Assessing the readability, quality and accuracy of online health information for patients with low anterior resection syndrome following surgery for rectal cancer.

AIM: Management of low anterior resection syndrome (LARS) requires a high degree of patient engagement. This process may be facilitated by online health-related information and education. The aim of this study was to systematically review current online health information on LARS. METHOD: An online search of Google, Yahoo and Bing was performed using the search terms 'low anterior/anterior resection syndrome' and 'bowel function/movements after rectal cancer surgery'. Websites were assessed for readability (eight standardized tests), suitability (using the Suitability Assessment of Materials instrument), quality (the DISCERN instrument), accuracy and content (using a LARS-specific content checklist). Websites were categorized as academic, governmental, nonprofit or private. RESULTS: Of 117 unique websites, 25 met the inclusion criteria. The median readability level was 10.4 (9.2-11.7) and 11 (44.0%) websites were highly suitable. Using the DISCERN instrument, seven (28.0%) websites had clear aims, two (8.0%) divulged the sources used and four (16.0%) had high overall quality. Only eight (32.0%) websites defined LARS and ten (40.0%) listed all five major symptoms associated with the LARS score. There was variation in the number of websites that discussed dietary modifications (80.0%), self-help strategies (72.0%), medication (68.0%), pelvic floor rehabilitation (60.0%) and neuromodulation (8.0%). The median accuracy of websites was 93.8% (88.2-96.7%). Governmental websites scored highest for overall suitability (P = 0.0079) and quality (P < 0.001). CONCLUSIONS: Current online information on LARS is suboptimal. Websites are highly variable, important content is often lacking and material is too complex for patients.

Ileal pouch-anal anastomosis for ulcerative colitis: a Canadian institution's experience.

BACKGROUND: We aimed to summarize the outcomes of ulcerative colitis (UC) patients receiving an ileal pouch-anal anastamosis (IPAA) over an 11-year period at a high-volume Canadian inflammatory bowel disease (IBD) center. METHODS: A retrospective chart review was performed for subjects with UC who underwent IPAA between 2002 and 2013. Patient charts were reviewed for demographic data, clinical characteristics, preoperative medical treatment, and surgical outcomes. Univariate and multivariate logistic regression modeling were used to determine significant factors in postoperative outcomes. RESULTS: Seven hundred fifty-eight were included from the IBD database. The median age at the time of surgery was 37.1 (±12.1). Mean preoperative disease duration was 8.1 years (±8.7). Three hundred sixty-nine patients (48.7 %) had systemic corticosteroids (>15 mg/day) within 30 days prior to surgery. Of these, 286 patients had high dose (>30 mg/day) corticosteroids within 7 days of their first surgery. One hundred nine (14.0 %) IPAA procedures were performed laparoscopically. Pelvic pouches were created in traditional 2 (n = 460) and 3 (n = 285) stages; the remainder (n = 13) was performed in non-traditional staged operations. Early complications, defined as occurring within the same stay in hospital, consisted of pelvic abscess (n = 135, 17.8 %), small bowel obstruction (n = 134, 17.7 %), wound infection (n = 108, 14.3 %), and deep vein thrombosis (n = 33, 4.4 %). The overall pouch leak rate was 92 (12.1 %). There was one death in our study. The median length of stay was 10.3 days (SD6.0). Late complications, defined as occurring after discharge from hospital, consisted of anal stricture (n = 55, 7.3 %), pouch fistula (n = 26, 3.4 %), and functional pouch failure (n = 7, 0.9 %). CONCLUSIONS: IPAA has been found to be a safe and effective method of surgical management of UC patients in a high-volume IBD center.

Morphology and Visual Acuity in Aflibercept and Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration in the VIEW Trials.

PURPOSE: To compare the efficacy of intravitreal aflibercept and ranibizumab on the exudative activity of neovascular age-related macular degeneration (nAMD) using optical coherence tomography (OCT) and to correlate morphologic findings with visual acuity (VA) outcomes. DESIGN: Post hoc analysis of the prospective VIEW trials. PARTICIPANTS: Data of 1815 patients randomized to 0.5 mg ranibizumab every 4 weeks (Q4wks), 2 mg aflibercept Q4wks, or 2 mg aflibercept every 8 weeks (Q8wks). METHODS: Standardized OCT evaluation was performed by masked reading centers for the presence of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment epithelial detachment (PED). Rates of feature resolution were compared between drugs and regimen. Associations between morphologic features and VA were analyzed using multivariate modeling. MAIN OUTCOME MEASURES: Resolution rates of IRC, SRF, and PED, and associations between morphology and VA. RESULTS: At baseline, the proportions of eyes with IRC, SRF, and PED were balanced between the aflibercept and ranibizumab groups. At week 12, IRC resolved in 50% of eyes with both agents. Subretinal fluid resolved in 70% of pooled aflibercept-treated eyes and in 59% of ranibizumab-treated eyes, and PED resolved in 29% and 24% of pooled aflibercept-treated eyes and ranibizumab-treated eyes, respectively. At week 52, IRC resolved in 57% (aflibercept Q4wks), 50% (aflibercept Q8wks), and 52% (ranibizumab) of patients; SRF resolved in 75% (both aflibercept Q4wks/Q8wks) and 66% (ranibizumab) of patients; and PED resolved in 40% (aflibercept Q4wks), 34% (aflibercept Q8wks), and 28% (ranibizumab) of patients. During fixed dosing (weeks 12-52) all exudative features showed synchronized fluctuations after treatment-free visits in the Q8wks aflibercept regimen. During pro re nata dosing (weeks 52-96), greater proportions of patients showed recurrent fluid in all treatment arms. Presence of IRC was generally associated with lower VA at baseline, which translated into poorer final VA outcomes. CONCLUSIONS: Fluid resolution in all compartments was consistently greater for aflibercept Q4wks than for aflibercept Q8wks and ranibizumab. At week 52, Q8wks aflibercept-treated eyes were, on average, as dry as or drier than with ranibizumab despite the extended treatment interval. Independent of agent or regimen, preexisting morphologic features of the retina at baseline markedly influenced VA outcomes.

A systematic review of the efficacy and tolerability of hydroxyethylrutosides for improvement of the signs and symptoms of chronic venous insufficiency.

WHAT IS KNOWN AND OBJECTIVE: Rutoside (rutin; quercetin rutinoside) is a glycoside found in various plant products, including apples, citrus fruits and cranberries. Hydroxyethylrutosides (HR) are semisynthetic derivatives sold as standardized products for the treatment of chronic venous insufficiency (CVI). Commercially available products include Relvène(®) (France), Venoruton(®) (Switzerland) and Paroven(®) (United Kingdom). However, the evidence for their efficacy is inconclusive. The aim of this systematic review was to evaluate the evidence of efficacy and tolerability of hydroxyethylrutosides for CVI. METHODS: We searched electronic databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and publisher databases, conference proceedings and references lists for randomized controlled trials published in English and non-English languages. We also performed hand searches for additional trials. We included all trials that assessed the effectiveness of HR for CVI. Comparisons include HR (with or without compression bandaging) vs. placebo (with or without compression bandaging) or HR vs. compression bandaging alone. Two review authors independently selected studies, extracted data and assessed risks of bias in the included trials. RESULTS AND DISCUSSION: The search identified 1474 records. Only 15 trials involving 1643 participants met our inclusion criteria. A meta-analysis based on similar studies that compared HR with placebo showed that HR significantly reduced symptoms of pain (SMD -1·07, 95% CI -1·44 to -0·70), symptoms of heavy legs (OR 0·50; 95% CI 0·28-0·91) and cramps (SMD -1·07, 95% CI -1·45 to -0·69). No serious adverse effect due to HR was reported. WHAT IS NEW AND CONCLUSION: The findings showed that HR produced modest improvements in several symptoms of CVI. However, all the included trials were of limited quality, and therefore, better-quality trials are still required to draw firm conclusions on the usefulness of HR for CVI.

Association analysis of genetic and environmental risk factors in the cuticular drusen subtype of age-related macular degeneration.

PURPOSE: To assess the association of gender, cigarette smoking, body-mass index, and nine genetic risk variants with cuticular drusen (CD), a well recognized subtype of age-related macular degeneration (AMD). METHODS: A total of 757 patients with AMD, including 217 patients with CD, and 553 control individuals were interviewed with a questionnaire and underwent an ophthalmic examination. Venous blood samples were obtained for genomic DNA extraction, and genotyping was performed of single nucleotide polymorphisms previously associated with AMD. Odds ratios were calculated for patients with CD, using unaffected control individuals as a reference. Furthermore, odds ratios in patients with CD were compared to those in patients with "non-CD" AMD. RESULTS: The CD subtype of AMD was significantly associated with current smoking as well as variants in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement factor B/complement component 2 (CFB/C2), complement component 3 (C3), and apolipoprotein E (APOE) genes. In patients with CD, the association with the CFH Y402H risk allele was significantly higher (p=0.022), whereas the association with current smoking was significantly lower (p<0.001) than in the heterogeneous group of patients with "non-CD" AMD. CONCLUSIONS: The AMD subtype of CD was associated with previously identified genetic AMD risk factors. However, the association with the CFH Y402H risk allele appeared to be stronger, whereas the association with smoking was less pronounced when compared to AMD as a whole. This study suggests a more important role for genetic factors than environmental factors in the development of this well defined subtype of AMD. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes, which may be associated with different risk factors and disease mechanisms. Such studies will improve the accuracy of predictive models and the effectiveness of preventive and therapeutic options in AMD.

The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application.

BACKGROUND: Dysregulation of the complement system has been shown to play a major role in the pathogenesis of age-related macular degeneration (AMD). METHODS: The current evidence from human studies derives from immunohistochemical and proteomic studies in donor eyes, genetic association studies, and studies of blood complement protein levels. These lines of evidence are corroborated by in vitro and animal studies. RESULTS: In AMD donor eyes, detection of complement proteins in drusen suggested local inflammatory processes involving the complement system. Moreover, higher levels of complement proteins in the Bruch's membrane/choroid complex could be detected in AMD donor eyes compared to controls. A large number of independent genetic studies have consistently confirmed the association of AMD with risk or protective variants in genes coding for complement proteins, including complement factor H (CFH), CFH-related proteins 1 and 3, factor B/C2, C3 and factor I. Another set of independent studies detected increased levels of complement activation products in plasma of AMD patients, suggesting that AMD may be a systemic disease and the macula a vulnerable anatomic site of minimal resistance to complement activation. Genotype-phenotype correlations, including the impact of genetic variants on disease progression, gene-environment and pharmacogenetic interactions, have been investigated. There is evidence that complement gene variants may be associated with the progression from early to late forms of AMD, whereas they do not appear to play a significant role when late atrophic AMD has already developed. There are indications for an interaction between genetic variants and supplementation and dietary factors. Also, there is some evidence that variants in the CFH gene influence treatment effects in patients with neovascular AMD. CONCLUSIONS: Such data suggest that the complement system may have a significant role for developing new prophylactic and therapeutic interventions in AMD. In fact, several compounds acting on the complement pathway are currently in clinical trials. Therapeutics that modulate the complement system need to balance inhibition with preservation of sufficient functional activity in order to maintain adequate immune responses and tissue homeostasis. Specifically, targeting the dysfunction appears more adequate than a global suppression of complement activation in chronic diseases such as AMD.

A pilot study on the combination treatment of reduced-fluence photodynamic therapy, intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for neovascular age-related macular degeneration.

AIM: To assess the safety and efficacy of the combined treatment of reduced-fluence verteporfin photodynamic therapy (PDT), intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for choroidal neovascularisa- tion (CNV) secondary to age-related macular degeneration (AMD). METHODS: Nineteen patients with subfoveal CNV secondary to AMD were recruited into the trial. All study eyes (n = 19) received a single cycle of reduced-fluence (25 mJ/cm(2)) PDT with verteporfin followed by an intravitreal injection of ranibizumab 0.3 mg/0.05 ml and dexamethasone 200 µg at baseline. Oral minocycline 100 mg daily was started the following day and continued for 3 months. Patients were followed up monthly for 12 months. Repeat intravitreal ranibizumab was given if best-corrected visual acuity (BCVA) deteriorated by >5 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or central retinal thickness (CRT) on ocular coherence tomography increased >100 µm. RESULTS: Eighteen patients completed the 12-month study. Stable vision (loss of ≤15 ETDRS letters) was maintained in 89% eyes (16/18). The mean change in BCVA was -5.0 ± 10.5 ETDRS letters. The mean number of ranibizumab injections was 3.4 (range 2-6). The mean reduction in the CRT was 66.3 µm (±75). CONCLUSION: This open-label clinical trial has demonstrated the safety in terms of adverse effects and maintenance of stable vision of combination treatment with verteporfin, ranibizumab, dexamethasone and minocycline in exudative AMD. However, the outcomes with reduced-fluence PDT combination therapy does not differ significantly with outcomes of clinical trials on combination treatment with standard dose PDT and intravitreal ranibizumab in neovascular AMD.

Computerized model of cost-utility analysis for treatment of age-related macular degeneration.

PURPOSE: To present a computerized model assessing individualized cost utility for current treatments for neovascular age-related macular degeneration (AMD) to enhance discussion regarding treatment options. DESIGN: Case- and eye-specific cost-utility analysis using individual case scenarios. PARTICIPANTS: Visual acuity data from published randomized controlled trials are incorporated into this analysis. METHODS: Computerized model (Microsoft Visual Basic 6.0 programming) to establish preference-based cost-utility analysis in association with individual cost of treatment and blindness for neovascular AMD for both the better and worst seeing eye, with extrapolation of results over a 5-year term. MAIN OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) and cost per QALY gained for comparison of treatments for specific visual acuities. RESULTS: All treatments show an increase in utility in comparison with best supportive care (BSC) if the better-seeing eye is treated. Ranibizumab, using the Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularisation (CNV) with or without Classic CNV Secondary to AMD (PIER) regimen, is the most cost effective at $626 938 per QALY gained for treatment of the better seeing eye. To increase utility value when treating the worst seeing eye, the vision must improve to such a degree that it becomes the better seeing eye. This level of improvement is only possible if there is <9 letters difference between the 2 eyes and treated with ranibizumab. Over 5 years, increasing influence from the cost of blindness results in increasing costs for those treatments unable to stabilize vision. Within 5 years, the cost per QALY for the BSC is greater than all treatments except monthly ranibizumab injections. CONCLUSIONS: Assessment of cost of treatment incorporates both effectiveness of treatment, cost of treatment, and cost of blindness. Cost analysis enables incorporation of these aspects of treatment with the quality of life data to provide a better comparison of treatments over time. This analysis has provided a method for individual analysis and therefore can provide the structure for resource allocation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund.

PURPOSE: To characterize the electrophysiological and histopathological features of a retinal degenerative disease in a colony of miniature longhaired dachshunds known to have a form of progressive retinal atrophy (PRA). METHODS: Serial electroretinograms were recorded from affected homozygous (n = 36) and heterozygous (n = 15) dogs. Morphologic investigations including immunohistochemistry and lectin histochemistry were performed on selected homozygous animals (n = 15). RESULTS: Clinical findings included loss of tapetal hyperreflectivity. The mode of inheritance was autosomal recessive. An early dramatic reduction of cone-specific ERG amplitude with a more modest reduction in rod b-wave amplitude was demonstrated. Progressively, rod specific responses diminished until there were no recordable responses to the ERG stimuli at 40 weeks of age. Morphologic changes confirmed early cone inner and outer segment loss. Other abnormalities included opsin mislocalization and outer nuclear layer thinning due to the subsequent loss of rod photoreceptors. CONCLUSIONS: A novel canine cone-rod dystrophy has been identified.

Classification of diabetic macular oedema using ultra-widefield angiography and implications for response to anti-VEGF therapy.

AIMS: To characterise differential pathogeneses of diabetic macular oedema (DMO) using ultra-widefield fluorescein angiography (UWFA) and evaluate responses to anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: Ninety-nine eyes (73 consecutive patients) with anti-VEGF naïve DMO underwent UWFA and optical coherence tomography, of which 60 with central retinal thickness (CRT) >400 µm received monthly intravitreal ranibizumab injections. Best-corrected visual acuity (BCVA) and CRT were measured at baseline and after three injections. RESULTS: After excluding tractional factors, DMO was categorised into three types based on UWFA: (A) microaneurysm driven (49%), (B) peripheral ischaemia (37%) and (C) neovascularisation (15%). While all three types showed similar mean CRT (p=0.257), types B and C were associated with more diffuse oedema, which extended beyond the 6.0 mm central macula (p=0.0034). Following anti-VEGF treatment, all three types showed improvement in CRT and BCVA, which reached statistical significance for types A and B. A positive correlation was found between the Peripheral Ischaemia Index and improvement in CRT (slope=2.09, R2=0.1169, p=0.0151) but not BCVA (slope=-0.00037, R2=0.001149, p=0.8152). CONCLUSIONS: UWFA facilitates the detection of peripheral ischaemia, which is associated with a significant proportion of DMO. While this group of DMO responded well to anti-VEGF therapy, it remains to be determined whether addressing the peripheral ischaemia may reduce recurrence.

Autofluorescence characteristics of early, atrophic, and high-risk fellow eyes in age-related macular degeneration.

PURPOSE: To assess the relationships of drusen, pigment, and focally increased autofluorescence (FIAF) and the reticular pattern of hypoautofluorescence, to distinguish the combined photographic and AF characteristics of early, atrophic, and high-risk fellow eyes in AMD. METHODS: In a retrospective interinstitutional clinical study, AF and color photograph pairs of 221 eyes were examined: 166 eyes of 83 patients with bilateral large, soft drusen, with and without geographic atrophy (GA), and 55 fellow eyes of 55 patients with unilateral choroidal neovascularization (CNV). Forty-two eyes (one eye from each of 42 patients with early or atrophic AMD) were divided into four groups: 14 with drusen only, 9 with drusen and pigment abnormalities, 11 fellow eyes of patients with unilateral GA, and 8 eyes of patients with bilateral GA (acronyms for the groups: D-D, D-Pig, D-GA and GA-GA, respectively). The 55 fellow eyes of patients with CNV were divided into three groups: 19 eyes with no FIAF (CNV-0), 16 with FIAF without reticular AF (CNV-1), and 20 eyes with reticular AF and/or pseudodrusen (CNV-R). Image pairs of eyes with FIAF were registered, and drusen, pigment, and FIAF were segmented using automated background leveling and thresholding. All 221 eyes were surveyed for reticular AF and reticular pseudodrusen. The main outcome measures were (1) the fraction and relative probability of FIAF colocalizing with drusen and pigment and (2) the presence or absence of reticular AF and reticular pseudodrusen. RESULTS: The mean fractions of FIAF that colocalized with large drusen were: D-D group, 0.46 +/- 0.21; D-Pig group, 0.42 +/- 0.29; D-GA group, 0.13 +/- 0.09; and GA-GA group, 0.11 +/- 0.12. Comparisons between groups showed significant differences when comparing either the D-D group or the D-Pig group with either the D-GA group or the GA-GA group (P between 0.0001 and 0.015), whereas other comparisons were nonsignificant (Mann-Whitney rank sum test). The mean probabilities of FIAF colocalizing with large drusen relative to chance (1.0) were: D-D group, 4.7 +/- 2.5; D-Pig group, 4.3 +/- 2.3; D-GA group, 1.4 +/- 0.8; and GA-GA group, 1.8 +/- 1.3, with similar significant differences as for the colocalization fractions. The mean probability of FIAF colocalizing with small to intermediate drusen in the D-D group was 1.5 +/- 1.3, which was not significantly different from chance. In the D-Pig group, the median probability of FIAF colocalizing with pigment abnormalities was 10.0 (range, 1.1-51.0). The AF patterns in 15 of 19 eyes in the CNV-0 group were normal; the remainder had nonreticular hypoautofluorescence only. In the CNV-1 group, the relations of FIAF with drusen and pigment were similar to those in the early AMD groups. CNV-R comprised 20 of 55 eyes in the CNV group, but reticular autofluorescence and/or pseudodrusen were found in only 14 of 166 eyes of the early and atrophic groups. Of the 34 total eyes with reticular AF or pseudodrusen, 28 had both, 4 had reticular AF only, and 2 had reticular pseudodrusen only. CONCLUSIONS: There are clear relationships between AF patterns and clinical AMD status. In early AMD, FIAF's colocalization with large, soft drusen and hyperpigmentation is several times greater than chance, suggesting linked disease processes. In advanced atrophic AMD, FIAF is found mostly adjacent to drusen and GA, suggesting that dispersal of drusen-associated lipofuscin is a marker of atrophic disease progression. In the neovascular case, a large group of fellow eyes have no FIAF abnormalities, suggesting that lipofuscin is not a major determinant of CNV. However, reticular hypoautofluorescence, consistent with widespread inflammatory damage to the RPE, appears to be a highly sensitive imaging marker for the disease that determines reticular pseudodrusen and is strongly associated with CNV.

