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Accurate diagnosis of partial hydatidiform moles (PHMs) is crucial for improving outcomes of gestational trophoblastic neoplasia. The use of short tandem repeat (STR) polymorphism analysis to distinguish between PHM and hydropic abortuses is instrumental; however, its diagnostic power has not been comprehensively assessed. Herein, we evaluated the diagnostic efficacy of STR in differentiating between PHM and hydropic abortus, thus providing an opportunity for early measurement of human chorionic gonadotropin for PHMs. We reviewed charts of STR polymorphism analysis performed on fresh villous specimens and patient blood samples using a commercial kit for 16 loci. The genetic classification of 79 PHMs was confirmed. STR was reliable in differentiating PHMs when at least 15 loci were available. Typically, PHMs are characterized by their triploidy, including two paternal and one maternal haploid contribution. In our sample, seven PHMs lacked the three-allelic loci, requiring fluorescence in situ hybridization (FISH) analysis to investigate imbalanced biparental conceptus and single-nucleotide polymorphism array analysis to reveal cytogenetic details. Of these PHMs, two, three, and one were identified as androgenetic/biparental mosaics (diploids), monospermic diandric monogynic triploids, and a typical dispermic diandric monogynic triploid, respectively. The remaining case was monospermic origin, but its ploidy details could not be available. Therefore, STR differentiated PHM from a biparental diploid abortus in most cases. However, PHM diagnosis may be compromised when STR is used as the sole method for cases displaying distinct cytogenetic patterns lacking the three-allelic loci, including androgenetic/biparental mosaicism. Therefore, FISH should be considered to confirm the diagnosis.
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Mola Hidatiforme , Hibridación Fluorescente in Situ , Repeticiones de Microsatélite , Polimorfismo de Nucleótido Simple , Humanos , Mola Hidatiforme/genética , Mola Hidatiforme/diagnóstico , Mola Hidatiforme/patología , Repeticiones de Microsatélite/genética , Femenino , Embarazo , Hibridación Fluorescente in Situ/métodos , Adulto , Neoplasias Uterinas/genética , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patología , Persona de Mediana EdadRESUMEN
OBJECTIVE: Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC). METHODS: All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs. RESULTS: Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months. CONCLUSIONS: Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis.
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Carcinoma Epitelial de Ovario , Síndromes Mielodisplásicos , Neoplasias Ováricas , Humanos , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Anciano , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/inducido químicamente , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Primarias Secundarias , Adulto , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Macular edema (ME) is caused with disruption of the blood-retinal barrier (BRB) followed by fluid accumulation in the subretinal space. Main components of the outer and inner BRB are retinal pigment epithelial (RPE) cells and retinal microvascular endothelial cells, respectively. In addition, glial cells also participate in the functional regulation of the BRB as the member of 'neurovascular unit'. Under various stresses, cells in neurovascular units secrete inflammatory cytokines. Neuroinflammation induced by these cytokines can cause BRB dysfunction by degrading barrier-related proteins and contribute to the pathophysiology of ME. Prostaglandins (PGs) are crucial lipid mediators involved in neuroinflammation. Among PGs, a novel EP2 agonist, omidenepag (OMD) acts on not only the uveoscleral pathway but also the conventional pathway, unlike F prostanoid (FP) receptor agonists. Moreover, the combination use of the EP and the FP agonist is not recommended because of the risk of inflammation. In this study, we investigated effects of OMD and latanoprost acid (LTA), a FP agonist, on BRB and microglia in vitro and in vivo. To investigate the function of outer/inner BRB and microglia, in vitro, ARPE-19 cells, human retinal microvascular endothelial cells (HRMECs), and MG5 cells were used. Cell viability, inflammatory cytokines mRNA and protein levels, barrier morphology/function, and microglial activation were evaluated using proliferation assays, qRT-PCR, ELISA, immunocytochemistry, trans-epithelial electrical resistance, and permeability assay. Moreover, after vitreous injection into the mouse, outer BRB morphology, glial activation, and cytokine expression were assessed. Each OMD and LTA alone did not affect the viability or cytokines expression of the three types of cells. In ARPE-19 cells, the co-stimulation of OMD and LTA increased the mRNA and protein levels of inflammatory cytokines (IL-6, TNF-α, and VEGF-A) and decreased the barrier function and the junction-related protein (ZO-1 and ß-catenin). By contrast in HRMECs, the co-stimulation affected significant differences in the mRNA levels of some cytokine (IL-6 and TNF-α) but enhanced the barrier function. In MG5 cells, the cytokines mRNA and size of Iba1-expressed cell were increased. A non-steroidal anti-inflammatory inhibited the barrier dysfunction and the junction-related protein downregulation in ARPE-19 cells and activation of MG5 cells. Also in vivo, the co-stimulation induced outer BRB disruption, cytokine increase, and retinal glial activation. Therefore, the co-stimulation of EP2 and FP induced the inflammatory cytokine-mediated outer BRB disruption, the enhanced inner BRB function, and the microglial activation. The BRB imbalance and the intrinsic prostaglandin production may be involved in OMD-related inflammation.
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Barrera Hematorretinal , Edema Macular , Ratones , Humanos , Animales , Microglía/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Células Endoteliales/metabolismo , Enfermedades Neuroinflamatorias , Edema Macular/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber's hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects.
RESUMEN
Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.
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Descubrimiento de Drogas , Pirrolidinas/farmacología , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Relación Estructura-ActividadRESUMEN
PURPOSE: The effects of aqueous mediators possibly increasing the outflow resistance, transforming growth factor-ß1 (TGF-ß1), TGF-ß2, autotaxin (ATX), and lysophosphatidic acid (LPA) on human trabecular meshwork (hTM) cells and monkey Schlemm's canal endothelial (SCE) cells were characterized and compared, and the effects of intracameral application of these mediators on intraocular (IOP) elevation were also examined. METHODS: Cells were treated with TGF-ß1, TGF-ß2, ATX, LPA, or vehicle, and mRNA and protein expression levels of α-SMA, COL1A1, fibronectin, ß-catenin, and ZO-1 were examined with real-time quantitative PCR (RT-qPCR) or immunofluorescence analyses or both. The permeability of cell monolayers was measured by determining the transendothelial electrical resistance (TEER) or with the fluorescein isothiocyanate (FITC)-dextran permeability assay. IOP was evaluated in rabbit eyes after intracameral administration of the mediators. RESULTS: All mediators induced upregulation of α-SMA, COL1A1, and fibronectin in hTM cells. The effect of TGF-ß2 on mRNA expression of fibrotic markers was statistically significantly greater than that of TGF-ß1. The effects of ATX and LPA indicated the time-dependent difference in the upregulation of α-SMA, COL1A1, and fibronectin. The TEER and FITC-dextran permeability of the SCE cells was evaluated after treatment with TGF-ß1 and TGF-ß2, but no statistically significant change was observed within 24 h. ATX and LPA also reduced permeability statistically significantly after 3 h and 0.5 h, respectively, and the effect of LPA was more rapid compared to that of ATX. Statistically significant IOP elevation was observed in rabbit eyes as early as 0.5-2.0 h after ATX and LPA treatment and at 24 h after treatment with TGF-ß2. CONCLUSIONS: TGF-ß2 and ATX and LPA regulate aqueous outflow by modulation of hTM cells and SCE cells, and differences in timing between the effects of each mediator were observed. ATX and LPA showed more rapid effects on IOP elevation than TGF-ß2. It was suggested that TGF-ß2 and ATX/LPA are involved in increases of IOP, but the timing and sustainability differ between mediators, and they may play specific roles in different glaucoma subtypes.
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Humor Acuoso/fisiología , Presión Intraocular/efectos de los fármacos , Lisofosfolípidos/farmacología , Hipertensión Ocular/inducido químicamente , Hidrolasas Diéster Fosfóricas/farmacología , Factor de Crecimiento Transformador beta1/farmacología , Factor de Crecimiento Transformador beta2/farmacología , Actinas/genética , Actinas/metabolismo , Administración Oftálmica , Animales , Western Blotting , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Fibronectinas/genética , Fibronectinas/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Macaca fascicularis , Persona de Mediana Edad , Hipertensión Ocular/genética , Hipertensión Ocular/metabolismo , Soluciones Oftálmicas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Malla Trabecular/efectos de los fármacos , Malla Trabecular/metabolismo , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
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Encéfalo/patología , Tauopatías/patología , Proteínas tau/metabolismo , Adulto , Edad de Inicio , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Femenino , Heterocigoto , Humanos , Cuerpos de Inclusión/patología , Masculino , Persona de Mediana Edad , Tauopatías/metabolismo , Proteínas tau/genéticaRESUMEN
The glutamate excitotoxicity has been suggested as a factor involved in the loss of retinal neuronal cells, including retinal ganglion cell (RGC), in various retinal degenerative diseases including ischemia-reperfusion injury, diabetic retinopathy, and glaucoma. Excitotoxic RGC death is caused not only by direct damage to RGCs but also by indirect damage due to the inflammation of retinal glial cells. Sphingosine 1-phosphate (S1P) and ceramides are bioactive sphingolipids which have been shown to possess important physiological roles in cellular survival and apoptosis, and the balance between S1P and ceramide, sphingolipid rheostat, has been suggested to be important for determining cellular fate. Therefore, we conducted the present study to clarify the neuroprotective role of sphingolipid rheostat in excitotoxic RGC death in vivo and in vitro. Acute RGC death was induced by intravitreal N-methyl-d-aspartate (NMDA) injection in the mouse. The mRNA expression of sphingosine kinase (SphK1/SphK2) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The expressions of SphK1/2, S1P, S1P-receptor (S1PR), glial fibrillary acidic protein (GFAP), Iba1, and CD31 were examined by immunostaining. Retinal sphingolipids and ceramides were quantified by liquid chromatography with tandem mass spectrometry. The neuroprotective effect of the sphingosine kinase inhibitor (SKI) on RGC death was assessed by RGC count and Terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Further, the in vitro effect of SKI was investigated using rat primary cultured RGCs and glial cells. In addition, MG5 cells and A1 cells, which were mouse microglia and astrocyte cell-line, were also used. The expression of cleaved-caspase-3, GFAP, and Iba1 in RGCs, primary glial cells, MG5 cells, and A1 cells was assessed by immunostaining. NMDA injection resulted in mRNA upregulation of SphK1; however, SphK2 was reduced in the mouse retina. SphKs, S1P, S1PR1, S1PR2, and GFAP expression increased in the early-stage NMDA group, whereas S1P and GFAP were higher in the late-stage NMDA + SKI group. In the NMDA group, S1P expression was lower whereas sphingosine, C20, C22, and C24 ceramides showed higher levels. The proportion of very-long-chain ceramide was elevated in the NMDA group but reduced in the NMDA + SKI group. SKI treatment significantly increased RGC survival in retinal wholemount analysis and decreased apoptosis in the ganglion cell layer and inner nuclear layer. In vitro, SKI suppressed excitotoxic RGC death, cleaved-caspase-3 expression, and activated glial cells. The findings in the present study provide the first evidence demonstrating the involvement of sphingolipid rheostat in the neuroprotection against excitotoxic RGC death. Therefore, regulation of sphingolipid rheostat might serve as a potential therapy for retinal degenerative disease.
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Muerte Celular/efectos de los fármacos , Ceramidas/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Proproteína Convertasas/metabolismo , Degeneración Retiniana/prevención & control , Células Ganglionares de la Retina/patología , Serina Endopeptidasas/metabolismo , Esfingolípidos/farmacología , Animales , Recuento de Células , Células Cultivadas , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Ratas , Ratas Wistar , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismoRESUMEN
Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.
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Antígeno AC133/genética , Genética de Población , Retina/patología , Enfermedades de la Retina/genética , Adulto , Anciano , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Retina/diagnóstico por imagen , Enfermedades de la Retina/diagnóstico por imagen , Enfermedades de la Retina/epidemiología , Enfermedades de la Retina/patología , Agudeza Visual/genética , Adulto JovenRESUMEN
The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.
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Proteínas de Unión al GTP/genética , Proteínas de la Membrana/genética , Retina/patología , Enfermedades de la Retina/genética , Agudeza Visual/genética , Adolescente , Adulto , Niño , Femenino , Estudios de Asociación Genética , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Retina/diagnóstico por imagen , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/epidemiología , Enfermedades de la Retina/patología , Adulto JovenRESUMEN
Purpose: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease). Methods: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the OPA1 gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications-that is, with simple DOA-were compared to those of DOA-plus patients. Results: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the OPA1 gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the OPA1 gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA. Conclusions: All the patients with the DOA-plus phenotype carried one of the missense mutations in the OPA1 gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications-such as auditory neuropathy, vestibular dysfunction, and ataxia-followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the OPA1 gene.
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Pueblo Asiatico/genética , GTP Fosfohidrolasas/genética , Pérdida Auditiva Central/complicaciones , Pérdida Auditiva Central/genética , Mutación/genética , Atrofia Óptica Autosómica Dominante/complicaciones , Atrofia Óptica Autosómica Dominante/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Fondo de Ojo , Humanos , Japón , Masculino , Atrofia Óptica Autosómica Dominante/fisiopatología , Linaje , Campos Visuales , Adulto JovenRESUMEN
PURPOSE: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD). DESIGN: International, multicenter, retrospective cohort studies. PARTICIPANTS: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea. METHODS: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions. MAIN OUTCOME MEASURES: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants. RESULTS: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201). CONCLUSIONS: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population.
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Degeneración Macular , Distrofias Retinianas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Niño , Proteínas del Ojo/genética , Femenino , Frecuencia de los Genes , Humanos , Degeneración Macular/genética , Degeneración Macular/patología , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Retina/patología , Distrofias Retinianas/genética , Distrofias Retinianas/patología , Distrofias Retinianas/fisiopatología , Estudios Retrospectivos , Agudeza Visual , Adulto JovenRESUMEN
Accurately interpreting persistent, low human chorionic gonadotropin (hCG) levels is essential for managing gestational trophoblastic disease. Erroneous interpretation can lead to inappropriate interventions, including unnecessary chemotherapy or hysterectomy, or unjustified changes in chemotherapeutic regimens due to misidentification of a false-positive hCG as a true positive. The predominant etiology of phantom hCG is the presence of heterophilic antibodies. Consequently, screening for urine hCG is indispensable for its diagnosis because immunoglobulin is not generally present in urine. Here, we report about phantom hCG after a complete hydatidiform mole. Initial urine hCG evaluations were negative, although the serum hCG levels remained positive, leading to the diagnosis of phantom hCG. After subsequent delivery, urine hCG levels persisted at diminished levels. However, a different assay yielded negative hCG results for both serum and urine samples. The patient subsequently gave birth. The absence of hCG was consistently confirmed over five years.
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Background/Aim: Single-agent chemotherapy typically has curative outcomes in patients with low-risk gestational trophoblastic neoplasia (GTN). Although surgical intervention is a potential alternative, its efficacy in these patients remains unclear. This report describes a case in which surgical excision of a uterine polypoid lesion resolved chemotherapy-resistant low-risk GTN. Case Report: A 43-year-old patient received pulse actinomycin D treatment for post-molar low-risk GTN without extrauterine metastasis. However, the patient showed resistance to the chemotherapy regimen. There was no initial evidence of protrusion of GTN into the uterine cavity; however, a polypoid lesion grew into the uterine cavity during therapy. This growth was successfully excised via a transvaginal approach using forceps with minimal blood loss. There was a postoperative decrease in human chorionic gonadotropin levels, which ultimately reached the predetermined threshold without the need for changing the therapeutic protocol. Conclusion: Surgical resection should be considered a viable therapeutic strategy for uterine polypoid growth in chemotherapy-resistant low-risk GTN.
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Glutamate excitotoxicity is involved in retinal ganglion cell (RGC) death in various retinal degenerative diseases, including ischemia-reperfusion injury and glaucoma. Excitotoxic RGC death is caused by both direct damage to RGCs and indirect damage through neuroinflammation of retinal glial cells. Omidenepag (OMD), a novel E prostanoid receptor 2 (EP2) agonist, is a recently approved intraocular pressure-lowering drug. The second messenger of EP2 is cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). In this study, we investigated the neuroprotective effects of OMD on excitotoxic RGC death by focusing on differences in cAMP downstream signaling from the perspective of glia-neuron interactions. We established a glutamate excitotoxicity model in vitro and NMDA intravitreal injection model in vivo. In vitro, rat primary RGCs were used in an RGC survival rate assay. MG5 cells (mouse microglial cell line) and A1 cells (astrocyte cell line) were used for immunocytochemistry and Western blotting to evaluate the expressions of COX-1/2, PKA, Epac1/2, pCREB, cleaved caspase-3, inflammatory cytokines, and neurotrophic factors. Mouse retinal specimens underwent hematoxylin and eosin staining, flat-mounted retina examination, and immunohistochemistry. OMD significantly suppressed excitotoxic RGC death, cleaved caspase-3 expression, and activated glia both in vitro and in vivo. Moreover, it inhibited Epac1 and inflammatory cytokine expression and promoted COX-2, pCREB, and neurotrophic factor expression. OMD may have neuroprotective effects through inhibition of the Epac pathway and promotion of the COX-2-EP2-cAMP-PKA pathway by modulating glia-neuron interaction.
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Proteínas Quinasas Dependientes de AMP Cíclico , AMP Cíclico , Ciclooxigenasa 2 , Neuroglía , Fármacos Neuroprotectores , Células Ganglionares de la Retina , Animales , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ciclooxigenasa 2/metabolismo , AMP Cíclico/metabolismo , Ratones , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Ratas Sprague-Dawley , Ratas , Ácido Glutámico/metabolismo , Ácido Glutámico/toxicidad , Ratones Endogámicos C57BL , Masculino , N-Metilaspartato/farmacología , N-Metilaspartato/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
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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Transportadoras de Casetes de Unión a ATP , Degeneración Retiniana , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Transportadoras de Casetes de Unión a ATP/genética , Análisis Mutacional de ADN , Pueblos del Este de Asia/genética , Secuenciación del Exoma , Angiografía con Fluoresceína/métodos , Genotipo , Japón/epidemiología , Mutación Missense , Fenotipo , Degeneración Retiniana/genética , Degeneración Retiniana/diagnóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). METHODS: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. RESULTS: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. CONCLUSIONS: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Canales de Potasio con Entrada de Voltaje/genética , Enfermedades de la Retina/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Demografía , Electrorretinografía , Familia , Femenino , Humanos , Japón , Masculino , Datos de Secuencia Molecular , Linaje , Canales de Potasio con Entrada de Voltaje/química , Enfermedades de la Retina/fisiopatología , Alineación de Secuencia , Adulto JovenRESUMEN
BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression.
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Anomalías del Ojo/fisiopatología , Degeneración Retiniana/genética , Distrofias Retinianas/fisiopatología , Agudeza Visual/fisiología , Adolescente , Distribución por Edad , Electrorretinografía , Femenino , Humanos , Masculino , Mutación/genética , Adulto JovenRESUMEN
Objectives: Human chorionic gonadotropin (hCG) levels are essential for the management of trophoblastic diseases. This study aimed to compare the sensitivities and relationships of two hCG measurement methods (total hCG and the free ß-subunit of hCG) in managing gestational trophoblastic disease (GTD). Design and Methods: We analyzed data from patients treated for GTD at Chiba University Hospital between 2008 and 2019. We focused on cases where both total hCG (mIU/mL) and the free ß-subunit of hCG (ng/mL) were measured on the same day. Results: Out of 80 patients (mean age 38.9 ± 11.7 years) and 158 measurements, 26 had values below the sensitivity threshold for both tests. Fifty-nine measurements were positive for total hCG but below the sensitivity threshold for the free ß-subunit of hCG, whereas only two showed the opposite. Seventy-one measurements were positive for both total hCG and the free ß-subunit of hCG. There was a significant correlation between total hCG and the free ß-subunit of hCG with both positive values, (r = 0.94, p < 0.001; Spearman's correlation test). Of the 85 measurements with undetectable free ß-subunit levels, 26 also had undetectable total hCG levels. However, total hCG was detectable in 59 patients from these cases, with a median value (interquartile range) of 2.9 (1.75-4.9) mIU/mL. Conclusions: In the management of GTD, the use of the free ß-subunit system alone cannot be recommended.
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Purpose: Prostaglandin-associated periorbitopathy in patients with glaucoma is reportedly not caused by EP2 agonist, but it has been a cosmetic problem with prostaglandin F receptor (FP) agonists. In this study, patients with prostaglandin-associated periorbitopathy on FP agonists were switched to EP2 agonist and changes were investigated. Methods: Patients complaining of prostaglandin-associated periorbitopathy were included. The FP agonist was switched to EP2 agonist (omidenepag isopropyl), and patients were followed up for 7 months. Frontal photographs were taken at every visit, and objective changes in deepening of the upper eyelid sulcus were assessed by three observers. Subjective questionnaires (self-awareness of deepening of the upper eyelid sulcus, eyelid/peri-eyelid skin pigmentation, eyelash elongation, and conjunctival hyperemia) were acquired at the start and the endpoint. Factors associated with the change of prostaglandin-associated periorbitopathy were investigated using logistic regression analysis. Results: Included were 23 eyes of 23 patients (17 women; 60.6 years). At 7 months, objective deepening of the upper eyelid sulcus improved by 76%. The subjective questionnaires showed that deepening of the upper eyelid sulcus improved in 95%, eyelid/peri-eyelid skin pigmentation in 76%. The less extent of myopia was a significant factor in the eyes with improved eyelid/peri-eyelid skin pigmentation. After switching, no change in intraocular pressure or visual acuity was observed (P ≥ 0.22). Conclusion: Switching to omidenepag isopropyl increased patient satisfaction and might be the first step to lightening deepening of the upper eyelid sulcus and eyelid/peri-eyelid skin pigmentation. It was suggested that pigmentation may be more easily improved in nonmyopic eyes.