Selection of Silica Type and Amount for Flowability Enhancements via Dry Coating: Contact Mechanics Based Predictive Approach.

PURPOSE: To investigate the effect of dry coating the amount and type of silica on powder flowability enhancement using a comprehensive set of 19 pharmaceutical powders having different sizes, surface roughness, morphology, and aspect ratios, as well as assess flow predictability via Bond number estimated using a mechanistic multi-asperity particle contact model. METHOD: Particle size, shape, density, surface energy and area, SEM-based morphology, and FFC were assessed for all powders. Hydrophobic (R972P) or hydrophilic (A200) nano-silica were dry coated for each powder at 25%, 50%, and 100% surface area coverage (SAC). Flow predictability was assessed via particle size and Bond number. RESULTS: Nearly maximal flow enhancement, one or more flow category, was observed for all powders at 50% SAC of either type of silica, equivalent to 1 wt% or less for both the hydrophobic R972P or hydrophilic A200, while R972P generally performed slightly better. Silica amount as SAC better helped understand the relative performance. The power-law relation between FFC and Bond number was observed. CONCLUSION: Significant flow enhancements were achieved at 50% SAC, validating previous models. Most uncoated very cohesive powders improved by two flow categories, attaining easy flow. Flowability could not be predicted for both the uncoated and dry coated powders via particle size alone. Prediction was significantly better using Bond number computed via the mechanistic multi-asperity particle contact model accounting for the particle size, surface energy, roughness, and the amount and type of silica. The widely accepted 200 nm surface roughness was not valid for most pharmaceutical powders.

Impact of Silica Dry Coprocessing with API and Blend Mixing Time on Blend Flowability and Drug Content Uniformity.

This paper considers two fine-sized (d50 ∼10 µm) model drugs, acetaminophen (mAPAP) and ibuprofen (Ibu), to examine the effect of API dry coprocessing on their multi-component medium DL (30 wt%) blends with fine excipients. The impact of blend mixing time on the bulk properties such as flowability, bulk density, and agglomeration was studied. The hypothesis tested is that blends with fine APIs at medium DL require good blend flowability to have good blend uniformity (BU). Moreover, the good flowability could be achieved through dry coating with hydrophobic (R972P) silica, which reduces agglomeration of not only fine API, but also of its blends while using fine excipients. For uncoated APIs, the blend flowability was poor, i.e. cohesive regime at all mixing times, and the blends failed to achieve acceptable BU. In contrast, for dry coated APIs, their blend flowability improved to easy-flow regime or better, improving with mixing time, and as hypothesized, all blends consequently achieved desired BU. All dry coated API blends exhibited improved bulk density and reduced agglomeration, attributed to mixing induced synergistic property enhancements, likely due to silica transfer. Despite coating with hydrophobic silica, tablet dissolution was improved, attributed to the reduced agglomeration of fine API.

Enhanced blend uniformity and flowability of low drug loaded fine API blends via dry coating: The effect of mixing time and excipient size.

Although previous research demonstrated improved flowability, packing, fluidization, etc. of individual powders via nanoparticle dry coating, none considered its impact on very low drug loaded blends. Here, fine ibuprofen at 1, 3, and 5 wt% drug loadings (DL) was used in multi-component blends to examine the impact of the excipients size, dry coating with hydrophilic or hydrophobic silica, and mixing times on the blend uniformity, flowability and drug release rates. For uncoated active pharmaceutical ingredients (API), the blend uniformity (BU) was poor for all blends regardless of the excipient size and mixing time. In contrast, for dry coated API having low agglomerate ratio (AR), BU was dramatically improved, more so for the fine excipient blends, at lesser mixing times. For dry coated API, the fine excipient blends mixed for 30 min had enhanced flowability and lower AR; better for the lowest DL having lesser silica, likely due to mixing induced synergy of silica redistribution. For the fine excipient tablets, dry coating led to fast API release rates even with hydrophobic silica coating. Remarkably, the low AR of the dry coated API even at very low DL and amounts of silica in the blend led to the enhanced blend uniformity, flow, and API release rate.

Disturbance of lipid metabolism in germ-free mice transplanted with gut microbiota of DSS-induced colitis mice.

Hepatobiliary abnormality and metabolic disorders are frequently observed complications in patients with inflammatory bowel diseases (IBD). Given that microbiota dysbiosis is a common pathophysiological feature of both IBD and metabolic diseases, we examined how the IBD-induced dysbiosis affects the host metabolism and contributes to the development of associated metabolic diseases using germ-free (GF) mice transplanted with fecal microbiota of DSS-induced colitis mice. There was no significant change in inflammation or barrier integrity in the gut of GF mice that received microbiota from colitis mice compared to their counterparts that were transplanted with microbiota from non-colitis healthy mice. Interestingly, it was observed that the GF recipients of colitis-induced altered microbiota showed a significant decrease in the weight of adipose tissues including mesenteric, epididymal, subcutaneous, and brown fat without any change in body weight, which was accompanied by abnormalities in adipose tissue functions such as fat storage and adiponectin production. Transplantation of colitis-induced altered microbiota also disrupted hepatic lipid metabolism in the GF recipient mice, which was observed by increases in synthesis and accumulation of cholesterol and bile acids in hepatocytes and a decrease in plasma HDL-cholesterol. Additional observations including elevated plasma levels of insulin, decreased hepatic production of FGF21, and decreased levels of fecal short chain fatty acids (SCFAs) and hepatic expression of SCFA receptors led to a conclusion that the transplantation of the colitis-associated dysbiotic microbiota was causally associated with impairments of insulin action and FGF21-adiponectin axis, possibly due to the low SCFA-producing capacity of the colonized microbiota, leading to metabolic abnormalities including adipose tissue dysfunction and dysregulated hepatic lipid metabolism. Our findings suggest potential mechanisms that explain how colitis-associated gut dysbiosis may contribute to the development of metabolic dysfunctions, which could be applied to clinical practice to improve the efficacy of treatment of IBD patients with comorbid metabolic disorders or vice versa.

Reduced Fine API Agglomeration After Dry Coating for Enhanced Blend Uniformity and Processability of Low Drug Loaded Blends.

PURPOSE: The impact of dry coating on reduced API agglomeration remains underexplored. Therefore, this work quantified fine cohesive API agglomeration reduction through dry coating and its impact on enhanced blend uniformity and processability, i.e., flowability and bulk density of multi-component blends API loading as low as 1 wt%. METHODS: The impact of dry coating with two different types and amounts of silica was assessed on cohesion, agglomeration, flowability, bulk density, wettability, and surface energy of fine milled ibuprofen (~ 10 µm). API agglomeration, measured using Gradis/QicPic employing gentler gravity-based dispersion, resulted in excellent size resolution. Multi-component blends with fine-sized excipients, selected for reduced segregation potential, were tested for bulk density, cohesion, flowability, and blend content uniformity. Tablets formed using these blends were tested for tensile strength and dissolution. RESULT: All dry coated ibuprofen powders exhibited dramatic agglomeration reduction, corroborated by corresponding decreased cohesion, unconfined yield strength, and improved flowability, regardless of the type and amount of silica coating. Their blends exhibited profound enhancement in flowability and bulk density even at low API loadings, as well as the content uniformity for the lowest drug loading. Moreover, hydrophobic silica coating improved drug dissolution rate without appreciably reducing tablet tensile strength. CONCLUSION: The dry coating based reduced agglomeration of fine APIs for all three low drug loadings improved overall blend properties (uniformity, flowability, API release rate) due to the synergistic impact of a minute amount of silica (0.007 wt %), potentially enabling direct compression tableting and aiding manufacturing of other forms of solid dosing.

Decoding Fine API Agglomeration as a Key Indicator of Powder Flowability and Dissolution: Impact of Particle Engineering.

PURPOSE: Fine API agglomeration and its mitigation via particle engineering, i.e., dry coating, remains underexplored. The purpose was to investigate agglomeration before and after dry coating of fine cohesive APIs and impact on powder processability, i.e., flowability (FFC), bulk density (BD), and dissolution of BCS Class II drugs. METHOD: Ibuprofen (three sizes), fenofibrate, and griseofulvin (5-20 µm), before and after dry coating with varying amounts of hydrophobic (R972P) or hydrophilic (A200) nano- silica, were assessed for agglomeration, FFC, BD, surface energy, wettability, and dissolution. The granular Bond number (Bog), a dimensionless parameter, evaluated through material-sparing particle-scale measures and particle-contact models, was used to express relative powder cohesion. RESULTS: Significant powder processability improvements after dry coating were observed: FFC increased by multiple flow regimes, BD increased by 25-100%, agglomerate ratio (AR) reduction by over an order of magnitude, and greatly enhanced API dissolution rate even with hydrophobic (R972P) silica coating. Scrutiny of particle-contact models revealed non-triviality in estimating API surface roughness, which was managed through the assessment of measured bulk properties. A power-law correlation was identified between AR and Bog and subsequently, between AR and FFC & bulk density; AR below 5 ensured improved processability and dissolution. CONCLUSION: Agglomeration, an overlooked material-sparing measure for powder cohesiveness, was a key indicator of powder processability and dissolution. The significant agglomerate reduction was possible via dry coating with either silica type at adequate surface area coverage. Reduced agglomeration after dry coating also countered the adverse impact of increased surface hydrophobicity on dissolution.

Effects of Glaucoma Medication on Dry Eye Syndrome and Quality of Life in Patients with Glaucoma.

PURPOSE: To investigate ocular surface diseases and changes in the quality of life of patients using glaucoma medications. METHODS: Participants were divided into the normal (31 individuals, 62 eyes) and glaucoma medication (30 patients, 60 eyes) groups. Changes in tear break-up time, lipid layer thickness (LLT), corneal and conjunctival staining scores, ocular surface disease index (OSDI), and Visual Function Questionnaire 25 (VFQ-25) score were assessed for 1 year. RESULTS: The change in mean LLT was lower in glaucomatous eyes than in control eyes (p = 0.019) after 1 year. The results of OSDI deteriorated (p' = 0.008), but conjunctival staining and Schirmer test results showed improvement in glaucomatous eyes compared to those in control eyes (p' =0.035 and 0.009, respectively). The average LLT decreased at 6 and 12 months, but there was no change at 24 months. In pairwise analysis, the decrease in LLT over the first 6 months was statistically significant (p < 0.001) and remained unchanged until 24 months. Among the VFQ items, scores for near activity and social function deteriorated over 1 year in the medication group (p' = 0.033 and 0.015, respectively). However, there was no difference in the total VFQ score. CONCLUSIONS: Significant reduction in LLT and deterioration of OSDI were observed in the medication group compared to the control group. However, this deterioration was observed only in the first 6 months. There was no significant difference in the VFQ total score. Nonetheless, there were significant differences in near activity and social function between the control and medication groups. Therefore, the results of this study showed that although glaucoma medication worsened eye dryness, the change was limited and did not worsen the quality of life. Glaucoma medication should be used with the consideration that they can limit near activity and social functioning.

Impact of altered hydrophobicity and reduced agglomeration on dissolution of micronized poorly water-soluble drug powders after dry coating.

The impact of dry coating with hydrophobic or hydrophilic nano-silica at 25-100% surface area coverage on dissolution of micronized poorly water-soluble drugs was investigated by examining their agglomeration and surface hydrophobicity. Ibuprofen (20 µm and 10 µm) and griseofulvin (10 µm) were selected having differing solubility, hydrophobicity, and surface morphology. Characterization involved particle agglomeration via two dry dispersion methods, drug dissolution using the USP IV method, cohesion reduction through shear testing, and powder wettability via the modified Washburn method. Dry coating dramatically reduced the cohesion hence agglomerate size of both the coated ibuprofen particles, but less for griseofulvin, attributed to its surface morphology. For hydrophobic silica, agglomerate size reduction outweighed the adverse impact of increased surface hydrophobicity for ibuprofen. For griseofulvin, the agglomerate reduction was much lower, not able to overcome the effect of increased drug particle hydrophobicity with hydrophobic silica coating. Hydrophilic silica coating reduced hydrophobicity for all three drug powders, leading to the synergistic improvement in the dissolution along with agglomerate size reduction. Overall, the combined effect of the drug particle surface hydrophobicity and agglomerate size, represented by specific surface area, could explain the dissolution behavior of these poorly water-soluble drugs.

Efficacy and Safety of Preservative-free Latanoprost Eyedrops Compared with Preserved Prostaglandin Analogues in Patients with Open-angle Glaucoma.

PURPOSE: To evaluate the safety and efficacy of preservative-free (PF) latanoprost in glaucoma patients. METHODS: In this prospective, open-label, observational study, a total of 27 primary open-angle glaucoma patients who used benzalkonium chloride-preserved prostaglandin analogues for at least 6 months were enrolled. After changing the eye drops to PF lataprost, the intraocular pressure (IOP) and ocular surface symptoms and signs were evaluated in all patients on days 0 (first visit, D0), 45 (D45), and 90 (D90). RESULTS: Mean IOP remained stable during the study period (14.0 ± 2.4 mmHg at D0, 13.9 ± 2.0 mmHg at D45, 13.7 ± 2.2 mmHg at D90; p = 0.603). Mean deviation, pattern standard deviation, and best-corrected visual acuity were similar before and after eye drops replacement. Bulbar conjunctival hyperemia, corneal staining, and conjunctival staining were significantly decreased over 90 days (p = 0.025, p < 0.001, p = 0.020, respectively). The ocular surface disease index score showed a statistically significant improvement from 26.4 ± 18.5 at D0 to 19.8 ± 17.0 at D45 and 15.7 ± 15.6 at D90 (p < 0.001). In the evaluation of ocular tolerability, burning symptoms and dryness were significantly decreased (p = 0.001, p = 0.040). CONCLUSIONS: The effects of PF latanoprost on reducing IOP were comparable with those of benzalkonium chloride-preserved prostaglandin analogues, but side effects on the ocular surface were much less pronounced when PF latanoprost was used. With this efficacy, PF latanoprost could slow the progression of glaucoma by increasing patient compliance.

Effect of systemic blood pressure on optical coherence tomography angiography in glaucoma patients.

BACKGROUND: The association between retinal microvascular structure and glaucoma has been revealed in multiple studies using optical tomography angiography (OCTA), but limited information on the macular vessel density (mVD) in patients with glaucoma is available. In this study, we tried to identity the factors that affected macular VD (mVD) in glaucomatous eyes. METHODS: This retrospective cross-sectional study evaluated OCT and OCTA images from 92 eyes from 58 healthy subjects and 179 eyes from 103 glaucoma patients using the SD-OCT database from July 2017 to July 2018. Glaucomatous eyes were further divided into two groups according to history of disc haemorrhage (DH). Association between mVD and demographic characteristics, ganglion cell-inner plexiform layer (GCIPL) thickness, visual field mean deviation (MD) and systemic blood pressure was analysed in each group. RESULTS: In both healthy and glaucomatous eyes, mVD was inversely associated with age (ß = -0.035, P = 0.025; ß = -0.039, P = 0.018). In the glaucomatous eyes, mVD was significantly decreased, as the MD value was worse (ß = 0.109, P = 0.002). In glaucomatous eyes with DH, mVD decreased as blood pressure increased (ß = -0.111, P = 0.003) CONCLUSIONS: Reduced mVD is more common in older individuals in both healthy and glaucomatous eyes, and correlates with functional deterioration than structural damage in glaucomatous eyes. In glaucomatous eyes with DH, high systemic BP is associated with a reduction in mVD. This may indicate that glaucoma patients with DH are more susceptible to vascular damage secondary to hypertension.

Development of a nomogram using fundus photography to predict glaucoma progression in patients showing disc hemorrhage.

To develop a nomogram to predict the progression of glaucoma by fundus photography in patients with disc hemorrhage. Retrospective review of the medical records of patients with disc hemorrhage, which was detected during follow up with open angle glaucoma, from January 2010 to March 2018. Patients were divided into glaucoma progression (n = 52) or non-progression (n = 38) groups. We assessed proximal location and morphology of disc hemorrhage; relationship to retinal nerve fiber layer defects with disc hemorrhage; and angular extent of disc hemorrhage, between groups using fundus photography. Multiple logistic regression analysis was performed to select prognostic factors, and we constructed a nomogram to predict glaucoma progression. The number of disc hemorrhage at the border of retinal nerve fiber layer defects (P = 0.001) and peripapillary disc hemorrhage (P = 0.008) were significantly higher in the progression group. We used angular extent; location of disc hemorrhage with retinal nerve fiber layer defects; and proximal location of disc hemorrhage to construct the nomogram. The area under the receiver operating characteristic curve of the nomogram was 0.847. We created the nomogram using fundus photography in patients showing disc hemorrhage as a novel and accurate screening method to predict glaucoma progression and aid clinicians to decide on the best treatment plan.

Incidence, Comorbidity, and Mortality of Primary Congenital Glaucoma in Korea from 2001 to 2015: A Nationwide Population-based Study.

PURPOSE: To report incidence rates of primary congenital glaucoma in Korea and evaluate comorbidity and mortality from 2001 to 2015. METHODS: This study is a nationwide and retrospective population-based study. We used claims data from the Korean National Health Insurance Service database between 2001 and 2015. Data for all patients diagnosed with primary congenital glaucoma were retrieved using the Korean Electronic Data Interchange and Korean Standard Classification of Diseases-6 codes. RESULTS: The number of patients with primary congenital glaucoma between 2001 and 2015 was 776, of which 437 were male (56.31%) and 339 were female (43.69%). The annual prevalence demonstrated a general decreasing trend since 2011, but this was not significant. Over the total survey period, the incidence rate was 11.0 per 100,000 births, with 12.0 cases among males and 10.0 among females. The incidence according to age was 518 (68.78%) patients at age 0, 112 (13.66%) at 1 year, 70 (8.39%) at 2 years, and 76 (9.17%) at 3 years. Of the 776 patients diagnosed with primary congenital glaucoma in the study population, 27 died. The observed mortality per 100,000 people is about 10 times higher than that of the general infant and child population under the age of 4 years. Visual impairment was the most common accompanying disability, followed by brain lesion. CONCLUSIONS: Our study's estimates of the nationwide population-based incidence of primary congenital glaucoma in a Korean population will expand our understanding of the disease and allow healthcare systems to plan for primary congenital glaucoma.

Fine grade engineered microcrystalline cellulose excipients for direct compaction: Assessing suitability of different dry coating processes.

Recent work showed that contrary to conventional wisdom, fine surface engineered excipients outperform their larger counterparts in blends of highly loaded blends of cohesive drug powders in terms of their packing, flowability and tablet tensile strength. Here, two continuous devices, fluid-energy mill (FEM) and conical mill (Comil), are compared with LabRAM, a batch device used in previous work, for nano-silica dry coating of microcrystalline cellulose (MCC) excipients, 20 and 30 µm. Coated MCCs from all three devices had higher bulk densities and flow function coefficients (FFCs) compared with Avicel PH-102. Silica coating quality was best with LabRAM, but also good with FEM and Comil, although Comil was less effective for the finer MCC. However, the better coating quality of LabRAM had a downside of having poorer compaction properties. The most surprising outcome was that multi-component blends of 17 wt% coated MCC with 60 wt % Ibuprofen 50 had higher bulk density, higher or similar flowability, higher tablet tensile strength, and comparable Ibuprofen dissolution from tablets, compared to those with Prosolv 50, a silicified excipient. The FEM dry coated MCC blends, having only 0.17 wt% silica, performed the best, having desirable bulk density, FFC, and tensile strength that could facilitate high-speed direct compression tableting. In summary, considering that achieving best coating quality need not be the primary objective, FEM may be the best option for producing desired sized dry coated fine excipients.

Crystal Structure of the LSD1/CoREST Histone Demethylase Bound to Its Nucleosome Substrate.

LSD1 (lysine specific demethylase; also known as KDM1A), the first histone demethylase discovered, regulates cell-fate determination and is overexpressed in multiple cancers. LSD1 demethylates histone H3 Lys4, an epigenetic mark for active genes, but requires the CoREST repressor to act on nucleosome substrates. To understand how an accessory subunit (CoREST) enables a chromatin enzyme (LSD1) to function on a nucleosome and not just histones, we have determined the crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome. We find that the LSD1 catalytic domain binds extranucleosomal DNA and is unexpectedly positioned 100 Å away from the nucleosome core. CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential function in demethylating nucleosome substrates. Our studies also show that the LSD1(K661A) frequently used as a catalytically inactive mutant in vivo (based on in vitro peptide studies) actually retains substantial H3K4 demethylase activity on nucleosome substrates.

Significance of dynamic contour tonometry in evaluation of progression of glaucoma in patients with a history of laser refractive surgery.

AIMS: In this study, we tested the hypothesis that intraocular pressure (IOP) parameters measured by dynamic contour tonometry (DCT) would be more relevant in progression of glaucoma when there is a history of laser refractive surgery (LRS) than the IOP parameters measured by Goldmann applanation tonometry (GAT) or calculated by correction formulae. METHODS: Ninety-eight eyes in 54 patients with open-angle glaucoma and a history of LRS were included in this retrospective study. IOP was measured by both GAT and DCT during follow-up. Baseline, mean, and peak IOP, IOP fluctuation, and IOP reduction were measured by each tonometry method. Corrected IOP parameters using central corneal thickness and mean keratometry values were also analysed. Clustered logistic regression was used to identify variables correlated with progression of glaucoma. Areas under the curve (AUCs) for correlated variables were also compared. RESULTS: The mean DCT value (OR 1.36, p=0.024), peak DCT value (OR 1.19, p=0.02) and pattern SD (OR 1.10, p=0.016) were significant risk factors for progression. There was a significant difference in the predictive ability of the mean DCT and GAT values (AUC 0.63 and 0.514, respectively; p=0.01) and of the peak DCT and GAT values (0.646 and 0.503, respectively, p=0.009). The AUCs for corrected IOP did not exceed those of DCT. CONCLUSIONS: IOP measurements were more associated with progression of glaucoma when measurements were obtained by DCT than by GAT or correction formulae in eyes with a history of LRS.

Meibomian gland dropout rate as a method to assess meibomian gland morphologic changes during use of preservative-containing or preservative-free topical prostaglandin analogues.

PURPOSE: To investigate the usefulness of meibomian gland (MG) dropout rate in the evaluation of MG morphological change associated with the use of prostaglandin for glaucoma treatment through the association between MG and the ocular surface parameters and medication duration and presence of preservative. METHODS: This cross-sectional study was conducted on 88 eyes of 88 patients who were diagnosed with glaucoma and used only Tafluprost as treatment. The patients were divided into four "user" groups: 1) 23 patients used preservative-free (PF) Tafluprost for 6 months; 2) 21 patients used preservative-containing (PC) Tafluprost for 6 months; 3) 23 patients used PF-Tafluprost for 24 months; 4) 21 patients used PC-Tafluprost for 24 months. Ocular surface parameters and the MG condition, including MG dropout rate and meiboscale, were evaluated. Multiple regression was used to identify associations. RESULTS: There were significant differences in age (p = 0.003), tear breakup time (p = 0.016), lid margin abnormality (p = 0.016), expressibility (p = 0.039), meiboscale (p<0.001), and MG dropout rate (p<0.001) among the 4 groups. MG dropout rate and meiboscale showed significant differences in all post hoc analyses, except for the comparison between the PF-Tafluprost and PC-Tafluprost 6-month user groups. Medication duration, preservative status, and meiboscale were significantly correlated with MG dropout rate (p<0.001, p = 0.024, p<0.001, respectively). In the 6-month user group, preservative status significantly correlated with MG dropout rate (p = 0.015). However, in the 24-month user group, meiboscale was the only parameter significantly associated with MG dropout rate (p<0.001). CONCLUSION: MG dropout rate in patients using Tafluprost showed a significant correlation with medication duration and preservative status. This result indicates MG dropout rate reflects MG morphologic change associated with prostaglandin.

Nomogram Using Optical Coherence Tomography and Visual Field Parameters to Predict Brain Lesions in Patients with Bitemporal Hemianopia.

PURPOSE: This study aims to develop a nomogram to predict brain lesions in patients with complete or incomplete bitemporal hemianopia by combining results from optical coherence tomography (OCT) and visual field (VF) testing. MATERIAL AND METHODS: We reviewed the medical records of patients who underwent magnetic resonance imaging (MRI) to identify brain lesions due to bitemporal hemianopia between January 2010 and March 2017, retrospectively. The patients were divided into two groups based on MRI findings: brain-lesion (+) group that had brain lesions on MRI (n = 63), and brain-lesion (-) group without brain lesions on MRI (n = 16). We compared OCT and VF findings between the two groups to find factors that could predict a brain lesion. Multiple logistic regression analysis was performed to select prognostic factors, and we constructed a nomogram to predict brain lesions on MRI. RESULT: The VF mean deviation was lower (p = 0.011) and all sectors of peripapillary retinal nerve fiber layer thickness except the temporal region were thicker in the brain-lesion (+) group. However, there was no statistically significant difference in macular ganglion cell-inner plexiform layer between the two groups. The area under the receiver operating characteristic curve of the nomogram for predicting brain lesions on MRI was 0.916. CONCLUSION: We developed a nomogram using VF and OCT examinations as a novel and accurate screening method to predict brain lesions in patients with bitemporal hemianopia and aid ophthalmologists and other clinicians in deciding whether to further evaluate a patient by MRI.

Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2.

The Gcn5 histone acetyltransferase (HAT) subunit of the SAGA transcriptional coactivator complex catalyzes acetylation of histone H3 and H2B N-terminal tails, posttranslational modifications associated with gene activation. Binding of the SAGA subunit partner Ada2 to Gcn5 activates Gcn5's intrinsically weak HAT activity on histone proteins, but the mechanism for this activation by the Ada2 SANT domain has remained elusive. We have employed Fab antibody fragments as crystallization chaperones to determine crystal structures of a yeast Ada2/Gcn5 complex. Our structural and biochemical results indicate that the Ada2 SANT domain does not activate Gcn5's activity by directly affecting histone peptide binding as previously proposed. Instead, the Ada2 SANT domain enhances Gcn5 binding of the enzymatic cosubstrate acetyl-CoA. This finding suggests a mechanism for regulating chromatin modification enzyme activity: controlling binding of the modification cosubstrate instead of the histone substrate.

Asymmetry of Peak Thicknesses between the Superior and Inferior Retinal Nerve Fiber Layers for Early Glaucoma Detection: A Simple Screening Method.

PURPOSE: To assess whether the asymmetry in the peripapillary retinal nerve fiber layer (pRNFL) thickness between superior and inferior hemispheres on optical coherence tomography (OCT) is useful for early detection of glaucoma. MATERIALS AND METHODS: The patient population consisted of Training set (a total of 60 subjects with early glaucoma and 59 normal subjects) and Validation set (30 subjects with early glaucoma and 30 normal subjects). Two kinds of ratios were employed to measure the asymmetry between the superior and inferior pRNFL thickness using OCT. One was the ratio of the superior to inferior peak thicknesses (peak pRNFL thickness ratio; PTR), and the other was the ratio of the superior to inferior average thickness (average pRNFL thickness ratio; ATR). The diagnostic abilities of the PTR and ATR were compared to the color code classification in OCT. Using the optimal cut-off values of the PTR and ATR obtained from the Training set, the two ratios were independently validated for diagnostic capability. RESULTS: For the Training set, the sensitivities/specificities of the PTR, ATR, quadrants color code classification, and clock-hour color code classification were 81.7%/93.2%, 71.7%/74.6%, 75.0%/93.2%, and 75.0%/79.7%, respectively. The PTR showed a better diagnostic performance for early glaucoma detection than the ATR and the clock-hour color code classification in terms of areas under the receiver operating characteristic curves (AUCs) (0.898, 0.765, and 0.773, respectively). For the Validation set, the PTR also showed the best sensitivity and AUC. CONCLUSION: The PTR is a simple method with considerable diagnostic ability for early glaucoma detection. It can, therefore, be widely used as a new screening method for early glaucoma.

Association between Previous Cataract Surgery and Age-Related Macular Degeneration.

PURPOSE: To assess the association between age-related macular degeneration (AMD) and previous cataract surgery. METHODS: We studied 17,987 randomly selected participants from the Korea National Health and Nutrition Examination Survey who were aged ≥40 years and underwent additional ophthalmologic examinations in 2008‒12. The associations between previous cataract surgery and early/late AMD were identified using multivariate logistic regression analysis of data from right or left eyes. Clustered multivariate logistic regression analysis was performed using both eyes to assess inter-eye correlation in same subject. Previous cataract surgery and cataract subtypes were based on slit-lamp examination without pupil dilation. Early and late AMD diagnoses were based on non-mydriatic digital retinal image. RESULTS: By univariate logistic regression, both early and late AMD prevalence were higher in subjects with pseudophakia/aphakia compared to subjects with cataract as a reference group, or subjects with phakic eye (including clear lens) as a reference group. In univariate logistic regression, both early and late AMD prevalence were higher in eyes with cataract or pseudo/aphakia compared to eyes with clear lens. However, after adjusting for age with multivariate logistic regression, all statistically significant differences in AMD prevalence among subgroups disappeared. CONCLUSIONS: We found no association between the previous cataract surgery and increased early/late AMD risk in our representative, large, national patient database. This suggests that increasing age, and not cataract surgery history, is predictive of AMD risk. These findings are limited by cross-sectional study and need to be replicated by other longitudinal observational studies.