An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration.

Age-related macular degeneration (AMD) is a blinding disease that afflicts millions of adults in the Western world. Although it has been proposed that a threshold event occurs during normal aging which leads to AMD, the sequelae of biochemical, cellular, and/or molecular events leading to the development of AMD are poorly understood. Although available data provide strong evidence that a significant proportion of AMD has a genetic basis, no gene(s) has yet been identified that causes a significant proportion of AMD. Moreover, no major molecular pathways involved in the etiology of this disease have been elucidated.Drusen, pathological deposits that form between the retinal pigmented epithelium (RPE) and Bruch's membrane, are significant risk factors for the development of AMD. In our view, the development of testable new hypotheses of drusen origins has been hindered significantly by the absence of a comprehensive profile of their molecular composition. In this review, we describe an integrated ultrastructural, histochemical, molecular biological, and biochemical approach to identify specific molecular pathways associated with drusen biogenesis. The implicit assumption underlying these recent investigations has been that a thorough understanding of the composition of drusen and source(s) of drusen-associated material is likely to provide fresh insight into the pathobiology underlying AMD. Significantly, these studies have revealed that proteins associated with inflammation and immune-mediated processes are prevalent among drusen-associated constituents. Transcripts that encode a number of these molecules have been detected in retinal, RPE, and choroidal cells. These data have also lead to the observations that dendritic cells, potent antigen-presenting cells, are intimately associated with drusen development and that complement activation is a key pathway that is active both within drusen and along the RPE-choroid interface. We propose herein a unifying hypothesis of drusen biogenesis that attempts to incorporate a large body of new and previously published structural, histochemical, and molecular data pertaining to drusen composition and development. This theory is put forth with the acknowledgment that numerous AMD genotypes may exist. Thus, only some aspects of the proposed hypothesis may be involved in any given AMD genotype. Importantly, this hypothesis invokes, for the first time, the potential for a direct role of cell- and immune-mediated processes in drusen biogenesis. We acknowledge that the proposed hypothesis clearly represents a paradigm shift in our conceptualization pertaining to pathways that participate in the development of drusen and age-related macular degeneration. It is our hope that other investigators will test, validate and/or refute various aspects of this hypothesis, and in so doing, increase our overall understanding of the biological pathways associated with early AMD.

In vivo demonstration of the anatomic differences between classic and occult choroidal neovascularization using optical coherence tomography.

PURPOSE: To determine architectural differences between classic and occult choroidal neovascularization (CNV) in vivo. DESIGN: Prospective observational case series. METHODS: Twenty-two patients with acute CNV underwent fluorescein angiography and optical coherence tomography (OCT), which were analyzed by separate blinded observers. RESULTS: In 87.5% of angiographically labeled "classic" CNV a discreet subretinal lesion corresponding to the neovascular complex could be seen above and separate to the retinal pigment epithelium on OCT. This was found in only 13.3% of "occult" CNV. CONCLUSION: With the latest commercially available OCT equipment it is now possible to confirm in vivo the previously proposed anatomic differences between fluorescein angiographically labeled classic and occult CNV. Classic CNV appear to grow predominantly in the subretinal space, whereas the majority of occult lesions do not. Optical coherence tomography features of CNV may correlate with response to photodynamic therapy or angiostatic treatments, as well as predicting the success of surgical removal.

An interinstitutional comparative study and validation of computer aided drusen quantification.

AIMS: To assess the portability and clinical applicability of a software program based on Photoshop (Adobe Systems Inc, San Jose, CA, USA) for digital drusen quantification. METHODS: Independent graders from the Digital Fundus Photo Reading Center of Columbia University and King's College Hospital used macular background levelling software to quantify the percentage of drusen in the central and middle Wisconsin subfields. 100 images of consecutive patients with choroidal neovascularisation in one eye and significant drusen in the other eye were analysed to determine suitability, and 10 were chosen for assessment by this software. RESULTS: Of the 10 images used in the interinstitutional validation, the random effects ANOVA for the central and middle subfields showed a high degree of interobserver agreement. The ICC for interobserver reliability was 0.83 (95% CI: 67 to 95) for the central subfield and 0.84 (95% CI: 69 to 99) for the middle subfield. Overall agreement with the manual grading results was good and the within patient coefficient of variation was about 20% for all the pairwise comparisons between observers and the manual stereo gradings. Of the 100 images used to assess practical applicability of the software, 79 were suitable for semiautomated analysis. 13 had extensive mixed retinal pigment epithelial (RPE) changes limiting drusen identification, five had a significant number of reticular drusen, which are poorly identified by the software, and three had multiple small areas of RPE atrophy, which are difficult to distinguish from drusen. CONCLUSIONS: The software was successfully used by two institutions demonstrating portability, with good correlation between graders and to the manual stereo grading. Digital drusen quantification was possible in 79% of the images analysed.

Can Novel Treatment of Age-Related Macular Degeneration Be Developed by Better Understanding of Sorsby's Fundus Dystrophy.

Sorsby's Fundus Dystrophy (SFD) is a rare autosomal dominant maculopathy that shares many clinical features with Age-Related Macular Degeneration (AMD). It is caused by a mutation in a single gene, TIMP-3, which accumulates in Bruch's membrane (BM). BM thickening and TIMP-3 accumulation can also be found in AMD. From our understanding of the pathophysiology of SFD we hypothesize that BM thickening could be responsible for making the elastic layer vulnerable to invasion by choriocapillaris, thereby leading to choroidal neovascularization in some cases of AMD, whilst in others it could deprive the retinal pigment epithelium of its blood supply, thereby causing geographic atrophy.

Optomap ultrawide field imaging identifies additional retinal abnormalities in patients with diabetic retinopathy.

PURPOSE: To compare diabetic retinopathy (DR) severity grading between Optomap ultrawide field scanning laser ophthalmoscope (UWFSLO) 200° images and an Early Treatment Diabetic Retinopathy Study (ETDRS) seven-standard field view. METHODS: Optomap UWFSLO images (total: 266) were retrospectively selected for evidence of DR from a database of eye clinic attendees. The Optomap UWFSLO images were graded for DR severity by two masked assessors. An ETDRS seven-field mask was overlaid on the Optomap UWFSLO images, and the DR grade was assessed for the region inside the mask. Any interassessor discrepancies were adjudicated by a senior retinal specialist. Kappa agreement levels were used for statistical analysis. RESULTS: Fifty images (19%) (P<0.001) were assigned a higher DR level in the Optomap UWFSLO view compared to the ETDRS seven-field view, which resulted in 40 images (15%) (P<0.001) receiving a higher DR severity grade. DR severity grades in the ETDRS seven-field view compared with the Optomap UWFSLO view were identical in 85% (226) of the images and within one severity level in 100% (266) of the images. Agreement between the two views was substantial: unweighted κ was 0.74±0.04 (95% confidence interval: 0.67-0.81) and weighted κ was 0.80±0.03 (95% confidence interval: 0.74-0.86). CONCLUSION: Compared to the ETDRS seven-field view, a significant minority of patients are diagnosed with more severe DR when using the Optomap UWFSLO view. The clinical significance of additional peripheral lesions requires evaluation in future prospective studies using large cohorts.

Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat.

The genetically epilepsy-prone rat is an animal model of inherited generalised tonic-clonic epilepsy that shows abnormal susceptibility to audiogenic seizures and a lowered threshold to a variety of seizure-inducing stimuli. Recent studies suggest a crucial role for glutamate and GABA transporters in epileptogenesis and seizure propagation. The present study examines the levels of expression of the messenger RNAs encoding the glial and neuronal glutamate transporters, GLT-1 and EAAC-1, and the neuronal GABA transporter, GAT-1, in paired male genetically epileptic-prone rats and Sprague Dawley control rats using the technique of in situ hybridization. In a parallel study, semiquantitative immunoblotting was used to assess GLT-1 and EAAC-1 protein levels in similarly paired animals. Animals were assessed for susceptibility to audiogenic seizures on six occasions, and killed seven days following the last audiogenic stimulus exposure. Rat brains were processed for in situ hybridization with radioactive 35S-labelled oligonucleotide probes (EAAC-1 and GAT-1), 35S-labelled riboprobes (GLT-1), and Fluorescein-labelled riboprobes (GLT-1 and GAT-1) or processed for immunoblotting using subtype-specific antibodies for GLT-1 and EAAC-1. Semiquantitative analyses were carried out on X-ray film autoradiograms in several brain regions for both in situ hybridization and immunoblotting studies. Reductions in GAT-1 messenger RNA were found in genetically epileptic-prone rats in all brain regions examined (-8 to -24% compared to control). Similar reductions in GLT-1 messenger RNA expression levels were seen in cortex, striatum, and CA1 (-8 to -12%) of genetically epileptic-prone rats; the largest reduction observed was in the inferior colliculus (-20%). There was a tendency for a reduced expression of EAAC-1 messenger RNA in most regions of the genetically epileptic-prone rat brain although this reached statistical significance only in the striatum (-12%). In contrast, no significant differences in GLT-1 and EAAC-1 protein between genetically epileptic-prone rats and control animals were observed in any region examined, although there was a tendency to follow the changes seen with the corresponding messenger RNAs. These results show differences in the messenger RNA expression levels of three crucial amino acid transporters. For the two glutamate transporters, GLT-1 and EAAC-1, differences in messenger RNA levels are not reflected or are only partially reflected in the expression of the corresponding proteins.

TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy.

PURPOSE: Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP-3) gene have previously been identified in patients with Sorsby's fundus dystrophy (SFD). We evaluated the ocular distribution of TIMP-3 and other extracellular constituents in SFD. METHODS: The eyes of an SFD donor with a confirmed TIMP-3 mutation were examined using histologic techniques demonstrating connective tissue, calcium, and lipid. Immunohistochemical analyses were performed using antibodies against TIMP-3, collagen type IV, V, and VI, laminin, fibronectin, elastin, and fibrillin. Electron microscopy also was used. RESULTS: A subretinal pigment epithelium (sub-RPE) deposit similar to that previously described was seen. A morphologically similar but different deposit was present internal to the nonpigmented ciliary epithelium (NPCE). Both deposits contained collagens, elastin, glycosaminoglycans, lipids, and calcium. Immunolabeling of TIMP-3 was found in the basement membrane of the NPCE, Bruch's membrane, and choroidal vessels in normal control subjects. In SFD, immunolabeling of TIMP-3 also was present in the sub-RPE deposit and in the inner portion of the ciliary body deposit. TIMP-3 immunoreactivity was more extensive in the SFD eye. The pattern of elastin immunoreactivity was remarkably similar to that of TIMP-3. Electron microscopy revealed a morphologically altered elastic layer of the Bruch's membrane. CONCLUSIONS: Sub-RPE TIMP-3 immunoreactivity appears more extensive in SFD than in control subjects. There is also a correspondence between TIMP-3 and elastin immunoreactivies, which invites speculation as to a link between the SFD TIMP-3 mutation and altered elastin processing. The accumulation of abnormal material in SFD is more widespread than previously reported. In view of this, SFD might be better termed Sorsby's ocular epitheliopathy.