Publications by authors named "Alfonso L Sabater"

29 Publications

  • Page 1 of 1

Dry eye: why artificial tears are not always the answer.

BMJ Open Ophthalmol 2021 8;6(1):e000697. Epub 2021 Apr 8.

Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA.

Dry eye disease (DED) is a multifactorial disease that manifests in patients with a variety of symptoms and signs such as ocular pain, visual issues, rapid tear evaporation and/or decreased tear production. It is a global health problem and is the leading cause of optometry and ophthalmology clinic visits. The mainstay therapy for DED is artificial tears (ATs), which mimics tears and improves tear stability and properties. ATs have been found to improve symptoms and signs of disease in all DED subtypes, including aqueous deficient DED and evaporative DED. However, given the heterogeneity of DED, it is not surprising that ATs are not effective in all patients. When AT fails to relieve symptoms and/or signs of DED, it is critical to identify the underlying contributors to disease and escalate therapy appropriately. This includes underlying systemic diseases, meibomian gland dysfunction, anatomical abnormalities and neuropathic dysfunction. Thus, this review will discuss the benefits and limitations of ATs and review conditions when escalation of therapy should be considered in DED.
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http://dx.doi.org/10.1136/bmjophth-2020-000697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039249PMC
April 2021

Tumor necrosis factor-alpha and interferon-gamma induce inflammasome-mediated corneal endothelial cell death.

Exp Eye Res 2021 Apr 17;207:108574. Epub 2021 Apr 17.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Purpose: Chronic corneal endothelial cell (CEC) loss results in corneal edema and vision loss in conditions such as pseudophakic bullous keratopathy (PBK), Fuchs' dystrophy, and corneal graft failure. Low CEC density has been associated with an elevation of intraocular pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. These cytokines are capable of triggering pyroptosis, a programmed cell death mechanism mediated by the inflammasome, prompting the activation of the pro-inflammatory cytokine interleukin (IL)-1β, the perpetuation of inflammation, and subsequent damage of corneal endothelial tissue. Therefore, the purpose of this study was to determine the deleterious contribution of the inflammasome and pyroptosis to CEC loss.

Methods: CECs from human donor corneas were treated ex vivo with TNF-α and IFN-γ for 48 h. Levels of caspase-1 and IL-1β were then assayed by ELISA, and the expression of caspase-1 and gasdermin-D (GSDM-D) were confirmed by immunofluorescence. Endothelial cell damage was analyzed by a lactate dehydrogenase (LDH) release assay, and oxidative stress was determined by measuring the levels of reactive oxygen species (ROS) in the culture media.

Results: Inflammasome activation and oxidative stress were elevated in CECs following exposure to TNF-α and IFN-γ, which resulted in cell death by pyroptosis as determined by LDH release which was inhibited by the caspase-1 inhibitor Ac-YVAD-cmk.

Conclusion: CEC death is induced by the pro-inflammatory cytokines TNF-α and IFN-γ, which contribute to inflammasome activation. Moreover, the inflammasome is a promising therapeutic target for the treatment of chronic CEC loss.
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http://dx.doi.org/10.1016/j.exer.2021.108574DOI Listing
April 2021

Use of autologous plasma rich in growth factors fibrin membrane in the surgical management of ocular surface diseases.

Int Ophthalmol 2021 Mar 21. Epub 2021 Mar 21.

Department of Ophthalmology, Bascom Palmer Eye Institute, Ocular Surface Center, University of Miami Miller School of Medicine, Miami, USA.

Purpose: To evaluate the safety and efficacy of the surgical use of autologous plasma rich in growth factors fibrin membrane (mPRGF) in improving corneal wound healing and regeneration in a variety of complex ocular surface defects.

Methods: Chart review on 15 eyes of 14 included patients undergoing ocular surface intervention using intraoperative mPRGF at the Bascom Palmer Eye Institute and at the Instituto Oftalmológico Fernández-Vega was performed. Patients were grouped based on type of intervention or condition (penetrating keratoplasty, superficial keratectomy, neurotrophic or persistent corneal ulcers, and corneal perforation). Patients were followed for an average of 11 ± 5 months. Main outcomes measured were mPRGF dissolving time, best-corrected visual acuity, and evidence of any persistent epithelial defects, rejections, or complications.

Results: All 15 eyes underwent successful placement of mPRGF. Average dissolving time for fibrin membrane was 21 ± 3 days. mPRGF resulted in total healing of the corneal defects in 13/15 (86.7%) of the treated eyes and partial healing in 2/15 (13.3%) eyes in which persistent epithelial defects were noted on follow-up. Visual acuity improvement was seen in 9/15 (60%) of the cases.

Conclusion: The use of autologous mPRGF in the healing and regeneration of the ocular surface is a secure and efficacious surgical option. Our data demonstrate that PRGF fibrin membrane should be contemplated as an important tool to optimize ocular surface regeneration in complex cases.
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http://dx.doi.org/10.1007/s10792-021-01788-zDOI Listing
March 2021

Discovering the Potential of Dental Pulp Stem Cells for Corneal Endothelial Cell Production: A Proof of Concept.

Front Bioeng Biotechnol 2021 28;9:617724. Epub 2021 Jan 28.

Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain.

Failure of corneal endothelium cell monolayer is the main cause leading to corneal transplantation. Autologous cell-based therapies are required to reconstruct the cell monolayer. Several strategies have been proposed using embryonic stem cells and induced pluripotent stem cells, although their use has ethical issues as well as limited clinical applications. For this purpose, we propose the use of dental pulp stem cells isolated from the third molars to form the corneal endothelium cell monolayer. We hypothesize that using dental pulp stem cells that share an embryological origin with corneal endothelial cells, as they both arise from the neural crest, may allow a direct differentiation process avoiding the use of reprogramming techniques, such as induced pluripotent stem cells. In this work, we report a two-step differentiation protocol, where dental pulp stem cells are derived into neural crest stem-like cells and, then, into corneal endothelial-like cells. Initially, for the first-step we used an adhesion culture and compared two initial cell sources: a direct formation from dental pulp stem cells with the differentiation from induced pluripotent stem cells. Results showed significantly higher levels of early stage marker AP2 for the dental pulp stem cells compared to induced pluripotent stem cells. In order to provide a better environment for neural crest stem cells generation, we performed a suspension method, which induced the formation of neurospheres. Results showed that neurosphere formation obtained the peak of neural crest stem cell markers expression after 4 days, showing overexpression of AP2, Nestin, and p75 markers, confirming the formation of neural crest stem-like cells. Furthermore, pluripotent markers Oct4, Nanog, and Sox2 were as well-upregulated in suspension culture. Neurospheres were then directly cultured in corneal endothelial conditioned medium for the second differentiation into corneal endothelial-like cells. Results showed the conversion of dental pulp stem cells into polygonal-like cells expressing higher levels of ZO-1, ATP1A1, COL4A2, and COL8A2 markers, providing a proof of the conversion into corneal endothelial-like cells. Therefore, our findings demonstrate that patient-derived dental pulp stem cells may represent an autologous cell source for corneal endothelial therapies that avoids actual transplantation limitations as well as reprogramming techniques.
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http://dx.doi.org/10.3389/fbioe.2021.617724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876244PMC
January 2021

Use of Acellular Umbilical Cord-Derived Tissues in Corneal and Ocular Surface Diseases.

Medicines (Basel) 2021 Feb 9;8(2). Epub 2021 Feb 9.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Blood derived products have become a valuable source of tissue for the treatment of ocular surface diseases that are refractory to conventional treatments. These can be obtained from autologous or allogeneic sources (patient's own blood or from healthy adult donors/umbilical cord blood, respectively). Allogeneic cord blood demonstrates practical advantages over alternatives and these advantages will be discussed herein. Umbilical cord blood (UCB) can be divided, generally speaking, into two distinct products: first, mononuclear cells, which can be used in regenerative ophthalmology, and second, the plasma/serum (an acellular fraction), which may be used in the form of eyedrops administered directly to the damaged ocular surface. The rationale for using umbilical cord serum (UCS) to treat ocular surface diseases such as severe dry eye syndrome (DES), persistent epithelial defects (PED), recurrent epithelial erosions, ocular chemical burns, graft versus host disease (GVHD), among others, is the considerably high concentration of growth factors and cytokines, mimicking the natural healing properties of human tears. Allogeneic serum also offers the opportunity for therapeutic treatment to patients who, due to poor heath, cannot provide autologous serum. The mechanism of action involves the stimulation of endogenous cellular proliferation, differentiation and maturation, which is highly efficient in promoting and enhancing corneal epithelial healing where other therapies have previously failed.
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http://dx.doi.org/10.3390/medicines8020012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916115PMC
February 2021

Clinicopathologic Correlations of Retrocorneal Membranes Associated With Endothelial Corneal Graft Failure.

Am J Ophthalmol 2021 02 15;222:24-33. Epub 2020 Aug 15.

Anne Bates Leach Eye Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

Purpose: To provide clinicopathologic correlations for retrocorneal membranes associated with Descemet stripping automated endothelial keratoplasty (DSAEK) failure.

Design: Retrospective case series.

Methods: The specimens and medical records of the patients diagnosed with clinically significant retrocorneal membranes associated with DSAEK failure at the Bascom Palmer Eye Institute or the University of Miami Veterans Hospital between October 2015 and March 2020 were reviewed for demographics, clinical presentation, comorbidities, and surgeries performed. Histopathologic analysis was performed on hematoxylin-eosin and periodic acid-Schiff sections. Immunohistochemical studies were performed for smooth muscle actin (α-SMA), pancytokeratin, and CK7. Immunofluorescence was performed for vimentin, N-cadherin, ROCK1, RhoA, ZEB1, and Snail.

Results: A total of 7 patients (3 male and 4 female) were identified to have a clinically significant retrocorneal membranes at the time of graft failure. The average age at the time of first DSAEK was 70 years (range: 55-85 years). All patients were pseudophakic and had a glaucoma drainage device in place; 1 had a history of failed DSAEK. Ranging from 0 to 47 months after surgery, a variably thick retrocorneal fibrous membrane was observed, eventually leading to graft failure. Four patients underwent subsequent penetrating keratoplasty and 3 underwent repeat DSAEK. On histopathologic evaluation, a pigmented fibrocellular tissue was identified along the posterior margin of the corneas and DSAEK buttons in all cases. Further characterization with immunohistochemistry and immunofluorescence demonstrated membranes to be negative for pancytokeratin and positive for α-SMA, vimentin, CK7, N-cadherin, ZEB1, Snail, ROCK1, and RhoA.

Conclusions: Fibrocellular retrocorneal membrane proliferation may be associated with DSAEK failure in patients with previous glaucoma drainage device surgery. Our results demonstrate myofibroblastic differentiation and a lack of epithelial differentiation. Positivity for markers of an endothelial-to-mesenchymal transition indicates possible endothelial origin and could be the hallmark for future targeted pharmacotherapy.
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http://dx.doi.org/10.1016/j.ajo.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882638PMC
February 2021

Association Between Early Sjögren Markers and Symptoms and Signs of Dry Eye.

Cornea 2020 Mar;39(3):311-315

Department of Ophthalmology, Miami Veterans Administration Medical Center, Miami, FL; and.

Purpose: Animal models suggest that early markers of Sjögren syndrome (EMS)-antibodies against salivary protein 1, parotid secretory protein, and carbonic anhydrase 6 (CA6)-are more accurate signals of early Sjögren when compared with classic markers (anti-Ro and anti-La). To further understand the relationship between EMS and dry eye (DE), we compared symptoms and signs of DE in subjects who tested positive versus negative for EMS.

Methods: In this cross-sectional study, patients at the Miami Veterans Affairs Eye Clinic who were tested for EMS underwent a standard ocular surface examination. Indications for EMS testing included DE symptoms in combination with dry mouth symptoms, low tear production, corneal staining, or a Sjögren disease-associated autoimmune disease. Statistical tests performed were the χ test, Fisher exact test, independent sample t test, and Spearman correlation.

Results: Seventy-three percent of 44 patients tested positive for 1 or more EMS. CA6 IgG was most frequently elevated, followed by CA6 IgM and parotid secretory protein IgG. EMS-positive versus EMS-negative subjects were more likely to escalate DE treatment past artificial tears to topical cyclosporine (n = 32, 100% vs. n = 9, 75%, P = 0.02). There were no demographic or comorbidity differences between EMS-positive and EMS-negative subjects, and marker levels did not correlate with more severe tear film measures.

Conclusions: Most of the individuals with DE tested positive for 1 or more EMS antibodies, including men and Hispanics. Future studies will be needed to understand how to incorporate EMS data into the care of an individual with DE.
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http://dx.doi.org/10.1097/ICO.0000000000002171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007845PMC
March 2020

Cellular and molecular assessment of rose bengal photodynamic antimicrobial therapy on keratocytes, corneal endothelium and limbal stem cell niche.

Exp Eye Res 2019 11 17;188:107808. Epub 2019 Sep 17.

Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Anne Bates Leach Eye Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Rose Bengal Photodynamic Antimicrobial Therapy (RB-PDAT) is a novel potential treatment for progressive infectious keratitis. The principle behind this therapy is using Rose Bengal as a photosensitizer that can be activated by green light and results in the production of oxygen free radicals which in turn eradicate the microorganism. Given RB-PDAT's mechanism of action and the potential cytotoxic effects, concerns regarding the safety of this technique have arisen. The purpose of this study was to evaluate the effect of RB-PDAT on keratocytes, while focusing on the safety profile that the photo-chemical reaction has on the limbal stem cell (LSC) niche and endothelial cell layer of the treated cornea. To perform RB-PDAT, Rose Bengal solution (0.1% RB in BSS) was applied to the right cornea of rabbits for 30 min and then irradiated by a custom-made green LED light source (525 nm, 6 mW/cm) for 15 min (5.4 J/cm). Three rabbits were sacrificed and enucleated after 24 h for evaluation. TUNEL assay and immunohistochemistry for endothelium and limbal stem cell viability were performed on whole mounts and frozen sections in treated and control eyes. LSC of both eyes were isolated and cultured to perform MTT viability and proliferation, and scratch wound healing assays under time-lapse microscopy. Interestingly, while Rose Bengal dye penetration was superficial, yet associated cellular apoptosis was evidenced in up to 1/3 of the stromal thickness on frozen sections. TUNEL assay on whole mounts showed no endothelial cell death following treatment. Immunohistochemistry on frozen sections of LSC displayed no structural difference between treated and non-treated eyes. There was no difference in LSC proliferation rates and scratch wound healing assay demonstrated adequate cell migration from treated and non-treated eyes. The current study suggests that even though penetration of the RB dye has been shown to be limited, oxidative stress produced by RB-PDAT can reach deeper into the corneal stroma. Nevertheless, our results show that performing RB-PDAT is safe on the corneal endothelium and has no effect on LSC viability or function.
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http://dx.doi.org/10.1016/j.exer.2019.107808DOI Listing
November 2019

Current strategies for human corneal endothelial regeneration.

Regen Med 2019 05 9;14(4):257-261. Epub 2019 May 9.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

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http://dx.doi.org/10.2217/rme-2018-0105DOI Listing
May 2019

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits.

JCI Insight 2018 03 22;3(6). Epub 2018 Mar 22.

Interdisciplinary Stem Cell Institute.

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr-/- mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.
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http://dx.doi.org/10.1172/jci.insight.94818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926939PMC
March 2018

Amniotic membrane use for management of corneal limbal stem cell deficiency.

Curr Opin Ophthalmol 2017 Jul;28(4):363-369

aDepartment of Ophthalmology, Ocular Surface Center, Bascom Palmer Eye Institute bDepartment of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Purpose Of Review: The current article reviews the most recent surgical techniques for management of corneal limbal stem cell deficiency (LSCD) using amniotic membrane tissue.

Recent Findings: Early successes with amniotic membrane transplantation (AMT) for the treatment of ocular surface disorders have encouraged clinicians to investigate new applications. The use of AMT as a temporary patch in emergency cases in which LSCD may develop has considerably improved the prognosis of these patients. Amniotic membrane does not have stem cells of its own, but it supports regeneration of limbal epithelial stem cells (LESCs). Similarly, the combination of AMT with classic surgical techniques has enhanced the surgical success rates in most case series. Furthermore, based on its advantageous properties as a cell carrier, new applications to support in-vivo and ex-vivo cell expansion have been reported recently.

Summary: LSCD constitutes a general indication for AMT. Based on the clinical scenario, AMT may be performed alone to support regeneration of LESCs, in combination with other surgical techniques, or even supporting the in-vivo or ex-vivo expansion of LESCs.
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http://dx.doi.org/10.1097/ICU.0000000000000386DOI Listing
July 2017

Combined PI3K/Akt and Smad2 Activation Promotes Corneal Endothelial Cell Proliferation.

Invest Ophthalmol Vis Sci 2017 02;58(2):745-754

Area of Cell Therapy, Clínica Universidad de Navarra, Pamplona, Navarra, Spain.

Purpose: The purpose of this study was to develop a culture method for expansion of corneal endothelial cells (CEC) based on the combined activation of PI3K/Akt and Smad2.

Methods: Morphology, proliferation, and migration of cultured rabbit and nonhuman primate CEC were examined in the presence of the PI3K/Akt activators IGF-1 and heregulin beta in combination with the Smad2 activator activin A. Phenotypic characterization of CEC was performed at the RNA and protein levels. Cell pump function and transepithelial electric resistance were used for in vitro functional assessment of CEC. Finally, ex vivo-expanded rabbit CEC were transplanted into a model of endothelial damage in rabbit corneas.

Results: Treatment of rabbit and nonhuman primate CEC in vitro with IGF-1, heregulin beta, and activin A induced an upregulation of PI3K/Akt and Smad2 signaling pathways and an increase in proliferation and migration of CEC expressing ZO-1, connexin-43, and Na+/K+-ATPase. Cell pump function evaluation revealed the complete functionality of cultured CEC. Injection of rabbit CEC successfully produced recovery of normal corneal thickness in a rabbit model of endothelial dysfunction.

Conclusions: We demonstrated that the combined activation of PI3K/Akt and Smad2 results in in vitro expansion of phenotypic and functional CEC. Expanded cells were able to contribute to restoration of corneal endothelium in a rabbit model. These findings may represent a new therapeutic approach for treating corneal endothelial diseases.
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http://dx.doi.org/10.1167/iovs.16-20817DOI Listing
February 2017

Graves' Ophthalmopathy: VISA versus EUGOGO Classification, Assessment, and Management.

J Ophthalmol 2015 17;2015:249125. Epub 2015 Aug 17.

Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain.

Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder associated with thyroid disease which affects ocular and orbital tissues. GO follows a biphasic course in which an initial active phase of progression is followed by a subsequent partial regression and a static inactive phase. Although the majority of GO patients have a mild, self-limiting, and nonprogressive ocular involvement, about 3-7% of GO patients exhibit a severe sight-threatening form of the disease due to corneal exposure or compressive optic neuropathy. An appropriate assessment of both severity and activity of the disease warrants an adequate treatment. The VISA (vision, inflammation, strabismus, and appearance), and the European Group of Graves' Orbitopathy (EUGOGO) classifications are the two widely used grading systems conceived to assess the activity and severity of GO and guide the therapeutic decision making. A critical analysis of classification, assessment, and management systems is reported. A simplified "GO activity assessment checklist" for routine clinical practice is proposed. Current treatments are reviewed and management guidelines according to the severity and activity of the disease are provided. New treatment modalities such as specific monoclonal antibodies, TSH-R antagonists, and other immunomodulatory agents show a promising outcome for GO patients.
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http://dx.doi.org/10.1155/2015/249125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553342PMC
September 2015

Case Report: Explantation of A Binkhorst Iridocapsular Lens >30 Years After Implantation in an Eye With Pseudoexfoliation Syndrome.

Medicine (Baltimore) 2015 Aug;94(34):e1444

From the Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain.

An 86-year-old man with a Binkhorst 2-loop intraocular lens (IOL) that was implanted in the pupillary sphincter 33 years earlier was examined. The pupil of the implanted eye with the Binkhorst IOL was irregular and the eye had pseudoexfoliation (PEX) syndrome. Pupillary erosion resulted from rubbing of the IOL edge against the pupillary sphincter with PEX material. The IOL was removed because of visual distortion and intense pseudophakodonesis. Gross and light microscopic analyses showed no irido-fibro-lenticular adhesions over the lens or fragments of iris tissue attached to the lens. Scanning electron microscopy showed several pores of different sizes. No inflammatory cells were present, suggesting that the IOL was well tolerated.The case suggested that the pupillary ruff was not a good location for implantation of an IOL in an eye with PEX. Caution is recommended before implanting or suturing an IOL close to the pupillary border in eyes with PEX during cataract surgery.
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http://dx.doi.org/10.1097/MD.0000000000001444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602921PMC
August 2015

Intraocular lens dislocation and tube shunt in the posterior chamber: a case report.

BMC Ophthalmol 2015 Jun 21;15:63. Epub 2015 Jun 21.

Department of Ophthalmology, Clínica Universidad de Navarra, Universidad de Navarra, Avda. Pio XII, 36-31008, Pamplona, Spain.

Background: To describe management of a case of intraocular lens (IOL) and capsular bag (CB) dislocation in an eye with an Ahmed glaucoma valve in the posterior chamber.

Case Presentation: A 75-year-old pseudophakic man with open-angle glaucoma and diabetic retinopathy developed neovascular glaucoma. After two intravitreous injections of bevacizumab and panretinal photocoagulation were administered, the new vessels regressed. However, goniosynechiae were observed over 360° of the angle. An Ahmed glaucoma valve model FP7 was implanted with the tube in the posterior chamber with adequate intraocular pressure control. Nineteen years after cataract surgery, when the IOL-CB complex became dislocated, they were sutured transclerally to the sulcus without Ahmed glaucoma valve modification. After a coughing episode, the vitreous pushed the IOL-CB complex forward and the tube was behind the IOL-CB complex. A 25-gauge posterior vitrectomy was performed, and the tube was returned to in front of the optic of the IOL using a forceps tip through a sclerotomy.

Conclusion: This case suggested that management of IOL-CB dislocation can modify glaucoma shunt function. A complete pars plana vitrectomy may be required in order to reposition the dislocated IOL-CB complex in the presence of a posterior chamber drainage tube implant.
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http://dx.doi.org/10.1186/s12886-015-0046-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475289PMC
June 2015

Quantification of corneal neovascularization after ex vivo limbal epithelial stem cell therapy.

Int J Ophthalmol 2014 18;7(6):988-95. Epub 2014 Dec 18.

Department of Cell Therapy, Clínica Universidad de Navarra, Pamplona 31008, Spain.

Aim: To assess cultured limbal epithelial stem cell transplantation in patients with limbal stem cell deficiency by analyzing and quantifying corneal neovascularization.

Methods: This retrospective, interventional case series included eight eyes with total limbal stem cell deficiency. Ex vivo limbal epithelial stem cells were cultured on human amniotic membrane using an animal-free culture method. The clinical parameters of limbal stem cell deficiency, impression cytology, and quantification of corneal neovascularization were evaluated before and after cultured limbal stem cell transplantation. The area of corneal neovascularization, vessel caliber (VC), and invasive area (IA) were analyzed before and after stem cell transplantation by image analysis software. Best-corrected visual acuity (BCVA), epithelial transparency, and impression cytology were also measured.

Results: One year after surgery, successful cases showed a reduction (improvement) of all three parameters of corneal neovascularization [neovascular area (NA), VC, IA], while failed cases did not. NA decreased a mean of 32.31% (P=0.035), invasion area 29.37% (P=0.018) and VC 14.29% (P=0.072). BCVA improved in all eyes (mean follow-up, 76±21mo). Epithelial transparency improved significantly from 2.00±0.93 to 0.88±1.25 (P=0.014). Impression cytology showed that three cases failed after limbal epithelial stem cell therapy before 1y of follow-up.

Conclusion: This method of analyzing and monitoring surface vessels is useful for evaluating the epithelial status during follow-up, as successful cases showed a bigger reduction in corneal neovascularization parameters than failed cases. Using this method, successful cases could be differentiated from failed cases.
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http://dx.doi.org/10.3980/j.issn.2222-3959.2014.06.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270994PMC
December 2014

Surgical pearl: capsular tension ring insertion technique.

J Cataract Refract Surg 2014 Oct;40(10):1753

Pamplona, Spain.

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http://dx.doi.org/10.1016/j.jcrs.2014.08.017DOI Listing
October 2014

Evaluation of macular retinal ganglion cell-inner plexiform layer thickness after vitrectomy with internal limiting membrane peeling for idiopathic macular holes.

Biomed Res Int 2014 7;2014:458631. Epub 2014 Jul 7.

Department of Ophthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain ; Red Temática de Investigación Cooperativa en Oftalmología (RETICS-Oftared RD12/0034), Instituto de Salud Carlos III, Madrid, Spain.

Purpose: To evaluate macular retinal ganglion cell-inner plexiform layer (GCIPL) thickness changes after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole repair using a high-resolution spectral-domain optical coherence tomography (SD-OCT).

Methods: 32 eyes from 32 patients with idiopathic macular holes who underwent vitrectomy with internal limiting membrane peeling between January 2011 and July 2012 were retrospectively analyzed. GCIPL thickness was measured before surgery, and at one month and at six months after surgery. Values obtained from automated and semimanual SD-OCT segmentation analysis were compared (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA).

Results: No significant differences were found between average GCIPL thickness values between preoperative and postoperative analysis. However, statistical significant differences were found in GCIPL thickness at the temporal macular quadrants at six months after surgery. Quality measurement analysis performed by automated segmentation revealed a significant number of segmentation errors. Semimanual segmentation slightly improved the quality of the results.

Conclusion: SD-OCT analysis of GCIPL thickness found a significant reduction at the temporal macular quadrants at 6 months after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole.
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http://dx.doi.org/10.1155/2014/458631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109220PMC
March 2015

Bilateral and Simultaneous Intraocular Lens Subluxation in Essential Blepharospasm.

Mov Disord Clin Pract 2014 Sep 13;1(3):247-248. Epub 2014 Jun 13.

Department of Neurology Clínica Universidad de Navarra Pamplona Navarra Spain.

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http://dx.doi.org/10.1002/mdc3.12049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183179PMC
September 2014

Clinical Evaluation of the New Rebound Tonometers Icare PRO and Icare ONE Compared With the Goldmann Tonometer.

J Glaucoma 2015 Sep;24(7):527-32

*Departamento de Oftalmología, Clínica Universidad de Navarra, Pamplona †Servicio de Oftalmología, Hospital Clínico San Carlos ‡Departamento de Oftalmología, Facultad de Medicina, Universidad Complutense de Madrid §Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.

Purpose: To compare the participant-obtained intraocular pressures (IOPs) using Icare ONE and the clinician-obtained values using Icare PRO, both rebound tonometers, with Goldmann tonometry (GAT) values and analyze the ease of use of Icare ONE.

Methods: One hundred fifty participants were included (60 normal controls, 90 patients with glaucoma/ocular hypertension). The participants measured the IOP 3 times using Icare ONE; a clinician measured the IOP once using Icare PRO. The instruments were used randomly. Clinical data were evaluated to analyze the difficulty of the technique, the effect on the results, and the ease of use of Icare ONE.

Results: The mean IOPs with GAT, Icare ONE, and Icare PRO were 16.6±4.43, 17.5±5.42, and 16.6±4.77 mm Hg, respectively. The participant-measured IOP values were within +3 mm Hg of the GAT values in 67.1% of eyes with Icare ONE and in 79.6% with Icare PRO. The limits of agreement were higher with Icare ONE compared with Icare PRO. IOP value errors were found with Icare ONE in eyes with low and high GAT-IOP. The areas under the curve to detect IOPs of 21 mm Hg or higher (GAT) exceeded 0.80 with both tonometers. Young participants reported better ease of use with Icare ONE. No other factors were related to the results.

Conclusions: Icare ONE may be useful for patients monitoring their IOP values; most individuals can use the device after a short training session. Icare PRO had better results compared with Icare ONE in all IOP ranges.
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http://dx.doi.org/10.1097/IJG.0000000000000058DOI Listing
September 2015

Histomorphological analysis of a Ridley intraocular lens implanted 45 years ago.

Br J Ophthalmol 2014 Jun 18;98(6):847-8. Epub 2014 Mar 18.

Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain.

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http://dx.doi.org/10.1136/bjophthalmol-2014-304909DOI Listing
June 2014

Comparative study measuring the dilatory effect of a mydriatic device (Mydriasert(®)) versus topical drops.

Int J Ophthalmol 2013 18;6(6):801-4. Epub 2013 Dec 18.

Department of Ophthalmology, University of Navarra, 36th Pio XII Ave, Pamplona 31008, Spain.

Aim: To compare the mydriatic efficacy of an ophthalmic insert (Mydriasert, MY) versus phenylephrine and tropicamide (PT) eye drops.

Methods: Two controlled, prospective, randomized, single-blind studies were performed. In the first study, a total of 80 eyes from 40 outpatient-clinic patients were analyzed. PT drops were applied to the right eye, and a MY device was inserted in the left eye for 30min. Time until maximal pupil dilation for each eye was then assessed. In the second study, 80 eyes from 80 patients undergoing cataract surgery were analyzed. Pupil dilation was achieved using either PT drops three-times for one hour prior to surgery (40 patients), or a MY device was inserted one hour prior to surgery (40 patients).

Results: In the first study, MY achieved superior mydriasis compared to PT eye drops at 90min (9.04±1.33mm vs 8.78±1.37mm, P=0.012). However MY took longer than PT drops to achieve maximal dilation, and mydriasis was inferior in eyes with MY compared to PT drops at 30min (7.21±1.73mm vs 8.22±1.43mm, P<0.001), the two groups only becoming similar by 60min (8.85±1.44mm vs 8.71±1.27mm, P=0.236). In the second study, both MY and PT achieved similar levels of mydriasis at the beginning of surgery (8.75±0.76mm with MY vs 8.77±0.63mm with PT), and also at the end of surgery (7.96±1.06mm with MY vs 8.32±0.72mm with PT), with no significant difference between groups (P=0.08). MY was well tolerated and cardiovascular effects were not influenced by dilation method.

Conclusion: MY could be a safe and efficacious alternative for mydriasis. The mydriatic effect of MY is as good as conventional PT eye drops after 60min, and is superior after 90min. MY also maintains good pupil dilation during cataract surgery.
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http://dx.doi.org/10.3980/j.issn.2222-3959.2013.06.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874519PMC
January 2014

Final incision size after cataract surgery with toric intraocular lens implantation using 2 techniques.

J Cataract Refract Surg 2013 Nov 22;39(11):1675-81. Epub 2013 Aug 22.

From the Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain. Electronic address:

Purpose: To analyze the changes in incision sizes after implantation of a toric intraocular lens (IOL) using 2 methods.

Setting: Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain.

Design: Prospective case series.

Methods: Coaxial phacoemulsification and IOL implantation through a 2.2 mm clear corneal incision using a cartridge injector were performed. Wound-assisted or cartridge-insertion techniques were used to implant the IOLs. The results were analyzed according to IOL spherical and cylindrical powers. Corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured and evaluated based on the changes in incision size.

Results: Incision size increased in 30 (41.7%) of 72 eyes in the wound-assisted group and 71 (98.6%) of 72 eyes in the cartridge-insertion group. The mean incision size after IOL implantation was 2.27 mm ± 0.06 (SD) and 2.37 ± 0.05 mm, respectively (P<.01). The final incision size and IOL spherical power in the wound-assisted technique group (P=.02) and the cartridge-insertion technique group (P=.03) were correlated significantly; IOL toricity was not (P=.19 and P=.28, respectively). The CH and CRF values were not correlated with the final incision size.

Conclusions: The final incision size and the changes in incision size after IOL implantation were greater with the cartridge-insertion technique than with the wound-assisted technique. The increase was related to IOL spherical power in both groups but not to IOL toricity. Corneal biomechanical properties were not correlated with the final incision size.
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http://dx.doi.org/10.1016/j.jcrs.2013.04.039DOI Listing
November 2013

Strategies of human corneal endothelial tissue regeneration.

Regen Med 2013 Mar;8(2):183-95

Department of Ophthalmology, Clínica Universidad de Navarra, Apartado 4209, 31080 Pamplona, Spain.

Penetrating keratoplasty has previously been the only surgical treatment for patients with corneal endothelial disorders. Recently, posterior lamellar keratoplasty has become a viable and less aggressive alternative technique. However, both transplantation techniques have disadvantages, such as non-immunologic graft failure, allograft endothelial rejection or a global shortage of donor corneas. Over the past few years, several groups have established methods for the isolation, preservation, in vitro cultivation, transplantation, and in vivo stimulation of human corneal endothelial cells in animal models. It is hoped that these new strategies will allow the treatment of more than one patient with one donor cornea, performing autologous corneal endothelium transplantation from a surgical biopsy sample, or stimulating the growth of corneal endothelial cells in vivo. However, several aspects need to be addressed before commencing clinical trials.
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http://dx.doi.org/10.2217/rme.13.11DOI Listing
March 2013

Ocular symptoms secondary to meningeal carcinomatosis in a patient with lung adenocarcinoma: a case report.

BMC Ophthalmol 2012 Dec 18;12:65. Epub 2012 Dec 18.

Department of Ophthalmology, Clínica Universidad de Navarra, Navarra, Apartado 4209, Pamplona, 31008, Spain.

Background: Meningeal carcinomatosis (MC) is a rare complication associated with hematologic and solid tumors. MC develops when malignant cells gain access to the leptomeningeal space, producing several clinical symptoms. Loss of vision and ocular motility deficit are the most frequent ocular symptoms reported. Fundus examination usually appears normal, although optic nerve alterations like optic atrophy or papilledema have been described. MC diagnosis is usually completed by magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. Indicated treatment for MC usually involves intrathecal chemotherapy combined with radiotherapy, although survival rate is extremely low.

Case Presentation: A 66-year old man with stage IV metastatic lung adenocarcinoma, presented to the Ophthalmology Department with a two-month history of double vision, soft headaches and dizziness episodes. The patient presented a best visual corrected acuity of 0.7 in his right eye and 0.8 in his left eye. Diplopia was corrected with 6-prism diopters base-out prism in right eye. Funduscopy showed a bilateral papilledema, juxtapapillary exudates and splinter hemorrhages. Brain MRI showed a diffuse leptomeningeal enhancement in cortical sulcus. Lumbar puncture was performed and cerebrospinal fluid (CSF) cytology revealed malignant cells compatible with a diagnosis of MC. Intrathecal chemotherapy was administered.

Conclusion: MC is a serious complication of systemic cancer patients, involving a poor prognosis. Early diagnosis is extremely important, although treatment is frequently aimed to reduce the symptoms and extend survival. Eye symptoms may be the chief complaint, so MC should be considered in any patient with vision loss or diplopia accompanied by neurologic symptoms and in the absence of an intraocular cause, especially in the context of systemic cancer.
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http://dx.doi.org/10.1186/1471-2415-12-65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548754PMC
December 2012

Risks factors and regression model for risk calculation of anesthesiologic intervention in topical and intracameral cataract surgery.

J Cataract Refract Surg 2012 Dec 22;38(12):2144-53. Epub 2012 Oct 22.

Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain.

Purpose: To determine risk factors for anesthesiologist intervention during routine cataract surgery performed with topical and intracameral anesthesia and establish a regression model to identify high-risk patients.

Setting: Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain.

Design: Prospective case series.

Methods: After cataract surgery at an ambulatory surgical center, anesthesia personnel completed a questionnaire to determine adverse medical events and risk factors related to anesthesiologist intervention. A Poisson regression model was used to calculate the interventional risks. Bootstrapping was performed for internal model validation.

Results: Of the 1010 cases, 50 (4.95%) required anesthesiologist intervention. Univariate analysis identified an association between anesthesiologist intervention and hypertension (P<.001), psychiatric history (P=.002), initial systolic blood pressure (P<.001), surgical duration (P=.001), and diabetes (P=.018). Scores were obtained using the following proposed regression model equation: (-8.68 + 0.33 × sex [men, 0; women, 1] + -0.02 × age [years] + 0.68 × hypertensive history [no, 0; yes, 1] + 1.18 × psychiatric background [no, 0; yes, 1] + 0.04 × initial systolic blood pressure [mm Hg]). The area under the receiver-operating curve was 0.803 (95% confidence interval [CI], 0.721-0.886). The area under the curve found in the validation method was 0.813 (95% CI, 0.727-0.887).

Conclusion: Hypertension was the main risk factor for anesthesiologist intervention. The regression model discriminated between patients at lower and higher risk for intraoperative intervention for monitored anesthesia care. The probability of anesthesiologist intervention was 11.7 times higher when the model obtained a high score.

Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.
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http://dx.doi.org/10.1016/j.jcrs.2012.08.051DOI Listing
December 2012

A novel method of isolation, preservation, and expansion of human corneal endothelial cells.

Invest Ophthalmol Vis Sci 2007 Feb;48(2):614-20

Ocular Surface Center, Miami, Florida 33173, USA.

Purpose: To explore new strategies for effective isolation, preservation, and expansion of human corneal endothelial cells (HCECs).

Methods: Human corneal Descemet's membrane and corneal endothelial cells were digested with collagenase A or Dispase II in supplemented hormonal epithelial medium (SHEM) for 1.5 to 16 hours. HCEC aggregates derived from collagenase A digestion were preserved in serum-free medium with low or high calcium for up to 3 weeks. Cryosections of HCEC aggregates were subjected to immunostaining with ZO-1, connexin 43, type IV collagen, laminin-5, and perlecan, and apoptosis was determined by TUNEL or cell-viability assay. For expansion, HCEC aggregates were seeded directly or after brief treatment with trypsin/EDTA in SHEM, with or without additional bovine pituitary extract (BPE), nerve growth factor (NGF), or basic fibroblast growth factor (bFGF). The resultant HCECs were immunostained with ZO-1, connexin 43, and Ki67.

Results: Digestion with collagenase A, but not Dispase, of the stripped Descemet's membrane generated HCEC aggregates, which preserved cell-cell junctions and basement membrane components. High cell viability of HCEC aggregates was preservable in a serum-free, high-calcium, but not low-calcium, medium for at least 3 weeks. Brief treatment of HCEC aggregates with trypsin/EDTA resulted in a higher proliferation rate than without, when cultured in SHEM, and the resultant confluent monolayer of hexagonal cells retained cell-cell junctions. However, additional BPE, NGF, or bFGF did not increase cell proliferation, whereas additional BPE or bFGF disrupted cell-cell junctions.

Conclusions: Collagenase A digestion successfully harvested aggregates with viable HCECs that were preservable for at least 3 weeks in a serum-free, high-calcium medium and, with brief trypsin/EDTA treatment, expanded in the SHEM into a monolayer with hexagonal cells that exhibited characteristic cell junctions.
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http://dx.doi.org/10.1167/iovs.06-1126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196988PMC
February 2007