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  • 1.
    Adil, Mohammed Yasin
    et al.
    Univ Oslo, Norway; Norwegian Dry Eye Clin, Norway.
    Xiao, Jiaxin
    Univ Oslo, Norway; Norwegian Dry Eye Clin, Norway.
    Olafsson, Jonatan
    Univ Oslo, Norway.
    Chen, Xiangjun
    Univ Oslo, Norway; Norwegian Dry Eye Clin, Norway; Arendal Hosp, Norway; Vestre Viken Hosp Trust, Norway; Univ Coll Southeast Norway, Norway.
    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.
    Raeder, Sten
    Norwegian Dry Eye Clin, Norway.
    Utheim, Oygunn A.
    Oslo Univ Hosp, Norway.
    Dartt, Darlene A.
    Harvard Med Sch, MA 02115 USA.
    Utheim, Tor P.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Oslo, Norway; Vestre Viken Hosp Trust, Norway; Univ Coll Southeast Norway, Norway; Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway.
    Meibomian Gland Morphology Is a Sensitive Early Indicator of Meibomian Gland Dysfunction2019In: American Journal of Ophthalmology, ISSN 0002-9394, E-ISSN 1879-1891, Vol. 200, p. 16-25Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the relationship between meibomian gland (MG) morphology and clinical dry eye tests in patients with meibomian gland dysfunction (MGD). DESIGN: Cross-sectional study. SUBJECTS: Total 538 MGD patients and 21 healthy controls. METHODS: MG loss on meibography images of upper (UL) and lower lids (LL) was graded on a scale of 0 (lowest degree of MG loss) to 3. MG length, thickness, and interglandular space in the UL were measured. Clinical tests included meibum expression and quality, tear film break-up time, ocular staining, osmolarity, Schirmer I, blink interval timing, and Ocular Surface Disease Index (OSDI) questionnaire. RESULTS: Mean UL and LL meibogrades were significantly higher in MGD patients compared to controls (P amp;lt; .001 for UL and LL). The sensitivity and specificity of the meibograde as a diagnostic parameter for MGD was 96.7% and 85%, respectively. Schirmer I was significantly increased in MGD patients with meibograde 1 compared to patients with meibograde 0, 2, and 3 in the UL (P amp;lt; .05 ). MG thickness increased with higher meibograde (P amp;lt; .001). MG morphology correlated significantly but weakly with several clinical parameters (P amp;lt; .05). OSDI did not correlate with any MG morphologic parameter. CONCLUSIONS: Grading of MG loss using meibograde effectively diagnoses MGD. Compensatory mechanisms such as increased aqueous tear production and dilation of MGs make early detection of MGD difficult by standard clinical measures of dry eye, whereas morphologic analysis of MGs reveals an early stage of MGD, and therefore represents a complementary clinical parameter with diagnostic potential. (C) 2018 Elsevier Inc. All rights reserved.

  • 2.
    Al-Hawasi, Abbas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Retinal ganglion cell layer thickness and volume measured by OCT changes with age, sex, and axial length in a healthy population2022In: BMC Ophthalmology, E-ISSN 1471-2415, Vol. 22, no 1, article id 278Article in journal (Refereed)
    Abstract [en]

    Background The ganglion cell layer (GCL) measurements with Optical Coherence Tomography (OCT) are important for both ophthalmologists and neurologists because of their association with many ophthalmic and neurological diseases. Different factors can affect these measurements, such as brain pathologies, ocular axial length (AL) as well as age and sex. Studies conducted to measure the GCL have overlooked many of these factors. The purpose of this study is to examine the effect of age, sex, and AL on normal retinal GCL thickness and volume in a healthy population without any neurological diseases. Methods A prospective cross-sectional study was designed to measure GCL thickness and total volume with OCT with automated segmentation and manual correction where needed. Visual acuity, AL, and autorefraction were also measured. A mixed linear model was used to determine the association of the effect of the various parameters on the GCL thickness and volume. Results One hundred and sixteen eyes of 60 subjects (12-76 years of age, 55% female) were examined of which 77% had 0 +/- 2 D of spherical equivalent, and mean axial length was 23.86 mm. About 25% of the OCT-automated GCL measurements required manual correction. GCL thickness did not differ in similar anatomic regions in right and left eyes (P > 0.05). GCL volume was greater in males relative to females after adjustment for age and axial length (1.13 +/- 0.07 mm(3) for males vs 1.09 +/- 0.09 mm(3) for females; P = 0.031). GCL thickness differed between males and females in the inner retinal ring (P = 0.025) but not in the outer ring (P = 0.66). GCL volume declined with age (P = 0.031) but not after adjustment for sex and axial length (P = 0.138). GCL volume declined with longer axial length after adjustment for age and sex (P = 0.048). Conclusion Age, sex and axial length should be taken into consideration when measuring the GCL thickness and volume with OCT. Automated OCT segmentation should be reviewed for manual adjustments.

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  • 3.
    Al-Hawasi, Abbas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Link, Yumin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Longitudinal Optical Coherence Tomography Measurement of Retinal Ganglion Cell and Nerve Fiber Layer to Assess Benign Course in Multiple Sclerosis2023In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 6, article id 2240Article in journal (Refereed)
    Abstract [en]

    A benign form of multiple sclerosis (BMS) is not easily diagnosed, but changes of the retinal ganglion cell layer-inner plexiform layer (GCL-IPL) and retinal nerve fiber layer (RNFL) may be sensitive to the disease. The aim of this study was to use optical coherence tomography (OCT) to investigate longitudinal changes of GCL-IPL and RNFL in BMS. Eighteen patients with BMS and 22 healthy control (HC) subjects were included, with a mean follow-up period of 32.1 months in BMS and 34.3 months in HC. Mean disease duration in BMS was 23.3 years, with 14 patients left untreated. Unilateral optic neuritis (ON) was found in eight patients. Non-ON eyes showed thinner GCL-IPL layer in the BMS group relative to HC (p < 0.001). The thinning rate of GCL-IPL in non-ON BMS, however, was -0.19 +/- 0.15 mu m/year vs. 0 +/- 0.11 mu m/year for HC (p = 0.573, age-adjusted). Thinning rate of RNFL in non-ON BMS was -0.2 +/- 0.27 mu m/year vs. -0.05 +/- 0.3 mu m/year for HC (p = 0.454, age adjusted). Conclusions: Thinning rate of the GCL-IPL and RNFL in BMS is similar to the healthy population but differs from the thinning rate in relapsing-remitting MS, presenting a non-invasive OCT-based criterion for assessing a benign course in multiple sclerosis.

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  • 4.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mukwaya, Anthonny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Univ Missouri, MO 65211 USA.
    Marass, Michele
    Max Planck Inst Lung and Heart Res, Germany.
    Gerri, Claudia
    Max Planck Inst Lung and Heart Res, Germany.
    Hildesjö, Camilla
    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 for Diagnostics, Clinical pathology.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    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. Bayer AB, Sweden.
    del Peso, Luis
    Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
    Kvanta, Anders
    Karolinska Inst, Sweden.
    Sandberg, Rickard
    Karolinska Inst, Sweden.
    Schraermeyer, Ulrich
    Univ Tubingen, Germany.
    Andre, Helder
    Karolinska Inst, Sweden.
    Steffensen, John F.
    Univ Copenhagen, Denmark.
    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.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1402-1418Article in journal (Refereed)
    Abstract [en]

    Objective—

    Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

    Approach and Results—

    Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

    Conclusions—

    Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

    Visual Overview—

    An online visual overview is available for this article.

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  • 5.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Zang, Jingjing
    Univ Zurich, Switzerland.
    Lagali, Neil S
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Schmitner, Nicole
    Univ Innsbruck, Austria.
    Salvenmoser, Willi
    Univ Innsbruck, Austria.
    Mukwaya, Anthony
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Neuhauss, Stephan C. F.
    Univ Zurich, Switzerland.
    Jensen, Lasse
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Kimmel, Robin A.
    Univ Innsbruck, Austria.
    Photoreceptor Degeneration Accompanies Vascular Changes in a Zebrafish Model of Diabetic Retinopathy2020In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, no 2, article id UNSP 43Article in journal (Refereed)
    Abstract [en]

    PURPOSE. Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness worldwide in the working-age population, and the incidence is rising. Until now it has been difficult to define initiating events and disease progression at the molecular level, as available diabetic rodent models do not present the full spectrum of neural and vascular pathologies. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 were previously shown to display a diabetic phenotype from larval stages through adulthood. In this study, pdx1 mutants were examined for retinal vascular and neuronal pathology to demonstrate suitability of these fish for modeling DR. METHODS. Vessel morphology was examined in pdx1 mutant and control fish expressing the fli1a:EGFP transgene. We further characterized vascular and retinal phenotypes in mutants and controls using immunohistochemistry, histology, and electron microscopy. Retinal function was assessed using electroretinography. RESULTS. Pdx1 mutants exhibit clear vascular phenotypes at 2 months of age, and disease progression, including arterial vasculopenia, capillary tortuosity, and hypersprouting, could be detected at stages extending over more than 1 year. Neural-retinal pathologies are consistent with photoreceptor dysfunction and loss, but do not progress to blindness. CONCLUSIONS. This study highlights pdx1 mutant zebrafish as a valuable complement to rodent and other mammalian models of DR, in particular for research into the mechanistic interplay of diabetes with vascular and neuroretinal disease. They are furthermore suited for molecular studies to identify new targets for treatment of early as well as late DR.

