Evidence of Pepsin-Related Ocular Surface Damage and Dry Eye (PROD Syndrome) in Patients with Laryngopharyngeal Reflux.

BACKGROUND: patients with laryngopharyngeal reflux (LPR) showed detectable levels of tear pepsin that explain the nasolacrimal obstruction. The purpose of this study was to determine whether patients with LPR show ocular surface changes and to investigate the relationship between lacrimal pepsin concentration and ocular alterations. METHODS: Fifty patients with positive endoscopic signs for LPR and an equal or higher score of 13 and 7 for Reflux Symptom Index and Reflux Finding Score were enrolled. Twenty healthy patients with no reflux disease and dry eye were included as the control group. After evaluation of ocular discomfort symptoms, the tear break-up time test, corneal staining, and tear sampling were performed. Tear pepsin levels were measured using Pep-testTM kit. RESULTS: Patients with LPR showed ocular surface changes including epithelial damage (48%) and impairment of lacrimal function (72%). Tear pepsin levels were detectable in 32 out of 50 (64%) patients with LPR (mean ± SD: 55.4 ± 67.5 ng/mL) and in none of the control subjects. Most of the LPR patients complained of ocular discomfort symptoms, including itching (38%), redness (56%), or foreign body sensation (40%). Tear pepsin levels were significantly correlated with the severity of LPR disease and with ocular surface changes. CONCLUSIONS: A multidisciplinary approach, including ophthalmological evaluation, should be considered in order to improve the management of patients with LPR.

Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells.

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((E)-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((E)-2-bromobenzylidene) cyclic compounds 4a-n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a-n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (4d), benzyl (4e), or acyl (4k-m) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (4f) and 3-phenylpropyl (4g) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (4h-j). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.

Macular Ganglion Cell Layer Thickness after Macula-Off Rhegmatogenous Retinal Detachment Repair: Scleral Buckling versus Pars Plana Vitrectomy.

(1) Background: We evaluated macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness in patients with primary macula-off rhegmatogenous retinal detachment (RRD) treated with scleral buckling (SB) or pars plana vitrectomy (PPV) using spectral domain optical coherence tomography (SD-OCT). (2) Methods: In this retrospective, observational study, we reviewed the medical records of patients undergoing SB or PPV surgery for macula-off RRD. SD-OCT was performed at three and 12 months after surgery. The central and parafoveal GCL-IPL thicknesses in treated eyes were compared with those of healthy fellow eyes. OCT measurements between the SB and PPV group were also compared using the analysis of covariance. (3) Results: Seventy-one eyes of 71 patients with a mean age of 61.2 ± 11.7 years were included. The parafoveal GCL-IPL thickness of the PPV group was significantly reduced, with respect to fellow eyes, at three and 12 months (p < 0.01). After adjusting for age, axial length, spherical equivalent, RD extent, preoperative intraretinal cysts, duration of symptoms and postoperative IOP, the parafoveal GCL-IPL thickness in the PPV group was significantly reduced with respect to the SB group, both at three and 12 months (F = 11.45, p = 0.001 and F = 12.37, p = 0.001, respectively). (4) Conclusions: In conclusion, the GCL-IPL is reduced in thickness in eyes with macula-off RRD treated with vitrectomy and is significantly thinner compared to eyes undergoing scleral buckling surgery.

Sturge-Weber Syndrome Associated with Monolateral Ocular Melanocytosis, Iris Mammillations, and Diffuse Choroidal Haemangioma.

We present the case of a 12-year-old boy with Sturge-Weber syndrome and ocular melanocytosis who presented with bilateral naevus flammeus of the face and hyperpigmentation of the right iris associated with ipsilateral iris mammillations. The patient had glaucoma and a diffuse choroidal haemangioma of the right eye. Optical coherence tomography of the anterior segment confirmed iris hyper-pigmentation and did not show abnormalities of the chamber angle structures. B-scan ultrasonography and enhanced depth imaging optical coherence tomography were performed and showed a marked difference in thickness and reflectance between the right and left choroid. Visual field examinations with perimetry showed early defects in the right eye. Peripapillary optical coherence imaging showed borderline values of retinal nerve fibre layer thickness reduction in the right eye. Sturge-Weber syndrome associated with ocular melanocytosis and iris mammillations is an extremely rare condition. This paper highlights the role of multi-imaging methods in the enhanced evaluation of rare diseases towards choosing the most appropriate management strategies and improving the follow-up of patients over time.

