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.

Should an iridectomy be routinely performed as a part of trabeculectomy? Two surgeons' clinical experience.

PURPOSE: To investigate the effects of performing peripheral iridectomy on the outcome of trabeculectomy. METHODS: Retrospective chart review of the medical records of 75 patients (75 eyes) who underwent trabeculectomy surgery, with or without peripheral iridectomy, who had been followed for more than 1 year. Data were collected preoperatively, 1 day postoperatively, on days 30-90 postoperatively, and 1-3 years postoperatively. The collected data included visual acuity, intraocular pressure, bleb development, postoperative inflammation, and complications. Thirty-six eyes (48%) had cataract extraction at the time of trabeculectomy. A peripheral iridectomy was performed in 43 cases (57%). Student's t-test was used for the statistical analyses. RESULTS: Patients having peripheral iridectomy had more inflammation on days 30-90 than those who did not have peripheral iridectomy performed (in patients having cataract extraction with trabeculectomy (P=0.018) and those not having cataract extraction (P=0.038)). There was no statistically significant difference in intraocular pressure in eyes with or without iridectomy. Postoperative complications were rare in both groups but greater in number in the eyes with peripheral iridectomy. CONCLUSIONS: Trabeculectomy performed without peripheral iridectomy appears to be as effective in lowering intraocular pressure as when performed with peripheral iridectomy, but it is a safer procedure, with a lower incidence of postoperative inflammation. It may be an advantage to avoid performing peripheral iridectomy during trabeculectomy in eyes that are not predisposed to postoperative shallowing of the anterior chamber or pupillary block.

The effect of personality on measures of quality of life related to vision in glaucoma patients.

AIM: To determine the effect of personality on vision-specific health-related quality of life (HRQoL). METHODS: Based on power calculations, 148 individuals diagnosed as having glaucoma or ocular hypertension, without ocular comorbidity, were selected using criteria that included age over 30, no recent or upcoming surgery, the absence of a diagnosis of clinical depression or any other psychiatric illness. Qualifying participants completed the 25-Item National Eye Institute's Visual Function Questionnaire (VFQ), the Neuroticism, Extraversion and Openness Personality Inventory Revised (NEO PI-R) and the 15-Item Geriatric Depression Scale (GDS-15), and provided information regarding their demographic characteristics and past medical history. Each patient also underwent an ocular examination. Data analysis was conducted to determine the relationship between NEO PI-R personality profiles and VFQ scoring, while controlling for the effects of a range of demographic, psychiatric, past medical and clinical ophthalmic variables. RESULTS: Multivariate analysis indicated that after controlling for a range of covariates, three out of five NEO PI-R personality domains shared statistically significant associations with a variety of VFQ total and subscale score measurements. CONCLUSION: Normal variations in personality characteristics influence how patients report their vision-specific HRQoL.

Intraocular pressure control after Nd:YAG laser posterior capsulotomy in eyes with glaucoma.

BACKGROUND AND OBJECTIVES: To evaluate the long-term intraocular pressure (IOP) control of glaucomatous eyes following Nd:YAG laser capsulotomy. MATERIALS AND METHODS: We performed a retrospective study of 69 glaucoma patients who underwent an Nd:YAG laser posterior capsulotomy over a 3 year period, following cataract extraction or a combined cataract-glaucoma procedure. All patients had a minimum follow-up period of at least 6 months and a median follow-up period of 2 years. We assessed IOP control, number of glaucoma medications required and whether the patient needed additional glaucoma surgery following the capsulotomy. Based on these outcome measures, we strictly defined "disease progression" as one of the following: an IOP rise of at least 5 mm Hg on two consecutive visits, addition of one or more glaucoma medications and additional glaucoma surgery following the capsulotomy. We calculated Kaplan-Meier event rate curves for these eyes with "disease progression". RESULTS: The rate of "disease progression" was 11.6% at 4 months, 20.3% at 6 months, 38.1% at 12 months, 46.1% at 24 months, 52.1% at 36 months and 52.1% at 47 months following the capsulotomy. CONCLUSION: Gradual IOP elevation or a need for more aggressive therapy is common in glaucoma patients following Nd:YAG laser posterior capsulotomy. It is unclear whether this progression is related directly to the Nd:YAG laser procedure or whether it is an independent progression of the patient's glaucoma unrelated to the Nd:YAG laser procedure.

Comparison of the 20-MHz ultrasound probe with ultrasound biomicroscopy in glaucoma.

The 20-MHz ultrasound probe was compared with ultrasound biomicroscopy to determine its usefulness in imaging various glaucomatous conditions. Ten patients with glaucoma underwent anterior segment imaging with both the 20-MHz probe, which attaches to the I3 B-scan (Innovative Imaging Inc., Sacramento, CA), and the Ultrasonic BioMicroscope (UBM; Paradigm Medical Industries, Salt Lake City, UT). All pathology was easily demonstrable using the 20-MHz probe, in one case showing a retinal detachment not seen with the UBM. However, anterior findings such as fluid in the suprachoroidal space and sclerostomy sites in postoperative trabeculectomy cases were more difficult to view with the 20-MHz probe. The use of coupling enhanced the quality of the latter images. The 20-MHz ultrasound probe may be a viable aid in diagnosis and follow-up of certain glaucomatous conditions, and the use of a coupling device enhances its images.

Exfoliation syndrome angle characteristics: a lack of correlation with amount of disc damage.

BACKGROUND/AIMS: The exact pathogenesis of glaucoma in exfoliation syndrome is unclear. There has been some suggestion that narrow angles are more common in exfoliation syndrome and that this may be a component in the disease. The degree of pigmentation has also been shown to influence the intraocular pressure. The aim was to determine whether gonioscopic features of the anterior chamber angle in patients with exfoliation syndrome correlate with severity of the glaucoma. METHODS: A prospective study of consecutive patients with exfoliation syndrome was carried out. 78 patients with exfoliation syndrome were examined by one clinician (GLS), and underwent gonioscopy and dilated funduscopy. RESULTS: Anterior chamber angle, level of iris insertion, degree of pigmentation and the presence or absence of a Sampaolesi line were not correlated with the degree of disc damage. CONCLUSIONS: There was no apparent association between angle characteristics and the severity of glaucoma in patients with exfoliation syndrome.

Association of the myocilin mt.1 promoter variant with the worsening of glaucomatous disease over time.

A major variant of myocilin (MYOC) [TIGR/MYOC mt.1 (-1000 C/G)], present in the gene's promoter, is found to be associated with more rapid progression of the glaucoma disease state. Time-to-event analyses using the Cox proportional hazards model produced substantial statistical evidence that this TIGR/MYOC mt.1(+) variant accelerates worsening for both optic disc and visual field measures of disease progression. These analyses were based on evaluations of 147 patients with primary open-angle glaucoma (POAG) over 35 years of age with an average follow-up of approximately 15 years. Our analyses showed that there are independent effects of the variant on disease progression, taking into account other relevant disease-related baseline risk factors, including age, family history, initial drug treatment, initial surgical treatment, diabetes, gender, myopia, and initial disease severity. The finding that a TIGR/MYOC mt.1(+) determination provided a strong marker for glaucoma progression, above and beyond the other baseline risk factors, suggests a clinical utility in testing for this promoter genotype.

A randomized trial of the long-term effects of digital ocular compression in the late postoperative period.

PURPOSE: To determine whether digital ocular compression is a viable technique to lower intraocular pressure in patients at least 3 months after trabeculectomy. PATIENTS AND METHODS: A 6-month prospective, randomized, controlled, single-masked trial of 29 patients who underwent a trabeculectomy at the Glaucoma Service of Wills Eye Hospital. Patients were assigned to two groups: ocular compression or cheekbone compression (control group). The ocular compression group performed compression to the operated eye three times a day in the pattern of 10 seconds of pressure, 5 seconds of rest, and 10 seconds of pressure. Pressure was applied with the index finger through the closed lid to the center of the cornea. Pressure was steady and firm, but not painful. No massaging was performed. The cheekbone compression group applied pressure to the zygomatic arch with an identical style and frequency. RESULTS: At 6 months, the change in mean intraocular pressure for the ocular compression group was 0.25 mm Hg compared with -0.44 mm Hg for the control group (P = 0.7). A few patients in both groups experienced large swings in intraocular pressure and mild to moderate discomfort. CONCLUSION: Ocular compression had little to no success in the long-term management of increased intraocular pressure in the late postoperative period in this study.

Angle-closure glaucoma in association with orbital pseudotumor.

PURPOSE: To describe the pathophysiology of angle-closure glaucoma secondary to idiopathic inflammatory orbital pseudotumor. DESIGN: Retrospective, small noncomparative case series. PARTICIPANTS: Three patients with angle-closure glaucoma and orbital pseudotumor. METHODS: The pathophysiology of this entity was investigated using magnetic resonant imaging (MRI) and ultrasound biomicroscopy (UBM). MAIN OUTCOMES MEASURES: Clinical features, anterior chamber angle configuration, and intraocular pressure. RESULTS: Angle closure from anterior rotation of the ciliary body caused by choroidal effusions secondary to pseudotumor was demonstrated using MRI and UBM. Two of the three cases resolved after treatment for orbital pseudotumor. CONCLUSIONS: Idiopathic orbital pseudotumor is a cause of secondary angle-closure glaucoma. The mechanism of angle closure is anterior rotation of the ciliary body secondary to choroidal effusions resulting from the orbital inflammation.

Complementary and alternative medicine for glaucoma.

Given the recent interest in complementary and alternative medicine (CAM), some patients may seek such treatments to supplement their traditional glaucoma management. The prevalence of CAM use for glaucoma is approximately 5%. We reviewed the literature to determine the potential benefit of various alternative treatments. Aside from a temporary osmotic effect from high dose intravenous ascorbic acid, there is no evidence that megavitamin supplementation has a beneficial effect on glaucoma. During exercise, autoregulation in healthy eyes seems to maintain a consistent blood flow rate to the optic nerve despite fluctuations in intraocular pressure (IOP). In a glaucomatous eye, the very modest IOP-lowering that follows exercise may be offset by the initial elevation in IOP that occurs when one first initiates exercise. At this time, there is no evidence to encourage or discourage the use of special diets, acupuncture, relaxation techniques, or therapeutic touch specifically for the treatment of glaucoma. Very little research has been done on the majority of herbal remedies with regard to their treatment of glaucoma. Marijuana can cause a profound lowering of IOP, but the high nonresponse rate, short half life, and significant toxicity are strong indicators that it is not an appropriate therapeutic agent. Ginkgo biloba and some other Chinese herbal remedies do not affect IOP, but may improve blood flow to the optic nerve and, as such, may have a beneficial effect on glaucoma. These agents have recognized toxicities. Although there are some well-designed studies of alternative treatments, many of the recommendations for using alternative treatments are currently unsupported by the data provided.

The use of antimetabolites with trabeculectomy: a critical appraisal.

PURPOSE: To examine why most ophthalmologists routinely use mitomycin C or 5-fluorouracil (antimetabolites) in association with filtering surgery for glaucoma. METHODS: Critical analysis of seven medical, social and economic trends. RESULTS: The rapid acceptance of the adjunctive use of antimetabolites at the time of filtration surgery may be explained by reasons other than anticipated increase in the "success" of glaucoma surgery. CONCLUSION: The use of antimetabolites in conjuction with filtering glaucoma surgery may be at least partially a consequence of changing medical-social-economic factors, rather than solely a desire on the part of physicians to improve the "success" of glaucoma surgery. This may indicate a need to reevaluate the proper place of antimetabolites in association with filtration surgery.