P 419 Comparison of tight junctions permeability and modulation in iris pigment epithelium and retinal pigment epithelium in vitro

Amb una superfície: 0,61 ha, de basalt i aigua nebulitzada.Barragán, Pedro (dissenyador)Gran pla general de El Volcà,conegut com la Carbonera. El carbó calent era mullat per aigua subterrània i desprenia vapor. Actualment està inactiu. Destaquen el pg. Josep Carner amb el monument a Colom i els edificis de Capitania i Duana

Our Administrative System of Criminal Justice

To commemorate our founding in 1914, the Board of Editors has selected six influential pieces published by the Law Review over the past 100 years and will republish one piece in each issue. The fourth piece selected by the Board is Our Administrative System of Criminal Justice, an article written by Gerard E. Lynch that is among the most cited works in the Law Review’s history. This article illustrates how the practice of plea bargaining blurs the boundaries between adversarial and inquisitorial criminal justice systems. Judge Lynch now sits on the Second Circuit having eventually succeeded the late Judge Joseph M. McLaughlin, who also is honored in the pages of this book for the permanent mark he left on Fordham Law School and the Law Review. We think it is fitting that the Law Review feature two of the many contributions that judges of the Second Circuit have made to legal education and scholarship in this issue

Improvements in vision-related quality of life in blind patients implanted with the Argus II Epiretinal Prosthesis

Background: The purpose of this analysis is to report the change in quality of life (QoL) after treatment with the Argus II Epiretinal Prosthesis in patients with end-stage retinitis pigmentosa. Methods: The Vision and Quality of Life Index (VisQoL) was used to assess changes in QoL dimensions and overall utility score in a prospective 30-patient single-arm clinical study. VisQoL is a multi-attribute instrument consisting of six dimensions (injury, life, roles, assistance, activity and friendship) that may be affected by visual impairment. Within each dimension, patients were divided into two groups based on how much their QoL was affected by their blindness at baseline (moderate/severe or minimal). Outcomes were compared within each dimension sub-group between baseline and the combined follow-up periods using the Friedman test. In addition, data from the six dimensions were combined into a single utility score, with baseline data compared to the combined follow-up periods. Results: Overall, 80 per cent of the patients reported difficulty in one or more dimensions preimplant. Composite VisQoL utility scores at follow-up showed no statistically significant change from baseline; however, in three of the six VisQoL dimensions (injury, life and roles), patients with baseline deficits showed significant and lasting improvement after implantation with Argus II. In two of the three remaining dimensions (assistance and activity), data trended toward an improvement. In the final VisQoL dimension (friendship), none of the patients reported baseline deficits, suggesting that patients had largely adjusted to this attribute. Conclusion: Patients whose vision negatively affected them with respect to three VisQoL dimensions (that is, getting injured, coping with the demands of their life and fulfilling their life roles) reported significant improvement in QoL after implantation of the Argus II retinal prosthesis. Furthermore, the benefit did not deteriorate at any point during the 36-month follow-up, suggesting a long-term, durable improvement

Molecular and functional characterization of BDNF-overexpressing human retinal pigment epithelial cells established by sleeping beauty transposon-mediated gene transfer

More and more patients suffer from multifactorial neurodegenerative diseases, such as age-related macular degeneration (AMD). However, their pathological mechanisms are still poorly understood, which complicates the development of effective therapies. To improve treatment of multifactorial diseases, cell-based gene therapy can be used to increase the expression of therapeutic factors. To date, there is no approved therapy for dry AMD, including late-stage geographic atrophy. We present a treatment option for dry AMD that transfers the brain-derived neurotrophic factor (BDNF) gene into retinal pigment epithelial (RPE) cells by electroporation using the plasmid-based Sleeping Beauty (SB) transposon system. ARPE-19 cells and primary human RPE cells were co-transfected with two plasmids encoding the (SB100X) transposase and the transposon carrying a BDNF transcription cassette. We demonstrated efficient expression and secretion of BDNF in both RPE cell types, which were further increased in ARPE-19 cell cultures exposed to hydrogen peroxide. BDNF-transfected cells exhibited lower apoptosis rates and stimulated neurite outgrowth in human SH-SY5Y cells. This study is an important step in the development of a cell-based BDNF gene therapy that could be applied as an advanced therapy medicinal product to treat dry AMD or other degenerative retinal diseases

A search for trachoma in Timor-Leste: no evidence to justify undertaking population-based prevalence surveys

Purpose: We sought evidence to justify undertaking population-based trachoma surveys in Timor-Leste, believing that in the absence of such evidence, the country could be categorized as not needing interventions to eliminate trachoma.Methods: We undertook a systematic review of published literature on trachoma in Timor-Leste, with results updated to 28 April 2018. We also undertook a series of clinic- and field-based screening exercises, consisting of: (1) in October 2015, conjunctival examination of all children attending a school in Vila, Atauro Island; (2) from 1 November 2016 to 30 April 2017, examination for trichiasis, by specifically-trained frontline eye workers, of all individuals presenting to the ophthalmic clinics of six referral hospitals and five district eye clinics; and (3) house-to-house case searches in a total of 110 households, drawn from three communities that were reported by investigators from the 2016 Rapid Assessment of Avoidable Blindness (RAAB) to include residents with trachoma.Results: Three RAABs (2005, 2009–2010, 2016) and two relevant published papers were identified. The 2016 RAAB reported one female subject to have been diagnosed with trachomatous corneal opacity. Re-examination of that individual revealed that she had ankyloblepharon, without evidence of trichiasis or entropion. No children on Atauro Island, no clinic attendees, and no individuals examined in the targeted house-to-house searches had any sign of trachoma.Conclusion: Trachoma is very unlikely to be a public health problem in Timor-Leste. It would not be appropriate to incur the costs of conducting formal population-based trachoma prevalence surveys here

Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus (R) II retinal prosthesis system

Background: The main objective of this study was to test Argus II subjects on three real‐world functional vision tasks. / Design: The study was designed to be randomized and prospective. Testing was conducted in a hospital/research laboratory setting at the various participating centres. / Participants: Twenty eight Argus II subjects, all profoundly blind, participated in this study. / Methods: Subjects were tested on the three real‐world functional vision tasks: Sock Sorting, Sidewalk Tracking and Walking Direction Discrimination task. / Main Outcome Measures: For the Sock Sorting task, percentage correct was computed based on how accurately subjects sorted the piles on a cloth‐covered table and on a bare table. In the Sidewalk Tracking task, an ‘out of bounds’ count was recorded, signifying how often the subject veered away from the test course. During the Walking Direction Discrimination task, subjects were tested on the number of times they correctly identified the direction of testers walking across their field of view. / Results: The mean percentage correct OFF versus ON for the Sock Sorting task was found to be significantly different for both testing conditions (t‐test, P < 0.01). On the Sidewalk Tracking task, subjects performed significantly better with the system ON than they did with the system OFF (t‐test, P < 0.05). Eighteen (18) of 27 subjects (67%) performed above chance with the system ON, and 6 (22%) did so with system OFF on the Walking Direction Discrimination task. / Conclusions: Argus II subjects performed better on all three tasks with their systems ON than they did with their systems OFF

Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruch's membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein

GMP-grade manufacturing and quality control of a non-virally engineered advanced therapy medicinal product for personalized treatment of age-related macular degeneration

The introduction of new therapeutics requires validation of Good Manufacturing Practice (GMP)-grade manufacturing including suitable quality controls. This is challenging for Advanced Therapy Medicinal Products (ATMP) with personalized batches. We have developed a person-alized, cell-based gene therapy to treat age-related macular degeneration and established a vali-dation strategy of the GMP-grade manufacture for the ATMP; manufacturing and quality control were challenging due to a low cell number, batch-to-batch variability and short production duration. Instead of patient iris pigment epithelial cells, human donor tissue was used to produce the transfected cell product ("tIPE"). We implemented an extended validation of 104 tIPE productions. Procedure, operators and devices have been validated and qualified by determining cell number, viability, extracellular DNA, sterility, duration, temperature and volume. Transfected autologous cells were transplanted to rabbits verifying feasibility of the treatment. A container has been engineered to ensure a safe transport from the production to the surgery site. Criteria for successful validation and qualification were based on tIPE's Critical Quality Attributes and Process Parameters, its manufacture and release criteria. The validated process and qualified operators are essential to bring the ATMP into clinic and offer a general strategy for the transfer to other manufacture centers and personalized ATMPs

A novel monoclonal anti-CD81 antibody produced by genetic immunization efficiently inhibits Hepatitis C virus cell-cell transmission

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. METHODS: Using genetic immunization, we produced four monoclonal antibodies (mAbs) against the HCV host entry factor CD81. The effects of antibodies on inhibition of HCV infection and dissemination were analyzed in HCV permissive human liver cell lines. RESULTS: The anti-CD81 mAbs efficiently inhibited infection by HCV of different genotypes as well as a HCV escape variant selected during liver transplantation and re-infecting the liver graft. Kinetic studies indicated that anti-CD81 mAbs target a post-binding step during HCV entry. In addition to inhibiting cell-free HCV infection, one antibody was also able to block neutralizing antibody-resistant HCV cell-cell transmission and viral dissemination without displaying any detectable toxicity. CONCLUSION: A novel anti-CD81 mAb generated by genetic immunization efficiently blocks HCV spread and dissemination. This antibody will be useful to further unravel the role of virus-host interactions during HCV entry and cell-cell transmission. Furthermore, this antibody may be of interest for the development of antivirals for prevention and treatment of HCV infection

The use of gamma-irradiation and ultraviolet-irradiation in the preparation of human melanoma cells for use in autologous whole-cell vaccines

<p>Abstract</p> <p>Background</p> <p>Human cancer vaccines incorporating autologous tumor cells carry a risk of implantation and subsequent metastasis of viable tumor cells into the patient who is being treated. Despite the fact that the melanoma cell preparations used in a recent vaccine trial (Mel37) were gamma-irradiated (200 Gy), approximately 25% of the preparations failed quality control release criteria which required that the irradiated cells incorporate ³H-thymidine at no more than 5% the level seen in the non-irradiated cells. We have, therefore, investigated ultraviolet (UV)-irradiation as a possible adjunct to, or replacement for gamma-irradiation.</p> <p>Methods</p> <p>Melanoma cells were gamma- and/or UV-irradiated. ³H-thymidine uptake was used to assess proliferation of the treated and untreated cells. Caspase-3 activity and DNA fragmentation were measured as indicators of apoptosis. Immunohistochemistry and Western blot analysis was used to assess antigen expression.</p> <p>Results</p> <p>UV-irradiation, either alone or in combination with gamma-irradiation, proved to be extremely effective in controlling the proliferation of melanoma cells. In contrast to gamma-irradiation, UV-irradiation was also capable of inducing significant levels of apoptosis. UV-irradiation, but not gamma-irradiation, was associated with the loss of tyrosinase expression. Neither form of radiation affected the expression of gp100, MART-1/MelanA, or S100.</p> <p>Conclusion</p> <p>These results indicate that UV-irradiation may increase the safety of autologous melanoma vaccines, although it may do so at the expense of altering the antigenic profile of the irradiated tumor cells.</p