility to cellular host defence mechanisms such as NO need to be taken into consideration when designing new therapeutic strategies.

  • 366.
    Ighe, Anna
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, The Swedish Institute for Disability Research. Linköping University, Faculty of Arts and Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Application of the 2012 systemic lupus international collaborating clinics classification criteria to patients on a Regional Swedish systemic lupus erythematosus register2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 3Article in journal (Refereed)
    Abstract [en]

    Introduction

    In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) network presented a new set of criteria (SLICC-12) to classify systemic lupus erythematosus (SLE). The present study is the first to evaluate the performance of SLICC-12 in an adult European study population. Thus, SLICC-12 criteria were applied to confirmed SLE cases in our regional SLE register as well as to individuals with a fair suspicion of systemic autoimmune disease who were referred to rheumatology specialists at our unit.     

    Methods

    We included 243 confirmed SLE patients who met the 1982 American College of Rheumatology (ACR-82) classification criteria and/or the Fries ‘diagnostic principle’ (presence  of antinuclear antibodies on at least one occasion plus involvement of at least two defined organ systems) and 55 controls with possible systemic autoimmune disease, including the presence of any SLE-related autoantibody.     

    Results

    SLICC-12 showed a diagnostic sensitivity of 94% (95% confidence interval (CI), 0.90 to 0.96) compared with 90% (95% CI, 0.85 to 0.93) for the updated set of ACR criteria from 1997 (ACR-97), whereas ACR-82 failed to identify every fifth true SLE case. However, the disease specificity of SLICC-12 reached only 74% (95% CI, 0.60 to 0.84) and did not change much when involvement of at least two different organs was required as an indicator of systemic disease. In addition, SLICC-12 misclassified more of the controls compared to ACR-82, ACR-97 and Fries.     

    Conclusions

    Establishing a standard definition of SLE continues to challenge lupus researchers and clinicians. We confirm that SLICC-12 has advantages with regard to diagnostic sensitivity, whereas we found the diagnostic specificity to be surprisingly low. To accomplish increased sensitivity and specificity figures, a combination of criteria sets for clinical SLE studies should be considered.

  • 367.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Edén, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Congenital Aniridia and the Ocular Surface2016In: OCULAR SURFACE, ISSN 1542-0124, Vol. 14, no 2, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface, in particular, can be severely affected by a progressive pathology termed aniridia-associated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micro-morphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition.

  • 368.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala Univ, Sweden.
    Carlsson Almlöf, Jonas Carlsson
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogrens Syndrome2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed)
    Abstract [en]

    Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogrens syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.

  • 369.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala Univ, Sweden.
    Carlsson Almlöf, Jonas
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden.
    Nordmark, Gunnel
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Padyukov, Leonid
    Karolinska Inst, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLADQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 370.
    Ingberg, Edvin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Challenges in experimental stroke research: The 17β-estradiol example2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ischemic stroke causes millions of deaths around the world each year, and surviving patients often suffer from long-term disability. Hundreds of promising drug candidates have been identified in animal models, but the clinical trials have repeatedly failed. Lack of methodological quality in the animal studies, e.g. low statistical power as a result of small group sizes in combination with high outcome variability and high mortality, has been suggested to in part explain the lack of translational success. In the meta-analytical Papers II and Paper V, we therefore investigated how method parameters impact infarct size variation and mortality in rodent stroke studies. These findings can help researchers to optimize their animal models or to more exactly predict variability and mortality given a certain experimental setup.

    The relation between ischemic stroke and estrogens is complex. Premenopausal women have a lower risk of stroke than men of the same age, suggesting that female sex hormones provide protection against cerebrovascular events. The idea of a beneficial effect on the brain of estrogens was also supported by epidemiological studies showing that estrogens given as postmenopausal hormone replacement therapy decreased the risk of stroke. However, subsequent clinical trials reported the opposite, an increased risk. Interestingly, discrepancies exist also in the animal stroke literature. The majority of the rodent studies on the effects of estrogens have shown protection, but there are also several examples of increased damage. Based on experimental results and a meta-analysis, it was hypothesized that differences in hormone administration methods and their resulting plasma concentrations of estrogens might explain the previous discordant animal findings. Paper I investigated the commonly used methods for 17β-estradiol administration and found that the popular slow-release pellets produced high and unpredictable serum concentrations. A novel method with 17β-estradiol administered orally in Nutella® was also evaluated with promising results. Paper III extracted data regarding methodological choices from all previously published estrogen-stroke studies, and showed through metaanalysis that slow-release pellets are more prone to render estrogens damaging. Finally, Paper IV tested whether estrogens could both exert neuroprotection and promote detrimental effects merely depending on dose and irrespective of the administration route. Surprisingly, and in contrast to the hypothesis, a significant negative correlation was found between 17β-estradiol dose group and infarct size meaning that the higher the dose, the smaller the infarcts.

    In summary, this thesis does not confirm the hypothesis of dose-related neuroprotective vs neurodamaging effects of estrogens on ischemic stroke. If high estrogen doses/plasma concentrations per se can cause increased stroke damage, such a phenomenon is not very robust, and seems to depend on tight dose ranges and/or other experimental circumstances. Although not directly applicable to the clinical situation, hopefully in a long-term perspective these findings may contribute in elucidating when estrogens are beneficial and when they are harmful. Further, it adds to the growing literature on how the quality of experimental stroke research can be increased to try to overcome translational difficulties.

    List of papers
    1. Methods for long-term 17β-estradiol administration to mice
    Open this publication in new window or tab >>Methods for long-term 17β-estradiol administration to mice
    2012 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, no 1, p. 188-193Article in journal (Refereed) Published
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

    Place, publisher, year, edition, pages
    Elsevier, 2012
    Keywords
    Estradiol; Slow-release pellets; Silastic capsule; Per os; Uterine weight
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-107100 (URN)10.1016/j.ygcen.2011.11.014 (DOI)000299065800022 ()22137913 (PubMedID)2-s2.0-84855192470 (Scopus ID)
    Available from: 2014-06-05 Created: 2014-06-05 Last updated: 2018-01-11Bibliographically approved
    2. Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    2013 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 14, no 41Article in journal (Refereed) Published
    Abstract [en]

    Background

    Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods

    We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results

    The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    Conclusions

    The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

    Place, publisher, year, edition, pages
    BioMed Central, 2013
    Keywords
    Brain infarction, Middle cerebral artery occlusion, Rats, Methods, Mortality, Variability
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-93981 (URN)10.1186/1471-2202-14-41 (DOI)000318616000001 ()23548160 (PubMedID)
    Note

    Funding Agencies|County Council of Ostergotland, Sweden||

    Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2017-12-06Bibliographically approved
    3. Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    Open this publication in new window or tab >>Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    2014 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, no 22Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    RESULTS:

    The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    CONCLUSIONS:

    We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Cerebral ischemia; Estradiol; Estrogens; Meta-analysis; Rats; Stroke
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-106875 (URN)10.1186/1471-2202-15-22 (DOI)000334885400001 ()24495535 (PubMedID)
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-01-11Bibliographically approved
    4. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    Open this publication in new window or tab >>Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    2016 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n=40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modifi ed sticky tape test was performed after 24 h and the rats were subsequently sacrifi ced for infarct size measurements. In contrast to our hypothesis, a signifi cant negative correlation between 17β-estradiol dose and infarct size was found (p=0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the fi ndings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

    National Category
    Clinical Medicine Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-123890 (URN)
    Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2018-01-10Bibliographically approved
    5. Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Open this publication in new window or tab >>Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed) Published
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specifi c pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters’ impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2016
    National Category
    Clinical Medicine Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-123892 (URN)10.1038/srep21086 (DOI)000370034300001 ()
    Note

    Funding agencies:  County Council of Ostergotland, Sweden

    Vid tiden för disputation förelåg publikationen endast som manuskript

    Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2018-01-10Bibliographically approved
  • 371.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden.
    Dock, Hua
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Orebro Univ, Sweden.
    Effect of laser Doppler flowmetry and occlusion time on outcome variability and mortality in rat middle cerebral artery occlusion: inconclusive results2018In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 19, article id 24Article in journal (Refereed)
    Abstract [en]

    Background: Stroke is among the leading causes of death and disability. Although intense research efforts have provided promising treatment options in animals, most clinical trials in humans have failed and the therapeutic options are few. Several factors have been suggested to explain this translational difficulty, particularly concerning methodology and study design. Consistent infarcts and low mortality might be desirable in some, but not all, studies. Here, we aimed to investigate whether the use of laser Doppler flowmetry (LDF) and the occlusion time (60 vs. 45 min) affected outcome variability and mortality in a rat stroke model. Eighty ovariectomized female Wistar rats were subjected to ischemic stroke using intraluminal filament middle cerebral artery occlusion with or without LDF and with occlusion times of 45 or 60 min. Outcome was evaluated by triphenyl tetrazolium chloride staining of brain slices to measure infarct size and a modified sticky tape test. Results: Neither LDF nor occlusion times of 45 versus 60 min significantly affected mortality, outcome variability or outcome severity. Conclusions: Due to the unexpectedly high mortality and variability the statistical power was very low and thus the results were inconclusive.

  • 372.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Dock, Hua
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Vårdvetenskapligt Forskningscentrum/Centre for Health Sciences, Örebro University Hospital, Region Örebro Län, Örebro, Sweden / School of Health and Medical Sciences, Örebro University, Örebro, Sweden..
    Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed)
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specifi c pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters’ impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

  • 373.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics.
    Gudjonsdottir, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Council Örebro, Sweden; University of Örebro, Sweden.
    Elevated body swing test after focal cerebral ischemia in rodents: methodological considerations2015In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 16, no 50Article in journal (Refereed)
    Abstract [en]

    Background: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. Results: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). Conclusions: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.

  • 374.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. veÖrebro University Hospital, Sweden; Unirsity of Örebro, Sweden.
    Effects of high and low 17 beta-estradiol doses on focal cerebral ischemia in rats2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 20228Article in journal (Refereed)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17 beta-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17 beta-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17 beta-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17 beta-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17 beta-estradiol, the smaller the infarct.

  • 375.
    Ingberg, Edvin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Ström, Jakob O
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Vårdvetenskapligt Forskningscentrum/Centre for Health Sciences, Örebro University Hospital, Region Örebro Län, Örebro, Sweden / School of Health and Medical Sciences, Örebro University, Örebro, Sweden..
    Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats2016Manuscript (preprint) (Other academic)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n=40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modifi ed sticky tape test was performed after 24 h and the rats were subsequently sacrifi ced for infarct size measurements. In contrast to our hypothesis, a signifi cant negative correlation between 17β-estradiol dose and infarct size was found (p=0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the fi ndings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

  • 376.
    Ingves, Simon
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vilhelmsson, Nathalie
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Edvin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Guldbrand, Hans
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala".
    Nyström, Fredrik H
    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 Endocrinology.
    A randomized cross-over study of the effects of macronutrient composition and meal frequency on GLP-1, ghrelin and energy expenditure in humans2017In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 93, p. 20-26Article in journal (Refereed)
    Abstract [en]

    Objective: Little is known about human postprandial increase of energy expenditure and satiety-associated hormones in relation to both meal frequency and macronutrient composition. Design: Randomized cross-over study with four conditions for each participant. Methods: Seven men and seven women (mean age 23 +/- 1.5 years) were randomly assigned to the order of intake of a 750 kcal drink with the same protein content while having either 20 energy-percent (E%) or 55 E% from carbohydrates and the remaining energy from fat. Participants were also randomized to consume the drinks as one large beverage or as five 150 kcal portions every 30 min, starting in the fasting state in the morning. Energy expenditure (EE) was determined every 30 min by indirect calorimetry. Hormonal responses and suppression of hunger (by visual-analogue scales) were also studied. A p amp;lt; 0.013 was considered statistically significant following Bonferroni-correction. Results: The area under the curve (AUC) for EE was higher during the 2.5 h after the high-carbohydrate drinks (p = 0.005 by Wilcoxon) and also after ingesting one drink compared with five (p = 0.004). AUC for serum active GLP-1 was higher after single drinks compared with five beverages (p = 0.002). Although GLP-1 levels remained particularly high at the end of the test during the low-carbohydrate meals, the AUC did not differ compared with the high-carbohydrate occasions (low-carbohydrate: 58.9 +/- 18 pg/ml/h, high-carbohydrate: 45.2 +/- 16 pg/ml/h, p = 0.028). Hunger sensations were suppressed more after single beverages compared with five small drinks (p = 0.009). Conclusions: We found higher EE during 2.5 h following one large drink compared with five smaller beverages. Since hunger was also suppressed more efficiently, and serum GLP-1 levels were higher after one compared with five smaller drinks, our findings do not support nibbling to avoid hunger or to keep up EE from morning to noon.

  • 377.
    Iranpour, Mahmoud
    et al.
    National Microbiology Laboratory, Canada.
    Moghadam, Adel R.
    Islamic Azad University.
    Yazdi, Mina
    University of Tehran.
    Ande, Sudharsana R.
    University of Manitoba.
    Alizadeh, Javad
    University of Manitoba.
    Wiechec, Emilia
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    Lindsay, Robbin
    National Microbiology Laboratory, Canada.
    Drebot, Michael
    National Microbiology Laboratory, Canada.
    Coombs, Kevin M.
    University of Manitoba.
    Ghavami, Saeid
    University of Manitoba.
    Apoptosis, autophagy and unfolded proteinresponse pathways in Arbovirus replicationand pathogenesis2016In: Expert Reviews in Molecular Medicine, ISSN 1462-3994, E-ISSN 1462-3994, Vol. 18, no e1, p. 21-Article, review/survey (Refereed)
    Abstract [en]

    Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

  • 378.
    Iredahl, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Löfberg, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, p. 1-15, article id e0133760Article in journal (Refereed)
    Abstract [en]

    Introduction Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. Method Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. Results Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9 +/- 6.2 PU; 10-min 100 +/- 25 PU; pless than0.001) and RBC concentration (TiVi: baseline 119 +/- 18; 10-min 150 +/- 41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0 +/- 4.4 PU; 10-min 38.9 +/- 5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6 +/- 11.8 AU; 10-min 54.4 +/- 13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8 +/- 3.6 PU; max 112 +/- 55 PU; pless than0.001, LSCI: baseline 50.8 +/- 8.0 PU; max 151 +/- 22 PU; pless than0.001) and RBC concentration (TiVi: baseline 49.2 +/- 32.9 AU; max 99.3 +/- 28.3 AU; pless than0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: pless than0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (pless than0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. Conclusion LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.

  • 379.
    Islam, Mohammad Mirazul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Harvard Medical School, Boston, MA USA.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Reddy, Jagadesh C
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Pasyechnikova, Nataliya
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Alarcon, Emilio I
    Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON Canada.
    Hayes, Sally
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Lewis, Philip
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    He, Chaoliang
    Key Laboratory of Polymer Eco-materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
    Iakymenko, Stanislav
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Liu, Wenguang
    School of Materials Science and Engineering, Tianjin University, Tianjin, China.
    Meek, Keith M
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Sangwan, Virender S
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Montreal, Montreal, Canada.
    Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation2018In: NPJ Regenerative medicine, ISSN 2057-3995, Vol. 3, article id 2Article in journal (Refereed)
    Abstract [en]

    The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients.

  • 380.
    Islam, Mohammad Mirazul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Ravichandran, Ranjithkumar
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Olsen, D.
    FibroGen Inc, CA 94158 USA.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lee, Chyan-Jang
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation2016In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 61, p. 55745-55749Article in journal (Refereed)
    Abstract [en]

    Extracellular matrix proteins like collagen promote regeneration as implants in clinical studies. However, collagens are large and unwieldy proteins, making small functional peptide analogs potentially ideal substitutes. Self-assembling collagen-like-peptides conjugated with PEG-maleimide were assembled into hydrogels. When tested pre-clinically as corneal implants in mini-pigs, they promoted cell and nerve regeneration, forming neo-corneas structurally and functionally similar to natural corneas.

  • 381.
    Ivars, Katrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nelson Follin, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Gothenburg University, Sweden.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Mörelius, Evalotte
    Linköping University, Department of Social and Welfare Studies, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Correction: Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151888Article in journal (Other academic)
    Abstract [en]

    BACKGROUND:

    Cortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity and daily life trauma on when the rhythm is established. Furthermore, we determine age-related reference intervals for cortisol concentrations in saliva during the first year of life.

    METHODS:

    130 healthy full-term infants were included in a prospective, longitudinal study with saliva sampling on two consecutive days, in the morning (07:30-09:30), noon (10:00-12:00) and evening (19:30-21:30), each month from birth until the infant was twelve months old. Information about development of behavioral regularity and potential exposure to trauma was obtained from the parents through the Baby Behavior Questionnaire and the Life Incidence of Traumatic Events checklist.

    RESULTS:

    A significant group-level circadian rhythm of salivary cortisol secretion was established at one month, and remained throughout the first year of life, although there was considerable individual variability. No correlation was found between development of cortisol circadian rhythm and the results from either the Baby Behavior Questionnaire or the Life Incidence of Traumatic Events checklist. The study presents salivary cortisol reference intervals for infants during the first twelve months of life.

    CONCLUSIONS:

    Cortisol circadian rhythm in infants is already established by one month of age, earlier than previous studies have shown. The current study also provides first year age-related reference intervals for salivary cortisol levels in healthy, full-term infants.

  • 382.
    Ivars, Katrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nelson Follin, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Gothenburg University, Sweden.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mörelius, Evalotte
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129502Article in journal (Refereed)
    Abstract [en]

    Background Cortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity and daily life trauma on when the rhythm is established. Furthermore, we determine age-related reference intervals for cortisol concentrations in saliva during the first year of life. Methods 130 healthy full-term infants were included in a prospective, longitudinal study with saliva sampling on two consecutive days, in the morning (07:30-09:30), noon (10:00-12:00) and evening (19:30-21:30), each month from birth until the infant was twelve months old. Information about development of behavioral regularity and potential exposure to trauma was obtained from the parents through the Baby Behavior Questionnaire and the Life Incidence of Traumatic Events checklist. Results A significant group-level circadian rhythm of salivary cortisol secretion was established at one month, and remained throughout the first year of life, although there was considerable individual variability. No correlation was found between development of cortisol circadian rhythm and the results from either the Baby Behavior Questionnaire or the Life Incidence of Traumatic Events checklist. The study presents salivary cortisol reference intervals for infants during the first twelve months of life. Conclusions Cortisol circadian rhythm in infants is already established by one month of age, earlier than previous studies have shown. The current study also provides first year age-related reference intervals for salivary cortisol levels in healthy, full-term infants.

  • 383.
    Ivars, Katrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Nelson, Nina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Department of Quality and Patient Safety, Karolinska University Hospital, Stockholm, Sweden.
    Theodorsson, Annette
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ström, Jakob O.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Department of Neurology, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden.
    Mörelius, Evalotte
    Linköping University, Department of Social and Welfare Studies, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Development of salivary cortisol circadian rhythm in preterm infants2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0182685Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life.

    METHODS: This prospective, longitudinal study included 51 preterm infants. 130 healthy full-term infants served as controls. Monthly salivary cortisol levels were obtained in the morning (07:30-09:30), at noon (10:00-12:00), and in the evening (19:30-21:30), beginning at gestational age week 28-32 and continuing until twelve months corrected age. Behavioral regularity was studied using the Baby Behavior Questionnaire.

    RESULTS: A salivary cortisol circadian rhythm was established by one month corrected age and persisted throughout the first year. The preterm infants showed a cortisol pattern increasingly more alike the full-term infants as the first year progressed. The preterm infants increase in behavioral regularity with age but no correlation was found between the development of salivary cortisol circadian rhythm and the development of behavior regularity. The time to establish salivary cortisol circadian rhythm differed between preterm and full-term infants according to postnatal age (p = 0.001) and was dependent on gestational age. Monthly salivary cortisol levels for preterm infants from birth until twelve months are presented. Additional findings were that topical corticosteroid medication was associated with higher concentrations of salivary cortisol (p = 0.02) and establishment of salivary cortisol circadian rhythm occurred later in infants treated with topical corticosteroid medication (p = 0.02).

    CONCLUSIONS: Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity.

  • 384.
    Iversen, Clara
    et al.
    Uppsala University, Sweden.
    Broström, Anders
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Jonköping University, Sweden.
    Ulander, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Balancing task focus and relationship building: asking sleepy patients about traffic risk in treatment initiation consultations2017In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 31, no 4, p. 895-903Article in journal (Refereed)
    Abstract [en]

    BackgroundThe use of traffic risk assessment questions is an understudied area in nursing research. Obstructive sleep apnoea is associated with an increased risk of traffic accidents. Therefore, traffic safety authorities demand adherent continuous positive airway pressure use. Nurses act as coaches to achieve treatment adherence, but they are also obliged to act as state agents by prohibiting obstructive sleep apnoea patients from drowsy driving. ObjectiveTo examine how nurses and obstructive sleep apnoea patients manage traffic risk assessment questions in the relation-building context of treatment initiation consultations. MethodsTo study, in detail, the actual practice of risk assessment, we used conversation analysis of 19 video-recorded initial treatment consultations with nurses and recently diagnosed obstructive sleep apnoea patients. EthicsThe study received ethical approval from the Central Ethical Review Board in Linkoping (registration number 214/231-32) and follows the ethical guidelines for qualitative research. ResultsPatients influence how nurses phrase questions about traffic risk by taking a stance to daytime sleepiness prior to the risk question. Nurses ask traffic risk questions in a way that assumes that driving is unproblematic if patients have not previously indicated problems. It may pose a significant problem when nurses, by accepting patients prior stance when asking about traffic risk, orient to relationship building rather than task focus. ConclusionTo clarify the difference between their two potentially conflicting roles, nurses need to refer to existing laws and official guidelines when they raise the issue of risk in treatment initiation consultations. Nurses should also ask risk assessment questions in a problem-oriented communicative environment. Traffic risk assessment is sensitive yet important, as obstructive sleep apnoea is a highly prevalent problem causing excessive sleepiness. It is essential to acknowledge nurses double roles with regard to coaching continuous positive airway pressure treatment and assessing traffic risk.

  • 385.
    Iversen, Clara
    et al.
    Uppsala Univ, Sweden.
    Broström, Anders
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. School of Health and Welfare, Jönköping University, Jönköping, Sweden.
    Ulander, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Traffic risk work with sleepy patients: from rationality to practice2018In: Health, Risk and Society, ISSN 1369-8575, E-ISSN 1469-8331, Vol. 20, no 1-2, p. 23-42Article in journal (Refereed)
    Abstract [en]

    In this article, we aim to contribute to the emerging field of risk-work studies by examining the relationship between risk rationality and risk practices in nurses conversations with Obstructive Sleep Apnoea patients about traffic risks. Legislation in Sweden towards traffic risk involves clinicians making risk assessment of patients prone to falling asleep while driving. In contrast to an overall care rationale, this means that the health of the patient is not the only risk object in treatment consultations. However, guidelines on how to implement legislation are missing. To examine the practical reality of nurses traffic-risk work, we draw on an analysis of data from a Swedish study in 2015. This study included qualitative interviews with specialist nurses and video-recorded interactions between nurses and Obstructive Sleep Apnoea patients. We found that a lack of clarity in traffic-risk guidelines on how risk should be addressed was evident in both interview accounts and in observed practice. While nurses primarily accounted for risk work as treatment-relevant education, they practised risk work as interrogation. Patients also treated nurses inquiries as assessment - not education - by responding defensively. We conclude that while confusing risk work and treatment enables clinicians to treat patients as competent actors, it obscures the controlling aspects of traffic-risk questions for individual patients and downplays the implications of drowsy driving for general traffic safety.

  • 386.
    Janelidze, S.
    et al.
    Lund University, Sweden; Lund University, Sweden.
    Suchankova, P.
    University of Gothenburg, Sweden.
    Ekman, A.
    University of Gothenburg, Sweden.
    Erhardt, S.
    Karolinska Institute, Sweden.
    Sellgren, C.
    Karolinska Institute, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Westrin, A.
    Lund University, Sweden.
    Minthon, L.
    Lund University, Sweden.
    Hansson, O.
    Lund University, Sweden.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Brundin, L.
    Michigan State University, MI USA; Van Andel Research Institute, MI USA.
    Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels2015In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 131, no 4, p. 269-278Article in journal (Refereed)
    Abstract [en]

    ObjectiveRecent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. MethodWe measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). ResultsPlasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. ConclusionWe suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

  • 387.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Correction: Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 81, p. 330-331Article in journal (Other academic)
    Abstract [en]

    n/a

  • 388.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 69, p. 120-130Article in journal (Refereed)
    Abstract [en]

    Short collagen-like peptides (CLPs) are being proposed as alternatives to full-length collagen for use in tissue engineering, on their own as soft hydrogels, or conjugated to synthetic polymer for mechanical strength. However, despite intended clinical use, little is known about their safety and efficacy, mechanism of action or degree of similarity to the full-length counterparts they mimic. Here, we show the functional equivalence of a CLP conjugated to polyethylene glycol (CLP-PEG) to full-length recombinant human collagen in vitro and in promoting stable regeneration of corneal tissue and nerves in a pre- clinicalmini-pig model. We also show that these peptide analogs exerted their pro-regeneration effects through stimulating extracellular vesicle production by host cells. Our results support future use of CLP-PEG implants for corneal regeneration, suggesting the feasibility of these or similar peptide analogs in clinical application in the eye and other tissues. Statement of significance Although biomaterials comprising full-length recombinant human collagen and extracted animal collagen have been evaluated and used clinically, these macromolecules provide only a limited number of functional groups amenable to chemical modification or crosslinking and are demanding to process. Synthetic, customizable analogs that are functionally equivalent, and can be readily scaled-up are therefore very desirable for pre-clinical to clinical translation. Here, we demonstrate, using cornea regeneration as our test bed, that collagen-like-peptides conjugated to multifunctional polyethylene glycol (CLP-PEG) when grafted into mini-pigs as corneal implants were functionally equivalent to recombinant human collagen-based implants that were successfully tested in patients. We also show for the first time that these materials affected regeneration through stimulation of extracellular vesicle production by endogenous host cells that have migrated into the CLP-PEG scaffolds. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd.

  • 389.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa Heart Inst, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Univ Ottawa Heart Inst, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2019In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 88, p. 556-557Article in journal (Refereed)
    Abstract [en]

    n/a

  • 390.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Lotfi, Kourosh
    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.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed)
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

  • 391.
    Jankipersadsing, Soesma A.
    et al.
    University of Groningen, Netherlands; University of Groningen, Netherlands.
    Hadizadeh, Fatemeh
    Karolinska Institute, Sweden; Isfahan University of Medical Science, Iran.
    Jan Bonder, Marc
    University of Groningen, Netherlands.
    Tigchelaar, Ettje F.
    University of Groningen, Netherlands; Top Institute Food and Nutr, Netherlands.
    Deelen, Patrick
    University of Groningen, Netherlands.
    Fu, Jingyuan
    University of Groningen, Netherlands.
    Andreasson, Anna
    Karolinska Institute, Sweden; Stockholm University, Sweden.
    Agreus, Lars
    Karolinska Institute, Sweden.
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Wijmenga, Cisca
    University of Groningen, Netherlands.
    Hysi, Pirro
    Kings Coll London, England.
    DAmato, Mauro
    Karolinska Institute, Sweden; BioDonostia Health Research Institute San Sebastian, Spain; Basque Fdn Science, Spain.
    Zhernakova, Alexandra
    University of Groningen, Netherlands.
    Letter: A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency in GUT, vol 66, issue 4, pp 756-7582017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 4, p. 756-758Article in journal (Other academic)
    Abstract [en]

    n/a

  • 392.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. World University of Network, Australia.
    The mother-offspring dyad: microbial transmission, immune interactions and allergy development2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 6, p. 484-495Article, review/survey (Refereed)
    Abstract [en]

    The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. During pregnancy, there is a close immunological interaction between the mother and her offspring, which provides important opportunities for the maternal microbial environment to influence the immune development of the child. In support of this theory, combined pre- and postnatal supplementations seem to be crucial for the preventive effect of probiotics on infant eczema. Here, the influence of microbial and immune interactions within the mother-offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic.

  • 393.
    Jennersjö, Pär
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Guldbrand, Hans
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, West County Primary Health Care.
    Björne, Stefan
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Länne, Toste
    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. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Torbjörn
    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 Endocrinology.
    Wijkman, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala".
    Nyström, Fredrik H
    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 Endocrinology.
    A prospective observational study of all-cause mortality in relation to serum 25-OH vitamin D-3 and parathyroid hormone levels in patients with type 2 diabetes2015In: Diabetology and Metabolic Syndrome, ISSN 1758-5996, E-ISSN 1758-5996, Vol. 7, no 53Article in journal (Refereed)
    Abstract [en]

    Background: Low levels of vitamin D have been related to increased mortality and morbidity in several non-diabetic studies. We aimed to prospectively study relationships between serum 25-OH vitamin D-3 (vitamin D) and of serum parathyroid hormone (PTH) to total mortality in type 2 diabetes. We also aimed to compare the levels of these potential risk-factors in patients with and without diabetes. Methods: The main study design was prospective and observational. We used baseline data from 472 men and 245 women who participated in the "Cardiovascular Risk factors in Patients with Diabetes-a Prospective study in Primary care" study. Patients were 55-66 years old at recruitment, and an age-matched non-diabetic sample of 129 individuals constituted controls for the baseline data. Carotid-femoral pulse-wave velocity (PWV) was measured with applanation-tonometry and carotid intima-media thickness (IMT) with ultrasound. Patients with diabetes were followed for all-cause mortality using the national Swedish Cause of Death Registry. Results: Levels of vitamin D were lower in patients with diabetes than in controls, also after correction for age and obesity, while PTH levels did not differ. Nine women and 24 men died during 6 years of median follow up of the final cohort (n = 698). Vitamin D levels were negatively related to all-cause mortality in men independently of age, PTH, HbA1c, waist circumference, 24-h systolic ambulatory-blood pressure (ABP) and serum-apoB (p = 0.049). This finding was also statistically significant when PWV and IMT were added to the analyses (p = 0.028) and was not affected statistically when medications were also included in the regression-analysis (p = 0.01). In the women with type 2 diabetes, levels of PTH were positively related with all-cause mortality in the corresponding calculations (p = 0.016 without PWV and IMT, p = 0.006 with PWV and IMT, p = 0.045 when also adding medications to the analysis), while levels of vitamin D was without statistical significance (p greater than 0.9). Conclusions: Serum vitamin D in men and serum PTH in women give prognostic information in terms of total-mortality that are independent of regular risk factors in addition to levels of ABP, IMT and PWV.

  • 394.
    Joensson, Emma H.
    et al.
    University of Gothenburg, Sweden.
    Backlund Wasling, Helena
    University of Gothenburg, Sweden.
    Wagnbeck, Vicktoria
    University of Gothenburg, Sweden.
    Dimitriadis, Menelaos
    University of Medical Centre Groningen, Netherlands.
    Georgiadis, Janniko R.
    University of Medical Centre Groningen, Netherlands.
    Olausson, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Croy, Ilona
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Technical University of Dresden, Germany.
    Unmyelinated Tactile Cutaneous Nerves Signal Erotic Sensations2015In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 12, no 6, p. 1338-1345Article in journal (Refereed)
    Abstract [en]

    Introduction. Intrapersonal touch is a powerful tool for communicating emotions and can among many things evoke feelings of eroticism and sexual arousal. The peripheral neural mechanisms of erotic touch signaling have been less studied. C tactile afferents (unmyelinated low-threshold mechanoreceptors), known to underpin pleasant aspects of touch processing, have been posited to play an important role. MethodIn two studies, we investigated the relationship between C tactile activation and the perception of erotic and pleasant touch, using tactile brushing stimulation. In total, 66 healthy subjects (37 women, age range 19-51 years) were examined. In study 1 (n=20), five different stroking velocities were applied to the forearm and the inner thigh. The participants answered questions about partnership, mood, and touch. In study 2 (n=46), the same five stroking velocities were applied to the forearm. The participants answered questions about partnership, touch, and sexuality. ResultsBoth touch eroticism and pleasantness were rated significantly higher for C tactile optimal velocities compared with suboptimal velocities. No difference was found between the ratings of the thigh and the forearm. The velocity-dependent rating curves of pleasantness, intensity, and eroticism differed from each other. Pleasantness was best explained by a quadratic fit, intensity by a linear fit, and eroticism by both. A linear transformation of pleasantness and intensity predicted the observed eroticism ratings reliably. Eroticism ratings were negatively correlated with length of relationship. ConclusionTouch was rated most erotic when perceived as pleasant and weak. In human hairy skin, perception of pleasantness is correlated with the firing rate of C tactile afferents, and perception of intensity is correlated with the firing rate of A afferents. Accordingly, eroticism may be perceived most readily for touch stimuli that induce high activity in C tactile fibers and low activity in A fibers. Jonsson EH, Backlund Wasling H, Wagnbeck V, Dimitriadis M, Georgiadis JR, Olausson H, and Croy I. Unmyelinated tactile cutaneous nerves signal erotic sensations. J Sex Med 2015;12:1338-1345.

  • 395.
    Johansson, Ann-Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    La Fleur, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Melissaridou, Styliani
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    The relationship between EMT, CD44(high)/EGFR(low) phenotype, and treatment response in head and neck cancer cell lines2016In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 45, no 9, p. 640-646Article in journal (Refereed)
    Abstract [en]

    BackgroundHead and neck squamous cell carcinoma (HNSCC) tumors are often therapy resistant and may originate from cancer stem cells or tumor cells with an epithelial-to-mesenchymal transition (EMT) phenotype. The aim of this study was to characterize HNSCC cell lines with regard to EMT profile and to investigate the influence of EMT on the response to treatment. MethodsmRNA expression of the EMT-associated genes CDH1 (E-cadherin), CDH2 (N-cadherin), FOXC2, TWIST1, VIM (vimentin), and FN1 (fibronectin) was determined using quantitative real-time PCR. Cell morphology and migration were investigated by phase-contrast microscopy and Boyden chamber assay, respectively. The cell surface expression of CD44 and epidermal growth factor receptor (EGFR) was examined by flow cytometry. The response to radiotherapy, cetuximab, and dasatinib was assessed by crystal violet staining. ResultsA total of 25 cell lines investigated differed greatly with regard to EMT phenotype. Cell lines with an EMT expression profile showed a mesenchymal morphology and a high migratory capacity. In addition, they exhibited a high cell surface expression of CD44 and a low expression of EGFR, a pattern previously associated with stemness. When the EMT inducer transforming growth factor- (TGF-) was added to non-EMT cells, changes in treatment responses were observed. Moreover, the expression of TWIST1 was found to correlate with radioresistance. ConclusionsThe data presented in this report suggest that EMT is associated with a CD44(high)/EGFR(low) phenotype and possibly negative impact on radiotherapy response in HNSCC cell lines.

  • 396.
    Johansson, Björn
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Application of Pedagogical Perspectives in the Teaching and Training of New Cataract Surgeons—A Literature-Based Essay2013In: Open Journal of Ophthalmology, ISSN 2165-7416, Vol. 3, no 3, p. 61-67Article in journal (Other academic)
    Abstract [en]

    Cataract is the most common cause of visual impairment that can be effectively treated by surgery and cataract surgery is the most commonly performed surgical procedure in the world. With modern cataract operation techniques, patients expect excellent results. Teaching and training of new surgeons involve both pedagogical and ethical challenges for teachers and trainees, and also may pose a potential risk to patients. This literature-based essay aims to describe how behavioristic, cognitive and conceptual learning perspectives can be recognized during the trainee surgeon’s progress. It also describes how teacher-pupil relationships may vary during the training process. Finally it presents the concept of situational tutorship, where the teacher adapts to the stages that the trainee passes through with increasing experience. Teaching and trainee surgeons who are aware of pedagogical concepts such as teacher-pupil relationships and tutoring strategies may use this knowledge to optimize the learning process. Further research is needed to clarify how using this knowledge may affect the training of new cataract surgeons.

  • 397.
    Johansson, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Glistenings, anterior/posterior capsular opacification and incidence of Nd:YAG laser treatments with two aspheric hydrophobic acrylic intraocular lenses - a long-term intra-individual study2017In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 95, no 7, p. 671-677Article in journal (Refereed)
    Abstract [en]

    Purpose: To compare two hydrophobic acrylic intraocular lenses (IOLs) regarding long-term anterior/posterior capsular opacification (ACO/PCO) development and need for neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) laser treatment due to visually disturbing PCO, and to study development of glistenings in the IOL materials. Methods: In a prospective, randomized, intra-individual, comparative trial, 50 cataract patients received either an AcrySof IQ((R)) SN60WF (Alcon, Fort Worth, TX, USA) or a Tecnis((R)) ZCB00 (Abbott Medical Optics, Santa Ana, CA, USA) IOL in the first operated eye, and the second eye received the IOL type not implanted in the first eye. Anterior/posterior capsular opacification (ACO/PCO) and fibrosis were monitored with slit-lamp photography and semi-automated digital analysis 2 and 3years postoperatively. Glistenings were semi-quantitatively assessed in slit-lamp photographs. Nd:YAG laser treatment for visually disturbing PCO was monitored. Results: Visual outcomes were similar for the two IOLs. Anterior capsular fibrosis and/or opacification developed more often in SN60WF eyes. Mean PCO area percentage was larger in ZCB00 eyes 3years after surgery, but severity score did not differ with statistical significance between the two IOLs. Six ZCB00 eyes and 2 SN60WF eyes underwent Nd:YAG laser treatment during a mean of 4years 8months after surgery. This difference was not statistically significant. A high amount of glistenings developed in most SN60WF IOLs, while only few ZCB00 IOLs displayed a low degree of glistenings. Conclusion: Visual outcomes, PCO development over time and need for Nd:YAG laser treatment were similar for the two IOLs. Anterior capsule fibrosis/contraction and glistenings were more pronounced with the SN60WF IOL.

  • 398.
    Johansson, Björn
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Opacification of anterior part of hydrophilic acrylic IOL or a prelenticular inflammatory membrane?2012In: Journal of cataract and refractive surgery, ISSN 0886-3350, E-ISSN 1873-4502, Vol. 38, no 6, p. 1115-1116Article in journal (Refereed)
    Abstract [en]

    In their recent case report, Park and Chuck1 describe the bilateral appearance of an opacification at the plane of the anterior surface of the hydrophilic acrylic Akreos MI60 intraocular lens (IOL) (Bausch & Lomb). The patient's general history of diabetes mellitus, proliferative retinopathy, and iris rubeosis explains the limited pupil dilation preventing visualization of the capsulorhexis opening in their slitlamp images.

  • 399.
    Johansson, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Visual field defect during low-dose methotrexate therapy1992In: Documenta Ophthalmologica, ISSN 0012-4486, E-ISSN 1573-2622, Vol. 79, p. 91-94Article in journal (Refereed)
    Abstract [en]

    A patient was treated with low-dose methotrexate because of psoriasis that did not respond to conventional therapy. During treatment, visual symptoms occurred; optic disc swelling was found, and later slight optic disc atrophy. Moreover, paracentral relative visual field defects showed fluctuations parallel to methotrexate dose changes. It seems likely that methotrexate affected optic nerve function.

  • 400.
    Johansson, Björn
    et al.
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Petranyi, Gabor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Claesson Armitage, Margareta
    Department of Ophthalmology, Sahlgrenska University Hospital, M € olndal, Sweden.
    Lagali, Neil
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Diagnostic and therapeutic challenges in a case of amikacin-resistant Nocardia keratitis.2017In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 95, no 1, p. 103-105Article in journal (Refereed)
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