Cystoid Macular Edema: Causes, Diagnosis and Treatment

The purpose of this paper is to conduct a review of studies on cystoid macular edema published in the last seven years. Cystoid macular edema is a major cause of loss of visual acuity. It is the final common pathway of many diseases and can be caused by numerous processes including inflammatory, vascular, adverse drug reactions, retinal dystrophy or intraocular tumors. These processes disrupt the blood-retinal barrier, with fluid extravasation to the macular parenchyma. Imaging tests are essential for both detection and monitoring of this pathology. Fluorescein angiography and autofluorescence show the leakage of liquid from perifoveal vessels into the tissue where it forms cystic spaces. Optical coherence tomography is currently the gold standard technique for diagnosis and monitoring. This allows objective measurement of retinal thickness, which correlates with visual acuity and provides more complete morphological information. Based on the underlying etiology, the therapeutic approach can be either surgical or medical with anti-inflammatory drugs. We found that disruption of the blood-retinal barrier for various reasons is the key point in the pathogenesis of cystoid macular edema, therefore we believe that studies on its treatment should proceed on this path.

Responsividade da escala de avaliação funcional do sentar e levantar do solo para distrofia muscular de Duchenne (FES-DMD - D4), no período de um ano

OBJETIVO: Avaliar a responsividade da escala de avaliação funcional para pacientes com distrofia muscular de Duchenne (FES-DMD-D4), sentar e levantar do solo, no período de um ano. MÉTODO: Estudo observacional, longitudinal e retrospectivo. Foi estudada, utilizando o software FES-DMDDATA, uma amostra com 25 pacientes na atividade sentar no solo e 28 pacientes para a atividade levantar do solo. As avaliações ocorreram a cada três meses no período de um ano. Para análise estatística da capacidade de resposta foram utilizados índices de tamanho de efeito, como, effect size (ES) e Standardized Response Mean (SRM). RESULTADOS: A responsividade da atividade de sentar no solo foi considerada baixa a moderada em intervalos de três meses (ES de 0.28 a 0.54 e SRM de 0.38 a 0.71), moderada a alta em intervalos de seis meses (ES de 0.69 a 1.07 e SRM de 0.86 a 1.19), alta em intervalos de nove meses (ES de 1.3 a 1.17 e SRM de 1.26 a 1.55) e doze meses (ES de 1.9 e SRM de 1.72). Na atividade levantar do solo, a responsividade variou em baixa, moderada e alta em intervalos de três meses (ES de 0.21 a 0.33 e SRM de 0.45 a 0.83), baixa a alta em intervalos de seis meses (ES de 0.46 a 0.59 e SRM de 0.73 a 0.97), moderada a alta em intervalos de nove meses (ES de 0.76 a 0.88 e SRM de 1.03 a 1.22) e alta em doze meses (ES de 1.14 e SRM de 1.25). CONCLUSÃO: Para detectar alterações clinicamente significativas e consistentes nas atividades funcionais sentar e levantar do solo recomendamos a utilização da FES-DMD-D4 em intervalos a partir de seis meses, pois foi neste período de tempo que a capacidade de resposta variou de moderada a alta

Relação entre força muscular e função motora em pacientes com distrofia muscular de Duchenne: acompanhamento de quatro anos

OBJETIVO: Investigar a relação entre força muscular e função motora, em pacientes com DMD, em um período de 4 anos consecutivos, a partir de avaliações semestrais. MÉTODO: A força muscular foi medida por meio de testes manuais e o cálculo por grupo muscular seguiu o proposto pelo Medical Research Council (MRC) e a função motora pelo método de Medida da Função Motora (MFM), em 43 pacientes (8-30 anos). Foi realizada uma análise descritiva e o teste de correlação de Spearman. Foram investigadas as relações entre pontuações totais e parciais da MRC e da MFM. RESULTADOS: O estudo evidenciou correlações classificadas de moderada a forte relação entre a força muscular e função motora, principalmente com o escore total da MFM e a dimensão D2 (musculatura axial e função motora proximal). Foi encontrada relação negativa moderada entre idade e essas variáveis. CONCLUSÃO: A perda progressiva da função motora tem relação direta e proporcional com a diminuição da força muscular. Quanto maior a idade do paciente, pior sua função motora e força muscular, fornecendo com essa informação, indicadores adicionais da progressão da doença

Modulação autonômica cardíaca na distrofia muscular de Duchenne durante tarefa no computador

Introdução: A Distrofia Muscular de Duchenne (DMD) é caracterizada como uma fraqueza muscular progressiva que leva à incapacidade. Devido às dificuldades funcionais enfrentadas pelos indivíduos com DMD, o uso da tecnologia assistiva é essencial para proporcionar ou promover habilidades funcionais. Na DMD, além do comprometimento musculoesquelético, uma disfunção autonômica cardíaca também tem sido relatada. Assim, visamos investigar as respostas autonômicas agudas de indivíduos com DMD durante a realização de uma tarefa no computador. Método: A variabilidade da frequência cardíaca foi avaliada através de métodos lineares e não lineares, utilizando uma cinta torácica com equipamento de monitoramento de eletrocardiograma (ECG). Assim, 45 indivíduos foram incluídos no grupo com DMD e 45 no grupo de desenvolvimento típico (controle), avaliados for 20 minutos em repouso sentado e 5 minutos com a realização de uma tarefa no computador. Resultados: Os indivíduos com DMD apresentaram menor modulação cardíaca parassimpática durante o repouso, que diminuiu ainda mais durante a tarefa no computador. Conclusão: Indivíduos com DMD exibiram respostas autonômicas cardíacas mais intensas durante a tarefa no computador

Responsividade do domínio subir e descer escada da escala de avaliação funcional para pessoas com distrofia muscular de Duchenne, no período de um ano

Objetivo: Determinar a responsividade do domínio subir e descer escada da escala de avaliação funcional em distrofia muscular de Duchenne (DMD), no período de um ano. Método: Participaram do estudo 26 pacientes com DMD. A análise utilizou o Tamanho do Efeito (ES) e a Média Padronizada de Resposta (SRM). Resultados: Atividade de subir escada: o ES mostrou responsividade baixa nos intervalos de avaliação de 3 meses (0,26; 0,35; 0,13; 0,17), baixa a moderada em 6 meses (0,58, 0,48; 0,33), moderada em 9 meses (0,70; 0,68) e alta em 1 ano (0,88). A análise com SRM mostrou responsividade baixa nos intervalos de avaliação de 3 meses (0,29; 0,38; 0,18 e 0,19), baixa a moderada em intervalos de 6 meses (0,59 e 0,51, 0,36), moderada em 9 meses (0,74 e 0,70) e alta em 1 ano (0,89). Atividade de descer escada: O ES apresentou responsividade baixa nos intervalos de avaliação de 3 meses (0,16; 0,25; 0,09; 0,08) e 6 meses (0,48; 0,35; 0,18), baixa a moderada em 9 meses (0,59, 0,44) e moderada em 1 ano (0,71). Análise com SRM mostrou responsividade baixa nos intervalos de 3 meses (0,25; 0,35; 0,12 e 0,09) e 6 meses (0,47; 0,38 e 0,21), moderada a baixa em 9 meses (0,62, 0,49) e moderada em 1 ano (0,74). Conclusão: A avaliação da atividade de subir escada, por meio da FES-DMD-D3, deve ser realizada em intervalos a partir de 9 meses, pois a responsividade é de moderada a alta. A avaliação do descer escadas deve ser realizada anualmente, pois houve responsividade moderada somente a partir de 12 meses

Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes.

Vertebrate limbs develop in a temporal proximodistal sequence, with proximal regions specified and generated earlier than distal ones. Whereas considerable information is available on the mechanisms promoting limb growth, those involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activator of the proximal determinant genes Meis1 and Meis2. RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb. RA synthesis and signaling range, which initially span the entire lateral plate mesoderm, become restricted to proximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main molecule responsible for this AER activity and propose a model integrating the role of FGF in limb cell proliferation, with a specific function in promoting distalization through inhibition of RA production and signaling.

The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes

Tricyclo-DNA (tcDNA) is a sugar-modified analogue of DNA currently tested for the treatment of Duchenne muscular dystrophy in an antisense approach. Tandem mass spectrometry plays a key role in modern medical diagnostics and has become a widespread technique for the structure elucidation and quantification of antisense oligonucleotides. Herein, mechanistic aspects of the fragmentation of tcDNA are discussed, which lay the basis for reliable sequencing and quantification of the antisense oligonucleotide. Excellent selectivity of tcDNA for complementary RNA is demonstrated in direct competition experiments. Moreover, the kinetic stability and fragmentation pattern of matched and mismatched tcDNA heteroduplexes were investigated and compared with non-modified DNA and RNA duplexes. Although the separation of the constituting strands is the entropy-favored fragmentation pathway of all nucleic acid duplexes, it was found to be only a minor pathway of tcDNA duplexes. The modified hybrid duplexes preferentially undergo neutral base loss and backbone cleavage. This difference is due to the low activation entropy for the strand dissociation of modified duplexes that arises from the conformational constraint of the tc-sugar-moiety. The low activation entropy results in a relatively high free activation enthalpy for the dissociation comparable to the free activation enthalpy of the alternative reaction pathway, the release of a nucleobase. The gas-phase behavior of tcDNA duplexes illustrates the impact of the activation entropy on the fragmentation kinetics and suggests that tandem mass spectrometric experiments are not suited to determine the relative stability of different types of nucleic acid duplexes.

Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning

Caveolae are an abundant feature of many animal cells. However, the exact function of caveolae remains unclear. We have used the zebrafish, Danio rerio, as a system to understand caveolae function focusing on the muscle-specific caveolar protein, caveolin-3 (Cav3). We have identified caveolin-1 (alpha and beta), caveolin-2 and Cav3 in the zebrafish. Zebrafish Cav3 has 72% identity to human CAV3, and the amino acids altered in human muscle diseases are conserved in the zebrafish protein. During embryonic development, cav3 expression is apparent by early segmentation stages in the first differentiating muscle precursors, the adaxial cells and slightly later in the notochord. cav3 expression appears in the somites during mid-segmentation stages and then later in the pectoral fins and facial muscles. Cav3 and caveolae are located along the entire sarcolemma of late stage embryonic muscle fibers, whereas beta-dystroglycan is restricted to the muscle fiber ends. Down-regulation of Cav3 expression causes gross muscle abnormalities and uncoordinated movement. Ultrastructural analysis of isolated muscle fibers reveals defects in myoblast fusion and disorganized myofibril and membrane systems. Expression of the zebrafish equivalent to a human muscular dystrophy mutant, CAV3P104L, causes severe disruption of muscle differentiation. In addition, knockdown of Cav3 resulted in a dramatic up-regulation of eng1a expression resulting in an increase in the number of muscle pioneer-like cells adjacent to the notochord. These studies provide new insights into the role of Cav3 in muscle development and demonstrate its requirement for correct intracellular organization and myoblast fusion.

Cholesterol and fatty acids regulate dynamic caveolin trafficking through the golgi complex and between the cell surface and lipid bodies

Caveolins are a crucial component of plasma membrane (PM) caveolae but have also been localized to intracellular compartments, including the Golgi complex and lipid bodies. Mutant caveolins associated with human disease show aberrant trafficking to the PM and Golgi accumulation. We now show that the Golgi pool of mainly newly synthesized protein is detergent-soluble and predominantly in a monomeric state, in contrast to the surface pool. Caveolin at the PM is not recognized by specific caveolin antibodies unless PM cholesterol is depleted. Exit from the Golgi complex of wild-type caveolin-1 or -3, but not vesicular stomatitis virus-G protein, is modulated by changing cellular cholesterol levels. In contrast, a muscular dystrophy-associated mutant of caveolin-3, Cav3P104L, showed increased accumulation in the Golgi complex upon cholesterol treatment. In addition, we demonstrate that in response to fatty acid treatment caveolin can follow a previously undescribed pathway from the PM to lipid bodies and can move from lipid bodies to the PM in response to removal of fatty acids. The results suggest that cholesterol is a rate-limiting component for caveolin trafficking. Changes in caveolin flux through the exocytic pathway can therefore be an indicator of cellular cholesterol and fatty acid levels.

Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle

The deficiency of dystrophin, a critical membrane stabilizing protein, in the mdx mouse causes an elevation in intracellular calcium in myocytes. One mechanism that could elicit increases in intracellular calcium is enhanced influx via the L-type calcium channels. This study investigated the effects of the dihydropyridines BAY K 8644 and nifedipine and alterations in dihydropyridine receptors in dystrophin-deficient mdx hearts. A lower force of contraction and a reduced potency of extracellular calcium (P < 0.05) were evident in mdx left atria. The dihydropyridine agonist BAY K 8644 and antagonist nifedipine had 2.7- and 1.9-fold lower potencies in contracting left atria (P < 0.05). This corresponded with a 2.0-fold reduction in dihydropyridine receptor affinity evident from radioligand binding studies of mdx ventricular homogenates (P < 0.05). Increased ventricular dihydropyridine receptor protein was evident from both radioligand binding studies and Western blot analysis and was accompanied by increased mRNA levels (P < 0.05). Patch-clamp studies in isolated ventricular myocytes showed no change in L-type calcium current density but revealed delayed channel inactivation (P < 0.05). This study indicates that a deficiency of dystrophin leads to changes in dihydropyridine receptors and L-type calcium channel properties that may contribute to enhanced calcium influx. Increased influx is a potential mechanism for the calcium overload observed in dystrophin-deficient cardiac muscle.

Biogenesis of caveolae: a structural model for caveolin-induced domain formation

Caveolae are striking morphological features of the plasma membrane of mammalian cells. Caveolins, the major proteins of caveolae, play a crucial role in the formation of these invaginations of the plasma membrane; however, the precise mechanisms involved are only just starting to be unravelled. Recent studies suggest that caveolae are stable structures first generated in the Golgi complex. Their formation and exit from the Golgi complex is associated with caveolin oligomerisation, acquisition of detergent insolubility, and association with cholesterol. Modelling of caveolin-membrane interactions together with in vitro studies of caveolin peptides are providing new insights into how caveolin-lipid interactions could generate the unique architecture of the caveolar domain.

Non-coding RNAs in the nervous system

Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.

An overview of eye-related photophobias

This chapter provides an overview of the various eye-related causes of photophobia and the likely mechanisms responsible. Photophobia is the experience of discomfort affecting the eyes as a result of exposure to light. It has a variety of causes, including the result of eye or brain disease, or it can be a side effect of various drugs or laser surgery. Photophobia can also be a symptom of a more serious disorder such as meningitis and therefore, requires appropriate investigation, diagnosis, and treatment. Trauma or disease affecting several structures of the eye are a common cause of photophobia and can be associated with: (1) the ocular adnexia, such as blepharitis and blepharospasm, (2) the cornea, including abrasion, ulcerative keratitis, and corneal dystrophy, (3) problems in eye development, such as aniridia, buphthalmos, coloboma, and aphakia, (4) various eye inflammations, including uveitis, and (5) retinal disorders, such as achromatopsia, retinal detachment, and retinal dystrophy. There may be two main explanations for photophobia associated with these conditions: (1) direct stimulation of the trigeminal nerve due to damage, disease, or excessive light entering the eye and (2) overstimulation of the retina including a specific population of light-sensitive ganglion cells.

Eye-related photophobia

This article provides an overview of the various eye-related causes of photophobia and the likely mechanisms responsible. Photophobia is an experience of discomfort affecting the eyes due to exposure to light. It has a variety of causes including the result of eye or brain disease, or it can be a side effect of various drugs or laser surgery. Photophobia can also be a symptom of a more serious disorder such as meningitis and therefore, requires appropriate investigation, diagnosis, and treatment. Trauma or disease affecting several structures of the eye are a common cause of photophobia and can be associated with: (1) the ocular adnexia, such as blepharitis and blepharospasm, (2) the cornea, including abrasion, ulcerative keratitis, and corneal dystrophy, (3) problems in eye development, such as aniridia, buphthalmos, coloboma, and aphakia, (4) various eye inflammations, including uveitis, and (5) retinal disorders, such as achromatopsia, retinal detachment, and retinal dystrophy. There may be two main explanations for eye-related photophobia: (1) direct stimulation of the trigeminal nerve due to damage, disease, or excessive light entering the eye and (2) overstimulation of the retina including a specific population of light-sensitive ganglion cells.

Efeito do ácido ascórbico sobre a espermatogênese de camundongos com distrofia muscular de Duchenne

The objective was to evaluate spermatogenesis alterations caused by DMD and the effect of the treatment using ascorbic acid in preventing those injuries. Twenty four mice were used, 12 from the C57BL/10 lineage (non-dystrophic) and 12 from the C57BL/10Mdx (dystrophic). The sample was divided in six groups containing 4 animals each, as: C30 = 30 days control; D30 = Dystrophic with 30 days; C60 = 60 days control; D60 = Distrophic with 60 days; CS60 = 60 days control supplemented with ascorbic acid and DS60 = Dystrophic with 60 days supplemented with ascorbic acid. The ascorbic acid supplementation was given in the water, 0,005 mg/day. After euthanasia, the testicles (right and left) were collected, weighted and cross sectioned. The material was fixed in the Karnovsky solution for 24 hours, included in resin for histological studies (morphological and morphometric analyzes) submitted to ultrastructural analysis and immunohistochemistry for caspase-3. There was a significant increase in the tunica propria percentage in D30 compared to C30 and D60. The ultrastructural analysis showed mitochondrial apoptosis evidence of Sertoli cells that can reduce sperm efficiency in CS60 and DS60. A higher volume density of apoptotic cells postivas to Caspase-3 in C30 and D30 versus DS60 compared to CS60. There was severe hypertrophy of the Leydig cells between D30 and D60. However, with supplementation was observed reversal of this change in DS60. The ultrastructure of Leydig cells to early presence of lipid vesicles was observed in the group pre-pubertal dystrophic (D30). Thus, the DMD affect the organization of the seminiferous tubules and intertubule, however, the ascorbic acid supplementation used for the treatment of DMD has been just enough to reduce the hypertrophy of the Leydig cells.