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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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    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.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. 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 Dysfunction2019Ingår i: American Journal of Ophthalmology, ISSN 0002-9394, E-ISSN 1879-1891, Vol. 200, s. 16-25Artikel i tidskrift (Refereegranskat)
    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.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Mukwaya, Anthonny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. 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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. 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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, nr 7, s. 1402-1418Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Ali, Zaheer
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Zang, Jingjing
    Univ Zurich, Switzerland.
    Lagali, Neil
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för logopedi, otorhinolaryngologi och audiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Schmitner, Nicole
    Univ Innsbruck, Austria.
    Salvenmoser, Willi
    Univ Innsbruck, Austria.
    Mukwaya, Anthonny
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för logopedi, otorhinolaryngologi och audiologi. Linköpings universitet, Medicinska fakulteten.
    Neuhauss, Stephan C. F.
    Univ Zurich, Switzerland.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Kimmel, Robin A.
    Univ Innsbruck, Austria.
    Photoreceptor Degeneration Accompanies Vascular Changes in a Zebrafish Model of Diabetic Retinopathy2020Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, nr 2, artikel-id UNSP 43Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    An in Vivo Method for Visualizing Flow Dynamics of Cells within Corneal Lymphatics2013Ingår i: Lymphatic Research and Biology, ISSN 1539-6851, E-ISSN 1557-8585, Vol. 11, nr 2, s. 93-100Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Letter: In vivo confocal microscopy visualization of presumed lymph vessels in a case of corneal transplant rejection2011Ingår i: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071, Vol. 39, nr 8, s. 832-834Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 6.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Transient Anterior Corneal Deposits in a Human Immunodeficiency Virus-Positive Patient2010Ingår i: CORNEA, ISSN 0277-3740, Vol. 29, nr 11, s. 1323-1327Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model2011Ingår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 14, nr 3, s. 393-405Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Lagali, Neil
    Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Cellular-Level Characterization of Lymph Vessels in Live, Unlabeled Corneas by In Vivo Confocal Microscopy2010Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, nr 2, s. 830-835Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Bourghardt Peebo, Beatrice
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Time-Lapse In Vivo Imaging of Corneal Angiogenesis: The Role of Inflammatory Cells in Capillary Sprouting2011Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, nr 6, s. 3060-3068Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    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 myeloma2019Ingår i: American journal of ophthalmology case reports, ISSN 2451-9936, Vol. 15, artikel-id 100505Artikel i tidskrift (Refereegranskat)
    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.

  • 11.
    Eden, U
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Pathologic epithelial and anterior corneal nerve morphology in congenital aniridic keratopathy in ACTA OPHTHALMOLOGICA, vol 88, issue , pp 52-522010Ingår i: ACTA OPHTHALMOLOGICA, Blackwell Publishing Ltd , 2010, Vol. 88, s. 52-52Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 12.
    Eden, Ulla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Danyali, Reza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Pathologic Epithelial and Anterior Corneal Nerve Morphology in Early-Stage Congenital Aniridic Keratopathy2012Ingår i: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 119, nr 9, s. 1803-1810Artikel i tidskrift (Refereegranskat)
    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.

  • 13.
    Edén, Ulla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Dellby, Anette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Letter: Cataract development in Norwegian patients with congenital aniridia2014Ingår i: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 92, nr 2, s. E165-E167Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 14.
    Fagerholm, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    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]2014Ingår i: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 7, nr 4, s. 347-347Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 15.
    Fagerholm, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Ong, Jeb A.
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Merrett, Kimberley
    Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM. 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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold2014Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, nr 8, s. 2420-2427Artikel i tidskrift (Refereegranskat)
    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.

  • 16.
    Fagerholm, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Lagali, Neil S
    Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet.
    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 Substitute2009Ingår i: CTS-CLINICAL AND TRANSLATIONAL SCIENCE, ISSN 1752-8054, Vol. 2, nr 2, s. 162-164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    n/a

  • 17.
    Fagerholm, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Lagali, Neil S
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study2010Ingår i: Science translational medicine, ISSN 1946-6234, Vol. 2, nr 46, s. 46-61Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    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 Microscopy2017Ingår i: Microscopy and Microanalysis, ISSN 1431-9276, E-ISSN 1435-8115, Vol. 23, nr 1, s. 88-96Artikel i tidskrift (Refereegranskat)
    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.

  • 19.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    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 Expressibility2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 5, s. e0155214-Artikel i tidskrift (Refereegranskat)
    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.

  • 20.
    Germundsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Koulikovska, Marina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    An Accurate Method to Determine Bowmans Layer Thickness In Vivo in the Human Cornea2012Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 53, nr 4, s. 2354-2359Artikel i tidskrift (Refereegranskat)
    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.

  • 21.
    Germundsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Clinical Outcome and Recurrence of Epithelial Basement Membrane Dystrophy after Phototherapeutic Keratectomy A Cross-sectional Study2011Ingår i: OPHTHALMOLOGY, ISSN 0161-6420, Vol. 118, nr 3, s. 515-522Artikel i tidskrift (Refereegranskat)
    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.

  • 22.
    Germundsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Letter: Corneal Dystrophy Recurrence Reply2011Ingår i: BMC Ophthalmology, ISSN 1471-2415, E-ISSN 1471-2415, Vol. 118, nr 6, s. 1223-1224Artikel i tidskrift (Övrigt vetenskapligt)
  • 23.
    Germundsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Karanis, Georgios
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Age-Related Thinning of Bowman's Layer in the Human Cornea In Vivo2013Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 54, nr 9, s. 6143-6149Artikel i tidskrift (Refereegranskat)
    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.

  • 24.
    Germundsson, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Pathologically reduced subbasal nerve density in epithelial basement membrane dystrophy is unaltered by phototherapeutic keratectomy treatment2014Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, nr 3, s. 1835-1841Artikel i tidskrift (Refereegranskat)
    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.

  • 25.
    Griffith, May
    et al.
    University of Ottawa.
    Jackson, W B
    University of Ottawa.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Merrett, K
    University of Ottawa.
    Li, F
    University of Ottawa.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Artificial corneas: a regenerative medicine approach2009Ingår i: EYE, ISSN 0950-222X, Vol. 23, nr 10, s. 1985-1989Artikel i tidskrift (Refereegranskat)
    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.

  • 26.
    Hackett, Joanne M.
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Edelhauser, Henry
    Emory University School of Medicine.
    Sun, Yifei
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Gan, Lisha
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Biosynthetic corneal implants for replacement of pathologic corneal tissue: performance in a controlled rabbit alkali burn model2011Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, nr 2, s. 651-657Artikel i tidskrift (Refereegranskat)
    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.

  • 27.
    Hammar, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    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, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Dystrophia Smolandiensis - recurrent corneal erosions with a novel morphological picture2010Ingår i: Acta Ophthalmologica, ISSN 1755-375X, Vol. 88, nr 4, s. 394-400Artikel i tidskrift (Refereegranskat)
    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.

  • 28.
    Harada, Fumiya
    et al.
    Health Science University of Hokkaido, Japan; Taipei Medical University, Taiwan.
    Morikawa, Tetsuro
    Health Science University of Hokkaido, Japan.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Far Eastern Federal University, Russia.
    Mukwaya, Anthony
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Schaupper, Mira
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Kitaichi, Nobuyoshi
    Hokkaido University, Japan; Health Science University of Hokkaido Hospital, Japan.
    Protective Effects of Oral Astaxanthin Nanopowder against Ultraviolet-Induced Photokeratitis in Mice2017Ingår i: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, artikel-id 1956104Artikel i tidskrift (Refereegranskat)
    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.

  • 29.
    Ihnatko, Robert
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Edén, Ulla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Congenital Aniridia and the Ocular Surface2016Ingår i: OCULAR SURFACE, ISSN 1542-0124, Vol. 14, nr 2, s. 196-206Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    Ihnatko, Robert
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Edén, Ulla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Dellby, Anette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Analysis of protein composition and protein expression in the tear fluid of patients with congenital aniridia2013Ingår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, s. 78-88Artikel i tidskrift (Refereegranskat)
    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.

  • 31.
    Johansson, Björn
    et al.
    Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Fagerholm, Per
    Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Petranyi, Gabor
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Claesson Armitage, Margareta
    Department of Ophthalmology, Sahlgrenska University Hospital, M € olndal, Sweden.
    Lagali, Neil
    Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Diagnostic and therapeutic challenges in a case of amikacin-resistant Nocardia keratitis.2017Ingår i: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 95, nr 1, s. 103-105Artikel i tidskrift (Refereegranskat)
  • 32.
    Koulikovska, Marina
    et al.
    Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Rafat, Mehrdad
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. 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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique2015Ingår i: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, nr 5-6, s. 1116-1130Artikel i tidskrift (Refereegranskat)
    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.

  • 33.
    Koulikovska, Marina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Szymanowski, Olena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Platelet Rich Plasma Prolongs Myofibroblast Accumulation in Corneal Stroma with Incisional Wound2015Ingår i: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 40, nr 11, s. 1102-1110Artikel i tidskrift (Refereegranskat)
    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.

  • 34.
    Koulikovska, Marina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Szymanowski, Olena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Topical Biglycan Modulates Stromal Cell Apoptosis in Corneal Incisional Wound Model2015Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Purpose: The purpose of this study was to determine whether exogenous topicallyapplied biglycan has an effect on corneal stromal cells during wound healing.

    Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine the effect of biglycan on cell survival in vitro following IL-1β induced cell death. In a corneal incisional wound model, 40 rats were wounded and treated with either topically administered biglycan or sodium chloride (sham control). At 4 hours and 1, 2, and 5 days after incision, α-smooth muscle actin (SMA) expression and apoptosis in stromal cells were evaluated by immunohistochemistry.

    Results: In vitro, biglycan significantly enhanced IL-1β-induced apoptosis of myofibroblasts (p = 0.038), but not corneal fibroblasts. Biglycan treated corneas exhibited reduced stromal cell apoptosis at 4 hours, day 1 and day 5 (p = 0.012, 0.040, and 0.048, respectively) and increased apoptosis at day 3 (p = 0.003) relative to controls. In wounded corneas, biglycan appeared to promote early accumulation of myofibroblasts and initiate an earlier subsequent apoptosis of these cells, relative to controls.

    Conclusion: Biglycan appears to accelerate corneal wound healing in vivo by modulating myofibroblast apoptosis, resulting in removal of myofibroblasts that may otherwise compromise corneal transparency.

  • 35.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Sorlandet Hosp Arendal, Norway.
    Corneal Stromal Regeneration: Current Status and Future Therapeutic Potential2020Ingår i: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 45, nr 3, s. 278-290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The corneal stroma comprises 90% of the corneal thickness and is critical for the corneas transparency and refractive function necessary for vision. When the corneal stroma is altered by disease, injury, or scarring, however, an irreversible loss of transparency can occur. Corneal stromal pathology is the cause of millions of cases of blindness globally, and although corneal transplantation is the standard therapy, a severe global deficit of donor corneal tissue and eye banking infrastructure exists, and is unable to meet the overwhelming need. An alternative approach is to harness the endogenous regenerative ability of the corneal stroma, which exhibits self-renewal of the collagenous extracellular matrix under appropriate conditions. To mimic endogenous stromal regeneration, however, is a challenge. Unlike the corneal epithelium and endothelium, the corneal stroma is an exquisitely organized extracellular matrix containing stromal cells, proteoglycans and corneal nerves that is difficult to recapitulate in vitro. Nevertheless, much progress has recently been made in developing stromal equivalents, and in this review the most recent approaches to stromal regeneration therapy are described and discussed. Novel approaches for stromal regeneration include human or animal corneal and/or non-corneal tissue that is acellular or is decellularized and/or re-cellularized, acellular bioengineered stromal scaffolds, tissue adhesives, 3D bioprinting and stromal stem cell therapy. This review highlights the techniques and advances that have achieved first clinical use or are close to translation for eventual therapeutic application in repairing and regenerating the corneal stroma, while the potential of these novel therapies for achieving effective stromal regeneration is discussed.

  • 36.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Need for technologies in advanced corneal research, diagnosis, and transplantation2019Ingår i: OPHTHALMIC TECHNOLOGIES XXIX, SPIE-INT SOC OPTICAL ENGINEERING , 2019, Vol. 10858, artikel-id 108580BKonferensbidrag (Refereegranskat)
    Abstract [en]

    Never before have optical, information, and biomedical technologies converged to the extent they do today. Moreover, the accessibility of enormous amounts of computing power at reasonable cost has transformed raw data into useable information that can enable biological discoveries and medical decisions to be made faster and more accurate than ever before. In the field of ophthalmology in particular, advanced optical instrumentation, devices, and procedures have revolutionized the standard of care and improved outcomes for millions, for the benefit of society. The cornea is the clear outer window of the eye and is directly accessible for examination and treatment using light-based approaches, and as such it provides us with a unique window into the physiology of the body in health and disease. At the same time, the cornea is a model tissue from which we have acquired much knowledge about light-tissue interactions. Finally, and importantly, diseases of the cornea compromising its transparency are responsible for millions of cases of corneal blindness globally, so there is much to gain from technological advancements in the field. Here, a need for new technological solutions is presented, that is not primarily technology-driven but instead motivated by real and pressing medical needs in the research, diagnosis and treatment of corneal blindness.

  • 37.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Allgeier, Stephan
    Karlsruhe Inst Technol, Germany.
    Guimaraes, Pedro
    Univ Padua, Italy.
    Badian, Reza A.
    Univ Coll Southeast Norway, Norway; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Ruggeri, Alfredo
    Univ Padua, Italy.
    Koehler, Bernd
    Karlsruhe Inst Technol, Germany.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Peterson, Magnus
    Uppsala Univ, Sweden.
    Dahlin, Lars B.
    Lund Univ, Sweden.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Wide-field corneal subbasal nerve plexus mosaics in age-controlled healthy and type 2 diabetes populations2018Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 5, artikel-id 180075Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A dense nerve plexus in the clear outer window of the eye, the cornea, can be imaged in vivo to enable non-invasive monitoring of peripheral nerve degeneration in diabetes. However, a limited field of view of corneal nerves, operator-dependent image quality, and subjective image sampling methods have led to difficulty in establishing robust diagnostic measures relating to the progression of diabetes and its complications. Here, we use machine-based algorithms to provide wide-area mosaics of the corneas subbasal nerve plexus (SBP) also accounting for depth (axial) fluctuation of the plexus. Degradation of the SBP with age has been mitigated as a confounding factor by providing a dataset comprising healthy and type 2 diabetes subjects of the same age. To maximize reuse, the dataset includes bilateral eye data, associated clinical parameters, and machine-generated SBP nerve density values obtained through automatic segmentation and nerve tracing algorithms. The dataset can be used to examine nerve degradation patterns to develop tools to non-invasively monitor diabetes progression while avoiding narrow-field imaging and image selection biases.

  • 38.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Sorlandet Hosp Arendal, Norway.
    Badian, Reza A.
    Univ South Eastern Norway, Norway; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Liu, Xu
    Oyelegesenteret Tromso, Norway.
    Feldreich, Tobias R.
    Uppsala Univ, Sweden; Dalarna Univ, Sweden.
    Arnlov, Johan
    Dalarna Univ, Sweden; Karolinska Inst, Sweden.
    Utheim, Tor Paaske
    Sorlandet Hosp Arendal, Norway; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Dahlin, Lars B.
    Lund Univ, Sweden.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Dendritic cell maturation in the corneal epithelium with onset of type 2 diabetes is associated with tumor necrosis factor receptor superfamily member 92018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 14248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.

  • 39.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Bourghardt Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Germundsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Edén, Ulla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Danyali, Reza
    Linköpings universitet, Hälsouniversitetet.
    Rinaldo, Marcus
    Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Laser-Scanning in vivo Confocal Microscopy of the Cornea: Imaging and Analysis Methods for Preclinical and Clinical Applications2013Ingår i: Confocal Laser Microscopy: Principles and Applications in Medicine, Biology, and the Food Sciences, INTECH, 2013Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 40.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Dellby, Anette
    Östergötlands Läns Landsting.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    In vivo confocal microscopy of the cornea in Darier-White disease.2009Ingår i: Archives of ophthalmology, ISSN 1538-3601, Vol. 127, nr 6, s. 816-818Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 41.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Edén, Ulla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Paaske Utheim, Tor
    Oslo University Hospital, Norway.
    Chen, Xiangjun
    Synslaser Kirurgi AS, Norway.
    Riise, Ruth
    Innland Hospital, Norway.
    Delby, Anette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Ögonkliniken US/LiM.
    In Vivo Morphology of the Limbal Palisades of Vogt Correlates With Progressive Stem Cell Deficiency in Aniridia-Related Keratopathy2013Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 54, nr 8, s. 5333-5342Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose. To investigate morphologic alterations in the limbal palisades of Vogt in a progressive form of limbal stem cell deficiency.

    Methods. Twenty Norwegian subjects (40 eyes) with congenital aniridia and 9 healthy family members (18 eyes) without aniridia were examined. Clinical grade of aniridia-related keratopathy (ARK) was assessed by slit-lamp biomicroscopy, and tear production and quality, corneal thickness, and sensitivity were additionally measured. The superior and inferior limbal palisades of Vogt and central cornea were examined by laser scanning in vivo confocal microscopy (IVCM).

    Results. In an aniridia patient with grade 0 ARK, a transparent cornea and normal limbal palisade morphology were found. In grade 1 ARK, 5 of 12 eyes had degraded palisade structures. In the remaining grade 1 eyes and in all 20 eyes with stage 2, 3, and 4 ARK, palisade structures were absent by IVCM. Increasing ARK grade significantly correlated with reduced visual acuity and corneal sensitivity, increased corneal thickness, degree of degradation of superior and inferior palisade structures, reduced peripheral nerves, increased inflammatory cell invasion, and reduced density of basal epithelial cells and central subbasal nerves. Moreover, limbal basal epithelial cell density and central corneal subbasal nerve density were both significantly reduced in aniridia compared to healthy corneas (P = 0.002 and 0.003, respectively).

    Conclusions. Progression of limbal stem cell deficiency in aniridia correlates with degradation of palisade structures, gradual transformation of epithelial phenotype, onset of inflammation, and a corneal nerve deficit. IVCM can be useful in monitoring early- to late-stage degenerative changes in stem cell–deficient patients.

  • 42.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US.
    Corneal injury by formic acid: one-year clinical course and in-vivo confocal microscopic evaluation2008Ingår i: Clinical and Experimental Ophthalmology, ISSN 1442-6404, E-ISSN 1442-9071, Vol. 36, nr 7, s. 692-694Artikel i tidskrift (Övrigt vetenskapligt)
  • 43.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Delayed Mustard Gas Keratitis: Clinical Course and In Vivo Confocal Microscopy Findings2009Ingår i: CORNEA, ISSN 0277-3740, Vol. 28, nr 4, s. 458-462Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To report the detailed clinical and in vivo confocal microscopic findings in a patient with delayed-onset mustard gas keratitis observed 20 years after initial exposure.

    Methods: A 38-year-old man who was exposed to mustard gas in Iraq at the age of 19 years was examined after presenting with ocular symptoms 17 years after initial recovery from the exposure. Slit-lamp biomicroscopy, corneal topography, and in vivo confocal microscopy were performed on both corneas.

    Results: The clinical symptoms were consistent with a delayed form of mustard gas keratitis, although the patient had clear central corneas and good visual acuity. Confocal microscopic findings included evidence of epithelial abnormalities, necrotic changes in the anterior stroma, subbasal and anterior stromal nerve proliferation, and deep stromal keratocyte activation.

    Conclusions: In vivo confocal microscopy revealed persistent morphologic abnormalities in the anterior stroma of both corneas 20 years after initial exposure to mustard gas. The detection of a population of dendritic cell bodies in the central epithelium and evidence of keratocyte activation and migration in the deep stroma indicated the presence of ongoing subclinical processes.

  • 44.
    Lagali, Neil
    et al.
    Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Letter: A case of chronic ocular irritation associated with progressive corneal opacification2009Ingår i: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 87, nr 8, s. 932-934Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 45.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Editorial Material: Biosynthetic corneas: prospects for supplementing the human donor cornea supply in EXPERT REVIEW OF MEDICAL DEVICES, vol 8, issue 2, pp 127-1302011Ingår i: Expert Review of Medical Devices, ISSN 1743-4440, E-ISSN 1745-2422, Vol. 8, nr 2, s. 127-130Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 46.
    Lagali, Neil
    et al.
    Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet.
    Germundsson, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    The Role of Bowmans Layer in Corneal Regeneration after Phototherapeutic Keratectomy: A Prospective Study Using In Vivo Confocal Microscopy2009Ingår i: INVESTIGATIVE OPHTHALMOLOGY and VISUAL SCIENCE, ISSN 0146-0404, Vol. 50, nr 9, s. 4192-4198Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE. To examine the role of Bowmans layer (BL) on the nature of anterior corneal regeneration after excimer laser phototherapeutic keratectomy (PTK). METHODS. A cohort of 13 patients underwent PTK to remove either 7 mu m of BL for treatment of primary recurrent corneal erosions (RCE; six patients) or complete BL removal (15-mu m ablation) to treat RCE or poor vision secondary to map-dot-fingerprint (MDF) dystrophy (seven patients). Clinical examinations and laser-scanning in vivo confocal microscopy (IVCM) were conducted before surgery and at a mean of 4 and 8 months after surgery. RESULTS. Total BL removal resulted in a significant decline in subbasal nerve density at 4 months (P = 0.007) that barely recovered to preoperative levels at 8 months (P = 0.055). With BL partially present, subbasal nerve density did not significantly change from preoperative levels. Superficial, wing, and basal epithelial cell density recovered to preoperative levels within 4 months after PTK, regardless of the presence of BL. Subepithelial keratocytes, however, were more densely distributed in corneas without BL relative to those with a partial BL present (P = 0.005), and increased anterior keratocyte reflectivity was noted in all eyes without BL and in no eye with a partial BL present. CONCLUSIONS. Subbasal nerve regeneration is delayed and subepithelial keratocyte density and reflectivity remain elevated up to 10 months after total BL removal by PTK. The results provide initial evidence for a possible role of BL in facilitating rapid stromal wound healing and an associated recovery of anterior corneal transparency and the restoration of epithelial innervation after epithelial trauma.

