Jose Sahel | University of Pittsburgh School of Medicine (original) (raw)

Papers by Jose Sahel

Acta Neuropathologica, 2000

Ischemic/hypoxic brain damage induced in 7day-old rats was significantly attenuated in a dose-dep... more Ischemic/hypoxic brain damage induced in 7day-old rats was significantly attenuated in a dose-dependent manner by intracerebral injection of glial cell linederived neurotrophic factor (GDNF; 2 or 4 µg) within 30 min after the insult. Whereas the great majority of the vehicletreated animals showed massive infarction involving more than 75% of the affected cerebral hemisphere, GDNF injection resulted in a remarkable reduction in both the incidence and severity of the brain damage (incidence ranging from 76% to 93% in controls to 34% to 64% in the 2.0-µg group and 7% to 29% in 4.0-µg group). The induction of immunoreactive 70-kDa heat shock protein (HSP70) in cerebral cortical neurons was also significantly reduced in GDNF-treated animals as compared to controls. The mechanisms responsible for the neuroprotective effects of GDNF remain unknown, although it has been speculated that these may be endogeneous. The higher expression of GDNF and its mRNA in developing brains may be one of the factors responsible for the relative resistance to ischemia of fetal and neonatal as opposed to adult brains. GDNF may possibly act by protecting against oxidative stress or by scavenging free radicals generated during ischemia. The results of our study strongly suggest that GDNF may prove to be an effective and potent protective agent against perinatal ischemic/hypoxic encephalopathy.

Compact multimodal TD-FF-OCT + SD-OCT device for diagnosing clinical cases in anterior eye

Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine XXVI

Design of a radial multi-offset detection pattern for in vivo phase contrast imaging of the inner retina in humans

Biomedical Optics Express, 2021

Previous work has shown that multi-offset detection in adaptive optics scanning laser ophthalmosc... more Previous work has shown that multi-offset detection in adaptive optics scanning laser ophthalmoscopy (AOSLO) can be used to image transparent cells such as retinal ganglion cells (RGCs) in monkeys and humans. Though imaging in anesthetized monkeys with high light levels produced high contrast images of RGCs, images from humans failed to reach the same contrast due to several drawbacks in the previous dual-wavelength multi-offset approach. Our aim here was to design and build a multi-offset detection pattern for humans at safe light levels that could reveal transparent cells in the retinal ganglion cell layer with a contrast and acquisition time approaching results only previously obtained in monkeys. Here, we present a new single-wavelength solution that allows for increased light power and eliminates problematic chromatic aberrations. Then, we demonstrate that a radial multi-offset detection pattern with an offset distance of 8-10 Airy Disk Diameter (ADD) is optimal to detect photo...

Photoreceptor Transplants Increase Host Cone Survival in the Retinal Degeneration (rd) Mouse

Ophthalmic Research, 1997

Retinal transplants offer a potentially interesting approach to treating human retinal degenerati... more Retinal transplants offer a potentially interesting approach to treating human retinal degenerations, but so far little quantitative data are available on possible beneficial effects. We isolated photoreceptor layers from normal-sighted mice and grafted them into the subretinal space of retinal degeneration (rd) mice lacking rod photoreceptors. At 2 weeks after surgery, the numbers of residual host cone photoreceptors outside the graft zone were quantified following specific labelling. Examination of operated retinas revealed highly significantly greater numbers of surviving cones (mean of 38% more at 2 weeks) within the central field compared to sham-operated paired control retinas (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). These are the first quantified data indicating a trophic effect of transplanted photoreceptors upon host cone cells. As cone cells are responsible for high acuity and colour vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to understanding underlying interactions between retinal photoreceptors.

Molecular Therapy, 2009

In retinitis pigmentosa (RP), a majority of causative mutations affect genes solely expressed in ... more In retinitis pigmentosa (RP), a majority of causative mutations affect genes solely expressed in rods; however cone degeneration inevitably follows rod cell loss. Following transplantation and studies we demonstrated the role of photoreceptor cell in vitro paracrine interactions and identified a Rod-derived-Cone Viability Factor, RdCVF, which increases cone survival. In order to establish the clinical relevance of such mechanism, we assessed the functional benefit afforded by the injection of this factor in a frequent type of rhodopsin mutation, the P23H rat. In this model of autosomal dominant RP, RdCVF expression decreases in parallel with primary rod degeneration, which is followed by cone loss. RdCVF protein injections induced an increase in cone cell number and, more importantly, a further increase in the corresponding electroretinogram. These results indicate that RdCVF can not only rescue cones but also preserve significantly their function. Interestingly, the higher amplitude of the functional versus the survival effect of RdCVF on cones indicates that RdCVF is acting more directly on cone function. The demonstration at the functional level of the therapeutic potential of RdCVF in the most frequent of dominant RP mutations paves the way towards the use of RdCVF for preserving central vision in many RP patients.

Journal Français d'Ophtalmologie, 2008

À propos d'une technique d'imagerie simple et peu onéreuse pour l'examen des structures oculaires... more À propos d'une technique d'imagerie simple et peu onéreuse pour l'examen des structures oculaires : fond d'oeil, corps ciliaires, angle irido-cornéen et angiographie fluorescéinique. A low cost and simple imaging technique for eye structures: eye fundus, ciliary bodies, fluorescein angiography and irido-corneal angle.

Investigative Opthalmology & Visual Science, 2003

PURPOSE. To investigate the effects of basic fibroblast and epidermal growth factor (FGF2 and EGF... more PURPOSE. To investigate the effects of basic fibroblast and epidermal growth factor (FGF2 and EGF, respectively) on the survival and phenotypic expression of photoreceptors isolated from adult mammalian retinas. METHODS. Primary cultures highly enriched in photoreceptors were prepared from adult domestic pig retinas and maintained in chemically defined medium. Cell culture composition was characterized through the use of specific antibody markers of retinal neurons, and neuronal survival was quantified through viability assays as a function of time in the presence or absence of different doses of FGF2 and EGF. Western blot analysis of phosphotyrosine residues was used to monitor activation of FGF2 and EGF signaling pathways. RESULTS. Reproducible survival of adult pig rod and cone photoreceptors was obtained for approximately 2 weeks in vitro, with the continued expression of rod opsin, recoverin, Santigen, cone arrestin, and neuron-specific enolase. Purity of cultures was routinely more than 95% photoreceptors, with a rod-cone ratio of 2:3.1. Photoreceptor survival was stable for the initial week, decreasing slowly during the second, with rapid cell loss occurring thereafter. In the presence of FGF2 (20 ng/mL), the percentage of photoreceptor survival during the second week in culture was statistically significantly different, at least two times higher than in control experiments. Photoreceptor survival correlated directly with increasing concentrations of FGF2, and also of EGF. Combined treatment with FGF2 and EGF did not induce higher survival than either factor alone. There was no detectable selective loss of rods or cones in the experimental model. Phosphotyrosine immunoblots after stimulation of cultures with FGF2 and EGF revealed time-dependent appearance of multiple immunoreactive bands. CONCLUSIONS. The adult pig photoreceptor culture in the current study exhibits reproducible neuronal survival in vitro and represents a useful novel experimental system for the study of potential neuroprotective effects and signaling pathways of neurotrophic factors such as FGF2 and EGF in fully adult higher mammalian retina.

Graefe's Archive for Clinical and Experimental Ophthalmology, 2008

Background The development of a functional retinal prosthesis for acquired blindness is a great c... more Background The development of a functional retinal prosthesis for acquired blindness is a great challenge. Rapid progress in the field over the last 15 years would not have been possible without extensive animal experimentation pertaining to device design and fabrication, biocompatibility, stimulation parameters and functional responses. This paper presents an overview of in vivo animal research related to retinal prosthetics, and aims to summarize the relevant studies. Methods A Pubmed search of the English language literature was performed. The key search terms were: retinal implant, retinal prosthesis, artificial vision, rat, rabbit, cat, dog, sheep, pig, minipig. In addition a manual search was performed based on references quoted in the articles retrieved through Pubmed. Results We identified 50 articles relevant to in vivo animal experimentation directly related to the development of a retinal implant. The highest number of publications related to the cat (n=18). Conclusion The contribution of animal models to the development of retinal prosthetic devices has been enormous, and has led to human feasibility studies. Grey areas remain regarding long-term tissue-implant interactions, biomaterials, prosthesis design and neural adaptation. Animals will continue to play a key role in this rapidly evolving field.

British Journal of Ophthalmology, 2006

Background: In age-related macular degeneration and inherited dystrophies, preservation of retina... more Background: In age-related macular degeneration and inherited dystrophies, preservation of retinal ganglion cells has been demonstrated. This finding has led to the development of various models of sub-or epi-retinal implant in order to restore vision. The present study addresses the development of a polyimide subretinal electrode platform in the dystrophic P23H rat in vivo. Material and methods: We developed a technique for implanting a subretinal electrode into the subretinal space and stabilising the distal extremity of the cabling on the rat cranium in order to allow future electrical stimulations of the retina. Results: In vivo imaging of the retina with the scanning laser ophthalmoscope (SLO) demonstrated reasorbption of the surgically induced retinal detachment and the absence of major tissue reactions. These in vivo observations were confirmed by retinal histology. The extraocular fixation system on the rat cranium was effective in stabilising the distal connector for in vivo stimulation. Conclusion: This study demonstrates that a retinal implant can be introduced into the subretinal space of a dystrophic rat with a stable external connection for repeatable electrical measurements and stimulation. This in vivo model should therefore allow us to evaluate the safety and efficacy of electrical stimulations on dystrophic retina.

Clinical uses of time-domain FF-OCT in anterior eye

Ophthalmic Technologies XXXII

Laser Doppler holography

Power Doppler spectral movie

Visualization 3.avi

Laser Doppler holography of human retina showing the Doppler power spectrum density as a function... more Laser Doppler holography of human retina showing the Doppler power spectrum density as a function of frequency

Contribution of "en face" SD-OCT in retinal and choroidal vascular abnormalities

Acta Ophthalmologica, 2014

ABSTRACT PURPOSE : To evaluate the retinal and choroidal aspect in retinal or choroidal vascular ... more ABSTRACT PURPOSE : To evaluate the retinal and choroidal aspect in retinal or choroidal vascular abnormalities using « en face » OCT images. METHODS : All the study patients underwent a complete ophthalmologic examination including biomicroscopic fundus examination, color photography, fundus autofluorescence, fluorescein angiography, indocyanin green angiography , B-scan and « en face » SD-OCT. RESULTS : A total of 11 patients with choroidal or retinal vascular abnormalities, 4 cases diagnosed with submacular choroidal varix, 2 cases of central serous chorioretinopathy with choroidal cavitations, 2 cases of retinal vein occlusion (RVO) with perivenular whitening and retinal ischemia, 3 cases of retinal arterial macroaneurysm were analysed. The B scan findings were correlated with the angiography findings as well as with the « en face » OCT scans. In all the cases the « en face » OCT providing a layer-by layer view of the involved retina and choroid (with EDI mode: enhanced-depth imaging). CONCLUSIONS : « En face » OCT imaging enables an easy analyse of the structural retinal and choroidal vascular abnormalities which are correlated with B scan OCT and angiography findings.

Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness... more Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/ 2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

Rods Produce a Diffusible Factor Promoting Cone Photoreceptor Survival In Vivo and in Vitro

Retinal Degenerative Diseases and Experimental Therapy, 1999

To investigate possible trophic effects of transplanted rod photoreceptors upon recipient cone ph... more To investigate possible trophic effects of transplanted rod photoreceptors upon recipient cone photoreceptors in mutant retinal degeneration (rd) mice retinas.

Science, 2010

Let There Be Light Retinitis pigmentosa, a disease that can result from a wide variety of genetic... more Let There Be Light Retinitis pigmentosa, a disease that can result from a wide variety of genetic defects, causes degeneration of photoreceptor cells in the retina and leads to blindness. In the course of the disease, it is generally the rod photoreceptor cells that degenerate first. Cone photoreceptor cells may persist, but in a damaged and nonfunctional state. Busskamp et al. (p. 413 , published online 24 June; see the cover; see the Perspective by Cepko ) have now applied a gene therapy approach to mouse models of retinitis pigmentosa. Inducing expression of a bacterial light-activated ion pump, halorho dopsin, in the damaged cone cells improved visual responses in the diseased mouse retinas. Thus, it may be possible to rescue cone photoreceptors therapeutically, even after they have already been damaged.

Proceedings of the National Academy of Sciences, 1998

The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration i... more The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration in inherited retinal degenerations in which the mutation specifically affects rod photoreceptors was studied. We developed an organ culture model of whole retinas from 5-week-old mice carrying the retinal degeneration mutation, which at this age contain few remaining rods and numerous surviving cones cocultured with primary cultures of mixed cells from postnatal day 8 normal-sighted mice (C57BL/6) retinas or retinal explants from normal (C57BL/6) or dystrophic (C3H/He) 5-week-old mice. After 7 days, the numbers of residual cone photoreceptors were quantified after specific peanut lectin or anti-arrestin antibody labeling by using an unbiased stereological approach. Examination of organ cultured retinas revealed significantly greater numbers of surviving cones (15–20%) if cultured in the presence of retinas containing normal rods as compared with controls or cocultures with rod-deprived re...

Nucleic Acids Research, 2007

Many recent microarrays hold an enormous number of probe sets, thus raising many practical and th... more Many recent microarrays hold an enormous number of probe sets, thus raising many practical and theoretical problems in controlling the false discovery rate (FDR). Biologically, it is likely that most probe sets are associated with un-expressed genes, so the measured values are simply noise due to non-specific binding; also many probe sets are associated with non-differentially-expressed (non-DE) genes. In an analysis to find DE genes, these probe sets contribute to the false discoveries, so it is desirable to filter out these probe sets prior to analysis. In the methodology proposed here, we first fit a robust linear model for probe-level Affymetrix data that accounts for probe and array effects. We then develop a novel procedure called FLUSH (Filtering Likely Uninformative Sets of Hybridizations), which excludes probe sets that have statistically small array-effects or large residual variance. This filtering procedure was evaluated on a publicly available data set from a controlled spiked-in experiment, as well as on a real experimental data set of a mouse model for retinal degeneration. In both cases, FLUSH filtering improves the sensitivity in the detection of DE genes compared to analyses using unfiltered, presence-filtered, intensity-filtered and variance-filtered data. A freely-available package called FLUSH implements the procedures and graphical displays described in the article.

British Journal of Ophthalmology, 2013

Background Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in out... more Background Retinal prosthesis systems (RPS) are a novel treatment for profound vision loss in outer retinal dystrophies. Ideal prostheses would offer stable, longterm retinal stimulation and reproducible spatial resolution in a portable form appropriate for daily life. Methods We report a prospective, internally controlled, multicentre trial of the Argus II system. Twenty-eight subjects with light perception vision received a retinal implant. Controlled, closed-group, forced-choice letter identification, and, open-choice two-, three-and fourletter word identification tests were carried out. Results The mean±SD percentage correct letter identification for 21 subjects tested were: