The serum angiotensin converting enzyme and lysozyme levels in patients with ocular involvement of autoimmune and infectious diseases.

BACKGROUND: Increased serum levels of angiotensin converting enzyme and lysozyme are considered as inflammatory markers for diagnosis of sarcoidosis which is an autoimmune inflammatory disease. The purpose of this study is to evaluate the significance of differences in serum angiotensin converting enzyme and lysozyme levels of patients with ocular involvement of other autoimmune inflammatory and infectious diseases. METHODS: This is a prospective study involving patients with ankylosing spondylitis, behcet's disease, presumed sarcoidosis, presumed latent tuberculosis, presumed latent syphilis, and control group. The serum levels of angiotensin converting enzyme and lysozyme were analyzed by enzyme-linked immunosorbent assay. Bonnferoni analysis was used to assess pairwise comparisons between the groups. RESULTS: There was a significant increase in serum angiotensin converting enzyme level in patients with presumed sarcoidosis compared to ankylosing spondylitis (p = 0.0001), behcet's disease (p = 0.0001), presumed latent tuberculosis (p = 0.0001), presumed latent syphilis (p = 0.0001), and control group (p = 0.0001). The increase in serum lysozyme level was significant for patients with presumed sarcoidosis with respect to ankylosing spondylitis (p = 0.0001), behcet's disease, (p = 0.0001) presumed latent tuberculosis (p = 0.001), presumed latent syphilis (p = 0.033), and control group (p = 0.0001). CONCLUSION: Elevated serum angiotensin converting enzyme levels are significant for patients with presumed sarcoidosis compared to ocular involvement of other autoimmune diseases such as behcet's disease and ankylosing spondylitis, and ocular involvement of infectious diseases such as presumed latent tuberculosis and presumed latent syphilis. However, elevated serum lysozyme level might be also detected in ocular involvement of infectious diseases such as presumed latent tuberculosis and presumed latent syphilis. TRIAL REGISTRATION NUMBER: NCT02627209. Date of registration: 12/09/2015.

The role of methotrexate in resolving ocular inflammation after specific therapy for presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis.

PURPOSE: This study was designed to investigate whether the antiinflammatory and antiproliferative activity of oral and intravitreal methotrexate (MTX) suppresses intraocular inflammation in patients with presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis. METHODS: Interventional prospective study including three cases with presumed latent syphilitic uveitis treated with intravenous penicillin and oral MTX, and two cases with presumed tuberculosis-related uveitis treated with standard antituberculosis therapy and intravitreal MTX injections. Treatment efficacy of all cases was assessed by best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography. RESULTS: Four eyes of 3 patients with presumed latent syphilitic uveitis had improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema in 6 months with oral MTX therapy. No recurrence of intraocular inflammation was observed in 6 months to 18 months of follow-up period after cessation of MTX. Two eyes of two patients with presumed tuberculosis-related uveitis showed improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema after intravitreal injections of MTX. No recurrence of intraocular inflammation was observed in 6 months to 8 months of follow-up period after cessation of antituberculous therapy. CONCLUSION: For the first time in the treatment of presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis, we believe that MTX might have an adjunctive role to suppress intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the diseases.

Molecular bases of corneal endothelial dystrophies.

The phrase "corneal endothelial dystrophies" embraces a group of bilateral corneal conditions that are characterized by a non-inflammatory and progressive degradation of corneal endothelium. Corneal endothelial cells exhibit a high pump site density and, along with barrier function, are responsible for maintaining the cornea in its natural state of relative dehydration. Gradual loss of endothelial cells leads to an insufficient water outflow, resulting in corneal edema and loss of vision. Since the pathologic mechanisms remain largely unknown, the only current treatment option is surgical transplantation when vision is severely impaired. In the past decade, important steps have been taken to understand how endothelial degeneration progresses on the molecular level. Studies of affected multigenerational families and sporadic cases identified genes and chromosomal loci, and revealed either Mendelian or complex disorder inheritance patterns. Mutations have been detected in genes that carry important structural, metabolic, cytoprotective, and regulatory functions in corneal endothelium. In addition to genetic predisposition, environmental factors like oxidative stress were found to be involved in the pathogenesis of endotheliopathies. This review summarizes and crosslinks the recent progress on deciphering the molecular bases of corneal endothelial dystrophies.

Domain adaptation for segmentation of critical structures for prostate cancer therapy.

Preoperative assessment of the proximity of critical structures to the tumors is crucial in avoiding unnecessary damage during prostate cancer treatment. A patient-specific 3D anatomical model of those structures, namely the neurovascular bundles (NVB) and the external urethral sphincters (EUS), can enable physicians to perform such assessments intuitively. As a crucial step to generate a patient-specific anatomical model from preoperative MRI in a clinical routine, we propose a multi-class automatic segmentation based on an anisotropic convolutional network. Our specific challenge is to train the network model on a unique source dataset only available at a single clinical site and deploy it to another target site without sharing the original images or labels. As network models trained on data from a single source suffer from quality loss due to the domain shift, we propose a semi-supervised domain adaptation (DA) method to refine the model's performance in the target domain. Our DA method combines transfer learning and uncertainty guided self-learning based on deep ensembles. Experiments on the segmentation of the prostate, NVB, and EUS, show significant performance gain with the combination of those techniques compared to pure TL and the combination of TL with simple self-learning ([Formula: see text] for all structures using a Wilcoxon's signed-rank test). Results on a different task and data (Pancreas CT segmentation) demonstrate our method's generic application capabilities. Our method has the advantage that it does not require any further data from the source domain, unlike the majority of recent domain adaptation strategies. This makes our method suitable for clinical applications, where the sharing of patient data is restricted.

Investigating the role of DCE-MRI, over T2 and DWI, in accurate PI-RADS v2 assessment of clinically significant peripheral zone prostate lesions as defined at radical prostatectomy.

PURPOSE: PI-RADS v2 dictates that dynamic contrast-enhanced (DCE) imaging be used to further classify peripheral zone (PZ) cases that receive a diffusion-weighted imaging equivocal score of three (DWI3), a positive DCE resulting in an increase in overall assessment score to a four, indicative of clinically significant prostate cancer (csPCa). However, the accuracy of DCE in predicting csPCa in DWI3 PZ cases is unknown. This study sought to determine the frequency with which DCE changes the PI-RADS v2 DWI3 assessment category, and to determine the overall accuracy of DCE-MRI in equivocal PZ DWI3 lesions. MATERIALS AND METHODS: This is a retrospective study of patients with pathologically proven PCa who underwent prostate mpMRI at 3T and subsequent radical prostatectomy. PI-RADS v2 assessment categories were determined by a radiologist, aware of a diagnosis of PCa, but blinded to final pathology. csPCa was defined as a Gleason score ≥ 7 or extra prostatic extension at pathology review. Performance characteristics and diagnostic accuracy of DCE in assigning a csPCa assessment in PZ lesions were calculated. RESULTS: A total of 271 men with mean age of 59 ± 6 years mean PSA 6.7 ng/mL were included. csPCa was found in 212/271 (78.2%) cases at pathology, 209 of which were localized in the PZ. DCE was necessary to further classify (45/209) of patients who received a score of DWI3. DCE was positive in 29/45 cases, increasing the final PI-RADS v2 assessment category to a category 4, with 16/45 having a negative DCE. When compared with final pathology, DCE was correct in increasing the assessment category in 68.9% ± 7% (31/45) of DWI3 cases. CONCLUSION: DCE increases the accuracy of detection of csPCa in the majority of PZ lesions that receive an equivocal PI-RADS v2 assessment category using DWI.

Predictive role of PI-RADSv2 and ADC parameters in differentiating Gleason pattern 3 + 4 and 4 + 3 prostate cancer.

PURPOSE: To compare the predictive roles of qualitative (PI-RADSv2) and quantitative assessment (ADC metrics), in differentiating Gleason pattern (GP) 3 + 4 from the more aggressive GP 4 + 3 prostate cancer (PCa) using radical prostatectomy (RP) specimen as the reference standard. METHODS: We retrospectively identified treatment-naïve peripheral (PZ) and transitional zone (TZ) Gleason Score 7 PCa patients who underwent multiparametric 3T prostate MRI (DWI with b value of 0,1400 and where unavailable, 0,500) and subsequent RP from 2011 to 2015. For each lesion identified on MRI, a PI-RADSv2 score was assigned by a radiologist blinded to pathology data. A PI-RADSv2 score ≤ 3 was defined as "low risk," a PI-RADSv2 score ≥ 4 as "high risk" for clinically significant PCa. Mean tumor ADC (ADCT), ADC of adjacent normal tissue (ADCN), and ADCratio (ADCT/ADCN) were calculated. Stepwise regression analysis using tumor location, ADCT and ADCratio, b value, low vs. high PI-RADSv2 score was performed to differentiate GP 3 + 4 from 4 + 3. RESULTS: 119 out of 645 cases initially identified met eligibility requirements. 76 lesions were GP 3 + 4, 43 were 4 + 3. ADCratio was significantly different between the two GP groups (p = 0.001). PI-RADSv2 score ("low" vs. "high") was not significantly different between the two GP groups (p = 0.17). Regression analysis selected ADCT (p = 0.03) and ADCratio (p = 0.0007) as best predictors to differentiate GP 4 + 3 from 3 + 4. Estimated sensitivity, specificity, and accuracy of the predictive model in differentiating GP 4 + 3 from 3 + 4 were 37, 82, and 66%, respectively. CONCLUSIONS: ADC metrics could differentiate GP 3 + 4 from 4 + 3 PCa with high specificity and moderate accuracy while PI-RADSv2, did not differentiate between these patterns.

Automatic Needle Segmentation and Localization in MRI With 3-D Convolutional Neural Networks: Application to MRI-Targeted Prostate Biopsy.

Image guidance improves tissue sampling during biopsy by allowing the physician to visualize the tip and trajectory of the biopsy needle relative to the target in MRI, CT, ultrasound, or other relevant imagery. This paper reports a system for fast automatic needle tip and trajectory localization and visualization in MRI that has been developed and tested in the context of an active clinical research program in prostate biopsy. To the best of our knowledge, this is the first reported system for this clinical application and also the first reported system that leverages deep neural networks for segmentation and localization of needles in MRI across biomedical applications. Needle tip and trajectory were annotated on 583 T2-weighted intra-procedural MRI scans acquired after needle insertion for 71 patients who underwent transperineal MRI-targeted biopsy procedure at our institution. The images were divided into two independent training-validation and test sets at the patient level. A deep 3-D fully convolutional neural network model was developed, trained, and deployed on these samples. The accuracy of the proposed method, as tested on previously unseen data, was 2.80-mm average in needle tip detection and 0.98° in needle trajectory angle. An observer study was designed in which independent annotations by a second observer, blinded to the original observer, were compared with the output of the proposed method. The resultant error was comparable to the measured inter-observer concordance, reinforcing the clinical acceptability of the proposed method. The proposed system has the potential for deployment in clinical routine.

Clinical and laboratory characteristics of ocular syphilis, co-infection, and therapy response.

PURPOSE: To describe the clinical presentation of patients diagnosed with presumed latent ocular syphilis and congenital ocular syphilis at tertiary referral center in Turkey, and to compare the clinical findings with patients described in other studies, specifically focusing on demographics and co-infections. METHODS: This is a retrospective study reviewing the medical records of patients diagnosed with ocular inflammation between January 2012 and June 2014 at a tertiary referral center in Turkey. Ocular syphilis was diagnosed on the basis of non-treponemal and treponemal antibody tests, and cerebrospinal fluid analysis. All the patients diagnosed with ocular syphilis were tested for human immunodeficiency virus (HIV), Toxoplasma gondii, rubella, cytomegalovirus, and herpes. RESULTS: A total of 1,115 patients were evaluated between January 2012 and June 2014, and 12 patients (1.07%) were diagnosed with ocular syphilis based on the inclusion criteria. None of the patients were seropositive for HIV. Two patients were seropositive for T. gondii-specific IgG. Clinical presentations include non-necrotizing anterior scleritis, non-necrotizing sclerokeratitis, anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, and optic neuritis. All of the patients showed clinical improvement in the level of ocular inflammation with intravenous penicillin 24 million U/day for 10 days. Three patients received additional oral methotrexate as an adjunctive therapy. Two cases received low-dose trimethoprim-sulfamethoxazole. CONCLUSION: Ocular syphilis is an uncommon cause of ocular inflammation in HIV-negative patients. Central retinochoroiditis is the most common ocular manifestation, and it is the most common cause of visual impairment. Ocular syphilis might present associated with co-infections such as T. gondii in developing countries. Oral methotrexate might be beneficial as an adjunctive therapy for ocular syphilis in resolving the residual intraocular inflammation and cystoid macular edema after specific therapy with intravenous penicillin.

The effect of implant thread design on stress distribution in anisotropic bone with different osseointegration conditions: a finite element analysis.

