Visual outcomes of acute bacterial endophthalmitis treated with adjuvant intravitreal dexamethasone: A meta-analysis and systematic review.

Adjunctive treatment of bacterial endophthalmitis with intravitreal steroids is a topic of controversy among many ophthalmologists. The objective of this study is to evaluate the effects of intravitreal dexamethasone on the visual outcomes of patients with acute bacterial endophthalmitis through a systematic review and meta-analysis. A literature search of PubMed, Scopus, and Cochrane Library databases was performed to include studies on the visual outcomes of adjuvant intravitreal dexamethasone in patients with acute bacterial endophthalmitis. The review is based on the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) protocol. A total of 1545 articles met our search criteria and after further review, two randomized controlled trials and three retrospective case series were included in the final analysis. A total of 126 eyes were treated with intravitreal dexamethasone combined with antibiotics, and another 139 eyes were treated with antibiotics alone. All cases of endophthalmitis were post-operative or post-intravitreal injection, with pooled results demonstrating no visual benefit with supplementation of intravitreal dexamethasone. Our meta-analysis does not show any visual benefit from steroid supplementation and yet, considering a relatively small number of patients included in each study, larger randomized controlled trials are required to further clarify the role of steroids in the treatment of acute bacterial endophthalmitis.

The Effects of Hyperbaric Oxygen Therapy in Patients with Central Retinal Artery Occlusion: A Retrospective Study, Systematic Review, and Meta-analysis.

PURPOSE: Central retinal artery occlusion (CRAO) is a vision-threatening condition with a potentially poor visual prognosis. Many different treatment modalities are suggested but controversy remains regarding effectiveness of these treatments. The purpose of this study is to perform a systematic review and meta-analysis in addition to analyzing retrospective data at our own tertiary care center regarding effectiveness of hyperbaric oxygen therapy (HBOT) in treatment of CRAO. METHODS: The PubMed, Scopus, and the Cochrane Library are searched from the date of database inception to September 2021 to conduct a review based on the PRISMA (preferred reporting items for systematic review and meta-analysis), evaluating the role of HBOT in visual recovery of CRAO patients. In addition, a retrospective chart review of patients clinically diagnosed with CRAO at our university-based hospital (University of Texas Health, San Antonio, TX, USA) from year 2011 to 2021 was conducted. RESULTS: After a review of 376 articles, three articles met the inclusion criteria for meta-analysis, where a total of 207 patients received HBOT versus 89 patients that did not receive any form of oxygen therapy. Analysis of these results demonstrate that HBOT in CRAO patients does not enhance the final visual outcome (p = 0.83). Similar conclusion was also drawn from retrospective analysis of 48 patients (15 HBOT versus 33 controls) at our tertiary care center, where no visual benefit was observed in the HBOT group. CONCLUSIONS: HBOT does not appear to improve final visual outcome and concerns remain regarding adverse reactions such as barotrauma and generalized seizures. Large, randomized studies are required for further understanding of the role of HBOT in treatment of CRAO.

Protective Role of 360° Laser Retinopexy in Patients with Rhegmatogenous Retinal Detachment: a Systematic Review and Meta-analysis.

PURPOSE: Visual impairment from retinal re-detachment could be debilitating. The aim of this review is to evaluate the role of 360° laser retinopexy on success rate of rhegmatogenous retinal detachment (RRD) repair by a meta-analysis study. METHODS: The PubMed, Scopus, and the Cochrane Library databases were searched comprehensively from the date of database inception to January 2021, evaluating the role of 360° laser retinopexy in visual and anatomical success rate of RRD repair. This review was conducted based on the preferred reporting items for systematic review and meta-analysis (PRISMA) protocols. RESULTS: Among 202 articles screened for eligibility, six studies were found to be eligible for inclusion in our final analysis. Our meta-analysis demonstrates that prophylactic treatment with circumferential laser photocoagulation has no significant effect on the initial rate of retinal re-detachment or final best-corrected visual acuity following pars plana vitrectomy repair of RRD. Subgroup analysis of studies (n = 3) with 23-gauge pars plana vitrectomy, however, favors attachment rate in patients undergoing 360° prophylactic laser treatment. CONCLUSIONS: Three hundred and sixty degree laser retinopexy appears to have favorable outcomes in patients undergoing 23-gauge retinal detachment repair. This protective effect, however, is not apparent with inclusion of 20-gauge vitrectomy studies.

Treatment of central serous chorioretinopathy with topical NSAIDs.

PURPOSE: Central serous chorioretinopathy (CSCR) is a common retinopathy that is often observed until resolution. The purpose of this study is to evaluate the effects of topical nonsteroidal anti-inflammatory drugs (NSAIDs) on timing of CSCR recovery. METHODS: An IRB-approved retrospective review was conducted on patients that had been diagnosed with a new-onset, symptomatic case of CSCR. Patients were either observed only (13 untreated eyes) or treated with topical bromfenac or nepafenac (14 eyes) over an average of about a 4-5 week follow-up period. RESULTS: There was no statistical significance between central macular thickness (CMT) and visual acuity of treatment and control groups at the initial presentation. However, at the follow-up visit, CMT reductions in the treatment group were significantly higher than in the control group (p<0.006). CONCLUSION: Use of topical NSAIDs in the treatment of acute CSCR leads to a faster rate of reduction in the subretinal fluid volume over a follow-up period of a few weeks.

The effects of temporary intraocular pressure spikes after intravitreal dexamethasone implantation on the retinal nerve fiber layer.

Background and objective: The dexamethasone (DEX) implant is known to cause temporary intraocular pressure (IOP) spikes after implantation. The purpose of this study is to determine if IOP spikes after DEX implant cause significant thinning in the retinal nerve fiber layer (RNFL). Study design, patients, and methods: A total of 306 charts were reviewed with 48 and 21 patients meeting inclusion criteria for the cross-sectional and prospective groups, respectively. Cross-sectional inclusion criteria: IOP spike ≥22 mmHg up to 16 weeks after DEX implant, DEX implant in only 1 eye per patient, and spectral-domain optical coherence tomography (OCT) RNFL imaging of both eyes ≥3 months after IOP spike. Prospective inclusion criteria: OCT RNFL performed within 1 year prior to DEX implantation, IOP spike ≥22 mmHg up to 16 weeks after DEX implant, and OCT RNFL performed ≥3 months after IOP spike. The average RNFL thickness in the contralateral eye was used as the control in the cross-sectional group. Institutional review board approval was obtained. Results: In the cross-sectional group, there was no statistically significant difference in the mean RNFL thicknesses in the treated vs untreated eyes (80.4±15.5 µm and 82.6±15.8 µm, respectively; P=0.33) regardless of treatment diagnosis, magnitude of IOP spike, or history of glaucoma. In the prospective group, mean RNFL thicknesses before and after IOP spikes ≥22 mmHg were similar (78.0±14.8 µm and 75.6±13.6 µm, respectively; P=0.13). Conclusion and relevance: Temporary elevation of IOP after DEX implantation when treated with topical IOP lowering drops does not appear to lead to a meaningful change in RNFL thickness.

A New Suggested Strategy for Safe Injection of Ozurdex.

BACKGROUND AND OBJECTIVES: Ozurdex intravitreal injection is performed via a patented injection device. However, there is a common misconception among ophthalmologists regarding the relation between the speed of applicator button depression and the speed of pellet injection. PATIENTS AND METHODS: Six dexamethasone intravitreal implants were injected into a calibrated ex vivo water bath. Three of the pellets were injected via rapid compression, whereas the other three implants were injected using a 3-second compression technique. The procedures were recorded using high-speed photography followed by calculation of pellet velocity and impact force. RESULTS: The mean impact velocity and force of the pellet insertion is significantly higher in the fast injection group compared to the slow injection group. CONCLUSIONS: By depressing the Ozurdex implant injector during a 3-second time interval, the impact force of the implant pellet is reduced by about 95%. This new technique will theoretically reduce the risk of retinal injury and vitreous hemorrhage from Ozurdex injections. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e23-e25.].

The effects of repeated Ozurdex injections on ocular hypertension.

PURPOSE: The purpose of this study was to correlate the degree of ocular hypertension with the number of Ozurdex injections. METHODS: Intraocular pressure (IOP) fluctuations for a total of 183 injections were studied over a period of at least 12 months. The main indications for treatment were uveitis, diabetic macular edema, and retinal vein occlusion. RESULTS: Results of the study demonstrate that repeated Ozurdex injections do not increase the frequency of IOP spikes beyond 30 mmHg. For lower IOPs, however, a positive correlation exists. Furthermore, patients with primary open angle glaucoma and uveitis had the highest IOP response to repeated injections. On average, patients with an IOP of ≥28.6 mmHg received pressure lowering medications, after which their IOP reached a stable level (16.7 mmHg) without the need for additional interventions. CONCLUSION: The data support the conclusion that multiple Ozurdex injections does not increase the frequency of IOP spikes beyond 30 mmHg, but patients still must be closely monitored if they have a history of primary open angle glaucoma.

Appointment Compliance in Patients With Diabetic Macular Edema and Exudative Macular Degeneration.

BACKGROUND AND OBJECTIVE: The purpose of this study is to compare cancellation and no-show rates in patients with diabetic macular edema (DME) and exudative macular degeneration (wet AMD). PATIENTS AND METHODS: An anonymous survey was sent to 1,726 retina specialists inquiring as to the number of appointments their patients with DME and wet AMD attended, cancelled, or did not show up for in 2014 and 2015. RESULTS: Data were obtained on 109,599 appointments. Patients with DME in the U.S. had a 1.591-times increased odds of cancelling or no-showing to their appointments than patients with wet AMD (P < .0001). Patients with DME in Europe had a 1.918-times increased odds of cancelling or no showing to their appointments than patients with wet AMD (P < .0001). CONCLUSION: Patients with DME in the U.S. and Europe cancelled and no-showed to their appointments significantly more often than patients with wet AMD. These findings can be taken into consideration when establishing treatment plans for patients with DME. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:186-190.].

Recent advances in the management and understanding of macular degeneration.

Current management of age-related macular degeneration (AMD) is directed at intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors for the treatment of wet AMD and supplementation with oral antioxidants for the treatment of dry AMD. In this article, we will review recent clinical trials for the treatment of dry and wet AMD.

Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells.

A functional decline in tissue stem cells and mitochondrial dysfunction have each been linked to aging and multiple aging-associated pathologies. However, the interplay between energy homeostasis, stem cells, and organismal aging remains poorly understood. Here, we report that expression of the single-subunit yeast alternative NADH dehydrogenase, ndi1, in Drosophila intestinal stem and progenitor cells delays the onset of multiple markers of intestinal aging and extends lifespan. In addition, expression of ndi1 in the intestine increases feeding behavior and results in organismal weight gain. Consistent with increased nutrient uptake, flies expressing ndi1 in the digestive tract display a systemic reduction in the activity of AMP-activated protein kinase (AMPK), a key cellular energy sensor. Together, these results demonstrate that ndi1 expression in the intestinal epithelium is an effective strategy to delay tissue and organismal aging.

Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction.

More than 130 different mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been associated with amyotrophic lateral sclerosis but the mechanism of this toxicity remains controversial. To gain insight into the importance of the zinc site in the pathogenesis of SOD1 in vivo, we generated a Drosophila model with transgenic expression of a zinc-deficient human SOD1. Expression of zinc-deficient SOD1 in Drosophila resulted in a progressive movement defect with associated mitochondrial cristae vacuolization and reductions in adenosine triphosphate (ATP) levels. Furthermore, these flies are sensitized to mitochondrial toxins, paraquat, and zinc. Importantly, we show that the zinc-deficient SOD1-induced motor defect can be ameliorated by supplementing the endogenous fly respiratory chain machinery with the single-subunit NADH-ubiquinone oxidoreductase from yeast (NADH is nicotinamide adenine dinucleotide, reduced form.). These results demonstrate that zinc-deficient SOD1 is neurotoxic in vivo and suggest that mitochondrial dysfunction plays a critical role in this toxicity. The robust behavioral, pathological, and biochemical phenotypes conferred by zinc-deficient SOD1 in Drosophila have general implications for the role of the zinc ion in familial and sporadic amyotrophic lateral sclerosis.

Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog.

In mammals, the PGC-1 transcriptional coactivators are key regulators of energy metabolism, including mitochondrial biogenesis and respiration, which have been implicated in numerous pathogenic conditions, including neurodegeneration and cardiomyopathy. Here, we show that overexpression of the Drosophila PGC-1 homolog (dPGC-1/spargel) is sufficient to increase mitochondrial activity. Moreover, tissue-specific overexpression of dPGC-1 in stem and progenitor cells within the digestive tract extends life span. Long-lived flies overexpressing dPGC-1 display a delay in the onset of aging-related changes in the intestine, leading to improved tissue homeostasis in old flies. Together, these results demonstrate that dPGC-1 can slow aging both at the level of cellular changes in an individual tissue and also at the organismal level by extending life span. Our findings point to the possibility that alterations in PGC-1 activity in high-turnover tissues, such as the intestine, may be an important determinant of longevity in mammals.

Neuronal expression of a single-subunit yeast NADH-ubiquinone oxidoreductase (Ndi1) extends Drosophila lifespan.

The 'rate of living' theory predicts that longevity should be inversely correlated with the rate of mitochondrial respiration. However, recent studies in a number of model organisms, including mice, have reported that interventions that retard the aging process are, in fact, associated with an increase in mitochondrial activity. To better understand the relationship between energy metabolism and longevity, we supplemented the endogenous respiratory chain machinery of the fruit fly Drosophila melanogaster with the alternative single-subunit NADH-ubiquinone oxidoreductase (Ndi1) of the baker's yeast Saccharomyces cerevisiae. Here, we report that expression of Ndi1 in fly mitochondria leads to an increase in NADH-ubiquinone oxidoreductase activity, oxygen consumption, and ATP levels. In addition, exogenous Ndi1 expression results in increased CO2 production in living flies. Using an inducible gene-expression system, we expressed Ndi1 in different cells and tissues and examined the impact on longevity. In doing so, we discovered that targeted expression of Ndi1 in fly neurons significantly increases lifespan without compromising fertility or physical activity. These findings are consistent with the idea that enhanced respiratory chain activity in neuronal tissue can prolong fly lifespan.

Perturbation of mitochondrial complex V alters the response to dietary restriction in Drosophila.

Studies in a broad spectrum of model organisms have reported that dietary restriction (DR) is associated with an increase in mitochondrial electron transport chain (ETC) function. However, the question of whether ETC function is required for DR-mediated longevity remains controversial. Here, we report that genetic and pharmacological interventions that target mitochondrial complex V affect Drosophila lifespan in a nutrient-dependent manner. These findings support a requirement for mitochondrial complex V in DR-mediated longevity in flies.

A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment.

Human Menkes disease is a lethal neurodegenerative disorder of copper metabolism that is caused by mutations in the ATP7A copper-transporting gene. In the present study, we attempted to construct a Drosophila model of Menkes disease by RNA interference (RNAi)-induced silencing of DmATP7, the Drosophila orthologue of mammalian ATP7A, in the digestive tract. Here, we show that a lowered level of DmATP7 mRNA in the digestive tract results in a reduced copper content in the head and the rest of the body of surviving adults, presumably owing to copper entrapment in the gut. Similar to Menkes patients, a majority of flies exhibit an impaired neurological development during metamorphosis and die before eclosion. In addition, we show that survival to the adult stage is highly dependent on the copper content of the food and that overexpression of the copper homeostasis gene, metal-responsive transcription factor-1 (MTF-1), enhances survival to the adulthood stage. Taken together, these results highlight the role of DmATP7-mediated copper uptake in the neurodevelopment of Drosophila melanogaster and provide a framework for the analysis of potential gene interactions influencing Menkes disease.

Overexpression of metal-responsive transcription factor (MTF-1) in Drosophila melanogaster ameliorates life-span reductions associated with oxidative stress and metal toxicity.

Heavy metals are essential components of many biological processes but are toxic at high concentrations. Our results illustrate that when metal homeostasis is compromised by a mutation in the metal-responsive transcription factor (MTF-1), the life-span is shortened. In contrast, MTF-1 overexpression results in resistant flies with prolonged longevity on iron or cadmium-supplemented media but shortened life-span on zinc-supplemented medium. This effect was mediated by the overexpression of MTF-1 in specific tissues, such as the gut, hemocytes and in particular in neurons, indicating that these tissues are particularly sensitive to the perturbance of metal homeostasis. Further, MTF-1 overexpression in a neuron-specific manner protects flies against hyperoxia and prolongs the life-span of Cu/Zn superoxide dismutase-deficient flies, suggesting the presence of a common mechanism for protection against both oxidative stress and metal toxicity. Finally, normal life-span is extended up to 40% upon MTF-1 overexpression in either the peripheral nervous system or motorneurons. These results document the tissue-specific import of heavy metal toxicity and oxidative damage in aging and life-span determination.

Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain.

BACKGROUND: Mitochondria have long been proposed to play an important role in the aging process. In the nematode Caenorhabditis elegans, genes important for mitochondrial electron transport chain (ETC) function stand out as a principal group of genes affecting life span. However, it has been suggested that this may be a peculiarity of nematode biology. In the present study, we have used an in vivo RNA interference (RNAi) strategy to inactivate ETC genes in Drosophila melanogaster and examine the impact on longevity. RESULTS: Here, we report that RNAi of five genes encoding components of mitochondrial respiratory complexes I, III, IV, and V leads to increased life span in flies. Long-lived flies with reduced expression of ETC genes do not consistently show reduced assembly of respiratory complexes or reduced ATP levels. In addition, extended longevity is not consistently correlated with reduced fertility or increased resistance to the free-radical generator paraquat. Targeted RNAi of two complex I genes in adult tissues or in neurons alone is sufficient to extend life span. CONCLUSIONS: Our data suggest that the role of mitochondrial ETC function in modulating animal aging is evolutionarily conserved and might also operate in humans. Furthermore, our findings suggest that the longer life span of flies with reduced ETC gene expression cannot simply be attributed to reduced energy production leading to decreased "rate of living."

Cocoa confers life span extension in Drosophila melanogaster.

Cocoa is thought to be an excellent source of antioxidants. Here, we investigated the effects of cocoa supplementation on Drosophila melanogaster life span under different oxidative stress conditions. Our results illustrate that a moderate supplementation of cocoa under normoxia increases the average life span, whereas, at higher concentrations, average life span is normal. Under hyperoxia or in a Cu/Zn-superoxide dismutase-deficient background, cocoa exhibited a strong antioxidant activity, significantly increasing the average life span. Nevertheless, cocoa supplementation in a Mn-superoxide dismutase-deficient background enhanced an earlier mortality accompanied by a loss of climbing ability, indicating that cocoa may act as a pro-oxidant in mitochondria under conditions of extreme oxidative stress. Finally, we illustrate that cocoa also acts as a metal chelator in the presence of excess heavy metals, enhancing larval survival to the adult stage on copper or iron-supplemented medium. Taken together, our results document the antioxidative, pro-oxidative, and metal-chelating effects of cocoa on Drosophila melanogaster life span.

Mutations of the withered (whd) gene in Drosophila melanogaster confer hypersensitivity to oxidative stress and are lesions of the carnitine palmitoyltransferase I (CPT I) gene.

Since some oxygen defense mutants of Drosophila melanogaster exhibit a crinkled wing phenotype, a screen was performed on strains bearing mutant alleles conferring a visible wing phenotype to determine whether any were hypersensitive to oxidative stress. One mutant, withered (whd), was found to be sensitive to both dietary paraquat and hyperoxia. New alleles of whd were induced on a defined genetic background and strains carrying these alleles were also found to be sensitive to oxidative stress. To identify the product of the whd gene we used a sequence-based positional candidate approach and by this method we determined that whd encodes carnitine palmitoyltransferase I (CPT I), an enzyme of the outer mitochondrial membrane that is required for the import of long-chain fatty acids into the mitochondria for beta-oxidation. Although this function is not vital under laboratory conditions, whd adults were found to be highly sensitive to starvation and to heavy metal toxicity relative to controls. This work uncovers a novel relationship between fatty acid metabolism and reactive oxygen metabolism. Further, these results in conjunction with past research on whd and on mammalian CPT I support the hypothesis that CPT I serves a vital function in the response to thymine supplementation.