Visual Acuity, and Macular and Peripapillary Thickness in High Myopia.

PURPOSE: To investigate best corrected visual acuity (BCVA), and choroidal and retinal thickness values between high myopes without myopic maculopathy and emmetropes. MATERIALS AND METHODS: Case control study where 53 myopes with axial length (AL) above 26 mm without myopic maculopathy and 53 age-matched emmetropes with AL between 21.50 and 24.50 were included as controls. Complete ophthalmological examination and biometry were performed. Choroidal and individual retinal layer thickness maps using spectral domain optical coherence tomography were obtained in the macular and peripapillary area with enhanced depth imaging. Peripapillary retinal nerve fiber layer (pRNFL) thickness was obtained using the circular 12°diameter scan. RESULTS: Mean age was 31.9 ± 9.9 and 32.5 ± 9.3 years in the myopes and controls, respectively (p > 0.05). Mean BCVA was 55.32 ± 2.50 versus 57.04 ± 2.27 ETDRS letters, in the myopes and controls, respectively (p = 0.0004). AL was the principal predictive factor for macular and peripapillary CT in myopes and macular CT in controls. BCVA was not influenced by choroidal thickness (CT). BCVA positively correlated with global pRNFL, following correction for age and AL, in both groups (r = 0.38, p = 0.008 and r = 0.38, p = 0.007 in the myopic and control groups, respectively). Statistical analysis following correction for the potential confounding factors of age, gender, AL, gender, AL, macular CT, and peripapillary CT, showed no significant differences in macular and peripapillary thicknesses between the two groups. CONCLUSIONS: AL is the principal predictive factor for macular and peripapillary CT in high myopes without maculopathy, and CT is not an independent predictor of visual acuity. Global pRNFL thickness is the only independent predictive factor of BCVA.

An Update on Oculodermal Melanocytosis and Rare Associated Conditions.

Oculodermal melanocytosis (ODM) is a rare disease, which is characterized by hyperpigmentation of facial skin and several parts of the eye, such as the sclera, conjunctiva, cornea, iris, ciliary body, and choroid. The condition usually affects the Asian female population. The most typical presenting ocular sign is iris heterocromia. Iris hyperpigmentation may be associated with iris mammillations, which are dome-shaped protuberations of the iris surface. They are linked to a higher risk of malignant transformation when present in patients with ODM. Glaucoma is a complication of ODM and is caused by angle abnormalities or mechanical occlusion by melanocytes in an open irido-corneal angle. Choroidal and ciliary body melanoma have a higher incidence in this condition characterized by melanocytosis. Patients presenting ODM should undergo routine ophthalmological examination in order to carefully monitor for glaucoma and melanoma.

An Update on the Ophthalmologic Features in the Phakomatoses.

Neurofibromatosis type 1, tuberous sclerosis complex, and Von Hippel-Lindau disease, historically classified as the phakomatoses, are hereditary multisystem disorders characterized by the presence of hamartoma, which carry the risk of malignant transformation. The alteration of tumor suppressor genes seems to be at the basis of their pathophysiogenetic mechanism. Lisch and choroidal nodules in neurofibromatosis type 1, retinal astrocytomas in tuberous sclerosis complex, and retinal capillary hemangioma in Von Hippel-Lindau disease are the principal ophthalmic hamartomatous manifestations. The advent of novel imaging techniques such as near infrared reflectance and optical coherence tomography has provided unprecedented insight on the choroidal and retinal features of these diseases. These methods have improved early diagnosis and the ongoing surveillance in these conditions. Among an array of treatment modalities, antivascular endothelial growth factor therapy has been used in the management of retinal hamartomas but results have been varied. This review is an update on the pathophysiogenetic mechanisms, ophthalmic manifestations, and novel treatment strategies in the phakomatoses with emphasis on the role of imaging techniques.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY EVIDENCE OF RETINAL NERVE FIBER LAYER AND GANGLION CELL LOSS IN ADULT PATIENTS WITH NEUROFIBROMATOSIS TYPE 1.

