Dexamethasone intravitreal implant as an adjuvant treatment for pediatric patients with Coats' disease / Implante intravítreo de dexametasona como tratamento adjuvante em pacientes pediátricos com doença de Coats

ABSTRACT We report two cases of stage 3A unilateral Coats' disease in pediatric patients. In both cases, disease control was achieved using a dexamethasone intravitreal implant in addition to other treatments. The treatment improved visual acuity in one patient and prevented the worsening of the decline in visual acuity in the other patient during follow-up periods of 7 and 3 years, respectively. One of the patients presented an increase in intraocular pressure, which was controlled with topical antiglaucoma medication, but developed a cataract that required surgery. In conclusion, dexamethasone intravitreal implant may be a useful adjuvant treatment to consider in some pediatric cases with Coats' disease.

RESUMO Relatamos dois casos de doença de Coats em estágio 3A unilateral em pacientes pediátricos. Em ambos os casos, o controle da doença foi obtido com implante intravítreo de dexametasona, além de outros tratamentos, com melhora da acuidade visual em um caso e sem piora da visão no outro, durante um período de acompanhamento de 7 e 3 anos. Um dos casos apresentou elevação da pressão intraocular controlada com medicação antiglaucoma tópica e desenvolveu catarata que exigiu cirurgia. Em conclusão, o implante intravítreo de dexametasona pode ser um tratamento adjuvante útil a ser considerado em alguns casos pediátricos com doença de Coats.

Dexamethasone intravitreal implant as an adjuvant treatment for pediatric patients with Coats' disease.

We report two cases of stage 3A unilateral Coats' disease in pediatric patients. In both cases, disease control was achieved using a dexamethasone intravitreal implant in addition to other treatments. The treatment improved visual acuity in one patient and prevented the worsening of the decline in visual acuity in the other patient during follow-up periods of 7 and 3 years, respectively. One of the patients presented an increase in intraocular pressure, which was controlled with topical antiglaucoma medication, but developed a cataract that required surgery. In conclusion, dexamethasone intravitreal implant may be a useful adjuvant treatment to consider in some pediatric cases with Coats' disease.

Signatures of genetic variation in human microRNAs point to processes of positive selection and population-specific disease risks.

The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last 20 years. Most of them have been focused on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We analyse the latest human microRNA annotations in the light of the most updated catalogue of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA genetic variation we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.

Adalimumab for the treatment of refractory noninfectious paediatric uveitis.

To report the experience of our center with the use of adalimumab (ADA) for the treatment of severe refractory noninfectious paediatric uveitis. The study is a retrospective case series of all paediatric patients with refractory uveitis who were treated with ADA at the Paediatric Uveitis Unit of our center from 2008 to 2015. We present 12 patients (6 Juvenile idiopathic arthritis-associated uveitis, 4 idiopathic panuveitis, 1 early-onset sarcoidosis-associated panuveitis, and 1 intermediate uveitis), with uveitis in 19/24 eyes. Once ADA therapy was started, all the patients presented improved activity according to Standardization of Uveitis Nomenclature (SUN) criteria. Nine out of the 12 patients had structural damage before ADA could be started: cataract (n = 4), glaucoma (n = 2), cystic macular edema (n = 1), exudative retinal detachment (n = 1), and optic disk edema (n = 5). Visual acuity improved or maintained stable in 17/19 affected eyes, and only 2 eyes decreased its visual acuity because of structural damage, which was already present before ADA therapy. In our experience, ADA presents a good safety profile and is efficacious in the treatment of paediatric patients with different forms of refractory noninfectious uveitis.

MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer.

Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine.

Functional Implications of Human-Specific Changes in Great Ape microRNAs.

microRNAs are crucial post-transcriptional regulators of gene expression involved in a wide range of biological processes. Although microRNAs are highly conserved among species, the functional implications of existing lineage-specific changes and their role in determining differences between humans and other great apes have not been specifically addressed. We analyzed the recent evolutionary history of 1,595 human microRNAs by looking at their intra- and inter-species variation in great apes using high-coverage sequenced genomes of 82 individuals including gorillas, orangutans, bonobos, chimpanzees and humans. We explored the strength of purifying selection among microRNA regions and found that the seed and mature regions are under similar and stronger constraint than the precursor region. We further constructed a comprehensive catalogue of microRNA species-specific nucleotide substitutions among great apes and, for the first time, investigated the biological relevance that human-specific changes in microRNAs may have had in great ape evolution. Expression and functional analyses of four microRNAs (miR-299-3p, miR-503-3p, miR-508-3p and miR-541-3p) revealed that lineage-specific nucleotide substitutions and changes in the length of these microRNAs alter their expression as well as the repertoires of target genes and regulatory networks. We suggest that the studied molecular changes could have modified crucial microRNA functions shaping phenotypes that, ultimately, became human-specific. Our work provides a frame to study the impact that regulatory changes may have in the recent evolution of our species.