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1.  Relationship between Violent Behavior and Repeated Weight-Loss Dieting among Female Adolescents in Japan 
PLoS ONE  2014;9(9):e107744.
Purpose
To examine whether interpersonal violence perpetration and violence toward objects are associated with body mass index (BMI), body weight perception (BWP), and repeated weight-loss dieting in female adolescents.
Methods
A cross-sectional survey using a self-report questionnaire was performed evaluating interpersonal violence perpetration, violence toward objects, the number of diets, BMI, BWP, the 12-item General Health Questionnaire (GHQ-12), victimization, substance use, and other psychosocial variables among 9,112 Japanese females aged between 12–18 years. Logistic regression analysis was conducted to analyze the contribution of BMI, BWP, and weight-control behavior to the incidence of violent behavior, while controlling for potential confounding factors.
Results
The number of diets was associated with both interpersonal violence perpetration (OR = 1.18, 95% CI 1.08–1.29, p<0.001) and violence toward objects (OR = 1.34, 95% CI 1.24–1.45, p<0.001), after adjusting for age, BMI, BWP, the GHQ-12 total score, victimization, and substance use. In terms of BMI and BWP, the “overweight” BWP was associated with violence toward objects (OR = 1.29, 95% CI 1.07–1.54, p<0.05). On the other hand, the “Underweight” and “Slightly underweight” BMI were related to violence toward objects [(OR = 1.28, 95% CI 1.01–1.62, p<0.05) and (OR = 1.27, 95% CI 1.07–1.51, p<0.05), respectively]. The “Underweight” BWP was related to interpersonal violence perpetration (OR = 2.30, 95% CI 1.38–3.84, p<0.05).
Conclusions
The cumulative number of diets is associated with violent behavior in female adolescents. In addition, underweight BMI and extreme BWP are associated with violent behavior.
doi:10.1371/journal.pone.0107744
PMCID: PMC4161440  PMID: 25210854
2.  Suicidal Feelings Interferes with Help-Seeking in Bullied Adolescents 
PLoS ONE  2014;9(9):e106031.
Purpose
Being bullied is associated with the manifestation of suicidal feelings, which sharply increase in middle(-late) adolescence. Whether or not bullied middle(-late) adolescents with suicidal feelings seek help is therefore a critical issue, given that help-seeking plays a key role in the prevention of suicide. The aim of the present study is to investigate the effects of bullying, suicidal feelings and the interaction between these two factors on help-seeking behavior in adolescents.
Methods
Japanese middle(-late) adolescents (aged 15–18 years; n = 9484) were studied using self-report questionnaires. The rate of adolescents who actually sought help was examined for bullying status and suicidal feelings.
Results
The rate of adolescents who sought help was significantly higher when they were bullied (p<0.001) and also when they had mild suicidal feelings (p<0.001), but not when they displayed serious suicidal feelings. In the case of adolescents who were bullied, however, having suicidal feelings significantly decreased the rate of help-seeking (OR = 0.47, p<0.05 and OR = 0.32, p = 0.002 for having mild and serious suicidal feelings, respectively). The decrease was remarkable when suicidal feelings were serious. Specifically, the decrease was significant in seeking help from peers and family members, who are the most frequent source of the help for adolescents, when they had serious suicidal feelings (OR = 0.21, p<0.01 and OR = 0.13, p<0.001, respectively).
Conclusions
Suicidal feelings may interfere with help-seeking behavior, which could be critical in suicide prevention in bullied middle(-late) adolescents.
doi:10.1371/journal.pone.0106031
PMCID: PMC4154872  PMID: 25188324
3.  Adolescent Self-control Predicts Midlife Hallucinatory Experiences: 40-Year Follow-up of a National Birth Cohort 
Schizophrenia Bulletin  2014;40(6):1543-1551.
