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 Sjögren's 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%; P<0.001). Patients with xerostomia (60 ± 15 years) were older than those without xerostomia (51 ± 17; P<0.001). The use of prescription drugs was more prevalent among xerostomia patients (65%) than among non-xerostomia patients (35%; P<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; P<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.
Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encompasses a wide spectrum of pathology, both with respect to its etiology and the anatomic location within the eye. Inflammation can be confined to the eye and may also be seen systemically. The cornerstone of management of ocular inflammatory disease historically has been corticosteroids, which are invaluable in the immediate control of inflammation; however, corticosteroids are inappropriate for long-term use as they are associated with a wide array of toxic side effects. As we continue to learn more about the various etiologies and elucidate the basic science pathways and mechanisms of action that cause intraocular inflammation, new therapeutic approaches have evolved. They include employment of immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our treatment options for these vision-threatening diseases. These pharmacologics provide therapy for ocular and systemic inflammation in an individualized, patient-tailored, stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We review the preferred practice patterns of a tertiary care center specializing in ocular inflammatory disease.
PURPOSE: To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts. DESIGN: Modified Delphi process. METHODS: A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement. RESULTS: There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies. CONCLUSIONS: Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study.
There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels. We observed that retinal ganglion cells (RGCs) seemed to be the cells most susceptible to VEGF-A antagonism, so we looked at anterograde transport in these cells, due to their long axons requiring optimal protein and organelle trafficking. Using cholera toxin B-subunit tracer studies, we found a distal reduction in transport in the superior colliculus following VEGF-A neutralization, which occurred prior to net RGC loss. This phenomenon of distal transport loss has been described as a feature of early pathological changes in glaucoma, Alzheimer's and Parkinson's disease models. Furthermore, we observed increased phosphorylation of p38 MAPK and downstream Hsp27 stress pathway signaling in the retinas from these experiments, potentially providing a mechanistic explanation for our findings. These experiments further highlight the possible risks of using VEGF-A antagonists to treat ocular neovascular disease, and suggest that VEGF-A may contribute to the maintenance and function of axonal transport in neurons of the retina.
Fritsche LG, Igl W, Bailey JCN, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HPN, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YTE, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GHS, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Saïd S, Sahel J-A, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze J-F, Igo RP, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith TR, Khan JC, Shahid H, Moore AT, McGrath AJ, Laux R, Brantley MA, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NTM, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CCW, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JRW, Allikmets R, Wang JJ, Schaumberg DA, Klein BEK, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BHF, Abecasis GR, Heid IM. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 2016;48(2):134-43.Abstract
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Neovascular eye diseases are a major cause of blindness including retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration in which new vessel formation is driven by hypoxia or metabolic abnormalities affecting the fuel supply. White-adipose-tissue derived adipokines such as adiponectin modulate metabolic responses. Increasing evidence shows that lack of adiponectin may result in retinal neovascularization. Activation of the adiponectin pathway may in turn restore energy metabolism, to suppress the drive for compensatory but ultimately pathological neovessels of retinopathy. In this review, we will summarize our current knowledge of the role of adiponectin in eye diseases of premature infants, diabetic patients as well as the elderly. Further investigations in this field are likely to lead to new preventative approaches for these diseases.
PURPOSE OF REVIEW: Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute optic nerve injury, and frequently presents to comprehensive ophthalmologists. We review the typical and atypical clinical features and current literature on various treatment modalities for NAION. RECENT FINDINGS: The epidemiology and clinical presentation of this disease can be variable, making a definitive diagnosis difficult in many cases. In addition, the differential diagnoses for this disorder, although comprising much less prevalent entities, are quite broad and can have substantial systemic implications if these alternatives go unrecognized. NAION has many systemic associations and comorbidities that deserve inquiry when the diagnosis is made. There are currently no widely accepted, evidence-based treatments for NAION. All recommendations made to patients to reduce their risk of sequential eye involvement, including avoidance of potential nocturnal hypotension, erectile dysfunction medication, and treatment of obstructive sleep apnea, have theoretical bases. SUMMARY: NAION is a common cause of acute vision loss in adult and older patients, and thus, comprehensive ophthalmologists need to be able to diagnose and appropriately manage this disorder. We anticipate fruitful results from current and future trials aimed at neuroprotection in the affected eye and prevention of sequential eye involvement.
The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender, and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1, and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci.
A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure.
Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991+1655A>G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential treatment of naked and AAV-packaged AONs in vitro and in vivo In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations.
Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein, we determined whether interferon gamma (IFN-γ), a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca(2+)] ([Ca(2+)]i), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-γ with or without the cholinergic agonist carbachol. IFN-γ itself increased [Ca(2+)]i in rat and human goblet cells and prevented the increase in [Ca(2+)]i caused by carbachol. Carbachol prevented IFN-γ-mediated increase in [Ca(2+)]i. This cross-talk between IFN-γ and muscarinic receptors may be partially due to use of the same Ca(2+)i reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca(2+)]i. IFN-γ blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-γ in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN-γ could also function similarly in respiratory and gastrointestinal tracts.
This review focuses on conjunctival goblet cells and their essential function in the maintenance of eye health. The main function of goblet cells is to produce and secrete mucins that lubricate the ocular surface. An excess or a defect in those mucins leads to several alterations that makes goblet cells central players in maintaining the proper mucin balance and ensuring the correct function of ocular surface tissues. A typical pathology that occurs with mucous deficiency is dry eye disease, whereas the classical example of mucous hyperproduction is allergic conjunctivitis. In this review, we analyze how goblet cell number and function can be altered in these diseases and in contact lens (CL) wearers. We found that most published studies focused exclusively on the goblet cell number. However, recent advances have demonstrated that, along with mucin secretion, goblet cells are also able to secrete cytokines and respond to them. We describe the effect of different cytokines on goblet cell proliferation and secretion. We conclude that it is important to further explore the effect of CL wear and cytokines on conjunctival goblet cell function.
The transfer of DNA between Enterococcus faecium strains has been characterized both by the movement of well-defined genetic elements and by the large-scale transfer of genomic DNA fragments. In this work, we report on the whole-genome analysis of transconjugants resulting from mating events between the vancomycin-resistant E. faecium C68 strain and the vancomycin-susceptible D344RRF strain to discern the mechanism by which the transferred regions enter the recipient chromosome. Vancomycin-resistant transconjugants from five independent matings were analyzed by whole-genome sequencing. In all cases but one, the penicillin binding protein 5 (pbp5) gene and the Tn5382 vancomycin resistance transposon were transferred together and replaced the corresponding pbp5 region of D344RRF. In one instance, Tn5382 inserted independently downstream of the D344RRF pbp5 gene. Single nucleotide variant (SNV) analysis suggested that entry of donor DNA into the recipient chromosome occurred by recombination across regions of homology between donor and recipient chromosomes, rather than through insertion sequence-mediated transposition. The transfer of genomic DNA was also associated with the transfer of C68 plasmid pLRM23 and another putative plasmid. Our data are consistent with the initiation of transfer by cointegration of a transferable plasmid with the donor chromosome, with subsequent circularization of the plasmid-chromosome cointegrant in the donor prior to transfer. Entry into the recipient chromosome most commonly occurred across regions of homology between donor and recipient chromosomes.
PURPOSE OF REVIEW: Papilledema associated with idiopathic intracranial hypertension (IIH) may result in irreversible, progressive visual loss. The development of tools for the evaluation of pediatric patients with IIH is particularly relevant as many patients may not be able to comply with the detailed clinical evaluation utilized in adults for the treatment and management of this disease. The purpose of this review is to summarize relevant articles on the diagnostic tools used in evaluation and management of pediatric IIH. RECENT FINDINGS: Studies suggest that characteristic pediatric IIH MRI findings include empty sella turcica, decreased pituitary gland size, optic nerve tortuosity, perioptic subarachnoid space enlargement, posterior globe flattering, and intraocular protrusion of the optic nerve head. On optical coherence tomography (OCT), increased retinal nerve fiber layer and macular thickness may be observed in children with IIH compared with controls. The retinal nerve fiber layer thickness seems to coincide with the severity of papilledema and may be more sensitive than funduscopy for detecting optic nerve head elevation. Research on ultrasound of the optic nerve shows increased size of the optic nerve sheath diameter in pediatric IIH patients, and this may correlate with increased opening pressure on lumbar puncture. SUMMARY: There appears to be characteristic findings on MRI, OCT, and ultrasound studies in pediatric IIH patients. Although ultrasound is rarely used for monitoring these patients nowadays, MRI and OCT can be useful in the evaluation and management of these individuals.
BACKGROUND: Pyogenic lacrimal gland abscesses are uncommon and thus may not be immediately clinically recognized without a high index of suspicion. FINDINGS: We present two patients with preseptal cellulitis and characteristic low-attenuation fluid collections in the lacrimal glands demonstrated on computed tomography (CT). CONCLUSIONS: Lacrimal gland abscesses should be considered when dacryoadenitis is refractory to medical treatment. Indeed, these cases highlight the value of prompt recognition of lacrimal abscess through ophthalmologic referral and the use of diagnostic imaging. Both patients were successfully treated via incision and drainage.
Goblet cells within the conjunctival epithelium are specialized cells that secrete mucins onto the surface of the eye. Recent research has demonstrated new characteristics of the cells, including factors influencing their differentiation, their gene products and their functions at the ocular surface. The following review summarizes the newly discovered aspects of the role of Spdef, a member of the Ets transcription factor family in conjunctival goblet cell differentiation, the newly discovered goblet cell products including claudin2, the Wnt inhibitor Frzb, and the transmembrane mucin Muc16. The current concepts of conjunctival goblet cell function, including debris removal and immune surveillance are reviewed, as are changes in the goblet cell population in ocular surface diseases. Major remaining questions regarding conjunctival cell biology are discussed.
PURPOSE: Accumulation of oxidized phospholipids/lipoproteins with age is suggested to contribute to the pathogenesis of AMD. We investigated the effect of oxidized LDL (ox-LDL) on human RPE cells. METHODS: Primary human fetal RPE (hf-RPE) and ARPE-19 cells were treated with different doses of LDL or ox-LDL. Assessment of cell death was measured by lactate dehydrogenase release into the conditioned media. Barrier function of RPE was assayed by measuring transepithelial resistance. Lysosomal accumulation of ox-LDL was determined by immunostaining. Expression of CD36 was determined by RT-PCR; protein blot and function was examined by receptor blocking. NLRP3 inflammasome activation was assessed by RT-PCR, protein blot, caspase-1 fluorescent probe assay, and inhibitor assays. RESULTS: Treatment with ox-LDL, but not LDL, for 48 hours caused significant increase in hf-RPE and ARPE-19 (P < 0.001) cell death. Oxidized LDL treatment of hf-RPE cells resulted in a significant decrease in transepithelial resistance (P < 0.001 at 24 hours and P < 0.01 at 48 hours) relative to LDL-treated and control cells. Internalized ox-LDL was targeted to RPE lysosomes. Uptake of ox-LDL but not LDL significantly increased CD36 protein and mRNA levels by more than 2-fold. Reverse transcription PCR, protein blot, and caspase-1 fluorescent probe assay revealed that ox-LDL treatment induced NLRP3 inflammasome when compared with LDL treatment and control. Inhibition of NLRP3 activation using 10 μM isoliquiritigenin significantly (P < 0.001) inhibited ox-LDL induced cytotoxicity. CONCLUSIONS: These data are consistent with the concept that ox-LDL play a role in the pathogenesis of AMD by NLRP3 inflammasome activation. Suppression of NLRP3 inflammasome activation could attenuate RPE degeneration and AMD progression.