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  • 6.
    Andreasson, Mattias
    et al.
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Badian, Reza A.
    Oslo Univ Hosp, Norway.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway.
    Scarpa, Fabio
    Univ Padua, Italy.
    Colonna, Alessia
    Univ Padua, Italy.
    Allgeier, Stephan
    Karlsruhe Inst Technol KIT, Germany.
    Bartschat, Andreas
    Karlsruhe Inst Technol KIT, Germany.
    Koehler, Bernd
    Karlsruhe Inst Technol KIT, Germany.
    Mikut, Ralf
    Karlsruhe Inst Technol KIT, Germany.
    Reichert, Klaus-Martin
    Karlsruhe Inst Technol KIT, Germany.
    Solders, Goran
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Samuelsson, Kristin
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; UCL Inst Neurol, England; UK Dementia Res Inst, England.
    Blennow, Kaj
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Svenningsson, Per
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Parkinson's disease with restless legs syndrome - an in vivo corneal confocal microscopy study2021In: NPJ Parkinson's disease, ISSN 2373-8057, Vol. 7, no 1, article id 4Article in journal (Refereed)
    Abstract [en]

    Small fiber neuropathy (SFN) has been suggested as a trigger of restless legs syndrome (RLS). An increased prevalence of peripheral neuropathy has been demonstrated in Parkinsons disease (PD). We aimed to investigate, in a cross-sectional manner, whether SFN is overrepresented in PD patients with concurrent RLS relative to PD patients without RLS, using in vivo corneal confocal microscopy (IVCCM) and quantitative sensory testing (QST) as part of small fiber assessment. Study participants comprised of age- and sex-matched PD patients with (n = 21) and without RLS (n = 21), and controls (n = 13). Diagnosis of RLS was consolidated with the sensory suggested immobilization test. Assessments included nerve conduction studies (NCS), Utah Early Neuropathy Scale (UENS), QST, and IVCCM, with automated determination of corneal nerve fiber length (CNFL) and branch density (CNBD) from wide-area mosaics of the subbasal nerve plexus. Plasma neurofilament light (p-NfL) was determined as a measure of axonal degeneration. No significant differences were found between groups when comparing CNFL (p = 0.81), CNBD (p = 0.92), NCS (p = 0.82), and QST (minimum p = 0.54). UENS scores, however, differed significantly (p = 0.001), with post-hoc pairwise testing revealing higher scores in both PD groups relative to controls (p = 0.018 and p = 0.001). Analysis of all PD patients (n = 42) revealed a correlation between the duration of l-dopa therapy and CNBD (rho = -0.36, p = 0.022), and p-NfL correlated with UENS (rho = 0.35, p = 0.026) and NCS (rho = -0.51, p = 0.001). Small and large fiber neuropathy do not appear to be associated with RLS in PD. Whether peripheral small and/or large fiber pathology associates with central neurodegeneration in PD merits further longitudinal studies.

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  • 7.
    Badian, Reza A.
    et al.
    Oslo Univ Hosp, Norway.
    Allgeier, Stephan
    Karlsruhe Inst Technol KIT, Germany.
    Scarpa, Fabio
    Univ Padua, Italy.
    Andreasson, Mattias
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Bartschat, Andreas
    Karlsruhe Inst Technol KIT, Germany.
    Mikut, Ralf
    Karlsruhe Inst Technol KIT, Germany.
    Colonna, Alessia
    Univ Padua, Italy.
    Belissario, Marco
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Köhler, Bernd
    Karlsruhe Inst Technol KIT, Germany.
    Svenningsson, Per
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    Wide-field mosaics of the corneal subbasal nerve plexus in Parkinsons disease using in vivo confocal microscopy2021In: Scientific Data, E-ISSN 2052-4463, Vol. 8, no 1, article id 306Article in journal (Refereed)
    Abstract [en]

    In vivo confocal microscopy (IVCM) is a non-invasive imaging technique facilitating real-time acquisition of images from the live cornea and its layers with high resolution (1-2 mu m) and high magnification (600 to 800-fold). IVCM is extensively used to examine the cornea at a cellular level, including the subbasal nerve plexus (SBNP). IVCM of the cornea has thus gained intense interest for probing ophthalmic and systemic diseases affecting peripheral nerves. One of the main drawbacks, however, is the small field of view of IVCM, preventing an overview of SBNP architecture and necessitating subjective image sampling of small areas of the SBNP for analysis. Here, we provide a high-quality dataset of the corneal SBNP reconstructed by automated mosaicking, with an average mosaic image size corresponding to 48 individual IVCM fields of view. The mosaic dataset represents a group of 42 individuals with Parkinsons disease (PD) with and without concurrent restless leg syndrome. Additionally, mosaics from a control group (n = 13) without PD are also provided, along with clinical data for all included participants.

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  • 8.
    Badian, Reza A.
    et al.
    Oslo Univ Hosp, Norway.
    Andreasson, Mattias
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Svenningsson, Per
    Acad Specialist Ctr, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    The pattern of the inferocentral whorl region of the corneal subbasal nerve plexus is altered with age2021In: The Ocular Surface, ISSN 1542-0124, Vol. 22, p. 204-212Article in journal (Refereed)
    Abstract [en]

    Purpose: To describe the pattern of the nerves in the inferocentral whorl region of the human corneal subbasal nerve plexus (SBNP) in health and diseases known to affect the subbasal nerves. Methods: Laser-scanning in vivo confocal microscopy (IVCM) was used to image the SBNP bilaterally in 91 healthy subjects, 39 subjects with type 2 diabetes mellitus (T2DM), and 43 subjects with Parkinsons disease (PD). Whorl regions were classified according to nerve orientation relative to age and health/disease status. Results: Of 346 examined eyes, 300 (86.7%) had an identifiable whorl pattern. In healthy subjects, a clockwise nerve orientation of the whorl was most common (67.9%), followed by non-rotatory or seam morphology (21.4%), and counterclockwise (10.7%). The clockwise orientation was more prevalent in healthy subjects than in T2DM or PD (P < 0.001). Healthy individuals below 50 years of age had a predominantly clockwise orientation (93.8%) which was reduced to 51.9% in those over 50 years (P < 0.001). Age but not disease status explained whorl orientation in T2DM and PD groups. Moreover, whorl orientation is bilaterally clockwise in the young, but adopts other orientations and becomes asymmetric across eyes with age. Finally, we report reflective dot-like features confined to the whorl region of the subbasal plexus, sometimes appearing in close association with subbasal nerves and present in 84-93% of examined eyes regardless of disease status, eye or sex. Conclusion: Subbasal nerves in the inferocentral whorl region are predominantly clockwise in young, healthy corneas. With aging and conditions of T2DM and PD, counterclockwise and non-rotatory configurations increase in prevalence, and bilateral symmetry is lost. Mechanisms regulating these changes warrant further investigation.

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  • 9.
    Badian, Reza A.
    et al.
    Oslo Univ Hosp, Norway.
    Ekman, Linnea
    Lund Univ, Sweden.
    Pripp, Are Hugo
    Oslo Univ Hosp, Norway.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Englund, Elisabet
    Lund Univ, Sweden.
    Dahlin, Lars
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Sorlandet Hosp Arendal, Norway.
    Comparison of Novel Wide-Field In Vivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes2023In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 72, no 7, p. 908-917Article in journal (Refereed)
    Abstract [en]

    Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnosticmodalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same participants, and at the same time point, no correlation between IENFD and corneal nerve densitywas found. Corneal nerve density did not correlate with clinicalmeasures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN.

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  • 10.
    Badian, Reza A.
    et al.
    Oslo Univ Hosp, Norway.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    Region of interest and directional analysis of subbasal nerves in wide-area corneal nerve plexus mosaics in type 2 diabetes mellitus2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 10802Article in journal (Refereed)
    Abstract [en]

    In vivo confocal microscopy (IVCM) imaging of the corneal subbasal nerve plexus (SBNP) is a clinical imaging modality gaining popularity for the diagnosis and follow-up of corneal neuropathy in various conditions such as diabetes mellitus. There remain, however, major limitations to the method, hindering its widespread clinical use. Finding the same exact area of the central cornea to standardize image acquisition is difficult without a reference point. Alternatively, creating wide-area mosaics of the SBNP is resource-intensive and has not yet been developed for routine clinical use. Here, we investigated whether IVCM analysis of the corneal SBNP in a predetermined, anatomically standardized region of interest (ROI) could be applied as an equivalent substitution for wide-area SBNP mosaic generation and analysis. Furthermore, we investigated nerve patterns outside the central corneal region for a possible relationship to type 2 diabetes mellitus status using a publicly available dataset. We found that corneal nerve fibre length density (CNFL) based on the ROI underestimated the mosaic-based CNFL by an average of 34% in 90% of cases (150 eyes), and did not exhibit a significant reduction with diabetes, as seen in the full SBNP. Outside the central cornea, nerve orientation differed depending on the anatomic region (left, central or right superior plexus, P<0.001). Moreover, in long-term type 2 diabetes mellitus (>= 10 years, 28 subjects), nerve density in the left superior sector of the SBNP was decreased (P<0.001) while that in the central superior SBNP increased (P=0.01) relative to 35 age-matched healthy subjects with normal glucose tolerance. These results indicate that subbasal nerve degeneration in type 2 diabetes mellitus can vary according to anatomic location, and regions with potential diagnostic value outside the central SBNP may warrant further investigation.

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  • 11.
    Bakken, Ingvild M.
    et al.
    Sorlandet Hosp Arendal, Norway.
    Jackson, Catherine J.
    Ifocus Eye Clin, Norway; Univ Oslo, Norway.
    Utheim, Tor P.
    Sorlandet Hosp Arendal, Norway; Oslo Univ Hosp, Norway; Univ Agder, Norway.
    Villani, Edoardo
    Univ Milan, Italy; San Giuseppe Hosp, Italy.
    Hamrah, Pedram
    Tufts Univ, MA 02111 USA.
    Kheirkhah, Ahmad
    UT Hlth San Antonio, TX USA.
    Nielsen, Esben
    Aarhus Univ Hosp, Denmark.
    Hau, Scott
    Moorfields Eye Hosp NHS Fdn Trust, England; UCL Inst Ophthalmol, England.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    The use of in vivo confocal microscopy in fungal keratitis - Progress and challenges2022In: Ocular Surface, ISSN 1542-0124, Vol. 24, p. 103-118Article in journal (Refereed)
    Abstract [en]

    Fungal keratitis (FK) is a serious and sight-threatening corneal infection with global reach. The need for prompt diagnosis is paramount, as a delay in initiation of treatment could lead to irreversible vision loss. Current "gold standard" diagnostic methods, namely corneal smear and culture, have limitations due to diagnostic insensitivity and their time-consuming nature. PCR is a newer, complementary method used in the diagnosis of fungal keratitis, whose results are also sample-dependent. In vivo confocal microscopy (IVCM) is a promising complementary diagnostic method of increasing importance as it allows non-invasive real-time direct visualization of potential fungal pathogens and manifesting infection directly in the patients cornea. In numerous articles and case reports, FK diagnosis by IVCM has been evaluated, and different features, approaches, sensitivity/specificity, and limitations have been noted. Here, we provide an up-to-date, comprehensive review of the current literature and present the authors combined recommendations for fungal identification in IVCM images, while also looking to the future of FK assessment by IVCM using artificial intelligence methods.

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  • 12.
    Behaegel, Josephine
    et al.
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Tassignon, Marie-Jose
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Consejo, Alejandra
    Univ Zaragoza, Spain.
    Koppen, Carina
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Dhubhghaill, Sorcha Ni
    Univ Antwerp, Belgium; Antwerp Univ Hosp, Belgium.
    Outcomes of Human Leukocyte Antigen-Matched Allogeneic Cultivated Limbal Epithelial Transplantation in Aniridia-Associated Keratopathy-A Single-Center Retrospective Analysis2022In: Cornea, ISSN 0277-3740, E-ISSN 1536-4798, Vol. 41, no 1, p. 69-77Article in journal (Refereed)
    Abstract [en]

    Purpose: To assess the efficacy and safety of human leukocyte antigen-matched allogeneic cultivated limbal epithelial stem cell grafts in the treatment of aniridia-associated keratopathy (AAK). Methods: Six eyes of 6 patients with severe AAK received an allogeneic stem cell graft between January 2010 and March 2017. Anatomical and functional results were assessed at 6 months, 1 year, 2 years, and the final follow-up visit available. Safety analysis was performed by considering all perioperative and postoperative adverse events and additional surgeries required during the follow-up period. Results: The mean follow-up was 53.6 months (range 24-104 months). In most patients (80%), there was an early improvement of the keratopathy postoperatively, which slowly regressed during longer follow-up. At the final follow-up, 4 of the eyes were graded as failure and 1 eye was graded as partial success. Grading the sixth eye was not possible because of an adverse event. None of the patients maintained a total anatomical success in the long-term. Only 1 patient maintained a modest improvement in best-corrected visual acuity from hand motion to counting fingers. Four serious adverse events were recorded in 2 patients. Conclusions: Severe AAK remains a challenging condition to manage. Transplantation of allogenic ex vivo cultivated limbal stem cells may provide a temporary improvement in ocular surface stability, but anatomical and functional results are poor in the long-term. The eyes are prone to adverse events, and any surgical treatment should take this into consideration.

  • 13.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    An in Vivo Method for Visualizing Flow Dynamics of Cells within Corneal Lymphatics2013In: Lymphatic Research and Biology, ISSN 1539-6851, E-ISSN 1557-8585, Vol. 11, no 2, p. 93-100Article in journal (Refereed)
    Abstract [en]

    Background: Monitoring the trafficking of specific cell populations within lymphatics could improve our understanding of processes such as transplant rejection and cancer metastasis. Current methods, however, lack appropriate image resolution for single-cell analysis or are incompatible with in vivo and longitudinal monitoring of lymphatics in their native state. We therefore sought to achieve high-resolution live imaging of the dynamic behavior of cells within lymph vessels in the rat cornea.

    Methods/Results: Inflammatory angiogenesis was induced by suture placement in corneas of Wistar rats. Pre- and up to 3 weeks post-induction, corneas were noninvasively examined by laser-scanning in vivo corneal confocal microscopy (IVCM) using only endogenous contrast. Lymph vessels and the cells harbored therein were documented by still images, real-time video, and 3D confocal stack reconstruction of live tissue. In vivo, conjunctival and corneal lymphatics were morphologically distinct, those with corneal location being one-quarter the diameter of those in the conjunctiva (p<0.001). Cells were recruited to initially empty pre-existing lymph vessels during the first day of inflammation and maintained a dense occupation of vessels for up to 7 days. A diverse population of cells (diameter range: 1.5–27.5 μm) with varying morphology was observed, and exhibited variable flow patterns and were transported singly and in clusters of at least 2–9 adherent cells.

    Conclusions: The in vivo microscopic technique presented enables lymph vessels and cell trafficking to be studied in high resolution in a minimally-perturbed physiologic milieu.

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  • 14.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Letter: In vivo confocal microscopy visualization of presumed lymph vessels in a case of corneal transplant rejection2011In: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071, Vol. 39, no 8, p. 832-834Article in journal (Other academic)
    Abstract [en]

    n/a

  • 15.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Transient Anterior Corneal Deposits in a Human Immunodeficiency Virus-Positive Patient2010In: CORNEA, ISSN 0277-3740, Vol. 29, no 11, p. 1323-1327Article in journal (Refereed)
    Abstract [en]

    Purpose: To report findings of pigmented anterior corneal deposits in a human immunodeficiency virus-positive patient. Methods: Case report. A 49-year-old human immunodeficiency virus-positive patient was examined after the appearance of pigmented corneal deposits. Slit-lamp biomicroscopy, fundus photography, and laser-scanning in vivo confocal microscopy were performed to visually document the ocular condition. Results: The patient had a history of Mycobacterium avium infection and was suspected to have recovery uveitis from a cytomegalovirus infection. Small, rounded, light brown-colored deposits were distributed across the anterior cornea from limbus to limbus, bilaterally. In vivo confocal microscopy revealed the deposits to be confined to the basal epithelium and Bowman layer, whereas the posterior stroma, Descemet membrane, and the endothelium appeared normal. Systemic steroid treatment was administered, and 2 weeks later, the deposits had vanished on slit-lamp examination, whereas remnants were observed at the microscopic level. Conclusions: The deposits were unusual for their anterior corneal location and pancorneal distribution. The response to systemic steroid treatment remains unexplained and illustrates the complexity of the underlying conditions, their treatment, and the associated pathways of ocular manifestation.

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  • 16.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model2011In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 14, no 3, p. 393-405Article in journal (Refereed)
    Abstract [en]

    In this study, we introduce a technique for repeated, microscopic observation of single regressing capillaries in vivo in inflamed murine corneas. Natural capillary regression was initiated by removal of inflammatory stimulus during an active pro-angiogenic phase, while the additional impact of anti-angiogenic treatment with triamcinolone or bevazicumab was investigated. Capillaries regressed naturally within 1 week and treatments did not further enhance the natural regression. Morphologically, early-phase regression was characterized by significant lumen narrowing and a significant reduction in CD11b+ myeloid cell infiltration of the extracellular matrix. By 1 week, vascular remodeling occurred concomitant with CD11b+CD68+KiM2R+ mature macrophage localization on capillary walls. Empty conduits without blood flow, positive for collagen IV and devoid of vascular endothelium and pericytes, were apparent in vivo and by 3 weeks were more numerous than perfused capillaries. By 3 weeks, macrophages aggregated around remaining perfused capillaries and were observed in apposition with degrading capillary segments. Abrupt termination of capillary sprouting in our regression model further revealed vascular endothelial abandonment of sprout tips and perfused capillary loop formation within a single angiogenic sprout, possibly as an intussusceptive response to cessation of the stimulus. Finally, we observed lumen constriction and macrophage localization on capillary walls in vivo in a clinical case of corneal capillary regression that paralleled findings in our murine model.

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  • 17.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lagali, Neil
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Cellular-Level Characterization of Lymph Vessels in Live, Unlabeled Corneas by In Vivo Confocal Microscopy2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 2, p. 830-835Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To determine whether in vivo confocal microscopy (IVCM) of the cornea can be used for the label-free detection and monitoring of lymph vessels in live corneas.

    METHODS. Parallel corneal hemangiogenesis and lymphangiogenesis was induced by the placement of a single suture in one cornea of male Wistar rats. Fourteen days after suture placement and under general anesthesia, laser-scanning IVCM was performed in the vascularized region. Corneas were subsequently excised for flat-mount double immunofluorescence with a pan-endothelial marker (PECAM-1/CD31) and a lymphatic endothelial specific marker (LYVE-1). Using the suture area and prominent blood vessels as points of reference, the identical microscopic region was located in both fluorescent and archived in vivo images. Additionally, vessel diameter, lumen contrast, and cell diameter and velocity within vessels were quantified from in vivo images.

    RESULTS. Comparison of identical corneal regions in fluorescence and in vivo revealed prominent CD31(+)/LYVE-1(3+) lymph vessels that were visible in vivo. In vivo, corneal lymph vessels were located in the vascularized area in the same focal plane as blood vessels but had a darker lumen (P andlt; 0.001) sparsely populated by highly reflective cells with diameters similar to those of leukocytes in blood vessels (P = 0.61). Cell velocity in lymph vessels was significantly reduced compared with blood particle velocity (P andlt; 0.001). Morphologic characteristics enabled subsequent identification of corneal lymphatics in live, vascularized rat corneas before immunofluorescence labeling.

    CONCLUSIONS. IVCM enabled the nondestructive, label-free, in vivo detection of corneal lymphatics. IVCM provides the possibility of observing lymphatic activity in the same live corneas longitudinally and, as a clinical instrument, of monitoring corneal lymphatics in live human subjects.

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  • 18.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Time-Lapse In Vivo Imaging of Corneal Angiogenesis: The Role of Inflammatory Cells in Capillary Sprouting2011In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, no 6, p. 3060-3068Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To elucidate the temporal sequence of events leading to new capillary sprouting in inflammatory corneal angiogenesis.

    METHODS. Angiogenesis was induced by corneal suture placement in Wistar rats. The inflamed region was examined by time-lapse in vivo confocal microscopy for up to 7 days. At 6 and 12 hours and 1, 2, 4, and 7 days, corneas were excised for flat mount immunofluorescence with primary antibodies for CD31, CD34, CD45, CD11b, CD11c, Ki-M2R, NG2, and alpha-SMA. From days 0 to 4, the in vivo extravasation and expansion characteristics of single limbal vessels were quantified.

    RESULTS. Starting hours after induction and peaking at day 1, CD45(+)CD11b(+) myeloid cells extravasated from limbal vessels and formed endothelium-free tunnels within the stroma en route to the inflammatory stimulus. Limbal vessel diameter tripled on days 2 to 3 as vascular buds emerged and transformed into perfused capillary sprouts less than 1 day later. A subset of spindle-shaped CD11b(+) myeloid-lineage cells, but not dendritic cells or mature macrophages, appeared to directly facilitate further capillary sprout growth. These cells incorporated into vascular endothelium near the sprout tip, co-expressing endothelial marker CD31. Sprouts had perfusion characteristics distinct from feeder vessels and many sprout tips were open-ended.

    CONCLUSIONS. Time-lapse in vivo corneal confocal microscopy can be used to track a temporal sequence of events in corneal angiogenesis. The technique has revealed potential roles for myeloid cells in promoting vessel sprouting in an inflammatory corneal setting.