PURPOSE: Whereas bone is anisotropic, nearly all previous mechanical analyses of implants assumed bone as an isotropic material. Another means to simplify a simulation of the biomechanics of the implant-bone interface is the assumption of complete or no osseointegration; in clinical reality, an implant never achieves 100% contact with the surrounding bone. This study evaluated different thread profiles while not taking into account these two common simplifications. This study sought to (1) investigate the effects of various implant thread designs on stress distribution in the peri-implant bone, (2) appraise previous efforts in this area, and (3) find an optimum basic thread-form design. MATERIALS AND METHODS: Through finite element analysis, four different basic commercial thread-form configurations for a solid screw-type implant were modeled: buttress, reverse buttress, V, and square. Bone was assumed to be transversely isotropic, and various degrees of osseointegration were simulated. RESULTS: Simulations showed that von Mises stresses were more distributed in the mesiodistal direction. Additionally, maximum stresses were concentrated at the cervical cortical bone region and the first thread. Moreover, in most of the models, von Mises stresses gradually increased in the supporting structure when the degree of osseointegration increased. CONCLUSION: The use of different thread designs and various osseointegration conditions did not affect the stress distribution patterns in the supporting bone. In this study, square threads showed the most favorable results according to the predicted values of von Mises equivalent stress, pressure, different shear stresses, and micromotion.

Central Corneal Thickness in Highly Myopic Eyes: Inter-device Agreement of Ultrasonic Pachymetry, Pentacam and Orbscan II Before and After Photorefractive Keratectomy.

PURPOSE: To determine inter-device agreement for central corneal thickness (CCT) measurement among ultrasound pachymetry, rotating Scheimpflug imaging (Pentacam, Oculus, Wetzlar, Germany), and scanning slit corneal topography (Orbscan II, Bausch & Lomb, Rochester, NY, USA) in highly myopic eyes before and after photorefractive keratectomy (PRK). METHODS: This prospective comparative study included 61 eyes of 32 patients with high myopia who underwent PRK. Six month postoperative CCT values were compared to preoperative values in 27 patients (51 eyes) who completed the follow up period. To determine the level of agreement, Pentacam and Orbscan II readings were compared to ultrasonic pachymetry measurements as the gold standard method. RESULTS: Mean CCT measurements with ultrasound, Pentacam, and Orbscan II before PRK were 557µm, 556µm, and 564µm, respectively; and 451µm, 447µm, and 438µm 6 months after surgery in the same order. Preoperatively, the 95% limits of agreement (LoA) with ultrasound measurements were -20µm to 17µm for Pentacam and -21µm to 33µm for Orbscan II. Six months postoperatively, the 95% LoA were -30µm to 23µm for Pentacam and -69µm to 43µm for Orbscan II. CONCLUSION: Preoperatively, CCT measurements were higher with Orbscan II as compared to ultrasound. Postoperatively, both Pentacam and Orbscan II measurements were lower than those obtained with ultrasound, but Pentacam had better agreement. The use of ultrasound, as the gold standard method, or Pentacam both appear to be preferable over Orbscan II among patients with high myopia.

Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: a novel treatment.

PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is an oxidative stress disorder that leads to age-related and gradual loss of corneal endothelial cells resulting in corneal edema and loss of vision. To date, other than surgical intervention, there are no treatment options for patients with FECD. We have shown that in FECD, there is a deficiency in nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidant defense due to decreased Nrf2 nuclear translocation and activation of antioxidant response element (ARE). In this study, we used sulforaphane (SFN) and D3T to investigate a strategy of targeting Nrf2-ARE in FECD. METHODS: FECD and normal ex vivo corneas and human corneal endothelial cell lines were pretreated with SFN or D3T and exposed to oxidative stress with tert-Butyl hydroperoxide (tBHP). Apoptosis was detected with TUNEL. Cellular localization of Nrf2 and p53 was assessed by immunohistochemistry. Effect of SFN was determined by using DCFDA assay, Western blot and real-time PCR. RESULTS: After pretreatment with SFN, oxidative stress was induced with tBHP. In ex vivo FECD specimens, SFN decreased CEC apoptosis by 55% in unstressed group and by 43% in tBHP-treated specimens. SFN enhanced nuclear translocation of Nrf2 in FECD specimens and decreased p53 staining under oxidative stress. Pretreatment with SFN enhanced cell viability by decreasing intracellular reactive oxygen species production. Upregulation of Nrf2 levels led to increased synthesis of DJ-1, heme oxygenase 1, and nicotinamide adenine dinucleotide quinone oxidoreductase-1. SFN significantly upregulated major ARE-dependent antioxidants and ameliorated oxidative stress-induced apoptosis in FECD. CONCLUSIONS: Our results suggest that targeting Nrf2-ARE pathway may arrest degenerative cell loss seen in FECD.

Ocular graft versus host disease following allogeneic stem cell transplantation: a review of current knowledge and recommendations.

Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT). Ocular GVHD develops in approximately 40-60% of patients following allo-SCT and its most common clinical manifestations include keratoconjunctivitis sicca and cicatricial conjunctivitis. Ocular GVHD may lead to severe ocular surface disease, which can significantly diminish quality of life and restrict daily activities. It is thus important to monitor the condition closely since with timely diagnosis, irreversible damage can be avoided. The current review will focus on updated information regarding ocular GVHD.

Decline in DJ-1 and decreased nuclear translocation of Nrf2 in Fuchs endothelial corneal dystrophy.

PURPOSE: This study sought to determine factors involved in nuclear factor erythroid 2-related factor 2 (Nrf2) regulation and their response to oxidative stress in Fuchs endothelial corneal dystrophy (FECD) and normal corneal endothelial cells (CECs). METHODS: FECD corneal buttons were obtained from transplantations and normal human corneas from tissue banks. Oxidative stress was induced by tert-butyl hydroperoxide (tBHP). Protein and mRNA levels of Nrf2, DJ-1, p53, and Kelch-like ECH-associated protein1 (Keap1) were investigated using Western blotting and real-time PCR. Immunoprecipitation was used to detect levels of oxidized DJ-1 protein and Cullin 3- (Cul3)-regulated degradation of DJ-1 in immortalized FECD (FECDi) and normal CEC (HCECi) cell lines. Nrf2 subcellular localization was assessed by immunocytochemistry. RESULTS: Nrf2 protein stabilizer, DJ-1, decreased significantly in FECD CECs compared with normal, whereas Nrf2 protein repressor, Keap1, was unchanged at baseline but increased under oxidative stress. Under oxidative stress, normal CECs upregulated DJ-1 protein synthesis, whereas FECD CECs did not. DJ-1 decline correlated with increased DJ-1 oxidative modification and carbonylation in FECDi as compared with HCECi. Increased labeling of immunoprecipitated DJ-1 protein with anti-Cul3 antibody indicated enhanced DJ-1 degradation in FECDi as compared with HCECi. Following tBHP treatment, Nrf2 translocated from cytoplasm to nuclei in normal CECs, whereas Nrf2 nuclear localization was not observed in FECD. CONCLUSIONS: Decreased levels of DJ-1 in FECD at baseline and under oxidative stress correlate with impaired Nrf2 nuclear translocation and heightened cell susceptibility to apoptosis. Targeting the DJ-1/Nrf2 axis could yield a mechanism to slow CEC degeneration in FECD.

p53-regulated increase in oxidative-stress--induced apoptosis in Fuchs endothelial corneal dystrophy: a native tissue model.

PURPOSE: This study compared susceptibility of Fuchs endothelial corneal dystrophy (FECD) and normal corneal endothelial cells (CECs) to oxidative stress, and studied the mechanism of oxidative-stress-induced apoptosis in FECD-affected endothelium. METHODS: For in vitro studies, immortalized normal and FECD human corneal endothelial cell lines (HCECi and FECDi, respectively) were exposed to tert-butyl hydroperoxide (tBHP). Apoptotic cell populations were distinguished using flow cytometry. Reactive oxygen species production was measured by a horseradish peroxidase assay. For ex vivo studies, CECs were exposed to tBHP. Oxidative DNA damage and apoptosis were assessed by anti-8-hydroxydeoxyguanosine antibody and TUNEL assay, respectively. p53 and phospho-p53 levels were assessed by Western blot and immunohistochemistry. RESULTS: Flow cytometry revealed a higher rate of apoptosis in FECDi than that in HCECi after exposure to 0.5 mM (P=0.010) and 1.0 mM tBHP (P=0.041). Further analysis showed increased production of H2O2 by FECDi than that by HCECi. Oxidative DNA damage increased in both normal and FECD CECs after exposure to 0.5 mM tBHP (P=0.031 and 0.022, respectively), leading to a 21% increase in TUNEL-positive CECs in FECD (P=0.015) but no change in normal. Baseline p53 expression was twofold higher in FECD than that in normal endothelium (P=0.002). Immunofluorescence revealed an increase in p53 and phospho-p53 levels in FECD compared with that in normal endothelium. CONCLUSIONS: FECD CECs are more susceptible to oxidative DNA damage and oxidative-stress-induced apoptosis than normal. Increased activation of p53 in FECD suggests that it mediates cell death in susceptible CECs. The authors conclude that p53 plays a critical role in complex mechanisms regulating oxidative-stress-induced apoptosis in FECD.