Induced pluripotent stem cell-based therapy for age-related macular degeneration

Introduction: In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor. Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells. Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive. Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression

Gene Therapy for Inherited Retinal and Optic Nerve Degenerations

Introduction: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber’s congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber’s hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype

Spatial Distributions of Tropical Cyclone Tornadoes by Intensity and Size Characteristics

Tropical cyclones that make landfall often spawn tornadoes. Previous studies have shown that these tornadoes are not uniformly distributed in the United States or in the tropical cyclone environment. They show that tornadoes tend to occur relatively close to the coastline and that they tend to cluster to the east-of-center in the tropical cyclone environment, particularly in the northeast and east-of-center quadrants. This study contributes to these studies by analyzing the spatial distributions of tropical cyclone tornadoes by intensity, path length, path width, and the damage potential index. The analyses confirm that most tornadoes occur relatively close to the coastline, but show that stronger tornadoes with larger paths are disproportionately common farther inland. They also confirm that the highest amount of activity is located within the northeast and east-of-center quadrants and show that the most potentially damaging tornadoes cluster in a sub region near the intersection of these two quadrants

The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review

The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields

Macroeconomic Modeling of Tax Policy: A Comparison of Current Methodologies

The macroeconomic effects of tax reform are a subject of significant discussion and controversy. In 2015, the House of Representatives adopted a new “dynamic scoring” rule requiring a point estimate within the budget window of the deficit effect due to the macroeconomic response to certain proposed tax legislation. The revenue estimates provided by the staff of the Joint Committee on Taxation (JCT) for major tax bills often play a critical role in Congressional deliberations and public discussion of those bills. The JCT has long had macroeconomic analytic capability, and in recent years, responding to Congress’ interest in macrodynamic estimates for purposes of scoring legislation, outside think tank groups — notably the Tax Policy Center and the Tax Foundation — have also developed macrodynamic estimation models. The May 2017 National Tax Association (NTA) Spring Symposium brought together the JCT with the Tax Foundation and the Tax Policy Center for a panel discussion regarding their respective macrodynamic estimating approaches. This paper reports on that discussion. Below each organization provides a general description of their macrodynamic modeling methodology and answers five questions posed by the convening authors

Experimental Inoculation of House Sparrows (\u3ci\u3ePasser domesticus\u3c/i\u3e) with Buggy Creek Virus

We performed experimental inoculations of house sparrows (Passer domesticus) with Buggy Creek virus (BCRV), a poorly known alphavirus (Togaviridae) vectored primarily by the swallow bug (Hemiptera: Cimicidae: Oeciacus vicarius) that is an ectoparasite of the cliff swallow (Petrochelidon pyrrhonota) and house sparrow. Viremias were detected by plaque assay in two of six birds on days 1–3 postinoculation; viremia was highest on day 2. Viral RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in blood of six of 12 birds ranging from day 1 to day 15 postinoculation. Infectious BCRV was detected in nasopharyngeal swab samples from two birds by plaque assay. Three control birds that were housed with viremic individuals showed evidence of BCRV RNA in blood (by RT-PCR), suggesting possible bird-to-bird transmission of this virus. Viral RNA also was detected by RT-PCR in brain and skin tissue of six birds on necropsy at the end of the 16-day experiment. Introduced house sparrows are apparently a competent amplifying host for BCRV, and their presence year-round at cliff swallow colonies may facilitate persistence of the virus locally, especially when cliff swallows abandon a site temporarily. The findings that BCRV can be shed orally, that it persists in bird skin, and that control birds could apparently be infected by conspecifics suggest that this virus may be transmitted from bird to bird in the crowded conditions of many cliff swallow colonies

Experimental Inoculation of House Sparrows (\u3ci\u3ePasser domesticus\u3c/i\u3e) with Buggy Creek Virus

We performed experimental inoculations of house sparrows (Passer domesticus) with Buggy Creek virus (BCRV), a poorly known alphavirus (Togaviridae) vectored primarily by the swallow bug (Hemiptera: Cimicidae: Oeciacus vicarius) that is an ectoparasite of the cliff swallow (Petrochelidon pyrrhonota) and house sparrow. Viremias were detected by plaque assay in two of six birds on days 1–3 postinoculation; viremia was highest on day 2. Viral RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in blood of six of 12 birds ranging from day 1 to day 15 postinoculation. Infectious BCRV was detected in nasopharyngeal swab samples from two birds by plaque assay. Three control birds that were housed with viremic individuals showed evidence of BCRV RNA in blood (by RT-PCR), suggesting possible bird-to-bird transmission of this virus. Viral RNA also was detected by RT-PCR in brain and skin tissue of six birds on necropsy at the end of the 16-day experiment. Introduced house sparrows are apparently a competent amplifying host for BCRV, and their presence year-round at cliff swallow colonies may facilitate persistence of the virus locally, especially when cliff swallows abandon a site temporarily. The findings that BCRV can be shed orally, that it persists in bird skin, and that control birds could apparently be infected by conspecifics suggest that this virus may be transmitted from bird to bird in the crowded conditions of many cliff swallow colonies

Obesity alters the muscle protein synthetic response to nutrition and exercise

Improving the health of skeletal muscle is an important component of obesity treatment. Apart from allowing for physical activity, skeletal muscle tissue is fundamental for the regulation of postprandial macronutrient metabolism, a time period that represents when metabolic derangements are most often observed in adults with obesity. In order for skeletal muscle to retain its capacity for physical activity and macronutrient metabolism, its protein quantity and composition must be maintained through the efficient degradation and resynthesis for proper tissue homeostasis. Life-style behaviors such as increasing physical activity and higher protein diets are front-line treatment strategies to enhance muscle protein remodeling by primarily stimulating protein synthesis rates. However, the muscle of individuals with obesity appears to be resistant to the anabolic action of targeted exercise regimes and protein ingestion when compared to normal-weight adults. This indicates impaired muscle protein remodeling in response to the main anabolic stimuli to human skeletal muscle tissue is contributing to poor muscle health with obesity. Deranged anabolic signaling related to insulin resistance, lipid accumulation, and/or systemic/muscle inflammation are likely at the root of the anabolic resistance of muscle protein synthesis rates with obesity. The purpose of this review is to discuss the impact of protein ingestion and exercise on muscle protein remodeling in people with obesity, and the potential mechanisms underlining anabolic resistance of their muscle