Charles W. Nichols

Paralysis of the awake human: Visual perceptions

Abstract Subparalytic doses ofcurarewere given to three observers. Four major perceptions were reported: (1)displacement or repositioning of the perceived visual world in the direction of a successfully executedeye movement; (2)jumping during a saccade; (3)movement associated with drift of the eye; (4) increasedeffort associated with each eye movement. Paralytic doses ofsuccinylcholinewere administered to a single observer. Three major perceptions were reported: (1)displacement in the direction of the intended eye movement without jumping: (2) a sensation that greateffort was required to move the eye; (3)fading of the visual image due to effective retinal stabilization. Similar visual perceptions were observed when the eye was paralyzed with a local anesthetic; however, nofading or sense ofeffort was reported. No deficits in pattern vision (except for intermittent fading) were reported in any of the studies.

Combined autophagy and proteasome inhibition: A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Retinal vascular autoregulation in diabetes mellitus.

The blue field entoptic technique was used to study autoregulation of the macular retinal circulation in response to acute alterations of intraocular pressure in 71 diabetic eyes and 30 normals matched for age, systemic blood pressure, and ophthalmic artery diastolic pressure. IOPmax, the maximal intraocular pressure at which flow is maintained normal by autoregulation, was normal in eyes with no retinopathy (30 +/- 3.2 mm Hg) but decreased with progression of retinopathy, approaching the resting intraocular pressure in eyes with proliferative retinopathy. The hyperemia observed by normals to an acute reduction of intraocular pressure was not observed frequently in the diabetics with no retinopathy. The frequency of observation of the hyperemia decreased with progression of retinopathy and was uniformly absent in eyes with proliferative retinopathy. A group of eyes with minimal microangiopathy was found to have an abnormal IOPmax and no hyperemic response. The prognostic significance of these parameters remains to be established.

Effects of High Oxygen Pressures on the Eye

WITH the increasing use of oxygen at greater than atmospheric partial pressure for treatment of patients and for clinical research, it is inevitable that oxygen intoxication is also being induced. ...

Acetylcholinesterase: Method for Demonstration in Amacrine Cells of Rabbit Retina

The activity of acetylcholinesterase in the inner plexiform layer of the rabbit retina was not affected detectably by prior section of the optic nerve. After the animals were treated with diisopropyl phosphorofluoridate, acetylcholinesterase reappeared in the somata of the amacrine cells and in certain cells of the ganglion cell layer before it reappeared in the inner plexiform fibers. This confirms the normal presence of acetylcholinesterase at the former site. The possible role of acetylcholine in intraretinal transmission is considered.

Visual Loss in Cytomegalovirus Retinitis Caused by Cystoid Macular Edema in Patients without the Acquired Immune Deficiency Syndrome

PURPOSE Although serous macular exudation has been described in patients with the acquired immune deficiency syndrome (AIDS) with active cytomegalovirus (CMV) retinitis, cystoid macular edema (CME) is not encountered in this clinical setting. In contrast to these findings, we describe vision loss due to CME occurring in immunosuppressed patients without AIDS treated for CMV retinitis. METHODS Three patients (four eyes) with systemic immunodeficiency presenting with vision loss underwent ophthalmologic examination, including fundus photography and fluorescein angiography. Systemic evaluation was performed to establish the etiology of immunodeficiency and to rule out human immunodeficiency virus infection. Patients were treated with topical corticosteroid and nonsteroidal anti-inflammatory medications for CME. RESULTS All patients had severe generalized immune deficiency, related either to drug-induced immunosuppression or primary immunodeficiency. Laboratory studies confirmed the presence of systemic CMV infection. Affected eyes had mild reduction of central vision (range, 20/40 to 20/60). Three of four affected eyes had resolving CMV retinitis outside the posterior pole with mild panuveitis. These eyes showed CME on clinical examination and fluorescein angiography. The CMV lesions regressed after reduction of immunosuppressive agents or after systemic antiviral treatment. Response of CME to topical anti-inflammatory medication was variable. CONCLUSIONS Cystoid macular edema can occur in the setting of resolving CMV retinitis in patients with immunodeficiency other than AIDS. This entity is distinct from serous macular exudation, which can occur in patients with AIDS with active CMV retinitis involving the posterior pole. The disparity between patients with and without AIDS in the development of CME may be important in understanding the pathogenesis of CME.

Orbital presentation of posttransplantation lymphoproliferative disorder: A small case series

OBJECTIVE To describe a small series of patients with orbital presentation of posttransplantation lymphoproliferative disorder (PTLD). DESIGN Retrospective, interventional case series. PARTICIPANTS Three patients with orbital presentation of histologically diagnosed PTLD. METHODS Review of medical records. MAIN OUTCOME MEASURES Measured parameters included vision, proptosis, and tumor extent. RESULTS Three cases of orbital PTLD are described. In two of the cases, the tumor initially demonstrated orbital signs and symptoms, whereas in the third case, orbital and systemic signs were synchronous. Two of three patients had disseminated disease discovered at the time of presentation. One adult patient had synchronous presentation of PTLD in the orbit and prostate. One pediatric patient had tumor dissemination to the liver at the time of presentation. The PTLD tumors were classified histologically as diffuse large cell lymphoma of monomorphic or immunoblastic type in all three cases. Treatment included local irradiation, decreased immunosuppression, and antilymphocyte monoclonal antibodies. CONCLUSIONS Orbital presentation is a rare manifestation of PTLD. However, ophthalmologists must consider this diagnosis carefully in organ transplant recipients with subtle orbital signs and symptoms at presentation. Early detection may alter prognosis. In each case presented, the diagnosis was established via lesion biopsy and subsequent histologic or flow cytometric evaluation, or both.

Intralesional Triamcinolone for Cutaneous Palpebral Sarcoidosis

Cosmetically disfiguring bilateral palpebral sarcoid dermatitis in a 32-year-old woman was treated with intradermal triamcinolone. There was rapid and complete resolution of lesions and there was no evidence of recurrence or hypopigmentation at a one-year follow-up examination. Thus, intradermal corticosteroid therapy can be useful for skin lesions in patients with sarcoidosis who do not require systemic therapy.

Localization of acetylcholinesterase in the teleost retina.

Acetylcholinesterase is the sole cholinesterase enzyme identifiable histochemically in the teleost retina. Acetylcholinesterase is present in both amacrine and ganglion cells in the retinas of all three species of fish studied. No sign of acetylcholinesterase activity was found in ganglion cell axons either in the nerve fiber layer of the retina or in the optic nerve. Evidence is presented for the presence of acetylcholinesterase activity in additional cell types within the nuclear layer. The distribution of acetylcholinesterase-containing cells in teleost retina is compared to that in other species.

The Primary Open-Angle African American Glaucoma Genetics Study: Baseline Demographics

PURPOSE To describe the baseline characteristics of the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study cohort, the largest African American population with primary open-angle glaucoma (POAG) recruited at a single institution (University of Pennsylvania [UPenn], Department of Ophthalmology, Scheie Eye Institute) to date. DESIGN Population-based, cross-sectional, case-control study. PARTICIPANTS A total of 2520 African American subjects aged 35 years or more who were recruited from the greater Philadelphia, Pennsylvania area. METHODS Each subject underwent a detailed interview and eye examination. The interview assessed demographic, behavioral, medical, and ocular risk factors. Current ZIP codes surrounding UPenn were recorded and US census data were queried to infer socioeconomic status. The eye examination included measurement of visual acuity (VA) and intraocular pressure, and a detailed anterior and posterior segment examination, including gonioscopy, dilated fundus and optic disc examination, visual fields, stereo disc photography, optical coherence tomography, and measurement of central corneal thickness. MAIN OUTCOME MEASURES The baseline characteristics of gender, age, and glaucoma diagnosis were collected. Body mass index (BMI), hypertension, diabetes, alcohol and tobacco use, ocular conditions (including blindness, cataract, nonproliferative diabetic retinopathy, and age-related macular degeneration), and use of ocular medication and surgery were examined. Median population density, income, education level, and other socioeconomic measures were determined for the study cohort. RESULTS Of the 2520 African Americans recruited to the POAAGG study to date, 2067 (82.0%), including 807 controls and 1260 POAG cases, met all inclusion criteria and completed the detailed clinical ocular examination. Cases were more likely to have a lower BMI (P < 0.01) and report a history of blindness (VA of ≤20/200; P < 0.001), whereas controls were more likely to have diabetes (P < 0.001), have nonproliferative diabetic retinopathy (P = 0.02), and be female (P < 0.001). Study participants were drawn largely from predominantly African American neighborhoods of low income, high unemployment, and lower education surrounding UPenn. CONCLUSIONS The POAAGG study has currently recruited more than 2000 African Americans eligible for a POAG genetics study. Blindness and low BMI were significantly associated with POAG. This population was predominantly recruited from neighborhoods whose population income exists at or near the federal poverty level.