34 research outputs found

    Innovative Treatment of a Fetal Lung Mass Model Using High-intensity Focused Ultrasound (HIFU)

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    Current therapy for space-occupying fetal lung mass lesions (fetal pulmonary lobectomy) is invasive and technically demanding. Accordingly, new therapeutic procedures are required which are much less invasive and more efficient. The purpose of this study was to investigate the feasibility of high-intensity focused ultrasound (HIFU) as a new therapeutic modality for fetal lung mass lesions, using an experimental animal model. We created a solid fetal lung model by differential lung ventilation using anesthetized adult rabbits. In this model, experimental animals with a unilateral independent (fluid-filled) lung were maintained by single lung ventilation of the other dependent lung. Within the independent lung, target blood vessels depicted by color flow Doppler were repeatedly irradiated with HIFU energy beams (n=19). Occlusion of these blood vessels in vivo was confirmed by evaluation of the flow using color flow Doppler. After the procedure, the animals were sacrificed and their harvested lungs were assessed grossly and microscopically. Pulmonary blood vessels (artery and/or vein) were effectively occluded with 2 to 5 cycles of HIFU energy delivery (10.5 seconds each) with a success rate of 62.5% (arteries) and 72.7% (veins). No clear changes including tissue perforations were observed grossly on the surface of the lungs. Ultrasound-guided HIFU energy delivery seems promising for occlusion of the pulmonary blood vessels within a fluid-filled independent lung (fetal lung model). Thus in the future, HIFU irradiation could be used as a less invasive technique to occlude the feeding vessels of fetal lung mass lesions in utero

    A Simple and Safe Procedure to Repair Rectal Prolapse Perineally Using Stapling Devices

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    Rectal prolapses are not life-threatening, however the bleeding and fecal incontinence associated with them significantly erode quality of life and can cause concern among patients' caregivers in nursing homes. Many procedures have been reported that repair rectal prolapses, and the procedure used depends on the severity of the prolapse; however, the treatments are yet to be established. Here we report a simple and safe procedure to repair rectal prolapse perineally using stapling devices. We performed this procedure on 5 patients within a short time. All patients were followed up for over 24 months and none had any recurrences of their rectal prolapses. No complications occurred during the operations and postoperative periods. Most patients who have prolapses are elderly and fragile, so the treatment must be easy, safe, and rapid. While rectal prolapse is not life-threatening, the goal of treatment is to alleviate its symptoms. The procedure we describe is consistent with this concept. We suggest that this procedure, which uses surgical stapling devices, might be a better option for the treatment of complete rectal prolapse. We will continue to surgically correct complete rectal prolapses and investigate the long-term outcomes of the procedure

    Systemic administration of the antisense oligonucleotide NS‐089/NCNP‐02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: Study protocol for a phase I/II clinical trial

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    Abstract Aim The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS‐089/NCNP‐02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. Methods This is an open‐label, dose‐escalation, two‐center phase I/II trial in ambulant patients with DMD, presence of an out‐of‐frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose‐finding stage (4 weeks) during which NS‐089/NCNP‐02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24‐week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12‐lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS‐089/NCNP‐02 concentrations, and changes in blood creatine kinase levels. Discussion Exon‐skipping therapy using ASOs shows promise in selected patients, and this first‐in‐human study is expected to provide critical information for subsequent clinical development of NS‐089/NCNP‐02

    Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C<sub>2</sub>C<sub>12</sub> Myocytes and <i>mdx</i> Mice

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    <div><p>Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder. Here, we show that the CD63 antigen, which is located on the surface of extracellular vesicles (EVs), is associated with increased levels of muscle-abundant miRNAs, namely myomiRs miR-1, miR-133a, and miR-206, in the sera of DMD patients and <i>mdx</i> mice. Furthermore, the release of EVs from the murine myoblast C<sub>2</sub>C<sub>12</sub> cell line was found to be modulated by intracellular ceramide levels in a Ca<sup>2+</sup>-dependent manner. Next, to investigate the effects of EVs on cell survival, C<sub>2</sub>C<sub>12</sub> myoblasts and myotubes were cultured with EVs from the sera of <i>mdx</i> mice or C<sub>2</sub>C<sub>12</sub> cells overexpressing myomiRs in presence of cellular stresses. Both the exposure of C<sub>2</sub>C<sub>12</sub> myoblasts and myotubes to EVs from the serum of <i>mdx</i> mice, and the overexpression of miR-133a in C<sub>2</sub>C<sub>12</sub> cells in presence of cellular stress resulted in a significant decrease in cell death. Finally, to assess whether miRNAs regulate skeletal muscle regeneration <i>in vivo</i>, we intraperitoneally injected GW4869 (an inhibitor of exosome secretion) into <i>mdx</i> mice for 5 and 10 days. Levels of miRNAs and creatine kinase in the serum of GW4869-treated <i>mdx</i> mice were significantly downregulated compared with those of controls. The tibialis anterior muscles of the GW4869-treated <i>mdx</i> mice showed a robust decrease in Evans blue dye uptake. Collectively, these results indicate that EVs and myomiRs might protect the skeletal muscle of <i>mdx</i> mice from degeneration.</p></div

    Effects of ceramide and S1P on EV secretion from C<sub>2</sub>C<sub>12</sub> myoblasts.

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    <p>C<sub>2</sub>C<sub>12</sub> cells were cultured in growth medium until confluent, and then incubated with serum-depleted medium with or without GW4869 for 72 hr (A), C6-ceramide for 24 hr (B), GW4869 and C6-ceramide (C) or GW4869 and C2-ceramide (D) for 72 hr, ebselen for 48 hr (E), D-erythro-MAPP (deMAPP) for 2 hr (F), and GW4869 or S1P for 48 hr (G). The EVs from these cells were extracted from the culture medium, and the amounts of the released EVs were quantified by measuring AChE activity. Data are represented as means + S.E. of absorbance at 405 nm. *: <i>P</i> < 0.05, **: <i>P</i> < 0.01, ***: <i>P</i> < 0.001. (H) Schematic figure of ceramide biogenesis and metabolism. H<sub>2</sub>O<sub>2</sub>: hydrogen peroxide; S1PR1/3: S1P receptor 1 or 3; Gαi: a subunit of G protein.</p
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