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  • 19.
    Chierego, Chiara
    et al.
    Eye Clinic, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
    Merz, Tommaso
    Eye Clinic, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
    Fasolo, Adriano
    Eye Clinic, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
    Lagali, Neil S
    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.
    Pedrotti, Emilio
    Eye Clinic, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.
    In vivo confocal microscopy of verticillata-like paraproteinemic keratopathy in a patient with monoclonal gammopathy of uncertain significance evolving into smoldering multiple myeloma2019In: American journal of ophthalmology case reports, ISSN 2451-9936, Vol. 15, article id 100505Article in journal (Refereed)
    Abstract [en]

    To highlight the utility of in vivo confocal microscopy (IVCM) in the microstructural characterization of corneal deposits resembling vortex keratopathy in a case of secondary deposition keratopathy due to an evolving monoclonal gammopathy.

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  • 20.
    Daruich, Alejandra
    et al.
    Paris Cite Univ, France; Sorbonne Paris Cite Univ, France.
    Duncan, Melinda
    Univ Delaware, DE USA.
    Robert, Matthieu P.
    Paris Cite Univ, France; Paris Cite Univ, France.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Sorlandet Hosp Arendal, Norway.
    Semina, Elena V.
    Med Coll Wisconsin, WI 53226 USA.
    Aberdam, Daniel
    Sorbonne Paris Cite Univ, France.
    Ferrari, Stefano
    Fdn Banca Occhi Veneto, Italy.
    Romano, Vito
    Univ Brescia, Italy.
    des Roziers, Cyril Burin
    Sorbonne Paris Cite Univ, France; Ctr Univ Paris, France.
    Benkortebi, Rabia
    Paris Cite Univ, France.
    De Vergnes, Nathalie
    Paris Cite Univ, France.
    Polak, Michel
    Pediatric Endocrinology, Gynecology and Diabetology, Hôpital Universitaire Necker Enfants Malades, Paris Cité University, INSERM, France.
    Chiambaretta, Frederic
    Department of Ophthalmology, CHU Gabriel Monpied, Clermont-Ferrand, France.
    Nischal, Ken K.
    Division of Pediatric Ophthalmology, Strabismus, and Adult Motility, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; UPMC Eye Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
    Behar-Cohen, Francine
    Sorbonne Paris Cite Univ, France.
    Valleix, Sophie
    Sorbonne Paris Cite Univ, France; Ctr Univ Paris, France.
    Bremond-Gignac, Dominique
    Paris Cite Univ, France; Sorbonne Paris Cite Univ, France.
    Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches2023In: Progress in retinal and eye research, ISSN 1350-9462, E-ISSN 1873-1635, Vol. 95, article id 101133Article, review/survey (Refereed)
    Abstract [en]

    Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.

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  • 21.
    Eden, U
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology . Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology . Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Pathologic epithelial and anterior corneal nerve morphology in congenital aniridic keratopathy in ACTA OPHTHALMOLOGICA, vol 88, issue , pp 52-522010In: ACTA OPHTHALMOLOGICA, Blackwell Publishing Ltd , 2010, Vol. 88, p. 52-52Conference paper (Refereed)
    Abstract [en]

    n/a

  • 22.
    Eden, Ulla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Danyali, Reza
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Pathologic Epithelial and Anterior Corneal Nerve Morphology in Early-Stage Congenital Aniridic Keratopathy2012In: Ophthalmology, ISSN 0161-6420, E-ISSN 1549-4713, Vol. 119, no 9, p. 1803-1810Article in journal (Refereed)
    Abstract [en]

    Objective: To document the clinical and morphologic corneal findings in the early stages of congenital aniridic keratopathy in Swedish families. less thanbrgreater than less thanbrgreater thanDesign: Prospective, observational, comparative case series. less thanbrgreater than less thanbrgreater thanParticipants: A total of 16 eyes of 16 subjects with congenital aniridic keratopathy and a clear central cornea, and 6 eyes from 6 healthy controls (unaffected relatives). Nine of the 16 eyes with aniridia came from 5 families with a documented familial history of aniridia. less thanbrgreater than less thanbrgreater thanMethods: Detailed ophthalmic examinations included best spectacle-corrected visual acuity (BSCVA), tear film production, tear break-up time (BUT), corneal touch sensitivity, intraocular pressure measurement, ultrasound pachymetry, slit-lamp biomicroscopy, and laser scanning in vivo confocal microscopy (IVCM). less thanbrgreater than less thanbrgreater thanMain Outcome Measures: Confirmed stage of aniridic keratopathy, clinical parameters of cornea and tear film (visual acuity, sensitivity, corneal thickness, tear production, and BUT), and the morphologic status of corneal epithelium, sub-basal nerves, and limbal palisades of Vogt. less thanbrgreater than less thanbrgreater thanResults: In early-stage aniridic keratopathy, BSCVA and tear BUT were reduced relative to controls (P andlt; 0.001 for both), and corneal thickness was increased (P = 0.01). Inflammatory dendritic cells were present in the central epithelium in aniridia, with significantly increased density relative to controls (P = 0.001). Discrete focal opacities in the basal epithelial region were present in 5 of 11 aniridia cases with an otherwise clear cornea. Opacities were associated with dendritic cells and harbored structures presumed to be goblet cells. Sub-basal nerves were extremely dense in 3 aniridia cases, and a prominent whorl pattern of nerves and epithelial cells was observed in 1 case. Normal limbal palisade morphology was absent in aniridia but present in controls. less thanbrgreater than less thanbrgreater thanConclusions: Early-stage aniridic keratopathy is characterized by the development of focal opacities in the basal epithelium, altered sub-basal nerves, infiltration of the central epithelium by dendritic cells, tear film instability, and increased corneal thickness and degradation of limbal palisade architecture. These findings may help to elucidate the pathogenesis of aniridic keratopathy. less thanbrgreater than less thanbrgreater thanFinancial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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  • 23.
    Edén, Ulla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Dellby, Anette
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Utheim, Tor P.
    Oslo University Hospital, Norway Harvard University, MA 02114 USA .
    Riise, Ruth
    Innland Hospital, Norway .
    Chen, Xiangjun
    Synslaser Kirurgi AS, Norway .
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Letter: Cataract development in Norwegian patients with congenital aniridia2014In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 92, no 2, p. E165-E167Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 24.
    Ekman, Linnea
    et al.
    Lund Univ, Sweden.
    Pourhamidi, Kaveh
    Karolinska Inst, Sweden.
    Englund, Elisabet
    Lund Univ, Sweden.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Dahlin, Lars B.
    Lund Univ, Sweden.
    Temporal trend of small nerve fibre degeneration in people with and without type 2 diabetes mellitus2022In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 39, no 3, article id e14691Article in journal (Refereed)
    Abstract [en]

    Aims We investigated the long-term temporal trend of intraepidermal nerve fibre density (IENFD) and the association between changes in IENFD and metabolic factors in individuals with and without type 2 diabetes. Methods A total of 66 participants were enrolled in this longitudinal population-based study, at baseline consisting of 35 individuals (median 61 years) without diabetes and 31 individuals with type 2 diabetes mellitus. Participants underwent clinical and electrophysiological examinations, as well as a skin biopsy both at baseline and at the follow-up visit (mean 8.1 +/- 0.5 years). IENFD was assessed in thin sections of 5 mu m, stained with the protein gene product 9.5-antibody and compared between the groups. Results IENFD decreased during the period in both groups, with a greater decline in the group without diabetes than in type 2 diabetes (-2.3 and -0.6 fibres/mm respectively; p &lt; 0.001). While IENFD at baseline was significantly reduced in type 2 diabetes relative to people without (p &lt; 0.001), no difference in IENFD was found between groups at the follow-up (p = 0.183). Linear mixed model analysis indicated that age, weight and HbA(1c) were associated with decrease in IENFD in the total population (p &lt; 0.007). IENFD also decreased with increasing age and weight, but not with HbA(1c), in the separate groups (p &lt; 0.049). Conclusions Despite lower IENFD levels at baseline in type 2 diabetes, IENFD was equal between the groups at follow-up. A decrease in IENFD is to a limited extent affected by body weight, and HbA(1c), but age seems to be the long-term determinant of IENFD in an elderly population.

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  • 25.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Carlsson, David J.
    National Research Council of Canada, Ottawa, Ontario; University of Ottawa Eye Institute, Ontario, Canada.
    Merrett, Kimberley
    University of Ottawa Eye Institute, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Canada.
    Corrigendum to “Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute”  [vol 2, Issue 2, pg 162-164, 2009]2014In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 7, no 4, p. 347-347Article in journal (Other academic)
    Abstract [en]

    n/a

  • 26.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Ong, Jeb A.
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Merrett, Kimberley
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Ottawa Hospital Research Institute, Canada.
    Jackson, W. Bruce
    Ottawa Hospital Research Institute, Canada .
    Polarek, James W.
    FibroGen Inc, San Francisco, CA, USA.
    Suuronen, Erik J.
    University of Ottawa Heart Institute, Canada .
    Liu, Yuwen
    CooperVision Inc, Pleasanton, CA, USA.
    Brunette, Isabelle
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 8, p. 2420-2427Article in journal (Refereed)
    Abstract [en]

    We developed cell-free implants, comprising carbodiimide crosslinked recombinant human collagen (RHC), to enable corneal regeneration by endogenous cell recruitment, to address the worldwide shortage of donor corneas. Patients were grafted with RHC implants. Over four years, the regenerated neo-corneas were stably integrated without rejection, without the long immunosuppression regime needed by donor cornea patients. There was no recruitment of inflammatory dendritic cells into the implant area, whereas, even with immunosuppression, donor cornea recipients showed dendritic cell migration into the central cornea and a rejection episode was observed. Regeneration as evidenced by continued nerve and stromal cell repopulation occurred over the four years to approximate the micro-architecture of healthy corneas. Histopathology of a regenerated, clear cornea from a regrafted patient showed normal corneal architecture. Donor human cornea grafted eyes had abnormally tortuous nerves and stromal cell death was found. Implanted patients had a 4-year average corrected visual acuity of 20/54 and gained more than 5 Snellen lines of vision on an eye chart. The visual acuity can be improved with more robust materials for better shape retention. Nevertheless, these RHC implants can achieve stable regeneration and therefore, represent a potentially safe alternative to donor organ transplantation.

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  • 27.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil S
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Carlsson, David J
    Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada.
    Merrett, Kimberley
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6, Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6, Canada.
    Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute2009In: CTS-CLINICAL AND TRANSLATIONAL SCIENCE, ISSN 1752-8054, Vol. 2, no 2, p. 162-164Article in journal (Refereed)
    Abstract [en]

    n/a

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  • 28.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil S
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Jackson, W Bruce
    University of Ottawa Eye Institute.
    Munger, Rejean
    University of Ottawa Eye Institute.
    Liu, Yuwen
    CooperVision Inc, Pleasanton, USA .
    Polarek, James W
    FibroGen Inc, San Francisco.
    Söderqvist, Monica
    Synsam Opticians, Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study2010In: Science translational medicine, ISSN 1946-6234, Vol. 2, no 46, p. 46-61Article in journal (Refereed)
    Abstract [en]

    Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.

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  • 29.
    Fineide, Fredrik
    et al.
    Oslo Univ Hosp, Norway; Norwegian Dry Eye Clin, Norway; Oslo Metropolitan Univ, Norway; SimulaMet, Norway.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    Adil, Muhammed Yasin
    Oslo Univ Hosp, Norway; Norwegian Dry Eye Clin, Norway.
    Arita, Reiko
    Dept Ophthalmol, Japan.
    Kolko, Miriam
    Univ Copenhagen, Denmark; Copenhagen Univ Hosp, Denmark.
    Vehof, Jelle
    Univ Copenhagen, Denmark; Kings Coll London, England; Univ Groningen, Netherlands; Vestfold Hosp, Norway.
    Utheim, Tor P.
    Oslo Univ Hosp, Norway; Norwegian Dry Eye Clin, Norway; Oslo Metropolitan Univ, Norway; Stavanger Univ Hosp, Norway; Vestre Viken Hosp, Norway; Vestfold Hosp, Norway; Univ Bergen, Norway; Oslo Univ Hosp, Norway; Oslo Metropolitan Univ, Norway; Univ Stavanger, Norway; Univ Oslo, Norway; Univ South Eastern Norway, Norway; Univ Agder, Norway; Sorlandet Hosp Arendal, Norway.
    Topical glaucoma medications - Clinical implications for the ocular surface2022In: Ocular Surface, ISSN 1542-0124, Vol. 26, p. 19-49Article in journal (Refereed)
    Abstract [en]

    Glaucoma is a leading cause of irreversible blindness. The use of topical eye drops to reduce intraocular pressure remains the mainstay treatment. These eye drops frequently contain preservatives designed to ensure sterility of the compound. A growing number of clinical and experimental studies report the detrimental effects of not only these preservatives but also the active pharmaceutical compounds on the ocular surface, with resultant tear film instability and dry eye disease. Herein, we critically appraise the published literature exploring the effects of preservatives and pharmaceutical compounds on the ocular surface.

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  • 30.
    Fostad, Ida G.
    et al.
    University of Oslo, Norway; Norwegian Dry Eye Clin, Norway.
    Eidet, Jon R.
    Norwegian Dry Eye Clin, Norway; Oslo University Hospital, Norway.
    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.
    Dartt, Darlene A.
    Harvard Medical Sch, MA 02114 USA.
    Raeder, Sten
    Norwegian Dry Eye Clin, Norway.
    Messelt, Edvard B.
    University of Oslo, Norway.
    Utheim, Tor P.
    University of Oslo, Norway; Norwegian Dry Eye Clin, Norway; Oslo University Hospital, Norway; Vestre Viken Hospital Trust, Norway.
    Identification of Objective Morphometric Markers of Xerostomia in the Oral Mucosa Epithelium with In Vivo Confocal Microscopy2017In: Microscopy and Microanalysis, ISSN 1431-9276, E-ISSN 1435-8115, Vol. 23, no 1, p. 88-96Article in journal (Refereed)
    Abstract [en]

    The purpose of this work was to determine whether the morphology of the oral mucosa epithelium (OME) of patients with xerostomia differ from patients without xerostomia. In total, 34 patients with dry eye disease (DED) with or without xerostomia were examined at The Norwegian Dry Eye Disease Clinic with in vivo confocal microscopy of the lower lip. In addition, age- and gender-matched healthy controls (HC) were included. DED patients with xerostomia had a higher superficial to deep backscatter ratio compared with DED patients without xerostomia (p=0.002) and HC (p=0.001). Regression analysis demonstrated that this ratio was related to xerostomia independently of gender and age (pamp;lt;0.001). Sensitivity and specificity of detecting xerostomia were 0.78 and 0.85, respectively, when using a superficial to deep backscatter ratio cut-off value of 0.995 (p=0.004). The mean nucleus to cytosol backscatter ratio in the superficial OME was lower in patients with xerostomia than in those without xerostomia (p=0.034). In vivo confocal microscopy is a potential tool for evaluating the oral cavity and to assess changes in the OME associated with xerostomia, objectively and quantitatively. The cause of the increased backscatter in the superficial OME in xerostomia, however, remains to be elucidated.

  • 31.
    Fostad, Ida G.
    et al.
    University of Oslo, Norway; Norwegian Dry Eye Clin, Norway.
    Eidet, Jon R.
    Norwegian Dry Eye Clin, Norway; Oslo University Hospital, Norway.
    Utheim, Tor P.
    University of Oslo, Norway; Norwegian Dry Eye Clin, Norway; Oslo University Hospital, Norway; Vestre Viken Hospital Trust, Norway; Buskerud and Vestfold University of Coll, Norway.
    Raeder, Sten
    Norwegian Dry Eye Clin, Norway.
    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.
    Messelt, Edvard B.
    University of Oslo, Norway.
    Dartt, Darlene A.
    Harvard University, MA USA.
    Dry Eye Disease Patients with Xerostomia Report Higher Symptom Load and Have Poorer Meibum Expressibility2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 5, p. e0155214-Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to investigate if xerostomia (dry mouth) is associated with symptoms and signs of dry eye disease (DED). At the Norwegian Dry Eye Clinic, patients with symptomatic DED with different etiologies were consecutively included in the study. The patients underwent a comprehensive ophthalmological work-up and completed self-questionnaires on symptoms of ocular dryness (Ocular Surface Disease Index [OSDI] and McMonnies Dry Eye Questionnaire) and the Sjogrens syndrome (SS) questionnaire (SSQ). Three hundred and eighteen patients (52% women and 48% men) with DED were included. Patient demographics were: 0 to 19 years (1%), 20 to 39 (25%), 40 to 59 (34%), 60 to 79 (35%) and 80 to 99 (5%). Xerostomia, defined as "daily symptoms of dry mouth the last three months" (as presented in SSQ) was reported by 23% of the patients. Female sex was more common among patients with xerostomia (81%) than among non-xerostomia patients (44%; Pamp;lt; 0.001). Patients with xerostomia (60 +/- 15 years) were older than those without xerostomia (51 +/- 17; Pamp;lt; 0.001). The use of prescription drugs was more prevalent among xerostomia patients (65%) than among non-xerostomia patients (35%; Pamp;lt; 0.021; adjusted for age and sex). Patients with xerostomia had a higher OSDI score (19.0 +/- 10.0) than those without xerostomia (12.9 +/- 8.0; Pamp;lt; 0.001). Moreover, xerostomia patients had more pathological meibum expressibility (0.9 +/- 0.7) than those without xerostomia (0.7 +/- 0.8; P = 0.046). Comparisons of OSDI and ocular signs were performed after controlling for the effects of sex, age and the number of systemic prescription drugs used. In conclusion, xerostomia patients demonstrated a higher DED symptom load and had poorer meibum expressibility than non-xerostomia patients.

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  • 32.
    Fries, Fabian N.
    et al.
    Saarland Univ, Germany; Saarland Univ, Germany.
    Moslemani, Kayed
    Saarland Univ, Germany.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Seitz, Berthold
    Saarland Univ, Germany.
    Kaesmann-Kellner, Barbara
    Saarland Univ, Germany.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    Early ocular surface and tear film status in congenital aniridia indicates a supportive treatment window2024In: British Journal of Ophthalmology, ISSN 0007-1161, E-ISSN 1468-2079, Vol. 108, p. 30-36Article in journal (Refereed)
    Abstract [en]

    AimTo evaluate changes in the ocular surface and tear film with age and mutational status in congenital aniridia. Methods45 participants with congenital aniridia (89 eyes) in a prospective, cross-sectional study. Whole-exome sequencing identified the causative mutation. Examinations included slit-lamp biomicroscopy, in vivo confocal microscopy, Ocular Surface Disease Index (OSDI) score, blink rate, Schirmer I test, Oxford Staining Score (OSS), tear film break-up time (TFBUT) and Ocular Protection Index (OPI). ResultsThere were age-dependent increases in OSDI (beta=0.34, 95% CI 0.03 to 0.66; p=0.030), blink rate (beta=0.18, 95% CI 0.08 to 0.27; p&lt;0.001) and OSS (beta=0.05, 95% CI 0.03 to 0.07; p&lt;0.001) and age-dependent reductions in tear production (beta=-0.23, 95% CI -0.43 to 0.02; p=0.029) and TFBUT (beta=-0.10, 95% CI -0.17 to -0.04; p&lt;0.001). Perturbed OSDI, OSS, blink rate, tear production and TFBUT were noted after the age of ten and OSDI, OSS, blink rate and TFBUT correlated with deficient corneal nerves and limbal stem cell function. OSDI, blink rate, Schirmer, OSS, TFBUT and OPI were not associated with type of PAX6 mutation, but OSDI, OSS and blink rate associated with grade of aniridia-associated keratopathy. ConclusionsOcular surface damage and dry eye signs appear in congenital aniridia regardless of mutation, appearing after 10 years of age and progressing thereafter. An early treatment window may exist for therapies to protect the ocular surface homoeostasis and limbal function, to possibly delay keratopathy development and progression.

