Kotaro Yoshioka

DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing

Antisense oligonucleotides (ASOs) are recognized therapeutic agents for the modulation of specific genes at the post-transcriptional level. Similar to any medical drugs, there are opportunities to improve their efficacy and safety. Here we develop a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from double-stranded RNA used for short interfering RNA and single-stranded DNA used for ASO. A DNA/locked nucleotide acid gapmer duplex with an α-tocopherol-conjugated complementary RNA (Toc-HDO) is significantly more potent at reducing the expression of the targeted mRNA in liver compared with the parent single-stranded gapmer ASO. Toc-HDO also improves the phenotype in disease models more effectively. In addition, the high potency of Toc-HDO results in a reduction of liver dysfunction observed in the parent ASO at a similar silencing effect. HDO technology offers a novel concept of therapeutic oligonucleotides, and the development of this molecular design opens a new therapeutic field.

A Score for Predicting Paroxysmal Atrial Fibrillation in Acute Stroke Patients: iPAB Score

BACKGROUND Detection of paroxysmal atrial fibrillation (PAF) after a stroke is challenging. The purpose of this study was to develop a clinical score to predict PAF in a cohort of acute ischemic stroke patients prospectively and to validate it in an independent cohort. METHODS Consecutive acute ischemic stroke patients without permanent atrial fibrillation were enrolled in a derivation sample (n = 294) or a validation sample (n = 155). We developed a score for predicting PAF by independent risk factors derived from a logistic regression analysis of the derivation cohort and validated the score in the external cohort. RESULTS Multivariate analysis in the derivation cohort identified 3 variables independently associated with PAF. We calculated a score from these variables (history of arrhythmia or antiarrhythmic agent use [yes, 3 points], left atrial dilation [≥40 mm, 1 point], brain natriuretic peptide [BNP, ≥50 pg/mL, 1 point; ≥90 pg/mL, 2 points; ≥150 pg/ml, 3 points], total score, 0-7). The iPAB score (identified by past history of arrhythmia or antiarrhythmic agent use, atrial dilation, and BNP elevation) predicted PAF in the derivation (c statistic, .90) and validation (.94) cohorts at levels statistically superior to other biomarkers and clinical scores. For a total score 2 or more, the sensitivity and specificity were 93% and 71%, respectively. For a total score of 4 or more, the corresponding values were 60% and 95%. CONCLUSIONS Our prospective study suggests that this simple risk score superior to other scores help clinicians predict PAF or identify good candidates for further evaluation to detect PAF.

Progressive Encephalomyelitis with Rigidity and Myoclonus Resolving after Thymectomy with Subsequent Anasarca: An Autopsy Case

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.