Heritability of tear fluid cytokines in healthy twins.

PURPOSE: Ocular surface disease is common and it is associated with elevated concentration levels of cytokines in tear fluid. Studies of the normal variation in tear fluid inflammatory markers are lacking. New knowledge may help guide research into ocular surface disease biomarkers and therapeutics. METHODS: In this prospective twin cohort study, healthy individuals were recruited from a population-based registry. Tear fluid was collected with the Schirmer test strips was submerged in phosphate buffered saline and stored at -80° before undergoing 27-cytokine multiplex immunoassay analysis. Broad-sense heritability (h2) of cytokine concentrations was analyzed. RESULTS: 90 participants (23 monozygotic and 22 dizygotic twin pairs) were included. Data availability allowed for heritability analysis of 15 cytokines, and a h2 >50% was seen for 10 cytokines. A statistical power of >80% was achieved for heritability analyses of the cytokines interferon gamma induced protein 10 (h2 = 94.8%), eotaxin (89.8%), interleukin 7 (86.6%), interleukin 1ß (82.2%) and monocyte chemoattractant protein 1 (68.2%). CONCLUSIONS: The tear fluid concentration of several analyzed cytokines was found to be highly heritable. A considerable amount of the inter-individual variation observed for the concentration of certain tear fluid cytokines can be linked to hereditary factors that cannot easily be modified by changing factors in the environment of patients. This suggests that a higher success in ocular surface disease drug discovery may be anticipated for drugs that have targets in specific populations, and points to the importance of emphasizing known preventive measures of ocular surface disease and examinations of close relatives of patients with ocular surface disease, such as dry eye disease.

Frail inner limiting membrane maculopathy suggested to describe a new retinal Alport-like condition with two variants in three generations of females.

BACKGROUND: We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes. METHODS: Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis. RESULTS: The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in COL4A3, COL4A4, and COL4A5. Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype. CONCLUSION: A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy."

Ocular and systemic associations and heritability of retinal arterial wall-to-lumen ratios in a twin cohort.

PURPOSE: To investigate ocular and systemic factors associated with the retinal arterial wall-to-lumen ratio (WLR) and to determine the relative contribution of genetic and environmental variation to WLR in healthy adults. METHODS: This cross-sectional twin study included 78 monozygotic and 67 dizygotic same-sex twin pairs aged 58.4 ± 9.8 (mean ± SD) years. Lumen diameter (LD) and outer diameter (OD) of a superotemporal retinal artery were measured using adaptive optics fundus photography, and the WLR was calculated. Linear mixed model regression analysis of associations with WLR comprised the descriptive variables ocular axial length (AL), intraocular pressure (IOP), height, weight, body mass index (BMI), smoking, blood pressure, high density (HDL), low density (LDL) and very low density (VLDL) lipoproteins, total cholesterol and triglycerides. The relative influence of genes and environment on WLR was calculated through polygenetic modelling. RESULTS: Increasing age and arterial blood pressure were associated with a higher WLR, while increasing retinal artery OD and ocular AL were associated with a lower WLR. Sex, smoking status, BMI, IOP, cholesterol levels or triglycerides had no detectable impact on the WLR. Broad-sense heritability of WLR was 21% (95% CI: 1-41%), while environmental factors accounted for the remaining 79% of the interindividual variance (95% CI: 59-99%). CONCLUSION: Retinal artery wall thickness was closely linked to increasing age and higher arterial blood pressure, the latter being mediated by the environment over genes.

Small hard drusen and associated factors in early seniority.

PURPOSE: The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 µm in diameter). METHODS: This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 µm), intermediate soft drusen (63-125 µm), and large soft drusen (> 125 µm), of which the soft drusen are compatible with a diagnosis of AMD. RESULTS: Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen. CONCLUSIONS: Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.

Comparison of Spectral-Domain OCT versus Swept-Source OCT for the Detection of Deep Optic Disc Drusen.

Deep optic disc drusen (ODD) are located below Bruch's membrane opening (BMO) and may go undetected due to the challenges in imaging them. The purpose of this study is a head-to-head comparison of currently widely used imaging technologies: swept-source optical coherence tomography (SS-OCT; DRI OCT-1 Triton, Topcon) and enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT; Spectralis OCT, Heidelberg Engineering) for the detection of deep ODD and associated imaging features. The eyes included in this study had undergone high-resolution imaging via both EDI SD-OCT and SS-OCT volume scans, which showed at least one deep ODD or a hyperreflective line (HL). Grading was performed by three graders in a masked fashion. The study findings are based on 46 B-scan stacks of 23 eyes including a total of 7981 scans. For scan images with ODD located above or below the level of BMO, no significant difference was found between the two modalities compared in this study. However, for HLs and other features, EDI SD-OCT scan images had better visualization and less artifacts. Although SS-OCT offers deep tissue visualization, it did not appear to offer any advantage in ODD detection over a dense volume scan via EDI SD-OCT with B-scan averaging.

Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up.

INTRODUCTION: The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. METHODS: Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 µm, or (4) ≥20 small hard drusen combined with drusen ≥63 µm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. RESULTS: Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 µm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 µm at follow-up (p = 0.02). Development of drusen ≥63 µm was attributable to 49% genetic effects and 51% environmental effects. CONCLUSION: The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 µm at baseline was associated with incident drusen ≥63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Long-term development of lens fluorescence in a twin cohort: Heritability and effects of age and lifestyle.

The blue-green autofluorescence of the ocular lens increases with age, glycemia and smoking, as the irreplaceable structural proteins of the lens slowly accumulate damage from the encounter with reactive molecular species. We have conducted a prospective study of lens autofluorescence over two decades in a twin cohort. The study included 131 phakic, non-diabetic adult twins (median age at follow-up 58 years, range 41-66 years) who were examined twice at an interval of 21 years. Change in anterior lens peak autofluorescence was analyzed in relation to age, current and baseline glycemia, cumulative smoking and heritability. The level of lens autofluorescence in the study population increased as a function of age and smoking (p ≤.002), but not as a function of glycemia (p ≥.069). Lens autofluorescence remained a highly heritable trait (90.6% at baseline and 93.3% at follow-up), but whereas the combined effect of age and cumulative smoking explained 57.2% of the variance in lens autofluorescence at baseline in mid-life, it only accounted for 31.6% at follow-up 21 years later. From mid to late adulthood, the level of blue-green fluorescence remained overwhelmingly heritable, but became less predictable from age, smoking habits and glycemic status. Presumably, as the lens ages, its intrinsic characteristics come to dominate over environmental and systemic factors, perhaps in a prelude to the development of cataract.

Heritability of retinal drusen in the Copenhagen Twin Cohort Eye Study.

PURPOSE: To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort. METHODS: This was a single-centre, cross-sectional, classical twin study with ophthalmic examination including refraction, biometry, best-corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location. RESULTS: The study enrolled 176 same-sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 µm), ≥20 small hard extramacular drusen, intermediate drusen (63-125 µm) anywhere, and large drusen (>125 µm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5-82.9], 69.1% [62.3-75.9], 30.1% [4.1-56.1], and 65.6% [26.4-100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier. CONCLUSION: Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.

Lens fluorescence and skin fluorescence in the Copenhagen Twin Cohort Eye Study: Covariates and heritability.

Lens and skin fluorescence are related to the systemic accumulation of advanced glycation end products, which is accelerated in diabetes. We have examined lens fluorescence and skin fluorescence in healthy adult twins. The study enrolled twins aged median 59 years from a national population-based registry. Diabetic individuals were excluded from analysis. The interrelatedness between fluorescence parameters and relations between fluorescence and age, current HbA1c and smoking pack years were examined using correlation tests and mixed model linear regression analyses. Broad-sense heritability was analyzed and compared for lens fluorescence, skin fluorescence and HbA1c. Lens fluorescence and skin fluorescence were crudely interrelated (R = 0.38). In linear regression analyses, age explained a larger fraction of the variance in lens fluorescence (R2 = 32%) than in skin fluorescence (R2 = 20%), whereas HbA1c explained smaller variance fractions (R2 = 3% and 8%, respectively) followed by smoking pack years (4% and 3%, respectively). In multivariate analyses, age, HbA1c and smoking pack years combined explained more of the variance in lens fluorescence (R2 = 35%) than in skin fluorescence (R2 = 21%), but the influence of HbA1c on lens fluorescence was not statistically significant (p = .2). Age-adjusted broad-sense heritability was 85% for lens fluorescence, 53% for skin fluorescence and 71% for HbA1c in best fitting heritability models. Both fluorescence parameters increased with age, current glycemia and cumulative smoking. Lens fluorescence was found to be a predominantly heritable trait, whereas skin fluorescence was more influenced by environmental factors and closer related to current glycemia. The results suggest that skin fluorophores have a faster turn-over than lens fluorophores.

Iron overload and iron chelating agent exposure in anemia-associated outer retinal degeneration: a case report and review of the literature.

BACKGROUND: Deferoxamine retinopathy is the informally designated term used to describe a characteristic pattern of outer retinal degeneration in iron-overloaded chronic anemia patients who are treated with deferoxamine. We hypothesize that insufficiently treated iron overloading and not only deferoxamine is the cause of the retinal degeneration. Our case report is based on exposure histories of two anemia patients and literature review. CASE PRESENTATION: Both anemia patients presented with bilateral visual loss secondary to photoreceptor and retinal pigment epithelium degeneration. Chart review showed that visual loss came after a year-long slow, and rather monotonous rise in plasma ferritin concentrations, with no obvious relation to iron chelator exposure. In one patient, the onset of symptomatic visual loss came after a bout of fever followed by two additional febrile episodes, all accompanied by plasma ferritin spikes. Adjustment of iron chelation therapy did not improve visual function. Experimental studies clearly show that both systemic and intraocular exposure to iron ions can induce retinal degeneration. CONCLUSION: The available evidence indicates that retinal degeneration in chronic anemia patients treated by deferoxamine is cause by insufficient iron chelation, not by deferoxamine. The actual role of iron chelating agents may be to promote a long enough survival to allow the slow development of retinal siderosis.

Peripheral bright streaks in tuberous sclerosis.

PURPOSE: To describe the finding of bright hyperautofluorescent streaks in the peripheral retina in tuberous sclerosis. OBSERVATIONS: A woman with a pathogenic TSC1 mutation and cutaneous manifestations of tuberous sclerosis underwent fundus examination and was found to have a cluster of thin, yellowish streaks in the inferior peripheral fundus of her left eye. The streaks were hyperautofluorescent in blue light and associated with irregular thickening of the photoreceptor-pigment epithelium complex on optical coherence tomography. CONCLUSIONS AND IMPORTANCE: The cluster of outer retinal abnormalities in a sector of the peripheral retina in one eye of a TSC1 patient has features in common with the more centrally located and less numerous lesions called achromatic patches. The resemblance of the streak pattern with the pattern of hypoautofluorescence in X-linked retinopathies suggests that the streaks may represent a clone of cells derived from a single somatic mutation in TSC1. The identification of this lesion type expands the scope of conditions that can be diagnosed by fundus imaging.

Migration of an outer retinal element in a healthy child followed by longitudinal multimodal imaging.

PURPOSE: To describe the migration of an outer retinal element using longitudinal multimodal imaging. OBSERVATIONS: In the retina of a healthy 7-year-old girl, movement of a hyperreflective element of 15 µm extent was seen using optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy (cSLO), and adaptive optics fundus photography (AO). On the OCT B-scan, the element initially appeared at the level of the outer limiting membrane with an umbra reaching the retinal pigment epithelium from where it gradually diminished and disappeared over 33 days. A corresponding disruption of the photoreceptor pattern on AO diminished over 52 days. CONCLUSIONS AND IMPORTANCE: This non-invasive observation of an isolated, cell-sized, migrating element in the human retina was made in vivo in the absence of confounding retinal disease or similar nearby elements. Based on prior preclinical observations we hypothesize that such a migrating element could be a macrophage. The case provides information about the time-scale and resolution needed for the monitoring of infiltrative processes in the retina.

Early response evaluation of neoadjuvant therapy with PET/MRI to predict resectability in patients with adenocarcinoma of the esophagogastric junction.

STUDY DESIGN AND PURPOSE: Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability. METHODS AND MATERIALS: Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. RESULTS: Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. CONCLUSION: Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication.

Comparison of "Nil by Mouth" Versus Early Oral Intake in Three Different Diet Regimens Following Esophagectomy.

BACKGROUND: The literature on oral intake after esophagectomy and its influence on anastomotic leakage and complications is sparse. METHODS: This retrospective study included 359 patients undergoing esophagectomy between January 2011 and August 2015. Three oral intake protocols were evaluated: regimen 1, nil by mouth until postoperative day (POD) 7 followed by a normal diet; regimen 2, oral intake of clear fluids from POD 1 followed by a normal diet; regimen 3, nil by mouth until POD 7 followed by a slow increase to a blended diet. The outcome endpoints were: (1) anastomotic leakage, (2) complications [severity and number described using the Dindo-Clavien Classification and Comprehensive Complication Index (CCI)] and (3) length of stay. A multivariate logistic regression model was obtained for CCI and anastomotic leakage using Wald's stepwise selection. RESULTS: CCI was significantly lower in regimen 3 (16 vs. 22 and 26 in regimen 1 and 2, p = 0.027). Additionally, significantly fewer patients in regimen 3 suffered from severe complications of Dindo-Clavien grade IIIb-IV (p = 0.025). The incidence of anastomotic leakage reached its lowest in regimen 3, 2%, compared to 7-9%. Multivariate analyses revealed that high American Society of Anesthesiologist score was a predicting factor for both CCI and anastomotic leakage. CONCLUSION: The study indicates that nil by mouth until postoperative day 7 followed by a slow increase to a blended diet after esophagectomy results in less severe complications and a tendency of fewer anastomotic leakages. Multiple comorbidities proved to be an important predictive factor of the postoperative course.