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  • 33.
    Fries, Fabian Norbert
    et al.
    Saarland Univ, Germany.
    Naray, Annamaria
    Saarland Univ, Germany; Semmelweis Univ, Hungary.
    Munteanu, Cristian
    Saarland Univ, Germany.
    Stachon, Tanja
    Saarland Univ, Germany.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Seitz, Berthold
    Saarland Univ, Germany.
    Kaesmann-Kellner, Barbara
    Saarland Univ, Germany.
    Szentmary, Nora
    Saarland Univ, Germany.
    The Effect of Glaucoma Treatment on Aniridia-Associated Keratopathy (AAK) - A Report from the Homburg Register for Congenital Aniridia2023In: Klinische Monatsblätter für Augenheilkunde, ISSN 0023-2165, E-ISSN 1439-3999Article in journal (Refereed)
    Abstract [en]

    Background Congenital aniridia is a severe malformation of almost all eye segments. Aniridia-associated keratopathy (AAK) and secondary glaucoma, which occur in more than 50% of affected individuals, are typically progressive and pose a high risk of blindness for patients with congenital aniridia. Our aim was to investigate the effect of glaucoma treatment on AAK in patients of the Homburg Aniridia Center.Methods Our retrospective monocentric study included patients who underwent a comprehensive ophthalmological examination at the Homburg Aniridia Center between June 2003 and January 2022.Results There were 556 eyes of 286 subjects (20.1 +/- 20.1 years; 45.5% males) included. In 307 (55.2%) eyes of 163 subjects (27.5 +/- 16.3 years; 43.1% males), glaucoma was present at the time of examination. The mean intraocular pressure in the glaucoma group was 19.0 mmHg (+/- 8.0), while in the non-glaucoma group, it was 14.1 mmHg (+/- 3.6) (p &lt; 0.001). In the glaucoma group, 68 patients used antiglaucomatous topical monotherapy, 51 patients used 2 agents, 41 patients used 3 agents, 7 patients used quadruple therapy, and 140 did not use topical therapy (e.g., after pressure-lowering surgery, pain-free end-stage glaucoma, or incompliance). Patients were classified according to the following stages of AAK: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). The mean stage of AAK was 1.4 (1.2 - 1.5) in the group without eye drops, 1.9 (1.5 - 2.2) in the group with monotherapy, 1.8 (1.5 - 2.1) in the group with 2 drugs, 1.9 (1.5 - 2.2) in the group with 3 drugs, 3.4 (2.3 - 4.6) in the group with 4 drugs, and 3.3 (3.1 - 3.6) after antiglaucomatous surgery. The stage of AAK was significantly positively correlated with the number of pressure-lowering eye drops (p &lt; 0.05) and prior pressure-lowering surgery (p &lt; 0.05). Prostaglandin analogues were not correlated with a higher AAK stage compared to the other drug groups.Conclusions At the Homburg Aniridia Center, patients using topical antiglaucomatous quadruple therapy or who had previously undergone antiglaucomatous surgery had by far the highest AAK stage. The different drug groups had no influence on the AAK stage.

  • 34.
    Fries, Fabian Norbert
    et al.
    Saarland Univ, Germany.
    Naray, Annamaria
    Saarland Univ, Germany; Semmelwe Univ, Hungary.
    Munteanu, Cristian
    Saarland Univ, Germany.
    Stachon, Tanja
    Saarland Univ, Germany.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Seitz, Berthold
    Saarland Univ, Germany.
    Szentmary, Nora
    Saarland Univ, Germany.
    Kaesmann-Kellner, Barbara
    Saarland Univ, Germany.
    A Cross-sectional Analysis of 556 Eyes Entering the Homburg Aniridia Centre2023In: Klinische Monatsblätter für Augenheilkunde, ISSN 0023-2165, E-ISSN 1439-3999Article in journal (Refereed)
    Abstract [en]

    Purpose Congenital aniridia is a severe malformation of almost all eye segments. In addition, endocrinological, metabolic, and central nervous systems diseases may be present. In order to develop better treatment options for this rare disease, an aniridia center must be established. The purpose of this work is to summarize ophthalmic findings of aniridia subjects examined at the Department of Ophthalmology, Saarland University Medical Center in Homburg.Methods Our retrospective single-center study included patients who underwent a comprehensive ophthalmic examination through the head of the KiOLoN ("Kinderophthalmologie", Orthoptics, Low Vision and Neuroophthalmology) Unit of the department between June 2003 and January 2022. Data at the first examination time point have been included.Results Of 286 subjects, 556 eyes of (20.1 & PLUSMN; 20.1 years; 45.5% males) were included. There was nystagmus in 518 (93.7%) eyes, and strabismus in 327 (58.8%) eyes. There were 436 (78.4%) eyes with age-appropriate axial length, 104 (18.7%) eyes with microphthalmos, and 13 (2.3%) eyes with buphthalmos. There was iris malformation with atypical coloboma in 34 eyes (6.1%), more than 6 clock hours of iris remnants in 61 eyes (10.9%), less than 6 clock hours of iris remnants in 96 eyes (17.2%), and complete aniridia in 320 (57.5%) eyes. The patients were graded according to the following aniridia-associated keratopathy (AAK) stages: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). There was secondary glaucoma in 307 (55.5%), macular hypoplasia in 395 (71.4%), and congenital optic nerve head pathology in 223 (40.3%) eyes. The iris malformation type was significantly positively correlated with AAK stage, lens properties, presence of glaucoma, congenital macular, and optic nerve head properties (p &lt; 0.001 for all), while complete aniridia showed the most complications.Conclusions At the Homburg Aniridia Center, the most common ophthalmic signs in congenital aniridia were AAK, iris malformation, cataract, and macular hypoplasia. The iris malformation type may indicate future expression of AAK, cataract, and glaucoma development and it is correlated with a congenital optic nerve head and macular pathology. Our registry will support further detailed longitudinal analysis of ophthalmic and systemic diseases of aniridia subjects during long-term follow-up.

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  • 35.
    Germundsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Koulikovska, Marina
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    An Accurate Method to Determine Bowmans Layer Thickness In Vivo in the Human Cornea2012In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 53, no 4, p. 2354-2359Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To determine an accurate value for Bowmans layer (BL) thickness in vivo in humans. less thanbrgreater than less thanbrgreater thanMETHODS. Seventeen corneal transplant patients were examined preoperatively by laser-scanning in vivo confocal microscopy (IVCM), and corneal buttons were removed post-operatively and sectioned for light microscopy (LM). Nine corneas with uniformly thick BL by LM were used for thickness measurement. In the uniformly thick samples, probable overestimation of BL thickness in vivo by a first in vivo method (Method 1) led to the development of a revised in vivo method (Method 2). Method 2 was used to measure BL thickness in 20 healthy volunteers. less thanbrgreater than less thanbrgreater thanRESULTS. In nine patients, mean BL thickness prior to transplantation was 13.7 +/- 1.6 mu m by IVCM (Method 1) while BL thickness of the removed corneal button was 9.7 +/- 1.7 mu m by LM (P andlt; 0.001). The correlation of BL thickness between IVCM (Method 1) and LM was poor (P = 0.226). In 20 right eyes of 20 normal corneas, both in vivo methods were used to determine BL thickness. Mean BL thickness by Method 1 was 13.2 +/- 1.6 mu m and by Method 2 was 9.1 +/- 1.4 mu m (P andlt; 0.001). BL thickness measurements by both in vivo methods were highly correlated (P andlt; 0.001). less thanbrgreater than less thanbrgreater thanCONCLUSION. BL thickness by a revised in vivo method was close to LM values in this study and to values reported in fixed tissue in other studies. The authors believe this revised method provides the most accurate estimates of BL thickness in vivo to date.

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  • 36.
    Germundsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Clinical Outcome and Recurrence of Epithelial Basement Membrane Dystrophy after Phototherapeutic Keratectomy A Cross-sectional Study2011In: OPHTHALMOLOGY, ISSN 0161-6420, Vol. 118, no 3, p. 515-522Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the outcome of phototherapeutic keratectomy (PTK) treatment of epithelial basement membrane dystrophy (EBMD) patients and to examine clinical and morphologic signs of recurrent dystrophy. Design: Cross-sectional, clinic-based study. Participants: Fifty-two eyes of 39 patients diagnosed with EBMD who underwent PTK between 2001 and 2008. Methods: Preoperative symptoms, best spectacle-corrected visual acuity (BSCVA), and refraction data were collected. At follow-up, refraction and BSCVA were measured, symptoms were noted, and slit-lamp biomicroscopy and in vivo confocal microscopy (IVCM) were performed. Main Outcome Measures: Best spectacle-corrected visual acuity and signs of recurrent EBMD based on symptoms and morphologic features. An assessment of EBMD severity after PTK additionally was considered. Results: Mean follow-up time was 43 months (range, 7-100 months). After PTK, BSCVA remained unchanged or improved in 49 (98%) of 51 eyes. Twenty-four (46%) of 52 eyes had recurrence of some form, and recurrence was correlated positively with postoperative time (P andlt; 0.001). Symptomatic recurrence occurred in 7 eyes (13%), whereas morphologic recurrence occurred in 21 eyes (40%). Symptoms were coupled with positive IVCM findings in 3 (43%) of 7 cases and with slit-lamp findings in 1 (14%) of 7 cases. Of 17 eyes with morphologic recurrence by IVCM, 9 eyes (53%) were classified as having grade 1 recurrence, 8 eyes (47%) were classified as having grade 2 recurrence, and none were classified as having grade 3 recurrence. Morphologic recurrence was associated with epithelial removal by laser ablation before PTK. Conclusions: Although PTK is an effective method of alleviating the clinical symptoms of EBMD, the dystrophy can recur with time. The relationship between the postoperative development of clinical symptoms and the corneal morphologic features is complex and requires further investigation.

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  • 37.
    Germundsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Letter: Corneal Dystrophy Recurrence Reply2011In: BMC Ophthalmology, E-ISSN 1471-2415, Vol. 118, no 6, p. 1223-1224Article in journal (Other academic)
  • 38.
    Germundsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Karanis, Georgios
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Age-Related Thinning of Bowman's Layer in the Human Cornea In Vivo2013In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 54, no 9, p. 6143-6149Article in journal (Refereed)
    Abstract [en]

    Purpose. To determine the thickness of Bowman's layer (BL) in vivo in a healthy population and to determine its variation with age.

    Methods. Eighty-two subjects aged 15 to 88 years with clear, healthy corneas were examined bilaterally with laser scanning in vivo confocal microscopy (IVCM). Bowman's layer thickness was determined from IVCM images of anterior and posterior BL boundaries. For a given eye, BL thickness was averaged across four central locations by two independent observers. In addition, central corneal thickness was measured by time-domain optical coherence tomography.

    Results. A significant negative correlation of BL thickness with age was found in right eyes (Pearson r = −0.579, P < 0.0001) and in left eyes (r = −0.558, P < 0.0001). Linear regression analysis yielded a decline in BL thickness of 0.06 μm per year. In 41 older subjects (mean age, 64.4 years), BL thickness was significantly thinner (mean ± SD, 8.6 ± 1.7 μm in right eyes) than that in 41 younger subjects (mean age, 31.6 years) (mean ± SD, 10.7 ± 1.6 μm in right eyes) (P < 0.001). No correlation of corneal thickness with age or of BL thickness with corneal thickness was observed. Strong intereye correlations in BL thickness (r = 0.771, P < 0.0001) and corneal thickness (r = 0.969, P < 0.001) were found.

    Conclusions. Bowman's layer thins with age in the normal cornea, losing one-third of its thickness between the ages of 20 and 80 years. In vivo measurement of BL thickness by IVCM could aid in clinical assessment and planned treatments of the anterior cornea.

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  • 39.
    Germundsson, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Pathologically reduced subbasal nerve density in epithelial basement membrane dystrophy is unaltered by phototherapeutic keratectomy treatment2014In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, no 3, p. 1835-1841Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the effect of phototherapeutic keratectomy (PTK) treatment on corneal epithelial wing cell and corneal subbasal nerve density in epithelial basement membrane dystrophy (EBMD).

    METHODS: A total of 39 patients with EBMD who underwent PTK treatment, 40 healthy volunteers, and 24 untreated eyes with EBMD were examined with laser-scanning in vivo confocal microscopy (IVCM). Corneal subbasal nerves and epithelial wing cells were manually quantified from IVCM images by two observers, while epithelial wing cells were additionally quantified by a fully automated method.

    RESULTS: Subbasal nerve density was significantly reduced in untreated (10,164 ± 4139 μm/mm(2); n = 24) and PTK-treated (10,624 ± 4479 μm/mm(2); n = 39) EBMD eyes, relative to healthy controls (18,241 ± 4479 μm/mm(2); n = 40) (P < 0.001). Subbasal nerve density in PTK-treated and untreated eyes did not differ (P > 0.05). Epithelial wing cell density did not differ between PTK-treated and untreated EBMD eyes, by either manual or automated analysis; however, epithelial wing cell density in PTK-treated EBMD corneas was significantly reduced (P = 0.008) relative to healthy corneas, by automated cell counting.

    CONCLUSIONS: Subbasal nerve density in EBMD is reduced by 45% and recovers only to the reduced level in the long term after PTK treatment, whereas epithelial wing cell density in EBMD is not affected by PTK in the long term. Fully automated cell analysis from IVCM images could provide an objective, standardized means to quantify and compare corneal cell densities in future studies.

  • 40.
    Griffith, May
    et al.
    University of Ottawa.
    Jackson, W B
    University of Ottawa.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, K
    University of Ottawa.
    Li, F
    University of Ottawa.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Artificial corneas: a regenerative medicine approach2009In: EYE, ISSN 0950-222X, Vol. 23, no 10, p. 1985-1989Article in journal (Refereed)
    Abstract [en]

    Corneal substitutes are being developed to address the shortage of human donor tissues as well as the current disadvantages in some clinical indications, which include immune rejection. In the past few years, there have been significant developments in bioengineered corneas that are designed to replace part or the full thickness of damaged or diseased corneas that range from keratoprostheses that solely address the replacement of the corneas function, through tissue-engineered hydrogels that permit regeneration of host tissues. We describe examples of corneal substitutes that encourage regeneration of the host tissue. We also contend that it is unlikely that there will be a single "one-size-fits-all corneal substitute for all indications. Instead, there will most likely be a small range of corneal substitutes ranging from prostheses to tissue-engineered matrix substitutes that are tailored to different clusters of clinical indications. The tissue-engineered matrices can either be produced as sterile acellular matrices, or complete with functional cells, ready for implantation.

  • 41.
    Hackett, Joanne M.
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Edelhauser, Henry
    Emory University School of Medicine.
    Sun, Yifei
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gan, Lisha
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Biosynthetic corneal implants for replacement of pathologic corneal tissue: performance in a controlled rabbit alkali burn model2011In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, no 2, p. 651-657Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the performance of structurally reinforced, stabilized recombinant human collagen-phosphorylcholine (RHCIII-MPC) hydrogels as corneal substitutes in a rabbit model of severe corneal damage.

    Methods: One eye each of 12 rabbits received a deep corneal alkali wound. Four corneas were implanted with RHCIII-MPC hydrogels. The other eight control corneas were implanted with either allografts or a simple crosslinked RHCIII hydrogel. In all cases, 6.25 mm diameter, 350 µm thick buttons were implanted by anterior lamellar keratoplasty to replace damaged corneal tissue. Implants were followed for nine months by clinical examination and in vivo confocal microscopy, after which implanted corneas were removed and processed for histopathological and ultrastructural examination.

    Results: Alkali exposure induced extensive central corneal scarring, ocular surface irregularity, and neovascularization in one case. All implants showed complete epithelial coverage by four weeks post-operative, but with accompanying suture-induced vascularization in 6/12 cases. A stable, stratified epithelium with hemidesmosomal adhesion complexes regenerated over all implants, and subbasal nerve regeneration was observed in allograft and RHCIII-MPC implants. Initially acellular biosynthetic implants were populated with host-derived keratocytes as stromal haze subsided and stromal collagen was remodeled. Notably, RHCIII-MPC implants exhibited resistance to vascular ingrowth while supporting endogenous cell and nerve repopulation.

    Conclusion: Biosynthetic implants based on RHC promoted cell and nerve repopulation in alkali burned rabbit eyes. In RHCIII-MPC implants, evidence of an enhanced resistance to neovascularization was additionally noted.

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  • 42.
    Hamam, Moustafa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Abdulnour, Elie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Setterud, Helen
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Johansson, Björn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Mirabelli, Pierfrancesco
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Real-Life Efficacy of Bevacizumab Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion according to Pro Re Nata or Treat-and-Extend Regimen in Eyes with or without Epiretinal Membrane2022In: Journal of Ophthalmology, ISSN 2090-004X, E-ISSN 2090-0058, Vol. 2022, article id 6288582Article in journal (Refereed)
    Abstract [en]

    Purpose. To present real-life data of patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO) treated with bevacizumab (BVZ); determine the possible influence of epiretinal membrane (ERM) on treatment efficacy; and compare treatment outcomes in a treat-and-extend regimen (TER) versus pro re nata (PRN). Methods. We carried out a retrospective analysis of 58 eyes (56 patients) with new-onset CRVO treated only with intravitreal bevacizumab according to TER or PRN. Outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline and 12 months after the first treatment, number of visits and injections, and presence of ERM confirmed by optical coherence tomography in the first 6 months. Results. At 12 months, the mean number of injections was 6.3 across all eyes, with significantly more injections given in TER (p &lt; 0.001). Mean CRT improved from 627 mu m to 359 mu m (p &lt; 0.001) in all eyes, with improvement noted in TER (p &lt; 0.001), PRN (p &lt; 0.001), ERM (p=0.003), and non-ERM (p &lt; 0.001) subgroups. The mean BCVA gain was +13.6 letters, and the mean BCVA improved from 0.81 to 0.54 LogMAR (p &lt; 0.001) in all eyes. BCVA improvement from baseline was significant in TER (p &lt; 0.001) and non-ERM (p &lt; 0.001) but not in PRN (p=0.08) or ERM (p=0.2) subgroups. Seven eyes, all receiving PRN treatment, developed neovascularization. Conclusions. Intravitreal bevacizumab according to either PRN or TER resolved edema and stabilized vision in the first 12 months, with TER yielding significant visual improvement and avoiding neovascular complications. ERM had no influence on bevacizumab efficacy in reducing ME in CRVO during 12 months of treatment.

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  • 43.
    Hammar, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Ek, Stefan
    Department of Ophthalmology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Seregard, Stefan
    St Eriks Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
    Dellby, Anette
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Dystrophia Smolandiensis - recurrent corneal erosions with a novel morphological picture2010In: Acta Ophthalmologica, ISSN 1755-375X, Vol. 88, no 4, p. 394-400Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of this study was to describe morphological changes in a new corneal disease, Dystrophia Smolandiensis, characterized by recurrent corneal erosive episodes and formation of central corneal keloid-like opacities in approximately half of those affected.

    Methods: The corneas of seven affected individuals were examined using in-vivo confocal microscopy. Specimens of one primary corneal graft, one regraft, and one biopsied keloid-like region, obtained from members of a large family with the disease, were re-examined with a light microscope, and sections were stained with Congo red and immunohistochemically analyzed for fibronectin and S100A4.

    Results: Light microscopic examination revealed epithelial hyperplasia, absence of Bowman’s layer and subepithelial fibrosis. Fibronectin was expressed in the area of subepithelial fibrosis, and the keratocytes in this area generally expressed S100A4. The biopsy specimen stained positive for Congo red, suggesting an amyloid deposit. In-vivo confocal microscopy confirmed epithelial abnormalities, loss of Bowman’s layer, and significant alterations of the subbasal nerve plexus in affected individuals.

    Conclusion: The morphologic picture in Dystrophia Smolandiensis is novel for a condition dominated by recurrent corneal erosions at the clinical level. Although no single morphologic feature unique to the disease could be found, the general morphologic pattern of pathology (true keloid formation, an absence of Bowman’s layer, subepithelial fibrosis, and abnormal subbasal nerves) likely reflects a novel phenotypic expression of the healing response to recurrent erosion of the corneal epithelium. The pathogenesis of Dystrophia Smolandiensis, however, remains to be fully elucidated.

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  • 44.
    Harada, Fumiya
    et al.
    Health Science University of Hokkaido, Japan; Taipei Medical University, Taiwan.
    Morikawa, Tetsuro
    Health Science University of Hokkaido, Japan.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Far Eastern Federal University, Russia.
    Mukwaya, Anthony
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Schaupper, Mira
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Uehara, Osamu
    Health Science University of Hokkaido, Japan.
    Takai, Rie
    Health Science University of Hokkaido, Japan.
    Yoshida, Koki
    Health Science University of Hokkaido, Japan.
    Sato, Jun
    Health Science University of Hokkaido, Japan.
    Horie, Yukihiro
    Hokkaido University, Japan.
    Sakaguchi, Hiroyuki
    FUJIFILM Corp, Japan.
    Wu, Ching-Zong
    Taipei Medical University Hospital, Taiwan; Lotung Poh Ai Hospital, Taiwan.
    Abiko, Yoshihiro
    Health Science University of Hokkaido, Japan.
    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.
    Kitaichi, Nobuyoshi
    Hokkaido University, Japan; Health Science University of Hokkaido Hospital, Japan.
    Protective Effects of Oral Astaxanthin Nanopowder against Ultraviolet-Induced Photokeratitis in Mice2017In: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, article id 1956104Article in journal (Refereed)
    Abstract [en]

    Purpose. Astaxanthin (AST) has a strong antioxidant cellular membrane chaperone protective effect. Recently, a water-soluble nanosized AST (nano-AST) form was produced, which is expected to improve the efficacy of oral intake effects. The purpose of this study was to examine whether oral nano-AST has therapeutic effects on UV-induced photokeratitis in mice. Methods. C57BL/6 mice were administered twice with either nano-AST, AST oil, lutein, or bilberry extracts 3 hours before and shortly before UV irradiation (dose: 400 mJ/cm2). The corneas were collected 24 hours after irradiation and stained with Hamp;E and TUNEL. NF-kappa B, dihydroethidium (DHE), COX-2, p-I kappa B-alpha, TNF alpha, and CD45 expression were evaluated through immunohistochemistry, Western blot analysis, and qPCR. Results. Corneal epithelium was significantly thicker in mice orally administered with nano-AST than in the others (p amp;lt; 0.01), with significantly less NF-kappa B nucleus translocation (p amp;lt; 0.001), and significantly fewer TUNEL cells (p amp;lt; 0.01). Weaker DHE signals were detected in the nano-AST group (p amp;lt; 0.05) relative to the others. Furthermore, reduced inflammation and decreased cell death in corneal tissue were observed in the nano-AST group, as indicated by a reduction in the expression of COX-2, p-I kappa B-alpha, TNFa, and CD45. Conclusions. Oral administration of nano-AST demonstrated a protective effect on UV-induced photokeratitis via antioxidative, anti-inflammatory, and antiapoptotic activity.

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  • 45.
    Holland, Grainne
    et al.
    Natl Univ Ireland Galway, Ireland.
    Pandit, Abhay
    Natl Univ Ireland, Ireland.
    Sanchez-Abella, Laura
    CIDETEC, Spain.
    Haiek, Andrea
    CIDETEC, Spain.
    Loinaz, Iraida
    CIDETEC, Spain.
    Dupin, Damien
    CIDETEC, Spain.
    Gonzalez, Maria
    AJL Ophthalm, Spain.
    Larra, Eva
    AJL Ophthalm, Spain.
    Bidaguren, Aritz
    Donostia Univ Hosp, Spain.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Moloney, Elizabeth B.
    Natl Univ Ireland Galway, Ireland; Natl Univ Ireland, Ireland.
    Ritter, Thomas
    Natl Univ Ireland Galway, Ireland; Natl Univ Ireland, Ireland.
    Artificial Cornea: Past, Current, and Future Directions2021In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 8, article id 770780Article, review/survey (Refereed)
    Abstract [en]

    Corneal diseases are a leading cause of blindness with an estimated 10 million patients diagnosed with bilateral corneal blindness worldwide. Corneal transplantation is highly successful in low-risk patients with corneal blindness but often fails those with high-risk indications such as recurrent or chronic inflammatory disorders, history of glaucoma and herpetic infections, and those with neovascularisation of the host bed. Moreover, the need for donor corneas greatly exceeds the supply, especially in disadvantaged countries. Therefore, artificial and bio-mimetic corneas have been investigated for patients with indications that result in keratoplasty failure. Two long-lasting keratoprostheses with different indications, the Boston type-1 keratoprostheses and osteo-odonto-keratoprostheses have been adapted to minimise complications that have arisen over time. However, both utilise either autologous tissue or an allograft cornea to increase biointegration. To step away from the need for donor material, synthetic keratoprostheses with soft skirts have been introduced to increase biointegration between the device and native tissue. The AlphaCor (TM), a synthetic polymer (PHEMA) hydrogel, addressed certain complications of the previous versions of keratoprostheses but resulted in stromal melting and optic deposition. Efforts are being made towards creating synthetic keratoprostheses that emulate native corneas by the inclusion of biomolecules that support enhanced biointegration of the implant while reducing stromal melting and optic deposition. The field continues to shift towards more advanced bioengineering approaches to form replacement corneas. Certain biomolecules such as collagen are being investigated to create corneal substitutes, which can be used as the basis for bio-inks in 3D corneal bioprinting. Alternatively, decellularised corneas from mammalian sources have shown potential in replicating both the corneal composition and fibril architecture. This review will discuss the limitations of keratoplasty, milestones in the history of artificial corneal development, advancements in current artificial corneas, and future possibilities in this field.

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  • 46.
    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.

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  • 47.
    Ihnatko, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Edén, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Dellby, Anette
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Analysis of protein composition and protein expression in the tear fluid of patients with congenital aniridia2013In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, p. 78-88Article in journal (Refereed)
    Abstract [en]

    Aniridia is a rare congenital genetic disorder caused by haploinsuffiency of the PAX6 gene, the master gene for development of the eye. The expression of tear proteins in aniridia is unknown. To screen for proteins involved in the aniridia pathophysiology, the tear fluid of patients with diagnosed congenital aniridia was examined using two-dimensional electrophoresis (2-DE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two-dimensional map of tear proteins in aniridia has been established and 7 proteins were differentially expressed with P less than 0.01 between aniridia patients and control subjects. Five of them were more abundant in healthy subjects, particularly alpha-enolase, peroxiredoxin 6, cystatin S, gelsolin, apolipoprotein A-1 and two other proteins, zinc-alpha 2-glycoprotein and lactoferrin were more expressed in the tears of aniridia patients. Moreover, immunoblot analysis revealed elevated levels of vascular endothelial growth factor (VEGF) in aniridia tears which is in concordance with clinical finding of pathological blood and lymph vessels in the central and peripheral cornea of aniridia patients. The proteins with different expression in patients tears may be new candidate molecules involved in the pathophysiology of aniridia and thus may be helpful for development of novel treatment strategies for the symptomatic therapy of this vision threatening condition. Biological significance This study is first to demonstrate protein composition and protein expression in aniridic tears and identifies proteins with different abundance in tear fluid from patients with congenital aniridia vs. healthy tears.

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  • 48.
    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)
  • 49.
    Koulikovska, Marina
    et al.
    Östergötlands Läns Landsting, 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.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. LinkoCare Life Sciences AB, Linköping, Sweden.
    Petrovski, Goran
    University of Debrecen, Debrecen, Hungary; University of Szeged, Szeged, Hungary.
    Veréb, Zoltán
    University of Debrecen, Debrecen, Hungary; University of Szeged, Szeged, Hungary.
    Akhtar, Saeed
    Department of Optometry, College of Applied Medicine, King Saud University, Riyadh, Saudi Arabia.
    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.
    Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique2015In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, no 5-6, p. 1116-1130Article in journal (Refereed)
    Abstract [en]

    Severe shortage of donor corneas for transplantation, particularly in developing countries, has prompted the advancement of bioengineered tissue alternatives. Bioengineered corneas that can withstand transplantation while maintaining transparency and compatibility with host cells, and that are additionally amenable to standardized low-cost mass production are sought. In this study, a bioengineered porcine construct (BPC) was developed to function as a biodegradable scaffold to promote corneal stromal regeneration by host cells. Using high-purity medical-grade type I collagen, high 18% collagen content and optimized EDC-NHS cross-linker ratio, BPCs were fabricated into hydrogel corneal implants with over 90% transparency and four-fold increase in strength and stiffness compared with previous versions. Remarkably, optical transparency was achieved despite the absence of collagen fibril organization at the nanoscale. In vitro testing indicated that BPC supported confluent human epithelial and stromal-derived mesenchymal stem cell populations. With a novel femtosecond laser-assisted corneal surgical model in rabbits, cell-free BPCs were implanted in vivo in the corneal stroma of 10 rabbits over an 8-week period. In vivo, transparency of implanted corneas was maintained throughout the postoperative period, while healing occurred rapidly without inflammation and without the use of postoperative steroids. BPC implants had a 100% retention rate at 8 weeks, when host stromal cells began to migrate into implants. Direct histochemical evidence of stromal tissue regeneration was observed by means of migrated host cells producing new collagen from within the implants. This study indicates that a cost-effective BPC extracellular matrix equivalent can incorporate cells passively to initiate regenerative healing of the corneal stroma, and is compatible with human stem or organ-specific cells for future therapeutic applications as a stromal replacement for treating blinding disorders of the cornea.

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  • 50.
    Koulikovska, Marina
    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, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Szymanowski, Olena
    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.
    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.
    Platelet Rich Plasma Prolongs Myofibroblast Accumulation in Corneal Stroma with Incisional Wound2015In: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 40, no 11, p. 1102-1110Article in journal (Refereed)
    Abstract [en]

    Purpose: The purpose of this study was to determine whether platelet rich plasma (PRP) has an effect on corneal stromal cells in a rat model of wound healing following corneal incision. Materials and Methods: The effect of PRP on corneal wound healing in vivo was investigated in a corneal incision wound model in rats. 40 rats were wounded by deep corneal incision, and treated with either topically administered PRP (20 rats) or sodium chloride (20 rats). At 4 hours and 1, 3, and 5 days after incision, α-smooth muscle actin (α SMA), SMAD2 and SMAD3 expression and apoptosis in stromal cells were evaluated by immunohistochemistry, and IL-1β mRNA expression was evaluated by real time PCR.

    Results: PRP treated corneas exhibited reduced stromal cell apoptosis at day 3 and day 5 (p = 0.038, and <0.001, respectively) relative to controls. Interleukin-1β mRNA expression, however, was unchanged in PRP treated corneas relative to controls. Topical PRP treatment resulted in a higher proportion of αSMA-positive myofibroblasts recruited to the wound site relative to control corneas. PRP did not affect activation of SMAD2 but activation of SMAD3 was significantly reduced at day 1 (p=0.001) and dramatically increased at day 5 (p=0.032).

    Conclusions: PRP treatment resulted in suppressed stromal cell apoptosis followed by SMAD3 activation and a greater proportion of myofibroblasts present at the wound site. Suppression of stromal cell apoptosis after corneal wounding by use of a growth factor rich formulation may lead to myofibroblast accumulation by modulation of the TGF-β pathway.

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