  • 47.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet.
    Fagerholm, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmiatrik. Linköpings universitet, Hälsouniversitetet.
    In vivo confocal microscopy of the cornea to assess tissue regenerative response after biomaterial implantation in humans.2013Ingår i: Corneal Regenerative Medicine: Methods and ProtocolsPart IV / [ed] Bernice Wright; Che J Connon, Humana Press, 2013, Vol. 1014, s. 211-23Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Laser-scanning in vivo confocal microscopy (IVCM) of the cornea is becoming an increasingly popular tool to examine the living human cornea with cellular-level detail in both healthy and pathologic states. Here, we describe the use of the IVCM technique to examine the processes of tissue healing and regeneration in the living human eye after biomaterial implantation. The regenerative response can be assessed by performing longitudinal IVCM imaging of a laboratory-made, cell-free biomaterial, after direct implantation into a pathologic eye as a primary alternative to human donor tissue transplantation.

  • 48.
    Lagali, Neil
    et al.
    University of Ottawa Eye Institute.
    Griffith, May
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada.
    Fagerholm, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oftalmologi. Östergötlands Läns Landsting, Rekonstruktionscentrum, Ögonkliniken US/LiM.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Huynh, Melissa
    University of Ottawa Eye Institute.
    Munger, Rejean
    University of Ottawa Eye Institute.
    Innervation of tissue-engineered recombinant human collagen-based corneal substitutes: A comparative in vivo confocal microscopy study2008Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 49, nr 9, s. 3895-3902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE. To compare reinnervation in recombinant human collagen-based corneal substitutes with allografts during a 1-year postimplantation follow-up period in pigs. A retrospective comparison to innervation in porcine collagen-based biosynthetic grafts was also performed. METHODS. Pigs received a corneal allograft or a substitute made of either recombinant human type-I or -III collagen. In vivo confocal microscopic examination of the central cornea of surgical and untouched control eyes before surgery and at 2, 6, and 12 months after surgery was performed to quantify the number, density, and diameter of nerves at various corneal depths. RESULTS. By 12 months after surgery, the number and density of regenerated nerves in the anterior and deep anterior corneal stroma recovered to preoperative and control levels in both types of substitute grafts and in the allografts. In the subepithelial and subbasal regions, however, significantly fewer nerves were detected relative to those in control subjects at 12 months, regardless of graft type ( P < 0.05), similar to the behavior of porcine collagen-based biosynthetic grafts. An absence of thick stromal nerve trunks (diameter, > 10 mu m) in all grafts, irrespective of material type, indicated that nerve regeneration in grafts was accompanied by persistent morphologic changes. CONCLUSIONS. Nerve regeneration in recombinant human collagen-based biosynthetic corneal grafts proceeded similarly to that in allograft tissue, demonstrating the suitability of recombinant human collagen constructs as nerve-friendly corneal substitutes. Furthermore, only minor differences were noted between type-I and -III collagen grafts, indicating an insensitivity of nerve regeneration to initial collagen type.

  • 49.
    Lagali, Neil
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Poletti, Enea
    University of Padua, Italy.
    Patel, Dipika V.
    University of Auckland, New Zealand.
    McGhee, Charles N. J.
    University of Auckland, New Zealand.
    Hamrah, Pedram
    Harvard University, MA USA.
    Kheirkhah, Ahmad
    Harvard University, MA USA.
    Tavakoli, Mitra
    University of Manchester, England.
    Petropoulos, Ioannis N.
    University of Manchester, England; Qatar Fdn, Qatar.
    Malik, Rayaz A.
    University of Manchester, England; Qatar Fdn, Qatar.
    Paaske Utheim, Tor
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Zhivov, Andrey
    University of Rostock, Germany.
    Stachs, Oliver
    University of Rostock, Germany.
    Falke, Karen
    University of Rostock, Germany.
    Peschel, Sabine
    University of Rostock, Germany.
    Guthoff, Rudolf
    University of Rostock, Germany.
    Chao, Cecilia
    University of New S Wales, Australia.
    Golebiowski, Blanka
    University of New S Wales, Australia.
    Stapleton, Fiona
    University of New S Wales, Australia.
    Ruggeri, Alfredo
    University of Padua, Italy.
    Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves2015Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, nr 9, s. 5102-5109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE. We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity. METHODS. Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linkoping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation. RESULTS. Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given graders ordering of images with the group average to 0.86 to 0.90. CONCLUSIONS. Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies.

  • 50.
    Lagali, Neil S
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Allgeier, Stephan
    Institute for Applied Computer Science, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Guimarães, Pedro
    Department of Information Engineering, University of Padova, Padova, Italy.
    Badian, Reza A.
    Faculty of Health Sciences, University College of Southeast Norway, Kongsberg, Norway; Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Ophthalmology, Stavanger University Hospital, Stavanger/Clinical Institute 1, Faculty of Medicine, University of Bergen, Bergen, Norway.
    Ruggeri, Alfredo
    Department of Information Engineering, University of Padova, Padova, Italy.
    Köhler, Bernd
    Institute for Applied Computer Science, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Utheim, Tor Paaske
    Faculty of Health Sciences, University College of Southeast Norway, Kongsberg, Norway; Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Peterson, Magnus
    Department of Public Health and Caring Sciences, Section of Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.
    Dahlin, Lars B.
    Department of Translational Medicine-Hand Surgery, Lund University, Skåne University Hospital, Malmö, Sweden.
    Rolandsson, Olov
    Department of Public Health and Clinical Medicine, Section of Family Medicine, Umeå University, Umeå, Sweden.
    Reduced Corneal Nerve Fiber Density in Type 2 Diabetes by Wide-Area Mosaic Analysis2017Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, nr 14, s. 6318-6327Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To determine if corneal subbasal nerve plexus (SBP) parameters derived from wide-area depth-corrected mosaic images are associated with type 2 diabetes.

    Methods: One hundred sixty-three mosaics were produced from eyes of 82 subjects by laser-scanning in vivo confocal microscopy (IVCM). Subjects were of the same age, without (43 subjects) or with type 2 diabetes (39 subjects). Mosaic corneal nerve fiber length density (mCNFL) and apical whorl corneal nerve fiber length density (wCNFL) were quantified and related to the presence and duration of diabetes (short duration < 10 years and long duration ≥ 10 years).

    Results: In mosaics with a mean size of 6 mm2 in subjects aged 69.1 ± 1.2 years, mCNFL in type 2 diabetes was reduced relative to nondiabetic subjects (13.1 ± 4.2 vs. 15.0 ± 3.2 mm/mm2, P = 0.018). Also reduced relative to nondiabetic subjects was mCNFL in both short-duration (14.0 ± 4.0 mm/mm2, 3.2 ± 3.9 years since diagnosis) and long-duration diabetes (12.7 ± 4.2 mm/mm2, 15.4 ± 4.2 years since diagnosis; ANOVA P = 0.023). Lower mCNFL was associated with presence of diabetes (P = 0.032) and increased hemoglobin A1c (HbA1c) levels (P = 0.047). By contrast, wCNFL was unaffected by diabetes or HbA1c (P > 0.05). Global SBP patterns revealed marked degeneration of secondary nerve fiber branches outside the whorl region in long-duration diabetes.

    Conclusions: Wide-area mosaic images provide reference values for mCNFL and wCNFL and reveal a progressive degeneration of the SBP with increasing duration of type 2 diabetes.

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