The direct, catalytic, asymmetric Michael addition of aldehydes to nitroolefins in the presence of a chiral diphenylprolinol silyl ether organocatalyst is described (see scheme). The desired ...1,4‐addition products were obtained in nearly optically pure form in good yield with high syn diastereoselectivity. TMS=trimethylsilyl.
Purpose
The aim of this study was to estimate the number of patients in Japan who had visited an ophthalmologist for macular dystrophy of various types, including Best vitelliform macular dystrophy ...(BVMD), Stargardt disease, occult macular dystrophy (OMD), cone (-rod) dystrophy, X-linked retinoschisis (XLRS), and central areolar choroid dystrophy (CACD).
Study design
Nationwide epidemiologic survey
Methods
Questionnaires were distributed to 965 major facilities, including all the university hospitals in Japan. The aim of the questionnaire was to determine the number of patients with each type of macular dystrophy who had visited an outpatient clinic during the past 5 years (January 2015 to December 2019).
Results
Over 70% of the patients were diagnosed and followed up at university hospitals. The estimated annual number of newly diagnosed cases was as follows: 55.3 for BVMD, 36.7 for Stargardt disease, 35.8 for OMD, 160.6 for cone (-rod) dystrophy, 31.0 for XLRS, 29.8 for CACD, and 174.1 for other types of macular dystrophy. The total number of patients with macular dystrophy diagnosed and followed at major institutions was estimated to be 6651.
Conclusion
This was the first nationwide survey of macular dystrophy in Japan and provided an approximate number of affected patients. The diagnosis of macular dystrophy is primarily carried out at facilities with affiliated specialists, such as university hospitals. By examining the incidence of multiple diseases simultaneously, we were able to compare the incidence of each type of macular dystrophy.
Background
Little is known about whether patients with complete congenital stationary night blindness (CSNB) maintain visual function throughout their lifetime. The purpose of this report was to ...describe clinical and genetic features of an elderly female patient with complete CSNB that we followed for 5 years.
Methods
Molecular genetic analysis using whole-exome sequencing (WES) was performed to detect disease-causing variants. We performed a comprehensive ophthalmic examination including full-field electroretinography (ERG).
Results
In the patient, WES identified two novel variants (c.1034delT; p.Phe345SerfsTer16 and c.1880T>A; p.Met627Lys) in the
TRPM1
gene. Her unaffected daughter has one of the variants. The patient reported that her visual acuity has remained unchanged since elementary school. At the age of 68 years old, fundus and fundus autofluorescence imaging showed no remarkable findings except for mild myopic changes. Goldmann perimetry showed preserved visual fields with all V-4e, I-4e, I-3e and I-2e isopters. Optical coherence tomography demonstrated preserved retinal thickness and lamination. Rod ERG showed no response; bright-flash ERG showed an electronegative configuration with minimally reduced a-waves, and cone and 30-Hz flicker ERG showed minimally reduced responses. Overall, the ERG findings of ON bipolar pathway dysfunction were consistent with complete CSNB.
Conclusions
This is the oldest reported patient with complete CSNB and biallelic
TRPM1
variants. Our ophthalmic findings suggest that some patients with
TRPM1
-related CSNB may exhibit preserved retinal function later in life.
Background
Although total laryngectomy is the standard treatment for advanced laryngeal cancer, the significance of elective neck dissection (END) for N0 laryngeal cancer remains unclear in Japan, ...which is an aging society.
Methods
We conducted a retrospective nationwide observational study on patients with T3–T4N0 laryngeal squamous cell carcinoma treated with curative total laryngectomy from 2011 to 2018 in Japan.
Results
A total of 1,218 patients were analyzed. The median patient age was 72 years, with 735 cases of T3N0 and 483 cases of T4N0. END was performed on the affected side in 850 patients (70%) and on the contralateral side in 502 patients (41.2%). END on the affected side was omitted in patients aged > 80 years (40.4%) and in patients with an advanced performance status. The occult lymph-node metastasis rate did not differ by age (18.8%–19.6%); it tended to increase chronologically from 2011 (11.1%) and was higher in cT4a (22.5%) and pT4a (24.3%) cases. In this study, coherent clinical information and follow-up data were available for 252 patients. Both univariate and multivariate analyses showed no significant prognostic factors for overall survival or recurrence-free survival for either affected or contralateral END. Older age and subglottic location were poor prognostic factors, but death due to factors other than laryngeal cancer could not be ignored in older patients.
Conclusion
Omission of END during laryngectomy for T3–T4N0 laryngeal cancer is acceptable for older patients who want their operation to be completed in a short time.
To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings.
Sixty-one patients from 33 families ...with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed.
The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed.
The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.
Purpose
To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization ...(CNV).
Methods
This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed.
Results
CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes.
Conclusions
CNV is a relatively common complication in
BEST1
-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.
Sordarin is a glycoside antibiotic with a unique tetracyclic diterpene aglycone structure called sordaricin. To understand its intriguing biosynthetic pathway that may include a Diels-Alder-type ...4+2cycloaddition, genome mining of the gene cluster from the draft genome sequence of the producer strain, Sordaria araneosa Cain ATCC 36386, was carried out. A contiguous 67 kb gene cluster consisting of 20 open reading frames encoding a putative diterpene cyclase, a glycosyltransferase, a type I polyketide synthase, and six cytochrome P450 monooxygenases were identified. In vitro enzymatic analysis of the putative diterpene cyclase SdnA showed that it catalyzes the transformation of geranylgeranyl diphosphate to cycloaraneosene, a known biosynthetic intermediate of sordarin. Furthermore, a putative glycosyltransferase SdnJ was found to catalyze the glycosylation of sordaricin in the presence of GDP-6-deoxy-d-altrose to give 4'-O-demethylsordarin. These results suggest that the identified sdn gene cluster is responsible for the biosynthesis of sordarin. Based on the isolated potential biosynthetic intermediates and bioinformatics analysis, a plausible biosynthetic pathway for sordarin is proposed.
It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive ...impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.
Background
In industrialized countries, vitamin A deficiency (VAD) is extremely rare, except association with bariatric surgeries and hepatobiliary disorders. It is unusual that VAD develops during ...hemodialysis due to reduced glomerular filtration of vitamin A-binding protein. We reported the case of a 58-year-old Japanese male hemodialysis patient diagnosed with VAD.
Case presentation
The patient undergoing hemodialysis for more than 15 years presented with progressive photophobia and night blindness and was ophthalmologically examined. He denied a history of cancer or hepatobiliary disease and reported that he loved eating prepackaged noodle bowls and foods, with prolonged low intake of fruits/vegetables. He had good visual acuity. Fundus images showed numerous white dots in the midperipheral retinae, but no degenerative changes. In baseline full-field electroretinography (ERG), b-wave responses were extremely reduced in rod ERG, a-wave amplitudes in standard-flash/strong-flash ERG were reduced to 20–25% of our controls, a- and b-wave amplitudes in cone ERG were reduced to 40–50% of the controls. Whole-exome sequencing identified no pathogenic variant for any inherited retinal disorder. He was diagnosed with VAD because of reduced serum vitamin A levels and treated with retinol palmitate. Two months after treatment commencement, the serum vitamin A level was within the normal range. Full-field ERG showed that the scotopic ERG responses markedly improved compared with baseline.
Conclusions
This is the first report of VAD associated with undernutrition in the Japanese hemodialysis population.
To determine the microstructure of the fovea in patients with Stickler syndrome using imaging by spectral-domain optical coherence tomography (SD OCT) and swept-source OCT.
Retrospective case series ...study.
A total of 39 eyes of 25 patients with genetically confirmed Stickler syndrome were studied.
All of the patients had mutations in the COL2A1 gene and were diagnosed with Stickler syndrome. Cross-sectional OCT images, OCT angiography (OCTA), and en face OCT images were assessed. The ratio of the foveal inner retinal layer (fIRL) thickness to the parafoveal inner retinal layer (pIRL) thickness, the ratio of the foveal outer retinal layer (fORL) thickness to the parafoveal outer retinal layer (pORL) thickness, and the size of the foveal avascular zone (FAZ) were determined.
The degree of foveal hypoplasia and the best-corrected visual acuity in patients with Stickler syndrome.
A persistence of the inner retinal layers in the fovea with an fIRL/pIRL ratio >0.2 was present in 32 of the 39 eyes (82%). Optical coherence tomography angiography showed that the FAZ was smaller, 0 to 0.19 mm
, than that of normal eyes, in 25 eyes of 17 patients who underwent OCTA. There was no significant correlation between the visual acuities and the fIRL/pIRL ratios.
A mild foveal hypoplasia with a persistence of the IRL is characteristic of eyes with Stickler syndrome. The visual acuities were not correlated with the fIRL/pIRL ratios.
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