Background: Associations between self-control in adolescence and adult mental health are unclear in the general population; to our knowledge, no study has investigated self-control in relation to psychotic-like symptoms. Aims: To investigate the relationship between adolescent self-control and the midlife mental health outcomes of anxiety and depression symptoms and psychotic-like experiences (PLEs), controlling for the effect of adolescent conduct and emotional problems and for parental occupational social class and childhood cognition. Methods: A population-based sample, the MRC National Survey of Health and Development (the British 1946 birth cohort) was contacted 23 times between ages 6 weeks and 53 years. Teachers completed rating scales to assess emotional adjustment and behaviors, from which factors measuring self-control, behavioral, and emotional problems were extracted. At age 53 years, PLEs were self-reported by 2918 participants using 4 items from the Psychosis Screening Questionnaire; symptoms of anxiety and depression were assessed using the scaled version of the General Health Questionnaire (GHQ-28). Results: After adjustment for the above covariates, poor adolescent self-control was associated with the presence of PLEs in adulthood, specifically hallucinatory experiences at age 53 years, even after adjustment for GHQ-28 scores. Conclusions: Lower self-control in adolescence is a risk factor for hallucinatory experiences in adulthood.
doi:10.1093/schbul/sbu050
PMCID: PMC4193720  PMID: 24714378
self-control; adolescent; psychotic-like experiences; longitudinal; conduct problems
4.  Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells 
The Journal of Experimental Medicine  2012;209(13):2383-2394.
The colitis-associated glycome mediates CD4+ T cell expansion and contributes to the exacerbation of T cell–mediated intestinal inflammation.
Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1–expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell–mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.
doi:10.1084/jem.20112631
PMCID: PMC3526363  PMID: 23209314
5.  The Membrane-Bound Mucin Muc1 Regulates T Helper 17-Cell Responses and Colitis in Mice 
Gastroenterology  2011;142(4):865-874.e2.
BACKGROUND & AIMS
T helper (Th) 17 cells produce the effector cytokine interleukin (IL)-17, along with IL-22, which stimulates colonic epithelial cells to produce a membrane-bound mucin, Muc1. Muc1 is a component of the colonic mucus, which functions as a lubricant and a physiologic barrier between luminal contents and mucosal surface. The gene MUC1 has been associated with susceptibility to inflammatory bowel disease; we investigated the role of Muc1 in development of colitis in mice.
METHODS
Muc1 and RAG1 were disrupted in mice (Muc/RAG double knockout mice); Th1-mediated colitis was induced by intravenous injection of CD4+CD45RBhigh T cells. We also studied Th2-mediated colitis using mice with disruptions in Muc1 and T-cell receptor α chain (Muc/TCR double knockout mice).
RESULTS
Muc1 deficiency led to the development of more severe forms of Th1- and Th2-induced colitis than controls. Loss of Muc1 increased colonic permeability and the Th17-cell, but not Th2 or Th1 cell, response in the inflamed colon. Loss of Muc1 also promoted expansion of an innate lymphoid cell population (Lin− ckit− Thy1+ Sca1+) that produces IL-17. The expansion of Th17 adaptive immune cells and innate lymphoid cells required the commensal microbiota.
CONCLUSIONS
Muc1, which is up-regulated by Th17 signaling, functions in a negative feedback pathway that prevents an excessive Th17 cell response in inflamed colons of mice. Disruption of this negative feedback pathway, perhaps by variants in Muc1, might contribute to inflammatory bowel disease in patients.
doi:10.1053/j.gastro.2011.12.036
PMCID: PMC3441148  PMID: 22202458
Susceptibility; Risk Factor; Mouse Model; Immune Regulation
6.  A greater number of somatic pain sites is associated with poor mental health in adolescents: a cross-sectional study 
BMC Psychiatry  2013;13:30.
Background
Identifying indicators of poor mental health during adolescence is a significant public health issue. Previous studies which suggested an association between the number of somatic pains and depression have mainly focused on adults or have employed samples with a narrow age range. To date, results from previous studies have been inconsistent regarding the association between somatic pain and academic impairment. Therefore, the main aims of the present study were to 1) investigate the association between the number of somatic pain sites and poor mental health using a community sample of adolescents aged 12 to 18 years and employing a simple method of assessment, and 2) examine the association between the number of somatic pain sites and perceived academic impairment.
Methods
Data analysis was conducted using a large cross-sectional survey of adolescents in grades 7 to 12. The one-month prevalence rates for three sites of somatic pain including head, neck and shoulders, and abdomen were examined. Poor mental health was evaluated using the General Health Questionnaire, and perceived academic impairment was measured using a self-report questionnaire.
Results
A total of 18,104 adolescents participated in the survey. A greater number of pain sites was associated with poor mental health, and this association was consistent across age and gender. There was no difference in effect on mental health between any of the pain sites. Although there was an association between the number of somatic pain sites and perceived academic impairment, the results suggested that the association was mediated by poor mental health.
Conclusions
Simple reporting methods for assessing the number of pain sites may be a feasible indicator of poor mental health in adolescents. Professionals working with adolescents should consider the possibility of poor mental health, especially when students report multiple somatic pains.
doi:10.1186/1471-244X-13-30
PMCID: PMC3598352  PMID: 23327684
Number; Somatic pain site; Poor mental health; Adolescents; Males and females; Academic impairment
7.  Help-seeking behavior among Japanese school students who self-harm: results from a self-report survey of 18,104 adolescents 
Background:
The aim of this study was to determine the prevalence of and factors associated with poor help-seeking among adolescents who self-harm and to explore the resources used for help.
Methods:
A cross-sectional survey using an anonymous questionnaire was conducted in 47 junior and 30 senior high schools in Japan. Adolescent self-harm was defined as an adolescent who had harmed himself or herself in the previous year, as in previous studies reported in Western countries. Poor help-seeking was defined as not consulting anyone despite reporting current psychological or somatic complaints. Information about sociodemographic and psychological factors possibly associated with help-seeking, such as suicidal thoughts, depression, anxiety, and psychotic-like experiences, was also collected. Regression analyses were performed to examine associated factors.
Results:
A total of 18,104 students (8620 aged 12–15 years, 9484 aged 15–18 years), accounting for 93% of all students in the relevant student classes, participated in the study. Two hundred and seventy-six (3.3%) junior and 396 (4.3%) senior high school students reported having self-harmed. Of these, 40.6% of adolescents in junior and 37.6% in senior high schools were classified as poor help-seeking. Poor help-seeking with regard to self-harm was significantly more common in those who reported not having consulted anyone about psychological problems (odds ratio 9.2, 95% confidence interval 4.6–18.4 in juniors; odds ratio 9.9, confidence interval 5.5–17.9 in seniors) and in those with current suicidal ideation (odds ratio 2.0, confidence interval 1.0–3.7 in juniors; odds ratio 1.9, confidence interval 1.1–3.4 in seniors). Family members were approached significantly less often as a resource for help by students who self-harmed than by those who did not, and school nurses were more often consulted by those who did self-harm.
Conclusion:
Around 40% of adolescents who self-harmed in the previous year did not seek help. School-based mental health should screen students at risk of self-harm, and educate school nurses about preventative care.
doi:10.2147/NDT.S37543
PMCID: PMC3509995  PMID: 23209369
self-harm; adolescence; help-seeking; prevention; Japan
8.  Irregular Bedtime and Nocturnal Cellular Phone Usage as Risk Factors for Being Involved in Bullying: A Cross-Sectional Survey of Japanese Adolescents 
PLoS ONE  2012;7(9):e45736.
Purpose
A number of studies have tried to identify risk factors for being involved in bullying in order to help developing preventive measures; however, to our knowledge, no study has investigated the effect of nocturnal lifestyle behavior such as sleep pattern or cellular phone usage. In the present study, we aimed to investigate the relationship between school bullying and sleep pattern or nocturnal cellular phone usage in adolescents. The effect of school size on school bullying was also examined.
Methods
Data from the cross-sectional survey of psychopathologies conducted for 19,436 Japanese students from 45 public junior high schools (7th–9th grade) and 28 senior high schools (10th–12th grade) were analyzed.
Results
Bullying status was significantly associated with irregular bedtime (OR = 1.23 and 1.41 for pure bullies and bully-victims, respectively) and e-mail exchange or calling after lights-out (OR = 1.53 and 1.31 for pure bullies and bully-victims, respectively) after controlling domestic violence and substance usage. In addition, school size was significantly associated with the increased risk of bullying in junior high school students (OR = 1.13 for bully-victims).
