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

In-depth rheological characterization of tungsten sol-gel inks for inkjet printing

The inkjet printing of the functional materials prepared by the sol-gel route is gaining the attention for the production of the variety of the applications not limited to the printed boards, displays, smart labels, smart packaging, sensors and solar cells. However, due to the gelation process associated with the changes from Newtonian to non-Newtonian fluid the inkjet printing of the sol-gel inks is extremely complex. In this study we reveal in-depth rheological characterization of the WO$_3$ sols in which we simulate the conditions of the inkjet printing process at different temperature of the cartridge (20–60 °C) by analyzing the structural and rheological changes taking place during the gelation of the tungsten oxide (WO$_3$) ink. The results provide the information on the stability of the sol and a better insight on the effects of the temperature on the gelation time. Moreover, the information on the temperature and the time window at which the inkjet printing of the sol-gel inks could be performed without clogging were obtained. The WO$_3$ ink was stable in a beaker and exhibited Newtonian flow behavior at room temperature over 3 weeks, while the gelation time decreased exponentially with increasing temperature down to 0.55 h at 60 °C

Inkjet printing of tungsten sol-gel ink

Tungsten (VI) oxide − WO3 is one of the widely studied inorganic semiconductors with outstanding chromogenic properties. Its unique optical and electrical properties enable application in energy efficient systems (e.g. smart windows), sensors, displays, storage units, electric and photo catalysts and solar cells. The WO3 layers are mostly made by expensive vacuum sputtering (PVD), chemical vapour deposition (CVD) and electro-deposition, but it is also possible to deposit layers from sol-gel solutions using dip-coating or spin-coating. On the other hand printing of the WO3 layers is unexplored area, although enabling flexibility of the substrates, patterning, multi-layer deposition and R2R mass production favouring low cost of the final devices. According to our knowledge this is the first report showing the feasibility of inkjet printing of tungsten sols

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

Stationary and Progressive Phenotypes Caused by the p.G90D Mutation in Rhodopsin Gene

Mutations in rhodopsin gene (RHO) are a frequent cause of retinitis pigmentosa (RP) and less often, congenital stationary night blindness (CSNB). Mutation p.G90D has previously been associated with CSNB based on the examination of one family. This study screened 60 patients. Out of these 60 patients, 32 were affected and a full characterization was conducted in 15 patients. We described the clinical characteristics of these 15 patients (12 male, median age 42 years, range 8–71) from three families including visual field (Campus Goldmann), fundus autofluorescence (FAF), optical coherence tomography (OCT) and electrophysiology. Phenotypes were classified into four categories: CSNB (N = 3, 20%) sector RP (N = 3, 20%), pericentral RP (N = 1, 6.7%) and classic RP (N = 8, 53.3% (8/15)). The phenotypes were not associated with family, sex or age (Kruskal–Wallis, p &gt; 0.05), however, cystoid macular edema (CME) was observed only in one family. Among the subjects reporting nyctalopia, 69% (22/32) were male. The clinical characteristics of the largest p.G90D cohort so far showed a large frequency of progressive retinal degeneration with 53.3% developing RP, contrary to the previous report

The clinical spectrum and disease course of DRAM2 retinopathy

Pathogenic variants in DNA-damage regulated autophagy modulator 2 gene (DRAM2) cause a rare autosomal recessive retinal dystrophy and its disease course is not well understood. We present two Slovenian patients harboring a novel DRAM2 variant and a detailed review of all 23 other patients described to date. Whole exome and whole genome sequencing were performed in the two patients, and both underwent ophthalmological examination with a 2-year follow-up. PubMed was searched for papers with clinical descriptions of DRAM2 retinopathy. Patient 1 was homozygous for a novel variant, p.Met1?, and presented with the acute onset of photopsia and retina-wide retinopathy at the age of 35 years. The patient was first thought to have an autoimmune retinopathy and was treated with mycophenolate mofetil, which provided some symptomatic relief. Patient 2 was compound heterozygous for p.Met1? and p.Leu246Pro and presented with late-onset maculopathy at the age of 59 years. On review, patients with DRAM2 retinopathy usually present in the third decade with central visual loss, outer retinal layer loss on optical coherence tomography and a hyperautofluorescent ring on fundus autofluorescence. Either cone–rod or rod–cone dystrophy phenotype is observed on electroretinography, reflecting the importance of DRAM2 in both photoreceptor types. Non-null variants can result in milder disease

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

Pathogenic variants in DNA-damage regulated autophagy modulator 2 gene (DRAM2) cause a rare autosomal recessive retinal dystrophy and its disease course is not well understood. We present two Slovenian patients harboring a novel DRAM2 variant and a detailed review of all 23 other patients described to date. Whole exome and whole genome sequencing were performed in the two patients, and both underwent ophthalmological examination with a 2-year follow-up. PubMed was searched for papers with clinical descriptions of DRAM2 retinopathy. Patient 1 was homozygous for a novel variant, p.Met1?, and presented with the acute onset of photopsia and retina-wide retinopathy at the age of 35 years. The patient was first thought to have an autoimmune retinopathy and was treated with mycophenolate mofetil, which provided some symptomatic relief. Patient 2 was compound heterozygous for p.Met1? and p.Leu246Pro and presented with late-onset maculopathy at the age of 59 years. On review, patients with DRAM2 retinopathy usually present in the third decade with central visual loss, outer retinal layer loss on optical coherence tomography and a hyperautofluorescent ring on fundus autofluorescence. Either cone–rod or rod–cone dystrophy phenotype is observed on electroretinography, reflecting the importance of DRAM2 in both photoreceptor types. Non-null variants can result in milder disease

Author&apos;s personal copy Metabolic plasticity and the energy economizing effect of ibogaine, the principal alkaloid of Tabernanthe iboga

a b s t r a c t Ethnopharmacological relevance: The root bark of iboga plant-Tabernanthe iboga has been used traditionally in Central Africa as a psychoactive substance in religious rituals, while in smaller doses it is appreciated due to its stimulant properties. The iboga root bark, iboga extract or pure ibogaine are being recognized in the West as an anti-addiction remedy and their use is increasing. Aim of the study: Our previous studies have demonstrated a transient ATP pool reduction under ibogaine accompanied by the induction of energy metabolism related enzymes. The present study aimed to find the cause of this energy deprivation and to foresee its immediate and long-term impact on metabolism. The overall project is designed to disclose the common mechanism of action at these seemingly diverse indications for iboga use, to predict eventual adverse effects and to build the grounds for its safe and beneficial utilization. Materials and methods: The rate of carbon dioxide (CO 2 ) as a marker of energy metabolism in stationary yeast model under aerobic conditions in the presence of ibogaine at concentration of 1, 4 and 20 mg/l was measured for 5 h by gas chromatography. The overall oxidative load was determined fluorimetrically by 2 0 ,7 0 -dichlorofluorescein diacetate (H 2 DCFDA) and in vitro antioxidant properties of ibogaine were defined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) test. Results: The CO 2 production under ibogaine was temporarily increased in a dose dependent manner. The increased energy consumption as an early effect of ibogaine was proven by the fact that in spite of energy mobilization, the ATP pool has been simultaneously decreased. Although increased cellular respiration co-produces reactive oxygen species (ROS), the overall oxidative load was significantly lowered by ibogaine. Since ibogaine does not show any significant in vitro antioxidant properties, the results indicate its stimulating influence on physiological oxidative stress defence system. Conclusion: Ibogaine triggers remodeling of the housekeeping metabolism. Under the initial energy cost it results in increased efficacy of physiological antioxidative systems, which reduce oxidative damage and lowers basal metabolic needs. Together with induced catabolic enzymes they set a new metabolic equilibrium that saves energy and makes it easily available in case of extra needs. While healthy organism profits from improved fitness and mental performance and can withstand higher stress without risking a disease, due to the same principle ibogaine provides beneficial support at the recovery after diseases including addiction syndrome

Metabolic plasticity and the energy economizing effect of ibogaine, the principal alkaloid of Tabernanthe iboga

Ethnopharmacological relevance: The root bark of iboga plant-Tabernanthe iboga has been used traditionally in Central Africa as a psychoactive substance in religious rituals, while in smaller doses it is appreciated due to its stimulant properties. The iboga root bark, iboga extract or pure ibogaine are being recognized in the West as an anti-addiction remedy and their use is increasing. Aim of the study: Our previous studies have demonstrated a transient ATP pool reduction under ibogaine accompanied by the induction of energy metabolism related enzymes. The present study aimed to find the cause of this energy deprivation and to foresee its immediate and long-term impact on metabolism. The overall project is designed to disclose the common mechanism of action at these seemingly diverse indications for iboga use, to predict eventual adverse effects and to build the grounds for its safe and beneficial utilization. Materials and methods: The rate of carbon dioxide (CO2) as a marker of energy metabolism in stationary yeast model under aerobic conditions in the presence of ibogaine at concentration of 1, 4 and 20 mg/l was measured for 5 h by gas chromatography. The overall oxidative load was determined fluorimetrically by 2',7'-dichlorofluorescein diacetate (H(2)DCFDA) and in vitro antioxidant properties of ibogaine were defined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) test. Results: The CO2 production under ibogaine was temporarily increased in a dose dependent manner. The increased energy consumption as an early effect of ibogaine was proven by the fact that in spite of energy mobilization, the ATP pool has been simultaneously decreased. Although increased cellular respiration co-produces reactive oxygen species (ROS), the overall oxidative load was significantly lowered by ibogaine. Since ibogaine does not show any significant in vitro antioxidant properties, the results indicate its stimulating influence on physiological oxidative stress defence system. Conclusion: Ibogaine triggers remodeling of the housekeeping metabolism. Under the initial energy cost it results in increased efficacy of physiological antioxidative systems, which reduce oxidative damage and lowers basal metabolic needs. Together with induced catabolic enzymes they set a new metabolic equilibrium that saves energy and makes it easily available in case of extra needs. While healthy organism profits from improved fitness and mental performance and can withstand higher stress without risking a disease, due to the same principle ibogaine provides beneficial support at the recovery after diseases including addiction syndrome. (C) 2012 Elsevier Ireland Ltd. All rights reserved.nul