Search PubMed⌕ Search

Biomedical subjects

Jonathan E Sears

Publications and source records attributed to Jonathan E Sears.

At least 19 recordsLinked to original sources
PubMed2007

Diurnal rhythm of the chromatin protein Hmgb1 in rat photoreceptors is under circadian regulation.

Hmgb1 belongs to a family of structure-specific DNA binding proteins with DNA chaperone-like properties that mediate chromatin remodeling in a wide range of nuclear processes including regulation of transcription, DNA repair, genome stability, and stress response. A diurnal oscillation of Hmgb1 at the protein level occurs in rat retinal photoreceptor cells and to a lesser extent in bipolar neurons. Expression of Hmgb1 was least at night at Zeitgeber time (ZT) 18 and maximal in the middle of the lights-on period (ZT6). Since rhythmic expression of Hmgb1 protein in photoreceptors continued in complete darkness, it is likely under control of a circadian clock. Within photoreceptor nuclei, Hmgb1 colocalized with acetylated histone H3, a marker of euchromatin. Outside the nucleus a distinct smaller-sized isoform of Hmgb1 was present in photoreceptor inner segments and bound to a membrane fraction with characteristics of endoplasmic reticulum membranes. The rhythmic expression of Hmgb1 protein may underlie the circadian change in chromatin remodeling in addition to histone acetylation.

Aged↗
PubMed2006

Predictive factors for short-term visual outcome after intravitreal triamcinolone acetonide injection for diabetic macular oedema: an optical coherence tomography study.

AIM: To evaluate the predictive factors for visual outcome after intravitreal triamcinolone acetonide injection to treat refractory diabetic macular oedema (DME). METHODS: A retrospective chart review of patients with DME who met the following inclusion criteria was performed: clinically significant diabetic macular oedema, receipt of a 4 mg/0.1 ml intravitreal triamcinolone acetonide injection and an optical coherence tomography (OCT) of the macula performed up to 10 days before injection. All patients received a full ophthalmic examination including best-corrected Snellen visual acuity (VA). The main outcome measure was the mean change in vision 3 months after injection. RESULTS: Data from 73 eyes of 59 patients were analysed. After a mean follow-up of 324 days, the mean change in vision was -0.075 logarithm of minimum angle of resolution (logMAR) units, with 27.3% improving > or =3 lines, 6.8% declining > or =3 lines and 60.2% remaining stable within 1 line of baseline vision. Statistical analysis was performed using multivariate generalised estimating equations on the basis of data from 52 eyes of 42 patients. Factors associated with an improvement in vision 3 months after injection were worse baseline VA (-0.27 logMAR units/unit increase in baseline VA, p = 0.002) and presence of subretinal fluid (-0.17 logMAR units, p = 0.06). The presence of cystoid macular oedema negatively affected the visual outcome (0.15 logMAR units, p = 0.03). In addition, the presence of an epiretinal membrane (ERM) was associated with less visual improvement. ERM modified the effect of baseline VA as demonstrated by a significant interaction between these two variables (0.34 logMAR units/unit increase in baseline VA, p = 0.04). CONCLUSIONS: OCT factors and baseline VA can be useful in predicting the outcomes of VA 3 months after intravitreal triamcinolone acetonide injection in patients with refractory DME.

Aged↗
PubMed2006

Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1.

Oxidative stress can induce a covalent disulfide bond between protein and peptide thiols that is reversible through enzymatic catalysis. This process provides a post-translational mechanism for control of protein function and may also protect thiol groups from irreversible oxidation. High mobility group protein B1 (Hmgb1), a DNA-binding structural chromosomal protein and transcriptional co-activator was identified as a substrate of glutaredoxin. Hmgb1 contains 3 cysteines, Cys23, 45, and 106. In mild oxidative conditions, Cys23 and Cys45 readily form an intramolecular disulfide bridge, whereas Cys106 remains in the reduced form. The disulfide bond between Cys23 and Cys45 is a target of glutathione-dependent reduction by glutaredoxin. Endogenous Hmgb1 as well as GFP-tagged wild-type Hmgb1 co-localize in the nucleus of CHO cells. While replacement of Hmgb1 Cys23 and/or 45 with serines did not affect the nuclear distribution of the mutant proteins, Cys106-to-Ser and triple cysteine mutations impaired nuclear localization of Hmgb1. Our cysteine targeted mutational analysis suggests that Cys23 and 45 induce conformational changes in response to oxidative stress, whereas Cys106 appears to be critical for the nucleocytoplasmic shuttling of Hmgb1.

Active Transport, Cell Nucleus↗
PubMed2006

Management of macular hole and submacular hemorrhage in the same eye.

