A network of epigenetic regulators guides developmental haematopoiesis in vivo.

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Novel corneal phenotype in a patient with alport syndrome.

PURPOSE: To report the clinical and histopathologic findings of an unusual keratopathy, which may represent a new corneal dystrophy in a patient with Alport syndrome (ATS). METHODS: A 59-year-old woman with longstanding diagnosis of autosomal recessive ATS was evaluated for progressively decreasing vision in the left eye. She had anterior lenticonus and cataract and central corneal stromal opacification with significant thinning and flattening bilaterally. She underwent penetrating keratoplasty and cataract extraction with posterior chamber intraocular lens implantation. We describe the light microscopic and ultrastructural findings from the cornea. RESULTS: Histopathology of the corneal button revealed marked stromal thinning with decreased keratocytes. The endothelial cells were attenuated and focally lost. Immunohistochemical stains for cytokeratin were positive, findings consistent with posterior polymorphous dystrophy (PPMD). Transmission electron microscopy showed necrosis and a marked loss of keratocytes. Multilayering of the endothelium was consistent with PPMD, but mature desmosomes and microvilli were absent. In vivo confocal microscopy on the fellow eye showed linear hyporeflective bands at the level of Descemet's membrane consistent with PPMD. In addition, there were fine linear changes in the deep stroma and diffuse hyperreflectivity of the mid and superficial stroma with lack of identifiable keratocytes throughout. CONCLUSIONS: We believe this to be the first reported case to demonstrate some histopathologic features of PPMD in ATS. However, the clinical, histopathologic, and ultrastructural characteristics are not typical of PPMD. This may represent a new phenotypic expression of PPMD or may be a distinct clinicopathologic dystrophy associated with ATS.

Evaluation of digital fundus images as a diagnostic method for surveillance of diabetic retinopathy.

OBJECTIVE: The goal was to evaluate a digital imaging system for diagnosing and grading diabetic retinopathy (DR) and cystoid macular edema (CME). METHODS: A single 45 degrees, nonmydriatic, digital color photograph was taken of 231 eyes of 120 patients with diabetes mellitus. The images were graded for DR and CME by a remote ophthalmologist, and the results were compared with dilated ophthalmoscopy performed by a retina specialist. RESULTS: For DR, the level of agreement between digital image review and ophthalmoscopy was moderate (kappa = 0.44). The sensitivity and specificity of digital image review were 0.60 and 1.00, respectively. For CME, the level of agreement was moderate (kappa = 0.60). The sensitivity and specificity of digital image review were 0.60 and 0.99, respectively. CONCLUSION: A single 45 degrees, nonmydriatic, digital image is not reliable as the sole modality for DR screening. However, with modifications, it may be useful where access to an experienced ophthalmologist is limited.

Ocular diseases and nonbattle injuries seen at a tertiary care medical center during the Global War on Terrorism.

We retrospectively reviewed the records of 107 U.S. military personnel referred to the Walter Reed Army Medical Center ophthalmology service with eye diseases and nonbattle injuries diagnosed during Operation Enduring Freedom and Operation Iraqi Freedom. Ocular diseases and nonbattle injuries ranged from minor to vision-threatening, represented a broad variety of conditions, and required the expertise of a number of ophthalmic subspecialists. The most common diagnoses were uveitis (13.1%), retinal detachment (11.2%), infectious keratitis (4.7%), and choroidal neovascularization (4.7%). Eighty-four patients (78.5%) met Army retention standards and were returned to duty. Twenty patients (18.7%) were referred to a medical evaluation board, seven (6.5%) of whom failed to meet retention standards for eye and vision; the retention status of three patients (2.8%) remains to be determined.

Feasibility of telerobotic microsurgical repair of corneal lacerations in an animal eye model.

We evaluated the feasibility of telerobotic microsurgical repair of corneal lacerations. The telerobotic microsurgical device consisted of a Robotic Slave Micromanipulator Unit (RSMU) coupled to a Telepresence Surgical System (TeSS). Five mm central full-thickness corneal wounds were fashioned in five enucleated rabbit eyes and repaired remotely using the telerobotic system. Five additional eyes were also repaired by hand using a standard technique. The primary outcome measure was creation of a watertight seal. All eyes in both groups maintained an intraocular pressure (IOP) of 25 mm Hg without leak. The mean repair time was 80 min (range 50-130) with telerobotic surgery compared to 8 min (range 7-9) by hand. Histological evaluation showed that suture placement was similar in robotically assisted repair and manual repair. Subjectively, the telerobotic system provided adequate three-dimensional visualization of the surgical field. The study showed that a surgeon could close standardized corneal wounds using the telerobotic system. The potential benefits of remote eye surgery include improved access, surgical teleconsultation and telementoring.

Delayed intraocular foreign body removal without endophthalmitis during Operations Iraqi Freedom and Enduring Freedom.

OBJECTIVE: To report the long-term follow-up results of intraocular foreign body (IOFB) removal at Walter Reed Army Medical Center during Operation Iraqi Freedom and Operation Enduring Freedom from February 2003 through November 2005 and to determine the prognostic factors for visual outcome in this patient population. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Seventy-nine eyes of 70 United States military soldiers deployed in support of operations Iraqi Freedom and Enduring Freedom sustained IOFB injuries and subsequently were treated at the Walter Reed Army Medical Center with a minimum of 6 months of follow-up. INTERVENTION: The principal procedure performed was 20-gauge 3-port vitrectomy with IOFB removal through limbal or pars plana incision. MAIN OUTCOME MEASURES: Final visual acuity, rate of proliferative vitreoretinopathy, rate of endophthalmitis. RESULTS: Average patient age was 27 years, with an average of 331 days of postoperative follow-up. Average IOFB size was 3.7 mm (range, 0.1-20 mm). Median time to IOFB removal was 21 days (mean, 38 days; range, 2-661 days). Mean preoperative visual acuity was 20/400 (1.36 logarithm of mean angle of resolution [logMAR] units) and mean final visual acuity was 20/120 (0.75 logMAR). Of the patients, 53.4% achieved visual acuity of 20/40 or better, whereas 77.5% achieved visual acuity of better than 20/200. There were no cases of endophthalmitis (0/79 eyes; 95% confidence interval, 0%-3.1%), siderosis bulbi, or sympathetic ophthalmia. Among the eyes, 10.3% evolved to no light perception or had been enucleated by the 6-month follow-up visit. Poor visual outcome correlated with extensive intraocular injury (P<0.032). Seventeen of 79 eyes (21%) experienced proliferative vitreoretinopathy. Proliferative vitreoretinopathy correlated with poor initial vision (hand movements or worse; P = 0.035) and extensive intraocular injury (P<0.001). Timing of vitrectomy did not correlate with visual outcome. The most common systemic antibiotic administered was levofloxacin, whereas the most common topical antibiotic administered was moxifloxacin. CONCLUSIONS: Poor visual outcome and postoperative complication rates are related to extensive intraocular injury. Delayed IOFB removal with a combination of systemic and topical antibiotic coverage can result in good visual outcome without an apparent increased risk of endophthalmitis or other deleterious side effects.

Acanthamoeba keratitis in a U.S. Army soldier after unauthorized use of contact lenses in the combat theater.

A 25-year-old active duty Army E-5 developed severe infectious keratitis in his left eye secondary to soft contact lens (CL) wear while deployed in Iraq, necessitating evacuation to Walter Reed Army Medical Center for further evaluation and treatment. Initial clinical examination at Walter Reed Army Medical Center was suggestive of Acanthamoeba keratitis, a serious corneal pathogen associated with CL wear. In vivo confocal microscopy demonstrated Acanthamoeba cysts in the epithelium and anterior stroma, and smears and cultures from an epithelial biopsy specimen confirmed the diagnosis of Acanthamoeba keratitis. To our knowledge this is the first reported case of Acanthamoeba keratitis in a soldier wearing CLs in the combat theater. Because of the inability to maintain proper lens hygiene in a combat or field environment, the risk of developing a potentially sight-threatening corneal infection is significant. This unfortunate case of a devastating eye infection serves as a reminder of the current Army policy, which prohibits the use of CLs during gas chamber exercises, field training, and combat.

The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy.

