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PURPOSE: The aim of this study was to explore the potential benefits of retinal pigment epithelium replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect. METHODS: Sixteen eyes from 16 patients with BCD and 16 eyes from 16 patients with RHO-associated retinitis pigmentosa were included. Fundus autofluorescence, optical coherence tomography, and Goldmann perimetry results were retrospectively reviewed and assessed using image analyses. RESULTS: In patients with BCD, the FAF abnormality area was not correlated with the overall visual field defect area and median overall visual field defect area (57.5%) was smaller than FAF abnormality area (98.5%). By contrast, the ellipsoid zone width was significantly correlated with the central visual field area (r = 0.806, P < 0.001). In patients with RHO-associated retinitis pigmentosa, the FAF abnormality area and ellipsoid zone width were significantly correlated with the overall visual field defect area (r = 0.833, P < 0.001) and central visual field area (r = 0.887, P < 0.001), respectively. CONCLUSION: The FAF abnormality shown in patients with BCD involves retinal pigment epithelium degeneration without complete loss of photoreceptors or visual function. These results suggest that patients with BCD are good candidates for retinal pigment epithelium replacement therapy for preservation of residual visual function.
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Distrofias Hereditárias da Córnea , Angiofluoresceinografia , Fundo de Olho , Epitélio Pigmentado da Retina , Tomografia de Coerência Óptica , Acuidade Visual , Testes de Campo Visual , Campos Visuais , Humanos , Campos Visuais/fisiologia , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/fisiopatologia , Angiofluoresceinografia/métodos , Adulto , Epitélio Pigmentado da Retina/patologia , Idoso , Acuidade Visual/fisiologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Transtornos da Visão/fisiopatologia , Transtornos da Visão/diagnóstico , Imagem Óptica , Retinose Pigmentar/fisiopatologia , Retinose Pigmentar/diagnóstico , Adulto JovemRESUMO
This study analyzed the linguistic and psychometric validation of the Japanese version of the Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS) consisting of six items which cover several TBI-relevant domains. We hypothesized that the Japanese version has good reliability, convergent validity, and divergent validity, compared with its long version, the 37-item QOLIBRI. The QOLIBRI-OS Japanese version was forward and back-translated from the English version. In total, 129 individuals participated in this study after experiencing a traumatic brain injury and attending clinics, rehabilitation centers, and support centers in Japan. The structure of the QOLIBRI-OS was investigated by confirmatory factor analyses and compared with the QOLIBRI. Only one factor was extracted, and a model with one underlying factor had a good fit. The QOLIBRI-OS showed good-to-excellent internal consistency and test-retest reliability. The QOLIBRI-OS was positively correlated with the QOLIBRI, Short Form Health Survey-36 version 2, and Glasgow Outcome Scale Extended, and negatively correlated with the Hospital Anxiety and Depression Scale. The results suggest that the QOLIBRI-OS Japanese version is a reliable and valid tool for assessing disease-specific health-related QOL in individuals after traumatic brain injury in Japan.
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Lesões Encefálicas Traumáticas , Lesões Encefálicas , Humanos , Qualidade de Vida , Japão , Reprodutibilidade dos Testes , Psicometria , Inquéritos e QuestionáriosRESUMO
We report a case involving a 31-year-old male without any known precipitating injuries presenting with involuntary finger movements and rare seizures. There was a noted family history of tremulous movements. Yet the characteristics of his finger movements were irregular and not typical of essential tremor (ET). Electrophysiological examinations, including video EEG, showed no epileptic discharges, and brain MRI results were normal. However, somatosensory evoked potentials (SEP) revealed the presence of giant SEP, and a positive cortical (C)-reflex was observed, leading to a clinical diagnosis of benign adult familial myoclonus epilepsy (BAFME). Management with valproic acid and perampanel resulted in a significant reduction of symptoms. This case highlights the necessity of considering BAFME in the differential diagnosis for atypical tremorous finger movements, especially with a relevant family history, and the critical role of electrophysiological findings indicative of cortical hyperexcitability.
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Background: Because dementia is a long-term condition, the appropriate involvement of health-care professionals is considered important. However, little is known about the factors associated with changes in family caregiver burden. Objective: To clarify changes in family caregiver burden and associated factors during follow-up at a memory clinic. Methods: A retrospective cohort study was conducted, enrolling 495 pairs of patients with dementia or mild cognitive impairment and their family caregivers. A total of 120 pairs completed the second evaluation. The caregiver burden was assessed using the Zarit Burden Interview (ZBI). Data at the initial visit and after an average follow-up of about 2 years were compared and analyzed. Results: At initial visit, the patients' mean age, Mini-Mental State Examination (MMSE) and ZBI scores were 78.6±5.6 years, 23.3±3.5, and 22.6±16.7, respectively. At follow-up, MMSE scores decreased (21.4±4.5, pâ<â0.001), but ZBI scores remained similar (22.5±13.6). When the difference in ZBI scores between the two time points was defined as ΔZBI, and the related factors were analyzed by multiple regression analysis, ZBI scores at the initial visit, start of psychotropic drug, and decrease of neuropsychiatric symptoms were identified as significant factors (pâ<â0.001, pâ=â0.003, pâ<â0.001, respectively). A significant negative correlation was found between ZBI scores at the initial visit and ΔZBI (râ=â-0.588, pâ<â0.001). Conclusions: These findings suggest the importance of assessing changes in the burden experienced by family caregivers during the disease follow-up.
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Objectives: To predict falls by adding an adherence assessment to a static balance ability assessment, and to evaluate fall prediction accuracy. Methods: This study included 416 patients who were admitted to a 45-bed convalescent rehabilitation ward over a 2-year period. The patients were assessed at the time of admission using the Standing Test for Imbalance and Disequilibrium (SIDE) and three additional, newly developed adherence items. Patients were divided into two groups: a group that experienced falls (fall group) and a group that did not experience falls (non-fall group) within 14 days of admission. The sensitivity and specificity of the assessment items for predicting falls were calculated. Results: Sensitivity was 0.86 and specificity was 0.42 when the cutoff was between SIDE levels 0-2a and 2b-4. Combining balance assessment using the SIDE with the memory and instruction adherence items improved fall prediction accuracy such that the sensitivity was 0.75 and the specificity was 0.64. Conclusions: Our analysis suggested that adherence assessment can improve fall risk prediction accuracy.
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OBJECTIVE: Cystoid macular edema (CME) in retinitis pigmentosa (RP) is an important complication causing visual dysfunction. We investigated the effect of CME on photoreceptors in RP patients with previous or current CME, using an adaptive optics (AO) fundus camera. METHODS: We retrospectively observed the CME and ellipsoid zone (EZ) length (average of horizontal and vertical sections) by optical coherence tomography. The density and regularity of the arrangement of photoreceptor cells (Voronoi analysis) were examined at four points around 1.5° from superior to inferior and temporal to nasal. We also performed a multivariate analysis using CME duration, central macular thickness and transversal length of CME. RESULTS: We evaluated 18 patients with previous or current CME (18 eyes; age, 48.7 ± 15.6 years) and 24 patients without previous or current CME (24 eyes; age, 46.0 ± 14.5 years). There were no significant differences in age, logMAR visual acuity, or EZ length. In groups with and without CME, cell density was 11967 ± 3148 and 16239 ± 2935 cells/mm2, and sequence regularity was 85.5 ± 3.4% and 88.5 ± 2.8%, respectively; both parameters were significantly different. The correlation between photoreceptor density and age was more negative in group with CME. The CME group tended toward greater reductions in duration of CME. CONCLUSION: Complications of CME in RP patients may lead to a decrease in photoreceptor density and regularity. Additionally, a longer duration of CME may result in a greater reduction in photoreceptor density.
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Edema Macular , Retinose Pigmentar , Humanos , Adulto , Pessoa de Meia-Idade , Edema Macular/complicações , Estudos Retrospectivos , Retinose Pigmentar/complicações , Retinose Pigmentar/diagnóstico por imagem , Fóvea Central , Tomografia de Coerência Óptica/métodos , Células FotorreceptorasRESUMO
This study aimed to investigate how the extent and central/peripheral location of the residual visual field (VF) in patients with late-stage inherited retinal diseases (IRDs) are related to retinal sensitivity detected using full-field stimulus testing (FST). We reviewed the results of Goldmann perimetry and FST from the medical records of patients with IRDs whose VF represents central (within 10°) and/or peripheral islands, or undetectable. In total, 19 patients (19 eyes) were analyzed in this study. The median value of residual VF area was 1.38%. The median values of rod and cone sensitivities were - 14.9 dB and 7.4 dB, respectively. Patients with only the peripheral island (- 33.9 dB) had better median rod sensitivity than other groups (only central, - 18.9 dB; both, - 3.6 dB). VF area significantly correlated with rod sensitivity (r = - 0.943, p = 0.005) in patients with only peripheral island, but not with cone sensitivity. Peripheral VF islands were significant contributors to FST results, especially rod sensitivity. With reduced or loss of central vision, the extent of residual peripheral VF significantly affected rod sensitivity, suggesting that FST can be useful in quantitatively estimating the overall remaining vision in patients with late-stage IRD.
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Degeneração Retiniana , Campos Visuais , Humanos , Testes de Campo Visual/métodos , Adaptação à Escuridão , RetinaRESUMO
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy and a major cause of blindness. RP is caused by several variants of multiple genes, and genetic diagnosis by identifying these variants is important for optimizing treatment and estimating patient prognosis. Next-generation sequencing (NGS), which is currently widely used for diagnosis, is considered useful but is known to have limitations in detecting copy number variations (CNVs). In this study, we re-evaluated CNVs in EYS, the main causative gene of RP, identified via NGS using multiplex ligation-dependent probe amplification (MLPA). CNVs were identified in NGS samples of eight patients. To identify potential CNVs, MLPA was also performed on samples from 42 patients who were undiagnosed by NGS but carried one of the five major pathogenic variants reported in Japanese EYS-RP cases. All suspected CNVs based on NGS data in the eight patients were confirmed via MLPA. CNVs were found in 2 of the 42 NGS-undiagnosed RP cases. Furthermore, results showed that 121 of the 661 patients with RP had EYS as the causative gene, and 8.3% (10/121 patients with EYS-RP) had CNVs. Although NGS using the CNV calling criteria utilized in this study failed to identify CNVs in two cases, no false-positive results were detected. Collectively, these findings suggest that NGS is useful for CNV detection during clinical diagnosis of RP.
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Variações do Número de Cópias de DNA , Proteínas do Olho , Sequenciamento de Nucleotídeos em Larga Escala , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Feminino , Masculino , Proteínas do Olho/genética , Pessoa de Meia-Idade , Adulto , Reação em Cadeia da Polimerase Multiplex/métodosRESUMO
Retinal pigment epithelium (RPE) cells show heterogeneous levels of pigmentation when cultured in vitro. To know whether their color in appearance is correlated with the function of the RPE, we analyzed the color intensities of human-induced pluripotent stem cell-derived RPE cells (iPSC-RPE) together with the gene expression profile at the single-cell level. For this purpose, we utilized our recent invention, Automated Live imaging and cell Picking System (ALPS), which enabled photographing each cell before RNA-sequencing analysis to profile the gene expression of each cell. While our iPSC-RPE were categorized into four clusters by gene expression, the color intensity of iPSC-RPE did not project any specific gene expression profiles. We reasoned this by less correlation between the actual color and the gene expressions that directly define the level of pigmentation, from which we hypothesized the color of RPE cells may be a temporal condition not strongly indicating the functional characteristics of the RPE.
The backs of our eyes are lined with retinal pigment epithelial cells (or RPE cells for short). These cells provide nutrition to surrounding cells and contain a pigment called melanin that absorbs excess light that might interfere with vision. By doing so, they support the cells that receive light to enable vision. However, with age, RPE cells can become damaged and less able to support other cells. This can lead to a disease called age-related macular degeneration, which can cause blindness. One potential way to treat this disease is to transplant healthy RPE cells into eyes that have lost them. These healthy cells can be grown in the laboratory from human pluripotent stem cells, which have the capacity to turn into various specialist cells. Stem cell-derived RPE cells growing in a dish contain varying amounts of melanin, resulting in some being darker than others. This raised the question of whether pigment levels affect the function of RPE cells. However, it was difficult to compare single cells containing various amounts of pigment as most previous studies only analyzed large numbers of RPE cells mixed together. Nakai-Futatsugi et al. overcame this hurdle using a technique called Automated Live imaging and cell Picking System (also known as ALPS). More than 2300 stem cell-derived RPE cells were photographed individually and the color of each cell was recorded. The gene expression of each cell was then measured to investigate whether certain genes being switched on or off affects pigment levels and cell function. Analysis did not find a consistent pattern of gene expression underlying the pigmentation of RPE cells. Even gene expression related to the production of melanin was only slightly linked to the color of the cells. These findings suggests that the RPE cell color fluctuates and is not primarily determined by which genes are switched on or off. Future experiments are required to determine whether the findings are the same for RPE cells grown naturally in the eyes and whether different pigment levels affect their capacity to protect the rest of the eye.
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Células-Tronco Pluripotentes Induzidas , Pigmentação , Epitélio Pigmentado da Retina , Transcriptoma , Humanos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/fisiologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Pigmentação/genética , Perfilação da Expressão Gênica , Células Cultivadas , Diferenciação Celular/genéticaRESUMO
Clinical studies using suspensions or sheets of human pluripotent cell-derived retinal pigment epithelial cells (hiPSC-RPE) have been conducted globally for diseases such as age-related macular degeneration. Despite being minimally invasive, cell suspension transplantation faces challenges in targeted cell delivery and frequent cell leakage. Conversely, although the RPE sheet ensures targeted delivery with correct cell polarity, it requires invasive surgery, and graft preparation is time-consuming. We previously reported hiPSC-RPE strips as a form of quick cell aggregate that allows for reliable cell delivery to the target area with minimal invasiveness. In this study, we used a microsecond pulse laser to create a local RPE ablation model in cynomolgus monkey eyes. The hiPSC-RPE strips were transplanted into the RPE-ablated and intact sites. The hiPSC-RPE strip stably survived in all transplanted monkey eyes. The expansion area of the RPE from the engrafted strip was larger at the RPE injury site than at the intact site with no tumorigenic growth. Histological observation showed a monolayer expansion of the transplanted RPE cells with the expression of MERTK apically and collagen type 4 basally. The hiPSC-RPE strip is considered a beneficial transplantation option for RPE cell therapy.
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Células-Tronco Pluripotentes Induzidas , Macaca fascicularis , Epitélio Pigmentado da Retina , Animais , Epitélio Pigmentado da Retina/transplante , Epitélio Pigmentado da Retina/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Degeneração Macular/patologiaRESUMO
Inherited retinal dystrophies comprise a clinically complex and heterogenous group of diseases characterized by visual impairment due to pathogenic variants of over 300 different genes. Accurately identifying the causative gene and associated variant is crucial for the definitive diagnosis and subsequent selection of precise treatments. Consequently, well-validated genetic tests are required in the clinical practice. Here, we report the analytical and clinical validation of a next-generation sequencing targeted gene panel, the PrismGuide IRD Panel System. This system enables comprehensive genome profiling of 82 genes related to inherited retinal dystrophies. The PrismGuide IRD Panel System demonstrated 100% (n = 43) concordance with Sanger sequencing in detecting single-nucleotide variants, small insertions, and small deletions in the target genes and also in assessing their zygosity. It also identified copy-number loss in four out of five cases. When assessing precision, we evaluated the reproducibility of variant detection with 2,160 variants in 144 replicates and found 100% agreement in terms of single-nucleotide variants (n = 1,584) and small insertions and deletions (n = 576). Furthermore, the PrismGuide IRD Panel System generated sufficient read depth for variant calls across the purine-rich and highly repetitive open-reading frame 15 region of RPGR and detected all five variants tested. These results show that the PrismGuide IRD Panel System can accurately and consistently detect single-nucleotide variants and small insertions and deletions. Thus, the PrismGuide IRD Panel System could serve as useful tool that is applicable in clinical practice for identifying the causative genes based on the detection and interpretation of variants in patients with inherited retinal dystrophies and can contribute to a precise molecular diagnosis and targeted treatments.
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Distrofias Retinianas , Humanos , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reprodutibilidade dos Testes , Feminino , Masculino , Testes Genéticos/métodos , Polimorfismo de Nucleotídeo Único , Genoma Humano/genéticaRESUMO
PURPOSE: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. DESIGN: Retrospective, multicenter cohort study. METHODS: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. RESULTS: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. CONCLUSIONS: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.
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Transportadores de Cassetes de Ligação de ATP , Degeneração Retiniana , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Transportadores de Cassetes de Ligação de ATP/genética , Análise Mutacional de DNA , População do Leste Asiático/genética , Sequenciamento do Exoma , Angiofluoresceinografia/métodos , Genótipo , Japão/epidemiologia , Mutação de Sentido Incorreto , Fenótipo , Degeneração Retiniana/genética , Degeneração Retiniana/diagnóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologiaRESUMO
Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder characterized by myoclonus, ataxia, and tremors. It can be classified as neoplastic or idiopathic, with small cell lung cancer being commonly associated. Herein, we present a rare case of refractory paraneoplastic neurological syndrome (PNS) caused by large cell neuroendocrine carcinoma (LCNEC), a rare form of non-small cell lung cancer (NSCLC). A 60-year-old otherwise healthy man presented with acute-onset dysarthria, gait instability, and numbness on the right side of his body. According to the clinical symptoms and neurological examination, we initially suspected cerebellar infarction; however, brain imaging revealed no abnormal findings. After a few days, the patient developed worsening horizontal nystagmus, irregular ocular rhythms, and generalized involuntary movements, indicative of OMS. A systemic evaluation revealed a solitary nodule in the lower lobe of the right lung, leading to a clinical diagnosis of PNS. The patient underwent segmentectomy to treat an early-stage LCNEC nodule after one month from onset. Despite all therapeutic interventions, OMS was refractory, and after consulting with the person himself and the family, palliative care was selected. However, the patient showed a clinical response belatedly five months after surgery. This case highlights the importance of considering PNS, and that it may be associated with a rare malignancy when cerebellar symptoms are observed, and the challenges in managing refractory PNS associated with rare forms of NSCLC.
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The Health Systems in Transition (HiT) profiles are country-based reports that provide a detailed description of a health system and of policyinitiatives in progress or under development. HiTs examine different approaches to the organization, financing and delivery of health services and therole of the main actors in health systems; describe the institutional framework, process, content and implementation of health and health care policies; and highlight challenges and areas that require more in-depth analysis. Croatia is a European country in transition with a population of 4.4million. The population generally enjoys good health and an increasing life expectancy of less than three years below the European Union (EU) average. Croatia’s health system is based on the principles of inclusivity, continuity and accessibility. Croatia spends a relatively high share of its gross domestic product (GDP) on health. Public funds for health care originate from two main sources: contributions for mandatory health insurance (predominantly) and funds collected by general taxation. The network of health care providers is organized in a way that makes it accessible to all citizens. The Croatian health system has good health outcomes in relation to countries at comparable income levels. Provision and funding of services are largely public, although private providers and insurers also increasingly operate in the market. Since 1991, the Croatian health system has been subject to a range of organizational reforms.These have mostly relied on decreasing public and increasing private expenditure in the system. While reforms have, up to a point, managed to decrease public spending on health care, they have failed to adequately address issues such asgrowing arrears and productivity. Important actions involving strengthening policy, monitoring, regulation and more advanced supply-side-oriented tools remain to be prioritized and implemented.