Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

High-frequency power of heart rate variability can predict the outcome of thoracic surgical patients with acute respiratory distress syndrome on admission to the intensive care unit: a prospective, single-centric, case-controlled study.

BACKGROUND: The morbidity and mortality of acute respiratory distress syndrome (ARDS) remains high, and the strategic focus of ARDS research has shifted toward identifying patients at high risk of mortality early in the course of illness. This study intended to identify the heart rate variability (HRV) measure that can predict the outcome of patients with ARDS on admission to the surgical intensive care unit (SICU). METHODS: Patients who had lung or esophageal cancer surgery were included either in the ARDS group (n = 21) if they developed ARDS after surgery or in the control group (n = 11) if they did not. The ARDS patients were further stratified into survivors and non-survivors subgroups according to their outcomes. HRV measures of the patients were used for statistical analysis. RESULTS: The mean RR interval (mRRI), high-frequency power (HFP) and product of low-/high-frequency power ratio tidal volume and tidal volume (LHR*VT) were significantly lower (p < 0.05), while the normalized HFP to VT ratio (nHFP/VT) was significantly higher in the ARDS patients (p = 0.011). The total power (TP), low-frequency power (LFP), HFP and HFP/VT were all significantly higher in the non-survived ARDS patients, whereas Richmond Agitation-Sedation Scale (RASS) was significantly lower in the non-survived ARDS patients. After adjustment for RASS, age and gender, firth logistic regression analysis identified the HFP, TP as the significant independent predictors of mortality for ARDS patients. CONCLUSIONS: The vagal modulation of thoracic surgical patients with ARDS was enhanced as compared to that of non-ARDS patients, and the non-survived ARDS patients had higher vagal activity than those of survived ARDS patients. The vagal modulation-related parameters such as TP and HFP were independent predictors of mortality in patients with ARDS on admission to the SICU, and the HFP was found to be the best predictor of mortality for those ARDS patients. Increased vagal modulation might be an indicator for poor prognosis in critically ill patients following thoracic surgery.

A role for antimetabolites in glaucoma tube surgery: current evidence and future directions.

PURPOSE OF REVIEW: Glaucoma is the leading cause of irreversible blindness worldwide. The main treatment modality for glaucoma is the reduction and control of the intraocular pressure (IOP). Glaucoma filtration surgery, including trabeculectomy and/or implantation of a glaucoma drainage device (GDD), is warranted if IOP remains medically uncontrolled. However, postoperative scarring remains a critical determinant of long-term bleb survival and IOP control after drainage surgery. Antimetabolites, such as mitomycin C and 5-fluorouracil, have been used for many years to increase survival time of filtration surgeries by preventing bleb fibrosis and scarring. The aim of this study is to provide an overview of: the current usage of these antimetabolites in GDD, the recent advancements of these antimetabolites in combination with other technologies, and the role of future antimetabolites. RECENT FINDINGS: Mitomycin C and 5-fluorouracil have been used in GDD and trabeculectomy to prevent the exaggerated cellular reaction that leads to fibrosis. The adjunctive administration of these drugs intraoperatively and postoperatively has resulted in a lower rate of the hypertensive phase, and possibly a better long-term success rate in Ahmed valve surgeries. However, the application of these antimetabolites and their multiple-dosing applications are associated with nonspecific cytotoxicity and potentially severe complications such as bleb leak and conjunctival erosion over the tube. Recent studies are thus focusing on different medications, targeting new molecular pathways, and designing new delivery vehicles to minimize current antimetabolites side-effects and increase their efficacy. Promising results of these studies have led to development of new collaborative medications and advanced drug delivery systems for better modulation of GDD surgeries' predictable outcomes. SUMMARY: The development of small molecule therapeutics, combination therapies, and innovative drug vehicles to prevent postsurgical fibrosis and achieve better surgical outcome in glaucoma filtration surgeries is promising.

Genome-wide association study in a Chinese population with diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10(-7)), LRP2-BBS5 (rs1399634, P = 2.0 × 10(-6)) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10(-6)). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.

Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.

AIMS/HYPOTHESIS: Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population. METHODS: A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression. RESULTS: We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1. CONCLUSIONS/INTERPRETATION: These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.

Systemic soluble tumor necrosis factor receptors 1 and 2 are associated with severity of diabetic retinopathy in Hispanics.