PURPOSE: To evaluate peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer thickness and analyze their correlations in adult patients with neurofibromatosis Type 1 (NF1) and disease-free controls. METHODS: This cross-sectional study was performed at the Azienda Policlinico Umberto I, University of Rome "La Sapienza." All participants underwent complete ophthalmologic examination. Spectral domain optical coherence tomography was used to evaluate peripapillary retinal nerve fiber layer and obtain retinal segmentation measurements to assess macular retinal nerve fiber layer and ganglion cell layer-inner plexiform layer at 1,000 µm nasal, temporal, superior, and inferior to the fovea. RESULTS: Thirty-four eyes of 17 patients with NF1 (mean age, 42.2 ± 14.3 years) and 34 eyes of 17 disease-free control subjects (mean age, 41.4 ± 12.2 years) were included. All participants had best-corrected visual acuity of 20/20. The mean thickness of peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer was lower in patients with NF1 with respect to controls (P = 0.003, P = 0.022, P < 0.001, respectively). Regression analysis showed a significant correlation (P < 0.001) between mean ganglion cell layer-inner plexiform layer thickness and mean peripapillary retinal nerve fiber layer thickness in patients with NF1. CONCLUSION: Retinal nerve fiber layer and ganglion cell loss correlate well with each other in adult patients with NF1 in comparison with a healthy control population.

Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma: A Review of the Literature with Updates on Surgical Management.

Pseudoexfoliation syndrome (PES) is a systemic disorder caused by progressive accumulation of extracellular material over various tissues. PES usually determines increased intraocular pressure, changes in the anatomical aspects of the optic nerve, and visual field alterations leading to the diagnosis of pseudoexfoliation glaucoma (PEG). Use of topical medical treatment usually leads to poor results in terms of long-term follow-up but many surgical techniques, such as Argon Laser or Selective Laser Trabeculoplasty, have been proposed for the management of PEG affected patients. The present paper is a review on the pseudoexfoliation syndrome and pseudoexfoliation glaucoma with an update on surgical management.

Investigation of pepsin in tears of children with laryngopharyngeal reflux disease.

OBJECTIVES: Numerous investigations postulated that laryngopharyngeal reflux (LPR) is implicated in the pathogenesis of various upper airway inflammatory diseases as sinusitis or dacryostenosis. The presence of pepsin in tears might be confirmed the presuntive hypothesis of the arrival in the nasolacrimal ducts and precorneal tears film through the laryngopharyngeal reflux of either gastric acid or stomach secretions (pepsin) with inflammatory potentialities. The aim of this preliminary study was to identify the presence or absence of pepsin in the tears collected from children with a high suspicion of LPR who underwent 24-h pH (MII-pH) monitoring to confirm the disease. METHODS: This study enrolled 20 patients suffering from symptoms of laryngopharyngeal reflux that underwent 24-h multichannel intraluminal impedance (MII)-pH monitoring to confirm the disease. The findings of the study group were compared with those of a control group of patients with negative pH monitoring. The quantitative analysis of human pepsin concentration in the tear samples was performed by ELISA method in both groups. RESULTS: Four children (20%) of the study group showed pepsin in the tears. All of the subjects belonging to the control group were negative for its presence. No difference differences in the total number of reflux episodes and the number of weakly basic reflux in the pepsin positive patients vs. pepsin negative children were present. CONCLUSIONS: 20% of the children with diagnosed LPR showed pepsin in the tears. Our specific investigation might provide information regarding sinusitis or dacryostenosis.

Potential regulatory molecules in the human trabecular meshwork of patients with glaucoma: immunohistochemical profile of a number of inflammatory cytokines.

Glaucoma occurs when there are imbalances between the production and the drainage of the eye liquid. The vast majority of the aqueous humor leaves the eye through the trabecular meshwork (TM). The cause of hypertonicity may be due to an alteration in the thickness of the TM. In the majority of cases the molecular changes that determine primary open­angle glaucoma (POAG) are unclear. However, it has been hypothesized that the significant increase in the extracellular matrix (ECM) of the fibrillary bands in the TM is associated with possible inflammatory conditions. In this study the tissue distribution of interleukin (IL)­6, IL­1ß, transforming growth factor-ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF­α) was analyzed in TM samples from patients with POAG by immunohistochemistry. Seven specimens from patients with POAG and three control tissues were analyzed by immunohistochemistry using specific antibodies against these cytokines. Morphological changes in the TM, such as increased cell content, macrophages, fibrosis and accumulation of neutrophils, were observed by transmission electron microscopy. In human TM tissues, an evident immunoreactivity for IL­6, IL­1ß and TNF­α was observed in patients with POAG when compared with the control subjects, indicating that these cytokines may be correlated with disease activity. TM endothelial cells secrete a number of factors and cytokines that modulate the functions of the cells and the ECM of the conventional outflow pathway. In the TM in glaucoma, macrophages produce cytokines, including IL­6, IL­1ß and TNF­α, leading to an acute inflammatory response and recruitment of other immune cells, including T lymphocytes. In addition, TGF­ß1 regulates and induces the expression of IL­6 in TM that indirectly induces angiogenesis by stimulating VEGF expression. The present results support previous evidence that suggests that growth factors and cytokines can induce ECM remodelling and alter cytoskeletal interactions in the TM.

Morphologic and vasculature features of the choroid and associated choroid-retinal thickness alterations in neurofibromatosis type 1.

BACKGROUND/AIMS: A normal structural and functional choroid is essential in supplying blood flow to the retina. Neurofibromatosis type 1 (NF1) is a neurocristopathy where the choroid is altered due to the presence of nodules. The present transversal study was conducted to examine choroidal nodules and their effect on choroidal and retinal thickness in NF1 patients. METHODS: Near-infrared reflectance and optical coherence tomography with enhanced depth imaging were used to evaluate choroidal morphology and vasculature in 19 patients with NF1 and 19 healthy, age-matched control subjects. Choroidal thickness, neuroepithelium thickness, photoreceptors together with retinal pigment epithelium (RPE) thickness and outer nuclear layer (ONL) thickness were measured at the fovea and 1000 µm nasal, temporal, superior and inferior to the fovea in NF1 patients and control subjects. Choroidal and neuroepithelium thickness were assessed overlying and adjacent to nodules in NF1 patients. RESULTS: Choroidal nodules were classified as 'dome-shaped' or 'placcoid' subtypes in 17 patients. Small and medium calibre choroidal vessels were observed above dome-shaped nodules where choroidal thickness was significantly reduced. There was a statistically significant reduction in mean choroidal thickness (p=0.013) in NF1 patients with respect to control subjects. The neuroepithelium, photoreceptors together with RPE and ONL had a statistically significant reduction in mean thickness in NF1 patients (p<0.001, p<0.001, p=0.012, respectively). CONCLUSIONS: In NF1, there are dome-shaped and placcoid choroidal nodules which alter choroidal morphology and thickness. There is reduction in mean choroid thickness with generalised thinning of the neuroepithelium, photoreceptors together with RPE and ONL in NF1 patients.

Role of the dopaminergic system in the development of myopia in children and adolescents.

This review summarizes the experimental evidence that supports the role of dopamine in the regulation of ocular axial growth. The most important functions attributed to dopamine are light adaptation and regulation of the retinal circadian rhythm. An increase of the retinal levels of dopamine activates D1 and D2 dopaminergic receptors present throughout the retina, generating a signal that inhibits axial growth once the eye has reached emmetropization. Researchers induced form-deprivation myopia in animal models in order to assess the different changes of ocular axial growth. Other studies have shown that phenylethylamine is an endogenous precursor-neurotransmitter capable of modulating the activity of dopamine. Considering the role of the dopaminergic system in the development of myopia (in children and adolescents) and the fact that phenylethylamine improves the consequences of a dopamine deficit, it would be interesting to study the effect of phenylethylamine on the regulation of axial growth, which represents the genesis of myopia.

Curcumin: therapeutical potential in ophthalmology.

Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

Iatrogenic dry eye disease: an eledoisin/carnitine and osmolyte drops study.

BACKGROUND: To evaluate the effects of an eye drop containing eledoisin and carnitine in patients suffering from primary open-angle glaucoma (POAG) and ocular discomfort syndrome secondary to a chronically treated with eye drops containing benzalkonium chloride (BAK) as preservative. The dry eye disease was defined as a multifactorial drop disease concerning tears and ocular surface, which brings to discomfort symptoms and visual disorders with potential damage to the ocular surface. Several studies underlined the beneficial effects of secretagogues drugs, such as eledoisin. It is a neuro-peptide extracted from the salivary glands of some shellfishes. Recently, it has been also showed the protective role of carnitine in respect of the ocular surface exposed to the tear film hyperosmolarity. MATERIALS AND METHODS: This randomized double-blind pilot study has been evaluated by lubricant eye drop solutions containing eledoisin and carnitine in 40 patients with ocular discomfort syndrome secondary to POAG, since that the patients were chronically treated with eye drops which decrease eye pressure and contain BAK as preservative. The subjects filled out a questions form concerning the severity of the symptoms and their impact on daily activities. Subsequently Fluorescein Breakup Time (FBUT), Schirmer Test 1 (ST), and Ocular Protection Index (OPI) were measured at baseline and after 15days of treatment. RESULTS: At the end of therapy it was possible to match the beneficial effects of eye drops with carnitin, taurine, sodium hyaluronate and eledoisin. In fact, after 15days of treatment, patients of group 1 showed a decrease of approximately 50% concerning the severity of symptoms and a significant improvement of the tests valued. CONCLUSION: In summary, lubricant eye drops that restore physiological hosmolarity and stimulate tear production represent a promising strategy for dry eye syndrome.

Gastroesophageal reflux disease and the presence of pepsin in the tears.

The nasolacrimal duct in association with the lacrimal puncta, lacrimal canaliculi and lacrimal sac functions to collect and drain the tear film into the nasal cavity at the inferior nasal meatus where a fold of nasal mucosa, the so-called valve of Hasner, prevents mucous from entering the nose. High-resolution computed tomography demonstrated air inside the sac and nasolacrimal duct in approximately 29.3% of healthy patients suggesting that the system is not completely competent and that air and secretions might reach the precorneal film. Gastroesophageal reflux disease may contribute to dacryostenosis and subsequent primary acquired nasolacrimal duct obstruction. However a cause-effect relationship is unclear and only presumptive unless the presence of pepsin in tears can be demonstrated. Gastroesophageal and extra-esophageal reflux could reach the tear film via the nasolacrimal duct in a retrograde fashion and the middle ear via the Eustachian tube. We postulated that the ascending products of gastroesophageal reflux could cause edema of the nasolacrimal duct mucosa, which might progress to fibrosis and chronic inflammation and, ultimately, complete obstruction of the duct with epiphora. The role of reflux in the initial phase of this pathophysiological mechanisms could be demonstrated indirectly by pepsin. By contrast, the development of dacryostenosis blocking the passage of the nasolacrimal duct and thereby preventing pepsin from reaching the lacrimal film failed to explain the influence of gastroesophageal reflux disease with certainty.

Surgical management by means of electroretinographic examination during extracorporeal circulation.

BACKGROUND: Neurological and/or neuropsychological damages are important complications of cardiosurgical interventions. This study determined if the timing of the electroretinographic (ERG) ocular exam can assess intraoperative brain damage of patients supported by extracorporeal circulation (ECC) during cardiosurgical interventions. MATERIALS AND METHODS: The authors illustrate an ERG technique being able to evaluate on 12 patients during cardiosurgical interventions and in conditions of ECC, both hypothermic and normothermic, the possibility to forecast the potential neurological and/or neuropsychological damages. RESULTS: The ERG waves obtained are compared before and after ECC in various conditions of corporeal temperature. During ECC all patients had a change of ERG waves, whom was particularly significant for patients operated in conditions of induced hypothermia. CONCLUSIONS: The observations reported by ERG provide new and important information in support of the potential organic suffering. This exam can assess the defect of the waves indicative of insufficient ocular and brain perfusion of patients supported by ECC during cardiosurgical interventions.