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AimsTo compare melanin-related near-infrared fundus autofluorescence (FAF; NIA, excitation 787 nm, emission >800 nm) with lipofuscin-related FAF (excitation 488 nm, emission >500 nm) in retinitis pigmentosa (RP).MethodsThirty-three consecutive RP patients with different modes of inheritance were diagnosed clinically, with full-field ERG, and if possible with molecular genetic methods. FAF and NIA imaging were performed with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2).ResultsRings of increased FAF were present within an area of preserved retinal pigment epithelium (RPE) at the posterior pole (31/33). Rings of increased NIA were located in the same region as rings of increased FAF. In contrast to FAF, NIA showed a precipitous decline of NIA peripheral to the ring. In larger areas of preserved NIA (11/31), pericentral and foveal NIA were of similar intensity with an area of lower NIA in between. In smaller areas of preserved NIA (20/31), NIA was homogeneous from the perifovea to the fovea. In one patient without a ring of increased FAF, NIA distribution was normal. In the remaining patient with severely advanced RP, no residual RPE as well as no FAF and NIA were detectable.ConclusionCharacteristic features for FAF and NIA alterations in a heterogeneous group of RP patients indicate a common pathway of RPE degeneration. Patterns of NIA and FAF indicate different pathophysiologic processes involving melanin and lipofuscin. Combined NIA and FAF imaging will provide further insight into the pathogenesis of RP and non-invasive monitoring of future therapeutic interventions.Eye (2009) 23, 1349–1359; doi:10.1038/eye.2008.280; published online 12 September 2008 [ABSTRACT FROM AUTHOR]

BACKGROUND: Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication. METHODS: Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program. RESULTS: Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p < 0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC >100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl). CONCLUSIONS: Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity. [ABSTRACT FROM AUTHOR]

Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are characterized by distinct genetic causes and molecular mechanisms that can lead to varying degrees of visual impairment. The discovery of pathogenic variants in numerous genes associated with these conditions has deepened our understanding of the molecular pathways that influence both vision and disease manifestation and may ultimately lead to novel therapeutic approaches. Over the past 18 years, our DNA diagnostics unit has been performing genetic testing on patients suspected of having IRD or ION, using state-of-the-art mutation detection technologies that are continuously updated. This report presents a retrospective analysis of genetic data from 6237 IRD and 780 ION patients. Out of these, 3054 IRD patients (49.0%) and 211 ION patients (27.1%) received a definitive molecular diagnosis, with disease-causing variants identified in 139 different genes. The genes most implicated in disease pathologies are ABCA4, accounting for 23.8% of all IRD/ION index cases, followed by BEST1 (7.8%), USH2A (6.2%), PRPH2 (5.7%), RPGR (5.6%), RS1 (5.5%), OPA1 (4.3%), and RHO (3.1%). Our study has compiled the most extensive dataset in combined IRD/ION diagnostics to date and offers valuable insights into the frequencies of mutant alleles and the efficiency of mutation detection in various inherited retinal conditions., (© 2024. The Author(s).)

Introduction: This study aimed to i) identify the care needs of families experiencing cardiac arrest; and ii) co-identify strategies for meeting the identified care needs. Cardiac arrest survivors and family members (of survivors and non-survivors) were engaged as "experience experts," collaborators and co-researchers in this study., Methods: A qualitative study using semi-structured interviews of cardiac arrest survivors and family members was conducted. Participants were recruited from the membership of the Family Centred Cardiac Arrest Care Project. Interviews were recorded, transcribed, and analysed using Framework analysis., Results: Twenty-eight participants described 22 unique cardiac arrest events. We identified five primary care need themes: 1) "Help us help our loved one"; 2) "Work with us as a cohesive team"; 3) "See us: treat us with humanity and dignity"; 4) "Address our family's ongoing emergency"; and 5) "Help us to heal after the cardiac arrest" as well as 29 subordinate care need themes. We performed touchpoint mapping to identify key moments of interaction between patients and families, and the health system to highlight potential areas for improvement, as well as strategies for meeting family care needs., Conclusion: Our participants identified varied family care needs during and long after cardiac arrest. Fortunately, many proposed strategies are inexpensive and have low barriers to adoption. However, some unmet care needs identified suggest larger systemic issues such as service gaps that leave families feeling abandoned and isolated. Overall, our findings suggest that care during and after cardiac arrest are critical components of a comprehensive cardiac arrest care system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Cardiac arrest care systems are being designed and implemented to address patients', family members', and survivors' care needs. We conducted a systematic review and a meta-synthesis to understand family experiences and care needs during cardiac arrest care to create treatment recommendations., Methods: We searched eight electronic databases to identify articles. Study findings were extracted, coded and synthesized. Confidence in the quality, coherence, relevance, and adequacy of data underpinning the resulting findings was assessed using GRADE-CERQual methods., Results: In total 4181 studies were screened, and 39 met our inclusion criteria; these studies enrolled 215 survivors and 418 family participants-which includes both co-survivors and bereaved family members. From these studies findings and participant data we identified 5 major analytical themes: (1) When the crisis begins we must respond; (2) Anguish from uncertainty, we need to understand; (3) Partnering in care, we have much to offer; (4) The crisis surrounding the victim, ignore us, the family, no longer; (5) Our family's emergency is not over, now is when we need help the most. Confidence in the evidence statements are provided along with our review findings., Discussion: The family experience of cardiac arrest care is often chaotic, distressing, complex and the aftereffects are long-lasting. Patient and family experiences could be improved for many people. High certainty family care needs identified in this review include rapid recognition and response, improved information sharing, more effective communication, supported presence and participation, or supported absence, and psychological aftercare., (Copyright © 2023 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Reports of allele frequencies encoding ion channel, or their interacting proteins associated with sudden cardiac death among different ethnic groups have been inconsistent. Here, we aimed to characterize the distribution of these genes and their alleles among various ethnicities through meta-analysis., Methods: We conducted a systematic review and meta-analysis to assess the mean allele frequencies of channelopathy genes SCN5A, NOS1AP, KCNH2, KCNE1 , and KCNQ1 among the Black, Caucasian, Asian, and Hispanic ethnicities. Searches in PubMed, Google Scholar, and Web of Science resulted in 18 reports published before July 2015 that met the eligible criteria. Allele frequencies were averaged by weight, and pooled values were calculated by inverse variance. Fixed-effects and random-effects models were used to pool effect sizes within each study and across different studies, respectively. Moreover, to extend our findings, we used sequenced genomic data from the Exome Aggregation Consortium to compare allele frequencies between different ethnicities., Results: Meta-analysis of published studies supports that Asians had the highest overall mean allele frequencies of NOS1AP (0.36%, 95% CI: 0.30, 0.43; P <0.001), and SCN5A frequencies (0.17%, 95% CI: 0.07, 0.27, P =0.001), and whereas Caucasians had the highest KCNH2 frequency (0.21%, 95% CI: 0.16, 0.25; P <0.001), and Hispanics the highest KCNQ1 frequency (0.16%). Analysis of the Exome Aggregation Consortium also provided consistent data in agreement the meta-analysis., Conclusion: Overall, Asians carried the most alleles of genes associated with sudden cardiac death. The meta-analysis reveals significant differences in allele distribution of channelopathy-associated genes among different ethnic groups., (© 2017 by the Association of Clinical Scientists, Inc.)

Background: Chloroquine (CQ) and hydroxychloroquine (HCQ) are used to treat auto-immune related diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Both drugs however can cause retinal toxicity eventually leading to irreversible maculopathy and retinopathy. Established risk factors are duration and dosage of treatment while the involvement of genetic factors contributing to toxic maculopathy is largely unclear. To address the latter issue, this study aimed to expand on earlier efforts by (1) evaluating risk-altering variants known to be associated with age-related macular degeneration (AMD), a frequent maculopathy in individuals over 55 years of age, and (2) determining the contribution of genetic variants in the coding sequence of the ABCA4 gene., Methods: The ABCA4 gene was analyzed by deep sequencing technology using a personal genome machine (Ion Torrent) with 200 bp read length. Assessment of AMD variants was done by restriction enzyme digestion of PCR products and TaqMan SNP genotyping. Effect sizes, p-values and confidence intervals of common variants were evaluated by logistic regression (Firth's bias corrected). To account for multiple testing, p-values were adjusted according to the false discovery rate., Results: We found no effects of known AMD-associated variants on the risk of toxic maculopathy. In contrast, we report a statistically significant association of common variants in the ABCA4 gene with retinal disease, assessed by a score-based variance-component test (PSKAT = 0.0055). This association remained significant after adjustment for environmental factors like age and duration of medication and was driven by three common variants in ABCA4 (c.5682G > C, c.5814A > G, c.5844A > G), all conferring a reduced risk for toxic maculopathy., Conclusions: Our findings demonstrate that minor alleles of common genetic variants in ABCA4 significantly reduce susceptibility to develop toxic maculopathy under CQ treatment. A refined risk profile based on genetic and environmental factors may have implications for revised recommendations in CQ as well as HCQ treatment.

Cln3(Δex7/8) mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Δex7/8) mice. Homozygous Cln3(Δex7/8) mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 weeks of age. Homozygous Cln3(Δex7/8) mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12-13 week old homozygous Cln3(Δex7/8) mice, which were also seen to a lesser extent in heterozygous Cln3(Δex7/8) mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15-16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3(Δ) (ex7/8) mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3(Δ) (ex7/8) neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3(Δ) (ex7/8) mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Δ) (ex7/8) mice that merit further study for JNCL biomarker development.

Purpose: Protein kinase (PKC)-α is abundant in retinal bipolar cells. This study was performed to explore its role in visual processing., Methods: PKCα-knockout (Prkca(-/-)) mice and control animals were examined by using electroretinography (ERG), light microscopy, and immunocytochemistry., Results: The Prkca(-/-) mice showed no signs of retinal degeneration up to 12 months of age, but ERG measurements indicated a decelerated increase in the ascending limb of the scotopic (rod-sensitive) b-wave as well as a delayed return to baseline. These results suggest that PKCα is an important modulator that affects bipolar cell signal transduction and termination. Confocal microscopy of retinal sections showed that PKCα co-localized with calbindin, which indicates a PKCα localization in close proximity to the horizontal cell terminals. In addition, the implicit time of the ERG c-wave originating from the retinal pigment epithelium (RPE) and the recovery of photoreceptors from bleaching conditions were substantially faster in the knockout mice than in the wild-type control animals., Conclusions: These results suggest that PKCα is a modulator of rod-bipolar cell function by accelerating glutamate-driven signal transduction and termination. This modulation is of importance in the switch between scotopic and photopic vision. Furthermore, PKCα seems to play a role in RPE function.

Purpose: To compare melanin-related near-infrared fundus autofluorescence (NIA; excitation 787 nm, emission > 800 nm) to lipofuscin-related fundus autofluorescence (FAF; excitation 488 nm, emission > 500 nm) in patients with retinal dystrophies associated with ABCA4 gene mutations (ABCA4-RD)., Design: Observational case series., Methods: Sixteen consecutive patients with ABCA4-RD diagnosed in one institution were included. FAF and NIA imaging were performed with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2; Heidelberg Engineering, Heidelberg, Germany). The pattern and size of retinal pigment epithelial (RPE) alterations detected with FAF and NIA were evaluated., Results: FAF and NIA alterations were detected in all patients. In 7 of 16 patients, the alterations progressed beyond the vascular arcades, and in 9 of 16, they were confined to the macula. Spots of increased NIA (4/16) were less frequent compared with spots of increased FAF (15/16). Confluent patches of reduced NIA were frequent (12/16), and severely reduced NIA was observed in 3 cases. Areas with reduced NIA corresponded to either increased or reduced FAF. Preservation of subfoveal FAF or NIA corresponded to visual acuity > or = 0.4. Abnormalities detected with NIA were more extensive or more severe compared to FAF in 15 of 16 patients., Conclusion: Patterns of FAF and NIA indicate different involvement of lipofuscin and melanin and their derivates in the pathophysiologic process of ABCA4-RD. NIA imaging provides a noninvasive in vivo visualization of RPE abnormalities that may precede FAF alterations during the degenerative process. Combined FAF and NIA imaging will provide further insight in the development of ABCA4-RD and could help to monitor future therapeutic interventions.

Age-related macular degeneration and cataract are the most frequent eye disorders of elderly people worldwide. The aim of this systematic review was to evaluate the effect of cataract surgery on the development and progression of age-related macular degeneration. Data were collected by means of a systematic literature search in 28 databases and an additional update in Pubmed. Search results were evaluated using pre-defined inclusion and exclusion criteria. All relevant publications were rated in terms of scientific quality and analyzed regarding their results. The literature search generated a total of 2,827 hits. Seven publications on five observational studies and two non-randomized clinical trials were eligible for analysis. The observational studies provided some evidence for an increased incidence of late age-related macular degeneration, respectively, for a promoting influence of cataract surgery on the progression of early types of age-related macular degeneration. The clinical trials did yield inconsistent results. In conclusion, only a small number of published studies investigated the development or progression of age-related macular degeneration following cataract surgery. The scientific level of evidence of these articles was not high and results were inconsistent, nevertheless a promoting influence of cataract surgery on the progression of early age-related macular degeneration can be assumed.

Purpose: In a spontaneous mutant substrain of C57BL/10 mice, severely affected retinal ribbon-type synapses have been described. The retinopathy was accompanied by a substantial loss in the activities of the second-order neurons. Rod photoreceptor responses were maintained with reduced amplitude, whereas cone activities were absent. This study was conducted to identify the genetic defect underlying this hitherto unknown autosomal recessive cone-rod dysfunction., Methods: Genome-wide linkage analysis and screening of positional candidate genes were used to identify the causative mutation. Tissue-specific transcriptional activity of the defective gene was determined by Northern blot analysis and RT-PCR approaches. The number of cone photoreceptors was estimated by immunohistochemistry., Results: The mutation was localized to a 275-kb region of chromosome 6. Within this candidate interval, a homozygous frameshift mutation (c.2367insC) was identified in the Cacna2d4 gene of affected animals. This gene codes for an L-type calcium channel auxiliary subunit of the alpha2delta type. The mutation introduces a premature stop codon that truncates one third of the predicted Cacna2d4 protein. A severe reduction in Cacna2d4 transcript levels observed in mutant retinas probably results in the lack of Cacna2d4 protein. The mutation leads to significant loss of rods, whereas the number of cone cells remains unaffected until 6 weeks of age., Conclusions: The Cacna2d4 mutation underlies a novel channelopathy leading to cone-rod dysfunction in the visual system of mice and provides a new candidate gene for human retinal disorders including night blindness, retinitis pigmentosa, and cone-rod dystrophies.

ClC-7 is a chloride channel of late endosomes and lysosomes. In osteoclasts, it may cooperate with H(+)-ATPases in acidifying the resorption lacuna. In mice and man, loss of ClC-7 or the H(+)-ATPase a3 subunit causes osteopetrosis, a disease characterized by defective bone resorption. We show that ClC-7 knockout mice additionally display neurodegeneration and severe lysosomal storage disease despite unchanged lysosomal pH in cultured neurons. Rescuing their bone phenotype by transgenic expression of ClC-7 in osteoclasts moderately increased their lifespan and revealed a further progression of the central nervous system pathology. Histological analysis demonstrated an accumulation of electron-dense material in neurons, autofluorescent structures, microglial activation and astrogliosis. Like in human neuronal ceroid lipofuscinosis, there was a strong accumulation of subunit c of the mitochondrial ATP synthase and increased amounts of lysosomal enzymes. Such alterations were minor or absent in ClC-3 knockout mice, despite a massive neurodegeneration. Osteopetrotic oc/oc mice, lacking a functional H(+)-ATPase a3 subunit, showed no comparable retinal or neuronal degeneration. There are important medical implications as defects in the H(+)-ATPase and ClC-7 can underlie human osteopetrosis.

Several plasma membrane chloride channels are well characterized, but much less is known about the molecular identity and function of intracellular Cl- channels. ClC-3 is thought to mediate swelling-activated plasma membrane currents, but we now show that this broadly expressed chloride channel is present in endosomal compartments and synaptic vesicles of neurons. While swelling-activated currents are unchanged in mice with disrupted ClC-3, acidification of synaptic vesicles is impaired and there is severe postnatal degeneration of the retina and the hippocampus. Electrophysiological analysis of juvenile hippocampal slices revealed no major functional abnormalities despite slightly increased amplitudes of miniature excitatory postsynaptic currents. Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills.

Purpose: A preferential loss of ERG b-wave was detected in a substrain of C57BL/10 mice. Electroretinographic and histologic techniques were used to investigate this hitherto unknown retinopathy., Methods: ERGs were obtained from normal and affected C57BL/10. C57BL/6 mice served also as controls. a-Wave and c-wave analyses were performed. Microscopic investigations were done at two different ages., Results: In the scotopic ERG, a severe reduction of the b-wave amplitude could be observed, whereas the a-wave was only moderately attenuated ("negative ERG"). With age, the a-wave amplitude further decreased, but the rate of reduction was comparable to normals. Oscillatory potentials were severely altered, and the photopic ERG was absent. The ERG c-wave was comparable to normal. ERG a-wave analysis also revealed a reduced maximum amplitude, but no significant difference of receptor sensitivity. Light microscopy revealed a thinning of all retinal layers but mostly of the outer plexiform layer. The number of photoreceptor nuclei was reduced by one third. Electron microscopy revealed a profound loss of ribbon-shaped synapses between rod and rod-bipolar cells and severely abnormal ribbons in the case of cones., Conclusions: The so-called negative ERG was associated with alterations in the synaptic layer between rods and rod bipolars. The absent cone ERG may be due to the altered cone-on-bipolar synapses. The overall thinning of the retina as well as the moderately reduced scotopic a-wave amplitude remain unexplained.

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.

Thirty patients with a reduced central vision due to diseases of the posterior pole were examined with the VERIS system developed by Sutter and Tran (Vis Res 1992;32:433-446) to characterize the topography of electroretinographic (ERG) changes in comparison to the results in 30 normal volunteers. Diagnoses included Stargardt's macular dystrophy (SMD, n = 10), age-related macular degeneration (AMD, n = 5), cone dystrophy (CD, n = 5), central retinal vein occlusion (CRVO, n = 5), and autosomal dominant optic atrophy (ADOA, n = 5). The 61 local responses obtained from each subjects were grouped by eccentricity to form five concentric rings. The foveal ERG, originating from a central area of 2 degrees radius, was non-recordable or markedly diminished in all patients except those with optic atrophy, where amplitudes were found to be in the normal range. In patients with advanced stages of SMD, functional defects were larger and involved more peripheral areas than in patients with early stages of SMD or with AMD. A reduction of response amplitude even in the most peripheral ring (17-30.5 degrees eccentricity) was found in cone dystrophies and--moderately--in patients with advanced SMD and central retinal vein occlusion only. Prolonged implicit times were found in all but the patients in early stages of SMD and they were maximal in patients with CRVO. This study shows that the multifocal ERG (MFERG) can contribute to differential diagnosis of retinal diseases of the posterior pole especially in cases with a normal photopic Ganzfeld ERG.