Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease.

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Feasibility of Human Factors Immersive Simulation Training in Ophthalmology: The London Pilot.

IMPORTANCE: Human factors training can enhance teamworking and reduce error. It is used regularly in certain medical disciplines, but its use has not been established for ophthalmology to our knowledge. OBJECTIVE: To explore the feasibility of providing immersive simulation human factors training for ophthalmic surgical teams. DESIGN, SETTING, AND PARTICIPANTS: Prospective scenario-based simulation and concept description at University College London Hospital and Moorfields Eye Hospital, London, England, from December 12, 2013, to March 13, 2014. At both sites, fully immersive simulated operating theater environments were used, comprising live interactive communication with patients and theater staff, full anesthetic and operating facilities, replicated patient notes, active vital signs, and the ability to contact surgical or anesthetic teams outside of the theater via telephone. Participants were consultant (attending) and trainee ophthalmic surgeons and anesthetists, operating department assistants and practitioners, and ophthalmic nursing staff. MAIN OUTCOMES AND MEASURES: The following 4 previously validated rating tools for nontechnical skills were applied to a replicated series of scenarios based on actual patient safety incidents at Moorfields Eye Hospital and in the literature: Observational Teamwork Assessment for Surgery (OTAS), Non-Technical Skills Scale (NOTECHS), Anesthetists' Non-Technical Skills (ANTS), and Non-Technical Skills for Surgeons (NOTSS). The Pearson product moment correlation coefficient was calculated for each pair of scoring tools. Intertool and interassessor reliability was established. Interassessor consistency was compared by calculating a normalized standard deviation of scores for each tool across all assessors. RESULTS: Twenty simulation scenarios, including wrong intraocular lens implantation, wrong eye operation, wrong drug administration, and wrong patient, were provided. The intertool correlations were 0.732 (95% CI, 0.271-0.919; P = .01) for NOTECHS vs ANTS, 0.922 (95% CI, 0.814-0.968; P < .001) for NOTSS vs ANTS, 0.850 (95% CI, 0.475-0.964; P < .001) for OTAS vs ANTS, 0.812 (95% CI, 0.153-0.971; P = .03) for OTAS vs NOTECHS, 0.716 (95% CI, -0.079 to 0.955; P = .07) for OTAS vs NOTSS, and 0.516 (95% CI, -0.020 to 0.822; P = .06) for NOTECHS vs NOTSS. The normalized standard deviations of scores obtained using each tool across all assessors were 0.024 (95% CI, 0.014-0.091) for NOTSS, 0.060 (95% CI, 0.034-0.225) for OTAS, 0.068 (95% CI, 0.041-0.194) for ANTS, and 0.072 (95% CI, 0.043-0.206) for NOTECHS. CONCLUSIONS AND RELEVANCE: This study describes the feasibility of a high-fidelity immersive simulation course specifically for ophthalmic surgical teams. The ANTS and NOTSS had the highest intertool and interrater consistency, respectively. Human factors simulation in ophthalmology offers a new method of teaching team members, with the potential to reduce serious ophthalmic patient safety events. Further work will define its usefulness and practical applications.

Shunt Testing In Vivo: Observational Study of Problems with Ventricular Catheter.

Most shunt obstructions happen at the inlet of the ventricular catheter. Three hundred six infusion studies from 2007 to 2011 were classified as having a typical pattern of either proximal occlusion or patency. We describe different patterns of shunt ventricular obstruction.Solid block: Cerebrospinal fluid (CSF) aspiration was impossible. Baseline pressure was without pulse waveform (respiratory waveform may be visible). A quick increase of pressure to a level compatible with the shunt's setting was recorded in response to infusion. Distal occlusion of the shunt via transcutaneous compression resulted in a rapid increase in pressure to levels above 50 mmHg. This pattern was attributed to a solid ventricular block.Slit ventricles: At baseline, a pattern similar to that of the solid block was observed. After compression, the pressure increases, the pulse waveform appears, and the intracranial pressure is often stabilized at 25-40 mmHg. It is probable that previously slit ventricles were opened during the test.Partial block: In a partial block of the ventricular catheter by an in-growing choroid plexus, the pulse waveform at baseline was observed and CSF aspiration was possible. During infusion, the pressure increased, but the pulse amplitude disappeared. During the increase in the pressure in the shunt prechamber, the connection with the ventricles is disturbed by repositioning of the plexus.Infusion study via the shunt prechamber is able to visualize ventricular obstruction of the hydrocephalus shunt.

Optical coherence tomography imaging of the proximal lacrimal system.

INTRODUCTION: There are currently no routinely used imaging modalities for the proximal lacrimal system. Optical Coherence Tomography (OCT) is a safe and non-invasive method of high resolution cross-sectional imaging of tissue microstructures using infra-red radiation. In this study we investigate whether OCT may be used to image the punctum and proximal canaliculus. METHODS: A cohort of healthy subjects with normal ocular anatomy and no symptoms of epiphora were prospectively invited to enrol. Spectral OCT images of the lower punctae were captured with a Topcon 3D Optical Coherence Tomography 2000 machine. Measurements were made of the maximal punctal diameter, canalicular diameter and canalicular depth. Our data for depth of the vertical canaliculus was compared to the widely quoted figure of 2 mm using a two-tailed t-test to check for a statistically significant difference at p < 0.05. RESULTS: Thirty-six punctae of 18 subjects were scanned. The punctum was recognisable on the OCT image in all cases. The mean depth, width and cross- sectional area of the visualised canaliculi were 0.753 mm (SD 0.216), 0.110 mm (SD 0.067) and 9.49 × 10(-3)mm(2), respectively. The mean width of the punctum was 0.247 mm (SD 0.078). DISCUSSION: We have demonstrated the first in-vivo high resolution images of normal punctal and vertical canalicular anatomy using spectral OCT. There is currently no other practical way to accurately image punctal and proximal canalicular morphology in vivo. OCT is a convenient and readily available tool in most eye clinics with resolution ideally suited for imaging of the punctum and proximal canaliculus.

Antagonism at NMDA receptors, but not ß-adrenergic receptors, disrupts the reconsolidation of pavlovian conditioned approach and instrumental transfer for ethanol-associated conditioned stimuli.

RATIONALE: Reconsolidation is the process by which memories require restabilisation following destabilisation at retrieval. Since even old, well-established memories become susceptible to disruption following reactivation, treatments based upon disrupting reconsolidation could provide a novel form of therapy for neuropsychiatric disorders based upon maladaptive memories, such as drug addiction. Pavlovian cues are potent precipitators of relapse to drug-seeking behaviour and influence instrumental drug seeking through at least three psychologically and neurobiologically distinct processes: conditioned reinforcement, conditioned approach (autoshaping) and conditioned motivation (pavlovian-instrumental transfer or PIT). We have previously demonstrated that the reconsolidation of memories underlying the conditioned reinforcing properties of drug cues depends upon NMDA receptor (NMDAR)- and ß-adrenergic receptor (ßAR)-mediated signalling. However, it is unknown whether the drug cue memory representations underlying conditioned approach and PIT depend upon the same mechanisms. OBJECTIVES: Using orally self-administered ethanol as a reinforcer in two separate experiments, we investigated whether the reconsolidation of the memories underlying conditioned approach and PIT requires ßAR- and NMDAR-dependent neurotransmission. RESULTS: For ethanol self-administering but non-dependent rats, the memories underlying conditioned approach and PIT for a pavlovian drug cue were disrupted by the administration of the NMDAR antagonist MK-801, but not the administration of the ßAR antagonist propranolol, when given in conjunction with memory reactivation. CONCLUSIONS: As for natural reinforcers, NMDARs are required for the reconsolidation of all aspects of pavlovian drug memories, but ßARs are only required for the memory representation underlying conditioned reinforcement. These results indicate the potential utility of treatments based upon disrupting cue-drug memory reconsolidation in preventing relapse.