Degenerated cones in cultured human retinas can successfully be optogenetically reactivated

Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into "artificial photoreceptors". However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these 'reactivated' retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant's condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.Therapeutic cell differentiatio

A novel method for engineering autologous non-thrombogenic in situ tissue-engineered blood vessels for arteriovenous grafting

The durability of prosthetic arteriovenous (AV) grafts for hemodialysis access is low, predominantly due to stenotic lesions in the venous outflow tract and infectious complications. Tissue engineered blood vessels (TEBVs) might offer a tailor-made autologous alternative for prosthetic grafts. We have designed a method in which TEBVs are grown in vivo, by utilizing the foreign body response to subcutaneously implanted polymeric rods in goats, resulting in the formation of an autologous fibrocellular tissue capsule (TC). One month after implantation, the polymeric rod is extracted, whereupon TCs (length 6 cm, diameter 6.8 mm) were grafted as arteriovenous conduit between the carotid artery and jugular vein of the same goats. At time of grafting, the TCs were shown to have sufficient mechanical strength in terms of bursting pressure (2382 +/- 129 mmHg), and suture retention strength (SRS: 1.97 +/- 0.49 N). The AV grafts were harvested at 1 or 2 months after grafting. In an ex vivo whole blood perfusion system, the lumen of the vascular grafts was shown to be less thrombogenic compared to the initial TCs and ePTFE grafts. At 8 weeks after grafting, the entire graft was covered with an endothelial layer and abundant elastin expression was present throughout the graft. Patency at 1 and 2 months was comparable with ePTFE AV-grafts. In conclusion, we demonstrate the remodeling capacity of cellularized in vivo engineered TEBVs, and their potential as autologous alternative for prosthetic vascular grafts.Vascular Surger

Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis

Objective To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding

A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands