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BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.MethodsâandâResults: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.
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Tromboangitis Obliterante , Humanos , Masculino , Persona de Mediana Edad , Femenino , Tromboangitis Obliterante/terapia , Médula Ósea , Estudios Prospectivos , Isquemia/etiología , Isquemia/terapia , Trasplante Autólogo , Dolor , Resultado del Tratamiento , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/métodosRESUMEN
BACKGROUND: Corneal endothelial cell (CEC) disorders, such as Fuchs's endothelial corneal dystrophy, induce abnormal corneal hydration and result in corneal haziness and vision loss known as bullous keratopathy. We investigated whether injection of cultured human CECs supplemented with a rho-associated protein kinase (ROCK) inhibitor into the anterior chamber could increase CEC density. METHODS: We performed an uncontrolled, single-group study involving 11 persons who had received a diagnosis of bullous keratopathy and had no detectable CECs. Human CECs were cultured from a donor cornea; a total of 1×106 passaged cells were supplemented with a ROCK inhibitor (final volume, 300 µl) and injected into the anterior chamber of the eye that was selected for treatment. After the procedure, patients were placed in a prone position for 3 hours. The primary outcome was restoration of corneal transparency, with a CEC density of more than 500 cells per square millimeter at the central cornea at 24 weeks after cell injection. Secondary outcomes were a corneal thickness of less than 630 µm and an improvement in best corrected visual acuity equivalent to two lines or more on a Landolt C eye chart at 24 weeks after cell injection. RESULTS: At 24 weeks after cell injection, we recorded a CEC density of more than 500 cells per square millimeter (range, 947 to 2833) in 11 of the 11 treated eyes (100%; 95% confidence interval [CI], 72 to 100), of which 10 had a CEC density exceeding 1000 cells per square millimeter. A corneal thickness of less than 630 µm (range, 489 to 640) was attained in 10 of the 11 treated eyes (91%; 95% CI, 59 to 100), and an improvement in best corrected visual acuity of two lines or more was recorded in 9 of the 11 treated eyes (82%; 95% CI, 48 to 98). CONCLUSIONS: Injection of human CECs supplemented with a ROCK inhibitor was followed by an increase in CEC density after 24 weeks in 11 persons with bullous keratopathy. (Funded by the Japan Agency for Medical Research and Development and others; UMIN number, UMIN000012534 .).
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Córnea/citología , Enfermedades de la Córnea/terapia , Trasplante de Córnea , Células Endoteliales/trasplante , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Células Cultivadas , Terapia Combinada , Córnea/anatomía & histología , Córnea/cirugía , Enfermedades de la Córnea/tratamiento farmacológico , Enfermedades de la Córnea/cirugía , Células Endoteliales/metabolismo , Femenino , Humanos , Presión Intraocular , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group. DESIGN: Prospective observational study. PARTICIPANTS: This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014. METHODS: All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded. MAIN OUTCOME MEASURES: The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period. RESULTS: At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean ± standard deviation central corneal ECD was 1257 ± 467 cells/mm2 (range, 601-2067 cells/mm2), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed. CONCLUSIONS: The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery.
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Amidas/uso terapéutico , Edema Corneal/terapia , Endotelio Corneal/trasplante , Distrofia Endotelial de Fuchs/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidores , Adulto , Anciano , Cámara Anterior , Recuento de Células , Células Cultivadas , Terapia Combinada , Edema Corneal/diagnóstico , Edema Corneal/fisiopatología , Endotelio Corneal/citología , Femenino , Estudios de Seguimiento , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/fisiopatología , Rechazo de Injerto/prevención & control , Humanos , Inyecciones Intraoculares , Presión Intraocular/fisiología , Masculino , Persona de Mediana Edad , Posición Prona , Estudios Prospectivos , Medicina Regenerativa , Microscopía con Lámpara de Hendidura , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To provide the long-term outcome of patients with end-stage severe ocular surface disease (OSD) consecutively treated with cultivated oral mucosal epithelial transplantation (COMET) followed by limbal-rigid contact lens (CL)-wear therapy. DESIGN: Retrospective cohort. METHODS: In 23 eyes of 18 patients with severe OSD who underwent COMET surgery between 2002 and 2019 and who were followed with limbal-rigid CL-wear therapy for at least 1 year postoperative, patient demographics, best-corrected visual acuity (BCVA, logMAR), Ocular Surface Grading Scores (OSGS), surgical indication and adverse events were reviewed. Primary and secondary outcomes were BCVA and OSGS changes at baseline and final examination, respectively. RESULTS: This study involved 16 patients with Stevens-Johnson syndrome and 2 patients with mucous membrane pemphigoid (mean age: 59±15 years). The indications for COMET were as follows: corneal reconstruction for vision improvement (10 eyes (43.5%)), corneal reconstruction for persistent epithelial defect (4 eyes (17.4%)) and conjunctival (fornix) reconstruction for symblepharon release (9 eyes (39.1%)). The mean duration of CL-wear postsurgery was 6.4±3.9 years (range: 1.4 to 13.3 years). The mean BCVA at baseline and at final follow-up was logMAR 1.9±0.5 and 1.3±0.7, respectively (p<0.05). Compared with those at baseline, the OSGSs for symblepharon and upper and lower fornix shortening showed significant improvement at each follow-up time point post treatment initiation. No serious intraoperative or postoperative adverse events were observed. CONCLUSION: In patients afflicted with severe OSD, COMET combined with limbal-rigid CL-wear therapy postsurgery was found effective for vision improvement and ocular surface stabilisation.
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PRCIS: We propose a new classification model to serve as a control for future genomic studies of glaucoma by distinguishing normal subjects maintaining non-glaucoma status for 10 years using the vertical cup-to-disc ratio (VCDR). PURPOSE: This study aimed to develop a classification for distinguishing subjects maintaining non-glaucoma status for 10 years using the VCDR. PARTICIPANTS AND METHODS: Among 842 volunteers 40 years and older, 421 volunteers participated in the second ophthalmic examination 10 years after their first examination. Each volunteer was diagnosed either as healthy normal or glaucoma suspect (GS) in the first glaucoma screening examinations. The former was further classified into the 3 grades of N1, N2, and N3. Specifically, N1 represented (1) VCDR <0.3; (2) no notching or nerve fiber layer defect; and (3) no undermining, N2 indicated 0.3≤VCDR<0.6 and conditions (2) and (3) of N1; and N3 represented 0.3≤VCDR<0.6 with undermining and condition (2), or 0.6≤VCDR<0.7 and condition (2) of N1. Glaucoma transition rates (GTRs) were evaluated in 421 volunteers who returned to participate after a 10-year period. RESULTS: GTRs were calculated as 1.3% in both N1 and N2, 3.9% in N3, and 18.2% in GS. The ratio of volunteers in the same category maintenance rate increased from N1 to N3. CONCLUSION: GTRs were lower in N1 and N2 than in N3 or GS during the 10-year study period. This novel classification of healthy non-glaucoma subjects may help identify those, especially Japanese males, who maintain a non-glaucoma status for an extended period of 10 years.
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Glaucoma , Hipertensión Ocular , Disco Óptico , Masculino , Humanos , Estudios Longitudinales , Presión Intraocular , Glaucoma/diagnóstico , Hipertensión Ocular/diagnósticoRESUMEN
Rivaroxaban, a direct oral anticoagulant, is effective against venous thromboembolism (VTE) recurrence without increasing the risk of major bleeding in patients with cancer-associated venous thromboembolism (CAT). However, its clot regression effects are poorly understood. This single-arm, prospective interventional study aimed to investigate the clot regression effects of rivaroxaban in 40 CAT patients, through a contrast-enhanced computed tomography at baseline, 3 weeks, and 3 months of rivaroxaban treatment. The primary endpoint was the clot-regression ratio calculated from the thrombus volumes at 3 weeks and 3 months. Compared with baseline, the total clot volume was significantly reduced at both 3 weeks and 3 months after initiation (p < 0.01). The clot-regression rates were statistically significant with 83.1% (95% confidence interval [CI], 73.8-92.3%) at 3 weeks and 98.7% (95% CI, 97.1-100.2%) at 3 months, with complete resolution in 36.1% and 80.8% of patients at 3 weeks and 3 months, respectively. One patient had recurrent VTE after dose reduction, and seven had non-fatal major bleeding. Therefore, rivaroxaban had a sufficient clot-regression effect against CAT with caution of bleeding complication.
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Neoplasias , Trombosis , Tromboembolia Venosa , Humanos , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , Tromboembolia Venosa/etiología , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Estudios Prospectivos , Hemorragia/inducido químicamente , Trombosis/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Anticoagulantes/efectos adversosRESUMEN
PURPOSE: To investigate the safety and efficacy of cultured human corneal endothelial cell (hCEC) injection therapy with mature differentiated (mature) cell subpopulations (SPs) for corneal endothelial failure (CEF). DESIGN: Comparative, interventional case series. METHODS: This study involved 18 eyes with CEF that underwent cultured hCEC injection therapy, categorized into 2 groups: (1) 11 eyes administered a relatively lower proportion (0.1 to 76.3%) of mature cell SPs (group 1 [Gr1]), and (2) 7 eyes administered a relatively higher proportion (>90%) of mature cell SPs (group 2 [Gr2]). From 1 week to 3 years postoperation, corneal endothelial cell (CEC) density (CECD), central corneal thickness (CCT), and best-corrected visual acuity (BCVA) were recorded, and the CEC parameter's "spring constant" was calculated. The proportion of mature SPs was evaluated by fluorescence-activated cell sorting analysis based on cell-surface markers. RESULTS: At 3 years postoperation, corneal restoration with improved BCVA was attained in 10 of the 11 Gr1 eyes and all Gr2 eyes, the median CECD in Gr2 (3083 cells/mm2; range, 2182-4417 cells/mm2) was higher than that in Gr1 (1349 cells/mm2; range, 746-2104 cells/mm2) (P < .001), and the spring constant verified the superiority of the mature cultured hCECs. From 24 weeks through 3 years postoperation, the median percentage of CECD decrease was 3.2% in Gr2 and 23.6% in Gr1 (P < .005). CCT recovery was prompt and constant in Gr2, while diverse in Gr1. No adverse events were observed. CONCLUSION: Our findings showed that mature cell SPs for hCEC injection therapy provide rapid recovery of CCT, better CECD, and low CECD attrition over 3 years postsurgery.
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Córnea , Endotelio Corneal , Recuento de Células , Diferenciación Celular , Células Cultivadas , Células Endoteliales , HumanosRESUMEN
PURPOSE: To investigate the trend of seasonal variation of intraocular pressure (IOP) in patients with normal-tension glaucoma over a 20-year period by retrospectively analyzing the Kyoto Prefectural University of Medicine Glaucoma Registry database as real-world data. DESIGN: Retrospective cohort study. METHODS: Data points (n = 49,007) were extracted retrospectively from the medical records of 1774 patients with normal-tension glaucoma (665 male patients and 1109 female patients; mean ± SD age was 59.8 ± 14.4 years; and mean ± SD observation period was 5.6 ± 4.4 years) seen over the 20-year period. We first calculated the mean IOP from all available data of each month from January 1997 through December 2016. The data were then categorized into 5 groups of 4 consecutive years each (1997-2000, 2001-2004, 2005-2008, 2009-2012, and 2013-2016) and the mean IOP of each month within the group was calculated. Seasonal variations of IOP over the 20-year study period and in the 5 consecutive groups were then investigated via nonlinear multiple regression analysis. RESULTS: A continuous decrease of IOP was detected throughout the 20-year period (P < .001), with distinct seasonal variation. The annual mean ± SD IOP was highest (13.9 ± 2.7 mm Hg) in the oldest group (1997-2000), with a gradual decrease in each subsequent group, finally becoming lowest (12.3 ± 2.7 mm Hg) in the most recent group (2013-2016) (P < .001), and all of them were accompanied by distinct seasonal variation (P < .001). CONCLUSIONS: Based on the Kyoto Prefectural University of Medicine Glaucoma Registry real-world longitudinal data, our findings revealed a continuous decrease and distinct seasonal variation of IOP in patients with normal-tension glaucoma throughout the 20-year study period.
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Glaucoma , Presión Intraocular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estaciones del Año , Tonometría OcularRESUMEN
PURPOSE: To analyze the therapeutic benefits of limbal-supported contact lens (CL) wear in patients with ocular sequelae due to Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). METHODS: This interventional study enrolled 10 chronic SJS/TEN eyes with a spectacle best-corrected visual acuity (BCVA) of between 0.01 and 0.7 that were fitted with a limbal-supported CL. At baseline and at after 3-months CL use, CL-wear BCVA and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores were measured, and then compared. Incidence rates and severities of adverse events were also analyzed. RESULTS: At after 3-months CL use, BCVA with the fitted CL significantly improved compared to that with spectacle correction at baseline (LogMAR: 0.76-0.15) (P = 0.0039), all NEI VFQ-25 scores improved, however, only in ocular pain and mental health showed statistically significant improvement (P = 0.0078 and 0.0039). No serious adverse events were observed during the follow-up. CONCLUSION: Wearing of the limbal-supported CL improved vision compared to spectacles and reduced ocular pain in patients with ocular sequelae due to SJS/TEN.
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Lentes de Contacto , Síndrome de Stevens-Johnson , Estudios de Seguimiento , Humanos , Estudios Retrospectivos , Síndrome de Stevens-Johnson/complicaciones , Síndrome de Stevens-Johnson/terapia , Agudeza VisualRESUMEN
Critical limb ischemia (CLI) is a potentially life-threatening condition that involves severely reduced blood flow to the peripheral arteries due to arteriosclerosis obliterans (ASO) of the limbs or a similar condition. CLI patients must undergo revascularization to avoid amputation of the lower limbs and improve their survival prognosis. However, the outcomes of conventional surgical revascularization or endovascular therapy are inadequate; therefore, establishing further effective treatment methods is an urgent task. We perform therapeutic angiogenesis using autologous bone marrow-derived mononuclear cells in clinical practice and demonstrated its safety and efficacy for CLI patients for whom conventional treatments failed or are not indicated. Exercise therapies must be devised for CLI patients who have undergone therapeutic angiogenesis to save their limbs and improve survival. Because evidence regarding the efficacy and safety of exercise therapy for CLI patients is lacking, we plan to perform a prospective trial of the efficacy and safety of optimal exercise therapy following therapeutic angiogenesis for CLI patients.The trial will enroll 30 patients between 20 and 79 years with Rutherford category 4 or 5 CLI caused by ASO who will undergo therapeutic angiogenesis. Participants will be randomly allocated to receive either optimal exercise therapy or fixed exercise therapy. Those receiving optimal exercise therapy will undergo tissue muscle oxygen saturation monitoring using near-infrared spectroscopy while performing exercises and will be prescribed optimal exercise therapy. The optimal amount of exercise will be determined on day 8, 31, 61, 91 and 181 after therapeutic angiogenesis. ETHICS AND DISSEMINATION: This protocol was approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine. In accordance with the Helsinki Declaration, written informed consent has been obtained from all participants prior to enrollment. The results of this trial will be disseminated by publication in a peer-reviewed journal. TRIAL REGISTRATION: This trial is registered at http://www.umin.ac.jp/ctr/index.htm (identifier: UMIN000035288).
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Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.
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Quemaduras Químicas/terapia , Lentes de Contacto , Células Epiteliales/trasplante , Quemaduras Oculares/inducido químicamente , Mucosa Bucal/citología , Penfigoide Benigno de la Membrana Mucosa/terapia , Síndrome de Stevens-Johnson/terapia , Quemaduras Químicas/fisiopatología , Células Cultivadas , Terapia Combinada , Enfermedades de la Córnea/fisiopatología , Enfermedades de la Córnea/terapia , Epitelio Corneal/citología , Epitelio Corneal/trasplante , Quemaduras Oculares/fisiopatología , Humanos , Penfigoide Benigno de la Membrana Mucosa/fisiopatología , Trasplante de Células Madre , Síndrome de Stevens-Johnson/fisiopatología , Trastornos de la Visión/rehabilitación , Agudeza Visual/fisiologíaRESUMEN
INTRODUCTION: Anticoagulant therapy in patients with cancer with venous thromboembolism (VTE) increases the risk of both VTE recurrence and haemorrhagic complication. Direct oral anticoagulants (DOACs) have been shown to be effective in preventing VTE recurrence, and comparable to conventional therapy in preventing VTE recurrence in patients with advanced cancer. Rivaroxaban is a DOAC that causes thrombus regression, possibly through a profibrinolytic effect. Thrombus regression with initial treatment is essential for VTE patients. However, the thrombolytic effect of DOAC for VTE patients with cancer has not been fully examined. Therefore, in this study, we investigate the thrombolytic effect of rivaroxaban in patients with cancer who develop VTE. METHODS AND ANALYSIS: This study is a single-arm, open-label, prospective interventional study. Forty patients aged from 20 to 75 years old at the time of consent who have been diagnosed with acute VTE and have active cancer are included. Patients are excluded if they have received thrombolytic therapy, have creatinine clearance of less than 30 mL/min, have expected a life expectancy of less than 6 months or have deep vein thrombosis limited to the distal lower leg. Eligible patients receive standard treatment with rivaroxaban (15 mg two times daily for 3 weeks, followed by 15 mg QD). The primary study endpoint is clot regression ratio as evaluated by contrast-enhanced CT imaging. CT imaging is obtained at baseline, 21±4 and 90±14 days after the start of rivaroxaban treatment. Secondary endpoints are the recurrence of VTE and haemorrhagic complications. ETHICS AND DISSEMINATION: This study was approved by the institutional review board of the Kyoto Prefectural University of Medicine. Study results will be disseminated through peer-reviewed journals.Trial registration numberUMIN000027793.
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Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Neoplasias/complicaciones , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , Trombosis/tratamiento farmacológico , Trombosis/etiología , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5âmg or anastrozole 1âmg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60âmg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.
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Inhibidores de la Aromatasa/efectos adversos , Densidad Ósea/efectos de los fármacos , Denosumab/administración & dosificación , Osteoporosis/inducido químicamente , Osteoporosis/prevención & control , Adulto , Inhibidores de la Aromatasa/uso terapéutico , Biomarcadores , Huesos/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Fracturas Óseas/epidemiología , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos de InvestigaciónRESUMEN
PURPOSE: We performed genetic association studies using a native Japanese population to examine the reproducibility of results of lysyl oxidase-like 1 (LOXL1) genetic association studies for exfoliation glaucoma (XFG) beyond the differences of ethnicity. We also quantified LOXL1 mRNA expression in the human lens capsule to examine the possible correlation between LOXL1 expression and XFG pathogenesis. METHODS: We performed a case-control study using 95 Japanese XFG patients and 190 controls. Real-time polymerase chain reaction (PCR) analysis was performed using lens capsules obtained during surgery. RESULTS: The TT genotype in the single nucleotide polymorphism (SNP) rs1048661 and the GG genotype in the SNP rs3825942 in exon 1 of LOXL1 were significantly associated with an increased risk of XFG under recessive models (chi(2) test, p=5.34 x 10(-34) and p=2.1 x 10(-8), respectively). Quantification of LOXL1 mRNA expression demonstrated no significant difference between XFG and senile cataract samples. CONCLUSIONS: Although the functional effects of the LOXL1 SNP appear to be qualitative rather than quantitative, the amino acid substitution (R141L) caused by SNP rs1048661 is not a simple decisive factor for XFG due to the inverted allele frequency between Japanese XFG and Caucasian XFG patients. Further genetic and functional studies are essential for clarifying XFG pathogenesis.
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Aminoácido Oxidorreductasas/genética , Pueblo Asiatico/genética , Síndrome de Exfoliación/complicaciones , Síndrome de Exfoliación/genética , Predisposición Genética a la Enfermedad , Glaucoma/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Regulación de la Expresión Génica , Glaucoma/complicaciones , Haplotipos , Humanos , Cápsula del Cristalino/metabolismo , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Steroid treatment is believed to be effective for frosted branch angiitis, but frosted branch angiitis with retinal circulatory insufficiency does not have a good prognosis by steroid treatment alone. Here, we present a case of a patient that had a good outcome when treated with long-term active systemic betamethasone and vasodilation therapy for bilateral frosted branch angiitis with acute chorioretinal circulatory insufficiency. CASE: A 69-year-old male presented with sudden visual loss in his left eye. The visual acuity was 1.0 in the right eye and 0.1 in the left eye. In his left eye, only mild inflammation occurred in the anterior chamber, but extensive inflammation such as sheathing of retinal vessels, retinal hemorrhage, and edema of the optic disc was present. Fluorescein angiography showed a delay of the arm-retinal artery circulation time and severe dye leakage from the retinal vessels. The following day, the visual acuity worsened to 0.1 in the right eye and hand motion in the left eye. Moreover, extensive inflammation was now present in both the anterior and posterior segments, and the sheathing of the retinal vessels developed to frosted branch-like angiitis. Doppler examination showed flow in the bilateral ophthalmic artery but did not show flow in the central retinal artery or posterior ciliary artery. These findings were compatible with the diagnosis of frosted branch angiitis with chorioretinal circulatory insufficiency. We initiated active systemic steroid therapy for 7 months and vasodilation therapy for 3 months. Two years later, the visual acuity improved to 0.5 in both eyes. CONCLUSION: Long-term active systemic steroid therapy for frosted branch angiitis with severe circulatory insufficiency in the retina and choroid may improve visual function.
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Coroides/irrigación sanguínea , Vasculitis Retiniana/tratamiento farmacológico , Esteroides/administración & dosificación , Anciano , Betametasona/administración & dosificación , Angiografía con Fluoresceína , Humanos , Masculino , Prostaglandinas/administración & dosificación , Arteria Retiniana/fisiopatología , Vasodilatadores/administración & dosificaciónRESUMEN
The common variants in lysyl oxidase-like 1 gene (LOXL1) are associated with exfoliation glaucoma (XFG) patients developed through exfoliation syndrome (XFS). However, the risk allele of a variant in LOXL1 has been found to be inverted between Asian and Caucasian populations. Therefore, we newly performed a genome-wide association study using 201 XFS/XFG and 697 controls in Japanese, and identified 34 genome-wide significant single-nucleotide polymorphisms (SNPs) distributing in not only LOXL1 but also TBC1D21 and PML at the 15q24.1 locus. These SNPs were confirmed by an independent population consisted of 121 XFS/XFG and 263 controls in Japanese. Moreover, further analyses revealed a unique haplotype structure only from the combination of TBC1D21 and LOXL1 variants showing a high XFS/XFG susceptibility specific for the Asian population. Although there still should be other gene(s) in the other region(s) contributing to the disease process, these results suggested that the combination of newly discovered variants in these genes might be useful for precise XFG risk assessment, as well as for elucidating the molecular mechanism of XFG pathogenesis through XFS.
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Aminoácido Oxidorreductasas/genética , Síndrome de Exfoliación/genética , Proteínas Activadoras de GTPasa/genética , Predisposición Genética a la Enfermedad/genética , Haplotipos , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Síndrome de Exfoliación/etnología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/métodos , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Japón , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteína de la Leucemia Promielocítica , Factores de Riesgo , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
PURPOSE: To investigate the impact of myopia and duration of hard contact lens (HCL) wear on the progression of ptosis. METHODS: This study involved 194 eyes of 98 patients with either bilateral or unilateral ptosis with long-term HCL wear. The ptosis of each eyelid was classified into 1 of 4 grades (no ptosis, mild, moderate and severe), and the average spherical equivalent refractive error (SERE), patient age and the duration of HCL wear were then examined. RESULTS: The average SERE (in diopters) in 99 severe eyes was -8.34, in 47 moderate eyes, -6.28, in 37 mild eyes -5.57 and in 11 no ptosis eyes, -4.80, while the average duration of HCL wear (in years) were 34, 30, 29, and 31, respectively. The average SERE was significantly higher in the severe than in the moderate, mild and no ptosis eyelids, and the average duration of HCL wear was significantly longer in the severe than in the moderate and mild ptosis eyelids. Path analysis showed that the severity of ptosis is significantly influenced by SERE, as well as by patient age and the duration of HCL wear. CONCLUSION: High myopia, patient age and long-term HCL wear are risk factors associated with the progression of ptosis.
Asunto(s)
Blefaroptosis/diagnóstico , Lentes de Contacto/efectos adversos , Miopía Degenerativa/complicaciones , Adulto , Anciano , Blefaroplastia , Blefaroptosis/clasificación , Blefaroptosis/etiología , Blefaroptosis/cirugía , Córnea/fisiopatología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miopía Degenerativa/fisiopatología , Refracción Ocular/fisiología , Factores de Riesgo , Factores de Tiempo , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: Further to our previous report of a genetic association between interferon-gamma (IFN-γ) receptor 1 gene and atopic cataract, we investigated the roles of plasminogen activator inhibitor-1 (PAI-1), a fibrosis-related, IFN-γ downstream molecule, in the pathogenesis of atopic cataracts. METHODS: Cultured lens epithelial cells (LECs) were stimulated by IFN-γ and quantified by PAI-1 mRNA/protein expression. PAI-1 and TGF-ß mRNA expression was quantified using cDNA samples obtained from the lens epithelium of atopic cataract patients (n = 7) and of senile cataract patients (n = 8). The anterior capsules obtained from atopic cataracts (n = 9) were immunostained with anti-PAI-1 and anti-alpha smooth muscle actin (α-SMA) antibodies. PAI-1 gene expression was knocked down by PAI-1 siRNA, and α-SMA expression was examined under TGF-ß1 stimulation. Expression of α-SMA was examined as a pathological hallmark of anterior subcapsular cataracts, commonly observed in atopic cataracts. RESULTS: The IFN-γ stimulation induced PAI-1 mRNA/protein expression in the LECs from 24 to 48 hours after stimulation. The expression of PAI-1 mRNA and TGF-ß1 mRNA was significantly higher in the cDNA samples obtained from the atopic cataracts than those obtained from the senile cataracts. PAI-1-positive immunostaining was observed at the fibrotic lesion of the atopic cataracts, and α-SMA-positive myofibroblasts were observed at the vicinity of the PAI-1-positive lesion in all nine samples examined. PAI-1 gene knockdown resulted in reduced α-SMA expression in the LECs. CONCLUSIONS: The findings of this study suggest that the IFN-γ, PAI-1, and TGF-ß1 are involved in the pathophysiology of atopic cataracts.
Asunto(s)
Catarata/genética , Regulación de la Expresión Génica , Cristalino/metabolismo , ARN Mensajero/genética , Western Blotting , Catarata/metabolismo , Catarata/patología , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Humanos , Inmunohistoquímica , Interferón gamma/farmacología , Cristalino/efectos de los fármacos , Cristalino/patología , Microscopía Electrónica , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Inhibidor 1 de Activador Plasminogénico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
BACKGROUND: To date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated. METHODS AND PRINCIPAL FINDINGS: We examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8 × 10(-10)). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)--POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)--and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients. CONCLUSIONS AND SIGNIFICANCE: In this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma.