Progressive Blindness Research Articles

Bilateral Chronic Subdural Hematoma and Blindness: Bilateral Infarction to the Posterior Cerebral Artery following Evacuation of Bilateral Chronic Subdural Hematoma — A Rare Case Report and Review of Literature

Objective The authors report a rare scenario in which evacuation of bilateral chronic subdural hematoma (CSDH) was followed by bilateral PCA infarction and blindness. A literature review was also conducted, which revealed only four cases of blindness after CSDH evacuation. Methods A 45-year-old man was admitted with the chief complaint of holocranial headache for 2 months with past history of head trauma. Clinical examination was normal. CT and MRI scanning showed bilateral frontotemperoparietal CSDH without midline shift and parenchymal and vascular abnormality. Bilateral frontal and parietal burr holes and evacuation of CSDH was done. Results The patient developed progressive blindness in both the eyes in the postoperative period. MRI revealed bilateral PCA infarction. Discussion Bilateral PCA infarction following bilateral CSDH evacuation is an extremely rare entity. Only four case of blindness following CSDH evacuation have been reported so far, and all the patients suffered permanent visual loss. The exact etiopathogenesis and mechanism of this rare complication remain unknown. Conclusion Bilateral CSDH is a separate entity with altered pathophysiology and deranged cerebral autoregulation. The authors conclude that Bilateral CSDH may be sentinel tags for bilateral PCA infarction secondary to altered hemodynamics in the posterior circulation, and hence, needs to be evaluated and treated with greater diligence.

Oligomeric State and Thermal Stability of Apo- and Holo- Human Ornithine \u03b4-Aminotransferase

Human ornithine δ-aminotransferase (hOAT) (EC 2.6.1.13) is a mitochondrial pyridoxal 5′-phosphate (PLP)-dependent aminotransferase whose deficit is associated with gyrate atrophy, a rare autosomal recessive disorder causing progressive blindness and chorioretinal degeneration. Here, both the apo- and holo-form of recombinant hOAT were characterized by means of spectroscopic, kinetic, chromatographic and computational techniques. The results indicate that apo and holo-hOAT (a) show a similar tertiary structure, even if apo displays a more pronounced exposure of hydrophobic patches, (b) exhibit a tetrameric structure with a tetramer-dimer equilibrium dissociation constant about fivefold higher for the apoform with respect to the holoform, and (c) have apparent Tm values of 46 and 67 °C, respectively. Moreover, unlike holo-hOAT, apo-hOAT is prone to unfolding and aggregation under physiological conditions. We also identified Arg217 as an important hot-spot at the dimer–dimer interface of hOAT and demonstrated that the artificial dimeric variant R217A exhibits spectroscopic properties, Tm values and catalytic features similar to those of the tetrameric species. This finding indicates that the catalytic unit of hOAT is the dimer. However, under physiological conditions the apo-tetramer is slightly less prone to unfolding and aggregation than the apo-dimer. The possible implications of the data for the intracellular stability and regulation of hOAT are discussed.

Vitamin Fortification of Fluid Milk.

Vitamin concentrates with vitamins A and D are used for fortification of fluid milk. Although many of the degradation components of vitamins A and D have an important role in flavor/fragrance applications, they may also be source(s) of off-flavor(s) in vitamin fortified milk due to their heat, oxygen, and the light sensitivity. It is very important for the dairy industry to understand how vitamin concentrates can impact flavor and flavor stability of fluid milk. Currently, little research on vitamin degradation products can be found with respect to flavor contributions. In this review, the history, regulations, processing, and storage stability of vitamins in fluid milk are addressed along with some hypotheses for the role of vitamin A and D fortification on flavor and stability of fluid milk.

Retinitis Pigmentosa and Other Dystrophies.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations characterized by progressive degeneration of rod and cone cells that affects predominantly peripheral visual fields. Macular edema may cause additional central visual acuity decrease. Cystoid macular edema (CME) is one of the few treatable causes of visual loss in RP. The prevalence of CME in RP has been found to be between 10 and 20% on fluorescein angiography-based studies, and as high as 49% on reports based on optical coherence tomography. Macular edema can manifest at any stage of the disease and may be unilateral or bilateral. It can be found in any genetic form, but is more often associated with RP caused by CRB1 mutations. The origin of macular edema in RP patients still remains poorly understood. Some mechanisms have been suggested, including antiretinal antibodies (retinal, carbonic anhydrase, and enolase antibodies), vitreous traction, retinal pigment epithelium dysfunction, and Müller cell edema. There is no gold standard therapeutic strategy. Drug therapy is the primary treatment. Systemic carbonic anhydrase inhibitors, such as oral acetazolamide or topical dorzolamide, are still the mainstays of initial therapy. If CME is refractory to acetazolamide, intravitreal corticosteroid injections may be a therapeutic option. However, antivascular endothelium growth factor injections have limited effect and should be avoided. Vitrectomy has also been evaluated, but its exact role remains to be determined. The benefits of these therapies are variable among patients. The establishment of therapeutic approaches is limited by our poor understanding of the pathophysiology of CME in patients with RP. Autoimmune retinopathies (AIRs) are a group of rare diseases characterized by acute or subacute progressive vision loss and are thought to be mediated by autoantibodies specific to retinal antigens. The AIRs encompass paraneoplastic syndromes, such as cancer-associated retinopathy and melanoma-associated retinopathy, and a larger group of AIRs that have similar clinical and immunological findings but without underlying malignancy. These diseases may also be complicated by macular edema. RP is one of the most common forms of inherited retinal degeneration. It displays extensive clinical and genetic variations and leads to progressive blindness with variable onset.

Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis

A 10‐month‐old spayed female Cane Corso dog was evaluated after a 2‐month history of progressive blindness, ataxia, and lethargy. Neurologic examination abnormalities indicated a multifocal lesion with primarily cerebral and cerebellar signs. Clinical worsening resulted in humane euthanasia. On necropsy, there was marked astrogliosis throughout white matter tracts of the cerebrum, most prominently in the corpus callosum. In the cerebral cortex and midbrain, most neurons contained large amounts of autofluorescent storage material in the perinuclear area of the cells. Cerebellar storage material was present in the Purkinje cells, granular cell layer, and perinuclear regions of neurons in the deep nuclei. Neuronal ceroid lipofuscinosis (NCL) was diagnosed. Whole genome sequencing identified a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos. Our findings indicate a novel mutation causing the CLN1 form of NCL in a previously unreported dog breed. A canine model for CLN1 disease could provide an opportunity for therapeutic advancement, benefiting both humans and dogs with this disorder.

Adherence to treatment in patients with open-angle glaucoma and its related factors.

IntroductionLack of adherence to medical treatments typically lead to burdensome consequences such as progressive visual impairment, blindness, and disabilities. This study aimed to determine the adherence to medication in patients with open-angle glaucoma and related factors in patients referred to the Matini Ophthalmology Hospital in Kashan, Iran.MethodsA cross-sectional study was conducted from 23 July 2015 to 20 January 2016 on all patients with open-angle glaucoma referred to the Matini Ophthalmology Hospital in Kashan, Iran. A questionnaire was used to gather data about patients’ demographics and factors affecting adherence to medical treatments. The Morisky Medication Adherence Scale was used to evaluate the adherence to glaucoma medication. Results were analyzed using SPSS version 13. Descriptive statistics, chi-square, and logistic regression analysis were used.ResultsIn total, 130 patients with a mean age of 55.36 ± 15.54 were studied. Only 34.6% of patients completely adhered to glaucoma medications. The chi-square test showed that age (p=0.007), education (p=0.01), life entourage (p=0.04), place of residence (p=0.06), average monthly income (p=0.005), the interval between medical visits (p=0.007), problem in scheduling the medical visits (p<0.001), number of medications (p<0.001), lifelong using and side-effects of medications (p<0.001), answers of the physician to the patient’s questions (p<0.001), financial and traveling problems (p<0.001), lack of skill in using eye drops (p<0.001), lack of awareness of glaucoma complications and symptoms (p<0.001), forgetting, fatigue, impatience, believing in uselessness of medications, and lack of support from family (p<0.001) were associated with patients’ adherence. Logistic regression showed that 89% of variance of patients’ adherence to glaucoma medications can be predicted by seven factors: problems in traveling and scheduling medical visits, the large number and side effects of medications, impatience, forgetting, and lack of skill in using eye drops.ConclusionAbout two-thirds of patients with open-angle glaucoma did not adhere to their own medications. Appropriate patient education and planning a patient follow-up strategy might positively affect the patients’ adherence to glaucoma medications.

Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre (Tα1-Cre). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that although Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients.

Glaucoma Disease Diagnosis Using Feed Forward Neural Network

Glaucoma is an eye disease which damages the optic nerve and or loss of the field of vision which leads to complete blindness caused by the pressure buildup by the fluid of the eye i.e. the intraocular pressure (IOP). This optic disorder with a gradual loss of the field of vision leads to progressive and irreversible blindness, so it should be diagnosed and treated properly at an early stage. In this paper, thedaubechies(db3) or symlets (sym3)and reverse biorthogonal (rbio3.7) wavelet filters are employed for obtaining average and energy texture feature which are used to classify glaucoma disease with high accuracy. The Feed-Forward neural network classifies the glaucoma disease with an accuracy of 96.67%. In this work, the computational complexity is minimized by reducing the number of filters while retaining the same accuracy.

Auxotrophy-Based Detection of Hyperornithinemia in Mouse Blood and Urine

Gyrate atrophy of the choroid and retina (GACR) is a hereditary form of progressive blindness caused by homozygosity for loss-of-function mutations in the ornithine aminotransferase gene (Oat). The...

Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis.

The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, progressive neuronal degeneration and massive glial activation. Advances have been made in genetic diagnosis and counseling for families. However, comprehensive treatment programs that delay or halt disease progression have been elusive. Current disease management is primarily targeted at controlling the symptoms rather than “curing” the disease. Recognizing the growing need for transparency and synergistic efforts to move the field forward, this review will provide an overview of the therapeutic approaches currently being pursued in preclinical and clinical trials to treat different forms of NCL as well as provide insight to novel therapeutic approaches in development for the NCLs.

Intraventricular Neurilemmoma (Schwannoma): Shall GFAP Immunostaining Be Regarded as a Histogenetical Tag or as a Mere Histomimetical Trait?

Neurilemmomas are benign neoplasms presumedly derived from Schwann cells which rarely originate within the central nervous system. Moreover, their intraventricular location has been seldom noticed with less than 30 cases reported worldwide. Here, we add another case study to the record as well as the fifth one in Latin American population. A 16-year-old boy without significant past clinical data debuted with headache and progressive left eye blindness during six months. Neuroimaging scans showed a bulky, multiloculated, intraventricular tumour emerging from the posterior horn of the left lateral ventricle. Microscopically, the lesion put on view the classical schwannian histology: spindle cells arranged in both compact and loosely textured areas. Verocay bodies were not present but vessel hyalinisation, pericellular reticulin, and senescent atypia were observed. The immunoperoxidase reactions were also consistent with neurilemmal differentiation; however, glial fibrillary acidic protein expression was widespread and unexpectedly seen. Traditionally conceived as “nerve sheath tumours” the dual immunophenotype herein demonstrated points to a different histogenetical pathway other than sheer Schwann cell derivation. As previously advised by some authors, neoplastic transformation from a multipotent stem cell may explain the occasional finding of these tumours in unconventional intracranial compartments.

Seronegative Neuromyelitis Optica After Cardiac Transplantation

We report a case of a 42-year-old man who presented with progressive weakness and blindness over the course of several months and met criteria for seronegative neuromyelitis optica. This presentation was in the setting of immunosuppression following cardiac transplant. No infectious causes were found within the neuroaxis, and he ultimately died with complete blindness, quadriplegia, and respiratory failure attributed to panmyelitis and brain stem inflammation despite aggressive therapies.

382. Osteopetrosis: An Unusual Presentation of a Rare Disease as a Candidate for Gene Therapy

Osteopetrosis refers to a group of genetic disorders characterized by increased bone density due to failure of osteoclastic bone resorption. Infantile malignant osteopetrosis (IMO; MIM 259700) is the most severe form of the disease. It presents in early infancy and can lead to significant morbidity and death if untreated. Osteosclerotic changes lead to progressive blindness and hearing loss, bone marrow failure, hypocalcemic seizures and pathological fractures. The majority of cases of IMO are due to complete loss-of-function mutations in TCIRG1, which codes for a subunit of the osteoclast vacuolar proton pump (V-ATPase). Currently, hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but can be associated with significant morbidity and toxicity and has a varying success rate depending on the donor source.We present a 9 year old boy from Pakistan in whom increased bone mass and x-ray changes typical of osteopetrosis were found incidentally at age 7. His prior medical history was mostly unremarkable, except for strabismus and dentition problems. Sequence analysis of the TCIRG1 gene revealed a homozygous c.630G>A mutation that changes the last nucleotide of exon 6 and is predicted to result in aberrant splicing, possibly creating a hypomorphic allele and explaining his milder phenotype. Detailed phenotypic evaluation of the patient after diagnosis showed normal bone marrow function, but identified visual impairment with impingement of the optic nerves, and hearing loss.Given the patient's milder phenotype, the morbidity and mortality of HSCT and uncertainty about his speed of disease progression we decided to not pursue HSCT at this point. Thus, novel therapeutic options should be contemplated. Given that the mutation likely results in a splicing defect, this patient could potentially benefit from splicemodifying drugs that are under development. Moreover, we suggest that this patient's clinical presentation makes him an ideal candidate for a trial of gene therapy. Indeed, considering the mortality and morbidity of IMO as well as the established role of HSCT as curative treatment, a randomized clinical trial for the severe form of the disease is not ethically acceptable. There have been encouraging steps towards establishing lentiviral-mediated gene transfer of TCIRG1 as a potential treatment of osteopetrosis in humans. Furthermore, considering the point mutation found in our patient, gene editing technologies, such as CRISPR/Cas9 could allow us to correct this defect by ex-vivo editing of affected CD34+ cells and subsequent re-engraftment. Finally, we suggest that patients with a similarly mild phenotype and mutations in TCIRG1 would be ideal candidates for a clinical trial for gene therapy of osteopetrosis and could be gathered through an international consortium.

Radiographic and clinical outcomes in cavernous carotid fistula with special focus on alternative transvenous access techniques

Carotid cavernous fistulae (CCF) are dangerous entities that may cause progressive cranial neuropathy, headache and blindness. Endovascular therapy for CCF is the treatment of choice and can be accomplished with minimal morbidity, but optimal treatment strategies vary according to CCF anatomy. We aimed to define a tailored endovascular treatment algorithm for CCF with a focus on traditional and aberrant venous anatomy. Retrospective cohort analysis of data for 57 patients (age range, 18–90years, mean 53years) with CCF (35 direct, 22 indirect) was performed. Treatment was transarterial (n=31), transvenous (n=18), combined (n=2), or observation (n=6). Non-conventional transvenous access (that is, via the facial vein, pterygoid plexus, or via direct puncture of the inferior ophthalmic or frontal vein) was employed in five patients. Mean follow-up period was 12months. Radiographic cure rate in treated CCF was 96%. Forty-five patients presented with ophthalmic symptoms (chemosis, proptosis, eye pain); all resolved within 6weeks of successful treatment. Forty-three patients presented with cranial nerve III, IV and/or VI palsy; complete recovery was seen in 54% and partial recovery in 18%. Five patients presented with blindness and five with declining visual acuity. No patient with blindness regained sight after treatment, but all five patients with declining vision recovered some visual acuity. The complication rate was 10.6% (one transient abducens nerve palsy, two symptomatic cerebral infarctions, and three groin hematomas). The permanent complication rate was 3.5%. Multimodal treatment of CCF, including non-traditional routes of transvenous access, results in excellent outcomes and low morbidity.

Chlamydia trachomatis as a cause of trachoma

Trachoma is keratoconjunctivitis caused by ocular infection with Chlamydia trachomatis. Endemic trachoma is caused by serovars A, B, Ba and C. Trachoma is probably the third most common cause of blindness worldwide, after cataracta and glaucoma. Active trachoma affects an estimated 84 million people; another 7.6 million have end-stage disease, of which about 1.3 million are blind. Most trachoma programmes use the WHO simplified grading system, by presence or absence of five clinical signs. The World Health Organization is leading a global effort to eliminate blinding trachoma by the year 2020, through the implementation of the SAFE strategy. This involves surgery for trichiasis (S-surgery), antibiotics for infection (A-antibiotic), facial cleanliness (F-face) and environmental improvements to reduce transmission of the organism (E-education). Treatment for trachoma includes local and systemic administration of appropriate antibiotics. Surgical correction of trachomatous trichiasis reduces the risk of progressive corneal opacification and blindness.

Surgical natural uveoscleral outflow activation in the primary and secondary glaucoma patients treatment

One of the leading causes of the visual acuity decrease and progressive blindness is glaucoma. Despite conservative treatment of this pathology achieved success, the results don't fully satisfy the ophthalmologists. It is necessary to invent new more effective intraocular pressure permanent compensation surgical techniques. Conventional glaucoma surgical treatment methods and their modifications don’t always improve an intraocular liquid outflow quite effectively. They do not lead to permanent everlasting intraocular pressure compensation in the remote postoperative period. In this case it is rather important to develop and introduce new surgical techniques into the clinic to activate intraocular liquid outflow additionally. It became a reason to induce our interest in a modified technique development directed to the natural uveoscleral outflow activation, allowing to reach long-lasting permanent intraocular pressure compensation in the remote period.The aim of the study: to improve glaucoma patients’ surgical treatment results by activation of the natural uveoscleral intraocular liquid outflow.Patients and methods: 86 patients’ treatment results (90 eyes, 18-89 y.o., mean age – 65,0±13,3) were analyzed. All the glaucoma patients were surgically treated by a modified technique of an intraocular liquid uveoscleral outflow activation by an angular-uveal drainage after an implantation of a collagenous drain (Patent of Ukraine № 46521 from 25.12.2009). Primary glaucoma was diagnosed in 52 (57,8 %) eyes, secondary glaucoma, namely, neovascular – in 38 (42,2 %) eyes. Primary glaucoma patients presented with an initial stage in 6 (11,4 %) eyes, developed – in 9 (17,3 %), advanced – in 15 (29,0 %) and terminal – in 22 eyes (42,3 %). In the early postoperative period and in 6, 12 and 24 months after the surgery all the patients underwent visual acuity examination, tonometry by Maklakov, biomicroscopy, ophthalmoscopy, examination of a vision field, tonography by Nesterov and comparison with preoperative results.Results. In the early and remote postoperative period (up to 24 months) all the patients had statistically significant intraocular pressure decrease. Before the surgery in primary glaucoma patients True intraocular pressure index (Р0) averaged 30,3±5,7 mm of mercury, Outflow easiness coefficient – 0,1±0,04. In 6 months after the surgery intraocular pressure remained within normal values (18,4±2,4 mm of mercury), Outflow easiness coefficient – 0,2±0,05. In 12 months intraocular pressure remained almost unchanged (Р0 index – 18,1±2,2 mm of mercury, Outflow easiness coefficient – 0,2±0,04). In 24 months intraocular pressure varied from 12 to 25 mm of mercury (on the average – 19,0±2,4 mm of mercury), Outflow easiness coefficient – 0,2±0,04. Before the surgery in secondary glaucoma patients True intraocular pressure index (Р0) averaged 32,3±6,3 mm of mercury, Outflow easiness coefficient – 0,1±0,03. In 6 months after the surgery intraocular pressure remained within normal values (18,2± 2,3 mm of mercury), Outflow easiness coefficient – 0,2±0,04. In 12 months some tendency to intraocular pressure increase was noted (Р0 index – 19,3±2,3 mm of mercury), which, however, remained within normal values, Outflow easiness coefficient – 0,2±0,03. In 24 months intraocular pressure remained almost unchanged (on the average – 19,6±2,7 mm of mercury), Outflow easiness coefficient – 0,2±0,05. These results correspond to the normal values and confirm a good hypotensive effect after the new proposed surgical technique. After the surgery visual acuity remained almost unchanged. Insignificant intraoperative bleeding from the cyclodialysis zone into the eye front camera with a consequence of postoperative hyphema was in 8 (8,9 %) eyes. The clot lysis after the treatment was within 7-10 days. Thus, in the remote period good treatment results were noted in 59 (65,6%) eyes, satisfactory – in 31 (34,4%). Unsatisfactory results were absent.Сonclusion.Our proposed technique of an angular-uveal drainage is an effective and safe glaucoma treatment surgical method.Use of the collagenous drain Xenoplast for the purpose of natural uveoscleral intraocular liquid outflow improvement leads to a long-lasting permanent normalization of an intraocular pressure in the early and remote postoperative period.Our positive glaucoma surgical treatment experience after the use of the proposed technique of a modified intraocular liquid natural uveoscleral outflow activation by the angular-uveal drainage with an implantation of a collagenous drain Xenoplast allows us to recommend it in the different stages of glaucomatous process.

Reversible nerve damage and corneal pathology in murine herpes simplex stromal keratitis.

Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4(+) T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. Importance: HSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4(+) T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.

Chaoptin, prominin, eyes shut and crumbs form a genetic network controlling the apical compartment of Drosophila photoreceptor cells

ABSTRACTThe apical surface of epithelial cells is often highly specialised to fulfil cell type-specific functions. Many epithelial cells expand their apical surface by forming microvilli, actin-based, finger-like membrane protrusions. The apical surface of Drosophila photoreceptor cells (PRCs) forms tightly packed microvilli, which are organised into the photosensitive rhabdomeres. As previously shown, the GPI-anchored adhesion protein Chaoptin is required for the stability of the microvilli, whereas the transmembrane protein Crumbs is essential for proper rhabdomere morphogenesis. Here we show that chaoptin synergises with crumbs to ensure optimal rhabdomere width. In addition, reduction of crumbs ameliorates morphogenetic defects observed in PRCs mutant for prominin and eyes shut, known antagonists of chaoptin. These results suggest that these four genes provide a balance of adhesion and anti-adhesion to maintain microvilli development and maintenance. Similar to crumbs mutant PRCs, PRCs devoid of prominin or eyes shut undergo light-dependent retinal degeneration. Given the observation that human orthologues of crumbs, prominin and eyes shut result in progressive retinal degeneration and blindness, the Drosophila eye is ideally suited to unravel the genetic and cellular mechanisms that ensure morphogenesis of PRCs and their maintenance under light-mediated stress.

Ocular hypotensive medications for the treatment of glaucoma.

The past 10 years have seen dramatic changes in the pharmacologic treatment of glaucoma. The treatment of glaucoma has changed from surgical to primarily medical. These treatments have improved the effectiveness and safety of lowering the intraocular pressure to prevent progressive vision loss and blindness, but no cure for glaucoma or reversal of blindness is available yet. Research is progressing and can hopefully achieve these final goals sometime in the future.

Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease

Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.