Copper-Catalyzed Arylstannylation of Arynes in Sequence

Copper-catalyzed arylstannylation of arynes has been developed. This transformation enables variously substituted ortho-stannylbiaryls and teraryls to be constructed straightforwardly. An electron-deficient tin center is the key, and thus the single or dual insertion of arynes into arylstannanes is precisely controllable by simply changing the equivalence of aryne precursors.This work was financially supported by JSPS KAKENHI Grant Number JP17K05864

A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy

BACKGROUND: Deficiency of 4-aminobutyrate aminotransferase (GABA-T) is a rare disorder of GABA catabolism, with only a single sibship reported. We report on a third case, a Japanese female infant with severe psychomotor retardation and recurrent episodic lethargy with intractable seizures, with the diagnosis facilitated by proton magnetic resonance (MR) spectroscopy ((1)H-MRS). METHODS: Neuroimaging was performed at the first episode of lethargy. For (1)H-MRS, locations were placed in the semioval center and the basal ganglia. Quantification of metabolite concentrations were derived using the LCModel. We confirmed the diagnosis subsequently by enzyme and molecular studies, which involved direct DNA sequence analysis and the development of a novel multiplex ligation-dependent probe amplification test. RESULTS: (1)H-MRS analysis revealed an elevated GABA concentration in the basal ganglia (2.9 mmol/l). Based on the results of quantitative (1)H-MRS and clinical findings, GABA-T deficiency was suspected and confirmed in cultured lymphoblasts. Molecular studies of the GABA-T gene revealed compound heterozygosity for a deletion of one exon and a missense mutation, 275G>A, which was not detected in 210 control chromosomes. CONCLUSIONS: Our results suggest that excessive prenatal GABA exposure in the central nervous system (CNS) was responsible for the clinical manifestations of GABA transaminase deficiency. Our findings suggest the dual nature of GABA as an excitatory molecule early in life, followed by a functional switch to an inhibitory species later in development. Furthermore, quantitative (1)H-MRS appears to be a useful, noninvasive tool for detecting inborn errors of GABA metabolism in the CNS

Factors associated with extremely poor visual outcomes in patients with central retinal vein occlusion

Here, we examined prognostic factors for extremely poor visual outcomes in patients with central retinal vein occlusion (CRVO) in actual practices. We included 150 consecutive eyes with treatment-naïve acute CRVO from four different facilities and observed them for over 24 months. Macular edema (ME) was treated with one or three monthly anti-vascular endothelial growth factor injections (1 or 3 + pro re nata). According to the final Snellen visual acuity (VA), we divided the patients into very poor VA (< 20/200) and control (≥ 20/200) groups and examined risk factors for poor final visual outcomes. The baseline Snellen VA was hand motion to 20/13. The mean number of anti-VEGF injections for ME was 5.3 ± 3.7 during the follow-up period. In total, 49 (32.7%) patients exhibited a very poor final VA; this group comprised significantly older patients with a significantly poorer baseline VA (P < 0.01 for both) than the control group. Comorbid internal carotid artery disease and diabetic retinopathy were significantly associated with a poor final VA. In actual clinical practice, visual outcomes may be extremely poor despite ME treatment in certain patients with CRVO, with advanced age, poor baseline VA, and comorbid internal carotid artery disease and diabetic retinopathy being significant risk factors

Foveal Thickness Fluctuation in Anti-VEGF Treatment for Branch Retinal Vein Occlusion: A Long-term Study

PURPOSE: Branch retinal vein occlusion (BRVO) causes macular edema (ME), which can be controlled with anti-VEGF treatments. However, these treatments are not curative, necessitating additional anti-VEGF treatments at recurrence. Long-term results, optimal anti-VEGF treatment regimens, and the comprehensive effects of ME recurrence are largely unknown. Thus, we aimed to examine the effects of foveal thickness (FT) fluctuation (FTF) on the visual and morphologic outcomes of anti-VEGF treatments for BRVO-ME administered via a pro re nata regimen. DESIGN: A retrospective, observational case series. SUBJECTS: This study analyzed 309 treatment-naïve patients (309 eyes) with BRVO-ME between 2012 and 2021 at a multicenter retinal practice. METHODS: The FT was assessed using OCT at each study visit. MAIN OUTCOME MEASURES: We evaluated the logarithm of the minimal angle of resolution (logMAR) best corrected visual acuity (BCVA) and the defect length of the foveal ellipsoid zone (EZ) band using OCT. RESULTS: At baseline, the mean logMAR BCVA was 0.30 ± 0.30 and the mean FT was 503 ± 162 μm. The number of anti-VEGF injections for BRVO-ME was 5.8 ± 4.6 during the mean follow-up period (50.6 ± 22.2 months). At the final examination, the mean logMAR BCVA and FT values were significantly improved compared with those at the baseline. Multiple regression analyses showed that age, baseline logMAR BCVA, and FTF were significantly associated with the final logMAR BCVA (β = 0.20, 0.35, and 0.30, respectively). Foveal thickness fluctuation (divided into groups 0-3 in ascending order of FTF) was significantly associated with logMAR BCVA and the defect length of the foveal EZ band at the final examination. The defect lengths of the foveal EZ band were longitudinally shortened in groups 0 and 1 and were slightly prolonged in groups 2 and 3. The logMAR BCVA showed improvements in groups 0 and 1 and worsened slightly in groups 2 and 3. CONCLUSIONS: Foveal thickness fluctuation was significantly associated with visual acuity and foveal photoreceptor status. Thus, the morphologic and functional prognoses of eyes with BRVO may improve with the identification of the characteristics of eyes with greater FTF and consequently controlling the FTF more strictly

Vaccination and Infection as Causative Factors in Japanese Patients With Rasmussen Syndrome: Molecular Mimicry and HLA Class I

Rasmussen syndrome is an intractable epilepsy with a putative causal relation with cellular and humoral autoimmunity. Almost half of the patients have some preceding causative factors, with infections found in 38.2%, vaccinations in 5.9% and head trauma in 8.9% of Japanese patients. In a patient with seizure onset after influenza A infections, cross-reaction of the patient's lymphocytes with GluRε2 and influenza vaccine components was demonstrated by lymphocyte stimulation test. Database analyses revealed that influenza A virus hemagglutinin and GluRε2 molecules contain peptides with the patient's HLA class I binding motif (HLA − A*0201). The relative risks of HLA class I genotypes for Rasmussen syndrome are 6.1 (A*2402), 6.4 (A*0201), 6.3 (A*2601) and 11.4 (B*4601). The relative risks of HLA class I-A and B haplotypes are infinity (A*2601+B*5401), 21.1 (A*2402+B*1501), 13.3 (A*2402+B*4801) and 5.1 (A*2402+B*5201). Some alleles and haplotypes of HLA class I may be the risk factors in Japanese patients. Cross-reactivity of cytotoxic T lymphocytes may contribute to the processes leading from infection to the involvement of CNS

Collision Tumor of Adenocarcinoma and Gastrointestinal Stromal Tumor in the Small Bowel

We report a very rare case of collision tumor composed of primary adenocarcinoma of the jejunum and gastrointestinal stromal tumor (GIST). The patient was a 63-year-old man who visited our hospital for epigastralgia and vomiting. Abdominal computed tomography revealed a mass in the upper jejunum, with gastric and duodenal dilatation. Endoscopy of the small bowel showed a circumferential tumor in the upper jejunum, which was diagnosed as primary adenocarcinoma by tissue biopsy. Thereafter, partial resection of the small bowel from the third part of the duodenum over the upper jejunum was performed. A tumor colliding with the primary adenocarcinoma was identified on the serosal side of the jejunum in the excised specimen and was histologically diagnosed as GIST. The annual incidence of primary adenocarcinoma of the small bowel (i.e., jejunum and ileum excluding the duodenum) has been reported to be 7 in 1 million people, and only 6 cases of collision tumor of the small bowel (i.e., duodenum: 5, ileum: 1) have been reported thus far. Although esophageal, gastric, and large intestinal collision tumors composed of primary cancer and GIST have been reported, to our knowledge, the present patient is the first case of the small bowel. The cause of or correlation between 2 tumors forming a collision tumor remains unclear. In the present patient, there was no pathological finding of infiltration between the 2 tumors. Although the collision of the 2 tumors was unclear, the findings indicate their independent development in closely located regions consistent with collision tumors

Impact of the omicron phase on a highly advanced medical facility in Japan

BackgroundEight waves of the coronavirus disease 2019 (COVID-19) epidemic have been observed in Japan. This retrospective study was conducted to clarify the clinical characteristics of pediatric COVID-19 patients.MethodsWe studied 121 patients admitted to the Jichi Children's Medical Center Tochigi between April 2020 and March 2023. Incidence of pediatric COVID-19 in Tochigi Prefecture was used to examine hospitalization and severe illness rates.ResultsThe mean age of the patients was 3 years and 8 months. One hundred and eleven patients (91.7%) were hospitalized after January 2022 (after the 6th wave), when the Omicron strain became endemic in Japan. Convulsions occurred in 30 patients (24.8%), all of whom were admitted after the 6th wave. Twenty-three of the 30 patients had no underlying disease. Eleven patients (9.1%) were diagnosed with acute encephalopathy. One patient died due to hemorrhagic shock and encephalopathy syndrome and two had sequelae after the 6th wave. The patient who died due to encephalopathy had hypercytokinemia. In the Tochigi Prefecture, the number of pediatric COVID-19 patients increased after the 6th wave, but the hospitalization rate declined. The rate of severe illness did not change before the end of 5th and after the 6th wave.ConclusionAlthough the rate of severe illness in patients with pediatric COVID-19 did not increase after the 6th wave, some patients had complicated critical illnesses. Systemic inflammatory reaction was considered to have been associated with the severe encephalopathy

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements