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Dejavniki, ki vplivajo na klinično sliko bolnikov s patogeno različico p.G90D gena za rodopsin

Izhodišče: Patogene različice v genu za rodopsin (RHO) največkrat povzročajo različne oblike pigmentne retinopatije (RP), ki je napredujoča degeneracija mrežnice, redkeje pa kongenitalno stacionarno nočno slepoto (CSNB). Do sedaj je bilo predpostavljeno, da posamezna različica povzroča bodisi eno ali drugo klinično sliko (npr. p.G90D CSNB), z redkimi izjemami (npr. p.E113K). V nekaterih raziskavah so pokazali, da lahko jemanje vitamina A upočasni napredovanje RP, vendar zdravljenje z vitaminom A ni sprejeto v klinični praksi. Namen: Ugotoviti ali lahko različica p.G90D poleg CSNB povzroča tudi druge klinične slike in ali obstajajo dejavniki, ki so s tem povezani. Metode: V prospektivni raziskavi smo pregledali vse znane bolnike s potrjeno patogeno različico p.G90D v RHO in vse njihove družinske člane, ki so poročali o nočni slepoti, skupaj 19 bolnikov iz treh družin (13 moških in 6 ženskmediana 41 let, razpon 8 – 71). Opravili so razširjen oftalmološki pregled, ki je vključeval preiskave vidne funkcije (vključno z elektroretinografijo) in slikovne preiskave (avtofluorescenco očesnega ozadja in optično koherentno tomografijo). Bolniki so izpolnili vprašalnik o pridruženih boleznih in življenjskemu sloguiz vzorca venske krvi smo določili serumsko koncentracijo vitamina A. Patogena različica p.G90D je bila potrjena z uporabo sekvenciranja nove generacije ali Sangerjevega sekvenciranja. Rezultati: Bolniki so imeli bodisi nočno slepoto brez strukturne okvare (NBWD) (26 %) klasično RP (48 %), pericentralno RP (5 %) ali sektorsko RP (21 %). Bolniki z NBWD so bili mlajši od ostalih, vendar razlika ni bila statistično značilna. Pridužene bolezni so navajali izključno bolniki s klasično in sektorsko RP (v 75 % in v 56 %), ki pa so bili tudi starejši. Med bolniki starimi 40 let ali več, so imeli tisti z blažjo klinično sliko (NBWD, sektorska RP) statistično značilno višjo koncentracijo vitamina A kot tisti z večjo strukturno okvaro (klasična RP, pericentralna RP) (mediana 3,0 vs. 2,0 μmol/L, Mann-Whitneyev test, p < 0,05). Zaključki: V nasprotju z dosedanjimi raziskavami patogena različica p.G90D poleg disfunkcije paličnic (CSNB oz. NBWD) povzroča tudi različne oblike distrofije mrežnice (klasična RP, pericentralna RP in sektorska RP). Taka fenotipska raznolikost je posebnost med ostalimi več kot 200 različicami v RHO, ki zanje ni značilna. Serumski vitamin A je možen modifikator bolezni vendar je za potrditev potrebna raziskave na večih bolnikih in z daljšim sledenjem.Background: Pathogenic variants in the rhodopsin gene (RHO) most commonly cause various forms of retinitis pigmentosa (RP), which is a progressive retinal degeneration, and less commonly congenital stationary blindness (CSNB). Until now, it has been assumed that a single variant produces either one or the other clinical outcome (e.g. p.G90D CSNB), with rare exceptions (e.g. pE113K). Some studies have shown that taking vitamin A can slow the progression of RP, but vitamin A treatment is not accepted in clinical practice. Aim: To determine whether the p.G90D causes other clinical pictures in addition to CSNB and identify potential modifying factors associated with this. Methods: A prospective study included all known patients harboring p.G90D in RHO and all their family members who reported night blindness, a total of 19 patients from three families (13 male and 6 femalemedian age 41 years, range 8 – 71). They underwent an extended ophthalmologic examination which included examinations of visual function (including electroretinography) and imaging (fundus autofluorescence and optical coherence tomography). Patients completed a questionnare on associated diseases and lifestyle. Serum vitamin A concentration was determined from a venous blood sample. The pathogenic variant p.G90D was confirmed using next-generation sequencing or Sanger sequencing. Results: Patients had either night blindness without degeneration (NBWD) (26%), classic RP (48%), pericentral RP (5%) or sectoral RP (21%). Patients with NBWD were younger than the others, however the diffrence was not significant. Systemic diseases were reported exlusievely by patients with classic and sectoral RP (75 % and 56 %), who were also oldest. In a subgroup of patients aged 40 years or more, patients with a milder clinical signs (NBWD, sectoral RP) had significantly higher vitamin A concentration than patients with greater structural impairment (classic RP, pericentral RP) (median 3.0 vs 2.0 μmol/L, Mann-Whitney test, p < 0.05). Conclusions: Contrary to the previous report, p.G90D also causes various forms of retinal dystrophy (classic RP, sector RP and pericentral RP) in addition to rod dysfunction (CSNB or NBWD). Such phenotypic variability is unusual even among more than 200 variants in RHO, which is not characteristic of them. Serum vitamin A concentration is a possible disease modifier, however studies on larger cohorts and longer follow-up are needed to confirm this

Table_1_Comparison of visual requirements and regulations for obtaining a driving license in different European countries and some open questions on their adequacy.DOCX