BACKGROUND: To report the management of patients with a macular hole and submacular hemorrhage in the same eye. METHODS: Case reports of two eyes of two patients undergoing pars plana vitrectomy (PPV), subretinal injection of tissue plasminogen activator (t-PA) and air-fluid exchange to displace a submacular hemorrhage. In one eye with a submacular hemorrhage due to age-related macular degeneration, a macular hole formed during subretinal t-PA injection. In another patient with a submacular hemorrhage due to a ruptured retinal arterial macroaneurysm (RAM), a sub-internal limiting membrane (ILM) hemorrhage was noted, and a macular hole was found after peeling the ILM, overlying the subretinal hemorrhage. RESULTS: In the first case, after 45 min was allowed for the subretinal clot to liquefy, the macular hole was noted to be closed. A partial air-fluid exchange was performed and the patient was positioned upright, to displace the submacular hemorrhage and tamponade the macular hole. Two weeks later, visual acuity had improved from 20/400 with eccentric viewing to 20/100, the macular hole was closed by optical coherence tomography, and the patient subsequently underwent two sessions of verteporfin photodynamic therapy (PDT) to treat choroidal neovascularization detected by fluorescein angiography. At last follow-up 7 months after surgery, vision was 20/200, the CNV was active angiographically, and another session of PDT was performed. In the second case, PPV was combined with phacoemulsification and intraocular lens implantation. An 80% air-fluid exchange was performed after injecting the subretinal t-PA, the air was exchanged for 14% perfluoropropane gas, and the patient was positioned upright. Visual acuity improved from 20/400 to 20/200 at last follow-up 4 months after surgery, with the RAM spontaneously sclerosed and the macular hole closed clinically and angiographically. CONCLUSIONS: Intraoperative evacuation of subretinal hemorrhage is not necessary in cases with coexisting macular hole and submacular hemorrhage. The submacular hemorrhage can be displaced using air or gas, and the bubble can be used to tamponade the macular hole.

Aged↗
PubMed2006

High glucose concentration induces elevated expression of anti-oxidant and proteolytic enzymes in cultured human retinal pigment epithelial cells.

We investigated the differential protein expression patterns of retinal pigment epithelial (RPE) cells exposed to increased glucose concentrations. Cultured human RPE cells (ARPE-19) were exposed for 4 days with normal blood glucose concentration (5.5 mM D-glucose), followed by exposure to either normal (5.5 mM) or high (33 mM) concentrations of D-glucose for 48h. Protein extracts of glucose-treated RPE cells were then subjected to comparative proteome analysis based on 2-D gel electrophoresis. Protein spots were visualized by silver staining. The differentially expressed proteins were excised and digested in-gel with trypsin, then analysed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The expression levels of cathepsin B, glutathione peroxidase and heat shock protein 27 were increased, and that of protein disulfide isomerase decreased in high glucose treated RPE compared to normal glucose. The isoelectric point of copper/zinc-containing superoxide dismutase (Cu/Zn-SOD) shifted toward acidic region in response to high glucose. Cu/Zn-SOD activity in high glucose group was significantly lower than that in normal glucose group (P<0.05, Mann-Whitney U-test). Systematic survey of protein expression has revealed that RPE cells respond to acute, pathologically high glucose levels by the elevated expression of anti-oxidant and proteolytic enzymes.

Antioxidants↗
PubMed2006

Retinal pigment epithelial tears after pegaptanib injection for exudative age-related macular degeneration.

PURPOSE: To report two cases of retinal pigment epithelium (RPE) tears following intravitreal pegaptanib injections for occult choroidal neovascularization. DESIGN: Noncomparative case series. METHODS: The charts of two patients with pigment epithelial tears after receiving intravitreal pegaptanib were reviewed. Approval from the institutional review board and informed consent were obtained before chart review. Fundus photos, intravenous fluorescein angiograms, and optical coherence tomography (OCT) were obtained before and after therapy confirmed the diagnosis. RESULTS: Two patients had turbid pigment epithelial detachments (PEDs) and occult choroidal neovascular membranes (CNVMs) treated with intravitreal pegaptanib. Both patients developed RPE tears weeks following one intravitreal pegaptanib injection. CONCLUSIONS: This report describes the development of RPE tears after intravitreal pegaptanib injection. Caution should be taken in cases of turbid pigment epithelial detachments in the monocular patient when treatment with intravitreal pegaptanib is entertained. Future studies should be performed to evaluate which subtypes of lesions are most susceptible to this devastating visual complication.

Aged↗
PubMed2006

Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors.

PURPOSE: To test whether triamcinolone acetonide (TA) inhibits angiogenesis induced by IL-6 or VEGF and whether this inhibition is through antagonism of the IL-6 or the VEGF receptor 2. METHODS: A rat cornea micropocket assay was used to initiate IL-6- and VEGF-mediated angiogenesis. The ability of TA or neutralizing VEGF antibody to inhibit IL-6- or VEGF-mediated neovascularization was analyzed by measuring vessel length, vessel extension, and vessel area. The phosphorylation of signal transduction activator 3 (STAT3), VEGF receptor, and extracellular signal-regulated kinase 1/2 (ERK1/2) was determined by Western blot in human umbilical vein endothelial cell (HUVEC) lysates after stimulus with IL-6 or VEGF, with and without TA pretreatment. The effect of IL-6 or TA on STAT3 expression in cornea was determined by Western blot. RESULTS: IL-6 induced corneal angiogenesis in a dose-dependent manner, with 350 ng producing a peak at day 6. VEGF antibodies and TA blocked IL-6-mediated limbal neovascularization. TA also directly inhibited angiogenesis stimulated by a VEGF pellet; the glucocorticoid receptor antagonist mifepristone neutralized TA inhibition of angiogenesis. TA did not inhibit IL-6-induced STAT3 phosphorylation and did not inhibit VEGF-induced phosphorylation of the VEGF receptor 2 or of ERK1/2 in endothelial cells, but TA decreased IL-6-induced STAT3 expression in cornea. CONCLUSIONS: IL-6- and VEGF-mediated corneal neovascularization are blocked by TA through the mifepristone-sensitive steroid receptor. TA inhibits IL-6-induced STAT3 expression in cornea, but it does not inhibit activation of the IL-6 or the VEGF receptor in cultured human endothelial cells. This finding has two implications. The fact that TA directly inhibits VEGF action implies that other factors may be critical to angiogenesis and sensitive to glucocorticoids.

Animals↗
PubMed2005

Choroidal hemangioma.

Choroidal hemangioma is an uncommon benign vascular tumor of the choroid that can be circumscribed or diffuse. Circumscribed choroidal hemangiomas are usually diagnosed between the second to fourth decade of life when they cause visual disturbances owing to the development of an exudative retinal detachment. Circumscribed tumors occur sporadically, without any associated local or systemic anomalies. Diffuse choroidal hemangiomas are usually evident at birth and generally occur as a part of neuro-oculo-cutaneous hemangiomatosis (Sturge-Weber syndrome).

Choroid↗
PubMed2005

Triamcinolone acetonide destabilizes VEGF mRNA in Müller cells under continuous cobalt stimulation.

PURPOSE: To identify the molecular mechanism of steroid-induced downregulation of vascular endothelial growth factor (VEGF) synthesis in Müller cells. METHODS: Confluent cultures of human Müller cells (MIO-M1) were treated with 100 microM CoCl(2), 1 microg/mL triamcinolone acetonide (TA), or both. VEGF secretion was measured with respect to time by ELISA. VEGF mRNA quantity and stability were analyzed by reverse transcriptase-polymerase chain reaction. The activity of hypoxia-inducible factor (HIF)-1 was measured by the relative binding of HIF-1 protein to the hypoxia response element (HRE), by gel shift and ELISA. The HIF-1alpha protein level was determined with Western blot. RESULTS: TA decreased VEGF secretion by at least 50% in the presence of continuous cobalt stimulus. VEGF mRNA decreased 50- to 100-fold 6 hours after treatment with TA and cobalt compared with cobalt alone. VEGF mRNA stability was decreased in cobalt-stimulated, TA-treated cells compared with cobalt alone in cells synchronized by exposure to actinomycin D. HIF-1alpha protein level was sustained for the entire 24-hour treatment period and partitioned into nuclear, not cytosolic, fractions. HIF-1 activity was decreased by 20% to 30% in the presence of TA and cobalt compared with cobalt alone. CONCLUSIONS: TA may decrease VEGF synthesis by nongenomic destabilization of VEGF mRNA in cobalt-stimulated Müller cells. There was little effect on the total HIF-1alpha protein level, HIF-1 partitioning, and HIF-1 activity.

Blotting, Western↗
PubMed2004

Removal of retained subfoveal perfluoro-n-octane liquid.

PURPOSE: To report a novel technique to remove retained submacular perfluorocarbon liquid. DESIGN: Retrospective cases series. METHODS: Two patients with retained subfoveal perfluorocarbon liquid were treated with this technique. With a three-port pars plana approach, a 39-gauge flexible cannula was used to perform a retinotomy adjacent to the subfoveal perfluorocarbon bubble. The tip of the cannula was inserted into the bubble, which was removed with active suction. RESULTS: Both patients underwent successful removal of the perfluorocarbon liquid without complications. In one patient, visual acuity improved from 20/70 to 20/30, with resolution of his preoperative central scotoma. The second patient required removal of subfoveal perfluorocarbon liquid at the time of silicone oil removal. The preoperative vision of finger counting improved to 20/60. CONCLUSIONS: Subretinal perfluorocarbon can be removed using a flexible 39-gauge cannula without inducing retinal detachment or making a large retinotomy. This technique may benefit patients with retained subfoveal perfluorocarbon liquid.

Catheterization↗
PubMed2004

Appositional suprachoroidal hemorrhage: a case-control study.

PURPOSE: To identify the risk factors, prognostic factors, and clinical outcomes of patients with perioperative appositional suprachoroidal hemorrhage (ASCH). DESIGN: Case-control study. SETTING: Tertiary referral center. METHODS: Subjects included all patients with perioperative ASCH documented by B-scan ultrasound between May 1990 and March 2001. Two or three control patients were selected for each case, matched by surgeon, procedure, and date of surgery within 1 month. Surgery was performed as necessary. main outcome measures. The odds of ASCH associated with clinical risk factors. secondary outcome measure: visual acuity. RESULTS: Thirty-seven cases with ASCH were identified. Ninety-two procedure- and surgeon-matched control subjects (2.48:1) were selected. Twenty-six cases (71%) of ASCH were related to a glaucoma operation. Risk factors for the development of ASCH included previous vitrectomy (P = .003, odds ratio of 12) and older age (P = .007, odds ratio 1.57/decade of increasing age). Hypertension was found to be protective (P = .02, odds ratio of 0.33). Factors associated with a poor visual outcome in patients with ASCH included apposition >30 days (P = .01), history of uveitis (P = .04), history of dry age-related macular degeneration (P = .05), and history of extracapsular cataract extraction (P = .05). Median pre-ASCH visual acuity was 20/100, and final median visual acuity was 20/1600. CONCLUSIONS: Risk factors for the development of ASCH include previous vitrectomy and older age. Patients with these risk factors should be informed of their greater chance of poor visual acuity and anatomic outcomes secondary to the development of ASCH.

Adolescent↗
PubMed2003

Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy.

PURPOSE: To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy. DESIGN: Interventional case series. METHODS: Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 microm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy. RESULTS: Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen. CONCLUSIONS: This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed.

Adult↗
PubMed2003

Acute endophthalmitis following intravitreal triamcinolone acetonide injection.

PURPOSE: To report the clinical features, causative organisms, management, and visual acuity outcomes of eight eyes of eight patients who developed acute postoperative endophthalmitis following intravitreal injection of triamcinolone acetonide (IVTA). DESIGN: Retrospective, multicenter, interventional, case series. METHODS: A retrospective, interventional, case series of all patients with acute postoperative endophthalmitis following IVTA at seven academic clinical centers between March 2001 and July 2002. RESULTS: A total of 922 IVTAs were performed. Eight eyes of eight patients with acute postoperative endophthalmitis were identified in the 6 weeks following IVTA for an incidence of 0.87% (95% confidence interval of 0.38% to 1.70%). The median time to presentation was 7.5 days (range, 1-15 days) after IVTA. The most common clinical findings were iritis (n = 8), vitritis (n = 8), hypopyon (n = 8), pain (n = 7), red eye (n = 6), and decreased vision (n = 5). The median presenting visual acuity was 20/1127 (range, 20/60 to light perception). Initial treatment consisted of vitreous tap and injection of antibiotics (n = 6) or pars plana vitrectomy and injection of intravitreal antibiotics (n = 2). Intraocular cultures yielded identification in seven patients. One demonstrated intracellular gram-positive cocci in chains with numerous polymorphonuclear cells on gram stain. The median postinfection vision was 20/400 (range, 20/40 to no light perception). Three patients ended up with no light perception visual acuity, including enucleation (n = 1) and phthisis (n = 1). CONCLUSIONS: Acute postoperative endophthalmitis following IVTA occurs rapidly and can result in severe loss of vision.

Acute Disease↗
PubMedDate not supplied

Plexiform pigmented schwannoma of the uvea.

Schwannoma is a slow growing solitary tumor that preferentially involves spinal nerve roots, and sympathetic, cervical, and vagus nerves. There are several clinico-pathologic variants of schwannoma, including schwannoma with a degenerative change (ancient schwannoma), cellular schwannoma, plexiform schwannoma, epithelioid schwannoma, and melanotic schwannoma. About 10% of cases of schwannomas are associated with multi-system disorders such as neurofibromatosis, schwannomatosis, multiple meningiomas, and Carney complex. Schwannoma rarely present as an intraocular tumor and is often misdiagnosed as malignant melanoma. Immunohistochemical positivity with S-100 stain and demonstration of long-spaced collagen (Luse bodies) are helpful in establishing the diagnosis. In this article, we review the clinical and histopathological findings of a sporadic plexiform pigmented schwannoma involving the iris, ciliary body, and the choroid.

Child↗