Unexplained vision loss following removal of epiretinal membrane.

PURPOSE: To report unexplained severe central vision loss accompanied by a dense central scotoma as an uncommon complication following epiretinal membrane removal. METHODS: Retrospective, multicentred, case series. RESULTS: Six patients underwent uncomplicated vitrectomy surgery between 2000 and 2007 at four separate retina practices for removal of an epiretinal membrane. Preoperative vision ranged from 20/60 to 20/100, with a median of 20/70. On the first day postoperatively, all patients noted decreased vision ranging from counting fingers to light perception and were found to have a dense central scotoma. Posterior segment examination revealed a white, oedematous macula in all affected eyes. Vision improved minimally during the follow-up period, which ranged from 2 months to 5 years. The final vision ranged from 20/200 to hand movements. No anatomic or physiologic cause for the decreased vision and central scotoma was identified. CONCLUSIONS: While uncommon, severe, permanent, central vision loss accompanied by a dense central scotoma can occur following epiretinal membrane removal and should be considered when assessing the risks and benefits of such surgery.

Morphometric analysis of the macula in eyes with disciform age-related macular degeneration.

PURPOSE: To evaluate the extent of neural cell death in eyes with disciform age-related macular degeneration. METHODS: Six eyes with disciform degeneration at various stages and five age-matched control eyes were selected for morphometric analysis using digitized light microscopic images. Disciform scars were classified as subneurosensory retinal, subretinal pigment epithelial, or combined lesions. The nuclei of the ganglion cell, inner nuclear, and outer nuclear layers were counted in contiguous 100 microm segments spanning a distance from 1,500 microm nasal to 1,500 microm temporal to the fovea. RESULTS: The outer nuclear layer was most severely attenuated in eyes with disciform scars, demonstrating a 69.4% reduction in cell number relative to control eyes. A loss in retinal ganglion cells (by 7.3%) and an increase in inner nuclear layer cells (by 10%) were observed, but these changes were not significant. Photoreceptor loss was most pronounced when the disciform scar was not covered by the retinal pigment epithelium. CONCLUSION: The nuclei of the outer nuclear layer are significantly attenuated in eyes with disciform age-related macular degeneration, while the ganglion cell and inner nuclear layers are relatively preserved. These findings suggest that replacement of outer nuclear function, by either retinal transplantation or implantation of the intraocular retinal prosthesis, might be a feasible therapeutic option for patients with this condition.

Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.

Airbags and eye injuries: epidemiology, spectrum of injury, and analysis of risk factors.

Although airbags measurably reduce the overall risk of injury to adults (including eye injury), and death from motor vehicle accidents, injuries attributed to airbag deployment have been reported. To identify reported cases of ocular trauma related to airbag deployment, a MEDLINE search from 1991 to 2000 was performed. A total of 263 injuries in 101 patients were identified. Patient demographics, details of the accident, specific ocular structures injured, and visual outcomes when available where tabulated and analyzed. The most common of these affect the eyes. Damage to the orbit and virtually every ocular and adnexal structure has been seen. Although most injuries are self-limited and do not significantly compromise vision, some result in severe, permanent visual loss. Most common is damage to anterior structures due to either blunt, contusive forces and/or chemical injury. Posterior segment trauma is less common but generally more visually devastating because of the involvement of the retina or optic nerve. Data are not available to determine whether the wearing of eyeglasses or previous intraocular surgery affects the nature, severity, or outcome of these injuries. Awareness of the spectrum of airbag-associated ocular trauma will help physicians recognize these problems early and optimize their management. Data derived from analyses of these injuries will be critical to the development of safer, more effective devices.

Serial motion assessment by reference tracking (SMART): application to detection of local functional impact of chronic myocardial ischemia.

PURPOSE: To compare measurements of wall motion and thickening with and without correcting for cardiac twisting and shortening. METHOD: Inversion recovery Gd-DPTA perfusion and cine motion MRI were performed on 12 pigs with chronic ischemia induced by ameroid occluder. Analyses were based on conventional fixed plane imaging and serial motion assessment by reference tracking (SMART). RESULTS: Normal motion was 31.3 +/- 1.9%, and normal wall thickening was 41.4 +/- 2.2%. At the maximum perfusion defect, SMART wall motion was 10.5 +/- 2.4% and fixed wall motion was 20.6 +/- 1.7% (p < 0.004), SMART wall thickening was 20.1 +/- 4.4%, and fixed wall thickening was 32 +/- 1.9% (p < 0.03). CONCLUSION: SMART measurements of wall thickening and motion detect much smaller thickening and motion in ischemic myocardium than fixed radial metrics. SMART data, covering the entire heart, should prove twice as sensitive to abnormalities in motion and thickening, such as any produced by ischemic heart disease or improved by treatment.

Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization.

In this study, we investigated whether overexpression of pigment epithelium-derived factor (PEDF) by gene transfer can inhibit neovascularization by testing its effect in three different models of ocular neovascularization. Intravitreous injection of an adenoviral vector encoding PEDF resulted in expression of PEDF mRNA in the eye measured by RT-PCR and increased immunohistochemical staining for PEDF protein throughout the retina. In mice with laser-induced rupture of Bruch's membrane, choroidal neovascularization was significantly reduced after intravitreous injection of PEDF vector compared to injection of null vector or no injection. Subretinal injection of the PEDF vector resulted in prominent staining for PEDF in retinal pigmented epithelial cells and strong inhibition of choroidal neovascularization. In two models of retinal neovascularization (transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors and mice with oxygen-induced ischemic retinopathy), intravitreous injection of null vector resulted in decreased neovascularization compared to no injection, but intravitreous injection of PEDF vector resulted in further inhibition of neovascularization that was statistically significant. These data suggest that sustained increased intraocular expression of PEDF by gene therapy might provide a promising approach for treatment of ocular neovascularization.

Outcomes of temporal clear cornea versus superior scleral tunnel phacoemulsification incisions in a university training program.

BACKGROUND AND OBJECTIVES: To evaluate the complication and visual outcomes of residents performing temporal clear cornea (TCC) compared to superior scleral tunnel (SST) phacoemulsification. PATIENTS AND METHODS: We conducted a retrospective analysis of complications and visual outcomes for 534 phacoemulsification procedures done by third-year residents over a five-year period (June 1992-July 1997) at the department of ophthalmology, University of Chicago. All cases were completed using a TCC or SST incision. RESULTS: There was vitreous loss in 6.0% of 348 eyes with TCC incisions and in 11.8% of 186 eyes with SST incisions (P < 0.02). Posterior capsule breaks occurred in 1 1.5% of the TCC group versus 17.7% in the SST group (P < 0.0453). Best corrected visual acuity of 20/40 or better was achieved in 82.5% of all eyes with TCC incisions and in 75.3% of all eyes with SST incisions (P < 0.05). When 151 patients with previous ophthalmic conditions were excluded, the difference in BCVA between the two groups was not statistically significant. CONCLUSIONS: Most institutions train residents with the SST technique prior to advancing to TCC. This study demonstrates that with proper teaching, residents can achieve excellent outcomes using TCC incisions, and can therefore be trained in this technique concurrently with SST incisions.

Sensitivity of human glioma U-373MG cells to radiation and the protein kinase C inhibitor, calphostin C.

We assessed the radiosensitivity of the grade III human glioma cell line U-373MG by investigating the effects of radiation and the specific protein kinase C inhibitor, calphostin C on the cell cycle and cell proliferation. Irradiated glioma U-373MG cells progressed through G1-S and underwent an arrest in G2-M phase. The radiosensitivity of U-373MG cells to graded doses of either photons or electrons was determine by microculture tetrazolium assay. The data was fitted to the linear-quadratic model. The proliferation curves demonstrated that U-373MG cells appear to be highly radiation resistant since 8 Gy was required to achieve 50% cell mortality. Compared to radiation alone, exposure to calphostin C (250 nM) 1 h prior to radiation decreased the proliferation of U-373MG by 76% and calphostin C provoked a weakly synergistic effect in concert with radiation. Depending on the time of application following radiation, calphostin C produced an additive or less than additive effect on cell proliferation. We postulate that the enhanced radiosensitivity observed when cells are exposed to calphostin C prior to radiation may be due to direct or indirect inhibition of protein kinase C isozymes required for cell cycle progression.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Biomechanical consequences of an isolated overload on the human vertebral body.

The biomechanical consequences of an isolated overload to the vertebral body may play a role in the etiology of vertebral fracture. In this context, we quantified residual strains and reductions in stiffness and ultimate load when vertebral bodies were loaded to various levels beyond the elastic regimen and related these properties to the externally applied strain and bone density. Twenty-three vertebral bodies (T11-L4, from 23 cadavers aged 20-90 years) were loaded once in compression to a randomized nominal strain level between 0.37 and 4.5%, unloaded, and then reloaded to 10% strain. Residual strains of up to 1.36% developed on unloading and depended on the applied strain (r2=0.85) but not on density (p = 0.25). Percentage reductions in stiffness and ultimate load of up to 83.7 and 52.5%, respectively, depended on both applied strain (r2 = 0.90 and r2 = 0.32, respectively) and density (r2 = 0.23 and r2 = 0.22, respectively). Development of residual strains is indicative of permanent deformations, whereas percentage reductions in stiffness are direct measures of effective mechanical damage. These results therefore demonstrate that substantial mechanical damage-which is not visible from radiographs-can develop in the vertebral body after isolated overloads, as well as subtle but significant permanent deformations. This behavior is similar to that observed previously for cylindrical cores of trabecular bone. Taken together, these findings indicate that the damage behavior of the lumbar and lower thoracic vertebral body is dominated by the trabecular bone and may be an important factor in the etiology of vertebral fracture.

Coronary angiogenesis: detection in vivo with MR imaging sensitive to collateral neocirculation--preliminary study in pigs.

PURPOSE: To assess the ability to track neovascularization over time with a magnetic resonance (MR) imaging technique sensitized to new intramyocardial collateral development as a means of evaluating therapeutic angiogenesis. MATERIALS AND METHODS: Magnetization preparation plus spatial frequency reordering was applied to distinguish new intramyocardial collateral vessels from normal circulation on the basis of geometric differences. A vascular occluder was inserted in 34 pigs, and they were assigned randomly to treatment groups with either placebo or angiogenic growth factor. Collateral extent determined with collateral-sensitive MR imaging was correlated with direct measurements by means of three-dimensional (3D) computed tomography (CT), coronary blood flow distribution determined with microspheres, and findings at histologic examination. Changes in the signal at collateral-sensitive MR imaging before and after treatment were assessed by two observers blinded to treatment. RESULTS: The collateral extent determined with collateral-sensitive MR imaging correlated well with findings at 3D CT (r = 0.95) and with microspheres (r = 0.86). Furthermore, the collateral extent determined with collateral-sensitive MR imaging increased significantly (P < .001) in response to the administration of an angiogenic growth factor but not to placebo. The correspondence of findings at collateral-sensitive MR imaging to collateral neovascularization was confirmed at histologic examination. CONCLUSION: The presence of intramyocardial collateral microvessels was accurately determined with collateral-sensitive MR imaging. The technique may be useful in clinical studies of therapeutic angiogenesis.

A splice variant of the transcript for guanylyl cyclase C is expressed in human colon and colorectal cancer cells.

Guanylyl cyclase C is a sensitive and specific biomarker for metastatic colorectal cancer. A variant of the guanylyl cyclase C transcript was identified that possesses a 142-bp deletion at the 3' end of exon 1 reflecting alternative splicing of mRNA, introducing a shift in the open reading frame that prevents translation of a guanylyl cyclase C-related product. This variant was identified in human intestine and colon carcinomas, but not in extraintestinal tissues or tumors. These studies demonstrate that GCC and the splice variant contribute to the pool of GCC transcripts detected by RT-PCR in human tissues. They indicate that primers for RT-PCR that amplify regions downstream from the deletion are required to assess the full complement of GCC transcripts (GCC + GCC(var)) in human tissues and body fluids for staging and postoperative surveillance of patients with colorectal cancer.

Intrapericardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia.

Therapeutic angiogenesis is a novel approach to the treatment of myocardial ischemia based on the use of proangiogenic growth factors to induce the growth of new blood vessels to supply the myocardium at risk. This study was designed to assess the safety and efficacy of a single intrapericardial injection of basic fibroblast growth factor (FGF-2) in a porcine model of chronic myocardial ischemia. Yorkshire pigs underwent ameroid placement around the left circumflex coronary artery. At 3 weeks, animals were randomized to receive a single intrapericardial injection of either saline (n = 10), 3 mg of heparin (n = 9), 3 mg of heparin + 30 microgram of FGF-2 (n = 10), 200 microgram of FGF-2 (n = 10), or 2 mg of FGF-2 (n = 10). Coronary angiography, microsphere flow, magnetic resonance functional, and perfusion imaging were performed before and 4 weeks after treatment, at which time histologic analysis was also performed on 3 animals in each group. In ischemic pigs, FGF-2 treatment resulted in significant increases in left-to-left angiographic collaterals and left circumflex coronary artery blood flow. These benefits were accompanied by improvements in myocardial perfusion and function in the ischemic territory, as well as histologic evidence of increased myocardial vascularity without any adverse effects. Not one of these benefits was seen in saline- or heparin-treated ischemic animals. A single intrapericardial injection of FGF-2 in a porcine model of chronic myocardial ischemia results in functionally significant myocardial angiogenesis, without any adverse outcomes. This mode of FGF-2 administration may prove to be a useful therapeutic strategy for the treatment of patients with ischemic heart disease.

Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia.

BACKGROUND: Therapeutic angiogenesis in ischemic myocardium has been shown to be a feasible and effective strategy to improve regional blood flow and myocardial function. However, the optimal mode of growth factor administration still needs to be established. METHODS: Using a pig model of chronic myocardial ischemia, we evaluated the efficacy of intravenous and intracoronary infusion of FGF-2 at 2 and 6 microg/kg compared with a vehicle control. Improvement in myocardial perfusion and function was assessed by angiography, colored microspheres, and function and perfusion magnetic resonance imaging. RESULTS: Intracoronary 6-microg/kg FGF-2 increased angiographic collaterals (p = 0.046) and increased regional blood flow to the ischemic area from 0.36 +/- 0.07 to 0.59 +/- 0.08 mL/min/g at stress (vs control, p = 0.032). Also, after 6 microg/kg intracoronary FGF-2, ejection fraction, regional wall motion, and thickening improved significantly by 9.9% +/- 1.9%, 126% +/- 39%, and 13.8% +/- 3.6%, respectively. Intravenous FGF-2 and intracoronary 2 microg/kg FGF-2 were ineffective. CONCLUSIONS: A single 6-microg/kg intracoronary treatment with FGF-2 resulted in significant improvement in collateralization and regional and global function of chronically ischemic myocardium. Single intravenous infusion of FGF-2 was not effective in this model.

Echo-planar functional MR imaging of epilepsy with concurrent EEG monitoring.

BACKGROUND AND PURPOSE: The role of functional MR (fMR) imaging in the evaluation of patients with epilepsy has not been systematically studied. Our purpose was to identify the fMR correlates of interictal epileptiform discharges. METHODS: Twenty patients with epilepsy and frequent interictal discharges were studied with concurrent EEG monitoring on a 1.5-T echo-planar magnet to acquire blood-oxygenation-level-dependent (BOLD) images in the baseline (OFF) and immediate post-discharge (ON) states. Analysis was performed using subtraction of average ON and OFF data (method I); cross-correlation analysis between the ON and OFF states (method II); and individual spike analysis (ISA), with which signal intensity in the individual ON states was statistically analyzed using a weighted comparison with the mean and variance of the OFF states (method III). Agreement of fMR activation with EEG localization was determined. RESULTS: Eighteen of 20 patients had interictal discharges during the monitoring period. Method I yielded visually detectable sites of BOLD signal differences in only one patient. Method II resulted in two patients with sites of BOLD activation. Method III, ISA, resulted in regions of increased BOLD signal corresponding to the EEG focus in nine of 10 patients. CONCLUSION: fMR studies can often reveal sites of increased BOLD signal that correspond to sites of interictal EEG discharge activity. Because of variable intensity changes associated with discharge activity, ISA resulted in increased sensitivity.

Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4-(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylproprionic++ + acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. PATIENTS AND METHODS: In this multi-institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over 1 hour by central venous access with 4 L/min of O(2 )by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (PD) determinations were performed. The PD end point was shift in P50, the oxygen half-saturation pressure of HgB. RESULTS: Grade 3 dose-limiting toxicity occurred in none of the patients with every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10, respectively. PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related to RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 +/- 2.6 mmHg (a 34% increase from baseline), which indicates a substantial increase in tendency toward oxygen unloading. CONCLUSION: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.

Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial.

BACKGROUND: Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 microg of bFGF (n=8), 100 microg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0+/-6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-microg bFGF group had angina, whereas all patients in the 100-microg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7+/-3.7% to 23.8+/-5.7%, P=0.06), no significant change in the 10-microg bFGF group, and significant improvement in the 100-microg bFGF group (19.2+/-5.0% to 9.1+/-5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-microg bFGF group (10.7+/-3.9% to 3. 7+/-6.3%, P=0.06). CONCLUSIONS: This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.

Fourth cranial nerve palsy in pediatric patients with pseudotumor cerebri.

PURPOSE: To describe three children with acute fourth cranial nerve palsy secondary to pseudotumor cerebri. METHODS: We reviewed the medical records of children younger than 18 years who were diagnosed with pseudotumor cerebri between 1977 and 1997. Pseudotumor cerebri was defined by normal neuro-imaging, elevated intracranial pressure measured by lumbar puncture, and normal cerebrospinal fluid composition. RESULTS: Three children with pseudotumor cerebri presented with vertical diplopia and clinical signs of fourth cranial nerve palsy including a hypertropia of the affected eye, which increased with adduction and ipsilateral head tilt. The fourth cranial nerve palsy resolved after reduction of the intracranial pressure in all three children. CONCLUSIONS: Fourth cranial nerve palsy may occur in children with pseudotumor cerebri and may be a nonspecific sign of elevated intracranial pressure.