New insight into flavivirus maturation from structure/function studies of the yellow fever virus envelope protein complex.

IMPORTANCE: All enveloped viruses enter cells by fusing their envelope with a target cell membrane while avoiding premature fusion with membranes of the producer cell-the latter being particularly important for viruses that bud at internal membranes. Flaviviruses bud in the endoplasmic reticulum, are transported through the TGN to reach the external milieu, and enter other cells via receptor-mediated endocytosis. The trigger for membrane fusion is the acidic environment of early endosomes, which has a similar pH to the TGN of the producer cell. The viral particles therefore become activated to react to mildly acidic pH only after their release into the neutral pH extracellular environment. Our study shows that for yellow fever virus (YFV), the mechanism of activation involves actively knocking out the fusion brake (protein pr) through a localized conformational change of the envelope protein upon exposure to the neutral pH external environment. Our study has important implications for understanding the molecular mechanism of flavivirus fusion activation in general and points to an alternative way of interfering with this process as an antiviral treatment.

SPARCS and Pelli-Robson contrast sensitivity testing in normal controls and patients with cataract.

PurposeTo determine the ability of the newly developed internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) test to assess contrast sensitivity centrally and peripherally in cataract subjects and controls, in comparison with the Pelli-Robson (PR) test.MethodsIn this prospective cross-sectional study, cataract subjects and age-matched normal controls were evaluated using the SPARCS and PR tests. Contrast sensitivity testing was performed in each eye twice in a standardized testing environment in randomized order. SPARCS scores were obtained for central, right upper (RUQ), right lower (RLQ), left upper (LUQ), and left lower quadrants (LLQ). PR scores were obtained for central contrast sensitivity. PR and SPARCS scores in cataract subjects were compared with controls. Intraclass correlation coefficients (ICC) and Bland Altman analysis were used to determine test-retest reliability and correlation.ResultsA total of 162 eyes from 84 subjects were analyzed: 43 eyes from 23 cataract subjects, and 119 eyes from 61 controls. The mean scores for SPARCS centrally were 13.4 and 14.5 in the cataract and control groups, respectively (P=0.001). PR mean scores were 1.31 and 1.45 in cataract and control groups, respectively (P<0.001). ICC values for test-retest reliability for cataract subjects were 0.75 for PR and 0.61 for the SPARCS total. There was acceptable agreement between the ability of PR and SPARCS to detect the effect of cataract on central contrast sensitivity.ConclusionsBoth SPARCS and PR demonstrate a significant influence of cataract on contrast sensitivity. SPARCS offers the advantage of determining contrast sensitivity peripherally and centrally, without being influenced by literacy.

[Possibilities and limitations of eye drops for glaucoma therapy]. / Möglichkeiten und Grenzen der medikamentösen Glaukomtherapie.

BACKGROUND: In Germany, chronic open-angle glaucoma is mostly treated by daily eye drop application. The possibilities and limitations of this form of therapy are presented. Reasons for the change in the selection of the preferred substances over time are also discussed and the limits of local drug therapy are described. OBJECTIVES: What effects can be expected of the available drugs? MATERIALS AND METHODS: The article provides a review of the literature from PubMed and clinical experience. RESULTS: In chronic open-angle glaucoma, eye drops containing a single agent can achieve an intraocular pressure decrease of 15-35 % compared to the initial pressure level. This is dependent on the substance and is achievable when used as directed. Difficulties in administration are often observed in older patients where regular use over extended periods of time is required. In addition, there are limits in the achievable pressure reduction by combining several active ingredients. Novel systems are being developed for future applications. The idea is to achieve a continuous slow release of the active substance by surgical application of a biodegradable carrier. CONCLUSION: A treatment regimen which is individually tailored to the individual patient's needs should be developed by the attending physician and the achievement of the set objectives should be monitored at regular intervals. However, restrictions induced by patients due to inadequate adherence or by the drug due to limited efficacy of the drug have to be considered. Therefore, eye drop therapy in open-angle glaucoma is not always sufficient. It should be supplemented in due time by laser or filtering surgery before the affected patients and their optic nerves suffer advanced glaucomatous damage.

Detection of asymmetric glaucomatous damage using automated pupillography, the swinging flashlight method and the magnified-assisted swinging flashlight method.