PURPOSE: To investigate the associations of serum amyloid A (SAA) protein and soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2) with diabetic retinopathy (DR) in Hispanics. DESIGN: Prospective, nonrandomized, cross-sectional, family-based observational cohort study. PARTICIPANTS: A total of 473 Hispanic type II diabetic subjects in families ascertained via proband with DR. METHODS: Levels of SAA, sTNF-R1, and sTNF-R2 were measured with enzyme-linked immunosorbent assay. Diabetic retinopathy was assessed by fundus photography and graded using modified Airlie House classification. MAIN OUTCOME MEASURES: Levels of SAA, sTNF-R1, and sTNF-R2 to severity of DR with and without covariates. RESULTS: A direct association of sTNF-R1 (2.37±0.13, 2.15±0.09, 3.09±0.24, 3.25±0.46, 5.02±0.61 ng/ml; P < 0.0001) and sTNF-R2 (6.04±0.20, 6.25±0.52, 7.96±0.70, 8.14±1.13, 14.83±1.68 ng/ml; P < 0.0001) was found for no DR, mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR, respectively. These associations remained significant after adjusting for age, gender, body mass index, glycosylated hemoglobin, diabetes duration, systolic blood pressure, and serum creatinine (P < 0.0001 for sTNF-R1 and P=0.0004 for sTNF-R2). A similar pattern was observed when we adjusted for urinary albumin:creatinine ratio in place of serum creatinine (P=0.005 for sTNF-R1 and P=0.02 for sTNF-R2). CONCLUSIONS: Levels of sTNF-R1 and sTNF-R2 are highly correlated with the severity of DR, suggesting that inflammation and insulin resistance may play a critical role in the development of DR. These may be useful biomarkers for DR, aiding in etiologic studies and possibly identifying at-risk patients for active intervention.

Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy.

To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS: We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was <.05. RESULTS: Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS: These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Predictive factors for visual outcome to intravitreal bevacizumab in young Chinese patients with myopic choroidal neovascularization.

PURPOSE: To report the anatomical and functional outcomes of intravitreal bevacizumab in both young and old Chinese patients with myopic choroidal neovascularization. METHODS: Consecutive series of 56 eyes (52 patients) with myopic choroidal neovascularization treated exclusively with intravitreal bevacizumab were reviewed retrospectively. Data from clinical examination, fundus photography, fluorescein angiography, and optical coherence tomography were collected. RESULTS: Vision significantly improved after intravitreal bevacizumab in this patient series (P < 0.0001), with an average of 2.2 injections. Higher myopia was positively correlated to a worse outcome (r = -0.3, P = 0.036). Stratifying by age, the correlation between spherical equivalent and final outcome showed statistical significance (r = -0.44, P = 0.027) only in younger patients. In younger patients, both spherical equivalent (P = 0.036) and initial visual acuity (P = 0.004) were predictive factors for visual outcome after adjusting for age, spherical equivalent, and number of injections, whereas in older patients, only initial visual acuity (P < 0.0001) was predictive of visual outcome after similar adjustments. CONCLUSION: Younger patients do not have a better outcome when compared with older patients. Initial visual acuity, regardless of age, plays a more significant role. Both initial visual acuity and spherical equivalent are predictive factors for final visual acuity in young Chinese patients.

Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan.

PURPOSE: To investigate the clinical settings, treatment given, and visual outcomes for eyes with Pseudomonas aeruginosa endophthalmitis in Taiwan. METHODS: This is a retrospective, noncomparative, consecutive case series. Medical records were reviewed in 72 eyes of 71 patients with culture-proven P. aeruginosa endophthalmitis between January 1997 and December 2007. RESULTS: The clinical settings included keratitis/scleritis (44.4%), cataract surgery (15.3%), penetrating keratoplasty (13.9%), endogenous source (12.5%), trauma (6.9%), penetrating keratoplasty with cataract surgery (2.8%), trabeculectomy with cataract surgery (1.4%), trabeculectomy (1.4%), and secondary implant (1.4%). Initial visual acuity ranged from counting fingers to no light perception. Final visual acuity was better than 5/200 in 6 of 72 eyes (8.3%), 4/200 to hand motions in 4 eyes (5.6%), and light perception to no light perception in 62 eyes (86.1%). In vitro testing, the susceptibility patterns of organisms isolated were as follows: ceftazidime (100%), cefepime (100%), aztreonam (100%), imipenem (99%), amikacin (94%), and gentamicin (86%). Five of 16 eyes (31.3%) that underwent primary or secondary pars plana vitrectomy with intravitreal antibiotics achieved a final visual acuity of 5/200 or better compared with 1 of 45 eyes (2.2%) treated with 1 or multiple vitreous tap(s) and intravitreal antibiotics (Fisher's exact test, P = 0.004). CONCLUSION: Despite early diagnosis and treatment with intravitreal antibiotics, visual acuity outcomes were generally poor.

Serum concentration of bevacizumab after intravitreal injection in experimental branch retinal vein occlusion.

AIM: To compare the serum concentration of bevacizumab after intravitreal injection of bevacizumab (IVB) in an experimental model of branch retinal vein occlusion (BRVO) with control injections in albino rats. METHODS: BRVO was created in one eye of each of the 24 albino rats. Another 24 rats served as controls. The BRVO was generated by argon laser photothrombosis after intravenous injection with Rose Bengal. Three days later, IVB (5 µl) was administered to both BRVO and control eyes. The serum concentration of bevacizumab was examined at baseline, 6 h, 1 day, 3 days, 7 days, 14 days, and 28 days after IVB. RESULTS: At baseline, no serum bevacizumab was detected in either group. The serum concentration of bevacizumab reached a peak concentration at 1 day with 5,020 ± 1,602 ng/ml in the BRVO group and 4,103 ± 1,790 ng/ml in the control group (p < 0.001). The concentration decreased subsequently on days 3, 7, 14 and 28. The serum concentration of bevacizumab was significantly higher in BRVO rats up to 28 days after IVB. CONCLUSIONS: The serum concentration of bevacizumab after IVB reached its peak on day 1 in both BRVO and control eyes. This value was significantly higher in BRVO rats than in control rats up to 28 days after intravitreal injection.

Individuals with and without normal tension glaucoma exhibit comparable performance on tests of cognitive function.

AIM: To evaluate aspects of cognition impacted by individuals with and without normal tension glaucoma. METHODS: Fifty normal tension glaucoma (NTG) and 50 control patients ≥50y of age were recruited from the UCSF Department of Ophthalmology. Demographic data and glaucoma parameters were extracted from electronic medical records for both groups. Tests of executive function [Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER)] and learning and memory [California Verbal Learning Test-Second Edition (CVLT-II)] were administered to both NTG and controls. Race, handedness, best-corrected visual acuity, maximum intraocular pressure, optic nerve cup-to-disc ratio, visual field and optic nerve optical coherence tomography parameters, and a measure of general health (Charlson Comorbidity Index) were compared between NTG and controls as well as within NTG subgroups. Multivariate linear regression was used to compare group performances on the EXAMINER battery and CVLT-II while controlling for age, sex, and years of education. RESULTS: NTG and controls were comparable with respect to age, sex, race, education, handedness, and the Charlson Comorbidity Index (P>0.05 for all). Performance on the EXAMINER composite score and the CVLT-II did not differ between NTG and controls (P>0.05 for both). CONCLUSION: This is the first prospective study in which the cognitive function of subject with NTG were evaluated using a comprehensive, computerized neurocognitive battery. Subjects with NTG do not perform worse than unaffected controls on tests of executive function, learning, and memory. Results do not support the hypothesis that individuals with NTG are at higher risk for cognitive dysfunction and/or dementia.

Central retinal vein occlusion in a young Chinese population: risk factors and associated morbidity and mortality.

PURPOSE: The purpose of this study was to assess the risk factors for central retinal vein occlusion and associated morbidity and mortality in a Chinese population. METHODS: The participants included patients with central retinal vein occlusion 40 years old and younger. Predisposing factors, mortality, and systemic complications were examined in this group. RESULTS: Unilateral (n = 19) and bilateral (n = 3) central retinal vein occlusions were identified in a total of 22 patients (25 eyes), with a mean follow-up time of 37 months. Hypercholesterolemia (65%), hypertriglyceridemia (64%), and hyperhomocysteinemia (42%) were all identified as risk factors. Three patients (14%) developed stroke and 1 (5%) developed transient ischemic attacks during follow-up. Renal failure and pulmonary hypertension resulted in the death of two patients. The mean initial and final visual acuities (+ or - standard deviation) were 20/400 (+ or - 20/250) and 20/500 (+ or - 20/320), respectively, and treatments did not result in vision improvement (P = 0.57). The poor visual prognosis was likely due to macular edema in 7 eyes (28%), optic atrophy in 4 eyes (16%), and secondary glaucoma in 3 eyes (12%). CONCLUSION: Morbidity and mortality are high in young Chinese patients with central retinal vein occlusion who may have associated serious complications including stroke, blindness, and death. Central retinal vein occlusion may serve as an initial clinical presentation of serious systemic diseases.

Retinopathy of prematurity and maternal age.

PURPOSE: To determine the risk factors, especially maternal risk factors, associated with the development of retinopathy of prematurity (ROP) in premature babies. METHODS: A matched case-control study involving premature patients was undertaken retrospectively. The case group consisted of premature babies with the subsequent development of ROP. The control group consisted of gestational age-matched and sex-matched premature babies that did not develop ROP during the follow-up period. Risk factors involving patient demographics and maternal characteristics were compared between the case and control groups. RESULTS: A total of 144 patients were included in this study (72 patients in the case group and 72 patients in the control group). Among the 66 possible risk factors compared, only birth weight and maternal age were found to be significant risk factors. Birth weight was significantly lower in the case group (1,248.7 +/- 257.8 g vs. 1,335.5 +/- 297.2 g, P = 0.01), and maternal age was significantly older in the case group compared with that in the control group (31.2 +/- 5.1 years vs. 28.2 +/- 5.3 years, P < 0.001). The odds ratio of having babies with ROP was 2.9 when the maternal age was >30 years. CONCLUSION: Older maternal age is a newly identified risk factor for the development of ROP in premature babies.

Blood-assisted internal limiting membrane peeling for macular hole repair.

PURPOSE: To evaluate the efficacy of autologous heparinized whole blood in assisting internal limiting membrane (ILM) peeling by coating the ILM for macular hole (MH) repair. DESIGN: Prospective, interventional case series. PARTICIPANTS: Twenty-nine patients (32 eyes) who underwent blood-assisted ILM peeling for MH repair. METHODS: Patients in whom stage 2-4 idiopathic MHs had developed and who desired surgery were enrolled in this study. After core vitrectomy, autologous heparinized whole blood was applied to cover the macula and to coat the surface of the macular area in the fluid-filled vitreous cavity. The redundant blood was removed and only a very thin film of blood was left on the macular area. The blood-coated ILM was removed by forceps in a circular fashion. To confirm the removed membrane was the ILM, the first 10 specimens were examined by electron microscopy (EM). MAIN OUTCOME MEASURES: The MH closure rate, the interval mean visual acuity (before and after surgery), retinal changes, and the EM results of the ILM specimens. RESULTS: All 32 eyes in 29 patients completed 12 months of follow-up. The ILM were coated by autologous heparinized whole blood, removed without difficulty, and confirmed by EM. The whole blood highlighted the contrast of the coated and noncoated areas during the ILM peeling procedure. The MHs were closed in all surgical eyes with a single surgery (100%). Compared with study entry, the mean logMAR best-corrected visual acuity 12 months after surgery improved significantly (1.02 and 0.53, respectively; P<0.001). At 12 months of follow-up, 31 eyes (96.9%) had stable or improved vision. No toxic fundus changes were observed during follow-up. CONCLUSIONS: Autologous heparinized whole blood coated the ILM and facilitated visibility during ILM peeling. Autologous heparinized whole blood is a cost-effective and useful tool for assisting MH surgery.

The Clinical Utility of a Precision Medicine Blood Test Incorporating Age, Sex, and Gene Expression for Evaluating Women with Stable Symptoms Suggestive of Obstructive Coronary Artery Disease: Analysis from the PRESET Registry.

Background: Evaluating women with symptoms suggestive of coronary artery disease (CAD) remains challenging. A blood-based precision medicine test yielding an age/sex/gene expression score (ASGES) has shown clinical validity in the diagnosis of obstructive CAD. We assessed the effect of the ASGES on the management of women with suspected obstructive CAD in a community-based registry. Materials and Methods: The prospective PRESET (A Registry to Evaluate Patterns of Care Associated with the Use of Corus® CAD in Real World Clinical Care Settings) Registry (NCT01677156) enrolled 566 patients presenting with symptoms suggestive of stable obstructive CAD from 21 United States primary care practices from 2012 to 2014. Demographics, clinical characteristics, and referrals to cardiology or further functional and/or anatomical cardiac studies after ASGES testing were collected for this subgroup analysis of women from the PRESET Registry. Patients were followed for 1-year post-ASGES testing. Results: This study cohort included 288 women with a median age 57 years. The median body mass index was 29.2, with hyperlipidemia and hypertension present in 48% and 43% of patients, respectively. Median ASGES was 8.5 (range 1-40), with 218 (76%) patients having low (≤15) ASGES. Clinicians referred 9% (20/218) low ASGES versus 44% (31/70) elevated ASGES women for further cardiac evaluation (odds ratio 0.14, p < 0.0001, adjusted for patient demographics and clinical covariates). Across the score range, higher ASGES were associated with a higher likelihood of posttest cardiac referral. At 1-year follow-up, low ASGES women experienced fewer major adverse cardiac events than elevated ASGES women (1.3% vs. 4.2% respectively, p = 0.16). Conclusions: Incorporation of ASGES into the diagnostic workup demonstrated clinical utility by helping clinicians identify women less likely to benefit from further cardiac evaluation.

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model.

The receptor protein tyrosine phosphatase beta (RPTPbeta) is a functional biomarker for several solid tumor types. RPTPbeta expression is largely restricted to the central nervous system and overexpressed primarily in astrocytic tumors. RPTPbeta is known to facilitate tumor cell adhesion and migration through interactions with extracellular matrix components and the growth factor pleiotrophin. Here, we show that RPTPbeta is expressed in a variety of solid tumor types with low expression in normal tissue. To assess RPTPbeta as a potential target for treatment of glioblastoma and other cancers, antibodies directed to RPTPbeta have been developed and profiled in vitro and in vivo. The recombinant extracellular domain of human short RPTPbeta was used to immunize mice and generate monoclonal antibodies that selectively recognize RPTPbeta and bind to the antigen with low nanomolar affinities. Moreover, these antibodies recognized the target on living tumor cells as measured by flow cytometry. These antibodies killed glioma cells in vitro when coupled to the cytotoxin saporin either directly or via a secondary antibody. Finally, in vivo studies showed that an anti-RPTPbeta immunotoxin (7E4B11-SAP) could significantly delay human U87 glioma tumors in a mouse xenograft model. Unconjugated 7E4B11 provides a modest but statistically significant tumor growth delay when delivered systemically in mice bearing U87 glioma tumors.

Utility of a Precision Medicine Test in Elderly Adults with Symptoms Suggestive of Coronary Artery Disease.

BACKGROUND: Diagnosing obstructive coronary artery disease (CAD) is challenging in elderly adults, and current diagnostic approaches for CAD expose these individuals to risks from contrast dye and invasive procedures. DESIGN: A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings (PRESET; NCT01677156), pragmatic clinical trial. SETTING: Community, 21 primary care practices. PARTICIPANTS: Of 566 stable, nonacute outpatients presenting with symptoms suggestive of obstructive CAD, the 176 who were aged 65 and older (median age 70, 61% female) were the current study participants. INTERVENTION: Blood-based precision medicine test, incorporating age, sex, and gene expression score (ASGES) to improve clinical decision-making and quality of care. MEASUREMENTS: Information on demographic characteristics, clinical factors, ASGES results (range 1-40; low (≤15), high (>15)), referral patterns to cardiology and advanced cardiac testing, and major adverse cardiac events (MACEs) was collected in a subgroup analysis of elderly adults in the PRESET Registry. Follow-up was for 1 year after ASGES testing. RESULTS: Median ASGES was 25, and 40 (23%) participants had a low score. Clinicians referred 12.5% of participants with a low ASGES and 49.3% with a high ASGES to cardiology or advanced cardiac testing (odds ratio for referral = 0.12, P < .001, adjusted for participants demographics and clinical covariates). Higher scores were associated with greater likelihood of posttest cardiac referral. At 1-year follow-up, the incidence of a MACE or revascularization was 10% (13/136) in the high ASGES group and 0% (0/40) in the low ASGES group (P = .04). CONCLUSION: The ASGES test showed potential clinical utility in the evaluation of elderly outpatients with symptoms suggestive of obstructive CAD. Test use may reduce unnecessary referrals and the risk of procedure-related complications in individuals with low ASGES, who are unlikely to benefit from further testing, while also identifying individuals who may benefit from further cardiac evaluation and management.

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.