Ophthalmologists
11 years of experience
Video profile
Accepting new patients
University City
Scheie Eye Institute
51 N 39th St
Philadelphia, PA 19104
215-662-8100
Locations and availability (3)

Education ?

Medical School Score Rankings
Washington University at St. Louis (1999)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Appointments
University of Pennsylvania
Assistant Professor of Ophthalmology
Associations
American Academy of Ophthalmology
American Board of Ophthalmology

Affiliations ?

Dr. Shindler is affiliated with 6 hospitals.

Hospital Affilations

Score

Rankings

  • Hospital of the University of PA
    3400 Spruce St, Philadelphia, PA 19104
    • Currently 4 of 4 crosses
    Top 25%
  • Pennsylvania Hospital University PA Health System
    800 Spruce St, Philadelphia, PA 19107
    • Currently 4 of 4 crosses
    Top 25%
  • University of PA Medical Center/Presbyterian
    51 N 39th St, Philadelphia, PA 19104
    • Currently 3 of 4 crosses
    Top 50%
  • Graduate Hospital
    1800 Lombard St, Philadelphia, PA 19146
    • Currently 1 of 4 crosses
  • Presbyterian Medical Center Of The University Of Pennsylvania Health System
  • Clinical Practices of the University of Pennsylvania
  • Publications & Research

    Dr. Shindler has contributed to 29 publications.
    Title Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration.
    Date October 2010
    Journal Molecular Therapy : the Journal of the American Society of Gene Therapy
    Excerpt

    The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.

    Title Timing of Corticosteroid Therapy is Critical to Prevent Retinal Ganglion Cell Loss in Experimental Optic Neuritis.
    Date March 2010
    Journal Investigative Ophthalmology & Visual Science
    Excerpt

    Acute vision loss from optic neuritis typically resolves; however, recovery is often not complete. Permanent vision loss from retinal ganglion cell (RGC) death occurs in 40% to 60% of patients. Current therapy (high-dose corticosteroids) speeds recovery but does not change final visual outcomes. Here the authors examined whether corticosteroids administered early in the disease course can prevent RGC loss in experimental optic neuritis.

    Title Age-dependent Effects of Rpe65 Gene Therapy for Leber's Congenital Amaurosis: a Phase 1 Dose-escalation Trial.
    Date November 2009
    Journal Lancet
    Excerpt

    Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis.

    Title Mechanisms of Primary Axonal Damage in a Viral Model of Multiple Sclerosis.
    Date September 2009
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. Studies demonstrate that a demyelinating strain of MHV causes concomitant axonal loss and macrophage-mediated demyelination. The mechanism of axonal loss and demyelination in MHV infection is dependent on successful transport of virus from gray matter to white matter using the MHV host attachment spike glycoprotein. Our data show that axonal loss and demyelination can be independent direct viral cytopathic events, and suggest that similar direct axonal damage may occur in MS. These results have important implications for the design of neuroprotective strategies for CNS demyelinating disease, and our model identifies the spike protein as a therapeutic target to prevent axonal transport of neurotropic viruses.

    Title Functional Interleukin-17 Receptor A is Expressed in Central Nervous System Glia and Upregulated in Experimental Autoimmune Encephalomyelitis.
    Date June 2009
    Journal Journal of Neuroinflammation
    Excerpt

    Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood.

    Title Annual Meeting of the Association for Research in Vision and Ophthalmology (arvo) Fort Lauderdale, April 27-may 1, 2008.
    Date April 2009
    Journal Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society
    Title Experimental Optic Neuritis Induced by a Demyelinating Strain of Mouse Hepatitis Virus.
    Date September 2008
    Journal Journal of Virology
    Excerpt

    Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS). Pathological mechanisms and potential treatments for ON have been studied via experimental autoimmune MS models. However, evidence suggests that virus-induced inflammation is a likely etiology triggering MS and ON; experimental virus-induced ON models are therefore required. We demonstrate that MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting mixed inflammatory cell infiltration. In contrast, MHV-2, a nondemyelinating MHV strain, does not induce ON. Results reveal a reproducible virus-induced ON model important for the evaluation of novel therapies.

    Title Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis.
    Date June 2008
    Journal The New England Journal of Medicine
    Excerpt

    Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

    Title Sirt1 Activation Confers Neuroprotection in Experimental Optic Neuritis.
    Date September 2007
    Journal Investigative Ophthalmology & Visual Science
    Excerpt

    PURPOSE: Axonal damage and loss of neurons correlate with permanent vision loss and neurologic disability in patients with optic neuritis and multiple sclerosis (MS). Current therapies involve immunomodulation, with limited effects on neuronal damage. The authors examined potential neuroprotective effects in optic neuritis by SRT647 and SRT501, two structurally and mechanistically distinct activators of SIRT1, an enzyme involved in cellular stress resistance and survival. METHODS: Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, was induced by immunization with proteolipid protein peptide in SJL/J mice. Optic neuritis developed in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization. RGCs were labeled in a retrograde fashion with fluorogold by injection into superior colliculi. Optic neuritis was detected by inflammatory cell infiltration of the optic nerve. RESULTS: Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. A single dose of SRT501 on day 11 was sufficient to limit RGC loss and to preserve axon function. CONCLUSIONS: SIRT1 activators provide an important potential therapy to prevent the neuronal damage that leads to permanent neurologic disability in optic neuritis and MS patients. Intravitreal administration of SIRT1 activators does not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies.

    Title The Pd-1/pd-l Pathway is Up-regulated During Il-12-induced Suppression of Eae Mediated by Ifn-gamma.
    Date June 2007
    Journal Journal of Neuroimmunology
    Excerpt

    Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.

    Title Retinal Ganglion Cell Loss Induced by Acute Optic Neuritis in a Relapsing Model of Multiple Sclerosis.
    Date December 2006
    Journal Multiple Sclerosis (houndmills, Basingstoke, England)
    Excerpt

    Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in MS and EAE lesions, but it is not known whether neuronal loss occurs secondary to inflammation, or as a primary process. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during acute optic neuritis is examined. RGCs were labelled with Flourogold, and EAE was induced in SJL/J mice by immunization with proteolipid protein peptide 139-151 (PLP). At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltrates. No optic neuritis was detected prior to day 9 following immunization. Incidence of optic neuritis was 30% at day 9 and increased to over 70% by day 11, remaining high through day 18. In contrast, no RGC loss was detected in eyes with optic neuritis until day 14. A 43.1% reduction in RGC numbers at day 14 increased to 50.8% by day 18. No RGC loss occurred in eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process.

    Title Retinal Ganglion Cell Damage Induced by Spontaneous Autoimmune Optic Neuritis in Mog-specific Tcr Transgenic Mice.
    Date November 2006
    Journal Journal of Neuroimmunology
    Excerpt

    Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in EAE, including retinal ganglion cell (RGC) loss in eyes with optic neuritis, but the finding of RGC loss in relation to optic nerve inflammation differs in different EAE settings. Recently, Myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgenic mice were found to develop spontaneous isolated optic neuritis in the absence of EAE. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during isolated optic neuritis is examined. RGCs of MOG-specific TCR transgenic mice were labeled with Flourogold and then treated with pertussis toxin (PT) or observed untreated. At various time points, RGCs were counted, retinas were TUNEL labeled, and optic nerves were examined for inflammatory cell infiltrates. 29% of untreated MOG-specific TCR transgenic mice developed periocular inflammation by 4 months of age, and 32% of optic nerves of TCR transgenic mice had histological lesions in the optic nerve. Incidence of histological optic neuritis was 20% at day 8 following injection of PT and increased to 48% by day 12, and 68% by day 16. In contrast, no RGC loss or TUNEL staining was detected in eyes with optic neuritis until day 12 in the mice injected with PT. A 28% reduction in RGC numbers at day 12 increased to 39% by day 16, and RGC loss of eyes with severe or massive inflammation was significantly higher than that of eyes with mild or moderate inflammation. No RGC loss occurred in TCR transgenic mouse eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process in isolated optic neuritis.

    Title Automated Combined Kinetic and Static Perimetry: an Alternative to Standard Perimetry in Patients with Neuro-ophthalmic Disease and Glaucoma.
    Date March 2006
    Journal Archives of Ophthalmology
    Excerpt

    OBJECTIVES: To create a fully automated, combined perimetry program consisting of a static examination and a kinetic examination, and to compare the results of this test with standard static and kinetic visual fields (VFs). METHODS: Fifty-six patients (74 eyes) undergoing neuro-ophthalmic or glaucoma evaluation who had standard static or kinetic perimetry examinations underwent the combined perimetry test. This automated, combined test, performed on the Octopus 101 perimeter, consisted of a static tendency-oriented perimetry examination and a preprogrammed kinetic examination. Three masked physician reviewers independently classified all of the VFs. The VF pairs were considered a match if the consensus descriptions of the standard and combined VFs matched. RESULTS: Thirty-seven eyes underwent evaluation for neuro-ophthalmic disease (comparison standard test, 20 static and 17 kinetic) and 37 for glaucoma (comparison standard test, 17 static and 20 kinetic). The VP pairs matched in 32 eyes (86%) in the neuro-ophthalmic group and 28 (76%) in the glaucoma group. On inspection by a fourth reviewer, many of the nonmatching VF pairs were those for which a consensus was not reached, but still conveyed similar information. Two glaucomatous eyes demonstrated central scotomata not delineated by the combined examination findings. Two subtle nasal steps were detected solely by the combined examination. The combined test ranged in time from 6 to 12 minutes per eye. CONCLUSIONS: The Octopus 101 perimeter can be used to create an automated test that combines the advantages of static and kinetic perimetry and produces equivalent results while not requiring examiner expertise.

    Title Intermittent Headaches As the Presenting Sign of Subacute Angle-closure Glaucoma.
    Date November 2005
    Journal Neurology
    Excerpt

    Subacute angle closure causes intermittent episodes of transiently elevated intraocular pressure. Headache is often the chief complaint, which may lead to misdiagnosis. The authors examined headache characteristics and consequences of delayed diagnosis. Patients presenting with headaches have a substantial delay in diagnosis, contributing to permanent ocular damage and glaucoma. Patients with subacute angle closure misdiagnosed with migraine are older and have shorter-duration headaches than patients with typical migraine.

    Title Long-term Follow-up and Prognosis of Orbital Apex Syndrome Resulting from Nasopharyngeal Rhabdomyosarcoma.
    Date August 2005
    Journal American Journal of Ophthalmology
    Excerpt

    PURPOSE: Nasopharyngeal rhabdomyosarcoma may present with a variety of ophthalmic symptoms. Direct extension of the tumor into the orbital apex can lead to ophthalmoplegia and loss of vision. The prognosis for recovery of vision and ocular motility in patients with an orbital apex syndrome due to nasopharyngeal rhabdomyosarcoma is examined. DESIGN: Retrospective case series. METHODS: Six eyes from four patients with nasopharyngeal rhabdomyosarcoma who presented to the Children';s Hospital of Philadelphia with a clinical orbital apex syndrome were identified. Complete ophthalmic examination, including visual acuity and extraocular motility at the time of presentation, was reviewed. Tumor extension into the orbital apex was confirmed radiographically. Follow-up ophthalmic evaluations were reviewed for all patients with an average follow-up of 5.5 +/- 3.1 years (range 1 to 8 years). RESULTS: Six eyes of four patients had limited ocular ductions along with marked loss of vision at presentation. All patients were treated with chemotherapy and radiation, with reduction of tumor mass. Ocular motility recovered in all patients, occurring by an average of 2.2 +/- 1.8 months after initiation of therapy. Four of six eyes had little or no recovery of visual acuity detected at long-term follow-up. CONCLUSIONS: Patients with ocular motor deficits in orbital apex syndromes caused by extension of nasopharyngeal rhabdomyosarcoma have an excellent prognosis for recovery after treatment of the tumor. The long-term prognosis for visual recovery, however, is poor.

