SummaryMany retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50–100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration.

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Although there is currently no gold standard of measurement for any of the newer anticoagulants, the published literature enables practitioners to evaluate the efficacy and sensitivity of a majority of these assays. Prohemostatic agents can be used in instances of severe, life-threatening hemorrhagic complications.

Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses.

Episodic memory loss is a defining feature of early-stage Alzheimer's disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three-component task that can be solved without reliance on episodic recall (What-Where-When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, whereas, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non-episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model.

Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.

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Ann R Coll Surg Engl 2010; 92: 206-210 206Common bile duct (CBD) stones remain a considerable source of morbidity and mortality, and their presence should be considered in all patients presenting with symptomatic calculi. Intra-operative cholangiography (IOC) has been shown to be a sensitive and specific method of demonstrating bile duct stones; 1 however, it is time consuming, has resource implications and may result in unnecessary bile duct explorations due to false-positive examinations.Other methods for pre-operative assessment of the CBD have previously been evaluated. Magnetic resonance cholangiopancreatography (MRCP) is a sensitive, non-invasive method of imaging the biliary tree.2,3 However, it lacks the immediate therapeutic options available during IOC or endoscopic retrograde cholangiopancreatography (ERCP) and consumes the valuable MRI resource. ERCP, however, is an invasive procedure with morbidity and mortality rates Common bile duct (CBD) stones can cause serious morbidity or mortality, and evidence for them should be sought in all patients with symptomatic gallstones undergoing cholecystectomy. Routine intra-operative cholangiography (IOC) involves a large commitment of time and resources, so a policy of selective cholangiography was adopted. This study prospectively evaluated the policy of selective cholangiography for patients suspected of having choledocholithiasis, and aimed to identify the factors most likely to predict the presence of CBD stones positively. PATIENTS AND METHODS Data from 501 consecutive patients undergoing laparoscopic cholecystectomy (LC) for symptomatic gallstones, of whom 166 underwent IOC for suspected CBD stones, were prospectively collected. Suspicion of choledocholithiasis was based upon: (i) deranged liver function tests (past or present); (ii) history of jaundice (past or present) or acute pancreatitis; (iii) a dilated CBD or demonstration of CBD stones on imaging; or (iv) a combination of these factors. Patient demographics, intra-operative findings, complications and clinical outcomes were recorded. RESULTS Sixty-four cholangiograms were positive (39%). All indications for cholangiogram yielded positive results. Current jaundice yielded the highest positive predictive value (PPV; 86%). A dilated CBD on pre-operative imaging gave a PPV of 45% for CBD calculi; a history of pancreatitis produced a 26% PPV for CBD calculi. Patients with the presence of several factors suggestive of CBD stones yielded higher numbers of positive cholangiograms. Of the 64 patients having a laparoscopic common bile duct exploration (LCBDE), four (6%) required endoscopic retrograde cholangiopancreatography (ERCP) for retained stones (94% successful surgical clearance of the common bile duct) and one (2%) for a bile leak. Of the 335 patients undergoing LC alone, three (0.9%) re-presented with a retained stone, requiring intervention. There were 12 (7%) requiring conversion to open operation. CONCLUSIONS A selective policy for intra-operative cholangiography yields acceptably high positive ...