We reviewed the current state of knowledge regarding visual function and its suitability as part of medical examinations for driving licenses. We focused only on Group 1 drivers. According to previous studies, visual acuity, which is the most common test, is weakly associated with a higher risk of road accidents, with a greater role of visual field. The inclusion of the visual field test in medical examinations is therefore important, but the actual limit value is still unclear and further research in specific situations is needed. Color vision impairment was not found a threat to traffic safety. Contrast sensitivity decreases with age and is affected by abnormal eye conditions. Resulting glare can lead to an increased risk of traffic accidents during night driving in the elderly and others with conditions that impair contrast sensitivity. However, the universal cut-off limits have not been established either. The current European Union (EU) regulations therefore reflect minimum common denominator across the member states which may not entirely translate to optimal driving safety. Due to these open questions, standardized testing in simulators or on polygons that simulate real life conditions would be needed to better determine safe limits of visual function in different conditions. As there is a need to have better standardization across Europe regarding the requirements and rules regarding driving licenses in European countries, we first analyzed existing rules and compared them with each other, also in terms of deviations from the EU directive itself. We reviewed the literature in this field and prepared proposals for a more optimal regulation of the rules in the future. Particular attention is paid to the new method of examining the visual field that was created to respect the European directive. The paper can serve as a basis of information for research teams to design further protocols, as it gathers research findings to date on the importance and impact of various visual functions on driving safety, as well as a starting point for a debate on revising existing rules for obtaining and maintaining licenses, as it compares the current regulations in European countries and differences between them.</p

Napovedovanje drevesnih vrst iz geometrije in intenzitete oblaka aerolaserskih točk vrhov drevesnih krošenj

Based on the laser point clouds of 240 individual trees that were also identified in the field, we developed decision trees to distinguish deciduous and coniferous trees and individual tree species: Picea abies, Larix decidua, Pinus sylvestris, Fagus sylvatica, Acer pseudoplatanus, Fraxinus excelsior. The volume of the upper part of the tree crown (height of 3 m) and the average intensity of the laser reflections were used as explanatory variables. There were four aerial laser datasets: May 2012, September 2012, March 2013 and July 2015. We found that the combination of the volume and the average intensity of the first three laser datasets was the most reliable for predicting the selected tree species (60% model performance). A slightly poorer model performance was obtained if only the average intensity of the first three datasets was used (54% model performance). The worst model performance was given by the intensities (31 % model performance) or the volumes (21 % model performance) of dataset 4, which represents the national laser scanning of Slovenia (LSS). The best performing was the deciduous and coniferous separation, which achieved 75% and 95% success based on the test data (combination of volume and average intensity of the first three laser datasets). Using only the LSS intensities, deciduous and coniferous trees could be separated with 81% success.Na osnovi laserskih oblakov točk 240 posameznih dreves, ki smo jih identificirali tudi na terenu, smo razvili odločitvena drevesa za ločevanje listavcev in iglavcev ter posameznih drevesnih vrst (rdeči bor, navadna bukev, gorski javor, veliki jesen, evropski macesen, navadna smreka). Kot pojasnjevalne spremenljivke smo uporabili volumen zgornjega dela drevesne krošnje (višine 3 m) in povprečno intenziteto laserskih odbojev. Uporabili smo štiri nize aerolaserskih podatkov: iz maja 2012, septembra 2012, marca 2013 in julija 2015. Ugotovili smo, da najzanesljivejše rezultate za napovedovanje izbranih drevesnih vrst daje kombinacija volumna in povprečne intenzitete prvih treh laserskih nizov (uspešnost modela 60 %). Nekoliko nižjo uspešnost modela dobimo, če uporabimo samo povprečno intenziteto prvih treh nizov (54 %). Najslabšo uspešnost modela daje intenziteta niza 4, ki predstavlja lasersko skeniranje Slovenije (LSS ) (31 %) oziroma volumen (21 %). Uspešnejše je razločevanje listavcev in iglavcev, ki na testnih podatkih dosega uspešnost 75 % oziroma 95 % (kombinacija volumna in povprečne intenzitete združenih prvih treh laserskih nizov). Če uporabimo samo intenzitete LSS, listavce in iglavce lahko ločimo z uspešnostjo 81 %

Correlation between the Serum Concentration of Vitamin A and Disease Severity in Patients Carrying p.G90D in <i>RHO</i>, the Most Frequent Gene Associated with Dominant Retinitis Pigmentosa: Implications for Therapy with Vitamin A

The pathogenic variant p.G90D in RHO is believed to be responsible for a spectrum of phenotypes, including congenital stationary blindness (for the purpose of this study termed night blindness without degeneration; NBWD), Sector RP, Pericentral RP, and Classic RP. We present a correlation between the serum concentration of vitamin A and disease severity in patients with this variant. This prospective study involved 30 patients from 7 families (17 male; median age 46 years, range 8–73). Full ophthalmological examination including visual acuity, Goldmann perimetry, slit-lamp exam, optical coherence tomography, fundus autofluorescence, and electrophysiology was performed to determine the presenting phenotype. The serum concentration of vitamin A was determined from a fasting blood sample taken on the day of the exam, where it was found that 23.3% (7/30) of patients had NBWD, 13.3% (4/30) had Sector RP, 3.3% (1/30) had Pericentral RP, and 60% (18/30) had Classic RP. Multiple logistic regression revealed a significantly higher probability of having a milder phenotype (NBWD or Sector RP) in association with younger age (p p cis-retinal form plays a role in stabilizing the constitutively active p.G90D rhodopsin and its supplementation could be a potential treatment strategy for p.G90D RHO patients