Whole genome sequencing of 45 Japanese patients with intellectual disability.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.

ε-Viniferin is more effective than its monomer resveratrol in improving the functions of vascular endothelial cells and the heart.

The present study compared the effects of resveratrol and its dimer ε-viniferin on vascular endothelial cells (VECs) functions, and on the blood pressure and cardiac mass of spontaneously hypertensive rats (SHRs). Treatment of VECs with these compounds enhanced cell proliferation via nitric oxide generation and protected the cells from oxidative stress by suppressing increases in intracellular oxygen species. ε-Viniferin was more potent than resveratrol in most of these effects. ε-Viniferin, but not resveratrol inhibited angiotensin-converting enzyme activity in vitro. Three weeks of ε-viniferin treatment (5 mg/kg) reduced the systolic blood pressure and improved the whole cardiac mass and left ventricle mass indexes in SHRs. In contrast, resveratrol administration (2.5 mg/kg) failed to lower the blood pressure and significantly improve these mass indexes. These data suggest that ε-viniferin as well as resveratrol may be involved in protecting the functions of VECs and the heart.

Protein tyrosine phosphatase PTPepsilonM negatively regulates PDGF beta-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase ε M (PTPεM) promotes VEC survival and migration. The present study investigates the biological functions of PTPεM in VSMCs and determines whether PTPεM is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTPεM and an small interfering RNA (siRNA) of PTPεM by using an adenovirus vector to investigate the effects of PTPεM upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTPεM decreased PDGF-induced DNA synthesis and migration by reducing the phosphorylation level of the PDGF ß-receptor (PDGFRß) with subsequently suppressed H(2)O(2) generation. The HG content in the medium generated H(2)O(2), upregulated PDGFRß expression and its tyrosine-phosphorylation, and elevated NADPH oxidase 1 (Nox1) expression even without exogenous PDGF, all of which were downregulated by PTPεM. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and H(2)O(2) production. Moreover, HG suppressed PTPεM expression itself, which was blocked by the antioxidant N-acetyl-l-cysteine. The effects of PTPεM siRNA were the opposite of those of wild-type PTPεM. Therefore, PTPεM negatively regulates PDGFRß-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTPεM may be involved in diabetes-accelerated atherosclerosis.

Drainage of the tracheal blind pouch created by laryngotracheal separation.

Laryngotracheal separation is a simple and reliable operation for the treatment of patients with repetitive and intractable aspiration; however, it is apprehended that pooling in the tracheal blind pouch may cause postoperative complications. In the present study, we examined drainage of the blind pouch created by laryngotracheal separation. Fourteen patients aged 3-63 years with repetitive aspiration pneumonia underwent laryngotracheal separation by the modified Lindeman procedure. A barium swallow was performed 10-30 days after surgery. X-rays of the lateral view of the neck were taken at 6 and 24 h after the swallow, and then every 24 h until the contrast medium cleared. The contrast medium in the blind pouch cleared within 24 h in nine patients. In the remaining five, the clearance time was < or =48 and < or =72 h in two patients each, and 96 h in one patient. The clearance time in patients aged under 20 years was < or =24 h, while middle-aged to elderly patients showed prolonged clearance time. No late complications of the blind pouch, such as infections, were observed. The potential risk of complications caused by pooling in the tracheal blind pouch in laryngotracheal separation is prevented presumably due to the slow but continuous turnover of pooling material. This result supports the validity and usefulness of laryngotracheal separation for the treatment of intractable aspiration.