OBJECTIVE: The objective of this study was to determine the sensitivity and specificity of Joslin Vision Network nonmydriatic digital stereoscopic retinal imaging (NMDSRI) as a screening tool in detecting diabetic retinopathy. RESEARCH DESIGN AND METHODS: We reviewed the records of 244 patients with diabetes who had a dilated funduscopic examination (DFE) and NMDSRI done within 1 year of each other at four locations in the metropolitan Washington, DC, area. The images were transmitted through a local area network to a central reading location where they were graded by a single retinal specialist. RESULTS: Images of 482 eyes from 243 patients were included in the study. Four images did not transmit, and 35% of the images were not gradable. Of the remaining 311 eyes, there was 86% agreement in the grading between NMDSRI and DFE: 227 eyes with no diabetic retinopathy and 40 eyes with diabetic retinopathy. In 46 eyes (15%) there was a disagreement between gradings made by the two techniques. NMDSRI detected diabetic retinopathy in 35 eyes reported as normal by DFE, and in the remaining 11 eyes, the DFE grade was one grade higher than the NMDSRI grade. Adjudicated nonconcordant examinations were within one grade. In the 76 eyes with diabetic retinopathy, retinal thickness could not be assessed in 17 (21%) eyes. When the NMDSRI result was gradable, the overall sensitivity of NMDSRI was 98% and the specificity was 100% for retinopathy within one grade of the DFE. In the limited number of eyes that had diabetic retinopathy with macular edema (six), agreement with the clinical examination was 100%. CONCLUSIONS: NMDSRI is a sensitive and specific method for the screening and diagnosis of diabetic retinopathy, which may help improve compliance with the standards of eye care for patients with diabetes.

Intraocular foreign body injuries during Operation Iraqi Freedom.

OBJECTIVE: To evaluate the number of intraocular foreign body (IOFB) injuries that occurred in Operation Iraqi Freedom, and to determine the cause of injury, the type of foreign body, and the associated injuries to other body systems. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Fifty-five United States military personnel with an IOFB injury during Operation Iraqi Freedom. INTERVENTION: Pars plana vitrectomy, foreign body removal, and additional surgical procedures as the clinical situation dictated. MAIN OUTCOME MEASURES: Cause of injury, size of corneal/scleral laceration, number of foreign bodies, type of foreign body, time to foreign body removal, visual acuity, number of enucleations, and injuries to other body systems. RESULTS: The foreign body was caused by a propelled explosive in 20 patients (36%) and a nonpropelled explosive in 31 patients (56%), and the cause of the foreign body was not known in 4 patients (7%). The size of the laceration of the cornea and/or sclera averaged 5.4 mm (range, 0.2-18). There were an average of 1.7 foreign bodies in the injured eye (range, 1-6). The size of those foreign bodies measured ranged from <1 mm to 12 x 14 mm. The most common type of foreign body was metal (68%), followed by glass (14%), stone/cement (14%), bone (5%), and cilia (3%). The time from injury to foreign body removal averaged 20.6 days (range, 0-90). No cases of endophthalmitis were seen. The most common associated injury was to the upper extremity, face, lower extremity, and neck. CONCLUSIONS: Unlike trauma in the civilian sector, IOFB injuries in a military setting tend to be caused by explosive devices, which often result in multiple foreign bodies and simultaneous injuries to other body systems. Because of the lack of availability of specialty care in the combat theater, there is often a delay in removal of the foreign body.

Ocular complications in the Department of Defense Smallpox Vaccination Program.

OBJECTIVE: The purpose of this case series was to present an overview of the nature and frequency of ocular complications in the Department of Defense (DoD) Smallpox Vaccination Program. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: The authors retrospectively evaluated data collected on individuals with an ophthalmologic complaint after receiving smallpox vaccination or after contact with a recently immunized individual. The vaccinee and contact cases occurred secondary to inoculations given between December 13, 2002 and May 28, 2003 as part of the DoD Smallpox Vaccination Program. METHODS: Data were collected primarily from reports to military headquarters or to the Vaccine Adverse Event Reporting System and individual medical records. MAIN OUTCOME MEASURES: The incidence, types, and timing of ocular complications were evaluated. Diagnostic and treatment considerations also were reviewed. RESULTS: Between December 13, 2002 and May 28, 2003, 450,293 smallpox vaccinations were given. We identified 16 confirmed or probable cases of ocular vaccinia, with an incidence of 3.6 per 100,000 inoculations. Of these cases, 12 (75%) were seen in the vaccinees, and 4 (25%) in close contacts. Of the 12 self-inoculation cases, 7 (58.3%) were seen in individuals receiving the vaccine for the first time (primary vaccination), and 3 (25.0%) were seen in individuals previously vaccinated (revaccination); the vaccination status in 2 cases was unknown. Clinical manifestations included lid pustules, blepharitis, periorbital cellulitis, conjunctivitis, conjunctival ulcers, conjunctival membranes, limbal pustules, corneal infiltrates, and iritis, with onset of symptoms 3 to 24 days after inoculation or contact. Five of 9 tested cases were culture or polymerase chain reaction positive for vaccinia. Treatment for most cases was topical trifluridine 1% (Viroptic; King Pharmaceuticals, Inc., Bristol, TN). Vaccinia immune globulin was used in 1 case. In all patients, recovery occurred without significant visual sequelae. CONCLUSIONS: When compared with historical data on the ocular complications of smallpox vaccination, the incidence of ocular complications during the DoD Smallpox Vaccination program has been low. In addition, the severity of disease seems to be less than during other vaccination periods. These findings perhaps are the result of improved screening of vaccinees, prevaccination counseling, postvaccination wound care, and the suggested efficacy of trifluridine in the treatment of ocular vaccinia.

