Publications by authors named "Hiroyuki Kondo"

82 Publications

Epidemiologic study of rhegmatogenous retinal detachment in Japan from the Diagnosis Procedure Combination database over a 2-year period (2014-2015).

Jpn J Ophthalmol 2021 Aug 31. Epub 2021 Aug 31.

Department of Ophthalmology, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Yahatanishiku, Iseigaoka, Kitakyushu, 807-8556, Japan.

Purpose: To determine the incidence of rhegmatogenous retinal detachments (RRDs) and proliferative vitreoretinopathies (PVRs) and their distribution by age and sex in hospitalized patients in Japan.

Study Design: Retrospective nationwide observational study.

Methods: Information on the number of inpatients primarily diagnosed with RRD or PVR and their age and sex were collected from the Diagnosis Procedure Combination (DPC) database for 2014 and 2015. The incidence was determined using the Japanese population report published by the Public Management Ministry's Statistics Bureau.

Results: The incidence of RRD in these hospitalized patients was 10.9/100,000, with 15.0/100,000 in men and 7.1/100,000 in women, and that of PVR was 2.1/100,000, with 2.9/100,000 in men and 1.3/100,000 in women. The incidence in men was twice that in women for both RRD and PVR. The distribution of RRD by age was monophasic, with a peak at 50 years for both sexes, and that of PVR was at peak in the 60 s for men and in the 70 s for women. PVR was more common than RRD in children aged younger than 10 years, but the incidence of RRD was higher in the other age groups.

Conclusion: A study of the DPC database can provide useful information on the incidences of RRD and PVR in hospitalized patients in Japan.
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http://dx.doi.org/10.1007/s10384-021-00867-zDOI Listing
August 2021

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

Headache 2021 Jul 29;61(7):1092-1101. Epub 2021 Jul 29.

Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.

Objective: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM).

Background: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene-related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large-scale, international Phase 3 trials.

Methods: Randomized, placebo-controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12 weeks after the first dose.

Results: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least-squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (-4.1 ± 0.4) and fremanezumab quarterly (-4.1 ± 0.4) than with placebo (-2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was -1.7 days (-2.54, -0.80) for the fremanezumab monthly group and -1.7 days (-2.55, -0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12-week period ± SE: fremanezumab monthly, -3.7 ± 0.4; fremanezumab quarterly, -3.9 ± 0.4; placebo, -2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six-item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, -8.1 ± 0.7; fremanezumab quarterly, -8.0 ± 0.7; placebo, -6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection-site reactions as placebo (patients with at least one treatment-emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]).

Conclusion: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.
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http://dx.doi.org/10.1111/head.14169DOI Listing
July 2021

Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

Headache 2021 Jul 29;61(7):1102-1111. Epub 2021 Jul 29.

Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.

Objective: To evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine.

Background: Episodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene-related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine.

Methods: This Phase 3 randomized, placebo-controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12-week treatment period after the first dose.

Results: Of 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least-squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (-4.0 ± 0.4, n = 121) and fremanezumab quarterly (-4.0 ± 0.4, n = 117) than with placebo (-1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12-week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection-site reactions were more common in fremanezumab-treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%).

Conclusion: Fremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns.
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http://dx.doi.org/10.1111/head.14178DOI Listing
July 2021

Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity.

BMJ Open 2021 07 27;11(7):e047003. Epub 2021 Jul 27.

Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Introduction: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP.

Methods And Analysis: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints.

Ethics And Dissemination: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals.

Trial Registration Numbers: NCT04621136 and jRCT2071200047.
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http://dx.doi.org/10.1136/bmjopen-2020-047003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317081PMC
July 2021

Revesz syndrome with bilateral retinal detachments successfully treated by pars plana vitrectomy.

Am J Ophthalmol Case Rep 2021 Sep 16;23:101137. Epub 2021 Jun 16.

Department of Ophthalmology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

Background: Revesz syndrome is a rare type of the dyskeratosis congenita spectrum disorder that is characterized by nail dystrophy, oral leukoplakia, and abnormal skin pigmentation. The retinal features are similar to those of exudative retinopathy with avascular areas of the peripheral retina. There are only a few publications describing patients with Revesz syndrome who underwent ocular treatments for the retinal complications. We report a Case of Revesz syndrome with bilateral retinal detachments that were successfully reattached by pars plana vitrectomy.

Observations: A 3-year-old Japanese girl with Revesz Syndrome had progressive vitreal hemorrhages and tractional retinal detachments in both eyes. She underwent pars plana vitrectomy with lensectomy on both eyes. A retinal attachment with vision improvement was achieved by a single surgery for the right eye and after repeated surgeries for the left eye. Postoperative electroretinographic (ERG) examinations of the right eye showed a negative type ERG with the b-wave/a-wave ratio <1.0. There were extensive areas of avascular retina detected by fluorescein angiography and a thinning of the inner and outer retina detected by optical coherence tomography.

Conclusion And Importance: Pars plana vitrectomy can effectively treat the extensive retinal detachment in an eye with Revesz syndrome. However, postoperative retinal ischemia can be detected by careful imaging.
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http://dx.doi.org/10.1016/j.ajoc.2021.101137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220311PMC
September 2021

Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene.

Transl Vis Sci Technol 2021 06;10(7):18

Department of Ophthalmology, Kindai University Faculty of Medicine, Osakasayama, Japan.

Purpose: To determine the clinical characteristics of patients and family members with familial exudative vitreoretinopathy (FEVR) caused by mutations in the KIF11 gene.

Methods: Twenty-one patients from 10 FEVR families with mutations in the KIF11 gene were studied. The retinal and systemic features were examined. The genetic analyses performed included Sanger sequencing of the KIF11 gene, whole exome sequencing, as well as array comparative genomic hybridization (CGH) analysis and multiple ligation probe assay (MLPA).

Results: Sequence analysis revealed seven different KIF11 mutations. Array CGH with MLPA revealed two different exon deletions. All probands had advanced FEVR with retinal detachments (RDs) and microcephaly with or without developmental disabilities. Patients with bilateral RDs were more frequently associated with developmental disabilities (P = 0.023). Multimodal imaging of the family members revealed that six of nine patients without RDs (66%) had varying degrees of chorioretinopathy. The retinal folds in FEVR patients were associated with severe retinal avascularization. However, funduscopic changes in the peripheral retina were unremarkable in family members without RDs. A score representing the peripheral vascular anomalies determined from the fluorescein angiograms was lower than that of control eyes of patients with mutations of the Wnt signaling genes (P = 0.0029).

Conclusions: The probands with KIF11 mutations were associated with severe ocular and systemic pathologies, whereas affected family members showed highly variable clinical manifestations. Peripheral vascular anomalies can often be unremarkable in eyes without RDs.

Translational Relevance: These findings highlight more diverse mechanisms that underlie the pathological changes in patients with FEVR.
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http://dx.doi.org/10.1167/tvst.10.7.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212440PMC
June 2021

Familial exudative vitreoretinopathy with mutation without signs of Loeys-Dietz syndrome.

Ophthalmic Genet 2021 Jun 9:1-4. Epub 2021 Jun 9.

Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan.

: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder with high genetic heterogeneity, and it is characterized by a defect in the development of the retinal vascular system. Loeys-Dietz syndrome (LDS) is an autosomal dominant systemic connective tissue disorder that is caused by mutations in the genes related to transforming growth factor signaling systems including the gene. Two earlier studies reported that patients with LDS from mutations in the gene were associated with FEVR-like retinal phenotype. The purpose of this study was to determine the characteristics of a case of FEVR without systemic abnormalities who had a mutation in the gene.: The clinical appearances and surgical outcomes were determined from the medical records. Genetic analysis was performed by whole exome sequencing.: A 15-year-old boy was diagnosed with FEVR by the appearance of the peripheral retina of both eyes and a retinal detachment in the left eye. Whole exome sequencing revealed a heterozygous deletion mutation in the gene. A mutation was confirmed by examining the family members. No systemic abnormalities were detected in the patient including those associated with LDS.: FEVR can be associated with a mutation without showing signs of LDS.
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http://dx.doi.org/10.1080/13816810.2021.1938137DOI Listing
June 2021

Genotype-Phenotype Correlations in -Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Department of Ophthalmology, The Jikei University School of Medicine, 3-19-18, Nishi-shimbashi, Minato-ku, Tokyo 105-8471, Japan.

Background: Little is known about genotype-phenotype correlations of -associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of variants and provide a detailed description of the clinical findings in Japanese patients.

Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD.

Results: We identified 18 pathogenic variants, including seven novel variants. Interestingly, the element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients.

Conclusions: Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the element insertion was the most major variant in Japanese patients with -associated retinal dystrophies.
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http://dx.doi.org/10.3390/jcm10112265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197273PMC
May 2021

Homozygous single nucleotide duplication of SLC38A8 in autosomal recessive foveal hypoplasia: The first Japanese case report.

Doc Ophthalmol 2021 May 26. Epub 2021 May 26.

Department of Ophthalmology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan.

Purpose: To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene.

Methods: We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation.

Results: In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting.

Conclusions: This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.
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http://dx.doi.org/10.1007/s10633-021-09842-yDOI Listing
May 2021

Correlation between improvement in visual acuity and QOL after Ranibizumab treatment for age-related macular degeneration patients: QUATRO study.

BMC Ophthalmol 2021 Jan 23;21(1):58. Epub 2021 Jan 23.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: To evaluate the correlation between visual acuity improvement and vision-related QOL after ranibizumab treatment in Japanese patients with AMD.

Methods: In this one-year prospective, interventional, open-label, multicenter study involving four sites, patients with neovascular AMD were enrolled and observed for 12 months. Treatment-naïve patients received 0.5 mg ranibizumab as needed after three initial monthly doses. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at every visit. Evaluations with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and patient satisfaction questionnaire were performed at baseline and 3 and 12 months after initial treatment. The primary endpoint was change in BCVA and QOL 3 months after ranibizumab treatment. QOL outcomes were also assessed in the better and poor BVCA subgroups.

Results: The study enrolled 100 patients. The mean logMAR BCVA after treatment improved significantly from 0.43 to 0.30 at 3 months (p< 0.0001), and 0.28 at 12 months (p< 0.0001). The mean NEI-VFQ-25 composite scores improved from 79.48 to 84.13 at 3 months (p< 0.0001), and 86.0 at 12 months (p< 0.0001). The 3 and 12-month changes in NEI-VFQ-25 score and BCVA showed significant correlation. In the poor baseline visual acuity group (decimal BCVA ≤0.5), there was a significant correlation between the changes in the NEI-VFQ-25 score and BCVA (p=0.02) but not in the better baseline visual acuity group (decimal BCVA > 0.6, p=0.1) at 3 months. There were no significant differences in the satisfaction questionnaire score from baseline to at 3 months (p=0.54) and 12 months (p=0.23). The average CMT improved significantly from 340 to 264 μm at 3 months (p< 0.0001) and to 268 μm at 12 months (p< 0.0001).

Conclusions: Intravitreal ranibizumab treatment resulted in improvement in visual acuity, anatomical change, and visual function change in Japanese AMD patients. Significant improvement was seen in patient visual function, and this was correlated with changes in VA, except immediately after loading dose treatment in patients with higher baseline VA. The patients' satisfaction with the treatment remained unchanged during the study period.

Trial Registration: This study is registered at UMIN Clinical Trials Registry ( UMIN000012013 ). Registered October 10, 2013, as prospective study.
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http://dx.doi.org/10.1186/s12886-021-01816-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825175PMC
January 2021

Smelling the Dark Proteome: Functional Characterization of PITH Domain-Containing Protein 1 (C1orf128) in Olfactory Metabolism.

J Proteome Res 2020 12 13;19(12):4826-4843. Epub 2020 Nov 13.

Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain.

The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1 mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.
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http://dx.doi.org/10.1021/acs.jproteome.0c00452DOI Listing
December 2020

Autosomal dominant foveal hypoplasia without visible macular abnormalities and PAX6 mutations.

Jpn J Ophthalmol 2020 Nov 28;64(6):635-641. Epub 2020 Aug 28.

Department of Ophthalmology, University of Occupational and Environmental Health, Japan, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan.

Purpose: Autosomal dominant foveal hypoplasia (FVH1) is a rare disorder associated with mutations in the PAX6 gene. As an isolated disease entity, FVH1 does not include ocular disorders such as aniridia, microphthalmia, albinism, and achromatopsia. However, it only includes isolated foveal hypoplasia and foveal hypoplasia with presenile cataract. The purpose of this report is to present our findings in four patients from two families with FVH1 without visible ophthalmic macular abnormalities.

Study Design: A review of the medical records of two families with FVH1 and genetic confirmation of mutations in the PAX6 gene.

Methods: Fundus photographs, optical coherence tomographic (OCT) and OCT angiographic (OCTA) images, and slit-lamp anterior segment findings were determined. The type of mutation of the PAX6 gene was determined.

Results: A 3-year-old girl (Patient 1) had signs and symptoms of an impairment in the development of vision without other retinal abnormalities OU. OCT images showed a shallow foveal pit, and OCTA showed the absence of the foveal avascular zone. The second patient (Patient 2) was a 6-year-old girl with unilateral mild cataract and shallow foveal pits OU. Similar shallow foveal pits were found in her asymptomatic mother (Patient 3) and maternal grandfather (Patient 4). Although the iris and posterior fundus were normal, all patients with FVH1 had goniodysgenesis. Genetic testing of the PAX6 gene revealed that Patient 1 had a novel heterozygous mutation (p.Asn365Lys) as a de novo mutation, and Patients 2, 3 and 4 had a novel heterozygous mutation (p.Pro20Ser).

Conclusions: Heterozygous mutations in the PAX6 gene can cause FVH1 with nearly normal appearing macula. FVH1 is difficult to diagnose, but detailed observations of the foveal structure and vasculature, and detecting the presence of goniodysgenesis can be helpful in identifying patients with FVH1.
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http://dx.doi.org/10.1007/s10384-020-00766-9DOI Listing
November 2020

Real-world safety and effectiveness of rotigotine in patients with Parkinson's disease: analysis of a post-marketing surveillance study in Japan.

Int J Neurosci 2020 Aug 26:1-11. Epub 2020 Aug 26.

Pharmacovigilance, Otsuka Pharmaceutical Co., Ltd, Osaka, Japan.

Objective: The aim of this study was to evaluate the safety and effectiveness of rotigotine under daily clinical practice in Parkinson's disease patients.

Methods: The study was a prospective, non-interventional, observational study targeting patients who were treated with rotigotine for the first time, with a 1-year follow-up period from September 2013 to August 2016.

Results: There were 603 patients in the safety population and 599 patients in the effectiveness population. The mean age was 71.6 years, and the age group of ≥65 and ≥80 years accounted for 80% and 18.6% of all patients, respectively. The frequency of adverse drug reaction (ADR) was 34.3%, and common ADRs were application site reaction (20.2%), typical for transdermal patches. However, the majority of patients recovered or was recovering from these ADRs and were non-serious. Although ADRs related to non-motor symptoms of Parkinson's disease were observed, most of them were non-serious. Total scores of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (ON-time) significantly decreased from baseline in the effectiveness population. In the analysis of overall improvement in 12 months of post-treatment, ≥70% of patients achieved mild or greater improvement. The safety profiles and improvements in the UPDRS-III score were similar in both the ≥80 years of age group and younger age group.

Conclusion: There were no new or notable safety concerns observed, and the effectiveness of rotigotine was suggested in daily clinical practice.
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http://dx.doi.org/10.1080/00207454.2020.1807976DOI Listing
August 2020

Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Filtration Bleb Leaks: An In Vivo and Histologic Study.

Transl Vis Sci Technol 2020 05 22;9(6):24. Epub 2020 May 22.

Department of Ophthalmology, University of Occupational and Environmental Health, Fukuoka, Japan.

Purpose: To evaluate the efficacy of polyethylene glycol (PEG)-based synthetic sealant for closing bleb leaks after glaucoma filtration surgery.

Methods: Tube shunt surgery that included implantation of a 22-gauge indwelling catheter and intraoperative mitomycin C was performed in the left eyes of 11 New Zealand white rabbits. Seven days postoperatively, all filtration blebs were perforated with an 18-gauge needle to create a bleb hole. In six rabbits, the holes were covered with the sealant and irradiated with blue-green light for 60 seconds; in the five control rabbits, the holes were untreated. For 3 weeks after the tube shunt surgery, the eyes were checked for bleb leaks, and the intraocular pressure (IOP) was measured in both eyes. Finally, the operated eyes were enucleated for histologic examination.

Results: The bleb leaks stopped in the eyes in which sealant was used and persisted in the other eyes. The sealant preserved the bleb function; the IOPs in these eyes were significantly ( < 0.05) lower than the right eyes that did not undergo surgery. Hematoxylin and eosin staining showed that the holes were closed and covered with conjunctival epithelial cells in the eyes in which sealant was applied; the holes were open in the control eyes. Immunohistochemical staining showed that the bleb holes in which the sealant was applied had fewer inflammatory cells.

Conclusions: The PEG sealant has the potential to seal bleb leaks effectively.

Translational Relevance: Application of the PEG sealant can be used as adjunct therapy for bleb leaks in glaucoma surgery.
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http://dx.doi.org/10.1167/tvst.9.6.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409081PMC
May 2020

ULTRA-WIDE FIELD FUNDUS AUTOFLUORESCENCE IMAGING OF EYES WITH STICKLER SYNDROME.

Retina 2021 Mar;41(3):638-645

Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan.

Purpose: To determine the characteristics of fundus autofluorescence (FAF) images and visual functions in eyes with Stickler syndrome using ultra-widefield FAF images.

Methods: Forty-six eyes of 26 patients with mutations in the COL2A1 gene underwent ultra-widefield FAF imaging. The eyes were categorized into three types; no signs of abnormal AF, predominantly hyperfluorescent AF (hyper-AF), and predominantly hypofluorescent AF (hypo-AF). Goldmann perimetry was performed on 34 eyes, and line-scan images of the abnormal AF lesions were obtained by swept-source optical coherence tomography in 4 eyes.

Results: Abnormal AF lesions were found in 37 eyes of 21 (80.7%) of the 26 patients. Hyper-AF was found in 15 eyes and hypo-AF was found in 22 eyes. The FAF changes corresponded with the funduscopically observed radial paravascular retinal degeneration. The average age at the examination was significantly younger in patients who had eyes with hyper-AF or no abnormal AF than in those with hypo-AF (12.8 vs. 28.4 years; P = 0.009). Abnormal AF-associated visual field defects were found in 5/10 (50%) eyes with hyper-AF and 17/18 (94%) eyes with hypo-AF. Hyper-AF changes tended to appear before retinal changes were detectable by fluorescein angiography. An absence of the ellipsoid zone and the outer nuclear layer and a thinning of the overall retinal thickness were found corresponding to the hypo-AF lesions in the swept source optical coherence tomography images.

Conclusion: Abnormal FAF is characteristic of eyes with Stickler syndrome. Age-related alterations of the FAF was associated with visual field defects and disruption of the photoreceptors and retinal pigment epithelial cells.
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http://dx.doi.org/10.1097/IAE.0000000000002879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889284PMC
March 2021

RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.

Invest Ophthalmol Vis Sci 2020 03;61(3):53

,.

Purpose: To investigate clinical characteristics of RDH5-related fundus albipunctatus (FAP) in a Japanese cohort.

Methods: Twenty-five patients from 22 pedigrees with RDH5-related FAP were studied. Ophthalmic medical records were reviewed. For genetic analysis, either Sanger sequencing of the RDH5 gene or whole-exome sequencing was performed.

Results: Genetic analysis identified eight different RDH5 variants, including seven known RDH5 variants (p.G35S, p.G107R, p.R167H, p.A240GfsX19, p.R278X, p.R280H, and p.L310delinsEV) and a novel variant: c.259C>T (p.Q87X). The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles). Of 50 eyes examined, 44 eyes (88.0%) showed logMAR best-corrected visual acuity (BCVA) of 0.10 or better. In optical coherence tomography, macular involvement was observed in 12 patients (24 eyes). Ten patients (83.3%) who had good BCVA (0.10 or better) exhibited diffuse disruption of the outer retina with foveal sparing, and two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA. Among the 24 eyes, ring-or crescent-shaped hyperautofluorescence or irregular autofluorescence around the fovea was observed in 15 eyes (83.3%) of 18 eyes examined by fundus autofluorescence imaging. Full-field electroretinography showed extinguished or severely decreased rod responses in all 23 examined patients, whereas decreased cone responses were seen in 17 patients (73.9%).

Conclusions: Multimodal imaging and electroretinography of RDH5-related FAP revealed high frequencies of macular involvement in older patients and decreased cone responses. Our findings suggest that progressive macular/cone dysfunction, as well as delayed rod function, may be key phenotypic features of RDH5-related FAP.
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http://dx.doi.org/10.1167/iovs.61.3.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401827PMC
March 2020

PITHD1 is a proteasome-interacting protein essential for male fertilization.

J Biol Chem 2020 02 8;295(6):1658-1672. Epub 2020 Jan 8.

Division of Experimental Immunology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan. Electronic address:

The proteasome is a protein-degrading molecular complex that is necessary for protein homeostasis and various biological functions, including cell cycle regulation, signal transduction, and immune response. Proteasome activity is finely regulated by a variety of proteasome-interacting molecules. PITHD1 is a recently described molecule that has a domain putatively capable of interacting with the proteasome. However, it is unknown whether PITHD1 can actually bind to proteasomes and what it does Here we report that PITHD1 is detected specifically in the spermatids in the testis and the cortical thymic epithelium in the thymus. Interestingly, PITHD1 associates with immunoproteasomes in the testis, but not with thymoproteasomes in the thymus. Mice deficient in PITHD1 exhibit severe male infertility accompanied with morphological abnormalities and impaired motility of spermatozoa. Furthermore, PITHD1 deficiency reduces proteasome activity in the testis and alters the amount of proteins that are important for fertilization capability by the sperm. However, the PITHD1-deficient mice demonstrate no detectable defects in the thymus, including T cell development. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system.
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http://dx.doi.org/10.1074/jbc.RA119.011144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008373PMC
February 2020

Electroretinograms of eyes with Stickler syndrome.

Doc Ophthalmol 2020 06 28;140(3):233-243. Epub 2019 Nov 28.

Department of Ophthalmology, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan.

Purpose: To determine the characteristics of the full-field electroretinograms (ERGs) of eyes with Stickler syndrome.

Methods: Twenty-two eyes of 14 Japanese patients from nine families with Stickler syndrome were studied. All of the patients were found to have mutations in the COL2A1 gene and had undergone ERG recordings. The ERGs from one of the two eyes were compared to 11 eyes of 11 normal control subjects who were matched by age, sex, and refractive error.

Results: One patient had non-recordable ERGs under both scotopic and photopic conditions. For the remaining 13 patients, the amplitudes of the b-waves of the scotopic combined, rod, and cone responses were significantly smaller than those of the control subjects (P = 0.0001, P = 0.015, P = 0.0006, respectively). The implicit times of the b-wave of the scotopic combined and photopic responses were significantly prolonged (P = 0.0037 and P = 0.0126). The age was inversely and significantly correlated with the amplitudes of the scotopic combined a-wave (P = 0.0184) and b-wave (P = 0.0076) in 13 eyes. The amplitudes of the scotopic combined b-wave amplitudes were not significantly correlated with the refractive error.

Conclusions: The reduced or absent full-field ERGs in eyes with Stickler syndrome indicate that the physiology of the entire retina was negatively altered. The greater reduction in the ERGs with increasing age suggests that the physiological alterations of the retina are progressive.
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http://dx.doi.org/10.1007/s10633-019-09739-xDOI Listing
June 2020

Trans-omics Impact of Thymoproteasome in Cortical Thymic Epithelial Cells.

Cell Rep 2019 11;29(9):2901-2916.e6

Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

The thymic function to produce self-protective and self-tolerant T cells is chiefly mediated by cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs). Recent studies including single-cell transcriptomic analyses have highlighted a rich diversity in functional mTEC subpopulations. Because of their limited cellularity, however, the biochemical characterization of TECs, including the proteomic profiling of cTECs and mTECs, has remained unestablished. Utilizing genetically modified mice that carry enlarged but functional thymuses, here we show a combination of proteomic and transcriptomic profiles for cTECs and mTECs, which identified signature molecules that characterize a developmental and functional contrast between cTECs and mTECs. Our results reveal a highly specific impact of the thymoproteasome on proteasome subunit composition in cTECs and provide an integrated trans-omics platform for further exploration of thymus biology.
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http://dx.doi.org/10.1016/j.celrep.2019.10.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897492PMC
November 2019

Early vitrectomy to reverse macular dragging in a one-month-old boy with familial exudative vitreoretinopathy.

Am J Ophthalmol Case Rep 2019 Sep 11;15:100493. Epub 2019 Jun 11.

Department of Ophthalmology, Kindai University Faculty of Medicine, Osakasayama, Japan.

Purpose: Vitrectomy is usually only indicated for familial exudative vitreoretinopathy (FEVR) cases with progressive retinal folds or macular dragging. In this report, we present our experience reversing the progression of macular dragging by performing early eye vitrectomies in a 1-month-old male baby with FEVR.

Observations: A 7-day-old, full-term male baby was examined by a pediatric ophthalmologist. His sister had a laser ablation treatment after being diagnosed with FEVR. The ophthalmologist found the baby had avascular retinas, fibrovascular membranes, and vitreous hemorrhages in both eyes, and performed retinal photocoagulations the next day. Although the retinal folds had not yet formed, the arcade vessels began to linearize after the procedure, strongly suggesting disease progression. Therefore, we performed lens-sparing vitrectomies in both eyes on the twenty-ninth day of life. After surgery, the macular dragging reversed, as evidenced by vascular arcade angle measurements. Three years after the surgery, the boy's visual acuity was 0.4 in both eyes.

Conclusions And Importance: In this case, we believe the good postoperative outcomes were due to early vitrectomies before the vitreoretinal traction became severe. In addition, the retinal photocoagulation performed on the eighth day of life may have reduced disease activity, at least partially. This case highlights the importance of prompt diagnosis and appropriate treatment of FEVR.
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http://dx.doi.org/10.1016/j.ajoc.2019.100493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595075PMC
September 2019

Novel mutations in the gene in Japanese patients with X-linked congenital retinoschisis.

Hum Genome Var 2019 8;6. Epub 2019 Jan 8.

12Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.

X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the gene. We have identified 37 different mutations in the gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations.
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http://dx.doi.org/10.1038/s41439-018-0034-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325138PMC
January 2019

Foveal hypoplasia and optical coherence tomographic imaging.

Authors:
Hiroyuki Kondo

Taiwan J Ophthalmol 2018 Oct-Dec;8(4):181-188

Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan.

Foveal hypoplasia is a retinal disorder in which there is a lack of full development of the morphology of the fovea. The optical coherence tomography (OCT) and functional findings are presented in relation to the underlying genetic and developmental conditions. Recent advancements of high-resolution OCT imaging have unveiled characteristics of foveal hypoplasia that were not detected by conventional imaging methods. An absence of a foveal pit does not necessarily imply poor visual acuity, and the maturation of the cone photoreceptors is important for the visual acuity. Regardless of the degree of the development of the inner retinal layers, the visual acuity can be preserved as in diseases such as Stickler syndrome that is a newly identified retinal disorder associated with foveal hypoplasia.
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http://dx.doi.org/10.4103/tjo.tjo_101_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302563PMC
January 2019

Recognizability of heterologous co-chaperones with Streptococcus intermedius DnaK and Escherichia coli DnaK.

Microbiol Immunol 2018 Nov 5;62(11):681-693. Epub 2018 Nov 5.

Field of Biomolecular Functions and Technology, Department of Bioscience and Bioindustry, Graduate School of Bioscience and Bioindustry, Tokushima University Graduate School, Minami-josanjima-cho, Tokushima 770-8513, Japan.

Streptococcus intermedius DnaK complements the temperature-sensitive phenotype of an Escherichia coli dnaK null mutant only when co-chaperones DnaJ and GrpE are co-expressed. Therefore, whether S. intermedius DnaK and E. coli DnaK can recognize heterologous co-chaperones in vitro was examined. Addition of heterologous GrpE to DnaK and DnaJ partially stimulated adenosine triphosphatase (ATPase) activity, and almost completely stimulated luciferase refolding activity. Addition of heterologous DnaJ to GrpE and DnaK also stimulated ATPase activity; however, significant luciferase refolding activity was not observed. Moreover, E. coli DnaJ had a negative effect on the luciferase refolding activity of the S. intermedius DnaK chaperone system. In E. coli chaperone mutants, with the exception of E. coli DnaJ, stronger expression of the heterologous co-chaperones partially or almost completely complemented the temperature-sensitive-phenotype. These results indicate that all heterologous co-chaperones can at least partially recognize DnaK of a distantly related species. A region of the ATPase domain that is present in the DnaK of gram-negative bacteria is absent from the DnaK of gram-positive bacteria. This region is believed to be important for recognition of co-chaperones from gram-negative bacteria. However, insertion of this segment into S. intermedius DnaK failed to increase its ability to recognize E. coli co-chaperones, implying that this region is unnecessary or insufficient for the recognition of E. coli co-chaperones. Thus, our data suggest that a basic structural similarity is conserved among the components of the S. intermedius and E. coli DnaK chaperone systems, allowing weak associations between heterologous components.
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http://dx.doi.org/10.1111/1348-0421.12651DOI Listing
November 2018

Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy.

Sci Rep 2018 07 31;8(1):11507. Epub 2018 Jul 31.

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.

Blue cone monochromacy (BCM) is characterized by loss of function of both OPN1LW (the first) and OPN1MW (the downstream) genes on the X chromosome. The purpose of this study was to investigate the first and downstream genes in the OPN1LW/OPN1MW array in four unrelated Japanese males with BCM. In Case 1, only one gene was present. Abnormalities were found in the promoter, which had a mixed unique profile of first and downstream gene promoters and a -71A > C substitution. As the promoter was active in the reporter assay, the cause of BCM remains unclear. In Case 2, the same novel mutation, M273K, was present in exon 5 of both genes in a two-gene array. The mutant pigments showed no absorbance at any of the wavelengths tested, suggesting that the mutation causes pigment dysfunction. Case 3 had a large deletion including the locus control region and entire first gene. Case 4 also had a large deletion involving exons 2-6 of the first gene. As an intact LCR was present upstream and one apparently normal downstream gene was present, BCM in Case 4 was not ascribed solely to the deletion. The deletions in Cases 3 and 4 were considered to have been caused by non-homologous recombination.
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http://dx.doi.org/10.1038/s41598-018-29891-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068165PMC
July 2018

Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing.

Sci Rep 2018 05 29;8(1):8279. Epub 2018 May 29.

Department of Ophthalmology, Hamamatsu University School of Medicine, Shizuoka, Japan.

Leber congenital amaurosis (LCA) is a genetically and clinically heterogeneous disease, and represents the most severe form of inherited retinal dystrophy (IRD). The present study reports the mutation spectra and frequency of known LCA and IRD-associated genes in 34 Japanese families with LCA (including three families that were previously reported). A total of 74 LCA- and IRD-associated genes were analysed via targeted-next generation sequencing (TS), while recently discovered LCA-associated genes, as well as known variants not able to be screened using this approach, were evaluated via additional Sanger sequencing, long-range polymerase chain reaction, and/or copy number variation analyses. The results of these analyses revealed 30 potential pathogenic variants in 12 (nine LCA-associated and three other IRD-associated) genes among 19 of the 34 analysed families. The most frequently mutated genes were CRB1, NMNAT1, and RPGRIP1. The results also showed the mutation spectra and frequencies identified in the analysed Japanese population to be distinctly different from those previously identified for other ethnic backgrounds. Finally, the present study, which is the first to conduct a NGS-based molecular diagnosis of a large Japanese LCA cohort, achieved a detection rate of approximately 56%, indicating that TS is a valuable method for molecular diagnosis of LCA cases in the Japanese population.
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http://dx.doi.org/10.1038/s41598-018-26524-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974356PMC
May 2018

Correction to: Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials.

J Neurol 2018 Feb;265(2):266-272

Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.

Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tables are given in the following page.
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http://dx.doi.org/10.1007/s00415-017-8706-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828037PMC
February 2018

Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials.

J Neurol 2018 Feb 21;265(2):253-265. Epub 2017 Nov 21.

Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.

Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo-controlled trials performed in Japan to clarify the difference of anti-parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, significantly improved in both elderly and non-elderly patients. Regarding safety, the incidence of total adverse event tended to be lower in elderly patients than non-elderly patients, although it was not significant. No difference was observed in maintenance dosage of rotigotine between the two groups. In conclusion, the improvement in motor symptoms and frequency of adverse events were shown to be similar in elderly and non-elderly patients with rotigotine-levodopa combination therapy. Further, there was no major difference in maintenance dosage of rotigotine between the age groups. These results suggest good tolerability of rotigotine among elderly patients.
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http://dx.doi.org/10.1007/s00415-017-8671-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808069PMC
February 2018

Risk allele of the FZD4 gene for familial exudative vitreoretinopathy.

Ophthalmic Genet 2018 06 14;39(3):405-406. Epub 2017 Nov 14.

d Human Disease Genomics, Center for Genomic Medicine , Kyoto University Graduate School of Medicine , Kyoto , Japan.

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http://dx.doi.org/10.1080/13816810.2017.1401090DOI Listing
June 2018

Lack of FOXE3 coding mutation in a case of congenital aphakia.

Ophthalmic Genet 2018 Jan-Feb;39(1):95-98. Epub 2017 Aug 14.

a Department of Ophthalmology , University of Occupational and Environmental Health , Kitakyushu , Japan.

Purpose: To report the findings in a patient with congenital primary aphakia, a rare disease known to be caused by mutations in the FOXE3 gene.

Methods: The clinical appearances and visual functions of the patient were determined from the medical records. Genetic analyses were performed to search for mutations in the FOXE3 gene by Sanger sequencing and whole exome sequencing.

Results: The 2-month-old male patient first presented with bilateral congenital aphakia associated with microphthalmia, corneal opacity, and dysplasia of the anterior segment. At the age of 2-years, his visual acuity in the left eye was 20/1000 at 30 cm, he was able to discriminate red, blue, and yellow light stimuli, and a b-wave was recorded by scotopic combined rod-cone electroretinograms. The right eye became blind during the follow-up period. No mutation in the FOXE3 gene was detected.

Conclusion: Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease.
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http://dx.doi.org/10.1080/13816810.2017.1350722DOI Listing
March 2018

Essential role of CCL21 in establishment of central self-tolerance in T cells.

J Exp Med 2017 Jul 13;214(7):1925-1935. Epub 2017 Jun 13.

Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima, Japan

The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.
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http://dx.doi.org/10.1084/jem.20161864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502431PMC
July 2017
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