Intracellular AIBP (Apolipoprotein A-I Binding Protein) Regulates Oxidized LDL (Low-Density Lipoprotein)-Induced Mitophagy in Macrophages.

OBJECTIVE: Atherosclerotic lesions are often characterized by accumulation of OxLDL (oxidized low-density lipoprotein), which is associated with vascular inflammation and lesion vulnerability to rupture. Extracellular AIBP (apolipoprotein A-I binding protein; encoded by APOA1BP gene), when secreted, promotes cholesterol efflux and regulates lipid rafts dynamics, but its role as an intracellular protein in mammalian cells remains unknown. The aim of this work was to determine the function of intracellular AIBP in macrophages exposed to OxLDL and in atherosclerotic lesions. Approach and Results: Using a novel monoclonal antibody against human and mouse AIBP, which are highly homologous, we demonstrated robust AIBP expression in human and mouse atherosclerotic lesions. We observed significantly reduced autophagy in bone marrow-derived macrophages, isolated from Apoa1bp-/- compared with wild-type mice, which were exposed to OxLDL. In atherosclerotic lesions from Apoa1bp-/- mice subjected to Ldlr knockdown and fed a Western diet, autophagy was reduced, whereas apoptosis was increased, when compared with that in wild-type mice. AIBP expression was necessary for efficient control of reactive oxygen species and cell death and for mitochondria quality control in macrophages exposed to OxLDL. Mitochondria-localized AIBP, via its N-terminal domain, associated with E3 ubiquitin-protein ligase PARK2 (Parkin), MFN (mitofusin)1, and MFN2, but not BNIP3 (Bcl2/adenovirus E1B 19-kDa-interacting protein-3), and regulated ubiquitination of MFN1 and MFN2, key components of mitophagy. CONCLUSIONS: These data suggest that intracellular AIBP is a new regulator of autophagy in macrophages. Mitochondria-localized AIBP augments mitophagy and participates in mitochondria quality control, protecting macrophages against cell death in the context of atherosclerosis.

VISUAL ACUITY IMPROVEMENT WHEN SWITCHING FROM RANIBIZUMAB TO AFLIBERCEPT IS NOT SUSTAINED.

PURPOSE: To assess whether visual benefits exist in switching to aflibercept in patients who have been chronically treated with ranibizumab for neovascular age-related macular degeneration. METHODS: A multicenter, national, electronic medical record database study was performed. Patients undergoing six continuous monthly ranibizumab injections and then switched to continuous aflibercept were matched to those on continuous ranibizumab therapy. Matching was performed in a 2:1 ratio and based on visual acuity 6 months before and at the time of the switch, and the number of previous ranibizumab injections. RESULTS: Patients who were switched to aflibercept demonstrated transiently significant improvement in visual acuity that peaked at an increase of 0.9 Early Treatment Diabetic Retinopathy Study letters 3 months after the switch, whereas control patients continued on ranibizumab treatment showed a steady decline in visual acuity. Visual acuity differences between the groups were significant (P < 0.05) at 2, 3, and 5 months after the switch. Beginning at 4 months after the switch, the switch group showed a visual acuity decline similar to the control group. CONCLUSION: Transient, nonsustained improvement in visual acuity occurs when switching between anti-vascular endothelial growth factor agents, which may have implications in treating patients on chronic maintenance therapy on one anti-vascular endothelial growth factor medication.

Evaluation of the effects of circular Descemet's membrane incision on the biomechanical, topographic and optical properties of rabbit corneas.

BACKGROUND: Prospective interventional animal case series to investigate quantitatively changes in corneal light-scattering, corneal hysteresis, keratometry and pachymetry induced by circular Descemet's membrane incision. METHODS: Thirty mature New Zealand White rabbits were divided into three study groups: (i) surgical intervention with circular Descemet's incision; (ii) surgical control; and (iii) medical control. Group 1 eyes had two paracenteses placed 120 degrees apart and an 8.5-mm-diameter Descemetorhexis was created with a reverse Sinskey hook. Group 2 eyes had two paracenteses placed 120 degrees apart. The main outcome measures were scatterometry, corneal hysteresis, pachymetry and keratometry measurements, which were performed prior to and 2 weeks following the interventions. Histology and transmission electron microscopy were performed post-mortem in representative eyes. RESULTS: Eyes that had undergone circular Descemet's incision had significantly decreased mean keratometry (43.9 ± 0.7 dioptres [mean ± standard deviation] preoperatively vs. 43.5 ± 0.9 dioptres postoperatively, P = 0.007). Circular Descemet's membrane incision did not significantly change corneal hysteresis (4.4 ± 1.1 mmHg preoperatively vs. 4.6 ± 0.9 mmHg postoperatively, P = 0.664). Corneal light scattering decreased after Descemet's scoring (0.00254 ± 0.00059 preoperatively vs. 0.00206 ± 0.00031 postoperatively, P = 0.0025). Pachymetry measurements remained relatively stable (341.3 ± 18.6 µm preoperatively vs. 330.6 ± 20.0 µm postoperatively) without postoperative oedema. CONCLUSIONS: Circular Descemet's scoring flattened the corneal curvature by a mean of 0.4 dioptres without affecting corneal hysteresis in rabbit corneas. These findings may have important implications for ongoing developments in endothelial keratoplasty.

Wavefront-guided customized corneal ablation.

PURPOSE OF REVIEW: This review highlights some of the advantages and limitations with our current wavefront technology and reviews the evidence supporting the efficacy and safety of wavefront-guided corneal ablations. RECENT FINDINGS: While older studies often assessed visual outcomes based upon visual acuity, recent studies incorporate more sensitive parameters to assess quality of vision and to better understand the impact of high-order aberrations. Recently, the US Food and Drug Administration approved wavefront-guided monovision for mild to moderate myopia. Advances in wavefront sensing and laser technology continue to improve outcomes with wavefront-guided corneal ablations in primary treatments and enhancements. In addition to ablations based upon mapping of total ocular aberrations, customized ablations that integrate topographical data appear to be promising. Lastly, femtosecond laser technology allows for flap creation that induces less change in high-order aberrations and corneal biomechanics. SUMMARY: Wavefront guided customized corneal ablations are safe, effective, and predictable. Compared with conventional treatments, wavefront-guided ablations can achieve a reduction in preexisting higher-order aberrations and less induction of new higher-order aberrations, resulting in improved outcomes with contrast sensitivity and visual symptoms under mesopic and scotopic conditions. Wavefront technology is still evolving to address current limitations and to optimize customization of corneal ablations.

Intraocular lens power calculation after corneal refractive surgery.

PURPOSE OF REVIEW: Corneal refractive procedures have become increasingly popular over the past decade, allowing patients to have excellent uncorrected visual acuity and spectacle independence. As these individuals mature, many will eventually undergo cataract surgery. With the advances in modern cataract surgery and lens implant technology, particularly presbyopic intraocular lens implants, patients and physicians have greater expectations regarding visual outcomes and independence from glasses after cataract surgery. Therefore, it is important to understand methods to accurately determine intraocular lens power calculation after keratorefractive procedures to avoid refractive surprises and patient dissatisfaction. RECENT FINDINGS: In this review article, we provide an overview of intraocular lens power determination after corneal refractive surgery, highlighting sources of errors and potential methods to improve the accuracy of the lens power estimation. SUMMARY: Newer methods to address errors in intraocular lens power calculations after keratorefractive surgery represent a paradigm shift from the previous gold standard of the clinical history method. Understanding the advantages and limitations of the various methods may be beneficial in obtaining more accurate estimations of the intraocular lens power after corneal refractive surgery, resulting in improved visual outcomes.

Hemorheologic abnormalities associated with HIV infection: altered erythrocyte aggregation and deformability.

PURPOSE: To investigate possible alterations of erythrocyte aggregation and deformability, which are factors that can influence blood flow, in human immunodeficiency virus (HIV)-infected individuals and to determine whether these factors are related to the severity of immunodeficiency. METHODS: Laboratory evaluations were performed on 46 HIV-infected individuals and 44 HIV-negative control subjects. Current and nadir (lowest previous) CD4+ T-lymphocyte counts were identified for each subject. Erythrocyte aggregation was measured using a fully automatic erythrocyte aggregometer. Factors related to erythrocyte aggregation were also determined: erythrocyte sedimentation rate (ESR), zeta sedimentation ratio (ZSR), and plasma fibrinogen levels. Erythrocyte deformability was observed at various fluid shear stress levels, with a laser diffraction ektacytometer. Correlations were sought between each of these measures and current or nadir CD4+ T-lymphocyte counts, and each measure was compared between three subgroups based on current and nadir CD4+ T-lymphocyte counts (severely immunosuppressed, immune reconstituted, never severely immunosuppressed). RESULTS: The following parameters were significantly different between HIV-infected subjects and controls: increased erythrocyte aggregation, at stasis (P < 0.001) and low shear stress (P < 0.001), increased ESR (P < 0.001), increased ZSR (P < 0.028), increased serum fibrinogen (P = 0.015), and decreased erythrocyte deformability (P < 0.001). Only erythrocyte aggregation at stasis correlated significantly with current CD4+ T-lymphocyte count (r = - 0.344, P = 0.022). None of the parameters was significantly different between HIV-infected subgroups. CONCLUSIONS: Increased aggregation and decreased deformability of erythrocytes are associated with HIV-infection regardless of the severity of immunodeficiency. HIV-infected individuals may be at risk for progressive retinal microvascular damage from persistent hemorheologic abnormalities, despite immune reconstitution associated with potent antiretroviral drug therapies.

Hemorheologic abnormalities associated with HIV infection: in vivo assessment of retinal microvascular blood flow.

PURPOSE: To evaluate retinal microvascular blood flow in human immunodeficiency virus (HIV)-infected individuals using scanning laser Doppler flowmetry (SLDF) and to seek correlations between flow and various laboratory measures that may predict alterations in flow. METHODS: The Heidelberg Retina Flowmeter and SLDF software were used to acquire in vivo retinal blood flow data from 24 HIV-infected individuals and 16 HIV-negative control subjects. In each subject, separate scans were performed in each of six retinal regions: nasal parapapillary retina; macula; and the superior, nasal, inferior, and temporal periphery. Erythrocyte aggregation (assessed in vitro by a fully automatic erythrocyte aggregometer and by zeta sedimentation ratio [ZSR, a hematocrit-independent sedimentation rate]), serum fibrinogen level, plasma viscosity, and leukocyte rigidity (assessed in vitro with a cell transit analyzer) were compared with flow in selected regions. RESULTS: Flow was significantly higher in the periphery (superior, nasal, inferior, temporal) than in the posterior retina (nasal parapapillary retina, macula). Flow was highest in the temporal periphery for both HIV-infected subjects and control subjects. Flow in the posterior retina was significantly lower in HIV-infected subjects than in control subjects (P < 0.0001). Among HIV-infected individuals, flow in the macula correlated negatively with ZSR (r = -0.397, P = 0.0547) and leukocyte rigidity (r = -0.505, P = 0.0119). CONCLUSIONS: Microvascular blood flow in the posterior retina is reduced in HIV-infected individuals. Both increased erythrocyte aggregation and increased leukocyte rigidity contribute to this hemorheologic abnormality.

Aqueous penetration of moxifloxacin 0.5% ophthalmic solution and besifloxacin 0.6% ophthalmic suspension in cataract surgery patients.

PURPOSE: To determine the aqueous humor concentrations of moxifloxacin and besifloxacin after routine preoperative topical dosing in patients having cataract surgery. SETTING: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. METHODS: In this prospective randomized parallel double-masked clinical trial, 1 drop of commercially available moxifloxacin 0.5% ophthalmic solution or besifloxacin 0.6% ophthalmic suspension was administered every 10 minutes for a total of 4 doses beginning 1 hour before routine cataract surgery. Aqueous humor was sampled via the paracentesis, and antibiotic concentrations were determined using validated high-performance liquid chromatography procedures. RESULTS: The study enrolled 50 patients. The aqueous concentration of the antibiotic agent was detectable in all 23 moxifloxacin samples and in 10 (40%) of the 25 besifloxacin samples (P<.0001, Pearson chi-square test). The mean aqueous concentration in the moxifloxacin samples was 50-fold higher than in the besifloxacin samples (1.6108 microg/mL versus 0.0319 microg/mL) when all samples were included (P<.0001, Wilcoxon test), while the moxifloxacin concentration was 38-fold higher than the besifloxacin concentration (1.6108 microg/mL versus 0.0422 microg/mL) in the samples with detectable antibiotic agent (P<.0001). CONCLUSIONS: After topical preoperative administration, moxifloxacin 0.5% ophthalmic solution had a 38-fold to 50-fold higher concentration in the aqueous humor than besifloxacin 0.6% ophthalmic suspension. Besifloxacin was undetectable in more than half the aqueous humor samples.