Perinatal and neonatal outcomes for fetoscopic laser ablation for the treatment of twin twin transfusion syndrome at a single center.

OBJECTIVE: To describe the perinatal and neonatal outcomes of fetal laser ablation (FLA) for the treatment of twin-twin transfusion syndrome (TTTS) in our single center institution. STUDY DESIGN: Retrospective study of 76 treated pregnant women. Procedural complications, perinatal and neonatal outcomes analyzed. Differences in outcomes between two procedural techniques, selective and Solomon, compared. RESULTS: FLA occurred at median gestational age (GA) of 20.8 weeks (IQR 18.1-22.9) with low incidence of procedural complications (5.3%). High survival rate with delivery of at least one neonate (96%) [95% CI: 88.9-99.2%]; 73.7% [95% CI: 62.3-83.1%] were twins. Median GA at birth was 33.1 weeks (IQR 28.0-35.0). Neonatal mortality and morbidities were 9.4% and 48.3% of cases respectively, and associated with lower GA. Solomon cases had comparatively higher median GA, and lower incidences of neonatal morbidities. CONCLUSION: Our small single center study showed favorable outcomes for using the Solomon technique in the treatment of TTTS.

In Utero Diagnoses of Strikingly Similar Presentations of Complete Atrioventricular Septal Defects in a Pair of Dizygotic Twins Concordant for Trisomy 21.

Trisomy 21, or Down syndrome (DS), is a genetic disorder affecting approximately 1 in 500-750 live births. The prevalence of DS has increased over the past two decades, correlating with a rise in the proportion of pregnancies complicated by advanced maternal age. There is also a correlation between advanced maternal age and dizygotic twinning rates. There is an increased risk of at least one twin being affected in dizygotic pregnancies compared to singletons. However, despite this greater relative risk, reports of concordance of DS in both dizygotic twins are very rare. Congenital heart disease (CHD) occurs in roughly 40% of individuals with DS, but there can be considerable phenotypic variation. The most common, atrioventricular septal defect accounts for only 40% of CHD seen in DS. There is also a higher incidence of CHD in twins, but also with a low incidence of concordance. There have been only five reported cases of concordant DS in dizygotic twins with confirmed chromosomal analyses; none of which describe concordant congenital heart disease. Here, we describe an unusual case of dizygotic twins of differing genders concordant for both Down syndrome and congenital heart disease of a strikingly similar presentation.

CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses.

Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14(++)CD16(+) cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14(++)CD16(+) monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14(++)CD16(+) monocytes with classical CD14(++)CD16(-) and nonclassical CD14(+)CD16(++) monocytes revealed that the intermediate CD14(++)CD16(+) subset had an attenuated capacity to promote both naive CD4(+) T cell proliferation and polarization into a Th1 phenotype, and memory CD4(+) T cell proliferation and IL-17 expression. Furthermore, CD14(++)CD16(+) cells inhibit CD4(+) T cell proliferation induced by other monocyte subsets and enhance CD4(+) T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses.

The role of macrophage class a scavenger receptors in a laser-induced murine choroidal neovascularization model.

PURPOSE: Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS: Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS: Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. CONCLUSIONS: The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.

The tellurium redox immunomodulating compound AS101 inhibits IL-1ß-activated inflammation in the human retinal pigment epithelium.

PURPOSE: AS101 is a non-toxic organotellurium-IV compound with demonstrated immunomodulating activity in vitro and in vivo. Inflammatory responses are attributed to the pathophysiology of numerous ocular diseases. In this study, we wished to elucidate whether AS101 could mitigate pro-inflammatory activity in human retinal pigment epithelial (RPE) cells, which are heavily involved in ocular immune responses, induced by pro-inflammatory IL-ß activity. METHODS: Primary and transformed RPE cells treated with varying concentrations of AS101 were used in this study. Real-time PCR and ELISA assays were used to detect cytokine/chemokine mRNA expression and protein production. Western blot was used to detect changes in the NFκB pathway. Cell viability and proliferation were detected using a Vi-Cell XR cell counter. To measure the cytoprotective capacity of AS101, cell numbers were compared between cells treated with IL-1ß or lipopolysaccharide (LPS) and cells treated with IL-1ß or LPS in the presence of AS101. RESULTS: AS101 inhibited IL-1ß-induced mRNA expression and protein production of IL-6 and IL-8 in RPE cells. The viability of RPE cells treated with IL-1ß and LPS was unaffected. AS101 slightly inhibited RPE cell growth in the presence of higher levels of IL-1ß. Also, AS101 downregulated the IL-1ß activity by inhibiting the phosphorylation of p65, an NFκB subunit. CONCLUSIONS: The results demonstrate that AS101 reduces IL-1ß-induced inflammatory responses in the RPE. In previous studies, AS101 exhibited therapeutic effects in various disease models and was a safe profile in clinical trials. These results suggest that AS101 may have potent anti-inflammatory potential in the eye and confer the downregulation of RPE inflammatory responses in a pathological environment.

Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.

C5a contributes to intraocular inflammation by affecting retinal pigment epithelial cells and immune cells.

BACKGROUND: The complement activation molecule C5a has been found in the eye and is implicated in the pathogenesis of ocular inflammatory diseases. In this study, the authors sought to investigate C5a's effects on human retinal pigment epithelial (RPE) cells and peripheral blood mononuclear cells (PBMCs), and on the interaction between RPE cells and PBMCs. METHODS: Arising retinal pigment epithelia cell line-19 and PBMCs isolated from healthy donors were used in this study. Western blot, real-time PCR and cell surface receptor staining were used to detect C5a receptor expression. Real-time PCR was used to detect cytokine mRNA expression. A thiazolyl blue tetrazolium bromide assay was used to detect cell viability. Cells were stained with Annexin V and 7-aminoactinomycin D for an apoptosis assay. Cell proliferation was measured using a tritiated thymidine incorporation assay. RESULTS: C5a receptors were present on RPE cells, and receptor expression was increased by pro-inflammatory cytokines. C5a suppressed RPE cells' production of transforming growth factor ß2, an important immunosuppressive agent in the eye. In addition, the viability of RPE cells was decreased in the presence of C5a, and this effect was not due to apoptosis. C5a increased proliferation of PBMCs and upregulated their production of pro-inflammatory cytokines. Finally, C5a decreased RPE cells' ability to suppress immune cell proliferation. CONCLUSION: The results provide a direct link between complement activation and intraocular inflammation. This line of information may help to understand the mechanism of the pathogenesis of intraocular inflammatory diseases. Moreover, the authors show that a close, reciprocal interaction between the innate immune system and the adaptive immune system may be involved in the development of such diseases.