Pachydermoperiostosis Presenting With Vision Loss Secondary to Severe Phlyctenular Keratoconjunctivitis.

PURPOSE: To report a case of severe phlyctenular keratoconjunctivitis in a patient with pachydermoperiostosis (PDP). METHODS: A 29-year-old Hispanic man presented with a 1-year history of vision loss in the right eye and redness, photophobia, and pain in both eyes. Associated symptoms included enlargement of his hands and feet for 3 years, acne, and joint pain. Examination was notable for severe meibomian gland dysfunction, corneal and limbal phlyctenules in both eyes, and central stromal scarring of the right cornea. He had cystic acne of the face and a coarse, wrinkled forehead and scalp. Examination of his hands and feet revealed clubbing of the digits. RESULTS: The patient had an extensive laboratory workup that was significant for elevated erythrocyte sediment rate and C-reactive protein. X-ray of his hands and feet revealed diffuse periosteal hyperostosis with diffuse bone expansion. The patient was diagnosed with PDP with severe meibomian gland dysfunction, phlyctenular keratoconjunctivitis, and corneal scarring. His pain and photophobia resolved with medical management of the phlyctenular keratoconjunctivitis but decreased vision in the right eye persisted because of neovascularization and scarring of the cornea. CONCLUSIONS: We report a rare case of phlyctenular keratoconjunctivitis associated with PDP. To our knowledge, this is the first case of PDP to initially present with vision loss.

CHOROIDAL LESIONS UNRESPONSIVE TO FLUOCINOLONE ACETONIDE INTRAVITREAL IMPLANT IN BIRDSHOT CHORIORETINOPATHY.

PURPOSE: To report the persistence of choroidal lesions despite fluocinolone acetonide intravitreal implants and their resolution with oral prednisone treatment. METHODS: Retrospective chart review of a birdshot chorioretinopathy patient at a tertiary referral clinic. RESULTS: Indocyanine angiography revealed resolution of choroidal lesions with oral prednisone and recurrence after discontinuation of oral prednisone. CONCLUSION: Choroidal lesions responded to oral prednisone despite bilateral active fluocinolone acetonide intravitreal implant in a birdshot chorioretinopathy patient.

The Association between QuantiFERON-TB Gold Test and Clinical Manifestations of Uveitis in the United States.

PURPOSE: To report the prevalence of QuantiFERON-TB Gold (QFT-G) positivity among uveitis patients compared to general population and to evaluate the differences in clinical features of uveitis. DESIGN: Retrospective cohort study. METHODS: SETTING: Institutional. PATIENT POPULATION: 418 consecutive new uveitis patients, regardless of clinical suspicion, were tested for QFT-G. OBSERVATION PROCEDURES: Demographics, TB risk factors, clinical characteristics of uveitis were collected. MAIN OUTCOME MEASURES: The frequency of QFT-G positivity among uveitis patients and characteristic clinical features among QFT-G positive patients. RESULTS: QFT-G positivity was found in 60/418 patients with uveitis (14.4%, 95% CI: 11.18 - 18.14) higher than the general US population (5%, 95% CI: 4.2 - 5.8, p<.001). Age, gender and residence were similar between QFT-G positive and negative groups. Uveitis patients with positive QFT-G were more likely to be foreign born or have a recent travel history (OR:5.84; 95% CI: 2.83 - 12.05; p<.001). QFT-G positive patients were more likely to present with granulomatous uveitis (OR 2.90; 95%CI 1.36 - 6.21; p=.006). No significant association was found with specific clinical features such as choroiditis, retinal vasculitis, occlusive vasculitis, and serpiginoid choroiditis (p>.05 for each). Prevalence of TB-uveitis based on treatment response was 1.19%. CONCLUSIONS: Our study demonstrates significantly higher prevalence of QFT-G positivity among uveitis patients compared to average US population. Characteristic signs of TB uveitis reported in endemic countries were not seen in this cohort. Implications of higher prevalence of QFT-G positivity among uveitis patients require further investigation.

Reproducibility of Full-field Electroretinogram Measurements in Birdshot Chorioretinopathy Patients: An Intra- and Inter-visit Analysis.

Purpose: Aims to determine the variability of ffERG measurements in patients with clinically stable birdshot chorioretinopathy (BCR).Methods: Repeatability coefficients (RC) of ffERG amplitudes and implicit times were calculated from 11 BCR patients. Jackknife resampling estimated 95% confidence intervals of each ERG parameter's RC and the percentage change explained by variability alone was calculated.Results: Intra-visit variability in ffERG parameters was lower than inter-visit. Intravisit RCs demonstrated that for intravisit ERG testing, there was less than 30% variation in ERG amplitude for most parameters. For inter-visit ERG testing, a greater than 40% reduction in ERG amplitude may be clinically meaningful for 6 of 8 ERG parameters. Photopic single flash responses have <2 msec of test-retest variability both within and across visits.Conclusions: A 40% reduction in ERG amplitude and/or a delay of >2 msec in the photopic single flash response may be suitable criteria for meaningful change in BCR patients.

Repeatability of Optical Coherence Tomography Angiography in Uveitic Eyes.

PURPOSE: To investigate the intravisit repeatability of optical coherence tomography angiography (OCTA) in a cohort of uveitis patients. METHODS: One hundred ten patients were imaged twice per eye, per visit, using the Zeiss Cirrus HD-OCT Model 5000 device. To calculate choriocapillaris flow void area (CC FV) 6 × 6-mm images were used, and 3 × 3-mm images were used to calculate vessel density (VD) and the foveal avascular zone area (FAZ) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Repeatability was measured using Bland-Altman analyses and intraclass correlation coefficients (ICC) with associated coefficient of variation (CV). RESULTS: The level of intravisit repeatability differed across indices ranging from moderate to excellent. CC FV had the highest intravisit repeatability with an ICC of 0.980 (95%CI, 0.966-0.989), a CV of 15.9% and Bland-Altman limits of agreement from -0.398 to 0.411 mm2. DCP FAZ had the lowest intravisit repeatability with an ICC of 0.677 (95%CI, 0.510-0.796), a CV of 17.4% and Bland-Altman limits of agreement from -0.395 to -0.355 mm2. Intraoperator repeatability was excellent across all indices. CONCLUSIONS: This study demonstrates that OCTA is a reliable tool to quantitatively assess specific indices of vascular structure in uveitis patients with good intravisit repeatability. However, the range of variability for each index should be taken into account when evaluating clinically meaningful changes. TRANSLATIONAL RELEVANCE: The repeatability of the metrics we have described has implications in supporting the development of OCTA-derived quantitative assessments of the retinal and choroidal vasculature in uveitis patients as potential imaging biomarkers.

Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition.

ARPP-16, ARPP-19, and ENSA are inhibitors of protein phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall kinase inhibit PP2A during mitosis. ARPP-16 is expressed in striatal neurons where basal phosphorylation by MAST3 kinase inhibits PP2A and regulates key components of striatal signaling. The ARPP-16/19 proteins were discovered as substrates for PKA, but the function of PKA phosphorylation is unknown. We find that phosphorylation by PKA or MAST3 mutually suppresses the ability of the other kinase to act on ARPP-16. Phosphorylation by PKA also acts to prevent inhibition of PP2A by ARPP-16 phosphorylated by MAST3. Moreover, PKA phosphorylates MAST3 at multiple sites resulting in its inhibition. Mathematical modeling highlights the role of these three regulatory interactions to create a switch-like response to cAMP. Together, the results suggest a complex antagonistic interplay between the control of ARPP-16 by MAST3 and PKA that creates a mechanism whereby cAMP mediates PP2A disinhibition.

Repressed SIRT1/PGC-1α pathway and mitochondrial disintegration in iPSC-derived RPE disease model of age-related macular degeneration.

BACKGROUND: Study of age related macular degeneration (AMD) has been hampered by lack of human models that represent the complexity of the disease. Here we have developed a human in vitro disease model of AMD to investigate the underlying AMD disease mechanisms. METHODS: Generation of iPSCs from retinal pigment epithelium (RPE) of AMD donors, age-matched normal donors, skin fibroblasts of a dry AMD patient, and differentiation of iPSCs into RPE (AMD RPE-iPSC-RPE, normal RPE-iPSC-RPE and AMD Skin-iPSC-RPE, respectively). Immunostaining, cell viability assay and reactive oxygen species (ROS) production under oxidative stress conditions, electron microscopy (EM) imaging, ATP production and glycogen concentration assays, quantitative real time PCR, western blot, karyotyping. RESULTS: The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE present functional impairment and exhibit distinct disease phenotypes compared to RPE-iPSC-RPE generated from normal donors (Normal RPE-iPSC-RPE). The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE show increased susceptibility to oxidative stress and produced higher levels of reactive oxygen species (ROS) under stress in accordance with recent reports. The susceptibility to oxidative stress-induced cell death in AMD RPE-iPSC-RPE and Skin-iPSC-RPE was consistent with inability of the AMD RPE-iPSC-RPE and Skin-iPSC-RPE to increase SOD2 expression under oxidative stress. Phenotypic analysis revealed disintegrated mitochondria, accumulation of autophagosomes and lipid droplets in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE. Mitochondrial activity was significantly lower in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE compared to normal cells and glycogen concentration was significantly increased in the diseased cells. Furthermore, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a regulator of mitochondrial biogenesis and function was repressed, and lower expression levels of NAD-dependent deacetylase sirtuin1 (SIRT1) were found in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE as compared to normal RPE-iPSC-RPE. CONCLUSIONS: Our studies suggest SIRT1/PGC-1α as underlying pathways contributing to AMD pathophysiology, and open new avenues for development of targeted drugs for treatment of this devastating neurodegenerative disease of the visual system.

Current progress of human trials using stem cell therapy as a treatment for diabetes mellitus.

Diabetes mellitus affects millions of people worldwide, and is associated with serious complications that affect nearly all body systems. Because of the severity of this global health concern, there is a great deal of research being performed on alternative treatments and possible cures. Previous treatments for diabetes have included exogenous insulin injection and pancreatic islet transplantations. These treatment methods have several limitations; thus, the use of stem cells in treating diabetes is currently a significant area of research. This review outlines current research on stem cell therapy for diabetes mellitus. Numerous studies have been performed on animals using various types of stem cells, including mesenchymal stem cells and embryonic stem cells. Moreover, results and limitations of animal studies have been confirmed in various clinical trials. Overall, stem cell treatment shows prospective advantages over insulin injections and other current treatment options, and ongoing clinical trials suggest that this therapy may be a viable treatment option for diabetics in the near future.

Differential effects of cocaine on histone posttranslational modifications in identified populations of striatal neurons.

Drugs of abuse, such as cocaine, induce changes in gene expression and epigenetic marks including alterations in histone posttranslational modifications in striatal neurons. These changes are thought to participate in physiological memory mechanisms and to be critical for long-term behavioral alterations. However, the striatum is composed of multiple cell types, including two distinct populations of medium-sized spiny neurons, and little is known concerning the cell-type specificity of epigenetic modifications. To address this question we used bacterial artificial chromosome transgenic mice, which express EGFP fused to the N-terminus of the large subunit ribosomal protein L10a driven by the D1 or D2 dopamine receptor (D1R, D2R) promoter, respectively. Fluorescence in nucleoli was used to sort nuclei from D1R- or D2R-expressing neurons and to quantify by flow cytometry the cocaine-induced changes in histone acetylation and methylation specifically in these two types of nuclei. The two populations of medium-sized spiny neurons displayed different patterns of histone modifications 15 min or 24 h after a single injection of cocaine or 24 h after seven daily injections. In particular, acetylation of histone 3 on Lys 14 and of histone 4 on Lys 5 and 12, and methylation of histone 3 on Lys 9 exhibited distinct and persistent changes in the two cell types. Our data provide insights into the differential epigenetic responses to cocaine in D1R- and D2R-positive neurons and their potential regulation, which may participate in the persistent effects of cocaine in these neurons. The method described should have general utility for studying nuclear modifications in different types of neuronal or nonneuronal cell types.