Conclusions
The present results suggested that sleep pattern and nocturnal cellular phone usage might be risk factors for being involved in school bullying in adolescents. Although further accumulation of data is needed, progressive trend towards nocturnal lifestyle and increasing usage of cellular phone might impair the well-being of adolescents. School-based interventions for lifestyle including sleep pattern and cellular phone usage may be encouraged to reduce school bullying.
doi:10.1371/journal.pone.0045736
PMCID: PMC3446940  PMID: 23029211
9.  Season of birth effect on psychotic-like experiences in Japanese adolescents 
A number of studies have investigated seasonality of birth in schizophrenia. Most of the studies have consistently observed an excess of winter births, often associated with decreased summer births. We postulated that psychotic-like experiences (PLEs), subclinical hallucinatory and delusional experiences, may also be affected by birth season. In the present study, we assessed the season of birth effect on the prevalence of PLEs using data from the cross-sectional survey of 19,436 Japanese adolescents. As a result, significant excess of winter births was observed in the prevalence of PLEs, accompanied by a decreased proportion of summer births. The odds ratios for the prevalence of PLEs were estimated to be 1.11, which was on the same order with those for the development of schizophrenia in the previous meta-analytic studies. To our knowledge, this is the first to show the seasonality of birth in the prevalence of PLEs and implicate the winter birth effect on subclinical stage of schizophrenia.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-012-0326-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-012-0326-1
PMCID: PMC3562433  PMID: 22983561
Schizophrenia; Winter birth; Summer birth; Hallucination; Delusion
10.  Cost-effectiveness of family psychoeducation to prevent relapse in major depression: Results from a randomized controlled trial 
BMC Psychiatry  2012;12:40.
Background
Family psychoeducation is a relatively simple and straightforward intervention whose prophylactic effectiveness and cost-effectiveness is well-established for schizophrenia. We have recently demonstrated its effectiveness for unipolar depression, but its cost-effectiveness has never been examined. We hereby report a cost-effectiveness analysis alongside a randomized controlled trial in order to assess its cost-effectiveness for preventing relapse/recurrence in depression.
Methods
Fifty-seven patients diagnosed with major depression and undergoing its maintenance treatment, and their primary family members were randomized to treatment as usual (TAU) only or to TAU plus family psychoeducation, which consisted of four 2-hour multiple-family sessions consisting of didactic lectures about depression (30 minutes) and group discussion and problem solving (60–90 minutes). The economic analyses were undertaken from the perspective of the National Health Insurance (NHI), assuming the most reasonable price of US$50 per psychoeducation session per patient. The main outcome measures included relapse-free days and direct costs to the NHI.
Results
The intervention group enjoyed 272 (SD: 7.1) relapse-free days, while the control group spent 214 (SD: 90.8) relapse-free days (Cox proportional hazard ratio = 0.17, 95%CI: 0.04 to 0.75, p = 0.002). Cost-effectiveness acceptability curves suggested that the family psychoeducation has 90% or more chances of being cost-effective if the decision-maker is prepared to pay US$20 for one additional relapse-free day. This cost-effectiveness finding was robust when the price for family psychoeducation ranged between 50% to 150% of the baseline scenario in sensitivity analyses. If a relapse-free day is considered to be worth $30 or more, all the pricing scenarios have a close to 100% probability of being cost-effective.
Conclusion
Family psychoeducation is effective in the relapse prevention of depression and is highly likely to be cost-effective if a relapse-free day is valued as US$20 or more.
Trial registration
UMIN-CTR (UMIN000005555)
doi:10.1186/1471-244X-12-40
PMCID: PMC3473266  PMID: 22583708
11.  The development of agoraphobia is associated with the symptoms and location of a patient's first panic attack 
Background
The place where a patient experiences his/her first panic attack (FPA) may be related to their agoraphobia later in life. However, no investigations have been done into the clinical features according to the place where the FPA was experienced. In particular, there is an absence of detailed research examining patients who experienced their FPA at home. In this study, patients were classified by the location of their FPA and the differences in their clinical features were explored (e.g., symptoms of FPA, frequency of agoraphobia, and severity of FPA).
Methods
The subjects comprised 830 panic disorder patients who were classified into 5 groups based on the place of their FPA (home, school/office, driving a car, in a public transportation vehicle, outside of home), The clinical features of these patients were investigated. Additionally, for panic disorder patients with agoraphobia at their initial clinic visit, the clinical features of patients who experienced their FPA at home were compared to those who experienced their attack elsewhere.
Results
In comparison of the FPAs of the 5 groups, significant differences were seen among the 7 descriptors (sex ratio, drinking status, smoking status, severity of the panic attack, depression score, ratio of agoraphobia, and degree of avoidance behavior) and 4 symptoms (sweating, chest pain, feeling dizzy, and fear of dying). The driving and public transportation group patients showed a higher incidence of co-morbid agoraphobia than did the other groups. Additionally, for panic disorder patients with co-morbid agoraphobia, the at-home group had a higher frequency of fear of dying compared to the patients in the outside-of-home group and felt more severe distress elicited by their FPA.
Conclusion
The results of this study suggest that the clinical features of panic disorder patients vary according to the place of their FPA. The at-home group patients experienced "fear of dying" more frequently and felt more distress during their FPA than did the subjects in the other groups. These results indicate that patients experiencing their FPA at home should be treated with a focus on the fear and distress elicited by the attack.
doi:10.1186/1751-0759-6-12
PMCID: PMC3349583  PMID: 22494552
Place of first panic attack; Panic attack symptoms; Subtype of panic disorder; Agoraphobia
12.  Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers 
BMC Genetics  2012;13:23.
Background
Duchenne muscular dystrophy, a fatal muscle-wasting disease, is characterized by dystrophin deficiency caused by mutations in the dystrophin gene. Skipping of a target dystrophin exon during splicing with antisense oligonucleotides is attracting much attention as the most plausible way to express dystrophin in DMD. Antisense oligonucleotides have been designed against splicing regulatory sequences such as splicing enhancer sequences of target exons. Recently, we reported that a chemical kinase inhibitor specifically enhances the skipping of mutated dystrophin exon 31, indicating the existence of exon-specific splicing regulatory systems. However, the basis for such individual regulatory systems is largely unknown. Here, we categorized the dystrophin exons in terms of their splicing regulatory factors.
Results
Using a computer-based machine learning system, we first constructed a decision tree separating 77 authentic from 14 known cryptic exons using 25 indexes of splicing regulatory factors as decision markers. We evaluated the classification accuracy of a novel cryptic exon (exon 11a) identified in this study. However, the tree mislabeled exon 11a as a true exon. Therefore, we re-constructed the decision tree to separate all 15 cryptic exons. The revised decision tree categorized the 77 authentic exons into five groups. Furthermore, all nine disease-associated novel exons were successfully categorized as exons, validating the decision tree. One group, consisting of 30 exons, was characterized by a high density of exonic splicing enhancer sequences. This suggests that AOs targeting splicing enhancer sequences would efficiently induce skipping of exons belonging to this group.
Conclusions
The decision tree categorized the 77 authentic exons into five groups. Our classification may help to establish the strategy for exon skipping therapy for Duchenne muscular dystrophy.
doi:10.1186/1471-2156-13-23
PMCID: PMC3350383  PMID: 22462762
Splicing; Dystrophin; Exon; Splicing enhancer; Decision tree
13.  Comprehensive early intervention for patients with first-episode psychosis in Japan (J-CAP): study protocol for a randomised controlled trial 
Trials  2011;12:156.
Introduction
Comprehensive approaches for patients with psychotic symptoms play essential roles in the symptomatic and functional outcomes of patients, especially during disease onset. In Japan, the shortage of mental health services, particularly for outpatients, and community-based supports has been a major problem. The purpose of this trial is to investigate the effectiveness and affordability of 18-month comprehensive early intervention services for patients with first-episode psychosis compared with typical treatment.
Methods
This interventional, parallel, single-blinded (open but blinded raters trial) was effectively designed. The participants are patients with a diagnosis of F2 or F3 (International Classification of Disease, 10 th revision), with psychotic symptoms. The inclusion criteria were an age of 15-35 years, onset of psychotic symptoms within 5 years, first-episode psychosis, and residence in the catchment area of each site. Allocation will be conducted equally between case management and standard care groups. After enrollment, standard care will be provided for both groups, and community-based care to promote recovery for 18 months will be provided for the comprehensive approach group. The primary outcome will be the function domain of the global assessment of functioning scores at 18 months after enrollment. Data assessment will be performed at enrollment and 18, 36, and 60 months after enrollment. The target sample size will be 150, and registration will occur from March 1, 2011, to September 30, 2012.
Discussion
This trial will provide promising results about the effectiveness and cost-effectiveness of early intervention services in Japan to improve the quality and quantity of community mental health services.
Trial registration
This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (No. UMIN000005092).
doi:10.1186/1745-6215-12-156
PMCID: PMC3148989  PMID: 21689393
14.  Do Japanese Style Acupuncture and Moxibustion Reduce Symptoms of the Common Cold?† 
We summarize the results from a series of investigations of Japanese style acupuncture and moxibustion therapies on symptoms of the common cold that have been conducted (FTLE 1999–03, supported by the Foundation for Training and Licensure Examination in Anma- Massage- Acupressure, Acupuncture and Moxibustion). We also discuss the various interventions and concerns that we faced during these investigations. The subjects were students and teachers. The pilot study (FTLE1999) of a two arm (real and non-treatment control) RCT at a Japanese acupuncture school showed that manual acupuncture to a specific needling point at the throat clearly reduced symptoms of the common cold. The first multi-center (five centers) RCT (FTLE 2000) revealed a significant reduction in cold symptoms, by general linear model analysis (between groups, P = 0.024). To reduce the technical variation, we employed indirect moxibustion to the neck points as a uniform intervention in the next project (FTLE 2001) without statistically significant results. Then we elongated the periods of treatment from 2 to a maximum of 12 weeks (FTLE 2002) with different interventions accompanied by 4 weeks follow-up. The results were still not statistically significant. As the final project, we tried to develop a new experimental design for individualized intervention by conducting n-of-1 trials using elderly subjects in a health care center but without detecting a clear effect. In conclusion, the safety of Japanese acupuncture or moxibustion was sufficiently demonstrated; however, a series of clinical trials could not offer convincing evidence to recommend the use of Japanese style acupuncture or moxibustion for preventing the common cold. Further studies are required as the present trials had several limitations.
doi:10.1093/ecam/nem055
PMCID: PMC2586319  PMID: 18955215
multi-center RCTs; common cold symptoms; acupuncture; moxibustion; japanese style
15.  FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice 
AIM: To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.
METHODS: BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4+ T cell and F4/80+ macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR.
RESULTS: The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were found to be markedly reduced in FR167653-treated DSS mice.
CONCLUSION: Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.
doi:10.3748/wjg.14.5851
PMCID: PMC2751895  PMID: 18855984
p38; Inflammatory bowel disease; Cytokine; Experimental colitis; Tumor necrosis factor-α
16.  Mucosal cytokine network in inflammatory bowel disease 
Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by ongoing mucosal inflammation in which dysfunction of the host immunologic response against dietary factors and commensal bacteria is involved. The chronic inflammatory process leads to disruption of the epithelial barrier, and the formation of epithelial ulceration. This permits easy access for the luminal microbiota and dietary antigens to cells resident in the lamina propria, and stimulates further pathological immune cell responses. Cytokines are essential mediators of the interactions between activated immune cells and non-immune cells, including epithelial and mesenchymal cells. The clinical efficacy of targeting TNF-α clearly indicates that cytokines are the therapeutic targets in IBD patients. In this manuscript, we focus on the biological activities of recently-reported cytokines [Interleukin (IL)-17 cytokine family, IL-31 and IL-32], which might play a role through interaction with TNF-α in the pathophysiology of IBD.
doi:10.3748/wjg.14.5154
PMCID: PMC2744005  PMID: 18777592
Cytokine; Inflammatory bowel disease; Interleukin-17; Interleukin-31; Interleukin-32
17.  Chemical treatment enhances skipping of a mutated exon in the dystrophin gene 
Nature Communications  2011;2:308-.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon, a small amount of internally deleted, but functional, dystrophin protein is produced in the patient cells. An analysis of the mRNA reveals that the mutation promotes exon skipping and restores the open reading frame of dystrophin. Presumably, the mutation disrupts an exonic splicing enhancer and creates an exonic splicing silencer. Therefore, we searched for small chemicals that enhance exon skipping, and found that TG003 promotes the skipping of exon 31 in the endogenous dystrophin gene in a dose-dependent manner and increases the production of the dystrophin protein in the patient's cells.
Duchenne muscular dystrophy is caused by a loss of the dystrophin gene, and control of dystrophin mRNA splicing could aid treatment of the disease. Nishida et al. show that a small molecule promotes skipping of exon 31 and increases production of a functional dystrophin protein in a patient.
doi:10.1038/ncomms1306
PMCID: PMC3113229  PMID: 21556062

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