Michio Yamamoto

Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model

Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson’s disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

A randomized controlled clinical trial of topical insulin-like growth factor-1 therapy for sudden deafness refractory to systemic corticosteroid treatment

BackgroundTo date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy.MethodsWe randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events.ResultsIn the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9-78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7-67.0%) of the patients in the Dex group (P = 0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P = 0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3-27.4%) of the patients in the Dex group (P = 0.001).ConclusionsThe positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness.Trial registrationUMIN Clinical Trials Registry Number UMIN000004366, October 30th, 2010.

Sparse estimation via nonconcave penalized likelihood in factor analysis model

We consider the problem of sparse estimation in a factor analysis model. A traditional estimation procedure in use is the following two-step approach: the model is estimated by maximum likelihood method and then a rotation technique is utilized to find sparse factor loadings. However, the maximum likelihood estimates cannot be obtained when the number of variables is much larger than the number of observations. Furthermore, even if the maximum likelihood estimates are available, the rotation technique does not often produce a sufficiently sparse solution. In order to handle these problems, this paper introduces a penalized likelihood procedure that imposes a nonconvex penalty on the factor loadings. We show that the penalized likelihood procedure can be viewed as a generalization of the traditional two-step approach, and the proposed methodology can produce sparser solutions than the rotation technique. A new algorithm via the EM algorithm along with coordinate descent is introduced to compute the entire solution path, which permits the application to a wide variety of convex and nonconvex penalties. Monte Carlo simulations are conducted to investigate the performance of our modeling strategy. A real data example is also given to illustrate our procedure.

Estimation of an oblique structure via penalized likelihood factor analysis

The problem of sparse estimation via a lasso-type penalized likelihood procedure in a factor analysis model is considered. Typically, model estimation assumes that the common factors are orthogonal (i.e., uncorrelated). However, if the common factors are correlated, the lasso-type penalization method based on the orthogonal model frequently estimates an erroneous model. To overcome this problem, factor correlations are incorporated into the model. Together with parameters in the orthogonal model, these correlations are estimated by a maximum penalized likelihood procedure. Entire solutions are computed by the EM algorithm with a coordinate descent, enabling the application of a wide variety of convex and nonconvex penalties. The proposed method is applicable even when the number of variables exceeds that of observations. The effectiveness of the proposed strategy is evaluated by Monte Carlo simulations, and its utility is demonstrated through real data analysis.

Clustering of functional data in a low-dimensional subspace

To find optimal clusters of functional objects in a lower-dimensional subspace of data, a sequential method called tandem analysis, is often used, though such a method is problematic. A new procedure is developed to find optimal clusters of functional objects and also find an optimal subspace for clustering, simultaneously. The method is based on the k-means criterion for functional data and seeks the subspace that is maximally informative about the clustering structure in the data. An efficient alternating least-squares algorithm is described, and the proposed method is extended to a regularized method. Analyses of artificial and real data examples demonstrate that the proposed method gives correct and interpretable results.

Prognostic impact of salvage treatment on hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic corticosteroids: A retrospective observational study

OBJECTIVE To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment. METHODS This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone). RESULTS The linear regression model identified age (P=0.001), pretreatment hearing level (P<0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (<60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery. CONCLUSION The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment.

Functional factorial K-means analysis

A new procedure for simultaneously finding the optimal cluster structure of multivariate functional objects and finding the subspace to represent the cluster structure is presented. The method is based on the k-means criterion for projected functional objects on a subspace in which a cluster structure exists. An efficient alternating least-squares algorithm is described, and the proposed method is extended to a regularized method for smoothness of weight functions. To deal with the negative effect of the correlation of the coefficient matrix of the basis function expansion in the proposed algorithm, a two-step approach to the proposed method is also described. Analyses of artificial and real data demonstrate that the proposed method gives correct and interpretable results compared with existing methods, the functional principal component k-means (FPCK) method and tandem clustering approach. It is also shown that the proposed method can be considered complementary to FPCK.

A cluster‐based factor rotation

A new oblique factor rotation method is proposed, the aim of which is to identify a simple and well-clustered structure in a factor loading matrix. A criterion consisting of the complexity of a factor loading matrix and a between-cluster dissimilarity is optimized using the gradient projection algorithm and the k-means algorithm. It is shown that if there is an oblique rotation of an initial loading matrix that has a perfect simple structure, then the proposed method with Kaisers normalization will produce the perfect simple structure. Although many rotation methods can also recover a perfect simple structure, they perform poorly when a perfect simple structure is not possible. In this case, the new method tends to perform better because it clusters the loadings without requiring the clusters to be perfect. Artificial and real data analyses demonstrate that the proposed method can give a simple structure, which the other methods cannot produce, and provides a more interpretable result than those of widely known rotation techniques.

Open versus Laparoscopic Surgery for Advanced Low Rectal Cancer: A Large, Multicenter, Propensity Score Matched Cohort Study in Japan

Background: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. Objective: The aim of this study was to investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for locally advanced low rectal cancer. Patients and Methods: Data from patients with clinical stage II to III low rectal cancer below the peritoneal reflection were collected and analyzed. The operations were performed from 2010 to 2011. Short-term outcomes and long-term prognosis were analyzed with propensity score matching. Results: Of 1608 cases collated from 69 institutes, 1500 cases were eligible for analysis. The cases were matched into 482 laparoscopic and 482 open cases. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 vs 625 mL, P < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, P = 0.005). Three-year overall survival rates were 89.9% [95% confidence interval (95% CI) 86.7–92.4] and 90.4% (95% CI 87.4–92.8) in the laparoscopic and open groups, respectively, and no significant difference was seen between the 2 groups. No significant difference was observed in recurrence-free survival (RFS) between the 2 groups (3-year RFS: 70.9%, 68.4 to 74.2 vs 71.8%, 67.5 to 75.7). Conclusion: Laparoscopic surgery could be considered as a treatment option for advanced, low rectal cancer below the peritoneal reflection, based on the short-term and long-term results of this large cohort study (UMIN-ID: UMIN000013919).

Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study)

Introduction This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). Methods and analysis The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. Ethics and dissemination The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. Trial registration number The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.