Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date

The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease’s progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases

Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date

The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease’s progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases

Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed

A guardiã das tradições: a História e o seu código curricular

Este trabalho estuda a permanência de conteúdos da História do Brasil nos programas escolares. Considera desde as primeiras formulações curriculares da disciplina nos programas do Colégio Pedro II até as propostas curriculares surgidas no final do século XX, para analisar a concepção da História escolar. Fundamenta-se no conceito de código curricular formulado por Raimundo Cuesta Fernández, que o entende como uma tradição social composta por ideias e princípios e por um conjunto de práticas profissionais que contribuem para fixar a História como disciplina escolar

MicroRNAs as potential biomarkers and innovative therapeutic targets in retinal degenerations

The human retina, as a part of the central nervous system, is distinctively designated to the initiation of the visual processing. In accordance with its complex anatomy and physiology, a broad number of coding and noncoding regions of the genome have been implicated in the heterogeneous pathogenesis of several retinal degenerative diseases, i.e. monogenic disorders, such as the various Mendelian-inherited forms of retinitis pigmentosa (RP), and multifactorial polygenic/environmental disorders, such as age-related macular degeneration (AMD) and pathologic myopia (PM). Both occurrence and progression of these chronic vision-threatening diseases can be influenced by genetic and epigenetic factors, affecting different retinal and sub-retinal structures: the neural retina (NR), composed by the inner neurosensory layer with its vascular capillary nets and the outer photoreceptor cells (PRCs) layer with the underlying retinal pigment epithelium (RPE), which is separated from choriocapillaris by a modified basement stratum named Bruch’s membrane (BM), while the supporting glial Müller cells span the NR from external to inner limiting membranes sealing the axonal fibers of the retinal ganglion cells from the vitreous. The diverse retinal degenerations primarily involve a specific target-structure: (i) RP phenotypes are primary caused by damages of PRCs; (ii) AMD lesions depend on degenerative RPE modifications; (iii) PM-related scleral expansion irreversibly modifies the RPE-BM complex. Both health and function of the human retina rely on a collaborative interaction among diverse classes of molecular regulators. Starting from 1993, small non-coding endogenous RNAs of approximately 21-25 nucleotides in length, named microRNAs (miRNAs), have been recognized as key factors of posttranscriptional gene regulation in mammalian genomes. At present, our knowledge about either origin or functions of circulating exosomal miRNAs is going to be implemented, and there are several investigative methods that allow the identification of miRNAs contribution to heterogeneous disorders. The perceived opportunity appears especially large in neoplastic diseases, even if the evaluation of diagnostic specificity and reproducibility of miRNAs assessment remains a work in progress. In the last years, transcriptome analyses have documented the presence of several miRNAs expressed in the human adult retina, indicating the pivotal role of miRNAs as regulators for homeostasis, function and survival of the differentiated cell types at the level of mature retinal and sub-retinal tissues. The demanding physiologic tasks of the retina postulate the action of a continuous gene regulation to render its perennial post-mitotic cells less vulnerable to premature damage or death secondary to the most frequent causes of irreversible low-vision and blindness, i.e. AMD, PM, and RP. Moreover, because miRNAs are involved in transferring inflammatory signals among cells, they may have a crucial prognostic value in the above-mentioned diseases, whose modalities of onset and/or progression are invariably related to complex para-inflammatory processes. Particularly, in Alzheimer’s disease and AMD, a group of five miRNAs (miRNA-9, -34a, -125b, -146a and -155) has been found up-regulated during several independent experimental tests, indicating the presence of progressive inflammatory damages in both pathologic patterns of these age-related neurodegenerative disorders. In an all-embracing view, this scenario highlights the potential relevance of miRNAs to advance the clinical management of the most severe retinal diseases. Notionally, the pathogenic mechanisms of each different retinal disorder express specific miRNA-genes inside pathologic cells. Part of these expressed miRNAs are then secreted by exosomes and become circulating miRNAs, which can be detected in patients’ serum samples as biomarkers of vision-threatening diseases. It has been shown that altered miRNA expression patterns in the human fluids might be the result of various eye disorders. Recent studies are beginning to document the possible role of circulating miRNAs as biomarkers for both pathologic conditions and severity of disease progression. It is very challenging to approach the question whether each cell type of the retinal complex has its own miRNA phenotype, since one miRNA can target different gene products that might be expressed in different microstructures. Although some patterns of miRNAs expression have been tentatively labeled as distinctive signatures of specific retinal cell types, no unequivocal data have been hitherto obtained in patients on the correlations between dysregulated miRNA profiles and pathologic retinal phenotypes, i.e. AMD, PM, and RP. The miRNAs identified in human serum and plasma are known to be relatively stable, as they have been found to be resistant to RNAase degradation, even in stored samples. This remarkable extracellular stability has made miRNAs desirable candidates for epidemiological and clinical studies, indicating their potential role as non- or minimal-invasive biomarkers particularly because small serum or plasma samples are needed for miRNAs profiling. However, despite a multitude of investigations of basic research, there are only few independent validation studies on blood-born miRNAs as disease biomarkers. Toward clinical applications in ophthalmology numerous obstacles still need to be overcome, starting from the lack of data resulting from trials conducted on homogeneous study groups. Because no study has been hitherto conducted in patients with retinal degenerative disorders to assess the degree of intra-individual consistency in correlating the clinical changes in diseases’ expressivity with putative modifications of miRNAs profile, this comparative approach of investigation should be recommended to advance our levels of knowledge and to provide concrete answers about the translational potentialities of miRNAs, as recently advocated by Andreas Keller and Eckart Meese emphasizing a very challenging question: "Can circulating miRNAs live up to the promise of being minimal invasive biomarkers in clinical settings?". Circulating miRNAs vary in their expression and concentration in serum samples, and these variations indicate the potential role of miRNAs as biomarkers of pathologic status vs. health condition. Indeed, several investigations have been recently conducted on patients suffering from cancers, infections, cardiovascular, metabolic, neurodegenerative or genetic diseases, in which miRNAs were found variably dysregulated compared to those detected in healthy controls. Expression of circulating miRNAs may change in the course of the pathologies exemplified above and/or their complications. In this context, it is important to note that, during the period of illness, circulating miRNAs can be modified either at the level of their panel expression or at the single-miRNA concentration. The detection of dysregulated circulating miRNAs could have application in early diagnosis and progression of retinal degenerations, as already shown for other degenerative disorders of the central nervous system. Just for example, starting from the available knowledge about a multifactorial degenerative disease characterized by both environmental and gene-related pathogenetic mechanisms such as AMD, the future steps for translational miRNAs application might be focused on the ability of correlating differences in miRNAs profiles to: (i) status of AMD patient versus matched healthy control; (ii) morpho-functional deteriorations of RPE cells and/or PRCs layers characterizing the dry AMD forms; (iii) occurrence of choroidal neovascularization complicating the wet AMD forms. Considering both technology and cost of the analyses, the miRNAs detection in serum samples of patients with disorders of neural ocular structures has the potential to become an affordable approach. It may be especially helpful when the eye disease is asymptomatic or paucisymptomatic and/or when it is characterized by critical patterns of heterogeneity. In these cases, the detection of one or more dysregulated circulating miRNAs could be used as a specific parameter to facilitate the phenotypic and/or genotypic interpretation of the disease, and the ophthalmologists may benefit of these new diagnostic parameters/tools. At the same time, miRNAs are now investigated as potential target for innovative therapies. One of the most promising experimental strategies foresees the use of liposome-like structures loaded with anti-sense miRNAs when a specific miRNA is over-expressed. On the other hand, the same strategy with liposomes loaded with miRNAs can be used when a specific miRNA is down-expressed, with the aim to re-establish the normal level of miRNAs. It is noteworthy to recall that miRNAs play an important role during the expression process of different genes. It has been shown that more than 2,000 genes encode for miRNAs which, in turn, recognize distinct and multiple mRNAs as targets. This biological process is crucial for the cell because the protein production is affected by the amount of mRNA, which is translated at the ribosomes level. In this context, the protein concentration and bioavailability into the cell is determined by the accessible amount of the specific mRNA. More recently, it has been shown that miRNAs can be "secreted" by cells with exosomes, which are liposome-like particles filled of specific miRNAs and circulating into the blood stream. This loop resembles the so-called autocrine and paracrine loops, employed by the cells for their cell-to-cell talks with growth/differentiation factors. It represents one the main mechanism used by a living cell to control its development and functions, as well as to maintain its homeostasis. Similarly, miRNAs are released by cells with exosomes to reach new cells, in distant or near tissues, using the blood/serum/plasma as a vehicle. This mechanism ensures a sort of equilibrium mediated, at distance, by miRNAs. In case of altered equilibrium, a specific pathology may occur. This alteration can be used to recognize a serum miRNA as parameter/biomarker for diagnostic and/or prognostic purposes. Indeed, by improving our understanding about the pathogenesis of AMD, PM and RP, together with the clinical laboratory-based screening and the forthcoming development of new therapeutic strategies, it will be possible to ameliorate the clinical management of numerous patients at high risk of low-vision and blindness. In the near future, new miRNA-based assays, which are highly sensitive and specific, might be able to attain a "customized" classification of the different eye diseases. The study of miRNA biomarkers implicating in pathogenesis, diagnosis and prognosis of retinal degenerations represents a translational topic of increased research interest, especially because miRNAs themselves might be considered as therapeutic targets or even therapeutic agents as anti-miRNAs. In view of these elements of miRNA-related exploratory context, additional studies will help us in assessing miRNAs potential as upstream regulators and/or downstream targets of the common vision-disabling diseases

Detection of phospholipase Cγ in sea urchin eggs

International audiencePhosphorylation on tyrosine and turnover of polyphosphoinositide metabolism are rapidly stimulated after fertilization. However, the interconnection between these pathways remains to be determined. In the present paper it is demonstrated that eggs of two different sea urchin species contain tyrosine phosphorylated proteins with calcium‐sensitive phospholipase C activity. We have investigated whether phospholipase Cγ (PLCγ), characteristic of tyrosine kinase receptors, could be responsible for this activity. Western blot and immunocytochemistry performed with antibodies directed against PLCγ revealed the presence of this protein in cortical regions. It was also observed that PLCγ displayed calcium‐sensitive activity. The present results suggest that PLCγ may be part of the cascade of events leading to the calcium signal responsible for egg activation at fertilization

Eredo-distrofia tapeto-retinica e miopia degenerativa: variabilità fenotipica familiare in tre pazienti di razza caucasica

Descriviamo gli aspetti clinici di tre membri della stessa famiglia affetti da ipovisione centrale di diversa gravità, associata a difetti campimetrici in entrambi gli occhi. Ciascun paziente è stato sottoposto a valutazione oftalmologica, esame del campo visivo computerizzato, fluorangiografia retinica ed elettroretinogramma dinamico. Le indagini diagnostico-strumentali hanno comprovato, bilateralmente, la presenza di: miopia degenerativa nella madre di 73 anni e distrofie tapeto-retiniche nei due figli maschi rispettivamente di 43 e 37 anni. L’albero genealogico familiare appare indicativo di un’ereditarietà di tipo X-linked. Queste osservazioni cliniche sottolineano l’esistenza, all’interno dei membri di una stessa famiglia, di una notevole eterogeneità fenotipica. Tali patologie familiari rendono auspicabile, nel prossimo futuro, la possibilità di effettive identificazioni del gene-malattia mediante ricerche molecolari con tecniche di macro-array ed eventuale analisi di linkage in pazienti con eredo-distrofie tapeto-retiniche. We describe the clinical aspects of three members of a family with central visual impairment of varying severity associated with visual field defects in both eyes. Each patient underwent ophthalmologic evaluation, computerized visual field, fluorescein angiography and dynamic electroretinography. These diagnostic examinations have bilaterally documented the presence of: degenerative myopia (mother of 73 years) and hereditary tapeto-retinal dystrophies in the two sons (43 and 37 years respectively). The family pedigree is indicative of an X-linked inheritance. These clinical observations emphasize the existence, within the members of the same family, a remarkable phenotypic heterogeneity. These familial diseases warrant, in the near future, an effective opportunity of identification of the causative gene by molecular researches including macro-array technique and possible linkage analyses in patients with hereditary tapeto-retinal dystrophies

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of-function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures

Optical coherence tomography imaging in the management of the Argus II retinal prosthesis system

Purpose: To report a real-life experience with the Argus II retinal prosthesis system in blind patients with end-stage retinitis pigmentosa (RP) or choroideremia (CHM), focusing on the pivotal role of optical coherence tomography (OCT) in both preoperative and postoperative management. Methods: This hospital-based case series included 3 blind patients who were uneventfully implanted with Argus II epiretinal device. These patients (2 with RP and 1 with CHM) were selected during the ArgusTM II Retinal Prosthesis System PostMarket Surveillance Study Protocol. Complete screening procedures had involved 66 eyes of 33 patients afferent to the Center for Retinitis Pigmentosa of the Veneto Region. Results: Preoperative OCT examination resulted in the exclusion of 8 eyes in 4 patients with bilateral posterior staphyloma diagnosing unexpected staphylomatous macular patterns in 2 patients with RP and no sign of pathologic myopia. Postoperative OCT study of Argus II proximity to retinal surface indicated a plausible correlation between electrode-retina distance and perceptual threshold in 2 of our 3 patients. In particular, during the first 6 months of follow-up, the patient with the closest contact between device and macula showed a continuous vision-related improvement in the performance of several real-life tasks. Conclusions: The present findings illustrate the modalities by which each different OCT examination is an essential tool to optimize safety and efficacy profiles during Argus II protocol. Optical coherence tomography will be crucial for future investigative approaches on patient selection criteria and next-generation implant design