Assess the relationship between photoreceptor degeneration and visual function after retinal reattachment surgery (RRS) in a prospective cohort. Patients with rhegmatogenous retinal detachment (RRD) were reviewed before and 6 months after vitreoretinal surgery. Optical coherence tomographical thickness of the outer nuclear layer (ONL), outer retinal segment (ORS), retinal pigmented epithelium to ellipsoid zone (RPE-EZ) and external limiting membrane to EZ (ELM-EZ) were recorded 6 months post-operatively. These were compared to best corrected visual acuity (BCVA) and retinal sensitivity (Humphrey visual field). Thirteen macula-off and 8 macula-on RRD patients were included. The mean ONL thickness was higher after macula-on RRD compared to macula-off RRD (97.70 ± 3.62 μm vs. 73.10 ± 4.98 μm). In all RRD eyes, every 1 μm decrease in ONL thickness correlated with a 0.052 dB decrease and in retinal sensitivity and every 1 μm decrease in ORS thickness was associated with a 0.062 dB reduction in retinal sensitivity. ORS, ELM-EZ and RPE-EZ thickness did not correlate with BCVA post-RRS. There was greater ONL and ORS thinning following macula-off compared to macula-on RRD. Correlations between ONL and ORS thinning with decreased retinal sensitivity may be explained by RRD-induced photoreceptor death.

Purpose: Proliferative vitreoretinopathy (PVR) occurs in 5%-10% of rhegmatogenous retinal detachment cases and is the principle cause for failure of retinal reattachment surgery. Although there are a number of surgical adjunctive agents available for preventing the development of PVR, all have limited efficacy. Discovering predictive molecular biomarkers to determine the probability of PVR development after retinal reattachment surgery will allow better patient stratification for more targeted drug evaluations. Methods: Narrative literature review. Results: We provide a summary of the inflammatory and fibrogenic factors found in ocular fluid samples during the development of retinal detachment and PVR and discuss their possible use as molecular PVR predictive biomarkers. Conclusions: Studies monitoring the levels of the above factors have found that few if any have predictive biomarker value, suggesting that widening the phenotype of potential factors and a combinatorial approach are required to determine predictive biomarkers for PVR. Translational Relevance: The identification of relevant biomarkers relies on an understanding of disease signaling pathways derived from basic science research. We discuss the extent to which those molecules identified as biomarkers and predictors of PVR relate to disease pathogenesis and could function as useful disease predictors. (http://www.umin.ac.jp/ctr/ number, UMIN000005604)

Background: Common cocaine cutting agent Levamisole is known to cause agranulocytosis. However, a lesser known public health issue is levamisole-induced granulomatosis with polyangiitis. This case series explores this link. Methods and Results: A three case-series report with findings confirmed through clinical history, examination, biopsy and urine toxicology screens. Conclusions: Our case-series highlights a possible link between levamisole and extensive necrosis of the nasal cavity; caused by polyangiitis with granuloma formation and secondary vasculitis. A high degree of suspicion is needed if young patients present with ANCA positive vasculitis, or in patients with cocaine use, if there is a disproportionate destruction of tissues- particularly the lateral wall of the nose. If diagnosed and treated early, this can be lifesaving.

Crohn's disease (CD) causes changes in the lymphatic system which have been studied using MRI. Dfusion Weighted Imaging with Background Suppression (DWIBS) provides a powerful method to isolate the nodes which are otherwise hard to identify on 3T images. DWIBS has been used to show a difference in Apparent Diffusion Coefficient (ADC) between benign and malignant enlarged nodes but work in inflammatory diseases is absent, and T2 measures may provide additional information on inflammatory activity. We hypothesised that lymph node ADC, T2, size and number may be useful disease activity measures. Aim: to undertake a pilot study to investigate ADC, T2, number and size of abdominal lymph nodes in healthy volunteers and CD patients. Healthy participants (HP) and CD patients were scanned on a Phillips 3T Ingenia (Best, the Netherlands). CD patients had active disease (CRP of >5 mg/dl or faecal calprotectin (FCP) of >250 μg/g or ileocolonoscopy or MR enterography). Slices were orientated sagittally, respiratory triggering was used to reduce through plane motion. The DWIBS sequence was used to measure ADC and T2. The length of the major and minor axes of the lymph nodes were recorded. HP (4 males, 3 females, mean age 32 ± 13 years) and patients with CD (3 males, 3 females, mean age 29 ± 11 years) were recruited. In CD, CRP was 7.9 ± 2.9 mg/dl and FCP was 755 ± 225 μg/g. Figure 1 shows lymph nodes identified on DWIBS images. Top: Healthy volunteer. Bottom: CD patient. Two lymph nodes shown for each by the red arrows on an ADC image on the left and the same two nodes on a T2 image on the right. Figure 2. shows the number, ADC, T2 and length of the major and minor axes calculated with the results summarised Figure 3. ADC, T2 and length of the major and minor axis calculated for each group as a whole along with the standard error of the mean. The p values for comparisons between the healthy volunteers and CD patients with significant changes highlighted. Violin plot showing the distribution of the measurements from the healthy volunteers and CD patients. Fewer nodes were identified in CD than in the HP, but this was highly dependent on the quality of respiratory triggering which was worse in CD patients. The size of the lymph nodes increased and ADC decreased in CD probably, indicating an increase in cellularity of inflamed lymph nodes. A non-significant increase in T2 was noted in CD possibly reflecting the inflammatory response in the lymph node. Lymph node size, ADC and T2 could provide a novel inflammatory marker in CD. These data need replicating in larger cohorts with changes after CD therapy assessed.

Contrast-based Magnetic resonance (MR) enterography has a diagnostic accuracy of up to 90%1 to detect ulcer healing in Crohn’s disease (CD). Intravenous gadolinium T1-based imaging carries a risk of nephrogenic systemic fibrosis and allergic reaction. FDA safety alerts have been issued regarding its use in humans. Moreover, T2-based measures are still presently subjective. Increased small bowel (SB) permeability has been described in CD.2 The best validated gold standard measure of SB permeability is the Lactulose/Mannitol (LMR) urinary excretion test. A change in intestinal permeability may be induced with an oral indomethacin challenge.3 We aimed to develop non-invasive contrast-free T2 relaxometry MRI measure of intestinal inflammation using intestinal permeability as a surrogate of intestinal injury. Healthy participants (n = 24) were enrolled on a 2 × 2 double-blind provocation study consisting of placebo and indomethacin (75 mg dose taken 16 h and 4 h prior to the scan) to induce increased permeability with >2 weeks washout time between arms.3 Newly developed quantitative MR measures of SB wall thickness, T2 relaxometry, and motility [4] were compared with a 2 h lactulose/mannitol urinary excretion ratio (LMR). Coronal MR scans were performed on 3 Tesla Philips MRI scanner (Best, the Netherlands) in prone position. Two doses of 20 mg intravenous Buscopan were administered to reduce peristalsis. Ethical permission was granted by the University of Nottingham. Data are presented as median and Interquartile range (IQR). Non-parametric analyses were undertaken. Data from 22 participants (14 females; 23 years (IQR 22–25), BMI of 23.7 (IQR 21.8–27.8) kg/m2) were available for a per-protocol analyses. Indomethacin induced significant changes from placebo in LMR from 0.019 (IQR 0.016–0.026) to 0.025 (IQR 0.021–0.039) (p = 0.002) and T2 SB decay from 0.09 s to 0.13 s (p = 0.009). SB wall thickness of 2.56 mm (2.41–2.72) showed no significant change with the challenge. Global SB motility showed a decreasing trend with the indomethacin challenge (0.300 (0.251–0.353) to 0.272 (0.253–0.305). Newly developed non-contrast MRI techniques can sensitively measure in vivo SB wall thickness, T2 relaxometry and motility in healthy volunteers. MR measures of SB wall T2 are significantly increased with increased permeability associated with indomethacin provocation. Further validation to analyse the intra-class correlation is underway. Dowstream analyses will correlate these outcomes to standard endoscopy and MR measures of disease activity in CD. 1. Ordas I, Rimola J, Rodriguez S, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease. Gastroenterology, 2014:374–82. 2. Hollander D, Vadheim CM, Brettholz E, et al. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann Intern Med, 1986;105:883–5. 3. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut, 2013;63:1–7. 4. Menys A, Taylor SA, Emmanuel A, et al. Global small bowel motility: Assessment with dynamic MR imaging. Radiology, 2013;269:443–50.

PurposeTo determine if vitreous levels of the pro-fibrotic cytokine transforming growth factor beta2 (TGF-β2) and its opposing regulator decorin predict subsequent proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RRD).MethodsWe examined the effect of TGF-β2 and decorin on epithelial-mesenchymal transition (EMT) and collagen expression in vitro using ARPE-19 cells, and we analyzed extracellular matrix marker expression in PVR membrane and internal limiting membrane patient samples. We performed a prospective noninterventional cohort study, recruiting 125 patients undergoing vitrectomy for RRD and macular hole surgery, measured vitreous levels of TGF-β2 and decorin by ELISA, and followed them up for 6 months. Patients who did not develop PVR were compared to those who did, in order to determine whether vitreous TGF-β2 and decorin levels predicted PVR development.ResultsIn vitro, TGF-β2 induced EMT and collagen production. Decorin strongly inhibited EMT and collagen production at high levels. PVR membranes expressed high levels of fibrosis-associated proteins, consistent with EMT. Vitreous TGF-β2 levels were unchanged between patients with macular holes and RRD who did or did not subsequently develop PVR. Average decorin levels were higher in the vitreous of RRD patients who subsequently developed PVR compared to those who did not, but at the measured vitreous concentrations (1-2 μg/mL), decorin did not demonstrate an in vitro inhibitory effect on EMT.ConclusionsIn vitro, high concentrations of decorin inhibited EMT and fibrosis. At the levels seen in human vitreous, decorin did not prevent fibrosis or EMT in vitro, and higher initial vitreous decorin levels were associated with the development of postoperative PVR after vitrectomy to treat RRD, but did not reliably predict the outcome.

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Background: In the past decades, a number of non-invasive methods have emerged for detecting and estimating liver fibrosis; these include both serum-based panels and imaging-based technology. Some of these methods are now being incorporated in clinical practice. However, the limitations of the current techniques include lack of organ specificity, sampling errors and limited ability to reflect the efficacy of interventions. Key Messages: Novel magnetic resonance (MR)-based techniques provide an opportunity to bring about further changes in the investigations and management of patients with liver diseases. Multimodal quantitative MR techniques enable the estimation of fat, iron accumulation, degree of liver injury/inflammation and fibrosis within the whole liver without the need for administering contrast agents. Architectural changes within the liver can be evaluated concurrently with portal haemodynamic changes allowing non-invasive assessment of portal hypertension and effects of interventions. A combination ultra-high field (7T) provides greater sensitivity with a potential to distinguish inflammation from fibrosis on imaging and determine specific types of fats (saturated vs. unsaturated) present within the liver using MR spectroscopy. 13C MR spectroscopy can estimate glutathione flux and rate of beta oxidation in-vivo providing novel tools for experimental studies that evaluate the efficacy of interventions as well as underlying mechanisms. Conclusions: Translational research should focus on converting the potentials of these innovative methodologies into clinical applications for the benefit of patients.

Purpose To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection. Methods CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV. Results CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment. Conclusions CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

The disability of blindness is a learned social role. The various attitudes and patterns of behavior that characterize people who are blind are not inherent in their condition but, rather, are acquired through ordinary processes of social learning. The Making of Blind Men is intended as a systematic and integrated overview of the blindness problem in America. Dr. Scott chronicles which aspects of this problem are being dealt with by organizations for the blind and the effectiveness of this intervention system. He details the potential consequences of blind people becoming clients of blindness agencies by pointing out that many of the attitudes, behavior patterns, and qualities of character that have been assumed to be given to blind people by their condition are, in fact, products of socialization. As the self-concepts of blind men are generated by the same processes of socialization that shape us all, Dr. Scott puts forth the challenge of reforming the organized intervention system by critically evaluating the validity of blindness workers' assumptions about blindness and the blind. It is felt that an enlightened work force can then render the socialization process of the blind into a rational and deliberate force for positive change.

Purpose: To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801. Methods: Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a+ RGC survival, GFAP+ reactive gliosis, and GAP43+ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. Results: Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43+ axon regeneration at 400 to 1200 μm beyond the ONC site, and potentiated the reactive GFAP+ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP+ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity. Conclusions: The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

PURPOSE:To investigate the feasibility of conducting a randomised controlled trial in patients undergoing pars plana vitrectomy surgery following open globe trauma (OGT). Additionally, to investigate the treatment effect and toxicity of intensive anti-inflammatory agents.METHODS:A 2-year, pilot, single-centre prospective, participant and surgeon-masked randomised controlled trial (RCT). Forty patients requiring vitrectomy surgery following OGT were randomised to either standard (control) or study treatment (adjuncts) in a 1:1 allocation ratio. Perioperatively, the adjunct group received intravitreal and subtenons triamcinolone acetonide, oral flurbiprofen and guttae prednisolone acetate 1%. The control group received standard care. Primary outcome was anatomical success at 6 months. Secondary outcomes included final visual acuity, occurrence of proliferative vitreoretinopathy, intraocular pressure rise, number of operations and recruitment rate.RESULTS:40 patients were recruited within 21 months. Primary outcome assessment showed similar results in anatomical success with 50% (10/20) in the adjunct group compared with 47% (9/19) in the standard group (OR 1.11, 95% CI 0.316 to 3.904). Visual outcomes were better in the adjunct group with a final median visual acuity of 31 Early Treatment Diabetic Retinopathy Study (ETDRS) letters compared with 25 ETDRS letters in the standard group. A higher proportion of patients gained 10, 20 and 30 ETDRS letters in the adjunct group (80%, 65% and 50%, respectively) compared with the standard group (52.6%, 52.6% and 42.1%). Fewer adjunct patients (15%, n=3) had poor visual outcomes (Zero ETDRS letters) compared with 42.1%, (n=8).CONCLUSIONS:An RCT in this population is deliverable and estimated recruitment rates are realistic. Results and patient discussions determined that the definitive study should have vision as a primary outcome. This pilot study is supportive of there being a positive treatment effect of intensive anti-inflammatory agents in OGT.TRIAL REGISTRATION NUMBER:European Clinical Trials Database 2007-005138-35; Results.