AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity

Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel α-conotoxin (α-TxIA) in the venom of Conus textile. α-TxIA bound with high affinity to AChBPs from different species and selectively targeted the α3β2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases

Heavy tamponade 2 Densiron 68® in routine clinical practice: Anatomical and functional outcomes of a consecutive case series

Purpose: To evaluate the safety and efficacy of Densiron 68® in the clinical management of complex vitreoretinal cases with inferior retinal pathology. Methods: We present a prospective interventional non-comparative case series of 122 eyes of 121 consecutive patients. The primary end point was anatomical re-attachment of the retina, defined as retinal re-attachment in the absence of any tamponade agent. The secondary end point was to record the visual function and surgical complications. Inclusion criteria were proliferative vitreoretinopathy, posterior or inferior retinal breaks, and the patient's inability to posture. Results: Patients were 59.9 years (±19.6), (m/f=72:49), (R/L=65:57). Seventy-seven (63.1%) had previous unsuccessful retinal surgery and 45 had Densiron 68 at first procedure. The extent of the detachments was 2.21 quadrants (±1.07) with macular involvement in 66 cases (54%). Eighty-seven (71.3%) patients achieved retinal re-attachment with one retinal operation and ultimately no tamponade, 102 (83.6%) achieved retinal re-attachment with more than one operation and ultimately no tamponade, and 112 (91.3%) patients achieved flat retina with tamponade in situ. Visual acuity rose from 1.38 LogMar (±0.87) to 1.06 (±0.83) (P=0.007). Densiron was removed after 135 days (±73.2; range 35-405). Conclusion: No tamponade agent can provide simultaneous support for the superior as well as the inferior retina; therefore, a tamponade agent that 'sinks' is a welcome new tool at the surgeon's disposal. The sequential use of heavy silicone oil followed by conventional silicone oil may be an acceptable management strategy in recurrent detachment.link_to_subscribed_fulltex

Intravitreal Pegaptanib Sodium for Choroidal Neovascularisation Secondary to Age-Related Macular Degeneration: Pan-European Experience

Purpose To evaluate visual outcomes in patients with neovascular age-related macular degeneration (NV-AMD) who were treated with pegaptanib sodium in European clinical ophthalmology practices. Methods Thirteen centres in eight European countries participated in this retrospective study. Medical records for patients with any angiographic subtype of subfoveal choroidal neovascularisation secondary to NV-AMD with visual acuities (study eye) of 20/40-20/320 treated with 0.3mg pegaptanib as first-line treatment and with at least 24 weeks of follow-up were identified. Anonymised data reflecting at least 24 and up to 54 weeks of follow-up were recorded. Primary end points were visual acuity outcomes at weeks 24 and 54 compared with those reported at week 54 in the vascular endothelial growth factor (VEGF) Inhibition Study in Ocular Neovascularisation (VISION) trial. Results In all, 253 patients were followed for at least 24 weeks; 62 patients completed 54 weeks of follow-up. A mean of 4.4 (SD, 1.8) pegaptanib injections were administered through 24 weeks. Compared with the VISION trial, the European experience showed that >90% of patients in the current cohort lost <15 letters from baseline at both time points compared with 70% in the VISION trial at 54 weeks. Pegaptanib was well tolerated with no reported cases of endophthalmitis, traumatic cataract, or iatrogenic retinal detachment. Conclusions Pegaptanib was found to stabilise vision in a greater percentage of patients and produced greater overall visual improvement in this group of treatment-naive patients with NV-AMD compared with outcomes reported in the VISION trial; however, interpretation of these results should be tempered given the differences in design between this retrospective study and the prospective controlled trial. Eye (2010) 24, 793-798; doi:10.1038/eye.2009.232; published online 25 September 2009WoSScopu