Tatsuya Kawaguchi

Objective: The employment outcomes of childhood-onset drug-resistant epilepsy (DRE) has not been studied enough. The aim of this retrospective cohort study is to investigate the employment outcomes of childhood-onset DRE in June 2022 and identify the risk factors associated with non-employment.Materials and methods: The sample consisted of 65 participants ≥18 years of age with a history of childhood-onset DRE. Fifty participants (77%) were salaried employees and 15 participants (23%) were non-employed. Clinical and psychosocial information were evaluated for calculating the relative risk (RR) of non-employment.Results: Regarding medical factors, lower IQ [RR, 0.645; 95% confidence interval (CI), 0.443–0.938; p = 0.022] was positively associated with employment. In contrast, age at follow-up (RR, 1.046; 95% CI, 1.009–1.085; p = 0.014); number of ASMs at follow-up (RR, 1.517; 95% CI, 1.081–2.129; p = 0.016); use of medications such as phenobarbital (RR, 3.111; 95% CI, 1.383–6.997; p = 0.006), levetiracetam (RR, 2.471; 95% CI, 1.056–5.782; p = 0.037), and topiramate (RR, 3.576; 95% CI, 1.644–7.780; p = 0.001) were negatively associated with employment. Regarding psychosocial factor, initial workplace at employment support facilities (RR, 0.241; 95% CI, 0.113–0.513; p < 0.001) was positively associated with employment. In contrast, complication of psychiatric disorder symptoms (RR, 6.833; 95% CI, 2.141–21.810; p = 0.001) was negatively associated with employment. Regarding educational factor, graduating schools of special needs education (RR, 0.148; 95% CI, 0.061–0.360; p < 0.001) was positively associated with employment.Conclusions: Specific medical, psychosocial, and educational factors may influence the employment outcomes of childhood-onset DRE. Paying attention to ASMs’ side effects, adequately preventing the complications of psychiatric disorder symptoms, and providing an environment suitable for each patient condition would promote a fine working status for people with childhood-onset DRE.

The European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score predicts disease‐specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML‐related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML‐CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML‐CSG), which included patients diagnosed with CML‐CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first‐line therapy. Among 342 eligible patients, the ELTS scores indicated low‐, intermediate‐, and high‐risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease‐specific mortality and worse event‐free survival, progression‐free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low‐, intermediate‐, and high‐risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML‐CP.

The DMD gene is one of the largest human genes, being composed of 79 exons, and encodes dystrophin Dp427m which is deficient in Duchenne muscular dystrophy (DMD). In some DMD patient, however, small size dystrophin reacting with antibody to N-terminal but not to C-terminal has been identified. The mechanism to produce N-terminal small size dystrophin remains unknown. Intronic polyadenylation is a mechanism that produces a transcript with a new 3′ terminal exon and a C-terminal truncated protein. In this study, intronic alternative polyadenylation was disclosed to occur in the middle of the DMD gene and produce the half-size N-terminal dystrophin Dp427m, Dpm234. The 3′-rapid amplification of cDNA ends revealed 421 bp sequence in the downstream of DMD exon 41 in U-251 glioblastoma cells. The cloned sequence composing of the 5′ end sequence of intron 41 was decided as the terminal exon, since it encoded poly (A) signal followed by poly (A) stretch. Subsequently, a fragment from DMD exon M1 to intron 41 was obtained by PCR amplification. This product was named Dpm234 after its molecular weight. However, Dpm234 was not PCR amplified in human skeletal and cardiac muscles. Remarkably, Dpm234 was PCR amplified in iPS-derived cardiomyocytes. Accordingly, Western blotting of cardiomyocyte proteins showed a band of 234 kDa reacting with dystrophin antibody to N-terminal, but not C-terminal. Clinically, DMD patients with mutations in the Dpm234 coding region were found to have a significantly higher likelihood of two ECG abnormal findings. Intronic alternative splicing was first revealed in Dp427m to produce small size dystrophin.

Background: Dystrophin Dp71 is one of the isoforms produced by the DMD gene which is mutated in patients with Duchenne muscular dystrophy (DMD). Although Dp71 is expressed ubiquitously, it has not been detected in normal skeletal muscle. This study was performed to assess the expression of Dp71 in human skeletal muscle. Methods: Human skeletal muscle RNA and tissues were obtained commercially. Mouse skeletal muscle was obtained from normal and DMD^mdx mice. Dp71 mRNA and protein were determined by reverse-transcription PCR and an automated capillary Western assay system, the Simple Western, respectively. Dp71 was over-expressed or suppressed using a plasmid expressing Dp71 or antisense oligonucleotide, respectively. Results: Full-length Dp71 cDNA was PCR amplified as a single product from human skeletal muscle RNA. A ca. 70 kDa protein peak detected by the Simple Western was determined as Dp71 by over-expressing Dp71 in HEK293 cells, or suppressing Dp71 expression with antisense oligonucleotide in rhabdomyosarcoma cells. The Simple Western assay detected Dp71 in the skeletal muscles of both normal and DMD mice. In human skeletal muscle, Dp71 was also detected. The ratio of Dp71 to vinculin of human skeletal muscle samples varied widely, indicating various levels of Dp71 expression. Conclusions: Dp71 protein was detected in human skeletal muscle using a highly sensitive capillary Western blotting system.

Mer proto-oncogene tyrosine kinase (MerTK), which is expressed in the retinal pigment epithelium (RPE), regulates phagocytosis of shed photoreceptor outer segments (POS). To investigate the effects of drug-induced MerTK inhibition on the retina, UNC569, a specific MerTK inhibitor, was orally administered to male mice at a concentration of 60, 100, or 150 mg/kg for up to 14 days. Furthermore, MerTK inhibition in the retinal tissue sample was examined using a phosphorylation assay following a single dose of UNC569 at 100 mg/kg. In electron microscopic examination, UNC569 at 100 mg/kg or more increased phagosomes and phagolysosomes in the RPE. In addition, UNC569 at 150 mg/kg increased chromatin-condensed nuclei in the outer nuclear layer, indicating the early phase of apoptosis of photoreceptor cells. MiR-183, miR-96, and miR-124, which are enriched in photoreceptor cells, were elevated in the plasma of mice following treatment of 150-mg/kg UNC569, in conjunction with the photoreceptor lesion. Additionally, 100-mg/kg UNC569 inhibited MerTK phosphorylation in the retina. These results suggest that MerTK inhibition impaired phagocytic function of the retina, leading to accumulation of shed POS within the POS layer and increasing phagosomes and phagolysosomes in the RPE to delay POS renewal, resulting in apoptosis of photoreceptor cells.

The Duchenne muscular dystrophy (DMD) gene is one of the largest genes in the human genome. The gene exhibits a complex arrangement of seven alternative promoters, which drive the expression of three full length and four shorter isoforms. Dp116, the second smallest product of the DMD gene, is a Schwann cell-specific isoform encoded by a transcript corresponding to DMD exons 56–79, starting from a promoter/exon S1 within intron 55. The physiological roles of Dp116 are poorly understood, because of its extensive homology with other isoforms and its expression in specific tissues. This review summarizes studies on Dp116, focusing on clinical findings and alternative activation of the upstream translation initiation codon that is predicted to produce Dp118.

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