Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.

Scleral buckling surgery for stage 4A and 4B retinopathy of prematurity in critically ill neonates.

PURPOSE: To determine the efficacy of scleral buckling in eyes with stage 4A and 4B retinopathy of prematurity (ROP). METHODS: Seven eyes of five premature infants underwent scleral buckling for stage 4 ROP in zone II. Five eyes had stage 4A ROP, and two eyes had stage 4B ROP. Six eyes had previous diode laser photocoagulation, and one eye had received an intravitreal ranibizumab injection. Scleral buckling was the procedure of choice due to lack of access to specialized pediatric vitrectomy instrumentation. Average age at surgery was 3.4 months. Postoperative anatomic retinal status, visual acuity outcome and refractive error were assessed. RESULTS: The scleral buckle was removed on average 8 months after surgery. Retinal reattachment was achieved in all seven eyes. At final follow-up one eye had macular ectopia and disc dragging, one eye had a macular traction fold and two eyes had optic disc pallor. Average myopic error after buckle removal was -7.5 D. CONCLUSION: Scleral buckling can be performed safely and effectively in 4A and 4B stage ROP in critically ill infants, when access to specialized pediatric vitrectomy instrumentation is limited. This surgical technique may provide adequate relief of vitreoretinal traction with improved visual potential.

Quality-adjusted life years in macular oedema due to age-related macular degeneration, diabetes and central retinal vein occlusion: the impact of anti-VEGF agents in a tertiary centre in Greece.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME), and macular oedema due to central retinal vein occlusion (CRVO) are leading causes of vision loss, currently managed with anti-vascular endothelial growth factor injections (anti-VEGF). The aim of this study was to calculate QALYs in patients with nAMD, DME, and CRVO treated with anti-VEGF agents (QALYs+) in a Greek tertiary hospital setting and compare them to theoretical QALYs that the patients would have without treatment (QALYs-). MATERIAL AND METHODS: The study included 143 treatment-naive patients with macular oedema due to nAMD (n = 79), DME (n = 57), and CRVO (n = 7), who received anti-VEGF injections as monotherapy according to the Treat-and-Extend (T&E) protocol. The anti-VEGF agents were ranibizumab and aflibercept in equivalent fractions. QALYs where calculated by the formula QALY = Utility Value × Time, where "Time" refers to the follow-up period of the study. For QALYs-, we assumed that visual acuity remained unchanged during this period. RESULTS: Mean follow-up time was 1.3 ± 1.2 years in the nAMD group, 1 ± 1.3 years in the DME group, and 0.5 ± 1 years in the CRVO group. There was no statistically significant difference between QALYs- and QALYs+ in all three ocular pathologies for the study period (p > 0.05 for each of the three statistical tests performed). DISCUSSION/CONCLUSION: Possible explanations for the lack of significant difference between QALYs - and QALYs + in nAMD, DME, and CRVO groups, may be the short time horizon used in this analysis, the inclusion of data from the better-seeing eye (BSE) and the specific socio-economic, geographical and health care characteristics of this rural Greek area.

Subperiosteal Orbital Hemorrhage: An Unusual Complication During Labor.

ABSTRACT: Subperiosteal orbital hemorrhage in the postpartum period has been rarely reported. The authors herein present a female patient who developed acute-onset vertical diplopia, proptosis, mild retro-orbital pain, and restriction of upgaze immediately after labor. Neuroimaging revealed a subperiosteal hematoma along the right orbital roof. Diplopia, motility limitation, and retro-orbital pain gradually resolved in the following weeks. Subperiosteal orbital hematomas are a rare complication of labor, with only 12 cases reported so far. They result from straining during labor, which increases central and orbital venous pressure by means of the Valsalva-maneuver. In order to evaluate ocular motility and exclude optic nerve compression, an urgent ophthalmological examination is required.

Blood flow velocity comparison in the eye capillaries and postcapillary venules between normal pregnant and non-pregnant women.

