Myelomeningocele (MMC) is the most common form of congenital neural tube defect. Current fetal surgical repair performed to prevent the exposed spinal cord from being injured until delivery cannot reverse those injuries already inflicted in utero. “Cell sheet” technology has been adopted successfully for the regeneration of diverse organs and tissues, although this promising modality has not yet been used for fetal therapy. This study thus tested our hypothesis that fetal MMC tissue histologically injured in utero could be regenerated using cell sheet technology. We used the L6 myoblast cell line derived from rat skeletal muscle for the cell sheet engineering. A fetal MMC model was also obtained from pregnant Sprague-Dawley (SD) rats fed orally with retinoic acid (60mg/kg, embryonic day 10). Cell sheets were then transplanted onto the fetal MMC lesion (embryonic day 19) following maternal anesthesia, laparotomy, and hysterotomy. The incisional wound of the uterus was kept open for 4 hours under anesthesia with the MMC lesion maintained outside the body with the transplanted cell sheet. Subsequently, the experimental fetuses were sacrificed for histological (HE stain) and immunohistochemical studies to evaluate viability and differentiation potential based on cell markers of the transplanted L6 myoblasts. Immunohistochemical studies clearly demonstrated cell-sheet markers specific to neurons, skeletal muscle, and myoblasts within the treated MMC lesions, confirming that the cell sheet was biologically implanted within 4 hours after the procedure. Cell sheet technology could be useful for intrauterine regeneration of the fetal rat spinal cord injured by an associated MMC.

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Living donor liver transplantation (LDLT) is now an established therapeutic option for end-stage liver disease with overall survival comparable to that following deceased donor liver transplantation. However, the long-term quality of life (QOL)-related issues following LDLT remain to be investigated. In LDLT, the recipient receives an organ from a living donor, often a family member with strong emotional bonds. Unlike in the case of deceased donors, the lasting bond may strongly affect QOL following transplantation. The aims of the present study were to clarify the health-related QOL of LDLT recipients and to evaluate whether live liver donation affects outcomes. Adult LDLT recipients who made regular follow-up outpatient clinic visits to the liver transplantation service at The University of Tokyo Hospital were enrolled in the study. Subjects were surveyed using two self-administered questionnaires, the standard Short Form 36 (SF36) and a self-designed questionnaire addressing social issues specific to LDLT. Over the 3 months of the study, 88 recipients visited the clinic for regular follow-up examinations. Of these, 83 agreed to be interviewed for the study, of whom 72 (87%) provided complete responses. The SF36 scores for physical functioning, role physical (role limitations due to physical health), and social functioning were significantly lower for study participants than for the general Japanese population. A higher level of education and the degree to which the recipient felt indebted to the donor had significant negative effects on SF36 scores. QOL after LDLT may be lower than that of the general population. The continuing emotional bond with live donors after surgery may strongly affect the QOL of adult LDLT recipients.

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The aim of this study was to assess the non-inferiority of on-demand (OD) inhaled corticosteroid (ICS) and fast-onset beta-2 agonist (FOBA) combination therapy. Although the guidelines recommend regular inhalation of ICS and long-acting beta-2 agonist (LABA), we investigated whether OD-ICS/FOBA is as effective as regular inhalation. A network meta-analysis of randomized controlled trials was conducted to inspect the non-inferiority of OD-ICS/FOBA efficacy compared with conventional best practice, i.e. regular low – to medium-dose ICS with or without LABA, plus OD short-acting beta-2 agonist (REG-ICS+OD-SABA or REG-ICS/LABA+OD-SABA) in patients with mild to moderate asthma. PubMed, the Cochrane library database, and Scopus were searched to identify relevant articles. Outcome measures were the incidence of asthma exacerbation or aggravation. A network meta-analysis was performed to estimate risk ratios (RRs) with 95% confidence intervals (CIs) and the probability of being the best treatment for the outcome. Four randomized controlled trials of treatment for mild to moderate asthma met the criteria and were included in the study. We could not demonstrate non-inferiority of OD-ICS/FOBA to REG-ICS+OD-SABA (RR, 1.17; 95% CI, 0.61 to 2.26) or to REG-ICS/LABA+OD-SABA (RR, 1.47; 95% CI, 0.79 to 2.71) for mild to moderate asthma. The probability of being the best treatment to reduce asthma exacerbation or aggravation was 10.5% for OD-ICS/FOBA, 10.3% for REG-ICS+OD-SABA, and 79.3% for REG-ICS/LABA+OD-SABA. Surface under the cumulative ranking (SUCRA) curves were 0.4, 0.2 and 0.9 for OD-ICS/FOBA, REG-ICS+OD-SABA, and REG-ICS/LABA+OD-SABA, respectively. Although non-inferiority of OD-ICS/FOBA to conventional best practice was not shown, SUCRA was higher for OD-ICS/FOBA than for REG-ICS+OD-SABA. From these results, we propose that OD-ICS/FOBA can be an effective alternative to REG-ICS+OD-SABA to reduce asthma exacerbation or aggravation in patients with mild to moderate asthma.

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This study investigated the relationships between the perceptual evaluation of “wetness” of both pre-swallow voice and expiratory sound and video fluoroscopic swallowing study (VFSS) findings. Pre-swallow phonation of the vowel “a” and expiratory sounds were recorded immediately before VFSS in 51 patients with head and neck cancer. During VFSS, subjects were requested to swallow 3 ml of a jelly-like, radiopaque test food. A total of 61 samples of “a” phonations and expiratory sounds were investigated in this study. These sound samples were randomized and presented to 12 examiners with various years of experience in dysphagia management. The examiners perceptually evaluated the wetness of sound samples using a 5-point “wetness” grade. VFSS findings were evaluated using the 8-point penetration aspiration (PA) scale. The relationships between the wetness of sound samples and VFSS findings were analyzed. Penetration/aspiration without materials ejected out of the airway can be predicted by the wetness of sound samples. In this study, both the pre-swallow wet voice and wet expiratory sounds were suitable for predicting penetration/aspiration after swallowing. High inter-rater and intra-rater reliabilities were verified in the high – and low-experience examiners, with no significant difference evident between these groups. These findings suggest that clinicians could predict penetration/aspiration in head and neck cancer patients by perceptually evaluating the wetness of pre-swallow voice and expiratory sounds regardless of clinical experience.

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This study aimed to evaluate the neurophysiological effects of gentle cutaneous stimulation by acupuncture on muscle tone in patients with chronic spastic paresis. We conducted a randomized, double-blind, crossover trial comparing the effects of contact acupuncture on the H/M ratios of soleus muscles between 8 patients with spastic paresis and 17 healthy volunteers. The study subjects were randomly assigned to two groups, and then they received gentle stimulations to their lower limb (affected side) using skin attachment-type contact acupuncture and sham acupuncture in different order. Fourteen acupuncture points were selected according to the Meridian-Test (M-Test). The soleus muscle in both stimulated and unstimulated limbs was analyzed by electromyography following tibial electrical stimulation at the popliteal fossa, and the H/M ratios were then calculated. Paretic subjects showed a significant decrease in H/M ratio after both contact and sham acupunctures in the stimulated limbs, but not in the unstimulated limbs (unaffected side), and this result was not affected by the order of stimulation. Healthy subjects showed a significant decrease in the H/M ratio after both contact and sham acupunctures in both stimulated and unstimulated limbs. The H/M ratio decrease indicates a decreased overall percentage of activated α-motor neurons. Our results therefore suggest that gentle cutaneous stimulation could reduce α-motor neuron excitability at rest under some conditions.

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We examined vomer morphology using 3-dimensional (3D) analysis and investigated the influence of the surrounding sutures (clefts) and maxilla on nasal septum (vomer) morphology. We evaluated 60 patients who visited our institution. Patients underwent lateral cephalometry and cone-beam computed tomography (CBCT) upon initial examination. Patients with no significant differences in cranial growth were selected and divided into 3 groups of 20: the bilateral cleft lip and palate (BCLP), unilateral cleft lip and palate (UCLP), and non-cleft (Control) groups. We investigated vomer and facial morphologies by using 2-dimensional (2D) cephalometry and we also determined vomer morphology by using 3D cephalometry. Results were analyzed using Bonferroni multiple comparison, logistic regression analysis, and factor analysis. Vomer morphology was significantly different between the 3 groups. Sagitally, the vomer shape was a narrow quadrilateral that tapered at one end in the BCLP group, trapezoidal in the Control group, and intermediate, like a parallelogram, in the UCLP group. The vomer width was significantly greater in the BCLP group. (P <0.05). A significant difference was only found in the posterior vomer width between the UCLP and Control groups. The vomer volume was significantly larger in the BCLP group. The volume in the UCLP group was larger than in the Control group, but this was not significant. Factor analysis revealed that vomer morphology could be clearly distinguished between the 3 groups. Cleft-associated differences in the vicinity of the vomer–maxilla (palatine bone) fusion may influence vomer formation and may cause the differences observed in vomer morphology between the 3 groups. This suggests that cleft and maxillary morphologies may affect nasal septum morphology.

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Nivolumab has recently been approved as a second-line treatment for squamous and non-squamous advanced non-small cell lung cancers (NSCLC). However, no studies have statistically evaluated the adverse event profiles for nivolumab and conventional second-line agents, such as docetaxel. Thus, there is unmet medical need for statistical analysis comparing the adverse effects of nivolumab and docdetaxel in patients with advanced NSCLC. This meta-analysis evaluated the non-inferiority and superiority of the adverse event profiles for nivolumab and docetaxel in patients with previously-treated or refractory advanced NSCLC. The meta-analysis examined two phase 3 trials and compared the incidences of drug-induced adverse events for the nivolumab-treated and docetaxel-treated patient groups. The primary outcomes were the odds ratios (ORs) and 95% confidence intervals (CIs) for any adverse event, fatigue, nausea, decreased appetite, diarrhea, myalgia, anemia, alopecia, neutropenia, febrile neutropenia, and leukopenia. Compared to docetaxel, the adverse event profile for nivolumab was non-inferior and superior for any adverse event (OR, 0.27; 95% CI, 0.19-0.39), fatigue (OR, 0.44; 95% CI, 0.31-0.62), nausea (OR, 0.37; 95% CI, 0.25-0.54), decreased appetite (OR, 0.58; 95% CI, 0.39-0.87), diarrhea (OR, 0.29; 95% CI, 0.19-0.45), myalgia (OR, 0.18; 95% CI, 0.09-0.38), anemia (OR, 0.08; 95% CI, 0.04-0.16), alopecia (OR, 0.01; 95% CI, 0.00-0.06), neutropenia (OR, 0.01; 95% CI, 0.00-0.04), febrile neutropenia (OR, 0.02; 95% CI, 0.00-0.16), and leukopenia (OR, 0.04; 95% CI, 0.01-0.19). These results suggest that, compared to docetaxel, nivolumab may be better tolerated for managing advanced NSCLC.

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Previous studies have reported elevated serum soluble thrombomodulin (sTM) concentrations in acute pulmonary thromboembolism (APTE), but no study has evaluated the relationship between the serum sTM concentration and prognosis. In the present study we investigated the correlation between the serum sTM concentration on admission and the duration of oxygen supplementation in patients admitted to the coronary care unit (CCU) for APTE to evaluate whether serum sTM is a useful predictor of treatment response. The study included 38 consecutive patients [14 men, 24 women; mean (±SD) age 59.9±16.8 years] admitted to the CCU between March 2012 and July 2014 with a diagnosis of APTE confirmed by contrast-enhanced computed tomography within 7 days of onset. The severity of pulmonary embolism was classified as collapse and cardiac arrest type in three patients (8%), massive type in two (5%), submassive type in 19 (50%), and non-massive type in 14 (38%). Significant positive correlations were found for both age and creatinine clearance with duration of hospitalization, but not with duration of oxygen supplementation. There was a significant positive correlation between admission sTM concentrations and both days of hospitalization (R=0.57, P<0.005) and duration of oxygen supplementation (R=0.56, P<0.01). The findings of the present study suggest that serum sTM concentrations are promising predictors of treatment response and short-term prognosis in patients with APTE.

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The technique of fetal endoscopic tracheal occlusion (FETO) was developed to totally occlude the fetal trachea using an intratracheal balloon in the treatment of congenital diaphragmatic hernia with lung hypoplasia. To improve this approach, we developed a method for non-contact, rapid destruction of the balloon using high intensity focused ultrasound (HIFU), a specific balloon injection fluid, and euthanized rabbits (1kg). In an initial experiment (5rabbits), we inflated an intratracheal balloon by injecting in 1.0ml of fluid and demonstrated that HIFU could successfully burst the balloon in all cases, although the tracheal membranous portion and the skin overlying the trachea were injured in 4 and 2cases, respectively. In our second experiment (6animals), we inflated the balloon using only 0.5-0.6ml of fluid. In all cases, HIFU either burst (1animal) or deflated (5animals) the balloon and there was substantially decreased injury of the tracheal membranous portion (2cases) or overlying skin (2cases). The total HIFU energy output revealed no significant difference between the first and second experimental groups. In conclusion, the intratracheal balloon placed by FETO can be removed using HIFU alone.

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