    Title Caspase Inhibitors Block Zinc-chelator Induced Death of Retinal Ganglion Cells.
    Date January 2001
    Journal Neuroreport
    Excerpt

    Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.

    Title Epistatic and Independent Functions of Caspase-3 and Bcl-x(l) in Developmental Programmed Cell Death.
    Date February 2000
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    The number of neurons in the mammalian brain is determined by a balance between cell proliferation and programmed cell death. Recent studies indicated that Bcl-X(L) prevents, whereas Caspase-3 mediates, cell death in the developing nervous system, but whether Bcl-X(L) directly blocks the apoptotic function of Caspase-3 in vivo is not known. To examine this question, we generated bcl-x/caspase-3 double mutants and found that caspase-3 deficiency abrogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the bcl-x mutation. In contrast, caspase-3, but not bcl-x, deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X(L) in the proliferative population of the embryonic cortex. Thus, although Caspase-3 is epistatically downstream to Bcl-X(L) in postmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell death in regulating the size of progenitor population in the central nervous system, a function that is distinct from the classic role of cell death in matching postmitotic neuronal population with postsynaptic targets.

    Title Trophic Support Promotes Survival of Bcl-x-deficient Telencephalic Cells in Vitro.
    Date May 1999
    Journal Cell Death and Differentiation
    Excerpt

    Survival of immature neurons is regulated by Bcl-xL, as targeted disruption of bcl-x significantly increases cell death in vivo and in vitro. Death of cultured bcl-x-deficient and wild-type telencephalic cells can be prevented by fetal calf serum or chemically-defined medium (ITS), suggesting trophic factors in these media potentiate survival through a pathway independent of Bcl-xL. Addition of trophic factors to basal medium revealed that insulin and insulin-like growth factors (IGFs), but not other trophic factors, reduced apoptosis of wild-type and bcl-x-deficient telencephalic cells. Antibodies raised against IGF-I receptors and wortmannin both attenuated the effects of IGF-I, indicating survival was mediated by IGF-I receptors and phosphatidylinositol 3'-kinase signaling, whereas effects of ITS were only partially reduced by these agents. The survival promoting effects of ITS were reduced in cells lacking both bcl-x and bcl-2, indicating Bcl-2 plays a supportive role to Bcl-xL in maintaining telencephalic cell survival. Furthermore, the ratio of expression of the pro-apoptotic bax gene to the anti-apoptotic bcl-2 gene was reduced in bcl-x-deficient cultures grown in ITS, suggesting that the interaction between these bcl-2 family members may, in part, regulate a Bcl-xL independent survival pathway. Finally, the pro-apoptotic bad gene does not appear to play a role in these interactions as targeted disruption of bad did not alter apoptosis in telencephalic cultures.

    Title In Situ Immunodetection of Activated Caspase-3 in Apoptotic Neurons in the Developing Nervous System.
    Date March 1999
    Journal Cell Death and Differentiation
    Excerpt

    Activation of caspase-3 requires proteolytic processing of the inactive zymogen into p18 and p12 subunits. We generated a rabbit polyclonal antiserum, CM1, which recognizes the p18 subunit of cleaved caspase-3 but not the zymogen. CM1 demonstrated an apparent specificity for activated caspase-3 by specifically immunolabelling only apoptotic but not necrotic cortical neurons in vitro. In the embryonic mouse nervous system, CM1 immunoreactivity was detected in neurons undergoing programmed cell death and was markedly increased in Bcl-xL-deficient embryos and decreased in Bax-deficient embryos. CM1 immunoreactivity was absent in the nervous system of caspase-3-deficient mouse embryos and in neurons cultured from caspase-3-deficient mice. Along with neuronal somata, extensive neuritic staining was seen in apoptotic neurons. These studies indicate that caspase-3 is activated during apoptosis in the developing nervous system in vivo and that CM1 is a useful reagent for its in situ detection.

    Title Bax Deficiency Prevents the Increased Cell Death of Immature Neurons in Bcl-x-deficient Mice.
    Date May 1997
    Journal The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
    Excerpt

    The intracellular balance between pro- and antiapoptotic members of the Bcl-2 gene family is thought to regulate cell death. Targeted disruption of bcl-x, a death repressing member, causes massive cell death of immature neurons in the developing mouse CNS, whereas targeted disruption of bax, a proapoptotic member, blocks the death of specific populations of sympathetic and motor neurons. In the present study, mice deficient in both Bcl-xL and Bax (bcl-x-/-/bax-/-) are used to examine the relative significance and potential interactions of Bcl-xL and Bax during early CNS development. bcl-x-/-/bax-/- mice demonstrate greatly reduced levels of apoptosis both in vivo and in vitro compared with the CNS of Bcl-xL-deficient mice, as assessed by histology and terminal deoxytransferase-mediated deoxyuridine triphosphate nick end-labeling. Bax-deficient mice, however, contain occasional apoptotic cells in the developing CNS, and cultures of bax-deficient telencephalic cells demonstrate similar levels of apoptosis as wild-type cultures. These results suggest that Bax critically interacts with Bcl-xL to regulate survival of immature neurons, but indicate that other cell death regulating proteins, in addition to Bcl-xL and Bax, also function during CNS development.

    Title Double Immunofluorescent Staining Using Two Unconjugated Primary Antisera Raised in the Same Species.
    Date December 1996
    Journal The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society
    Excerpt

    Monoclonal antibodies (MAbs) capable of recognizing developmental stage-specific neuronal epitopes are becoming increasingly available. Because most of these MAbs are raised in a single species (mouse), simultaneous immunofluorescent detection of multiple epitopes has been difficult. We have taken advantage of the high sensitivity of tyramide signal amplification to develop a protocol that permits simultaneous detection of two antibodies raised in the same species. One primary antibody was applied at a concentration below the detection limit of fluorescently labeled secondary antibodies, yet sufficient for detection with the tyramide system. This first primary antibody was then effectively neglected during application of a second primary antibody that was detected by conventional fluorescently labeled secondary antibodies. Specifically, dual labeling for nestin and MAP2 was used to distinguish neuronal stem cells and precursor cells from immature postmitotic neurons, and synapsin I and GAP43 immunostaining was used to distinguish neurons with established synaptic connections from developing neurons. We have used this technique for staining both tissue sections and cultured cells from the embryonic mouse brain. This technique should be widely applicable and offers a simple procedure for simultaneously detecting two antigens when antibodies from only a single species are available.

    Title Cholera Toxin Binds to Differentiating Neurons in the Developing Murine Basal Ganglia.
    Date November 1996
    Journal Brain Research. Developmental Brain Research
    Excerpt

    Cell-surface expression of gangliosides in the developing mammalian central nervous system is temporally-regulated in a cell-type and regionally specific fashion. Gangliosides may be involved in cell-cell and cell-matrix interactions, and can act synergystically with several growth factors or growth factor receptors. Thus, a role for gangliosides in the regulation of neuronal stem cell proliferation and differentiation has been suggested. We have previously shown that cholera toxin B subunit (CTB), which binds to the ganglioside GM1, binds heterogeneously to dissociated neuroepithelial cells from the developing mouse telencephalon. We stained fixed sections of the ganglionic eminences (GE) of fetal mouse brains and found that CTB labels regions which contain differentiating neurons, but does not stain the rapidly dividing neuroepithelial cells in the ventricular zone. We dissociated cells from the GE on day 14 of gestation (E14), labeled the cells with CTB-FITC, and separated them by flow cytometry. We found the highest level of CTB binding in postmitotic cells which had begun to express markers of neuronal differentiation. When CTB-sorted cells were placed into short-term (48 h) cell culture, high CTB binding continued to correlate with fewer numbers of proliferating cells and larger numbers of differentiating neurons. CTB binding and fluorescence activated cell sorting appear to be useful for separating populations of differentiating neurons from immature, proliferating cells. These studies further lead us to suggest that GM1 plays a role in the differentiation of neurons in the basal ganglia.

    Title Developmentally-regulated Lectin Binding in the Embryonic Mouse Telencephalon.
    Date August 1995
    Journal Brain Research
    Excerpt

    Cell-surface carbohydrate epitopes are important determinants in cell-cell and cell-matrix interactions, and oligosaccharide groups are structural components of many growth factor receptors and cell adhesion molecules. These epitopes may participate in the regulation of stem cell proliferation and differentiation during central nervous system development. To further understand these cellular phenomena, it is important to define the changes in neuroepithelial cell-surface carbohydrate expression during development. We used a panel of fluorescein-conjugated lectins to label live, freshly dissociated cells from the embryonic day 11 to 18 (E11 to E18) mouse telencephalon. The intensity and heterogeneity of lectin labeling was assessed by flow cytometry. The lectins that we examined exhibited widely varying levels of labeling intensity. Lectins with the highest degree of binding included cholera toxin B subunit (CTB), which binds primarily to the gangliosides GM1 and GD1b, phaseolus vulgaris erythroagglutinating lectin (PHA-E), which binds to a variety of cell adhesion molecules, and wheat germ agglutinin (WGA). Many lectins showed increasing labeling intensity and cellular heterogeneity as development progressed. To determine if the observed cellular heterogeneity in lectin binding reflected biological differences in neuroepithelial cell subpopulations, cells from the E14 telencephalon were separated into two populations based on their intensity of CTB labeling using a fluorescence activated cell sorter. The population of weakly CTB labeled cells contained more than four times as many cells in S-phase of the cell cycle than the population of intensely CTB labeled cells. These observations suggest that lectin cytochemistry and flow cytometry can be useful in identifying specific cell subpopulations of neuroepithelial precursor cells during development, allowing their isolation and characterization in vitro.

    Title Type Iib Mutation His-505-->asp Implicates a New Segment in the Control of Von Willebrand Factor Binding to Platelet Glycoprotein Ib.
    Date October 1993
    Journal The Journal of Biological Chemistry
    Excerpt

    Type IIB von Willebrand disease is characterized by increased affinity of mutant von Willebrand factor (vWF) for platelet glycoprotein Ib. Eight different missense mutations that cause this phenotype have been reported within the disulfide loop defined by Cys-509 and Cys-695 of the mature vWF subunit; this disulfide loop is required for normal binding of vWF to platelet glycoprotein Ib. A new mutation was identified in a patient with type IIB von Willebrand disease (vWD) characterized by a lifelong bleeding disorder, mild thrombocytopenia, normal levels of factor VIII, vWF antigen, and ristocetin cofactor activity but increased ristocetin-induced platelet agglutination at low concentrations of ristocetin. Exon 28 of the patient's vWF gene was amplified, cloned, and sequenced. At nucleotide 3802 (numbering the cDNA from translation initiation), a C to G transversion was identified, which changes the encoded amino acid sequence from His-505 to Asp. The corresponding mutant recombinant vWF was expressed in transiently transfected COS cells. Relative to wild type vWF, the mutant vWF exhibited markedly increased binding to platelets at low concentrations of ristocetin, confirming the association between the His-505-->Asp substitution and the type IIB vWD phenotype. The His-505-->Asp mutation lies outside the disulfide loop affected by other type IIB vWD mutations and implicates a new segment of vWF in the regulation of platelet glycoprotein Ib binding.

    Title Functional Visual Loss.
    Date
    Journal Current Treatment Options in Neurology
    Excerpt

    Patients who present with visual loss that cannot be explained by organic lesions represent a wide spectrum of patients from those with no physiologic problem to those patients who have a true underlying condition. Regardless of where a patient falls within this spectrum, all patients need to be approached with a clinical evaluation to ensure that no underlying physiologic deficit exists. After excluding organic causes with appropriate examination and testing, a patient's visual loss still should not be labeled as functional until it is proven that they can see better than they claim to see. Only after convincingly demonstrating better vision can the physician begin to consider treatment options to help the patient's vision recover. Although functional visual loss places the physician in an unusual adversarial position of refuting a patient's symptoms, exposing the patient in a confrontational manner rarely helps. Instead, an approach that allows patients to resolve the symptoms on their own through reassurance and support often leads to successful restoration of vision. Reassurance that their condition is not serious, and may recover with time, allows patients to slowly admit their vision is improving without ever suggesting that the concern and medical attention they sought was unwarranted.

    Title Bowman-birk Inhibitor Suppresses Autoimmune Inflammation and Neuronal Loss in a Mouse Model of Multiple Sclerosis.
    Date
    Journal Journal of the Neurological Sciences
    Excerpt

    The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor. BBI concentrate (BBIC) is an extract enriched with BBI, but predominantly contains other ingredients including several protease inhibitors. We previously found that BBIC administration to Lewis rats with experimental autoimmune encephalomyelitis (EAE) significantly suppresses disease. In the present study we determined whether BBI mediates the suppressive effects of BBIC in EAE, evaluated its potential neuroprotective effects, and investigated mechanisms of BBI action. We tested effects of purified BBI on clinical and histopathological parameters of EAE in two models (relapsing/remitting EAE in SJL/J mice and chronic EAE in C57BL/6 mice). Effects of BBI were compared to BBIC in relapsing/remitting EAE, and effects of BBI on neuronal survival were examined during acute optic neuritis. Treatment with BBI in both EAE models significantly improved EAE disease parameters (onset, severity, weight loss, inflammation and demyelination). BBI significantly reduced the incidence of optic neuritis and prevented loss of retinal ganglion cells. In most experiments proliferation of immune cells derived from BBI-treated mice was significantly lower relative to control groups. Using Boyden's chamber assay we found that BBI inhibited invasiveness of activated splenocytes through the matrigel barrier. BBI also induced higher production of EAE-suppressive cytokine IL-10 by immune cells. These results demonstrate that BBI is the active component of BBIC that ameliorates clinical EAE. BBI reduces inflammation and attenuates neuronal loss, making it an excellent candidate for oral therapy in MS. BBI likely ameliorates EAE by inhibiting multiple pathways involved in disease pathogenesis.

    Title Inflammatory Demyelination Induces Axonal Injury and Retinal Ganglion Cell Apoptosis in Experimental Optic Neuritis.
    Date
    Journal Experimental Eye Research
    Excerpt

    Optic neuritis is an inflammatory disease of the optic nerve that often occurs in patients with multiple sclerosis and leads to permanent visual loss mediated by retinal ganglion cell (RGC) damage. Optic neuritis occurs with high frequency in relapsing-remitting experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, with significant loss of RGCs. In the current study, mechanisms of RGC loss in this model were examined to determine whether inflammation-induced axonal injury mediates apoptotic death of RGCs. RGCs were retrogradely labeled by injection of fluorogold into superior colliculi of 6-7 week old female SJL/J mice. EAE was induced one week later by immunization with proteolipid protein peptide. Optic neuritis was detected by inflammatory cell infiltration on histological examination as early as 9 days after immunization, with peak incidence by day 12. Demyelination occurred 1-2 days after inflammation began. Loss of RGC axons was detected following demyelination, with significant axonal loss occurring by day 13 post-immunization. Axonal loss occurred prior to loss of RGC bodies at day 14. Apoptotic cells were also observed at day 14 in the ganglion cell layer of eyes with optic neuritis, but not in control eyes. Together these results suggest that inflammatory cell infiltration mediates demyelination and leads to direct axonal injury in this model of experimental optic neuritis. RGCs die by an apoptotic mechanism triggered by axonal injury. Potential neuroprotective therapies to prevent permanent RGC loss from optic neuritis will likely need to be initiated prior to axonal injury to preserve neuronal function.

    Title Limited Sufficiency of Antigen Presentation by Dendritic Cells in Models of Central Nervous System Autoimmunity.
    Date
    Journal Journal of Autoimmunity
    Excerpt

    Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.

    Title Oral Resveratrol Reduces Neuronal Damage in a Model of Multiple Sclerosis.
    Date
    Journal Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society
    Excerpt

    Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited the ability to prevent neuronal damage.


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