Elevated intracranial pressure associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome.

The idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome typically occurs in young patients and may produce multiple retinal macroaneurysms, neuroretinitis, and peripheral capillary nonperfusion. Optic disc edema has been described, but elevated intracranial pressure has not been previously documented. We report a case of a 12-year-old girl who presented with bilateral disc swelling and peripapillary hemorrhage. Brain magnetic resonance imaging (MRI) was normal, but lumbar puncture yielded an opening pressure of 360 mm H2O with normal constituents. Fluorescein angiography delineated saccular aneurysms of the retinal arteriolar vasculature, and IRVAN syndrome was diagnosed. MR venography disclosed poor filling of both transverse venous sinuses. Acetazolamide treatment of 14 months did not alter the fundus findings. IRVAN syndrome may present initially with optic nerve swelling and elevated intracranial pressure with subsequent development of the characteristic retinal vascular abnormalities.

Adult orbital xanthogranuloma with associated adult-onset asthma.

: The authors report a case of adult orbital xanthogranuloma with associated adult-onset asthma in a 44-year-old man. Adult orbital xanthogranuloma was diagnosed on the basis of the clinical findings of bilateral, indurated, yellow eyelid lesions in a patient presenting with adult-onset asthma. Incisional biopsy of the eyelid lesions demonstrated a diffuse histiocytic infiltrate of the orbit and Touton giant cells without evidence of necrobiosis. Systemic evaluation failed to show evidence of bone lesions or paraproteinemia. When patients present with atypical indurated yellow eyelid lesions, a biopsy should be considered. If Touton giant cells are present, a systemic evaluation should be undertaken to rule out both Erdheim-Chester disease and necrobiotic xanthogranuloma. If no systemic findings are present, other than the possibility of adult-onset asthma, the rare entity of adult orbital xanthogranuloma should be considered.

Homocysteine: a risk factor for retinal venous occlusive disease.

PURPOSE: Recent studies have shown a relationship between elevated levels of homocysteine and vascular disease including cerebrovascular accidents and myocardial infarctions. We evaluated patients with a recent retinal vein occlusion to determine if there was an associated elevation of homocysteine. DESIGN: Age and gender matched case-controlled study. PARTICIPANTS: Twenty patients with retinal venous occlusive disease within the previous 6-month period and 40 control patients without retinal venous occlusive disease were enrolled in the study. METHODS: Twenty patients with a history of retinal vein occlusion underwent laboratory testing to determine serum homocysteine levels. In addition, a health survey was completed and several laboratory tests relating to vascular disease including cholesterol were checked. Two control groups were selected. The first group included patients with diabetes and no history of retinal vascular occlusive disease. The second control group included nondiabetic patients who also had no prior history of retinal vascular occlusive disease. MAIN OUTCOME MEASURES: The main parameter measured in this study is fasting homocysteine. RESULTS: Fifteen of 20 patients (75%) with retinal vein occlusion disease had an elevated fasting serum homocysteine level, whereas only 5 of 40 control patients (13%) had an abnormal homocysteine level (P < 0.0005). CONCLUSIONS: Patients with retinal venous occlusive disease have higher levels of homocysteine, which may serve as a modifiable risk factor.