Connectomic Identification and Three-Dimensional Color Tuning of S-OFF Midget Ganglion Cells in the Primate Retina

In the trichromatic primate retina, the “midget” retinal ganglion cell is the classical substrate for red–green color signaling, with a circuitry that enables antagonistic responses between long (L)- and medium (M)-wavelength-sensitive cone inputs. Previous physiological studies showed that some OFF midget ganglion cells may receive sparse input from short (S)-wavelength-sensitive cones, but the effect of S-cone inputs on the chromatic tuning properties of such cells has not been explored. Moreover, anatomical evidence for a synaptic pathway from S cones to OFF midget ganglion cells through OFF midget bipolar cells remains ambiguous. In this study, we address both questions for the macaque monkey retina. First, we used serial block-face electron microscopy to show that every S cone in the parafoveal retina synapses principally with a single OFF midget bipolar cell, which in turn forms a private-line connection with an OFF midget ganglion cell. Second, we used patch electrophysiology to characterize the chromatic tuning of OFF midget ganglion cells in the near peripheral retina that receive combined input from L, M, and S cones. These “S-OFF” midget cells have a characteristic S-cone spatial signature, but demonstrate heterogeneous color properties due to the variable strength of L, M, and S cone input across the receptive field. Together, these findings strongly support the hypothesis that the OFF midget pathway is the major conduit for S-OFF signals in primate retina and redefines the pathway as a chromatically complex substrate that encodes color signals beyond the classically recognized L versus M and S versus L+M cardinal mechanisms

Maintenance Requirements of Implant Supported Fixed Prostheses Opposed by Either Implant Supported Fixed Prostheses or Natural Teeth: 5 Years Results

AIM: To compare the maintenance requirements of implant supported fixed prostheses opposed by implant supported fixed prostheses natural teeth or complete dentures. METHOD: The maintenance requirements were obtained by examining the dental records of 15 people, of whom 6 were edentulous in both arches and 9 edentulous in one arch. The results were compared to those obtained from 22 edentulous people in whom implants had been used in the mandible (control group). All the patients were treated with Nobel Biocare implants using standard implant and prosthetic protocols. RESULTS: The main maintenance requirement was the need to repair part of the superstructure. The artificial teeth and the acrylic resin had to be repaired on 44 occasions in the group with implants in both jaws and 14 occasions in the group with implants opposed by natural teeth. This compared with 2 occasions in the control group. Similarly the group with implants in both jaws were more likely to fracture the gold alloy framework, an event which occurred on 6 occasions. The Kruskal- Wallis one way analysis of variance on ranks was used to identify significant differences and Dunn’s method of All Pairwise Multiple Comparison Procedures was used to distinguish which group differed from the other. The group with implants in both jaws was significantly different to the other two groups in relation to the higher incidence of fracture of the teeth and acrylic resin superstructure (p<0.0001) and fracture of the gold alloy framework (p = 0.0002). CONCLUSION: The maintenance requirements of implant supported fixed prostheses opposed by implant supported fixed prostheses are much greater than when opposed by natural teeth or complete dentures

Fast non-negative deconvolution for spike train inference from population calcium imaging

Calcium imaging for observing spiking activity from large populations of neurons are quickly gaining popularity. While the raw data are fluorescence movies, the underlying spike trains are of interest. This work presents a fast non-negative deconvolution filter to infer the approximately most likely spike train for each neuron, given the fluorescence observations. This algorithm outperforms optimal linear deconvolution (Wiener filtering) on both simulated and biological data. The performance gains come from restricting the inferred spike trains to be positive (using an interior-point method), unlike the Wiener filter. The algorithm is fast enough that even when imaging over 100 neurons, inference can be performed on the set of all observed traces faster than real-time. Performing optimal spatial filtering on the images further refines the estimates. Importantly, all the parameters required to perform the inference can be estimated using only the fluorescence data, obviating the need to perform joint electrophysiological and imaging calibration experiments.Comment: 22 pages, 10 figure

Nonselective Wiring Accounts for Red-Green Opponency in Midget Ganglion Cells of the Primate Retina

In primate retina, “red-green” color coding is initiated when signals originating in long (L) and middle (M) wavelength-sensitive cone photoreceptors interact antagonistically. The center-surround receptive field of “midget” ganglion cells provides the neural substrate for L versus M cone-opponent interaction, but the underlying circuitry remains unsettled, centering around the longstanding question of whether specialized cone wiring is present. To address this question, we measured the strength, sign, and spatial tuning of L- and M-cone input to midget receptive fields in the peripheral retina of macaque primates of either sex. Consistent with previous work, cone opponency arose when one of the cone types showed a stronger connection to the receptive field center than to the surround. We implemented a difference-of-Gaussians spatial receptive field model, incorporating known biology of the midget circuit, to test whether physiological responses we observed in real cells could be captured entirely by anatomical nonselectivity. When this model sampled nonselectively from a realistic cone mosaic, it accurately reproduced key features of a cone-opponent receptive field structure, and predicted both the variability and strength of cone opponency across the retina. The model introduced here is consistent with abundant anatomical evidence for nonselective wiring, explains both local and global properties of the midget population, and supports a role in their multiplexing of spatial and color information. It provides a neural basis for human chromatic sensitivity across the visual field, as well as the maintenance of normal color vision despite significant variability in the relative number of L and M cones across individuals

Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine

The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene–gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene–gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response

International Veterinary Epilepsy Task Force recommendations for systematic sampling and processing of brains from epileptic dogs and cats

Traditionally, histological investigations of the epileptic brain are required to identify epileptogenic brain lesions, to evaluate the impact of seizure activity, to search for mechanisms of drug-resistance and to look for comorbidities. For many instances, however, neuropathological studies fail to add substantial data on patients with complete clinical work-up. This may be due to sparse training in epilepsy pathology and or due to lack of neuropathological guidelines for companion animals. The protocols introduced herein shall facilitate systematic sampling and processing of epileptic brains and therefore increase the efficacy, reliability and reproducibility of morphological studies in animals suffering from seizures. Brain dissection protocols of two neuropathological centres with research focus in epilepsy have been optimised with regards to their diagnostic yield and accuracy, their practicability and their feasibility concerning clinical research requirements. The recommended guidelines allow for easy, standardised and ubiquitous collection of brain regions, relevant for seizure generation. Tissues harvested the prescribed way will increase the diagnostic efficacy and provide reliable material for scientific investigations

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible