PURPOSE: To evaluate corneal nerve and immune cell alterations in Fuchs' endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK) by laser in vivo confocal microscopy (IVCM) as correlated to corneal sensation and endothelial cell loss. DESIGN: Prospective, cross-sectional, controlled study. METHODS: Thirty-three eyes with FECD were compared to 13 eyes with PBK and 17 normal age-matched control eyes at a tertiary referral center. FECD was classified into early (without edema) and late stage (with edema). Corneal IVCM and esthesiometry were performed. Corneal nerve and immune dendritiform cell (DC) alterations were evaluated and correlated to clinical parameters. RESULTS: FECD and PBK eyes showed significantly (P = .001) diminished total nerve length (11.5 ± 1.3 and 2.9 ± 0.7 mm/mm) and number (8.8 ± 1.1 and 2.2 ± 0.4 n/frame), compared to controls (23.3 ± 8.1 mm/mm and 25.9 ± 1.3 n/frame). Decreased nerves corresponded to diminished sensation in FECD (4.9 ± 0.2 cm; R = 0.32; P = .045), compared to controls (5.9 ± 0.04 cm). Early- and late-stage FECD showed significantly reduced total nerve length (13.1 ± 1.4 and 9.9 ± 1.2 mm/mm, respectively) and number (8.2 ± 2.5 and 6.5 ± 2.1 n/frame), compared to controls (P < .001). DC density was significantly increased in FECD (57.8 ± 10.4 cells/mm; P = .01), but not in PBK (47.7 ± 11.6 cells/mm; P = .60) compared to controls (22.5 ± 4.5 cells/mm). A subset of early FECD patients (7/22) demonstrated very high DC density (>100/mm). CONCLUSION: IVCM demonstrates profound diminishment of subbasal corneal nerves in early- and late-stage FECD and in PBK, correlating to decreased sensation. Increased DC density in early FECD demonstrates potential subclinical inflammation. The data suggest that reduction in subbasal nerves and increased immune activation may play a role in the pathophysiology of FECD.
Mucin glycoproteins on the ocular surface are rich in O-glycans and have important roles in the protection from physical, chemical and microbial impact. In this work, we have cultured human corneal and conjunctival epithelial cells to examine the glycosyltransferase activities that synthesize the O-glycans of mucins. The results indicate that ocular surface epithelial cells have active enzymes that synthesize O-glycans with sialylated core 1, Galβ1-3GalNAcα, and core 2, GlcNAcβ1-6(Galβ1-3)GalNAcα structures which corresponds to previous structural studies. Eye cells also have enzymes that synthesize complex N-glycans that are found on mucins. Results from treatment of eye cells with TNFα suggest that epithelial O-glycosylation changes in a dynamic fashion during inflammatory stimuli of the eye surface.
If homonymous hemianopia develops in childhood it is frequently accompanied by strabismus. In some of these cases the strabismus increases the size of the binocular visual field. We determined how prevalent visual-field-expanding strabismus is in children who have homonymous hemianopia. Medical records were examined from 103 hemianopic patients with exotropia (XT) or esotropia (ET). For each participant, we determined whether their strabismus was in a direction that resulted in visual field expansion (i.e. left exotropia with left homonymous hemianopia). Ages at which hemianopia and strabismus were first noted were compared to determine which developed first. The prevalence of XT (24%) and ET (9%) with homonymous hemianopia were both much higher than in the general population (1.5% and 5%, respectively). More strabismic eyes pointed to the blind than seeing side (62 vs 41, 60% vs. 40%, p = 0.02). Exotropic eyes were five times more likely to point to the blind side than esotropic eyes (85% vs 15%). Strabismus, especially exotropia, is much more common in pediatric homonymous hemianopia than in the general population. The strabismus is significantly more often in a visual field-expanding direction. These results support an adaptive role for the strabismus. Patients with HH and exotropia or esotropia should be aware that their visual field could be reduced by strabismus surgery.
Background: It is unknown whether dietary quality modifies genetic association with body mass index (BMI). Objective: This study examined whether dietary quality modifies genetic association with BMI. Design: We calculated 3 diet quality scores including the Alternative Healthy Eating Index 2010 (AHEI-2010), the Alternative Mediterranean Diet score (AMED), and the Dietary Approach to Stop Hypertension (DASH) diet score. We examined the interactions of a genetic risk score (GRS) based on 97 BMI-associated variants with the 3 diet quality scores on BMI in 30,904 participants from 3 large cohorts. Results: We found significant interactions between total GRS and all 3 diet scores on BMI assessed after 2-3 y, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P-interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI (kg/m2) per 10-unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared with those in the lowest tertile (0.84; 95% CI: 0.72, 0.96 compared with 1.14; 95% CI: 0.99, 1.29). Results were consistent across the 3 cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for central nervous system GRSs (P < 0.01 for 3 diet scores) than for non-central nervous system GRSs (P > 0.05 for 3 diet scores). Conclusions: A higher diet quality attenuated genetic predisposition to obesity. These findings underscore the importance of maintaining a healthful diet for the prevention of obesity, particularly for those individuals with a strong genetic predisposition to obesity. This trial was registered with the Clinical Trial Registry as NCT03577639.
To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.
Objective: Otologic methicillin-resistant (MRSA) infection has historically been rare, but given the rise in community-acquired MRSA carriage and infection at other body sites, prevalence rates may be changing. The goal of this study was to determine the prevalence of MRSA in recent otologic cultures from patients with acute otitis externa (AOE). Study design: Retrospective review of an institutional microbiologic database. Methods: A retrospective analysis was performed on serial culture isolates taken from the ear at a quaternary care hospital from January 2014 to April 2016. The causative pathogen and antibiotic sensitivity was determined by culture isolation and end point mean inhibitory concentration (MIC) testing. Medical records were reviewed to document patient characteristics, chronicity of infection, symptomatology, and previous treatments. Results: Over the study period, 173 patients were diagnosed with AOE and underwent otologic cultures of the ear. Fifty-three (30.6%) of cultures grew (SA). Of SA infections, 15 (28.3%) were identified as MRSA. MRSA patients were typically older than patients with methicillin-sensitive SA (MSSA) (mean age 46.7 ± 17.9 29 ± 19.4, = 0.003) and had more medical comorbidities (4 1.7, = 0.001). Compared to patients with MSSA, patients with MRSA were significantly more likely to have had prior ototopical antibiotic exposure (37% 73%, = 0.019). Conclusion: Contemporary ear culture isolates at quaternary care center show higher rates of MRSA compared to historical reports in the literature. Clinicians should consider ear cultures to identify MRSA AOE. Level of Evidence: IV.
Ineffective eyelid closure can pose a serious risk of injury to the ocular surface and eye. In cases of eyelid paresis, systematic examination of the eye and ocular adnexa will direct appropriate interventions. Specifically, 4 distinct periorbital regions should be independently assessed: eyebrow, upper eyelid, ocular surface, and lower eyelid. Corneal exposure can lead to dehydration, thinning, scarring, infection, perforation, and blindness. Long-term sequelae following facial nerve palsy may also include epiphora, gustatory lacrimation, and synkinesis.
The purpose of this study was to evaluate absorbable polyethylene glycol (PEG)-based synthetic hydrogel as a sealant for retinal breaks in rhegmatogenous retinal detachment (RD). A three-port, 25-gauge vitrectomy was performed on nine Dutch pigmented rabbit eyes. Subsequently, RD was induced by creating a retinal break. The retina was then reattached by fluid-air exchange. In six of nine eyes (RD-PEG group), PEG sealant was applied to completely cover the retinal breaks, and then photopolymerized with light; thereafter, intravitreous air was replaced with balanced salt solution (BSS). In the remaining three eyes (RD group), PEG sealant was not applied, but the intravitreous air was replaced with BSS. Ophthalmological examinations and intraocular pressure measurements were conducted preoperatively, and at 1 and 7 days, and 1, 3, and 6 months postoperatively. Histological examinations of the eyes were performed after 6 postoperative months. At surgery, retinal reattachment with PEG sealant was achieved in all eyes in the RD-PEG group. Fundoscopic and optical coherence tomographic examinations revealed that the retina remained attached in all the eyes of the RD-PEG group throughout the 6-month observation period. Histological examination revealed no signs of damage in the retinal layers at the edges of the retinal breaks that were in contact with the sealant. In the RD group, the retinas detached in all eyes within 7 days postoperatively. The PEG sealant closed the retinal breaks and maintained retinal reattachment. Intraocular tamponade was not necessary.
Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations.
This review compared the clinical results of transepithelial corneal crosslinking (CXL) to epithelium-off (epi-off) CXL in progressive corneal ectasia using a metaanalysis. The Cochrane databases and Medline were searched for randomized controlled trials (RCTs). Seven RCTs involving 505 eyes that met the eligibility criteria were identified. The epi-off CXL group showed significantly better outcomes in postoperative changes in maximum keratometry (K) during 1-year observation periods. Transepithelial CXL resulted in significantly greater post-treatment central corneal thickness and best spectacle-corrected visual acuity (BSCVA). The presence of a postoperative demarcation line was significantly more frequent after epi-off CXL than that after transepithelial CXL. No statistically significant difference was found between other parameters. Although patients in the transepithelial CXL group demonstrated a greater improvement in BSCVA compared with patients in the epi-off CXL group at the 1 year follow-up, transepithelial CXL had less impact on halting progressive corneal ectasia in terms of maximum K than epi-off CXL.
PURPOSE: It has been suggested that female sex steroids have neuroprotective properties that may reduce risk of glaucoma in premenopausal women. In this study, we explored the associations of optic disc measures with female reproductive factors in a population of young women. DESIGN: Cohort study. METHODS: Young women (n = 494; age range, 18-22 years) were recruited as part of the Western Australian Pregnancy Cohort (Raine) Study. Information on age at menarche, parity, and use of hormonal contraceptives were obtained from questionnaires. Participants underwent an eye examination, including spectral-domain optical coherence tomography imaging, to obtain optic disc parameters. RESULTS: Women who had given birth at least once (parous women; n = 10) had larger vertical neuroretinal rim widths ( < 0.001) than nulliparous women (n = 484) after correcting for use of hormonal contraceptives, intraocular pressure, refractive error, and family history of glaucoma. Furthermore, vertical and horizontal cup-to-disc ratios, which are inherently related to neuroretinal rim width, were found to be smaller among parous women compared with nulliparous women (both < 0.001). Age at menarche and use of hormonal contraceptives were not significantly associated with any optic disc parameters. CONCLUSIONS: We found limited evidence that female reproductive factors were related with optic disc parameters during young adulthood. The association between parity and optic disc parameter, though significant, should be further investigated given the small number of parous women in the current sample. Future follow-ups of this cohort will allow us to explore for any associations of these factors with optic disc parameters and glaucoma risk at an older age.
PURPOSE: Optimal meibomian gland (MG) function is critically important for the health and wellbeing of the ocular surface. We hypothesize that low oxygen (O) conditions promote the function of human MG epithelial cells (HMGECs) and that human MGs exist in a relatively hypoxic environment. The purpose of this study was to test our hypotheses. METHODS: We used human and mouse eyelid segments, and immortalized human MG epithelial cells (IHMGECs) in our studies. To evaluate oxygen (O) levels in the mouse MG and vicinity, we injected pimonidazole (pimo), a hypoxia marker, before sacrifice. Human eyelid samples were stained with the hypoxia marker glucose transporter 1 (Glut-1). To determine the effect of low O levels on IHMGECs, we cultured cells under proliferating and differentiating conditions in both normoxic (21% O) and hypoxic (3% O) conditions for 5-15 days. IHMGECs were evaluated for cell number, neutral lipid content, lysosome accumulation, expression of biomarker proteins and DNase II activity. RESULTS: Our results demonstrate that human and mouse MGs, but not the surrounding connective tissue, exist in a relatively hypoxic environment in vivo. In addition, our findings show that hypoxia does not influence IHMGEC numbers in basal or proliferating culture conditions, but does stimulate the expression of SREBP-1 in differentiating IHMGECs. Hypoxia also significantly increased DNase II activity, and apparently IHMGEC terminal differentiation. CONCLUSIONS: Our Results support our hypotheses, and indicate that relative hypoxia promotes MG function.
Manoli I, Sysol JR, Epping MW, Li L, Wang C, Sloan JL, Pass A, Gagné J, Ktena YP, Li L, Trivedi NS, Ouattara B, Zerfas PM, Hoffmann V, Abu-Asab M, Tsokos MG, Kleiner DE, Garone C, Cusmano-Ozog K, Enns GM, Vernon HJ, Andersson HC, Grunewald S, Elkahloun AG, Girard CL, Schnermann J, DiMauro S, Andres-Mateos E, Vandenberghe LH, Chandler RJ, Venditti CP. FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight 2018;3(23)Abstract
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm, control 2.5 ± 0.3 CD163+ cells/mm, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.
PURPOSE: To assess the outcomes of resident-performed cataract surgeries with iris challenges and to compare these outcomes with similar surgeries performed by attending surgeons. SETTING: Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. DESIGN: Retrospective chart review. METHODS: All cases of cataract extraction by phacoemulsification with intraocular lens implantation, performed by comprehensive ophthalmologists between January 1 and December 31, 2014, were reviewed. Cases with preoperative or intraoperative miosis, iris prolapse, and intraoperative floppy iris syndrome, were included for analysis. Visual outcomes and the rate of perioperative adverse events were compared between resident and attending surgeon cases. Factors predicting adverse events were also assessed. RESULTS: In total, 1931 eye cases of 1434 patients were reviewed, and 65 resident cases and 168 attending surgeon cases were included. The mean logarithm of the minimum angle of resolution corrected distance visual acuity was better in the resident group 1 month after surgery (0.051 ± 0.10 [SD] versus 0.132 ± 0.30, P = .03); however, the difference was eliminated when controlling for macular disease. The mean operative time was 43.8 ± 26.5 minutes and 30.9 ± 12.6 minutes for cases performed by resident surgeons and attending surgeons, respectively (P .0001). Residents utilized supplemental pharmacologic dilation or retraction more frequently than attending surgeons (98% versus 87% of cases, P = .008). The overall rate of adverse events was no different between residents and attending surgeons (P = 0.16). Dense nuclear sclerosis predicted adverse events in cataract cases with iris challenges (adjusted odds ratio, 1.86; 95% confidence interval, 1.17-2.94; P = .001). CONCLUSION: Although requiring longer operative times and more surgical manipulation, residents who performed cataract surgeries with iris challenges achieved outcomes comparable to those performed by attending surgeons, and residents should be given the opportunity to operate on these eyes.