RESUMO
Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGRORF15 isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGRORF15 variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGRORF15 variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGRORF15 variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod-cone dystrophy into a cone dystrophy phenotype.
Assuntos
Distrofias de Cones e Bastonetes , Distrofias Retinianas , Humanos , Masculino , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Fases de Leitura Aberta/genética , Fases de Leitura Aberta/fisiologia , Fenótipo , Células Fotorreceptoras Retinianas Cones/metabolismo , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Ácido Glutâmico/metabolismoRESUMO
BACKGROUND: Intravitreal injections are one of the most commonly performed ophthalmic procedures. It is estimated that over 1 million intravitreal injections are performed in Germany annually. The aim of this study was to quantify the waste and carbon footprint associated with single-use injection sets, and to establish a waste reduction strategy. MATERIAL AND METHODS: The clinical waste and associated carbon footprint from standard disposable injection sets used by tertiary referral centres in Germany (n = 6) and the United Kingdom (n = 2) were assessed. The safety of performing intravitreal injections with a minimalistic material-sparing approach was evaluated. RESULTS: The average weight of an injection set (and hence the waste generated from each injection) was 165 g. On average, each injection set comprised 145 g (88%) of plastic, 2.1 g (1.3%) of metal, 4.3 g (2.6%) of paper, and 12.9 g (7.8%) of gauze/swabs. The production of such injection sets was extrapolated to a CO2 equivalent of 752.6 tonnes (t), and the incineration of the resulting waste to a CO2 equivalent of 301.7 t. For 1 million injections, this equates to 145.2 t of plastic, 2.1 t of metal, 4.3 t of paper, and 12.9 t of gauze/swabs. A material-sparing approach can reduce injection set-associated waste by 99% without necessarily compromising patient safety. CONCLUSION: A resource-saving approach to intravitreal injections can minimise the generation of clinical waste and its associated carbon footprint, thereby supporting sustainability.
RESUMO
BACKGROUND: The primary hyperoxalurias (PH1-3) are rare inherited disorders of the glyoxylate metabolism characterized by endogenous overproduction of oxalate. As oxalate cannot be metabolized by humans, oxalate deposits may affect various organs, primarily the kidneys, bones, heart, and eyes. Vision loss induced by severe retinal deposits is commonly seen in infantile PH1; less frequently and milder retinal alterations are found in non-infantile PH1. Retinal disease has not systematically been investigated in patients with PH2 and PH3. METHODS: A comprehensive ophthalmic examination was performed in 19 genetically confirmed PH2 (n = 7) and PH3 (n = 12) patients (median age 11 years, range 3-59). RESULTS: Median best corrected visual acuity was 20/20. In 18 patients, no retinal oxalate deposits were found. A 30-year-old male with PH2 on maintenance hemodialysis with plasma oxalate (Pox) elevation (> 100 µmol/l; normal < 7.4) demonstrated bilateral drusen-like, hyperreflective deposits which were interpreted as crystallized oxalate. Two siblings of consanguineous parents with PH2 presented with retinal degeneration and vision loss; exome-wide analysis identified a second monogenic disease, NR2E3-associated retinal dystrophy. CONCLUSIONS: Retinal disease manifestation in PH2 and PH3 is rare but mild changes can occur at least in PH2-associated kidney failure. Decline in kidney function associated with elevated plasma oxalate levels could increase the risk of systemic oxalosis. Deep phenotyping combined with genomic profiling is vital to differentiate extrarenal disease in multisystem disorders such as PH from independent inherited (retinal) disease. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Hiperoxalúria Primária , Doenças Retinianas , Masculino , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/diagnóstico , Hiperoxalúria Primária/genética , Oxalatos , Doenças Retinianas/etiologia , Doenças Retinianas/genética , FenótipoRESUMO
PURPOSE: To demonstrate different topographic distributions of multiple-evanescent white dot syndrome (MEWDS) and secondary MEWDS disease and to describe possible associations. METHODS: Clinical evaluation and multimodal retinal imaging in 27 subjects with MEWDS (29 discrete episodes of MEWDS). Ophthalmic assessment included best-corrected visual acuity testing and multimodal retinal imaging with OCT, blue-light autofluorescence, fluorescein and indocyanine green angiography, fundus photography, and widefield pseudocolor and autofluorescence fundus imaging. RESULTS: The topographic distribution of MEWDS lesions was centered on or around the optic disc (n = 17, 59%), centered on the macula (n = 7, 24%), sectoral (n = 2, 7%), or was indeterminate (n = 3, 10%). The MEWDS episodes either occurred in the absence ('primary MEWDS'; n = 14, 48%) or presence of concurrent chorioretinal pathology ('secondary MEWDS'; n = 15, 52%). In patients with the latter, MEWDS lesions were often centered around a coexisting chorioretinal lesion. The majority of patients in both groups experienced resolution of their symptoms and retinal changes on multimodal imaging by 3 months. CONCLUSIONS: Distinct distributions of MEWDS lesions were identified. MEWDS may occur in tandem with other chorioretinal pathology, which may impact the topography of MEWDS lesions.
Assuntos
Doenças Retinianas , Síndrome dos Pontos Brancos , Humanos , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica/métodos , Retina , Síndrome dos Pontos Brancos/diagnóstico , Angiofluoresceinografia/métodosRESUMO
PURPOSE: To describe photoreceptor damage in patients with Terson syndrome as a potential cause for inconsistent clinical outcomes. METHODS: Clinical evaluation and retinal imaging in six patients. RESULTS: Four patients were women and two men, with an average age of 46.8 years (SD 8.9). Four patients suffered aneurysmal subarachnoid hemorrhage, one vertebral artery dissection, and one superior sagittal sinus thrombosis. In 11 eyes, a consistent pattern of outer retinal changes within the central retina affecting the ellipsoid zone and the outer nuclear layer was observed, indicating photoreceptor damage. Areas of photoreceptor damage showed poor spatial correlation with intraocular hemorrhage, particularly subinternal limiting membrane hemorrhage. The observed retinal abnormalities demonstrated incomplete recovery over long-term follow-up 3.5 to 8 years posthemorrhage, irrespective of surgical or conservative treatment strategy, and had variable impact on the patients' visual function. CONCLUSION: The observations suggest that photoreceptor damage in Terson syndrome likely represents a distinct manifestation of this condition, which could be caused by transient ischemia of the outer retina secondary to acute rise in intracranial pressure.
Assuntos
Macula Lutea , Hemorragia Subaracnóidea , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Hemorragia Vítrea/etiologia , Hemorragia Vítrea/complicações , Retina , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico , Acuidade Visual , Tomografia de Coerência Óptica/métodosRESUMO
Biallelic deletions in the NPHP1 gene are the most frequent molecular defect of nephronophthisis, a kidney ciliopathy and leading cause of hereditary end-stage kidney disease. Nephrocystin 1, the gene product of NPHP1, is also expressed in photoreceptors where it plays an important role in intra-flagellar transport between the inner and outer segments. However, the human retinal phenotype has never been investigated in detail. Here, we characterized retinal features of 16 patients with homozygous deletions of the entire NPHP1 gene. Retinal assessment included multimodal imaging (optical coherence tomography, fundus autofluorescence) and visual function testing (visual acuity, full-field electroretinography, color vision, visual field). Fifteen patients had a mild retinal phenotype that predominantly affected cones, but with relative sparing of the fovea. Despite a predominant cone dysfunction, night vision problems were an early symptom in some cases. The consistent retinal phenotype on optical coherence tomography images included reduced reflectivity and often a granular appearance of the ellipsoid zone, fading or loss of the interdigitation zone, and mild outer retinal thinning. However, there were usually no obvious structural changes visible upon clinical examination and fundus autofluorescence imaging (occult retinopathy). More advanced retinal degeneration might occur with ageing. An identified additional CEP290 variant in one patient with a more severe retinal degeneration may indicate a potential role for genetic modifiers, although this requires further investigation. Thus, diagnostic awareness about this distinct retinal phenotype has implications for the differential diagnosis of nephronophthisis and for individual prognosis of visual function.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Doenças Renais Císticas/genética , Doenças Retinianas , Eletrorretinografia , Angiofluoresceinografia , Humanos , Doenças Retinianas/genética , Tomografia de Coerência Óptica , Campos VisuaisRESUMO
PURPOSE: To investigate multimodal retinal imaging characteristics including the retinal nerve fiber layer (RNFL) thickness in patients with RPGR-associated retinitis pigmentosa (RP). METHODS: This cross-sectional case-control study included 17 consecutive patients (median age, 21 years) with RPGR-associated RP who underwent retinal imaging including optical coherence tomography (OCT), short-wavelength fundus autofluorescence (AF) imaging, and RNFL scans centered on the optic disc. RNFL thickness was manually segmented and compared to clinical and imaging parameters including the transfoveal ellipsoid zone (EZ) width, the horizontal diameter of the macular hyperautofluorescent ring. RNFL thickness was compared to 17 age- and sex-matched controls. RESULTS: In patients with RPGR-associated RP, the EZ width (R2 = 0.65), the central hyperautofluorescent ring on AF images (R2 = 0.72), and visual acuity (R2 = 0.68) were negatively correlated with age. In comparison to controls, a significantly (p < 0.0001) increased global RNFL thickness was identified in RPGR-associated RP, which was, however, less pronounced in progressed disease as indicated by the EZ width or the diameter of the central hyperautofluorescent ring. CONCLUSIONS: This study describes retinal characteristics in patients with RPGR-associated RP including a pronounced peripapillary RNFL thickness compared to healthy controls. These results contribute to the knowledge about imaging biomarkers in RP, which might be of interest for therapeutic approaches such as gene replacement therapies.
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Retinose Pigmentar , Adulto , Biomarcadores , Estudos de Casos e Controles , Estudos Transversais , Proteínas do Olho , Humanos , Fibras Nervosas , Retinose Pigmentar/diagnóstico , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To report a case of multiple evanescent white dot syndrome (MEWDS) associated with acute progression of lacquer cracks in high myopia. CASE REPORT: A 41-year-old female patient with high myopia developed typical signs, symptoms, and disease course of MEWDS in her right eye. At the same time, the same eye showed progression of lacquer cracks when compared to images taken 2 months prior. Retinal imaging findings characteristic of MEWDS were most obvious on fundus autofluorescence, whereas alterations on color fundus photography, optical coherence tomography, fluorescein, and indocyanine green angiography were very mild, probably because of the myopia-related fundus pathology. CONCLUSION: We present a case of MEWDS co-occurring with acute progression of lacquer cracks. This adds to the increasing evidence that impaired integrity of the retinal pigment epithelium-Bruch's membrane complex may be a factor in causing MEWDS, possibly by exposing otherwise isolated antigens. The anatomy in a highly myopic eye may make it challenging to diagnose MEWDS-associated fundus changes.
Assuntos
Miopia , Doenças Retinianas , Síndrome dos Pontos Brancos , Adulto , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Laca , Miopia/complicações , Miopia/diagnóstico , Doenças Retinianas/diagnóstico , Tomografia de Coerência ÓpticaRESUMO
Inherited retinal diseases are a frequent cause of severe visual impairment or blindness in children and adults of working age. Across this group of diseases, there is great variability in the degree of visual impairment, the impact on everyday life, disease progression, and the suitability to therapeutic intervention. Therefore, an early and precise diagnosis is crucial for patients and their families. Characterizing inherited retinal diseases involves a detailed medical history, clinical examination with testing of visual function, multimodal retinal imaging as well as molecular genetic testing. This may facilitate a distinction between different inherited retinal diseases, as well as a differentiation from monogenic systemic diseases with retinal involvement, and from mimicking diseases.
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Doenças Retinianas , Baixa Visão , Adulto , Cegueira , Criança , Humanos , Retina , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Transtornos da VisãoRESUMO
BACKGROUND: Infantile oxalosis, the most devastating form of primary hyperoxaluria type 1 (PH1), often leads to end-stage renal disease (ESRD) during the first weeks to months of life. CASE-DIAGNOSIS: Here, we report the outcome of the therapeutic use of Oxalobacter formigenes (Oxabact OC5; OxThera AB, Stockholm, Sweden) in a female infant with PH1 who exhibited severely elevated plasma oxalate (Pox) levels, pronounced nephrocalcinosis, anuretic end-stage renal disease, and retinal oxalate deposits. Following the diagnosis of PH1 at an age of 8 weeks, a combined regimen of daily peritoneal dialysis, daily pyridoxine treatment and hemodialysis (3 times a week) was unable to reduce the pronounced hyperoxalemia. After the addition of Oxalobacter formigenes therapy to the otherwise unchanged treatment regimen, Pox levels first stabilized and subsequently declined from 130 µmol/L to around 80 µmol/L. Nephrocalcinosis and retinal deposits stabilized. Oxalobacter formigenes treatment was well-tolerated and no related adverse events were observed. The patient showed nearly age-appropriate growth and development and received successful combined liver-kidney transplantation at the age of two years. CONCLUSIONS: Treatment with O. formigenes combined with intensive dialysis led to reduction of Pox, stabilization of systemic oxalosis, and improvement in the clinical disease course. O. formigenes treatment may be an option for reduction of oxalosis in infantile patients with insufficient response to conservative treatments until combined liver-kidney transplantation can be performed.
Assuntos
Hiperoxalúria/terapia , Oxalobacter formigenes/metabolismo , Diálise Renal/métodos , Insuficiência Renal Crônica/complicações , Oxalato de Cálcio/sangue , Progressão da Doença , Feminino , Humanos , Hiperoxalúria/etiologia , Lactente , Transplante de Rim , Transplante de Fígado , Insuficiência Renal Crônica/diagnósticoRESUMO
PURPOSE: To evaluate the use of 2 mg intravitreal aflibercept for treatment of choroidal neovascularization (CNV) secondary to angioid streaks in patients with pseudoxanthoma elasticum (PXE). METHODS: In this 12-month prospective, open-label, uncontrolled, non-randomized interventional clinical trial, 15 PXE patients with CNV (mean age: 53 years, range 22-65) received one initial intravitreal injection of 2 mg aflibercept. Further injections were based on CNV activity at monthly examinations. The primary endpoint was change of best corrected visual acuity (BCVA) after 12 months. Secondary outcomes were change of central retinal thickness (CRT), leakage from CNV, retinal sensitivity, and vision-related quality of life. RESULTS: BCVA improved from 75.0 ± 10.8 (± SD, Snellen equivalent 20/32) to 79.3 ± 7.3 ETDRS letters (20/32) at final visit (p = 0.083). CRT decreased from 317 ± 81 to 279 ± 51 µm (p = 0.004). Retinal sensitivity on microperimetry changed from 17.8 ± 4.5 to 18.5 ± 4.3 dB (p = 0.103) and vision-related quality of life from a VQF-25 score of 80.7 ± 10.4 to 83.5 ± 14.5 (p = 0.554). The mean number of injections was 6.7 ± 2.6, and 5 participants had persistent or reactivated CNV activity at final visit. The observed adverse events were comparable with studies on aflibercept for other indications. CONCLUSION: The results of this study indicate that intravitreal aflibercept is a treatment option for CNV secondary to PXE.
Assuntos
Corioide/patologia , Neovascularização de Coroide/tratamento farmacológico , Pseudoxantoma Elástico/complicações , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Adulto , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/etiologia , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudoxantoma Elástico/diagnóstico , Qualidade de Vida , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To investigate the prognostic value of demographic, functional, genetic, and imaging parameters on retinal pigment epithelium atrophy progression secondary to ABCA4-related retinopathy. METHODS: Patients with retinal pigment epithelium atrophy secondary to ABCA4-related retinopathy were examined longitudinally with fundus autofluorescence imaging. Lesion area, perimeter, circularity, caliper diameters, and focality of areas with definitely decreased autofluorescence were determined. A model was used to predict the lesion enlargement rate based on baseline variables. Sample size calculations were performed to model the power in a simulated interventional study. RESULTS: Sixty-eight eyes of 37 patients (age range, 14-78 years) with a follow-up time of 10 to 100 months were included. The mean annual progression of retinal pigment epithelium atrophy was 0.89 mm. The number of atrophic areas, the retina-wide functional impairment, and the age-of-onset category constituted significant predictors for future retinal pigment epithelium atrophy growth, explaining 25.7% of the variability. By extension of a simulated study length and/or specific patient preselection based on these baseline characteristics, the required sample size could significantly be reduced. CONCLUSION: Trial design based on specific shape-descriptive factors and patients' baseline characteristics and the adaption of the trial duration may provide potential benefits in required cohort size and absolute number of visits.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação/genética , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Epitélio Pigmentado da Retina/patologia , Adolescente , Adulto , Idoso , Atrofia , Demografia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Prognóstico , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Acuidade Visual/fisiologia , Adulto JovemRESUMO
PURPOSE: To assess hyperreflective foci (HF) number and distribution in choroideremia (CHM) using spectral domain optical coherence tomography. METHODS: Observational, cross-sectional case series. Consecutive patients and matched controls (20 eyes each) underwent best-corrected visual acuity measurement, fundoscopy, blue-light autofluorescence (BL-FAF) and spectral domain optical coherence tomography. Hyperreflective foci were assessed on a horizontal spectral domain optical coherence tomography scan, in the 500-µm area centered on the umbo, and in the 500-µm-wide areas internal (preserved border) and external (pathologic border) to the chorioretinal atrophy of CHM patients, and in the parafovea of controls. Hyperreflective foci were subclassified as retinal or choroidal. The spared central islet was measured on BL-FAF. Primary outcome was HF quantification in CHM. Secondary outcomes included their relationships with atrophy extent. RESULTS: Choroideremia eyes disclosed a significantly higher HF number across the pathologic border and in the fovea when compared with controls; in particular, these HF were primarily located in the choroid (59-87%). Moreover, choroidal HF in the pathologic border inversely correlated with the area of the preserved central islet. CONCLUSION: Hyperreflective foci might turn out to be a potential biomarker of CHM activity or severity. In this regard, we hypothesize that HF may be related to macrophages activation or progressive retinal pigment epithelium degeneration.
Assuntos
Biomarcadores , Corioide/patologia , Coroideremia/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Coroideremia/genética , Coroideremia/fisiopatologia , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
PURPOSE: To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. METHODS: In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. RESULTS: Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. CONCLUSION: Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.
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Lâmina Basilar da Corioide/patologia , Adaptação à Escuridão/fisiologia , Pseudoxantoma Elástico/fisiopatologia , Doenças Retinianas/fisiopatologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Sensibilidades de Contraste/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudoxantoma Elástico/tratamento farmacológico , Qualidade de Vida , Doenças Retinianas/tratamento farmacológico , Acuidade Visual/fisiologia , Vitamina A/administração & dosagem , Adulto JovemRESUMO
In recent years, an increasing incidence of laser pointer-associated retinal injuries has been observed, likely due to easy access to incorrectly classified laser pointers, their labelling as toys, and lack of awareness concerning the associated risk. Laser pointer exposure can lead to irreversible retinal damage and associated vision loss, depending on the wavelength, radiation power, duration of exposure, localization, and spot size. Pronounced retinal laser damage is especially seen in children and teenagers. The structural appearance of retinal laser pointer damage varies and, in some cases, may be a diagnostic challenge. Besides often subtle findings on optical coherence tomography examination, characteristic alterations on near-infrared autofluorescence imaging may be valuable for the diagnosis of retinal laser pointer injuries and for differentiating other retinal lesions with similar appearance. The increase in laser pointer injuries indicates that regulatory actions and increased public awareness are required regarding the dangers of laser pointers.
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Retina , Doenças Retinianas , Adolescente , Criança , Humanos , Lasers , Retina/diagnóstico por imagem , Doenças Retinianas/etiologia , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
IMPORTANCE: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next-generation sequencing may be increased by a reasonable preselection of RP-patients. BACKGROUND: To systematically evaluate and compare features of genetically solved and unsolved RP-patients. DESIGN: Retrospective, observational study. PARTICIPANTS: One-hundred and twelve consecutive RP-patients who underwent extensive molecular genetic analysis. METHODS: Characterization of patients based on multimodal imaging and medical history. MAIN OUTCOME MEASURES: Differences between genetically solved and unsolved RP-patients. RESULTS: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease-onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years-of-age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing. CONCLUSIONS AND RELEVANCE: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP-patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease-causing mutations and may impact patient counselling.
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Testes Genéticos , Retinose Pigmentar/diagnóstico , Adulto , Eletrorretinografia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Retinose Pigmentar/genética , Retinose Pigmentar/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Campos Visuais/fisiologiaRESUMO
IMPORTANCE: The diagnostic accuracy of different retinal imaging modalities to detect active choroidal neovascularization (CNV) in pseudoxanthoma elasticum (PXE) is essential to enable a correct diagnosis but is currently poorly understood. BACKGROUND: Optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCT-A) are employed in daily practice, but a systematic comparison of these imaging techniques is lacking. DESIGN: Retrospective, observational study. PARTICIPANTS: Twenty patients (31 eyes) with PXE. METHODS: OCT, FA and OCT-A imaging was performed in each eye and graded separately by independent readers. MAIN OUTCOME MEASURES: Diagnostic accuracy, sensitivity and specificity to detect CNV-activity of each modality and longitudinal change of CNV size measured by OCT-A. RESULTS: OCT showed the highest diagnostic accuracy (kappa = 0.57) in comparison to OCT-A or FA (kappa = 0.39 and 0.37, respectively). OCT-A, OCT and FA showed a diagnostic sensitivity of 0.9, 0.85 and 0.6, and a diagnostic specificity of 0.45, 0.72 and 0.82, respectively. Evaluation of longitudinal OCT recordings (24 eyes) resulted in optimal sensitivity and specificity (kappa = 1.0). Although median CNV size assessed using OCT-A remained stable on longitudinal measures of seven eyes, two eyes showed a distinct increase over time despite anti-vascular endothelial growth factor treatment. CONCLUSIONS AND RELEVANCE: The systematic use of OCT, FA and OCT-A imaging can facilitate the diagnostic accuracy for detection and follow-up of CNV activity in PXE. While structural OCT is of high value, especially when longitudinal follow-up images are available, FA and OCT-A data might contribute to diagnostic accuracy in more complex cases.
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Neovascularização de Coroide/diagnóstico , Pseudoxantoma Elástico/diagnóstico , Adulto , Idoso , Neovascularização de Coroide/fisiopatologia , Feminino , Angiofluoresceinografia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pseudoxantoma Elástico/fisiopatologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
Cystic fibrosis (CF) is associated with chronic bacterial airway infections leading to lung insufficiency and decreased life expectancy. Staphylococcus aureus is one of the most prevalent pathogens isolated from the airways of CF patients. Mucoid colony morphology has been described for Pseudomonas aeruginosa, the most common pathogen in CF, but not for S. aureus. From the airways of 8 of 313 CF patients (2.5%) mucoid S. aureus isolates (n = 115) were cultured with a mean persistence of 29 months (range 1 month, 126 months). In contrast to non-mucoid S. aureus, mucoid isolates were strong biofilm formers. The upstream region of the ica operon, which encodes the proteins responsible for the synthesis of the polysaccharide intercellular adhesin (PIA), of mucoid isolates was sequenced. Spa-types of mucoid and non-mucoid strains were identical, but differed between patients. Mucoid isolates carried a 5 bp deletion in the intergenic region between icaR and icaA. During long-term persistence, from two patients subsequent non-mucoid isolates (n = 12) with 5 bp deletions were cultured, which did not produce biofilm. Sequencing of the entire ica operon identified compensatory mutations in various ica-genes including icaA (n = 7), icaD (n = 3) and icaC (n = 2). Six sequential isolates of each of these two patients with non-mucoid and mucoid phenotypes were subjected to whole genome sequencing revealing a very close relationship of the individual patient's isolates. Transformation of strains with vectors expressing the respective wild-type genes restored mucoidy. In contrast to the non-mucoid phenotype, mucoid strains were protected against neutrophilic killing and survived better under starvation conditions. In conclusion, the special conditions present in CF airways seem to facilitate ongoing mutations in the ica operon during S. aureus persistence.
Assuntos
Proteínas de Bactérias/genética , Fibrose Cística/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/patologia , Biofilmes , Humanos , Microscopia Confocal , Reação em Cadeia da Polimerase Multiplex , Mutação , Óperon/genética , Staphylococcus aureusRESUMO
Staphylococcus aureus colonizes the nose, throat, skin, and gastrointestinal (GI) tract of humans. GI carriage of S. aureus is difficult to eradicate and has been shown to facilitate the transmission of the bacterium among individuals. Although staphylococcal colonization of the GI tract is asymptomatic, it increases the likelihood of infection, particularly skin and soft tissue infections caused by USA300 isolates. We established a mouse model of persistent S. aureus GI colonization and characterized the impact of selected surface antigens on colonization. In competition experiments, an acapsular mutant colonized better than the parental strain Newman, whereas mutants defective in sortase A and clumping factor A showed impaired ability to colonize the GI tract. Mutants lacking protein A, clumping factor B, poly-N-acetyl glucosamine, or SdrCDE showed no defect in colonization. An S. aureus wall teichoic acid (WTA) mutant (ΔtagO) failed to colonize the mouse nose or GI tract, and the tagO and clfA mutants showed reduced adherence in vitro to intestinal epithelial cells. The tagO mutant was recovered in lower numbers than the wild type strain in the murine stomach and duodenum 1 h after inoculation. This reduced fitness correlated with the in vitro susceptibility of the tagO mutant to bile salts, proteases, and a gut-associated defensin. Newman ΔtagO showed enhanced susceptibility to autolysis, and an autolysin (atl) tagO double mutant abrogated this phenotype. However, the atl tagO mutant did not survive better in the mouse GI tract than the tagO mutant. Our results indicate that the failure of the tagO mutant to colonize the GI tract correlates with its poor adherence and susceptibility to bactericidal factors within the mouse gut, but not to enhanced activity of its major autolysin.