Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking.

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- (Aldh2-/-) and tissue-specific Aldh2-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior. Aldh2-/- mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specific Aldh2 knockout (Aldh2Hep-/-) mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed in Aldh2-/- mice. Energy expenditure and motility were dramatically dampened in Aldh2-/- mice, but moderately decreased in Aldh2Hep-/- mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model, Aldh2-/- mice drank negligible volumes from ethanol-containing bottles, whereas Aldh2Hep-/- mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specific Aldh2 deficiency did not affect voluntary alcohol consumption. Finally, specific liver Aldh2 knockdown via injection of shAldh2 markedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepatic ALDH2 targeting/editing for the treatment of AUD.

Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.

OBJECTIVE: Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. DESIGN: Wild-type (WT) and Aldh2 knockout (Aldh2-/-) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. RESULTS: Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2-/- mice despite higher acetaldehyde levels in Aldh2-/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2-/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2-/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2-/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. CONCLUSIONS: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.

Unregulated Decorative Lenses: A Brief Definitive Review.

ABSTRACT: Contact lenses are US Food and Drug Administration-regulated medical devices that are a safe and effective method for the correction of refractive error. They are worn by an estimated 45 million Americans. Decorative contact lenses (DCLs) can be used for patients with medical conditions such as failed corneas or aniridia. However, DCLs have also gained popularity in the young, contact lens-naïve population. DCL users often buy lenses through unregulated sources without a clinical examination and education on proper use by an eye care professional. These lenses have a significantly higher risk of infection when compared with contact lenses for the correction of refractive error. To reduce the incidence of microbial keratitis, regulators and eye care professionals must make coordinated efforts to generate and disseminate prevention messages to all contact lens users. In addition, physician and patient reporting of contact lens-related complications to regulatory agencies enhances the pathway to risk reduction. This article reviews DCL use and supply, with a specific focus on the increased risk of contact lens-related complications in unsupervised DCL use.

Use of Diagnostic Codes for Primary Open-Angle Glaucoma Polygenic Risk Score Construction in Electronic Health Record-Linked Biobanks.

PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review. DESIGN: Retrospective cohort study. METHODS: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma.

Outcomes of Secondary Intraocular Lens Implantation and Descemet Stripping Endothelial Keratoplasty-Comparing Staged Versus Combined Surgical Approach.

PURPOSE: The aim of this study was to compare the outcomes of staged versus combined surgical approach for secondary intraocular lens (IOL) implantation and Descemet stripping endothelial keratoplasty (DSEK). METHODS: This is a retrospective review of 124 eyes from 124 patients who underwent either staged or combined secondary IOL implantation in addition to DSEK over a 5-year period at 2 academic tertiary referral centers, between January 1, 2014, and October 1, 2019. Corrected distance visual acuity (CDVA), presence of graft detachment, primary graft failure (PGF), and cystoid macular edema were documented and analyzed. RESULTS: The CDVA for the 1- to 2- month follow-up period was significantly better in the staged group compared with the combined group ( P = 0.011). By the postoperative 6- to 9-month follow-up period, there was no significant difference in the CDVA between the groups ( P = 0.591). There was no significant difference in the incidence of PGF or graft detachment between the 2 groups ( P > 0.05). In addition, there was no significant difference in the CDVA or rate of postoperative complications between the different methods of IOL fixation. CONCLUSIONS: The short-term visual outcomes were significantly better in eyes that underwent staged secondary IOL implantation and DSEK versus the combined surgical approach, although the difference was no longer present at 6 to 9 months. There was no difference in the rate of PGF or graft detachment between the 2 groups.

Low-cost, smartphone-based frequency doubling technology visual field testing using a head-mounted display.

BACKGROUND: Current visual field screening machines are bulky and expensive, limiting their accessibility, affordability and use. We report the design and evaluation of a novel, portable, cost-effective system for glaucoma screening using smartphone-based visual field screening using frequency doubling technology (FDT) and a head-mounted display. METHODS: Nineteen eyes of 10 subjects with new-onset or chronic primary open angle glaucoma were tested and compared with the Humphrey Zeiss FDT and the newly developed Mobile Virtual Perimetry (MVP) FDT with the C-20 testing pattern. Mann-Whitney, Bland-Altman and linear regression analyses were performed to assess statistical difference, agreement and correlation, respectively, between the two devices. RESULTS: The average age of the participants was 58±15 years. No statistically significant difference was found between the MVP FDT and the Humphrey Zeiss FDT (p>0.05). Bland-Altman and linear regression analyses demonstrated good agreement and correlation between the two devices. CONCLUSION: The MVP FDT is a low-cost, portable visual field screening device that produces comparable results to the Humphrey Zeiss FDT and may be used as an easily accessible screening tool for glaucoma.

A unique case of coats plus syndrome and dyskeratosis congenita in a patient with CTC1 mutations.

Coats plus syndrome (CP) is a rare condition characterized by bilateral exudative retinal telangiectasias with associated systemic disorders primarily affecting the brain, bone and gastrointestinal tract due to a mutation in the CTC1 gene. CTC1 mutations are also known to cause dyskeratosis congenita (DC), which is an inherited bone marrow failure syndrome characterized by skin pigmentation abnormalities, nail dystrophy, and oral leukoplakia. This is the first reported case of a patient diagnosed with both CP and DC caused by compound heterozygous CTC1 gene mutations. Moreover, one of the variant mutations found in this patient has never been published before.

Transient effect of suction on the retinal neurovasculature in myopic patients after small-incision lenticule extraction.

PURPOSE: To characterize retinal neurovasculature changes after small-incision lenticule extraction (SMILE) in myopic patients. SETTING: Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, China. DESIGN: Prospective interventional study. METHODS: The corrected distance visual acuity/uncorrected distance visual acuity, corrected intraocular pressure (CIOP), and corneal tomography were evaluated at baseline (PRE), postoperative day (POD) 1, and POD 7. Ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were measured. The vessel area densities (VADs, %), vessel skeleton densities (VSDs, %), vessel diameter index (VDI), and fractal dimensions (Dbox) of the superficial vascular plexus (SVP) and deep vascular plexus (DVP) were measured in a circular area (ϕ 2.5 mm) centered on the fovea. RESULTS: A total of 38 myopic patients were recruited. The GCIPL thickness was increased after SMILE at POD 1 and POD 7 (P < .01) but no significant changes in the pRNFL thickness. The VAD, VSD, and Dbox of the SVP were decreased at POD 1 (P < .01), but not at POD 7. The VDI in small vessels of the SVP and DVP was decreased at POD 1 (P < .05) and increased at POD 7 (P < .05). Changes in CIOP were positively correlated with changes in the GCIPL thickness. Changes in CIOP were negatively correlated with changes in the VAD of small vessels and the Dbox of total vessels in the DVP. Changes in CIOP were negatively correlated with the VSD and VDI of small vessels in the DVP and changes in the VDI of big vessels in the SVP. CONCLUSIONS: The transient fluctuations in the retinal neurovasculature after SMILE may represent a characteristic homeostasis pattern in patients after refractive surgery.

Delayed Onset of Retinopathy of Prematurity Associated With Mitochondrial Dysfunction and Pearson Syndrome.

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].