Multiple-Community-Based Epidemiological Study of Stuttering among 3-Year-Old Children in Japan.

INTRODUCTION: Many epidemiological studies of the disorder of stuttering have been conducted during the 20th century, continuing during the current one. Unfortunately, only a few were carried out in Japan. This study aimed at assessing (1) the incidence and prevalence of stuttering in 3-year-old children in multiple Japanese communities and (2) factors associated with the onset of stuttering among these children. METHODS: A questionnaire aimed at screening for the presence of stuttering was employed for 2,055 children aged 3 years, who underwent a standard nationwide health checkup. Positive responses were confirmed in several ways: (1) direct interviews and assessment of the child's speech, (2) confirmatory questionnaire, or (3) telephone interviews by licensed Speech Language Hearing Therapists. RESULTS: Approximately 6.5% of the children were found to exhibit stuttering at the time of their health checkup. This figure rose to 8.9% after including individuals who previously, but not currently, were reported to have exhibited stuttering. Among the putative risk factors, higher stuttering odds (odds ratio, OR = 3.27) were detected in those with a family history of stuttering, those whose guardians had concerns about their child's development (OR = 1.75), and those with diagnosed diseases or disabilities (OR = 2.13). DISCUSSION/CONCLUSIONS: It was concluded that, in Japan, both the risk of stuttering incidence (8.9%) in children up to, and including, the age of 3 years, as well as its prevalence (6.5%) in this population, was similar to those reported by recent studies in other countries. Additionally, our findings also confirmed that an increased risk for stuttering at age 3 is associated with a family history of stuttering.

Effect of linguistic factors on the occurrence of stuttering-like disfluency among Japanese-speaking preschool children who stutter.

This study aimed to investigate the linguistic factors involved in stuttering among Japanese-speaking preschool children. The participants included 10 Japanese children who stutter, with a mean age of 5 years and 9 months. Speech samples comprised spontaneous conversations of the participants with their parents for about 20 minutes. We compared the percentages of the occurrence of stuttering-like disfluencies (SLDs) at the word and sentence levels, using the Wilcoxon signed-rank test. The results showed no significant differences in SLDs based on syllable structure when comparing light and heavy syllables and comparing consonants and vowels in the initial position of each content word. SLDs occurred more frequently in the initial than non-initial position of words and in longer rather than shorter words. Additionally, SLDs occurred more frequently in sentences that contained more 'bunsetsu' (a kind of linguistic unit in Japanese). Our study is the first to show that both word and sentence-level factors could contribute to SLDs in preschool children who stutter in agglutinating languages, such as Japanese. This aspect is rarely reported in psycholinguistic studies based on stuttering occurrence in inflecting languages, such as English.

Therapeutic Strategy for Rheumatoid Arthritis by Induction of Myeloid-Derived Suppressor Cells with High Suppressive Potential.

Combination treatment using fingolimod (FTY720), an immunomodulator, and a pathogenic antigen prevents the progression of glucose-6-phosphate isomerase (GPI)325-339-induced arthritis. In this study, we focused on myeloid-derived suppressor cells (MDSCs; CD11b+Gr-1+ cells) and investigated the effects of the combination treatment on these cells. DBA/1J mice with GPI325-339-induced arthritis were treated using FTY720 and/or GPI325-339 for five days. The expanded CD11b+Gr-1+ cell population and its inhibitory potential were examined. The percentage of CD369+CD11b+Gr-1+ cells effectively increased in the combination-treated mice. The inhibitory potential of CD369+CD11b+Gr-1+ cells was higher than that of cells not expressing CD369. Among bone marrow cells, the expression of CD369 in CD11b+Gr-1+ cells increased following stimulation with granulocyte-macrophage colony-stimulating factor, and the expression of CD11c increased accordingly. The increased CD11c expression indicated a decrease in the potential to suppress T cell proliferation based on the results of the suppression assay. The percentage of CD11c-CD369+ cells in CD11b+Gr-1+ cells that were induced by the combination treatment also increased, and these cells tended to have a higher capacity to inhibit T cell proliferation. In conclusion, the combination treatment using FTY720 and the pathogenic antigen effectively induces MDSC, which demonstrates a high potential for suppressing T cell proliferation in the lymph nodes, thereby establishing an immune-tolerant state.

Comparison of timing and force control of foot tapping between elderly and young subjects.

[Purpose] To examine the ability of young and elderly individuals to control the timing and force of periodic sequential foot tapping. [Subjects and Methods] Participants were 10 young (age, 22.1 ± 4.3 years) and 10 elderly individuals (74.8 ± 6.7 years) who were healthy and active. The foot tapping task consisted of practice (stimulus-synchronized tapping with visual feedback) and recall trials (self-paced tapping without visual feedback), periodically performed in this order, at 500-, 1,000-, and 2,000-ms target interstimulus-onset intervals, with a target force of 20% maximum voluntary contraction of the ankle plantar-flexor muscle. [Results] The coefficients of variation of force and intertap interval, used for quantifying the steadiness of the trials, were significantly greater in the elderly than in the young individuals. At the 500-ms interstimulus-onset interval, age-related effects were observed on the normalized mean absolute error of force, which was used to quantify the accuracy of the trials. The coefficients of variation of intertap interval for elderly individuals were significantly greater in the practice than in the recall trials at the 500- and 1,000-ms interstimulus-onset intervals. [Conclusion] The elderly individuals exhibited greater force and timing variability than the young individuals and showed impaired visuomotor processing during foot tapping sequences.

High-throughput, high-content screening for novel pigmentation regulators using a keratinocyte/melanocyte co-culture system.

Skin pigmentation is a complex process including melanogenesis within melanocytes and melanin transfer to the keratinocytes. To develop a comprehensive screening method for novel pigmentation regulators, we used immortalized melanocytes and keratinocytes in co-culture to screen large numbers of compounds. High-throughput screening plates were subjected to digital automated microscopy to quantify the pigmentation via brightfield microscopy. Compounds with pigment suppression were secondarily tested for their effects on expression of microphthalmia transcription factor (MITF) and several pigment regulatory genes, and further validated in terms of non-toxicity to keratinocytes/melanocytes and dose-dependent activity. The results demonstrate a high-throughput, high-content screening approach, which is applicable to the analysis of large chemical libraries using a co-culture system. We identified candidate pigmentation inhibitors from 4000 screened compounds including zoxazolamine, 3-methoxycatechol and alpha-mangostin, which were also shown to modulate expression of MITF and several key pigmentation factors and are worthy of further evaluation for potential translation to clinical use.

Semantic processing during continuous speech production: an analysis from eye movements and EEG.

Introduction: Speech production involves neurological planning and articulatory execution. How speakers prepare for articulation is a significant aspect of speech production research. Previous studies have focused on isolated words or short phrases to explore speech planning mechanisms linked to articulatory behaviors, including investigating the eye-voice span (EVS) during text reading. However, these experimental paradigms lack real-world speech process replication. Additionally, our understanding of the neurological dimension of speech planning remains limited. Methods: This study examines speech planning mechanisms during continuous speech production by analyzing behavioral (eye movement and speech) and neurophysiological (EEG) data within a continuous speech production task. The study specifically investigates the influence of semantic consistency on speech planning and the occurrence of "look ahead" behavior. Results: The outcomes reveal the pivotal role of semantic coherence in facilitating fluent speech production. Speakers access lexical representations and phonological information before initiating speech, emphasizing the significance of semantic processing in speech planning. Behaviorally, the EVS decreases progressively during continuous reading of regular sentences, with a slight increase for non-regular sentences. Moreover, eye movement pattern analysis identifies two distinct speech production modes, highlighting the importance of semantic comprehension and prediction in higher-level lexical processing. Neurologically, the dual pathway model of speech production is supported, indicating a dorsal information flow and frontal lobe involvement. The brain network linked to semantic understanding exhibits a negative correlation with semantic coherence, with significant activation during semantic incoherence and suppression in regular sentences. Discussion: The study's findings enhance comprehension of speech planning mechanisms and offer insights into the role of semantic coherence in continuous speech production. Furthermore, the research methodology establishes a valuable framework for future investigations in this domain.

Exploration of Metabolite Biomarkers to Predict the Efficacy of Dupilumab Treatment for Atopic Dermatitis.

Dupilumab (DUP) is the first biological agent used treating atopic dermatitis (AD). Notwithstanding its high cost, the type of patient group for which the drug is effective remains unclear. In this retrospective study, we aimed to identify novel and reliable biomarkers which can be measured before DUP administration and to predict the efficacy of DUP. Serum samples from 19 patients with AD treated with DUP were analysed by metabolome analysis using gas chromatography-mass spectrometry. Total 148 metabolites were detected, and the relative values of the metabolites were compared between the patient group that achieved 75% improvement in Eczema Area and Severity Index 16 weeks after administration of DUP (high responders: HR; n = 11) and that did not (low responders: LR; n = 8). The HR and LR groups had significant differences in the relative values of the eight metabolites (lactic acid, alanine, glyceric acid, fumaric acid, nonanoic acid, ribose, sorbitol, and ornithine), with ribose emerging as the best. Furthermore, we evaluated the serum concentrations of ribose and found that ribose may be a useful metabolite biomarker for predicting the efficacy of DUP in AD.

Treatment for School-Age Children Who Stutter: A Systematic Review of Japanese Literature.

PURPOSE: This systematic review identified and synthesized published research articles, written in Japanese, on the clinical effectiveness of a broad range of nonpharmacological interventions for school-age children who stutter. METHOD: A systematic review of Japanese literature published between January 1, 1980, and July 7, 2020, reporting interventions for school-age children who stutter, was carried out through a search of two databases (CiNii Article database and Japan Medical Abstract Society database) using the key words "stuttering" and "school-age" or "child" or "primary school students" or "children" or "school child" in Japanese. To be included in the review, the articles must report studies where data were subjectively reported by clinicians, where school-age participants were treated for developmental stuttering, where participants received interventions conducted by clinicians, and where quantitative outcomes (pre- and/or posttreatment) were measured; and they must be published in Japanese. RESULTS: Forty articles met all the inclusion criteria. Most articles adopted a case series or single-case study design. A total of 179 intervention programs were identified from all the articles and broadly classified into speech therapy, psychological therapy, interventions for modifying the child's environment, and others. CONCLUSIONS: Our systematic review provided a broad overview of the treatments used for school-age children who stutter in Japan. Future research should focus on gathering more reliable, systematic, and rigorous evidence to establish the effectiveness of stuttering treatments for school-age children and thereby develop evidence-based practices.

Comparisons of efficacy and safety in insulin glargine and lixisenatide plus glulisine combination therapy with multiple daily injection therapy in Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: Multiple daily injection therapy for early glycemic control in patients with type 2 diabetes mellitus is associated with hypoglycemia and weight gain. This study aimed to compare the efficacy (time in range of glucose level 70-180 mg/dL), safety (time below range level 1 of glucose <70 mg/dL), glycemic variability changes, therapeutic indices, body mass index and titration periods between multiple daily injection and insulin glargine U100 and lixisenatide (iGlarLixi) combination (iGlarLixi + insulin glulisine; injected once daily [evenings]) therapies using intermittent continuous glucose monitoring. MATERIALS AND METHODS: A total of 40 hospitalized patients with type 2 diabetes were randomly assigned to the iGlarLixi + insulin glulisine group or the multiple daily injection group. An intermittent continuous glucose monitoring system was attached, and each injection was adjusted to achieve the target glucose level according to the respective titration algorithm. Times in and below the range were analyzed using data collected on days 11-13 of the intermittent continuous glucose monitoring. RESULTS: The time in range did not significantly differ between the groups. However, the time below range level 1 was lower in the iGlarLixi + insulin glulisine group (P = 0.047). The changes in glycemic variability, therapeutic indices and body mass index were not significantly different between the groups, although the titration period was significantly shorter in the iGlarLixi + insulin glulisine group (P = 0.033). CONCLUSIONS: iGlarLixi + insulin glulisine combination therapy is safe and equally efficacious as multiple daily injection therapy for glycemic control, while avoiding hypoglycemia risk and reducing the number of injections are required.

Efficacy of IDegLira Versus IDegAsp Therapy in Patients with Type 2 Diabetes: A Randomized Crossover Study by isCGM.

INTRODUCTION: We aimed to compare the efficacy of insulin degludec/insulin aspart (IDegAsp) and insulin degludec/liraglutide (IDegLira) in controlling glucose fluctuation and suppressing postprandial glucose levels using intermittently scanned continuous glucose monitoring. METHODS: Twenty-four patients with type 2 diabetes mellitus were randomly allocated to receive either IDegLira or IDegAsp followed by IDegAsp or IDegLira, respectively. A crossover study was conducted with intermittently scanned continuous glucose monitoring. We compared the postprandial blood glucose level, time in range, and time below range from a 3-day intermittently scanned continuous glucose monitoring period for each treatment group. RESULTS: The time in range was significantly higher in IDegLira than in IDegAsp. Postprandial glucose levels 90 and 120 min after breakfast and 60, 90, and 120 min after lunch were significantly lower for IDegLira than for IDegAsp. However, postprandial glucose levels 90 and 120 min after supper were significantly lower for IDegAsp than for IDegLira. There was no significant difference in the time below range between IDegLira and IDegAsp. CONCLUSION: IDegLira was more effective in treating type 2 diabetes mellitus than IDegAsp, as indicated by a higher time in range and lower postprandial glucose level at breakfast and lunch. This study was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN 000039221).

Public attitudes toward people who stutter in the workplace: A questionnaire survey of Japanese employees.

PURPOSE: Negative attitudes toward stuttering by people in their work roles have been previously reported. These attitudes could differ depending on whether or not someone knows a person or has been in contact with a person who stutters. This study aimed to elucidate public attitudes toward people who stutter at work. METHODS: A web-based questionnaire survey of 730 adults drawn from the general public throughout Japan was conducted. It gathered information on respondents' demographics, contact experience with people who stutter, knowledge of stuttering, and attitudes and experiences toward stuttering at work, using a Likert-type scale. To investigate the factors associated with their attitudes and experiences toward stuttering at work, respondents' demographic information and contact experience were entered into a multivariable model using ordinal logistic regression analysis. RESULTS: We analyzed the data of 671 respondents, of whom 77.2 % were company employees; 41.3 % knew a person who stutters at their workplace, among their friends, and/or in their family, and 34.7 % had been in the position of hiring any individual. Respondents perceived the employment of people who stutter to be somewhat positive overall. Regression analysis revealed that only the factor of workplace contact experience to be significantly positively associated with the respondents' attitudes toward stuttering. That is, knowing a person who stutters in one's workplace was significantly associated with more positive attitudes. CONCLUSION: Previous studies have reported widespread negative public attitudes toward stuttering. Our results can supplement this literature, especially regarding attitudes in the workplace. Our findings suggest that the main factor that is associated with people's positive attitudes is their contact experience with people who stutter in their workplace.

A Questionnaire Survey About Support Requests From School-Age Children and Adolescents Who Stutter.

Purpose Children who stutter (CWS) face communication difficulties in school activities and at home. Although the importance of receiving support from their surroundings has been documented, few studies have investigated potential requests of CWS from their surroundings. This study aimed to elucidate such requests. Method A total of 43 school-age children and 25 adolescents who stutter completed a free-description questionnaire, including questions such as "what you want your classmates/your classroom teacher/your family to do about your stuttering?" Their descriptions were summarized and categorized based on similarity. Results The results indicate that 90.6% of the participants had more than one request for their classmates, classroom teacher, or family. A total of 197 items were extracted and categorized into seven themes. In particular, the responses included "listen attentively," "treat us naturally," and "make arrangements." While participants tended to hope for classmates or family to "listen attentively" and "treat us naturally," the request to "make arrangements" was higher for their teacher. Their potential requests varied by age: While school-age CWS wanted people around them to "listen carefully," the hope of adolescents who stutter was "treat us naturally." Conclusions The various potential requests of CWS were categorized, and the responses shed light on the importance of increasing knowledge of stuttering. The difference between the requests could reflect psychosocial differences between school-age children and adolescents who stutter. In addition, social interaction among peers is more developed in adolescents, and they could harbor fear of being excluded within their community.

RNA-binding proteins Rbm38 and Rbm24 regulate myogenic differentiation via p21-dependent and -independent regulatory pathways.

Skeletal muscle differentiation entails organized sequential events, including cell cycle arrest of proliferating myoblast cells and cell fusion, which lead to the formation of multinucleated myotubes. This process involves both transcriptional and post-transcriptional regulation of the gene expression of myogenic proteins, as well as cell-cycle related proteins. RNA-binding proteins bind to specific sequences of target RNA and regulate gene expression in a post-transcriptional manner. However, few tissue-specific RNA binding proteins have been identified. Herein, we report that the RNA binding proteins Rbm24 and Rbm38 were found to be preferentially expressed in muscle during differentiation in vitro. Further, knockdown of either by RNA interference suppressed cell-cycle arrest and delayed myogenic differentiation in C2C12 cells. In contrast, over-expression of Rbm24 or Rbm38 induced cell cycle arrest, and then had a positive effect on myogenic differentiation. Immunoprecipitation-RT-PCR analysis using tagged Rbm proteins indicated that Rbm38 binds to the p21 transcript in vivo. Consistent with this, differentiation of Rbm38 knockdown cells was rescued by over-expression of p21. Together, our results suggest that Rbm38 plays a crucial role in cell cycle arrest and myogenic differentiation via its binding to p21.

The Relationship Between Attentional Capture by Speech and Nonfluent Speech Under Delayed Auditory Feedback: A Pilot Examination of a Dual-Task Using Auditory or Tactile Stimulation.

Delayed auditory feedback (DAF) leads to nonfluent speech where the voice of a speaker is heard after a delay. Previous studies suggested the involvement of attention to auditory feedback in speech disfluency. To date, there are no studies that have revealed the relationship between attention and nonfluent speech by controlling the attention allocated to the delayed own voice. This study examined these issues under three conditions: a single task where the subject was asked to read aloud under DAF (single DAF task), a dual task where the subject was asked to read aloud while reacting to a pure tone (auditory DAF task), and a dual task where the subject was asked to read aloud while reacting to the vibration of their finger (tactile DAF task). The subjects also performed the single and dual tasks (auditory/tactile) under nonaltered auditory feedback where no delayed voices were involved. Results showed that the nonfluency rate under the auditory DAF task was significantly greater than that under the single DAF task. In contrast, the nonfluency rate under the tactile DAF task was significantly lower compared with that of the single DAF task. Speech became nonfluent when attention was captured by the same modality stimulus, i.e., auditory tone. In contrast, speech became fluent when attention was allocated to the stimulus that is irreverent to auditory modality, i.e., tactile vibration. This indicates that nonfluent speech under DAF is involved in attention capture owing to the delayed own voice.

A new simple performance test focused on agility in elderly people: The Ten Step Test.

BACKGROUND: Not only the reduction of muscle strength or balance, but also the reduction of the agility are regarded as important factors of falls in elderly people. If an agility test for elderly people is established, the precision of the fall prediction rises and can be used for individual training. OBJECTIVES: To develop a new performance test focused on agility for elderly people and to evaluate the usefulness of this test. DESIGN: Cross-sectional study. SETTING: The Welfare Center of Kagami Town, Kagami Town Office, etc., Kochi, Japan. PARTICIPANTS: 828 community-dwelling, independent adults aged 20-99 years with no obvious cognitive or functional disability, were randomly recruited from Kagami town and the surrounding areas. MEASUREMENTS: The Ten Step Test (TST, a new performance test), motor reaction time (MRT), knee extensor isometric strength, single leg standing time (SLST), and some other tests were used to evaluate the criterion-related validity and the content validity. TST was developed as a modified version of other step tests which require the subjects to place the whole foot on a block, then return it to the floor. In addition, female participants over 70 were asked whether or not they had fallen in the past year. RESULTS: Excellent reliability for TST was found for interrelation (intra-class correlation coefficients, ICC = 0.96), and re-test reliability was sufficient (ICC = 0.86). Evidence for criterion-related validity was found through high single correlation with the timed supine-to-stand (r = 0.68) and high single correlation with MRT (r = 0.59). In addition, content validity was found through low correlation with knee extensor strength (-0.35) and SLST (-0.36) in 112 women over 70 years of age. The error rate by TST to predict falls (35.2%) was lower than the error rate by muscle strength (44.4%) and the balance (38.7%). TST confirmed decline after 50 years of age, and it conformed to a cubic curve. CONCLUSION: The findings indicate that TST is a reliable measure of agility, and it can help to predict the risk of falls. The decline of agility accelerates after 50 years of age. It shows that the decline of agility differs from the decline of leg muscle strength and balance.

S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.

The calcium-binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiologic and pathophysiologic effects of this damage-associated "danger signal" are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN specifically bound to S100A9 but not S100A8. Induction of cytokines and matrix metalloproteases (MMP) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaling used the TNF receptor-associated factor TRAF2 distinct from the known S100-binding signaling pathway mediated by RAGE (AGER). S100A9 strongly promoted migration when EMMPRIN was highly expressed, independent of RAGE, whereas EMMPRIN blockade suppressed migration by S100A9. Immunohistologic analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions and the adjacent epidermis, where S100A9 was also strongly expressed. In epidermal-specific transgenic mice, tail vein-injected melanoma accumulated in skin expressing S100A9 but not S100A8. Together, our results establish EMMPRIN as a receptor for S100A9 and suggest the therapeutic use in targeting S100A9-EMMPRIN interactions.

Interaction interference between arm and leg: division of attention through muscle force regulation.

The first purpose of this study was to examine whether decreases in muscle force similar to the bilateral deficit occur during simultaneous use of arm and leg. The second purpose was to examine the effect on the muscle force of one leg by a division of attention through the regulation of the muscle force in the arm. Six participants completed each of the following three tasks in a random order: (1) maximal unilateral flexion of the right or left elbow, (2) maximal unilateral extension of the left knee, and (3) multilimb effort (a maximal contraction of the muscles in the leg while maintaining a constant submaximal isometric elbow flexion force at 25%, 50%, 75%, or 100% MVC). The results showed that muscle force was lower during simultaneous exertion of arm and leg than during exertion of one limb alone. The maximal knee extension force was significantly (p<.05) lower, by as much as 40% or so, during regulation at 25% MVC. The division of attention is also thought to be involved in task execution and may thus explain the test results. A decrease in the muscle force of the leg due to the level of regulation of the muscle force of the arm indicates that the regulation of the muscle force affects the division of attention, and the finer level of muscle force regulation is a task that requires greater attention. When the muscle force is precisely controlled, a more accurate and more appropriate adjustment is required to focus attention.