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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23813号 / 医博第4859号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中本 裕士, 教授 花川 隆, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Yes / Purpose: To demonstrate methods that enable visual field sensitivities to be compared with normative data without restriction to a fixed test pattern. Methods: Healthy participants (n = 60, age 19–50) undertook microperimetry (MAIA-2) using 237 spatially dense locations up to 13° eccentricity. Surfaces were fit to the mean, variance, and 5th percentile sensitivities. Goodness-of-fit was assessed by refitting the surfaces 1000 times to the dataset and comparing estimated and measured sensitivities at 50 randomly excluded locations. A leave-one-out method was used to compare individual data with the 5th percentile surface. We also considered cases with unknown fovea location by adding error sampled from the distribution of relative fovea–optic disc positions to the test locations and comparing shifted data to the fixed surface. Results: Root mean square (RMS) difference between estimated and measured sensitivities were less than 0.5 dB and less than 1.0 dB for the mean and 5th percentile surfaces, respectively. Root mean square differences were greater for the variance surface, median 1.4 dB, range 0.8 to 2.7 dB. Across all participants 3.9% (interquartile range, 1.8–8.9%) of sensitivities fell beneath the 5th percentile surface, close to the expected 5%. Positional error added to the test grid altered the number of locations falling beneath the 5th percentile surface by less than 1.3% in 95% of participants. Conclusions: Spatial interpolation of normative data enables comparison of sensitivity measurements from varied visual field locations. Conventional indices and probability maps familiar from standard automated perimetry can be produced. These methods may enhance the clinical use of microperimetry, especially in cases of nonfoveal fixation.

Yes / Fundus-controlled perimetry (FCP, also called 'microperimetry') allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.

No / PURPOSE. Previous studies suggest that optimal reading speed is unaffected by cataract, yet is significantly reduced in age-related macular degeneration (ARMD ). This raises the question of whether a reading speed test could be developed to assess potential vision after cataract surgery. METHODS. Nineteen subjects with cataract, 15 with ARMD, and 13 control subjects with normal, healthy eyes read Bailey-Lovie word charts aloud, and subsequently, critical print size and optimal reading speed were calculated. Measurements were also taken with the charts in reversed-contrast polarity and after pupillary dilation. RESULTS. Although the subjects with cataract had reduced word acuity and increased critical print size, optimal reading speed was similar to that of the control group at a mean of approximately 100 wpm. Optimal reading speed in the subjects with ARMD was substantially worse (mean of 39 wpm). Reversing the contrast polarity of the charts slightly increased the word acuity and optimal reading speed of the subjects with cataract. CONCLUSIONS. The results suggest that optimal reading speed would be useful as a potential-vision test. The proposed test would use text size of at least 1.32 degrees (1.2 log minimum angle of resolution [logMAR]), and pupil dilation would be unnecessary. A reading test with black letters on a white background would be adequate, because charts with reversed-contrast polarity made minimal difference in reading speed.

Åldersrelaterad makuladegeneration (AMD) är en kronisk ögonsjukdom och är den vanligaste orsaken till irreversibel synnedsättning hos äldre personer i den industriella världen. Bakomliggande orsaker kan vara både genetiska och miljömässiga varför prevention och behandling av ögonsjukdomar kan öka livskvaliteten samt minska nedsatt syn och de funktionshinder som synnedsättning medför. Syftet med studien var att belysa ögonsjuksköterskans hälsofrämjande arbete med patienter som har åldersrelaterad makuladegeneration. Denna integrativa litteraturstudie visade att kunskapsnivån om AMD var låg både hos den allmänna befolkningen och patienter. Även patienter med allvarlig synnedsättning på grund av en eller flera ögonsjukdomar var omedvetna om sin diagnos. Patienter med AMD upplevde att de inte fick tillräckligt med information om sjukdomen, riskfaktorer, undersökningar och vilka behandlingar som fanns. Att drabbas av AMD innebar en stor påverkan på patienternas livskvalitet. Det visade sig att det fanns ett starkt samband mellan förlust av synfunktionen och symtom på depression. Ingen av studierna var från Sverige eller belyste svenska förhållanden men belyser vikten av att hälsofrämjande arbete och ökad medvetenhet kring kroniska ögonsjukdomar och dess riskfaktorer är mycket viktigt. Det vore av stort intresse att undersöka de svenska förhållandena som jämförelse. / Age-related macular degeneration (AMD) is a chronic eye disease and is the most common cause of irreversible vision loss amongst elderly people within the industrial world. Underlying causes can be both genetical and environmental, prevention and treatment of AMD can increase quality of life and reduce visual impairment and all dysfunctionalities related to it. The aim of this study was to highlight ophthalmic nurses' health promoting work with patients with age-related macular degeneration. This integrative literature review showed that the level of awareness of AMD was low among both the general population and patients. Even patients with severe vision loss due to one or several eye diseases was unaware of their diagnosis. Patients with AMD felt that they were not given enough information about the disease, the risk factors, available health examinations and what possible treatments were available. To be affected with AMD entails a significant negative effect on patients quality of life. It was shown that there was a strong connection between vision loss and symptoms of depression. None of the studies were from Sweden or highlighted the Swedish conditions but highlights the importance of health promotion, awareness about chronic eye disease and its risk factors as very important. It would be of great interest to investigate the Swedish conditions for comparison.

The plasma protein complement factor H (fH, 155 kDa) regulates the activity of the alternative pathway of complement activation. Factor H is monomeric, and its 20 CCP modules are arranged in a predominantly elongated conformation, joined by linking sequences that vary in length, with the longest linkers occurring in the central portion of the molecule. CCP modules 1 through 4 of fH host its capacity to act as a cofactor for fI-mediated proteolytic degradation of C3b and its ability to accelerate the decay of the C3 convertase, C3bBb, thereby regulating the so-called tick-over activation of the alternative pathway. Mutations in this part of fH might compromise its function and lead to underregulation of the alternative pathway. It is hypothesized that this can cause predisposition to diseases such as atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD). In the current work, the known disease-associated mutations R53H and R78G were compared to wild-type in terms of fluid-phase cofactor assays, C3b-binding affinity and the ability to accelerate the decay of the convertase. In addition, the protective variant, I62, was also inspected because its protective role might be explained by an increased regulatory activity. The second, linked, aim of this project was to employ Forster resonance energy transfer (FRET) to study the link between conformation and function in fH. FRET is valuable for obtaining long-distance restraints up to a maximum of 100 °A and is therefore particularly useful for inferring domain orientations within multidomain proteins. This approach to measure long-range inter- and intramolecular distances is a convenient way to complement NMR-based structural investigations, which rely on short-range restraints. It is also a valuable complement to X-ray crystallography since it is a solution technique that can be conducted under physiological conditions. By using site-directed mutagenesis in the current work, free cysteines were introduced into CCP modules 1-4 at strategic points, which were then used for attachment of fluorescent tags. C3 possesses an internal thioester which can be labelled with a fluorophore upon activation to C3b. Intermolecular FRET measurements were thus undertaken to gain information about the interaction between the two proteins that is crucial for understanding functional activity. The CCP modules in the centre of fH may be responsible for introducing a bend into fH that brings the N-teminus close to the C-terminus (the latter is important for host versus non-host discrimination) joined by the longest linkers occurring in the whole molecule. This coincidence of two relatively small CCP modules, 12 and 13, with the highest number of eight amino acids between them, is hypothesised to reflect some unique architectural features. To explore the structural details of this portion of fH by FRET, single-labelled cysteine mutants were further modifed to provide a recognition site for transglutaminase (TGase), which can be enzymatically labeled with a second fluorophore. This stoichiometrically-labelled protein was used for intramolecular FRET studies.

The aims of this study were to analyse known and potential biomarkers of common and genetically complex human disorders and to identify genetic and environmental variation associated with plasma biomarker concentrations. Two groups of protein biomarkers were analysed. First, plasma complement factor H (CFH) was selected as a potential biomarker for age-related macular degeneration (AMD), since common variants in the CFH gene show strong association with this disorder. Secondly, two isoforms of amyloid-β (Aβ40 and Aβ42) were selected as biomarkers for Alzheimer disease (AD) since Aβ deposits are major constituents of the amyloid plaques characteristic of this disorder. Physiological and anthropometric measurements and samples of human and genomic DNA were collected from a population sample of 1,021 individuals from the Croatian island of Vis. Quantitative determination of plasma Aβ40 and Aβ42 concentrations was performed using enzyme-linked immunosorbent assays. Heritabilities and significant covariate effects were estimated for each trait in the Croatian data set. Genome-wide linkage and association analyses were conducted for the biomarker traits. A novel finding was the genome-wide significant association between a CFH and several polymorphisms close to and within the CFH gene. The strongest association was with an intronic SNP within CFH, which explained 28% of the total trait variance (P < 10-50). The association was also replicated in a Dutch sample set. A SNP haplotype was identified which accounted for a higher proportion of the phenotypic variance. Conditional haplotype analysis showed that the effect of this haplotype on plasma CFH concentration was independent of the CFH Y402H variant, and significantly stronger than a deletion of the adjacent CFHR3/CFHR1 which was already known to affect AMD susceptibility. Genetic analysis of 382 AMD cases and 201 controls was consistent with the CFH Y402H variant being the strongest AMD susceptibility locus. Variation in plasma CFH concentration was found to explain up to 1.8% of the variation in susceptibility to AMD with an odds 2.1 (95% C.I. 1.3-3.4, P = 0.003). SNPs that were strongly associated with a CFH concentration also influenced AMD susceptibility (P < 0.05) independently of the CFH Y402H polymorphism. Functional analysis of genomic regions associated with plasma CFH is needed to identify the causal variants. Associations were observed between plasma Aβ40 concentration and several novel candidate loci, spanning regions of approximately 0.2 Mb, on chromosomes 9 and X. Similarly, novel associations with plasma Aβ42 were found in several regions, each spanning 0.2-0.4 Mb, on chromosomes 2, 5, 9, 15 and 20. The proportion of the phenotypic variance in plasma Aβ42 explained by these putative associations ranged between 1.8 and 2.8%. However, none of the associated SNPs was significant after correction for multiple testing, therefore replication is required. Finally, attempts were made to identify and quantitate new protein biomarkers of disease in human plasma using mass spectrometry. Development and optimisation of techniques was initially undertaken to deplete high-abundance plasma proteins and improve signal:noise ratio. This allowed the assessment of downstream proteomic approaches including MALDI-TOF mass spectrometry (MS), capillary electrophoresis (CE) and ion exchange chromatography (IEC), each with the potential for large-scale quantitation of plasma proteins. Although the analysis of single protein analytes, using CE and IEC proved promising, the results highlighted the difficulty associated with MALDI-TOF and protein ionisation techniques in analysing complex mixtures such as plasma.

In patients with age-related macular degeneration, a monolayer of cells in the eyes called retinal pigment epithelium differ from healthy ones in morphology. It is therefore important to quantify the morphological changes, which will help us better understand the physiology, disease progression and classification. Classification of the RPE morphometry has been accomplished with whole tissue data. In this work, we focused on the spatial aspect of RPE morphometric analysis. We used the second-order spatial analysis to reveal the distinct patterns of cell clustering between normal and diseased eyes for both simulated and experimental human RPE data. We classified the mouse genotype and age by the k-Nearest Neighbors algorithm. Radially aligned regions showed different classification power for several cell shape variables. Our proposed methods provide a useful addition to classification and prognosis of eye disease noninvasively.