BACKGROUND: There is no consensus on how much and at what diameters the blood flow velocity changes in the female microcirculation during normal pregnancy. METHODS: A non-contact, digital slit-lamp biomicroscopy system was used to measure axial blood velocity (Vax) and diameter (D) in the conjunctival microcirculation of 28 normal non-pregnant women (Control Group), 17 women in the first semester of their normal pregnancy (Group 1) and 16 women in the third trimester of their normal pregnancy (Group 2). Blood volume flow (Q) was estimated from Vax and D. Microvessels were classified as "capillaries" (CAP) with D < 9 µm, "postcapillary venules of size 1" (PC1) with 9 ≤ D < 14 µm and "postcapillary venules of size 2" (PC2) with 14 ≤ D ≤ 24 µm. RESULTS: The women groups did not differ significantly in age, diastolic and systolic pressure and diameter of each size. Taking as baseline the capillary Vax of 0.51 mm/s of the Control Group, there was a statistically significant (p < 0.001) increase to 0.74 mm/s (45%) in Group 1 and to 0.95 mm/s (86%) in Group 2. This significant Vax increase in capillaries (CAP) was a consistent finding irrespective of the exact vessel size cut-off value for discriminating CAP from PC1. There was no statistical difference in Vax among groups at postcapillary venules of size 2 (PC2). Statistical conclusions for blood volume flows were similar to velocities. CONCLUSIONS: Normal pregnancy increases significantly axial blood velocity (Vax) in capillaries (CAP) with diameter <9 µm.

The treatment of amblyopia: current practice and emerging trends.

PURPOSE: The purpose of this review is to provide an update on current management and recent research for amblyopia treatment. Part I will review patching, atropine penalization, and pharmacological treatments. Part II will focus on perceptual learning, video gaming, and binocular dichoptic approaches. METHODS: A literature search was performed in PubMed, ClinicalTrials.gov , Google Scholar, and reference lists of retrieved articles until December 20, 2018, for all papers containing "amblyopia treatment" or "amblyopia therapy." We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS: The mainstay of treatment for amblyopia has been based on increasing visual stimulation of the amblyopic eye by occlusion, atropine, or optical penalization of the dominant eye. It has been established that refractive adaptation alone can significantly enhance visual acuity. However, the duration of optical correction varies between studies and the effectiveness of spectacle wear over early beginning of patching is still under investigation. Additionally, by means of occlusion dose monitors, it was found that adherence to occlusion affects the outcome, as a dose-response relationship exists between adherence and visual acuity. Treatment efficiency declines with age; however, recent evidence indicates cortical plasticity beyond the "critical period" and recommends that an attempt at treatment should be offered to all amblyopic children regardless of age, including those in later childhood. Novel approaches targeted to the restoration of binocular functions, such as perceptual learning, video gaming, and dichoptic training, have shown small effects on visual acuity and have failed to demonstrate non-inferiority over standard treatments. CONCLUSIONS: On review, significant evidence for the successful management of amblyopia, with occlusion therapy and atropine, has been found. However, the management of amblyopia remains challenging, mainly due to compliance issues and suboptimal treatment outcomes during occlusion and atropine penalization. Recent studies have found evidence of new ways of treating amblyopia particularly in regard to binocular treatment although these remain under investigation. Further robust clinical trials on these new treatment modalities are still warranted in order to establish their role in treating amblyopia.

SLC2A1 Tag SNPs in Greek Patients with Diabetic Retinopathy and Nephropathy.

Backround: Genetic variants are implicated in the development of diabetic retinopathy (DR) and nephropathy (DN). The role of solute carrier family 2-facilitated glucose transporter member 1 (SLC2A1), also known as glucose transporter (GLUT1), on DR and DN remain controversial. OBJECTIVE: Examination of the influence of tag SLC2A1 single-nucleotide polymorphisms (SNPs) on the development of DR and DN during the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 169 patients with DR or DN, 107 uncomplicated T2DM patients, and 315 controls were recruited and genotyped for 14 SLC2A1 tag SNPs. SNPs and haplotypes were tested for associations with microvascular diabetes' complications. RESULTS: rs3768029 TT genotype was associated with a lower risk of DR + DN, compared to the CC wild-type (p = 0.0024). Moreover, CT and TT rs841847 genotypes were associated with a higher risk of DR + DN compared to the CC genotype (p = 0.0028). A common haplotype (GGCCCGCATCAAT) was associated with an increased risk of DR, DN, DR ± DN, and DR + DN phenotypes. Mutational loads of rs3768029, rs3729548, rs841853, and rs841847 were found to influence the development of microvascular complications during the T2DM course. CONCLUSIONS: This study provides evidence that SLC2A1 gene variants might be implicated in the development of T2DM microvascular complications.

Case Series: Bilateral Homonymous Visual Field Defects Due to Bilateral Ischemic Strokes.

