There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we ...evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.
Money is changing and this may mean a new world order. David Birch sets out the economic and technological imperatives concerning digital money, and discusses its potential impact. Tensions will ...inevitably arise: between old and new, between public and private, and, most importantly, between East and West. This book contributes to the debate that we must have to shape the International Monetary and Financial System of the near future.
IMPORTANCE: Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. OBJECTIVE: To describe the yearly progression rate of atrophic lesions in the ...retrospective Progression of Stargardt Disease study. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. EXPOSURES: Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable. MAIN OUTCOMES AND MEASURES: Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence. RESULTS: A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean SD age, 29.9 14.7 years; mean SD age of onset of symptoms, 21.9 13.3 years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean SD age, 33.0 15.1 years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion. CONCLUSIONS AND RELEVANCE: In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.
To summarize the recent literature describing the application of modern technologies in the study of patients with geographic atrophy (GA) secondary to age-related macular degeneration.
Review of the ...literature describing the terms and definitions used to describe GA, imaging modalities used to capture and measure GA, and the tests of visual function and functional deficits that occur in patients with GA.
In this paper, we describe the evolution of the definitions used to describe GA. We compare imaging modalities used in the characterization of GA, report on the sensitivity and specificity of the techniques where data exist, and describe the correlations between these various modes of capturing the presence of GA. We review the functional tests that have been used in patients with GA, and critically examine their ability to detect and quantify visual deficits.
Ophthalmologists and retina specialists now have a wide range of assessments available for the functional and anatomic characterization of GA in patients with age-related macular degeneration. To date, studies have been limited by their unimodal approach, and we recommend that future studies of GA use multimodal imaging. We also suggest strategies for the optimal functional testing of patients with GA.
Fluorescence-based glucose sensors Pickup, John C.; Hussain, Faeiza; Evans, Nicholas D. ...
Biosensors & bioelectronics,
06/2005, Letnik:
20, Številka:
12
Journal Article
Recenzirano
There is an urgent need to develop technology for continuous in vivo glucose monitoring in subjects with diabetes mellitus. Problems with existing devices based on electrochemistry have encouraged ...alternative approaches to glucose sensing in recent years, and those based on fluorescence intensity and lifetime have special advantages, including sensitivity and the potential for non-invasive measurement when near-infrared light is used. Several receptors have been employed to detect glucose in fluorescence sensors, and these include the lectin concanavalin A (Con A), enzymes such as glucose oxidase, glucose dehydrogenase and hexokinase/glucokinase, bacterial glucose-binding protein, and boronic acid derivatives (which bind the diols of sugars). Techniques include measuring changes in fluorescence resonance energy transfer (FRET) between a fluorescent donor and an acceptor either within a protein which undergoes glucose-induced changes in conformation or because of competitive displacement; measurement of glucose-induced changes in intrinsic fluorescence of enzymes (e.g. due to tryptophan residues in hexokinase) or extrinsic fluorophores (e.g. using environmentally sensitive fluorophores to signal protein conformation). Non-invasive glucose monitoring can be accomplished by measurement of cell autofluorescence due to NAD(P)H, and fluorescent markers of mitochondrial metabolism can signal changes in extracellular glucose concentration. Here we review the principles of operation, context and current status of the various approaches to fluorescence-based glucose sensing.
IMPORTANCE Determining the annual rate of change in the width of the inner segment ellipsoid zone (EZ; ie, inner/outer segment border) in the context of short-term variability should allow us to ...better understand the value of this measure for future treatment trials in X-linked retinitis pigmentosa (XLRP). OBJECTIVES To identify the width of the central region showing an EZ and to determine the short-term repeat variability and the annual rate of change in the width of the EZ from spectral-domain optical coherence tomography (SD-OCT) measures in RP. DESIGN Patients with recessive or simplex RP (age range, 8-65 years; mean age, 40.5 years) underwent scanning twice on the same day to evaluate test-retest variability. Patients with XLRP (age range, 8-27 years; mean age, 15.2 years) from a larger group participating in an ongoing double-blind treatment trial (docosahexaenoic acid vs placebo; clinicaltrials.gov NCT00100230) underwent spectral-domain optical coherence tomography line scanning across the horizontal meridian at 3 yearly intervals. SETTING Research center specializing in medical retina. PARTICIPANTS Forty-eight patients with RP, including 20 with recessive or simplex RP and 28 with XLRP, and 23 healthy control subjects. MAIN OUTCOME AND MEASURE Widths of the EZ calculated and compared among the 3 annual visits. RESULTS Test-retest differences were normally distributed, and the magnitude of the difference was independent of mean EZ width. The mean (SD) for test-retest differences in EZ width was 0.08° (0.22°) (range, −0.30° to 0.60°). Thus, 95% of all test-retest differences fall within ±0.43° (124 μm). Of the 28 patients with XLRP, 27 showed a significant decrease in EZ width after 2 years. Patients with XLRP showed a mean annual decrease in EZ width of 0.86° (248 μm, or 7%). CONCLUSIONS AND RELEVANCE The mean rate of decline in EZ width (7%) translates into a mean rate of change of 13% for the equivalent area of functioning retina. This rate of change is consistent with that reported for visual fields and full-field electroretinograms. Unlike visual fields and electroretinograms, however, the repeat variability is less than the annual rate of change. These results support the validity of EZ width as an outcome measure in prospective clinical trials in RP.
The aim of this retrospective cohort study was to obtain three-dimensional (3D) photoreceptor outer segment (OS) metrics measurements with the assistance of a deep learning model (DLM) and to ...evaluate the longitudinal change in OS metrics and associated factors in retinitis pigmentosa GTPase regulator (RPGR) X-linked retinitis pigmentosa (XLRP).
The study included 34 male patients with RPGR-associated XLRP who had preserved ellipsoid zone (EZ) within their spectral-domain optical coherence tomography volume scans and an approximate 2-year or longer follow-up. Volume scans were segmented using a DLM with manual correction for EZ and apical retinal pigment epithelium (RPE). OS metrics were measured from 3D EZ-RPE layers of volume scans. Linear mixed-effects models were used to calculate the rate of change in OS metrics and the associated factors, including baseline age, baseline OS metrics, and follow-up duration.
The mean (standard deviation) of progression rates were -0.28 (0.43) µm/y, -0.73 (0.61) mm2/y, and -0.014 (0.012) mm3/y for OS thickness, EZ area, and OS volume, respectively. In multivariable analysis, the progression rates of EZ area and OS volume were strongly associated with their baseline values, with faster decline in eyes with larger baseline values (P ≤ 0.003), and nonlinearly associated with the baseline age (P ≤ 0.003). OS thickness decline was not associated with its baseline value (P = 0.32).
These results provide evidence to support using OS metrics as biomarkers to assess the progression of XLRP and as the outcome measures of clinical trials. Given that their progression rates are dependent on their baseline values, the baseline EZ area and OS volume should be considered in the design and statistical analysis of future clinical trials. Deep learning may provide a useful tool to reduce the burden of human graders to analyze OCT scan images and to facilitate the assessment of disease progression and treatment trials for retinitis pigmentosa.
A non‐invasive intrinsic fluorescence sensing of the early stages of Alzheimer's beta amyloid peptide aggregation in the presence of copper ions is reported. By using time‐resolved fluorescence ...techniques the formation of beta amyloid‐copper complexes and the accelerated peptide aggregation are demonstrated. The shifts in the emission spectral peaks indicate that the peptides exhibit different aggregation pathways than in the absence of copper.
Non‐invasive intrinsic fluorescence sensing of the early stages of Alzheimer's beta amyloid peptide aggregation in the presence of copper ions is reported.
Although over 150 unique mutations affecting the coding sequence of CHM have been identified in patients with the X‐linked chorioretinal disease choroideremia (CHM), no regulatory mutations have been ...reported, and indeed the promoter has not been defined. Here, we describe two independent families affected by CHM bearing a mutation outside the gene's coding region at position c.‐98: C>A and C>T, which segregated with the disease. The male proband of family 1 was found to lack CHM mRNA and its gene product Rab escort protein 1, whereas whole‐genome sequencing of an affected male in family 2 excluded the involvement of any other known retinal genes. Both mutations abrogated luciferase activity when inserted into a reporter construct, and by further employing the luciferase reporter system to assay sequences 5′ to the gene, we identified the CHM promoter as the region encompassing nucleotides c.‐119 to c.‐76. These findings suggest that the CHM promoter region should be examined in patients with CHM who lack coding sequence mutations, and reveals, for the first time, features of the gene's regulation.
Mutations in the previously unidentified CHM promoter result in choroideremia (CHM), characterized by progressive chorioretinal atrophy and vision loss. We report the first two mutations outside the gene's coding sequence causing CHM, at position c.−98: C>A and C>T. Both mutations abrogated luciferase activity in a promoter reporter construct, while a cell line from a patient bearing the mutation failed to express CHM mRNA. Additionally, full genome sequencing in a second patient excluded the involvement of any other known retinal gene.
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