Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination.

Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Intravitreal ketorolac for the treatment of chronic cystoid macular edema after cataract surgery.

To report two cases of chronic postoperative cystoid macular edema, resistant to topical therapy, treated with consecutive intravitreal injections of ketorolac tromethamine. Four daily intravitreal injections of 500 μg/0.05 mL of ketorolac were given to each patient. Complete clinical examination and OCT were performed before every injection, 1, 2, 3 weeks, and 1, 3, and 6 months after the last injection. Fluorescein angiography was performed at baseline examination, 1, 3, and 6 months after the last injection. In both cases, the edema regressed and visual acuity increased. At 6 months after the last injection, the leakage was significantly reduced at the fluorescein angiography. Both cases responded favorably to the consecutive intravitreal administration of ketorolac tromethamine. The long-lasting remission of the macular edema in these chronic cases underlines the therapeutic potential of these agents when delivered intravitreally

The effect of intense, short-term topical dexamethasone disodium phosphate eyedrops on blood glucose level in diabetic patients.

To evaluate the influence of an intensive course of topical (ophthalmic drops) steroid (dexamethasone disodium phosphate) application on blood glucose levels in diabetic patients. Fifty-five diabetic (type 2) patients were randomly assigned to receive either corticosteroid (study group: 30 patients, 1 drop of 0.1% dexamethasone disodium phosphate) or balanced salt solution (BSS; control group: 25 patients) eyedrops, every 2 h for 7 days (8 drops/day). Blood glucose monitoring (venous blood sample) was performed at the same time every day (10:00 a.m.). During the study no side effects (such as hypoglycemic/hyperglycemic crises) were observed in either study or control group. No statistically significant alterations in blood glucose levels were found (p = 0.19, paired t test) in either group. In the corticosteroid group, when we separately examined patients with controlled diabetes mellitus (initial glucose level <or=135 mg/dl), a statistically significant increase in blood glucose levels was found at the start of dexamethasone treatment (p = 0.003), but which returned to the pretreatment levels after discontinuation of dexamethasone drops. In contrast, similar results were not found for patients with uncontrolled diabetes mellitus (initial glucose level >or=135 mg/dl), while for control patients we did not find any statistically significant differences in any group. Intensive application of topical corticosteroids (drops) for a short period of time (7 days) seems to statistically raise the blood glucose levels in patients with controlled diabetes mellitus, which, however, return to pretreatment levels after discontinuation of eyedrops without any side effects

Treatment of inferior Descemet membrane detachment secondary to cataract surgery with air injection and supine head position.

To describe a case of a patient with inferior Descemet membrane detachment that resolved after injection of small air bubble and supine positioning. A patient presented two weeks after cataract surgery with inferior persistent corneal edema. A Descemet membrane detachment involving the inferior cornea was revealed. Injection of small air bubble was performed and the patient was advised to stay in a supine position for the next two hours and then as much as reasonably possible to allow the air bubble to press the Descemet to the posterior corneal stroma. Five days after injection, the Descemet membrane was reattached to the corneal stroma and the cornea became clear without any evidence of edema. One month post-air injection the cornea remained clear and the Descement membrane attached. Air injection with supine position was efficient for the resolution of inferior partial Descemet detachment after cataract surgery. The edema resolved without any further intervention

Descemet membrane detachment after heavy silicone oil removal from the anterior chamber.

The aim of this study was to report a case of a central Descemet membrane detachment after heavy silicone oil removal from the anterior chamber. This is a case report of a patient operated with scleral buckling and heavy silicone oil implantation for recurrent retinal detachment. In the patient's follow-up examination, silicone oil was found to completely fill the anterior chamber. He underwent silicone extraction through a paracentesis from the anterior chamber. Immediately after the surgery, a central Descemet membrane detachment combined with corneal edema was identified on slit-lamp examination, and confirmed by anterior segment optical coherence tomography. The detached Descemet membrane was tamponaded successfully with the air bubble injection technique. Four days later, the patient's cornea appeared to be clear, and the Descemet membrane was found to be attached to the corneal stroma with no presence of silicone oil in the anterior chamber. Descemet membrane detachment is a possible and rare complication that occurs after heavy silicone oil removal from the anterior chamber

Ocular rigidity in living human eyes.

To measure the rigidity coefficient of a large number of subjects at clinically encountered intraocular pressures (IOPs) and to examine the possible correlation of ocular rigidity with other factors, such as the age of the patients, ocular parameters (axial length and corneal thickness), and pathologic conditions affecting the eye. The pressure-volume relationship and the ocular rigidity coefficient (K) were determined in 79 eyes undergoing cataract surgery, by injecting 200 microL of saline solution (in steps of 4.5 microL) through the limbus into the anterior chamber, while continually monitoring the IOP with a transducer, up to the limit of 60 mm Hg. Data within an IOP range of 10 to 35 mm Hg were used to calculate the scleral rigidity coefficient. All measurements were taken at the same time of day, to eliminate any possible diurnal variation. The mean ocular rigidity coefficient was 0.0126 mm Hg/microL (95% confidence interval [CI], 0.0112-0.0149). A statistically significant positive correlation between the rigidity coefficient and age of the patient was found (P = 0.02), whereas similar findings were not observed for the examined ocular parameters (axial length, P = 0.09; and corneal thickness, P = 0.12). No correlation was found for patients with diabetes mellitus (P = 0.39), age-related macular degeneration (P = 0.55), and hypertension (P = 0.45). The present study provides quantitative data on the ocular rigidity coefficient based on measurements in a large series of living human eyes. A positive correlation between the ocular rigidity coefficient and the patient's age was documented

Estimating variability in placido-based topographic systems.

To describe a new software tool for the detailed presentation of corneal topography measurements variability by means of color-coded maps. Software was developed in Visual Basic to analyze and process a series of 10 consecutive measurements obtained by a topographic system on calibration spheres, and individuals with emmetropic, low, high, and irregular astigmatic corneas. Corneal surface was segmented into 1200 segments and the coefficient of variance of each segment's keratometric dioptric power was used as the measure of variability. The results were presented graphically in color-coded maps (Variability Maps). Two topographic systems, the TechnoMed C-Scan and the TOMEY Topographic Modeling System (TMS-2N), were examined to demonstrate our method. Graphic representation of coefficient of variance offered a detailed representation of examination variability both in calibration surfaces and human corneas. It was easy to recognize an increase in variability, as the irregularity of examination surfaces increased. In individuals with high and irregular astigmatism, a variability pattern correlated with the pattern of corneal topography: steeper corneal areas possessed higher variability values compared with flatter areas of the same cornea. Numerical data permitted direct comparisons and statistical analysis. We propose a method that permits a detailed evaluation of the variability of corneal topography measurements. The representation of the results both graphically and quantitatively improves interpretability and facilitates a spatial correlation of variability maps with original topography maps. Given the popularity of topography based custom refractive ablations of the cornea, it is possible that variability maps may assist clinicians in the evaluation of corneal topography maps of patients with very irregular corneas, before custom ablation procedures