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Biomedical subjects

Jacque L Duncan

Publications and source records attributed to Jacque L Duncan.

13 recordsLinked to original sources
PubMed2007

Neurotrophic factors minimize the retinal toxicity of verteporfin photodynamic therapy.

PURPOSE: A prior study showed that brain-derived neurotrophic factor (BDNF) rescues photoreceptors from collateral retinal damage caused by photodynamic therapy (PDT). This study was conducted to determine whether ciliary neurotrophic factor (CNTF), a combination of BDNF and CNTF, or pigment epithelial cell-derived growth factor (PEDF) might protect photoreceptors and retinal function more effectively than BDNF. Also investigated was whether protection would be observed after a second round of PDT with adjunctive BDNF treatment. METHODS: Normal rats received intravitreal injections of BDNF, CNTF, a combination of BDNF and CNTF, or PEDF in one eye and PBS in the other 2 days before PDT. Retinal function and photoreceptor survival were assessed with multifocal ERG (mfERG) and histology 1 week after PDT. Another group of rats received two courses of PDT 3 months apart, with injection of BDNF 2 days before each treatment. RESULTS: All factors significantly increased photoreceptor survival. The combination of BDNF and CNTF rescued more photoreceptors than either factor alone. Only BDNF improved retinal function 1 week after PDT, with CNTF and the combination of BDNF and CNTF reducing mfERG responses. BDNF injection before a second round of PDT improved mfERG responses and retinal structure. CONCLUSIONS: BDNF is the most effective single factor among those tested for neuroprotection and improvement of retinal function after PDT, although a combination of BDNF and CNTF rescues more photoreceptors. Adjunctive treatment with BDNF also protects retinal structure and function through two rounds of PDT, suggesting its potential value for patients who require multiple treatments.

Animals↗
PubMed2006

Scotopic visual signaling in the mouse retina is modulated by high-affinity plasma membrane calcium extrusion.

Transmission of visual signals at the first retinal synapse is associated with changes in calcium concentration in photoreceptors and bipolar cells. We investigated how loss of plasma membrane Ca2+ ATPase isoform 2 (PMCA2), the calcium transporter isoform with the highest affinity for Ca2+/calmodulin, affects transmission of rod- and cone-mediated responses. PMCA2 expression in the neuroblast layer was observed soon after birth; in the adult, PMCA2 was expressed in inner segments and synaptic terminals of rod photoreceptors, in rod bipolar cells, and in most inner retinal neurons but was absent from cones. To determine the role of PMCA2 in retinal signaling, we compared morphology and light responses of retinas from control mice and deafwaddler dfw2J mice, which lack functional PMCA2 protein. The cytoarchitecture of retinas from control and dfw2J mice was indistinguishable at the light microscope level. Suction electrode recordings revealed no difference in the sensitivity or amplitude of outer segment light responses of control and dfw2J rods. However, rod-mediated ERG b-wave responses in dfw2J mice were approximately 45% smaller and significantly slower than those of control mice. Furthermore, recordings from individual rod bipolar cells showed that the sensitivity of transmission at the rod output synapse was reduced by approximately 50%. No changes in the amplitude or timing of cone-mediated ERG responses were observed. These results suggest that PMCA2-mediated Ca2+ extrusion modulates the amplitude and timing of the high-sensitivity rod pathway to a much greater extent than that of the cone pathway.

Animals↗
PubMed2005

Bilateral endogenous Scedosporium prolificans endophthalmitis after lung transplantation.

PURPOSE: To report a case of bilateral endogenous fungal endophthalmitis resulting from disseminated Scedosporium prolificans. DESIGN: Observational case report. METHODS: A 56-year-old woman with cystic fibrosis status post dual lung transplantation on chronic immunosuppressive therapy presented with acute graft rejection. Cultures of bronchial brushings revealed S. prolificans. Three weeks after admission, the patient noted increased blurriness and a central scotoma in her right eye. Dilated fundus examination revealed profound vitritis in the right eye with hemorrhagic retinitis involving the macula. A peripheral, yellow choroidal infiltrate with overlying retinitis and localized vitritis was present in the left eye. RESULTS: Intravitreal antibiotics were initiated, and vitreous cultures revealed S. prolificans. The patient ultimately succumbed to her disseminated disease. Pathologic examination of the eyes confirmed bilateral endogenous fungal endophthalmitis. CONCLUSION: S. prolificans is an opportunistic infection resistant to standard antifungal therapy that can result in endogenous endophthalmitis in immunocompromised individuals.

Anti-Bacterial Agents↗
PubMed2004

Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia.

Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.

Animals↗
PubMed2004

Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration.

PURPOSE: To investigate the relationship between statin and aspirin use and the risk of choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). DESIGN: Retrospective consecutive case series. METHODS: All patients 60 years and older with AMD who were seen between January 1, 1990, and March 1, 2003, at the San Francisco Veterans Affairs Hospital Eye Clinic with fundus photographs were included. Patients with other diagnoses predisposing to CNV or incomplete medical records were excluded. The main outcome measure was angiographically evident CNV. Diagnosis was based on review of fundus photographs and fluorescein angiograms in masked fashion; medical records were reviewed for variables possibly predisposing to CNV or statin use. For patients with CNV, age of onset was recorded; those without CNV were treated as censored. Age-related macular degeneration disease status and time of onset of CNV was compared between patients treated or not treated with statins for at least 6 months. RESULTS: Of 326 patients with AMD, 104 had CNV, 204 had dry AMD, and 18 had geographic atrophy (GA). Of CNV subjects, 21 (20%) used statins, compared with 77 (38%) of dry AMD subjects without GA and 6 (33%) of controls with GA (hazard ratio = 0.51, 95% confidence interval (CI) = 0.31-0.86, P =.01). Aspirin use was also significantly associated with decreased rates of CNV; 62 CNV subjects (60%) used aspirin, compared with 154 (75%) dry AMD subjects without GA or 12 (67%) with GA (hazard ratio = 0.63, 95% CI = 0.40-0.98, P =.04). CONCLUSIONS: Therapy with statins or aspirin is associated with decreased rates of CNV among AMD patients. Additional study with a prospective and/or randomized trial of statin and aspirin use in AMD patients is warranted.

Age of Onset↗
PubMed2004

Acute zonal occult outer retinopathy in a patient with graft-versus-host disease.

PURPOSE: To investigate the mechanism of bilateral central vision loss in a patient with graft-versus-host disease. DESIGN: Observational case report. METHODS: A 43-year-old man with graft-versus-host disease developed acute painless progressive central vision loss, first in the left eye and then in the right. The patient underwent slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography, visual field testing, full-field electroretinography, multifocal electroretinography, and testing for paraneoplastic antibodies. RESULTS: Fundus examination and fluorescein angiography were unremarkable. Goldmann perimetry revealed enlarged blind spots with central scotomas bilaterally. An electroretinogram testing showed asymmetric retinal dysfunction, consistent with acute zonal occult outer retinopathy. No paraneoplastic autoantibodies were detected. The patient continued to have asymmetric progressive vision loss that stabilized over the next 6 months. CONCLUSIONS: Graft-versus-host disease should be included in the autoimmune conditions associated with AZOOR.

Acute Disease↗
PubMed2004

Detection of localized retinal dysfunction in a choroideremia carrier.

PURPOSE: To investigate severe unilateral vision loss in a choroideremia carrier. DESIGN: Case report. METHODS: Ocular examination, genetic testing, Humphrey visual fields, full-field and multifocal (mf) electroretinogram (ERG) tests were used to study a family with choroideremia. RESULTS: In a carrier with unilateral central vision loss, mfERG showed severely reduced amplitudes which correlated with a band of retinal pigment epithelial and choroidal atrophy in the macula, a dense central scotoma on Humphrey visual fields testing, and decreased ERG amplitudes. CONCLUSIONS: Multifocal ERG may be a sensitive tool to measure functional abnormalities in choroideremia carriers. Mosaic inactivation of the normal gene may cause expression of the mutation with severe vision loss in choroideremia carriers.

Aged↗
PubMed2004

BDNF reduces the retinal toxicity of verteporfin photodynamic therapy.

PURPOSE: Verteporfin photodynamic therapy (PDT) is the most effective treatment for age-related macular degeneration, using laser activation of a photosensitizing dye to achieve closure of choroidal neovascularization. Although PDT preferentially affects pathologic vessels, it can also cause collateral damage to the overlying retina. In the current study, it was found that the neuroprotective agent brain-derived neurotrophic factor (BDNF) reduces this retinal damage. METHODS: Normal adult rats received intravitreal BDNF in one eye and PBS or no injection in the other eye 2 days before PDT. RESULTS: Control eyes exhibited choroidal hypofluorescence, moderate to severe photoreceptor loss, and depression of local retinal function measured using multifocal ERG in the laser-treated area. BDNF-injected eyes had more surviving photoreceptors and improved multifocal ERG responses 1 week after PDT. BDNF did not diminish the effect of PDT on the choroidal circulation as assessed by fluorescein angiography, and there was no evidence of retinal toxicity due to BDNF treatment. CONCLUSIONS: These results suggest that adjunctive neuroprotective therapy may reduce collateral damage to photoreceptors and improve visual outcome after PDT.

Animals↗
PubMed2003

An RCS-like retinal dystrophy phenotype in mer knockout mice.

PURPOSE: To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (mer(kd)) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene MERTK: METHODS: Eyes of mer(kd) and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG). RESULTS: The mer(kd) mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to mer(kd) mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained. CONCLUSIONS: Ablation of Mer function in mer(kd) mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.

Animals↗
PubMed2002

Macular pigment and lutein supplementation in choroideremia.

Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6 month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15-65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study.

Adolescent↗
PubMed2002

Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation.

Past studies have shown that acute administration of ciliary neurotrophic factor (CNTF) can prolong the survival of retinal photoreceptor cells that have undergone phototoxic injury or that express gene mutations. Adenovirus-vectored CNTF has also been effective but for all of these treatments, the effect has been transient. On the other hand, adeno-associated virus-vectored minigenes offer considerable promise for long-term survival. The authors sought to provide long-term, CNTF-based protection of mouse photoreceptors expressing a dominant-negative point mutation in the rds gene by using recombinant adeno-associated virus (rAAV) to deliver minigenes that code for a secreted form of CNTF.Secreted CNTF, under control of a cytomegalovirus (CMV) or chick beta actin (CBA) promoter provided long-term, panretinal rescue of photoreceptors following single injections of rAAV vectors into the subretinal compartment. Rescue was much less effective and less reproducible when the vectors were placed in the vitreous compartment. However, there were unexpected side effects that appeared to be dose-related. One side effect was a change in rod photoreceptor nucleus phenotype, featuring an increase in euchromatin and an increase in nuclear size following subretinal injections but not intravitreal injections. These nuclear changes were panretinal when the putatively stronger CBA promoter was used but not panretinal when the CMV promoter was used. In the latter case, the nuclear changes were much more pronounced at the site of injection. Thus, chronic hyperstimulation of retinal cells with CNTF may up-regulate gene expression in photoreceptors. Based on current knowledge of retinal cell targets for CNTF, this effect may be indirect and may not represent direct stimulation of photoreceptors by CNTF.A second side effect was a paradoxical decrease in scotopic a- and b-wave amplitudes and a decrease in photopic b-wave amplitudes in the injected, rescued retina when compared to its contralateral, uninjected counterpart, in spite of the fact that these retinas had more photoreceptors than their untreated mates. The basis for these decreased ERG amplitudes may be related to changes in gene expression. The mechanisms for these side effects and proper doses of CNTF administration should be determined before human clinical trials are considered for the amelioration of inherited retinal degenerations with CNTF.

Adenoviridae↗