SIGNIFICANCE: Bilateral strokes are rare and should be considered when patients present with bilateral visual field loss characterized by patterns consistent with right and left-sided homonymous visual field defects. Perimetry, dilated funduscopy, and immediate neuroimaging are mandatory for diagnosis, because patients may present with vague symptoms. These cases reflect the retinotopic features of the striate cortex. PURPOSE: The purposes of this study were to describe the unusual presentation of bilateral homonymous visual field defects in three patients with bilateral ischemic strokes and to discuss the clinical and neuroanatomical correlations. CASE REPORTS: Neuro-ophthalmological examination including perimetry and brain magnetic resonance imaging (MRI) was performed in three patients with bilateral homonymous scotomas. Two of three patients presented with superior altitudinal hemianopia, resulting from right and left homonymous superior quadrantanopia due to bilateral occipital strokes below the calcarine fissure. A 57-year-old man (patient 1) with a history of atrial fibrillation presented with driving difficulties. Perimetry revealed bilateral superior altitudinal hemianopia. Brain MRI demonstrated a subacute right occipital stroke and a chronic left occipital stroke, both inferior to the calcarine fissure. An 83-year-old woman (patient 2) presented with reading disorders. Perimetry showed a left incomplete homonymous hemianopia and a right horizontal wedge-shaped homonymous scotoma. Brain MRI showed a chronic ischemic stroke in the left occipital lobe and acute ischemia in the right thalamus. A 40-year-old man (patient 3) was referred with headache, disorientation, and bilateral blurry vision. Perimetry showed bilateral superior altitudinal hemianopia, and MRI demonstrated acute bilateral occipital ischemia. Patients 1 and 2 suffered sequential bilateral strokes and were not aware of the initial scotoma, whereas patient 3 presented with bilateral concurrent strokes. CONCLUSIONS: Bilateral homonymous visual field defects due to bilateral strokes are rare. Patient history, a careful neuro-ophthalmological examination, and correlation of visual field defect patterns with neuroimaging should prompt the clinician to the presence of this unique entity.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Endoscopic dacryocystorhinostomy for acquired nasolacrimal duct obstruction: long-term results in 91 procedures.

BACKGROUND: The purpose of the present study was to evaluate long-term outcomes of endoscopic dacryocystorhinostomy (DCR) using a drill without the use of mucosal flaps. Ninety one procedures in eighty seven patients were reviewed. All patients showed epiphora, caused by primary or secondary nasolacrimal obstruction. METHODOLOGY: All patients underwent preoperative evaluation (irrigation and probing of the lacrimal drainage system, fluorescein tests, computerized tomography scan of the paranasal sinuses, dacryocystography and endoscopic examination of the nasal cavity). In 19 patients further intranasal procedures were conducted simultaneously with DCR (10 FESS, 2 septoplasties, 5 functional endoscopic sinus surgery (FESS) and septoplasties, 2 septoplasties and turbinoplasties). Stents were placed intraoperatively and removed 4 to 12 weeks, postoperatively. Postoperative follow-up ranged between 12 and 24 months. RESULTS: Long-term success was achieved in 87/91 procedures. No major complications were observed. Failure was caused by granulation tissue formation in three patients and inappropriate stent removal in one patient. CONCLUSION: The success rate achieved is comparable to success rates of external DCR.

Macular Ischemia Changes in Patients with Diabetic Macular Edema Treated with Aflibercept and Ranibizumab.

Τhis study aims to assess changes in the fovea avascular zone (FAZ) in treatment naïve patients receiving aflibercept or ranibizumab injections for diabetic macular edema (DME). Best corrected visual acuity (BCVA) testing, OCT, and OCT-angiography imaging were performed at baseline and 1 month after each injection. Injections of either aflibercept or ranibizumab were administered monthly for 6 consecutive months. FAZ in the superficial (SCP) and the deep capillary plexus (DCP) using OCT angiography was recorded for each visit. Fifty eyes from fifty patients with a mean age of 67.0 ± 10.7 years were included in the study. Twenty-five patients received aflibercept and twenty-five received ranibizumab. BCVA was 40.8 ± 10.0 and increased to 52.1 ± 7.9 ETDRS letters at the last visit (p < 0.001). CRT was 295.6 ± 34.0 at baseline and 247.9 ± 29.7 at the last study visit (p < 0.001). SCP FAZ was 350.6 ± 79.5 µm2 at baseline and 339.0 ± 71.3 µm2 after sox monthly injections (p = 0.132). DCP FAZ was 558.6 ± 199.0 µm2 at baseline and 459.5 ± 156.1 µm2 after six monthly injections (p < 0.001). There was no effect of the choice of ranibizumab or aflibercept on DCP FAZ change (p = 0.277). In conclusion, treatment with 6 monthly injections of ranibizumab and aflibercept led to an increase in BCVA and a decrease in CRT and DCP FAZ area. Both drugs led to an improvement in DCP ischemia.

Transscleral diode laser cyclophotocoagulation for refractory glaucoma secondary to juvenile idiopathic arthritis: a short term follow-up.

To evaluate the success rates of transscleral diode cyclophotocoagulation (TD-CPC) for refractory secondary glaucoma in a paediatric patient with juvenile idiopathic arthritis. Report of a case of a 6-year-old boy suffering from severe uveitis, and secondary open angle glaucoma. The patient had undergone bilateral cataract surgery, two prior trabeculectomies in the left and one in the right eye. He was under systemic immunomodulation with methotrexate and cyclosporine. He presented with medically uncontrolled glaucoma, with an intraocular pressure (IOP) of 36 and 34 mmHg in the right and left eye, respectively, under maximal medical antiglaucoma therapy. TD-CPC was performed under general anesthesia, including a total of 20 spots in the right and 34 in the left eye (2,000 mW, 2 s/spot) applied in one session. Visual acuity remained stable in the right eye and deteriorated in the left eye from 0.1 to no light perception. Postoperative hypotony was present 1 month post op and IOP was 14 mmHg in the left and 17 mmHg in the right eye, respectively, in the 6-month follow-up with a topical beta-blocker. The anterior chamber was quiet in both eyes. TD-CPC was effective in the short term as IOP lowering therapy in a pediatric patient with refractory uveitic glaucoma.

A normative blood velocity model in the exchange microvessels for discriminating health from disease: Healthy controls versus COVID-19 cases.

A usual practice in medicine is to search for "biomarkers" which are measurable quantities of a normal or abnormal biological process. Biomarkers can be biochemical or physical quantities of the body and although commonly used statistically in clinical settings, it is not usual for them to be connected to basic physiological models or equations. In this work, a normative blood velocity model framework for the exchange microvessels was introduced, combining the velocity-diffusion (V-J) equation and statistics, in order to define the normative range (NR) and normative area (NA) diagrams for discriminating normal (normemic) from abnormal (hyperemic or underemic) states, taking into account the microvessel diameter D. This is different from the usual statistical processing since there is a basis on the well-known physiological principle of the flow diffusion equation. The discriminative power of the average axial velocity model was successfully tested using a group of healthy individuals (Control Group) and a group of post COVID-19 patients (COVID-19 Group).

Optical Coherence Tomography Angiography (OCTA) of the eye: A review on basic principles, advantages, disadvantages and device specifications.

Optical Coherence Tomography Angiography (OCTA) is a relatively new imaging technique in ophthalmology for the visualization of the retinal microcirculation and other tissues of the human eye. This review paper aims to describe the basic definitions and principles of OCT and OCTA in the most straightforward possible language without complex mathematical and engineering analysis. This is done to help health professionals of various disciplines improve their understanding of OCTA and design further clinical research more efficiently. First, the basic technical principles of OCT and OCTA and related terminology are described. Then, a list of OCTA advantages and disadvantages, with a special reference to blood flow quantification limitations. Finally, an updated list of the basic hardware and software specifications of some of the commercially available OCTA devices is presented.

Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.

Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance. Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

Perimetric and retinal nerve fiber layer findings in patients with Parkinson's disease.

BACKGROUND: Visual dysfunction is common in Parkinson's disease (PD). It remains, however, unknown whether it is related to structural alterations of the retina. The aim of this study is to compare visual field (VF) findings and circumpapillary retinal nerve fiber layer (RNFL) thickness in a series of PD patients and normal controls, in order to assess possible retinal anatomical changes and/or functional damage associated with PD. METHODS: PD patients and controls were recruited and underwent VF testing with static automated perimetry and RNFL examination with optical coherence tomography (OCT). Cognitive performance using Mini Mental State Examination (MMSE), PD staging using modified Hoehn and Yahr (H-Y) scale and duration of the disease was recorded in PD patients. RESULTS: One randomly selected eye from each of 24 patients and 24 age-matched controls was included. OCT RNFL thickness analysis revealed no difference in the inferior, superior, nasal or temporal sectors between the groups. The average peripapillary RNFL was also similar in the two groups. However, perimetric indices of generalized sensitivity loss (mean deviation) and localized scotomas (pattern standard deviation) were worse in patients with PD compared to controls (p < 0.01). 73% of eyes of PD patients had glaucomatous-like asymmetrical hemifield defects with abnormal Glaucoma Hemifield Test and various combinations of arcuate defects (n = 12), nasal steps (n = 11) and paracentral scotomas (n = 16). Bilateral defects were found in 14 patients (58%). No correlation was found between VF indices and MMSE or H-Y scores. CONCLUSION: PD patients may demonstrate glaucomatous-like perimetric defects even in the absence of decreased RNFL thickness.