A. Huckenpahler, M. Wilk, R. F. Cooper, Francie Moehring, B. Link, J. Carroll, Ross F. Collery
{"title":"Imaging the adult zebrafish cone mosaic using optical coherence tomography","authors":"A. Huckenpahler, M. Wilk, R. F. Cooper, Francie Moehring, B. Link, J. Carroll, Ross F. Collery","doi":"10.1017/S0952523816000092","DOIUrl":"https://doi.org/10.1017/S0952523816000092","url":null,"abstract":"Abstract Zebrafish (Danio rerio) provide many advantages as a model organism for studying ocular disease and development, and there is great interest in the ability to non-invasively assess their photoreceptor mosaic. Despite recent applications of scanning light ophthalmoscopy, fundus photography, and gonioscopy to in vivo imaging of the adult zebrafish eye, current techniques either lack accurate scaling information (limiting quantitative analyses) or require euthanizing the fish (precluding longitudinal analyses). Here we describe improved methods for imaging the adult zebrafish retina using spectral domain optical coherence tomography (OCT). Transgenic fli1:eGFP zebrafish were imaged using the Bioptigen Envisu R2200 broadband source OCT with a 12-mm telecentric probe to measure axial length and a mouse retina probe to acquire retinal volume scans subtending 1.2 × 1.2 mm nominally. En face summed volume projections were generated from the volume scans using custom software that allows the user to create contours tailored to specific retinal layer(s) of interest. Following imaging, the eyes were dissected for ex vivo fluorescence microscopy, and measurements of blood vessel branch points were compared to those made from the en face OCT images to determine the OCT lateral scale as a function of axial length. Using this scaling model, we imaged the photoreceptor layer of five wild-type zebrafish and quantified the density and packing geometry of the UV cone submosaic. Our in vivo cone density measurements agreed with measurements from previously published histology values. The method presented here allows accurate, quantitative assessment of cone structure in vivo and will be useful for longitudinal studies of the zebrafish cone mosaics.","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2016-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523816000092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"56944968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin S. Sajdak, Y. Sulai, C. Langlo, G. Luna, S. Fisher, D. Merriman, A. Dubra
{"title":"Noninvasive imaging of the thirteen-lined ground squirrel photoreceptor mosaic","authors":"Benjamin S. Sajdak, Y. Sulai, C. Langlo, G. Luna, S. Fisher, D. Merriman, A. Dubra","doi":"10.1017/S0952523815000346","DOIUrl":"https://doi.org/10.1017/S0952523815000346","url":null,"abstract":"Abstract Ground squirrels are an increasingly important model for studying visual processing, retinal circuitry, and cone photoreceptor function. Here, we demonstrate that the photoreceptor mosaic can be longitudinally imaged noninvasively in the 13-lined ground squirrel (Ictidomys tridecemlineatus) using confocal and nonconfocal split-detection adaptive optics scanning ophthalmoscopy using 790 nm light. Photoreceptor density, spacing, and Voronoi analysis are consistent with that of the human cone mosaic. The high imaging success rate and consistent image quality in this study reinforce the ground squirrel as a practical model to aid drug discovery and testing through longitudinal imaging on the cellular scale.","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2016-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523815000346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"56944890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frances E Hauser, Ryan K. Schott, Gianni M. Castiglione, Alexander Van Nynatten, A. Kosyakov, Portia L. Tang, Daniel A. Gow, B. Chang
{"title":"Comparative sequence analyses of rhodopsin and RPE65 reveal patterns of selective constraint across hereditary retinal disease mutations","authors":"Frances E Hauser, Ryan K. Schott, Gianni M. Castiglione, Alexander Van Nynatten, A. Kosyakov, Portia L. Tang, Daniel A. Gow, B. Chang","doi":"10.1017/S0952523815000322","DOIUrl":"https://doi.org/10.1017/S0952523815000322","url":null,"abstract":"Abstract Retinitis pigmentosa (RP) comprises several heritable diseases that involve photoreceptor, and ultimately retinal, degeneration. Currently, mutations in over 50 genes have known links to RP. Despite advances in clinical characterization, molecular characterization of RP remains challenging due to the heterogeneous nature of causal genes, mutations, and clinical phenotypes. In this study, we compiled large datasets of two important visual genes associated with RP: rhodopsin, which initiates the phototransduction cascade, and the retinoid isomerase RPE65, which regenerates the visual cycle. We used a comparative evolutionary approach to investigate the relationship between interspecific sequence variation and pathogenic mutations that lead to degenerative retinal disease. Using codon-based likelihood methods, we estimated evolutionary rates (d N/d S) across both genes in a phylogenetic context to investigate differences between pathogenic and nonpathogenic amino acid sites. In both genes, disease-associated sites showed significantly lower evolutionary rates compared to nondisease sites, and were more likely to occur in functionally critical areas of the proteins. The nature of the dataset (e.g., vertebrate or mammalian sequences), as well as selection of pathogenic sites, affected the differences observed between pathogenic and nonpathogenic sites. Our results illustrate that these methods can serve as an intermediate step in understanding protein structure and function in a clinical context, particularly in predicting the relative pathogenicity (i.e., functional impact) of point mutations and their downstream phenotypic effects. Extensions of this approach may also contribute to current methods for predicting the deleterious effects of candidate mutations and to the identification of protein regions under strong constraint where we expect pathogenic mutations to occur.","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2016-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523815000322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"56944763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A tale of two neurotransmitters.","authors":"David W Marshak","doi":"10.1017/S0952523816000146","DOIUrl":"https://doi.org/10.1017/S0952523816000146","url":null,"abstract":"<p><p>Amacrine cells are a diverse set of local circuit neurons of the inner retina, and they all release either GABA or glycine, amino acid neurotransmitters that are generally inhibitory. But some types of amacrine cells have another function besides inhibiting other neurons. One glycinergic amacrine cell, the Aii type, excites a subset of bipolar cells via extensive gap junctions while inhibiting others at chemical synapses. Many types of GABAergic amacrine cells also release monoamines, acetylcholine, or neuropeptides. There is now good evidence that another type of amacrine cell releases glycine at some of its synapses and releases the excitatory amino acid glutamate at others. The glutamatergic synapses are made onto a subset of retinal ganglion cells and amacrine cells and have the asymmetric postsynaptic densities characteristic of central excitatory synapses. The glycinergic synapses are made onto other types of ganglion cells and have the symmetric postsynaptic densities characteristic of central inhibitory synapses. These amacrine cells, which contain vesicular glutamate transporter 3, will be the focus of this brief review.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E017"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523816000146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34869823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A Reiner, T T Wong, C C Nazor, N Del Mar, M E C Fitzgerald
{"title":"Type-specific photoreceptor loss in pigeons after disruption of parasympathetic control of choroidal blood flow by the medial subdivision of the nucleus of Edinger-Westphal.","authors":"A Reiner, T T Wong, C C Nazor, N Del Mar, M E C Fitzgerald","doi":"10.1017/S0952523816000043","DOIUrl":"https://doi.org/10.1017/S0952523816000043","url":null,"abstract":"<p><p>The medial part of the nucleus of Edinger-Westphal (EWM) in birds mediates light-regulated adaptive increases in choroidal blood flow (ChBF). We sought to characterize the effect of loss of EWM-mediated ChBF regulation on photoreceptor health in pigeons housed in either moderate intensity diurnal or constant light (CL). Photoreceptor abundance following complete EWM destruction was compared to that following a lesion in the pupil control circuit (as a control for spread of EWM lesions to the nearby pupil-controlling lateral EW) or following no EW damage. Birds were housed post-lesion in a 12 h 400 lux light/12 h dark light cycle for up to 16.5 months, or in constant 400 lux light for up to 3 weeks. Paraformaldehyde-glutaraldehyde fixed eyes were embedded in plastic, sectioned, slide-mounted, and stained with toluidine blue/azure II. Blinded analysis of photoreceptor outer segment abundance was performed, with outer segment types distinguished by oil droplet tint and laminar position. Brains were examined histologically to assess lesion accuracy. Disruption of pupil control had no adverse effect on photoreceptor outer segment abundance in either diurnal light or CL, but EWM destruction led to 50-60% loss of blue/violet cone outer segments in both light conditions, and a 42% loss of principal cone outer segments in CL. The findings indicate that adaptive regulation of ChBF by the EWM circuit plays a role in maintaining photoreceptor health and mitigates the harmful effect of light on photoreceptors, especially short wavelength-sensitive cone photoreceptors.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E008"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523816000043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34727059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joseph Bouskila, Vanessa Harrar, Pasha Javadi, Christian Casanova, Yoshio Hirabayashi, Ichiro Matsuo, Jyunpei Ohyama, Jean-François Bouchard, Maurice Ptito
{"title":"Scotopic vision in the monkey is modulated by the G protein-coupled receptor 55.","authors":"Joseph Bouskila, Vanessa Harrar, Pasha Javadi, Christian Casanova, Yoshio Hirabayashi, Ichiro Matsuo, Jyunpei Ohyama, Jean-François Bouchard, Maurice Ptito","doi":"10.1017/S095252381600002X","DOIUrl":"https://doi.org/10.1017/S095252381600002X","url":null,"abstract":"<p><p>The endogenous cannabinoid system plays important roles in the retina of mice and monkeys via their classic CB1 and CB2 receptors. We have previously reported that the G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, is exclusively expressed in rod photoreceptors in the monkey retina, suggesting its possible role in scotopic vision. To test this hypothesis, we recorded full-field electroretinograms (ERGs) after the intravitreal injection of the GPR55 agonist lysophosphatidylglucoside (LPG) or the selective GPR55 antagonist CID16020046 (CID), under light- and dark-adapted conditions. Thirteen vervet monkeys (Chlorocebus sabaeus) were used in this study: four controls (injected with the vehicle dimethyl sulfoxide, DMSO), four injected with LPG and five with CID. We analyzed amplitudes and latencies of the a-wave (photoreceptor responses) and the b-wave (rod and cone system responses) of the ERG. Our results showed that after injection of LPG, the amplitude of the scotopic b-wave was significantly higher, whereas after the injection of CID, it was significantly decreased, compared to the vehicle (DMSO). On the other hand, the a-wave amplitude, and the a-wave and b-wave latencies, of the scotopic ERG responses were not significantly affected by the injection of either compound. Furthermore, the photopic ERG waveforms were not affected by either drug. These results support the hypothesis that GPR55 plays an instrumental role in mediating scotopic vision.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E006"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S095252381600002X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34727305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Robert F Cooper, Marco Lombardo, Joseph Carroll, Kenneth R Sloan, Giuseppe Lombardo
{"title":"Methods for investigating the local spatial anisotropy and the preferred orientation of cones in adaptive optics retinal images.","authors":"Robert F Cooper, Marco Lombardo, Joseph Carroll, Kenneth R Sloan, Giuseppe Lombardo","doi":"10.1017/S0952523816000018","DOIUrl":"10.1017/S0952523816000018","url":null,"abstract":"<p><p>The ability to noninvasively image the cone photoreceptor mosaic holds significant potential as a diagnostic for retinal disease. Central to the realization of this potential is the development of sensitive metrics for characterizing the organization of the mosaic. Here we evaluated previously-described and newly-developed (Fourier- and Radon-based) methods of measuring cone orientation in simulated and real images of the parafoveal cone mosaic. The proposed algorithms correlated well across both simulated and real mosaics, suggesting that each algorithm provides an accurate description of photoreceptor orientation. Despite high agreement between algorithms, each performed differently in response to image intensity variation and cone coordinate jitter. The integration property of the Fourier transform allowed the Fourier-based method to be resistant to cone coordinate jitter and perform the most robustly of all three algorithms. Conversely, when there is good image quality but unreliable cone identification, the Radon algorithm performed best. Finally, in cases where the cone coordinate reliability was excellent, the method previously described by Pum and colleagues performed best. These descriptors are complementary to conventional descriptive metrics of the cone mosaic, such as cell density and spacing, and have the potential to aid in the detection of photoreceptor pathology.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E005"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068353/pdf/nihms821525.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34616869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diane R Nava, Bhavna Antony, L I Zhang, Michael D Abràmoff, Christine F Wildsoet
{"title":"Novel method using 3-dimensional segmentation in spectral domain-optical coherence tomography imaging in the chick reveals defocus-induced regional and time-sensitive asymmetries in the choroidal thickness.","authors":"Diane R Nava, Bhavna Antony, L I Zhang, Michael D Abràmoff, Christine F Wildsoet","doi":"10.1017/S0952523816000067","DOIUrl":"https://doi.org/10.1017/S0952523816000067","url":null,"abstract":"<p><p>Studies into the mechanisms underlying the active emmetropization process by which neonatal refractive errors are corrected, have described rapid, compensatory changes in the thickness of the choroidal layer in response to imposed optical defocus. While high frequency A-scan ultrasonography, as traditionally used to characterize such changes, offers good resolution of central (on-axis) changes, evidence of local retinal control mechanisms make it imperative that more peripheral, off-axis changes also be tracked. In this study, we used in vivo high resolution spectral domain-optical coherence tomography (SD-OCT) imaging in combination with the Iowa Reference Algorithms for 3-dimensional segmentation, to more fully characterize these changes, both spatially and temporally, in young, 7-day old chicks (n = 15), which were fitted with monocular +15 D defocusing lenses to induce choroidal thickening. With these tools, we were also able to localize the retinal area centralis, which was used as a landmark along with the ocular pectin in standardizing the location of scans and aligning them for subsequent analyses of choroidal thickness (CT) changes across time and between eyes. Values were derived for each of four quadrants, centered on the area centralis, and global CT values were also derived for all eyes. Data were compared with on-axis changes measured using ultrasonography. There were significant on-axis choroidal thickening that was detected after just one day of lens wear (∼190 µm), and regional (quadrant-related) differences in choroidal responses were also found, as well as global thickness changes 1 day after treatment. The ratio of global to on-axis choroidal thicknesses, used as an index of regional variability in responses, was also found to change significantly, reflecting the significant central changes. In summary, we demonstrated in vivo high resolution SD-OCT imaging, used in combination with segmentation algorithms, to be a viable and informative approach for characterizing regional (spatial), time-sensitive changes in CT in small animals such as the chick.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E010"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523816000067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34337060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Austin C Starnes, Carrie Huisingh, Gerald McGwin, Kenneth R Sloan, Zsolt Ablonczy, R Theodore Smith, Christine A Curcio, Thomas Ach
{"title":"Multi-nucleate retinal pigment epithelium cells of the human macula exhibit a characteristic and highly specific distribution.","authors":"Austin C Starnes, Carrie Huisingh, Gerald McGwin, Kenneth R Sloan, Zsolt Ablonczy, R Theodore Smith, Christine A Curcio, Thomas Ach","doi":"10.1017/S0952523815000310","DOIUrl":"10.1017/S0952523815000310","url":null,"abstract":"<p><strong>Background: </strong>The human retinal pigment epithelium (RPE) is reportedly 3% bi-nucleated. The importance to human vision of multi-nucleated (MN)-RPE cells could be clarified with more data about their distribution in central retina.</p><p><strong>Methods: </strong>Nineteen human RPE-flatmounts (9 ≤ 51 years, 10 > 80 years) were imaged at 12 locations: 3 eccentricities (fovea, perifovea, near periphery) in 4 quadrants (superior, inferior, temporal, nasal). Image stacks of lipofuscin-attributable autofluorescence and phalloidin labeled F-actin cytoskeleton were obtained using a confocal fluorescence microscope. Nuclei were devoid of autofluorescence and were marked using morphometric software. Cell areas were approximated by Voronoi regions. Mean number of nuclei per cell among eccentricity/quadrant groups and by age were compared using Poisson and binominal regression models.</p><p><strong>Results: </strong>A total of 11,403 RPE cells at 200 locations were analyzed: 94.66% mono-, 5.31% bi-, 0.02% tri-nucleate, and 0.01% with 5 nuclei. Age had no effect on number of nuclei. There were significant regional differences: highest frequencies of MN-cells were found at the perifovea (9.9%) and near periphery (6.8%). The fovea lacked MN-cells almost entirely. The nasal quadrant had significantly more MN-cells compared to other quadrants, at all eccentricities.</p><p><strong>Conclusion: </strong>This study demonstrates MN-RPE cells in human macula. MN-cells may arise due to endoreplication, cell fusion, or incomplete cell division. The topography of MN-RPE cells follows the topography of photoreceptors; with near-absence at the fovea (cones only) and high frequency at perifovea (highest rod density). This distribution might reflect specific requirements of retinal metabolism or other mechanisms addressable in further studies.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 1","pages":"e001"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523815000310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"56944739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea Helo, Pia Rämä, Sebastian Pannasch, David Meary
{"title":"Eye movement patterns and visual attention during scene viewing in 3- to 12-month-olds.","authors":"Andrea Helo, Pia Rämä, Sebastian Pannasch, David Meary","doi":"10.1017/S0952523816000110","DOIUrl":"https://doi.org/10.1017/S0952523816000110","url":null,"abstract":"<p><p>Recently, two attentional modes have been associated with specific eye movement patterns during scene processing. Ambient mode, characterized by short fixations and long saccades during early scene inspection, is associated with localization of objects. Focal mode, characterized by longer fixations, is associated with more detailed object feature processing during later inspection phase. The aim of the present study was to investigate the development of these attentional modes. More specifically, we examined whether indications of ambient and focal attention modes are similar in infants and adults. Therefore, we measured eye movements in 3- to 12-months-old infants while exploring visual scenes. Our results show that both adults and 12-month-olds had shorter fixation durations within the first 1.5 s of scene viewing compared with later time phases (>2.5 s); indicating that there was a transition from ambient to focal processing during image inspection. In younger infants, fixation durations between two viewing phases did not differ. Our results suggest that at the end of the first year of life, infants have developed an adult-like scene viewing behavior. The evidence for the existence of distinct attentional processing mechanisms during early infancy furthermore underlines the importance of the concept of the two modes.</p>","PeriodicalId":23556,"journal":{"name":"Visual Neuroscience","volume":"33 ","pages":"E014"},"PeriodicalIF":1.9,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0952523816000110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34869822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}