Dexamethasone Intracanalicular Insert versus Standard Topical Steroids for the Prophylaxis of Inflammation after Cataract Surgery.

PURPOSE: To compare the efficacy of an intracanalicular dexamethasone intracanalicular insert (DII) to a topical prednisolone acetate 1% taper for preventing breakthrough inflammation (iritis or cystoid macular edema [CME]) during the first postoperative month (POM1) after cataract surgery. DESIGN: Retrospective, nonrandomized comparative interventional study. METHODS: Patients received either DII or topical prednisolone acetate 1% eyedrops (control) during POM1. Exclusion criteria included history of iritis, glaucoma, intraoperative posterior capsular rupture or vitreous prolapse, immediate postoperative anterior chamber inflammation requiring treatment, or less than 1 month follow-up postoperatively. Outcomes included development of breakthrough inflammation after >3 days postoperatively necessitating additional antiinflammatory drops, CME, and increased intraocular pressure (IOP) at POM1. RESULTS: A total of 266 eyes of 174 patients were included in the DII group and 258 eyes of 167 patients in the control group. Demographics, comorbidities, and baseline IOP were comparable between groups. The breakthrough inflammation rate was significantly higher in the DII group compared to control (9.0% vs 3.1%; P < .01); CME rates were similar between groups (4.9% vs 4.3%; P = .75). There were no cases of increased IOP >10 mm Hg at POM1 compared to baseline in either group. CONCLUSIONS: After cataract surgery, DII demonstrated a higher rate of breakthrough inflammation than a standard topical steroid regimen with no significant differences in CME rate or IOP increase; however, overall, the rate of postoperative complications was low. DII can be a safe and effective alternative to topical corticosteroid therapy after cataract surgery.

Infectious and Noninfectious Corneal Ulcers in Ocular Graft-Versus-Host Disease: Epidemiology, Clinical Characteristics, and Outcomes.

PURPOSE: To evaluate the incidence, clinical characteristics, microbiological profile, and therapeutic outcomes of corneal ulcers in individuals with chronic ocular graft-vs-host disease (coGVHD). DESIGN: Retrospective clinical cohort study. METHODS: Review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021. Baseline demographics, clinical characteristics, microbiological profile, risk factors for corneal ulceration, and treatment outcomes were collected. Etiology was deemed infectious in individuals with a positive culture or appropriate clinical scenario (presence of stromal infiltrate or hypopyon); otherwise, ulcers were presumed to be noninfectious. Treatment success was defined as reepithelialization with infiltrate resolution, and treatment failure as progression to corneal perforation or keratoplasty. Kaplan-Meier survival analysis estimated the incidence of ulceration. Cox regression analyses examined demographic and risk factors. Infectious and noninfectious ulcer groups were compared using 2-way independent t tests, 1-way analysis of variances, and χ2 tests, as appropriate. RESULTS: 173 individuals were included (53.7±14.4 years old; 59.0% male). Thirty-three individuals developed an ulcer 74.5±54.3 months after HSCT, with estimated 5- and 10-year incidences of 14% and 30%, respectively. Twenty-two (66.6%) ulcers were deemed infectious (15 microbiologically confirmed, 7 clinically) and 11 (33.3%) were deemed noninfectious. Risk factors for corneal ulceration included Black race (hazards ratio [HR] 2.89, 95% CI 1.30-6.42, P < .01), previous ocular surgery (HR 9.16, 95% CI 3.86-21.72, P < .01), eyelid margin abnormalities (HR 3.44, 95% CI 1.69-6.99, P < .01), and topical steroid use (HR 2.74, 95% CI 1.33-5.62, P < .01). Conversely, contact lens use reduced the risk of corneal ulceration (HR 0.29, 95% CI 0.13-0.66, P < .01). Infectious ulcers had a significantly higher frequency of treatment failure than noninfectious ulcers (57.1% vs 20.0%, P = .04). CONCLUSION: Corneal ulceration is a potential complication of coGVHD, with several clinical features identified as risk factors. Infectious ulcers had worse outcomes than noninfectious ulcers.

Intraocular Lens Power Calculations in Keratoconus Eyes Comparing Keratometry, Total Keratometry, and Newer Formulae.

PURPOSE: To compare the utility of keratometry vs total keratometry (TK) for intraocular lens power calculations in eyes with keratoconus (KCN) using KCN and non-KCN formulae. DESIGN: Retrospective cohort study. METHODS: This study was conducted at 2 academic centers and included 87 eyes in 67 patients who underwent cataract surgery between 2019 and 2021. Biometry measurements were obtained using a swept-source optical coherence tomography biometer (IOL Master 700). Refractive prediction errors, including root mean square error (RMSE), were calculated for 13 formulae. These included 4 classical formulae (Haigis, Hoffer Q, Holladay 1 [H1], and SRK/T), 5 new formulae (NF) (Barrett Universal II [BU2], Cooke K6, EVO 2.0, Kane, and Pearl-DGS), 3 KCN formulae (BU2 KCN: M-PCA, BU2 KCN: P-PCA, and Kane KCN), and H1 with equivalent keratometry reading values (H1-EKR). Formulae were ranked by RMSE. Friedman analysis of variance with post hoc analysis and H-testing was used for statistical significance testing. RESULTS: KCN formulae had the lowest RMSEs in all eyes, and BU2 KCN:M-PCA performed the best among KCN formulae in all subgroups. In eyes with severe KCN, if TK values are unavailable, the BU2 KCN: P-PCA performed better than the top-ranked non-KCN formula (SRK/T). In eyes with nonsevere KCN, if TK values are unavailable, EVO 2.0 K was statistically superior to the next competitor (Kane K). H1-EKR had the highest RMSE. CONCLUSIONS: KCN formulae and TK are useful for intraocular lens power calculations in KCN eyes, especially in eyes with severe KCN. The BU2 KCN: M-PCA using TK values performed best for eyes with all severities of KCN. For eyes with nonsevere KCN, the EVO 2.0 TK or K can also be used.

Combined Therapeutic Penetrating Keratoplasty and Pars Plana Vitrectomy for the Treatment of Infectious Keratitis Endophthalmitis: Mexican Endophthalmitis Study Group Protocol 4.

PURPOSE: The purpose of this study was to assess the role of combined surgical treatment of therapeutic penetrating keratoplasty and pars plana vitrectomy in the anatomical and functional outcome of infectious keratitis endophthalmitis. METHODS: This study reviewed the medical records of 4 participating centers in the United States and Mexico. This study included patients with a clinical diagnosis of infectious keratitis endophthalmitis who had been treated with an early therapeutic penetrating keratoplasty and pars plana vitrectomy as the main treatment for endophthalmitis. From each medical record, the study retrieved demographic data, relevant medical and drug history, baseline clinical manifestation of endophthalmitis, best-corrected visual acuity, and the need for enucleation/evisceration for the control of the infection or any other reason through the follow-up. RESULTS: The study included 48 patients (50.15 ± 20.6 years). The mean follow-up time was 13 ± 0.5 months. The mean best-corrected visual acuity at baseline was 2.1 ± 0.25 logarithm of the minimum angle of resolution. At month 12 was 2.09 ± 0.61 logarithm of the minimum angle of resolution ( P = 0.9). The overall prevalence of enucleation/evisceration was 8.3% (95% confidence interval: 2.32%-19.98%). The prevalence of a vision of no-light perception was 20.8% (95% confidence interval: 2.32%-19.98%). CONCLUSIONS: Combined surgery for severe cases of infectious keratitis endophthalmitis eradicates the infection in most cases, while significantly improving the overall outcomes.

Long-Term Comprehensive Management of Bilateral Limbal Stem Cell Deficiency Secondary to Severe Chemical Burn: 10 Years of Follow-Up.

PURPOSE: To describe the long-term management of bilateral limbal stem cell deficiency secondary to a severe chemical burn. METHODS: Descriptive case report. IMPORTANCE: This case highlights the importance of early intervention in ocular chemical burns for the preservation of tissue integrity and avoidance of perforation. We also review the use of proper ocular surface reconstructive techniques to restore the function of the limbal area, as well as the immunomodulatory strategies and follow-up needed for these interventions.

Risk and Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Infection on Corneal Transplantation: A Case-Control Study.

PURPOSE: The purpose of this study was to evaluate the risk of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after corneal transplantation surgery, with cataract surgeries as controls, and the impact of the novel coronavirus disease pandemic in the clinical and surgical complications of corneal transplantation and cataract surgeries. METHODS: A retrospective matched case-control study of 480 consecutive individuals who underwent surgery at the Bascom Palmer Eye Institute between May 2020 and November 2020. A total of 240 patients who underwent corneal transplantation with tissue obtained from the Florida Lions Eye Bank were age, race, ethnicity, and sex matched with 240 patients who underwent cataract surgery during the same day and by the same surgical team. Only the first corneal transplant or cataract surgery during this period was considered for each individual. All donors and recipients were deemed SARS-CoV-2 negative by a nasopharyngeal polymerase chain reaction test before surgery. Postoperative SARS-CoV-2 infections were defined as previously SARS-CoV-2(-) individuals who developed symptoms or had a positive SARS-CoV-2 polymerase chain reaction test during the first postoperative month. RESULTS: Mean age, sex, race, and ethnicity were similar between groups. There were no differences between the corneal transplant and cataract groups in the rates of SARS-CoV-2 infection before (5.8% vs. 7.5%, P= 0.6) or after surgery (2.9% vs. 2.9%, P = 1). The rates of postoperative complications did not increase during the pandemic, compared with previously reported ranges. CONCLUSIONS: In this study, postoperative SARS-CoV-2 infection was similar for individuals undergoing corneal transplantation or cataract surgery. Further research is required to evaluate the transmission of SARS-CoV-2 through corneal tissue.

Considerations for Corneal Surgery With Patients in the 10th Decade of Life.

PURPOSE: The purpose of this study was to report the indications, ocular and systemic comorbidities, and surgical outcomes of corneal transplantation in patients older than 90 years. METHODS: A retrospective review was conducted to identify individuals 90 years and older who underwent corneal transplantation surgery at the Bascom Palmer Eye Institute between January 2013 and October 2020. Outcomes included best-corrected visual acuity and graft survival over time. Paired t tests were used to compare visual acuity preoperatively versus postoperatively. Graft survival was evaluated with Kaplan-Meier curves. RESULTS: Fifty-eight eyes of 52 consecutive individuals were included. The mean age of individuals was 92 ± 2 years; 26.9% were male; and 48.1% self-identified as non-Hispanic White and 38.5% as Hispanic. Postoperative follow-up was 14.7 ± 12.1 months. Of the 58 eyes, 44.8% (26/58) underwent penetrating keratoplasty, 46.6% (27/58) Descemet stripping automated endothelial keratoplasty, and 6.9% (4/58) keratoprosthesis. All surgeries were performed under monitored local anesthesia, without major complications. Surgical indications included pseudophakic bullous keratopathy (36.2%), glaucoma-associated corneal decompensation (27.6%), Fuchs endothelial dystrophy (25.9%), and perforated corneal ulceration (19.0%). The best-corrected visual acuity improved by 0.32 (95% confidence interval 0.14-0.50; P < 0.01) as early as 1 month postoperatively, and vision gains were sustained for at least 12 months. Graft survival probability at 12 months was 88%. CONCLUSIONS: Corneal transplantation is a safe and successful procedure in restoring the visual acuity for patients older than 90 years after careful preoperative evaluation. Further research is needed to evaluate the impact of corneal transplantation on quality of life in patients in the 10th decade of life.

Extra-virgin olive oil attenuates amyloid-ß and tau pathologies in the brains of TgSwDI mice.

Extra-virgin olive oil (EVOO) is one of the main elements of Mediterranean diet. Several studies have suggested that EVOO has several health promoting effects that could protect from and decrease the risk of Alzheimer's disease (AD). In this study, we investigated the effect of consumption of EVOO-enriched diet on amyloid- and tau-related pathological alterations that are associated with the progression of AD and cerebral amyloid angiopathy (CAA) in TgSwDI mice. Feeding mice with EVOO-enriched diet for 6months, beginning at an age before amyloid-ß (Aß) accumulation starts, has significantly reduced total Aß and tau brain levels with a significant improvement in mouse cognitive behavior. This reduction in brain Aß was explained by the enhanced Aß clearance pathways and reduced brain production of Aß via modulation of amyloid-ß precursor protein processing. On the other hand, although feeding mice with EVOO-enriched diet for 3months, beginning at an age after Aß accumulation starts, showed improved clearance across the blood-brain barrier and significant reduction in Aß levels, it did not affect tau levels or improve cognitive functions of TgSwDI mouse. Collectively, results of this study suggest that the long-term consumption of EVOO-containing diet starting at early age provides a protective effect against AD and its related disorder CAA.

Tritium-labeled (E,E)-2,5-bis(4'-hydroxy-3'-carboxystyryl)benzene as a probe for ß-amyloid fibrils.

Accumulation of Aß in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aß production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aß40 and Aß42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research. Radiolabeled probes for the detection of amyloid plaques and fibrils in living subjects are important for noninvasive evaluation of AD diagnosis, progression, and differentiation of AD from other neurodegenerative diseases and age-related cognitive decline. Tritium-labeled (E,E)-1-[(3)H]-2,5-bis(4'-hydroxy-3'-carbomethoxystyryl)benzene possesses an improved level of chemical stability relative to a previously reported radioiodinated analog for radiometric quantification of Aß plaque and tau pathology in brain tissue and in vitro studies with synthetic Aß and tau fibrils.

Exogenous seeding of cerebral ß-amyloid deposition in ßAPP-transgenic rats.

Deposition of the amyloid-ß (Aß) peptide in senile plaques and cerebral Aß angiopathy (CAA) can be stimulated in Aß-precursor protein (APP)-transgenic mice by the intracerebral injection of dilute brain extracts containing aggregated Aß seeds. Growing evidence implicates a prion-like mechanism of corruptive protein templating in this phenomenon, in which aggregated Aß itself is the seed. Unlike prion disease, which can be induced de novo in animals that are unlikely to spontaneously develop the disease, previous experiments with Aß seeding have employed animal models that, as they age, eventually will generate Aß lesions in the absence of seeding. In the present study, we first established that a transgenic rat model expressing human APP (APP21 line) does not manifest endogenous deposits of Aß within the course of its median lifespan (30 months). Next, we injected 3-month-old APP21 rats intrahippocampally with dilute Alzheimer brain extracts containing aggregated Aß. After a 9-month incubation period, these rats had developed senile plaques and CAA in the injected hippocampus, whereas control rats remained free of such lesions. These findings underscore the co-dependence of agent and host in governing seeded protein aggregation, and show that cerebral Aß-amyloidosis can be induced even in animals that are relatively refractory to the spontaneous origination of parenchymal and vascular deposits of Aß.

Dihydroxybenzoic acid isomers differentially dissociate soluble biotinyl-Aß(1-42) oligomers.

Polyphenolic compounds including a number of natural products such as resveratrol, curcumin, catechin derivatives, and nordihydroguaiaretic acid have effects on the assembly of Aß fibrils and oligomers as well as on fibril morphology. Based on a lead structure obtained from a screen of a small molecule diversity library, simple benzoic acid derivatives distinguished by the number and position of hydroxyls on the aromatic ring displayed different abilities to dissociate preformed biotinyl-Aß(1-42) oligomers. The 2,3-, 2,5-, and 3,4-dihydroxybenzoic acid (DHBA) isomers were active oligomer dissociators. The remaining DHBA isomers and the monohydroxy and unsubstituted benzoic acids were inactive and did not compete with the active compounds to block oligomer dissociation. None of the compounds blocked oligomer assembly, indicating that they do not interact with monomeric Aß to shift the oligomer-monomer equilibrium. Dissociating activity was not associated with quinone redox cycling capacity of the compounds. Gallic acid (3,4,5-trihydroxybenzoic acid) stabilized biotinyl-Aß(1-42) oligomers against intrinsic dissociation and blocked the effects of the active dissociators, independent of the concentration of dissociator. A model for the mechanism of action of the DHBA dissociators proposes that these compounds destabilize oligomer structure promoting progressive monomer dissociation rather than fissioning oligomers into smaller, but still macromolecular, species. Gallic acid blocks dissociation by stabilizing oligomers against this process.

Purified high molecular weight synthetic Aß(1-42) and biological Aß oligomers are equipotent in rapidly inducing MTT formazan exocytosis.

Synthetic soluble Aß oligomers are often used as a surrogate for biologic material in a number of model systems. We compared the activity of Aß oligomers (synthetic and cell culture media derived) on the human SH-SY5Y neuroblastoma and C2C12 mouse myoblast cell lines in a novel, modified MTT assay. Separating oligomers from monomeric peptide by size exclusion chromatography produced effects at peptide concentrations approaching physiologic levels (10-100 nM). Purified oligomers, but not monomers or fibrils, elicited an increase of a detergent-insoluble form of MTT formazan within 2h as opposed to a control toxin (H(2)O(2)). This effect was comparable for biological and synthetic peptide in both cell types. Monomeric Aß attenuated the effect of soluble oligomers. This study suggests that the activities of biological and synthetic oligomers are indistinguishable during early stages of Aß oligomer-cell interaction.

PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease.

Aged nonhuman primates accumulate large amounts of human-sequence amyloid ß (Aß) in the brain, yet they do not manifest the full phenotype of Alzheimer's disease (AD). To assess the biophysical properties of Aß that might govern its pathogenic potential in humans and nonhuman primates, we incubated the benzothiazole imaging agent Pittsburgh Compound B (PIB) with cortical tissue homogenates from normal aged humans, humans with AD, and from aged squirrel monkeys, rhesus monkeys, and chimpanzees with cerebral Aß-amyloidosis. Relative to humans with AD, high-affinity PIB binding is markedly reduced in cortical extracts from aged nonhuman primates containing levels of insoluble Aß similar to those in AD. The high-affinity binding of PIB may be selective for a pathologic, human-specific conformation of multimeric Aß, and thus could be a useful experimental tool for clarifying the unique predisposition of humans to Alzheimer's disease.

Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral beta-amyloid (Abeta) in patients with Alzheimer's disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer's disease with heavy Abeta deposition yet substantially diminished high-affinity binding of (3)H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro (3)H-PIB binding and (3)H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular beta-amyloidosis, higher levels of insoluble Abeta40 and Abeta42, and a higher ratio of Abeta40:Abeta42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Abeta from the PIB-refractory subject displayed an unusual distribution of low- and high-molecular weight Abeta oligomers, as well as a distinct pattern of N- and C-terminally truncated Abeta peptides in both the soluble and insoluble cortical extracts. Genetically, the patient was apolipoprotein-E3/4 heterozygous, and exhibited no known AD-associated mutations in the genes for the beta-amyloid precursor protein, presenilin1 or presenilin2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Abeta in humans with Alzheimer's disease. In addition, while the prevalence of PIB-refractory cases in the general AD population remains to be determined, the paucity of high-affinity binding sites in this AD case cautions that minimal PIB retention in positron-emission tomography scans of demented patients may not always rule out the presence of Alzheimer-type Abeta pathology.

NOX activity is increased in mild cognitive impairment.

This study was undertaken to investigate the profile of NADPH oxidase (NOX) in the clinical progression of Alzheimer's disease (AD). Specifically, NOX activity and expression of the regulatory subunit p47phox and the catalytic subunit gp91phox was evaluated in affected (superior and middle temporal gyri) and unaffected (cerebellum) brain regions from a longitudinally followed group of patients. This group included both control and late-stage AD subjects, and also subjects with preclinical AD and with amnestic mild cognitive impairment (MCI) to evaluate the profile of NOX in the earliest stages of dementia. Data show significant elevations in NOX activity and expression in the temporal gyri of MCI patients as compared with controls, but not in preclinical or late-stage AD samples, and not in the cerebellum. Immunohistochemical evaluations of NOX expression indicate that whereas microglia express high levels of gp91phox, moderate levels of gp91phox also are expressed in neurons. Finally, in vitro experiments showed that NOX inhibition blunted the ability of oligomeric amyloid beta peptides to injure cultured neurons. Collectively, these data show that NOX expression and activity are upregulated specifically in a vulnerable brain region of MCI patients, and suggest that increases in NOX-associated redox pathways in neurons might participate in the early pathogenesis of AD.

The synthesis and structure-activity relationship of substituted N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors.

It is believed that beta-amyloid aggregation is an important event in the development of Alzheimer's disease. In the course of our studies to identify beta-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for beta-amyloid inhibition activity. The synthesis, structure-activity relationship, and in vivo activity of these analogs are discussed.

Small molecule inhibitors of Abeta assembly.

The Abeta peptide assembles into a variety of distinct types of structures in vitro and in the brain which have different biological consequences. Differential effects of inhibitory small molecules suggest that a sequential monomer - oligomer - fibril mechanism is overly simplistic and that soluble toxic oligomers and fibrils can be formed in common or separate pathways depending on the local environment. As a result, the effects of inhibitors are often assay-dependent because multiple pathways are operating. This review discusses strategies for teasing apart the intricate protein-protein interactions that result in Abeta assembly.

Inducible proteopathies.

Numerous degenerative diseases are characterized by the aberrant polymerization and accumulation of specific proteins. These proteopathies include neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and the prion diseases, in addition to diverse systemic disorders, particularly the amyloidoses. The prion diseases have been shown to be transmissible by an alternative conformation of the normal cellular prion protein. Other proteopathies have been thought to be non-transmissible, but there is growing evidence that some systemic and cerebral amyloidoses can be induced by exposure of susceptible hosts to cognate molecular templates. As we review here, the mechanistic similarities among these diseases provide unprecedented opportunities for elucidating the induction of protein misfolding and assembly in vivo, and for developing an integrated therapeutic approach to degenerative proteopathies.

Koch's postulates and infectious proteins.

Koch's postulates were formulated in the late nineteenth century as guidelines for establishing that microbes cause specific diseases. Because the rules were developed for living agents--particularly bacteria--their applicability to inanimate pathogens such as viruses and infectious proteins has been problematic. The unorthodox mechanism by which prion diseases are transmitted, involving specific physicochemical characteristics of the protein as well as susceptibility traits of the host, has made these disorders refractory to analysis within the context of the original Koch's postulates. In addition, evidence is accumulating that other proteopathies, such as AA amyloidosis, apolipoprotein AII amyloidosis, and cerebral Abeta amyloidosis, can be induced in vulnerable recipients by cognate proteinaceous agents. In light of the salient differences in the mode of disease-transmission by microbes and proteins, we propose modifications of Koch's postulates that will specifically accommodate presumed infectious proteins.