PURPOSE: To determine the sensitivity and specificity of various methods of detecting a relative afferent pupillary defect (RAPD) in patients with glaucoma-related diagnoses. PATIENTS AND METHODS: Patients underwent RAPD evaluation using the swinging flashlight method (SFM), the magnifier-assisted SFM, and pupillography using the Konan RAPDx. Main outcome measures were sensitivity and specificity of three methods of RAPD evaluation in detecting visual field mean deviation (MD), cup to disc ratio (CDR), disc damage likelihood scale (DDLS), and retinal nerve fiber layer (RNFL) asymmetry. RESULTS: Eighty-one consecutive patients from the Wills Eye Hospital glaucoma service were enrolled, 60 with glaucoma and 21 with ocular hypertension or glaucoma suspect. Thirty-one percent of subjects had MD asymmetry>5 dB, 19.7% had CDR asymmetry≥0.20, 26.7% had DDLS asymmetry≥2, and 38.2% had RNFL asymmetry>10 microns. Sensitivity values for pupillography were 93.3% (95% CI, 68.1-99.8) for detecting MD asymmetry, 80.0% (95% CI, 51.9-95.7) for CDR asymmetry, 100.0% (95% CI, 73.5-100.0) for DDLS asymmetry, and 69.2% (95% CI, 38.6-90.9) for RNFL asymmetry. Specificity values were 41.2% (95% CI, 24.7-59.3) for detecting MD asymmetry, 32.8% (95% CI, 21.3-46.0) for CDR asymmetry, 33.3% (95% CI, 18.0-51.8) for DDLS asymmetry, and 42.9% (95% CI, 21.8-66.0) for RNFL asymmetry. Pupillography amplitude score was correlated with MD asymmetry (r2=0.41, P<0.001) and area under the curve was 0.84. CONCLUSION: Automated pupillography had higher sensitivity and lower specificity in detecting MD, CDR, DDLS, and RNFL asymmetry. Within the bounds of the cohort tested, this method had limited case-finding ability.

Signs and symptoms in the presentation of primary infantile glaucoma.

Delayed initiation of proper therapy for infants with primary infantile glaucoma results in an unnecessarily poor outcome. In an effort to understand why some infants and children had more advanced disease than others, researchers reviewed the records of 24 consecutive infants and children with this problem. The presenting signs and symptoms were studied in particular. As noted by the parents, only 32% had the full classic symptom complex of epiphora and photophobia/blepharospasm. Twenty-one percent of infants and children presented with parents having noted signs of infantile glaucoma without ever noting symptoms. More than 90% of infants and children had signs of glaucoma at their initial presentation to a physician. Signs of glaucoma are apparently more difficult to appreciate in bilateral cases. In each of the three cases in which physicians repeatedly failed to make the diagnosis or refer the patient to an ophthalmologist bilateral disease was present. Recognition of the signs and symptoms of primary infantile glaucoma will allow physicians to refer infants and children at a time when good vision may be maintained in the majority of cases.

A comparison of antinuclear antibodies and DNA-binding antibodies in chronic open-angle glaucoma.

Antinuclear antibodies (ANA) were examined in the sera of 28 patients with chronic open angle glaucoma (COAG) and 24 normal volunteers by an immunoperoxidase technique. Unlike the results of a previous report, no significant difference in titers was found between the two groups. A highly objective radioimmunoassay for DNA antibody was also employed, giving similar results. The increased incidence of ANA at low dilutions in both COAG and normal groups in this study and its absence when measured by radioimmunoassay suggest that positive ANA reactions at such low dilutions are the result of nonspecific binding. The lack of demonstrable differences from normal in ANA- or DNA-binding antibody does not support the results of earlier studies suggesting a humoral immune or autoimmune mechanism in COAG.

Temporal contrast sensitivity loss in primary open-angle glaucoma and glaucoma suspects.

The need for more sensitive tests for the early detection of compromised visual function in glaucoma is established by anatomic and psychophysical evidence of damage occurring to optic nerve fibers in eyes with normal visual fields. The results are reported of temporal frequency testing on 51 glaucoma suspects without visual field loss in either eye, 52 glaucoma patients with visual field deficits in the tested eye, and 11 normal subjects. Modulation transfer functions were obtained using a sinusoidally flickering 5 degrees spatially uniform white field viewed with central fixation and plotted at six frequencies from 5-30 Hz. The results showed a frequency-specific sensitivity loss centered at 15 Hz and a nonfrequency-specific mean sensitivity loss, that was greater, on average, in glaucoma patients than in suspects. Sensitivity losses of both kinds were seen in most glaucoma patients, but only in a minority of glaucoma suspects. About 12% of suspects were indistinguishable from the lowest performing one third of these glaucoma patients. A smaller number of suspects appeared to form a second mode in the frequency distribution for temporal sensitivity at 15 and 25 Hz. In patients with glaucoma, age was found to be a significant factor associated with the magnitude of mean sensitivity loss. Age was not a significant factor contributing to sensitivity loss in individual suspect data as measured by regression analysis, but it contributed to a small and consistent sensitivity loss across frequency for group-averaged data in those older than 55 years of age.

Neodymium-YAG transscleral cyclophotocoagulation. The role of pigmentation.

Using a rabbit model we investigated the role of pigmentation of the ciliary body in obtaining ciliodestruction by neodymium-YAG transscleral cyclophotocoagulation. There was marked destruction of the ciliary body in pigmented rabbit eyes, but no histologic effect was observed in albino rabbit eyes. These findings suggest that pigmentation of the ciliary body is important for obtaining the desired response from neodymium-YAG transscleral cyclophotocoagulation in rabbit eyes by our technique. Further study is necessary to define the role of pigmentation in human eyes in this treatment modality.

Static threshold examination of the peripheral nasal visual field in glaucoma.

Quantitative computerized threshold perimetry (OCTOPUS) was used to study the peripheral nasal field in patients with glaucoma and patients suspected to have glaucoma. Peripheral nasal defects (detected with a specially designed program) were found in the absence of abnormalities in the central field (as measured by OCTOPUS Program 31 or 32) in approximately 11% of all eyes being evaluated for glaucoma. Examination of the peripheral nasal field by sensitive quantitative threshold perimetry should be included in the careful evaluation of patients with glaucoma and those suspected to have glaucoma. This procedure not only will allow identification of early defects but also will allow careful follow-up of quantified abnormalities over time.

Comparison of the optic nerve head in high- and low-tension glaucoma.

The optic nerves of 34 eyes of 34 patients with low-tension glaucoma were compared with those of 41 eyes of 41 patients with high-tension glaucoma. Mean intraocular pressure in the low-tension group was 16.9 +/- 0.7 mm Hg (mean +/- SEM) compared with 31.7 +/- 0.8 mm Hg in the high-tension group. Mean total visual field loss was not significantly different in the two groups, as determined by computerized threshold perimetry (OCTOPUS). The optic disc rim in low-tension eyes was significantly thinner than in high-tension eyes (P = .018); the largest difference occurred inferiorly and inferotemporally (P less than .001). The appearance of the optic nerve is useful to distinguish between these two subtypes of glaucoma and may be a more meaningful indicator than intraocular pressure. Our findings support the hypothesis that there are at least two different mechanisms for optic nerve damage in glaucoma.

Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years.

Seventy-eight patients (109 eyes) with progressive glaucoma had argon laser trabeculoplasty as a substitute for filtration surgery and were then followed up for a minimum of 5 years. One hundred spots were placed at the anterior margin of the posterior trabecular meshwork over 360 degrees. Consecutive cases between 1980 and 1985 were reviewed, 95% of treated cases being included in the final analysis. Eighty-two eyes had primary open angle glaucoma. If only the group with primary open angle glaucoma is considered, the failure rate the first year was 19%. After that, the failure rate was approximately eight per year. At the end of 5 years, 65% of all eyes had failed. At the end of 10 years, data were available on 84 of the original 109 treated eyes; in 80 treatment had failed, and four were still receiving medical therapy.

Chandler's syndrome as a variant of essential iris atrophy. A clinicopathologic study.

Trabeculectomy and peripheral iridectomy specimens from one male and two female patients with Chandler's syndrome (age, 30 to 42 years) showed that all had unilateral corneal endothelial "dystrophy," corneal edema, mild to moderate iris atrophy without holes, peripheral anterior synechiae, and glaucoma. In one, fluorescein angiography of the iris disclosed a sector filling delay of limbal and conjunctival vessels and pupillary and extrapupillary leakage. Histopathologic examination showed a layer of degenerated corneal endothelium and Descemet's membrane extending across the inner uveal trabeculum. Descemet's membrane displayed irregular, nodular, scroll-like excrescences in some cases, and thinner placoid configurations with abnormal widely spaced collagen (100 nm) in others. Corneal endothelial cells exhibited increased microvilli, widened cellular interdigitations, and occasional shrunken cells with enlarged or disrupted cytoplasmic blebs. Peripheral iris specimens displayed mild to moderate stromal atrophy without vascular occlusions. Pigment epithelium was normal.

Agreement between clinicians and an image analyzer in estimating cup-to-disc ratios.

We studied optic disc photographs of 35 eyes to determine the level of agreement between estimates of vertical and horizontal cup-to-disc ratios (CDRs) provided by two clinicians and estimates of these ratios obtained using an image analyzer. We also evaluated the agreement of each clinician with himself and with the other clinician to provide a relative standard by which to judge agreement between the clinicians and the image analyzer. Agreement between the clinicians and the image analyzer was moderate. Differences of more than 0.2 disc diameters (DD) between the CDR estimates of clinicians and those obtained using the image analyzer were limited to discs having small (CDR of 0.4 DD or lower) or very large (CDR of 0.9 DD or higher) cups. The clinicians' agreement with themselves and with each other was substantial to near perfect.

Lack of side effects from topically administered 10% phenylephrine eyedrops. A controlled study.

A prospective double-blind study was designed to determine the systemic hypertensive effects of topically administered 10% aqueous buffered phenylephrine hydrochloride vs topically administered 1% aqueous tropicamide, a belladonna alkaloid devoid of vasopressor effect. One hundred persons received phenylephrine, while 50 persons received tropicamide. One drop of coded drug was administered in both eyes of each patient at two-minute intervals over a four-minute period. Blood pressure and pulse rate were measured immediately prior to drop instillation, and 5, 15, and 30 minutes following instillation of the final set of drops. Mean blood pressure and pulse rate dropped from baseline values in both groups at 5, 15, and 30 minutes after drug administration. There was no statistically significant difference between the experimental and control groups with respect to drug effect on either blood pressure or pulse rate throughout the study.

Argon laser iridotomy on primary angle closure or pupillary block glaucoma.

Scanning and transmission electron microscopy were performed on peripheral iridectomy specimens from seven patients with failed pulsed argon laser iridotomies. Four to seven hours after the laser, severe edema, coagulation necrosis, focal vascular occlusion, and hemorrhage were present. Five days after the laser, cell detritus and collapsed cell processes were noted. Forty-two days after the laser, the anterior iris surface appeared considerably thinned and irregular. Eight and one-half months after the laser, the burn site displayed a dense matted appearance. Two years after the laser, the anterior iris showed a depression with pigment dispersion, irregular stroma, and disruption of the dilator muscle. The lack of inflammation could be due to the use of pulsed argon laser heat delivered at very short intervals, with deep penetration and minimal heat dispersion, since the beam is highly collimated.

Formation of peripheral anterior synechiae following argon laser trabeculoplasty. A prospective study to determine relationship to position of laser burns.

One hundred eighteen eyes with primary open-angle glaucoma underwent argon laser trabeculoplasty . Laser burns were placed in the anterior trabecular meshwork (ATM) in 58 eyes and directly over Schlemm's canal in the posterior trabecular meshwork (PTM) in 60 eyes. Twenty-nine eyes received 100 burns and 89 eyes received 50 burns distributed equally over 360 degrees. Peripheral anterior synechiae (PAS) developed in seven (12%) of the eyes having anterior trabeculoplasty and in 26 (43%) of those having posterior trabeculoplasty . There was no correlation between the development of PAS and sex, width of the anterior chamber angle, or the number of laser burns. Eyes having anterior trabeculoplasty had a final decrease in intraocular pressure equal to those having posterior trabeculoplasties . Our results strongly suggest that trabeculoplasty is a safer but no less effective procedure when the laser burns are placed on the ATM rather than the PTM.

Plateau iris syndrome associated with multiple ciliary body cysts. Report of three cases.

OBJECTIVE: To describe plateau iris syndrome associated with multiple neuroepithelial cysts of the pars plicata. METHODS: Case reports of 3 patients with plateau iris syndrome who were found to have multiple bilateral ciliary body cysts on ultrasound biomicroscopic examination. RESULTS: Ultrasound biomicroscopy revealed classic features of plateau iris syndrome in each patient but also showed multiple neuroepithelial cysts of the ciliary body in each eye. CONCLUSION: Plateau iris syndrome may be associated with multiple ciliary body cysts.

Methazolamide-induced skin eruptions.

To our knowledge, this is the first histopathologic report of skin eruptions due to oral methazolamide. From the four cases studied, we conclude that there are at least two histopathologic types: one is characterized by perivascular lymphocytic infiltrate with a vacuolar alteration at the dermoepidermal junction, the other by perivascular eosinophils, lymphocytes, and scattered mast cells. There also seem to be at least two patterns of skin eruptions: one maculopapular and the other urticarial. The type of skin eruption and the histopathologic type appear to be related.

Cysts of Tenon's capsule following filtration surgery. Medical management.

Cysts of Tenon's capsule (encapsulated blebs) developed postoperatively in 77 (13%) of 607 eyes that underwent filtration surgery between 1980 and mid-1985. The annual incidence was not uniform, increasing markedly throughout the period. Seventy-four eyes were treated with medical therapy only. At a mean follow-up of 19 months, the success rate for these eyes, defined as an intraocular pressure (IOP) of 21 mm Hg or less, was 92%. The three eyes that underwent surgical revision subsequently failed clinically by the study criteria. Those patients in whom cysts of Tenon's capsule developed were compared with an age-matched control group to assess for possible differences in long-term outcome. There was a significantly higher IOP in the Tenon's cyst group at one and three months after surgery, and an increased proportion of IOPs above 30 and 40 mm Hg. At a six-month and later follow-up, there was no significant difference in the mean IOP or in progression of visual field loss. Causative factors were sought for the development of these cysts of Tenon's capsule. Prior conjunctival surgery, or previous cyst formation in the other eye, were the significant risk factors noted.

Race-, age-, gender-, and refractive error-related differences in the normal optic disc.

OBJECTIVE: To determine race-, age-, gender-, and refractive error-related differences in the size and topography of the optic disc in healthy Americans. DESIGN: Population-based study. SETTING: Eastern and southeastern health districts of Baltimore, Md. PARTICIPANTS: A population-based sample of 4877 non-institutionalized black and white individuals aged 40 years or older without evidence of optic nerve disease. MAIN OUTCOME MEASURE: Race-, age-, gender-, and refractive error-related differences in optic disc measurements: disc area, neural rim area, cup area, cup-to-disc ratio, and neural rim area-to-disc area ratio. RESULTS: We analyzed simultaneous stereoscopic optic disc photographs from 3387 (1534 black and 1853 white) of the 4877 healthy individuals using an image analyzer (Topcon Image Analyzer, Topcon Instrument Corporation, Paramus, NJ). A total of 1490 individuals were excluded owing to the absence of good-quality images from either eye. The image analyzer defined the cup margin 150 microns below the surface of the disc margin. On average, blacks had significantly larger disc areas (blacks, 2.94 mm2; whites, 2.63 mm2), larger cup areas (blacks, 1.04 mm2; whites, 0.71 mm2), larger cup-to-disc ratios (blacks, 0.56; whites, 0.49), similar neural rim areas (blacks, 1.90 mm2; whites, 1.92 mm2), and smaller neural rim area-to-disc area ratios (blacks, 0.66; whites, 0.74) compared with whites. There were no age-related differences in any of the disc measurements. Male subjects had 2% to 3% larger optic discs compared with female subjects. No association between refractive error and any of the optic disc measurements studied was detected. CONCLUSIONS: Racial differences in the normal optic disc are present among urban Americans, and these differences must be considered in evaluation of the optic disc for glaucoma and other optic neuropathies. Among the individuals in our study, all of whom were 40 years of age or older, no progressive age-related decline in neural rim area was detectable. Neither gender nor refractive error were associated with any significant differences in the size and topography of the normal optic disc.