Risk factors associated with throwing injuries in young baseball players.

BACKGROUND: Few studies have retrospectively analyzed the relationship between joint range of motion (ROM) and muscle flexibility and shoulder and elbow throwing injuries in a large number of elementary school baseball players. The purpose of this study was to retrospectively identify the physical factors related to shoulder and elbow throwing injuries in younger baseball players. METHODS: A total of 2466 younger baseball players belonging to our Prefecture Rubber Baseball Federation who participated in medical check-ups from 2016 to 2019 were analyzed. Players completed a questionnaire and had a medical check-up that included a physical examination and ultrasonography. ROM (internal rotation [IR] angle and external rotation angle) of the shoulder and hip and the finger-to-floor distance and heel-to-buttock distance were measured. The straight leg raise was also performed. The results of two groups (normal group and injury group) were compared using the χ2 test, Mann-Whitney U test, and Student t test. Stepwise forward logistic regression models were developed to identify risk factors. RESULTS: On univariate analysis, nine of the 13 evaluated items showed significant decreases in ROM and muscle flexibility in the injury group. On multiple logistic regression analysis, grade, finger-to-floor distance, IR angle of the dominant side shoulder, and IR angle of the nondominant side hip were significantly associated with the occurrence of throwing injuries. Decreased total shoulder angle was observed not only on the dominant side but also on the nondominant side in the injury group. CONCLUSION: Decreased ROM and muscle flexibility were risk factors for baseball-related throwing injuries in elementary school baseball players. To prevent shoulder and elbow throwing injuries, players, coaches, medical staff, and parents need to be aware of these findings.

Lithium in drinking water and Alzheimer's dementia: Epidemiological Findings from National Data Base of Japan.

OBJECTIVES: The aim of this study was to investigate the association between lithium levels in drinking water and prevalence of Alzheimer's dementia (AD). METHODS: Lithium levels in the drinking water of 808 cities and wards (i.e., 785 Japanese cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to the prevalence of AD during the 5 years from 2010 to 2014, which was calculated on the basis of the national data base of Ministry of Health, Labor, and Welfare of Japan. Multiple regression analyses were used to investigate the association of lithium levels with the prevalence of AD with adjustment for relevant factors (proportions of one-person households as a family factor and people in primary industry employment as a job factor, annual total sunshine hours as a meteorological factor, and total number of beds of psychiatric hospitals as a medical factor) in total, male, and female elderly populations. RESULTS: The adjusted model showed a significant inverse association of lithium levels with female, but not with male, or total prevalence of AD. CONCLUSIONS: These findings suggest that higher lithium levels in drinking water may be associated with lower prevalence of AD in female, but not male, populations.

Clinical outcomes of arthroscopic rotator cuff repair: a retrospective comparison of double-layer, double-row and suture bridge methods.

BACKGROUND: The suture-bridge (SB) method has recently become the mainstream means of repairing full-thickness rotator cuff tears. However, in some patients the deep and superficial layers have moved in different directions because of delamination of their rotator cuffs. In such cases, a simple suture (double-layer, double-row [DD] method) is used to repair the superficial and deep layers separately. The purpose of this study was to analyze the clinical outcomes and re-tear rates of the DD and SB methods, with patients selected according to the condition of their torn cuffs. METHODS: We retrospectively registered 74 patients with full-thickness rotator cuff tears that had been repaired arthroscopically, 35 shoulders by the DD and 39 by the SB method. Mean ages were 66.1 years in the DD and 62.9 years in the SB group. We evaluated clinical status before and after surgery (Japanese Orthopedic Association [JOA] scores) and re-tear rate. The Wilcoxon signed-ranks test was used to compare JOA scores and active ROM between before and after surgery in each group. Mann-Whitney's U test was used for comparing JOA scores, active ROM, re-tear rates, size of tear, duration of follow-up, sex, and presence of subscapular muscle repair between the DD and SB groups. A hazard ratio of less than 5% was considered to denote significance. RESULTS: JOA scores improved significantly in the DD and SB groups from preoperative means of 63.4 and 63.3 points, respectively, to postoperative means of 91.8 and 92.1 points, respectively. The active flexural ROM improved significantly from means of 110.1° and 100.0°, respectively, to postoperative means of 142.3° and 142.7°, respectively; the differences between groups were not significant. Re-tear occurred in 5.9% of the DD (two of 34 shoulders) and 7.9% of the SB group (three of 38 shoulders); its incidence did not differ significantly between the two groups. CONCLUSIONS: Both the DD and SB methods achieve satisfactory clinical outcomes that do not differ significantly. Our results suggest that careful selection of operative method on the basis of the delamination pattern in patients undergoing RCT may reduce the re-tear rate after utilizing the SB method.

Risk of low bone mineral density in patients with rheumatoid arthritis treated with biologics.

BACKGROUND: Osteoporosis is a complication of rheumatoid arthritis (RA). We identified risk factors for osteoporosis during treatment with biologics. METHODS: Femoral neck bone mineral density (BMD) was measured in 186 patients with biologics-treated RA. We compared the characteristics of those with BMD ≥70% of young adult mean (YAM) and those with BMD <70% of YAM, and undertook multivariable logistic regression analysis to identify risk factors for bone loss. RESULTS: Mean age and disease duration, the proportion of females, scores in the Modified Health Assessment Questionnaire and history of vertebral fracture were significantly greater in the BMD <70% of YAM group, but body mass index (BMI) was significantly lower in the BMD <70% of YAM group. There was no significant difference between the groups in terms of other biomarkers of RA activity, the proportion treated with methylprednisolone, or the duration or choice of biologics. The proportions of patients treated with anti-osteoporosis drugs and parathyroid hormone were significantly higher in the BMD <70% of YAM group. In the multivariable analysis, advanced age, female, longer disease duration, history of past thoracic or lumbar vertebral fracture, higher Steinbrocker classification and lower BMI were significant factors for BMD <70% of YAM. DISCUSSION: We identified risk factors for bone loss in patients with RA treated with biologics. Before suppression of disease activity by biologics, bone loss might already be advanced. CONCLUSIONS: We recommend that patients with RA who possess these risk factors be considered for earlier and more intense treatment to prevent bone loss, as well as addressing RA disease progression.

Depletion of Cryptosporidium parvum oocysts from contaminated sewage by using freshwater benthic pearl clams (Hyriopsis schlegeli).

The freshwater benthic pearl clam, Hyriopsis schlegeli, was experimentally exposed to Cryptosporidium parvum oocysts, and it was verified that the oocysts were eliminated predominantly via the fecal route, retaining their ability to infect cultured cells (HCT-8). The total fecal oocyst elimination rate was more than 90% within 5 days after exposure to the oocysts. H. schlegeli was able to survive in the final settling pond of a sewage plant for long periods, as confirmed by its pearl production. In the light of these findings, the clam was placed in the final settling pond in a trial to test its long-term efficacy in depleting oocysts contaminating the pond water. The number of clams placed was set to ensure a theoretical oocyst removal rate of around 50%, and the turbidity and the density of feed microbes in the overflow trough water of the pond were about 35% and 40 to 60% lower, respectively, than in the control water throughout the year. It was found that the clam feces containing oocysts were sufficiently heavy for them to settle to the bottom of the pond, despite the upward water flow. From these results, we concluded that efficient depletion of oocysts in the sewage water of small or midscale sewage treatment plants can be achieved by appropriate placement of H. schlegeli clams.

Naturally absorbed lithium may prevent suicide attempts and deliberate self-harm while eicosapentaenoic acid may prevent deliberate self-harm and arachidonic acid may be a risk factor for deliberate self-harm: The updated different findings in new analyses.

Background: Since our previous investigation on the effects of trace lithium, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) on deliberate self-harm and suicide attempts in 2018, to our knowledge, no replication study has been conducted on this topic. Subjects and methods: We increased 37 new patients and totally 234 patients were re-analyzed to further investigate the association of suicide-related behaviors with levels of trace lithium, EPA, DHA, and AA in a different way to avoid multicollinearity. Results: Higher lithium levels were significantly associated with fewer suicide attempts and deliberate self-harm, higher EPA levels were significantly associated with fewer deliberate self-harm, and higher AA levels were significantly associated with more deliberate self-harm. Discussion: Although the sample size was only slightly larger than the previous study, the present results were clearly different from the previous ones due to the use of different statistical analyses to avoid multicollinearity. Conclusion: The present findings suggest that naturally absorbed lithium may protect against suicide and deliberate self-harm, while naturally absorbed EPA may protect against deliberate self-harm. However, naturally absorbed AA may be a risk factor for deliberate self-harm.

Severe loss of invariant NKT cells exhibiting anti-HTLV-1 activity in patients with HTLV-1-associated disorders.

Invariant natural killer T (iNKT) cells are unique T cells that regulate the immune response to microbes, cancers, and autoimmunity. We assessed the characteristics of iNKT cells from persons infected with human T-lymphotropic virus type 1 (HTLV-1). Whereas most infected persons remain asymptomatic carriers (ACs) throughout their lives, a small proportion, usually with high equilibrium proviral loads,develop 2 diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). We demonstrated that the frequency of iNKT, NK, and dendritic cells in the peripheral blood of HAM/TSP and ATL patients is decreased. We also observed an inverse correlation between the iNKT cell frequency and the HTLV-1 proviral load in the peripheral blood of infected persons. Notably, in vitro stimulation of peripheral blood cells with alpha-galactosylceramide led to an increase in the iNKT cell number and a subsequent decrease in the HTLV-1-infected T-cell number in samples from ACs but not HAM/TSP or ATL patients. Our results suggest that iNKT cells contribute to the immune defense against HTLV-1, and iNKT-cell depletion plays an important role in the pathogenesis of HAM/TSP and ATL. Therefore, iNKT cell-based immunotherapy may be an effective strategy for preventing these HTLV-1-associated disorders.

Validation study of novel grading system for ulnar collateral ligament injury of the elbow with high-resolution magnetic resonance imaging.

BACKGROUND: Recently, magnetic resonance imaging (MRI) classification of medial ulnar collateral ligament (UCL) tears has been introduced, but little is known about the relationship between MRI grading and medial joint laxity. It has been reported that microscopy coils could make it possible to achieve high-resolution images of upper extremities with a superior diagnostic ability to conventional MRI. However, there is no report that has compared the diagnostic reliability between microscopic and conventional MRI. The purpose of this study was to assess the relationship between MRI findings and medial joint laxity evaluated with stress ultrasound (US). Secondary objective was to compare the reliabilities of UCL evaluation between microscopic and conventional MRI. METHODS: One-hundred thirty baseball players who underwent MRI of the elbow for the diagnosis of UCL injury using both conventional and microscopy MRI were included in this study. They also underwent stress US for assessment of medial joint laxity against valgus stress. Our MRI grading system for UCL injuries was compared to medial joint laxity evaluated with stress US. The intrarater and interrater reliabilities of our grading system were assessed with both microscopic and conventional MRI. RESULTS: Our grading system was related to valgus stability, especially with microscopic MRI. The reliabilities were fair when combined with microscopic MRI, which exhibited better intrarater and interrater reliabilities than conventional MRI. CONCLUSION: High-resolution microscopic MRI may contribute to the accurate diagnosis of UCL injuries.

Identification of a crucial site for synoviolin expression.

Synoviolin is an E3 ubiquitin ligase localized in the endoplasmic reticulum (ER) and serving as ER-associated degradation system. Analysis of transgenic mice suggested that synoviolin gene dosage is implicated in the pathogenesis of arthropathy. Complete deficiency of synoviolin is fatal embryonically. Thus, alternation of Synoviolin could cause breakdown of ER homeostasis and consequently lead to disturbance of cellular homeostasis. Hence, the expression level of Synoviolin appears to be important for its biological role in cellular homeostasis under physiological and pathological conditions. To examine the control of protein level, we performed promoter analysis to determine transcriptional regulation. Here we characterize the role of synoviolin transcription in cellular homeostasis. The Ets binding site (EBS), termed EBS-1, from position -76 to -69 of the proximal promoter, is responsible for synoviolin expression in vivo and in vitro. Interestingly, transfer of EBS-1 decoy into NIH 3T3 cells conferred not only the repression of synoviolin gene expression but also a decrease in cell number. Fluorescence-activated cell sorter analysis using annexin V staining confirmed the induction of apoptosis by EBS-1 decoy and demonstrated recovery of apoptosis by overexpression of Synoviolin. Our results suggest that transcriptional regulation of synoviolin via EBS-1 plays an important role in cellular homeostasis. Our study provides novel insight into the transcriptional regulation for cellular homeostasis.

Reduced white matter integrity in borderline personality disorder: A diffusion tensor imaging study.

BACKGROUND: Borderline personality disorder (BPD) has a pervasive pattern of instability in interpersonal relationships, self-image, and emotions. BPD may be linked to an abnormal brain anatomy, but little is known about possible impairments of the white matter microstructure in BPD or their relationship with impulsivity or risky behaviors. The aims of the present study were to explore the relationship between BPD and diffusion tensor imaging (DTI) parameters and psychological tests. METHODS: We evaluated 35 un-medicated BPD patients in a medication-free state and 50 healthy controls (HCs). We performed DTI tractography in BPD patients and HCs. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to BPD patients and HCs. RESULTS: A tract-based spatial statistics (TBSS) revealed that the BPD group had three clusters with a significantly lower axial diffusivity (AD) than the HC group: one located mainly in the cingulum and the other mainly in the inferior front-occipital fasciculus and inferior longitudinal fasciculus. Regarding the AD values, one cluster correlated negatively and significantly with POMS (Depression) and it was located in the cingulum, while another cluster correlated positively and significantly with DACS (Future Denial) and it was located in the inferior front-occipital fasciculus (IFOF). LIMITATIONS: The small sample size of this study prevents us from forming any definitive conclusions, meaning that more studies are needed to confirm our findings. We are unable to generalize our findings to include other ethnic groups. CONCLUSIONS: Our results suggested that hypo-metabolism in a front-limbic network dysfunction is characterized by the cingulum and a front-occipital network dysfunction characterized by the occipital lobe, while an occipital-temporal network dysfunction characterized by the inferior longitudinal fasciculus.

Different functioning of prefrontal cortex predicts treatment response after a selective serotonin reuptake inhibitor treatment in patients with major depression.

BACKGROUND: Major depressive disorder (MDD) is often resistant to treatment with usual approaches. Patients with MDD have shown hypofunction of the frontotemporal cortex in verbal fluency test (VFT)-related near-infrared spectroscopy (NIRS). METHODS: We examined whether the reactions to drug treatment in treatment-naive patients with MDD could be predicted by NIRS outcomes at the initial investigation. All subjects underwent psychological testing to determine levels of anxiety and depression. VFT was used to examine the functioning of the frontotemporal lobes. We administered selective serotonin reuptake inhibitors (SSRIs) for 12 weeks. Subjects included 28 patients with MDD with response to SSRIs (Response group), 19 with no response (Non-Response group), and 63 age-, sex-, and education years-matched healthy controls (HC). RESULTS: We found in the frontotemporal region that hemodynamic responses were significantly smaller in patients with Response and Non-Response groups than in HC before treatment. We also found in the medial frontal region that hemodynamic responses were significantly larger in patients with Response groups than in patients with Non-Response group before treatment. Patients with MDD scored significantly higher anxiety and depressive states than those in HC on several measures. The Response and Non-Response groups also had higher scores in future denial, threat prediction, self-denial, past denial, and interpersonal threat sections of Anxiety Cognition Scale (DACS). According to the stepwise regression analysis, one variable was determined as independent predictors of response: confusion (Post-POMS). LIMITATIONS: The number of patients and healthy controls was relatively small, and we will increase the number of participants in future studies. NIRS has reduced spatial resolution, which confuses the identification of the measurement position when using NIRS alone. CONCLUSION: Cognitive vulnerabilities are associated with predictors of SSRI treatment response. Different hemodynamic activities in the frontotemporal cortex predict response to SSRI treatment in MDD.

Gender differences in automatic thoughts and cortisol and alpha-amylase responses to acute psychosocial stress in patients with obsessive-compulsive personality disorder.

INTRODUCTION: Obsessive-compulsive personality disorder (OCPD) has a pervasive pattern of preoccupation with orderliness, perfection, and mental and interpersonal control at the expense of flexibility, openness, and efficiency. The aims of the present study were to explore the relationship between OCPD and psychological stress and psychological tests. METHODS: We evaluated 63 OCPD patients and 107 healthy controls (HCs). We collected saliva samples from patients and controls before and after a social stress procedure, the Trier Social Stress Test (TSST), to measure the concentrations of salivary alpha-amylase (sAA) and salivary cortisol. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to patients and HCs. RESULTS: Following TSST exposure, the salivary amylase and cortisol levels were significantly decreased in male patients compared with controls. Additionally, OCPD patients had higher CTQ, POMS, STAI, and BDI scores than HCs and exhibited significantly higher anxiety and depressive states. OCPD patients scored higher on future denial and threat prediction as per the DACS tool. According to a stepwise regression analysis, STAI, POMS, and salivary cortisol responses were independent predictors of OCPD. CONCLUSIONS: Our results suggested that attenuated sympathetic and parasympathetic reactivity in male OCPD patients occurs along with attenuated salivary amylase and cortisol responses to the TSST. In addition, there was a significant difference between OCPD patients and HCs in child trauma, mood, anxiety, and cognition. The finding support the modeling role of cortisol (20min) on the relationships between STAI trait and depression among OCPD.

Mitochondrial ubiquitin ligase activator of NF-κB regulates NF-κB signaling in cells subjected to ER stress.

The nuclear factor-κB (NF-κB) transcription factor family members control various biological processes, such as apoptosis and proliferation. The endoplasmic reticulum (ER) has emerged as a major site of cellular homeostasis regulation. The accumulation of misfolded protein in the ER causes stress and ER stress-induced NF-κB activation to protect cells from apoptosis. In this study, we found a putative ER stress-response element (ERSE) on the promoter of mitochondrial ubiquitin ligase activator of NF-κB (MULAN), and that MULAN expression was upregulated by ER stress. MULAN specifically activated NF-κB dependent gene expression in an E3 ligase activity-dependent manner. The ectopic expression of MULAN induced the nuclear translocation of endogenous p65 and the degradation of IκB. Binding assay revealed that MULAN was associated with transforming growth factor ß-activated kinase (TAK1). The knockdown of MULAN using siRNA inhibited the activation of NF-κB in the cells subjected to ER stress. The findings of our study indicate that MULAN is an E3 ligase that regulates NF-κB activation to protect cells from ER stress-induced apoptosis.

Identification of the neural correlates of cyclothymic temperament using an esthetic judgment for paintings task in fMRI.

BACKGROUND: There is a well-known association between artistic creativity and cyclothymic temperament but the neural correlates of cyclothymic temperament have not yet been fully identified. Recently, we showed that the left lingual gyrus and bilateral cuneus may be associated with esthetic judgment of representational paintings, we therefore sought to investigate brain activity during esthetic judgment of paintings in relation to measures of cyclothymic temperament. METHODS: Regions of interest (ROI) were set at the left lingual gyrus and bilateral cuneus using automated anatomical labeling, and percent signal changes of the ROIs were measured by marsbar toolbox. The associations between percent signal changes of the ROIs during esthetic judgments of paintings and cyclothymic temperament scores were investigated by Pearson׳s coefficient. Moreover, the associations were further analyzed using multiple regression analysis whereby cyclothymic temperament scores were a dependent factor and percent signal changes of the 3 ROIs and the other 4 temperament scores were independent factors. RESULTS: There was a significantly negative association of cyclothymic temperament scores with the percent signal changes of the left lingual gyrus during esthetic judgments of paintings, but not with those of bilateral cuneus. Even after adjustment using multiple regression analysis, this finding remained unchanged. LIMITATIONS: The number of subjects was relatively small and the task was limited to appreciation of paintings. CONCLUSIONS: The present findings suggest that cyclothymic temperament may be associated with the left lingual gyrus.

Difference in brain activations during appreciating paintings and photographic analogs.

Several studies have investigated neural correlates of aesthetic appreciation for paintings but to date the findings have been heterogeneous. This heterogeneity may be attributed to previous studies' measurement of aesthetic appreciation of not only the beauty of paintings but also the beauty of motifs of the paintings. In order to better elucidate the beauty of paintings, it seems necessary to compare aesthetic appreciation of paintings and photographic analogs which included corresponding real images. We prepared for famous painters' pictures and their photographic analogs which were set up to resemble each painting in order to investigate the hypothesis that there exist specific neural correlates associated with the aesthetic appreciation for paintings. Forty-four subjects participated in functional magnetic resonance study which required comparisons of aesthetic appreciation of paintings of still life and landscape versus photographic analogs including corresponding real images of still life and landscape. Bilateral cuneus and the left lingual gyrus were activated in the comparison of aesthetic appreciation of paintings versus photographic analogs. In conclusion, the present findings suggest a possibility of the existence of specific neural correlates associated with the aesthetic appreciation for paintings and that bilateral cuneus and the left lingual gyrus may be involved.

Hyperthymic temperament and brightness judgment in healthy subjects: involvement of left inferior orbitofrontal cortex.

BACKGROUND: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects. METHODS: We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t-test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed. RESULTS: Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex. LIMITATIONS: Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects. CONCLUSIONS: The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder.

E3 ubiquitin ligase synoviolin is involved in liver fibrogenesis.

BACKGROUND AND AIM: Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis. METHODS: The expression and localization of synoviolin in the liver were analyzed in CCl(4)-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno(+/-) mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno(+/-) mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno(-/-) mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno(-/-) MEF cells. RESULTS: In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno(+/-) mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno(+/-) mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno(-/-) MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum. CONCLUSION: Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.

Abnormally high levels of virus-infected IFN-gamma+ CCR4+ CD4+ CD25+ T cells in a retrovirus-associated neuroinflammatory disorder.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified. PRINCIPAL FINDINGS: Here, we demonstrate that CD4(+)CD25(+)CCR4(+) T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2), Th17, and regulatory T (Treg) cells in healthy individuals, we demonstrate that IFN-gamma production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4(+)CD25(+)CCR4(+) T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-gamma-producing CD4(+)CD25(+)CCR4(+)Foxp3(-) T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity. CONCLUSIONS: We have defined a unique T cell subset--IFN-gamma(+)CCR4(+)CD4(+)CD25(+) T cells--that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.

Activation of synoviolin promoter in rheumatoid synovial cells by a novel transcription complex of interleukin enhancer binding factor 3 and GA binding protein alpha.

OBJECTIVE: Synoviolin is an E3 ubiquitin ligase, and its overexpression is implicated in the pathogenesis of rheumatoid arthritis (RA). We reported previously that Ets binding site 1 (EBS-1) within the synoviolin promoter is crucial for the expression of synoviolin, and GA binding protein (GABP) binds to this site. This study was undertaken to elucidate the precise mechanisms of transcriptional regulation via EBS-1. METHODS: We performed purification and identification of complex components that bind to EBS-1 and inspected their contributions to the transcriptional regulation of synoviolin in rheumatoid synovial cells. We biochemically purified proteins that had EBS-1 binding activity and identified the proteins using liquid chromatography tandem mass spectrometry analysis. The identified proteins were verified to recruit and form the complex on EBS-1 using electrophoretic mobility shift assay and coimmunoprecipitation assay. Furthermore, their transcription activities were tested by reporter assays and RNA interference experiments. RESULTS: We identified interleukin enhancer binding factor 3 (ILF-3) as a novel factor in the complex. ILF-3 was demonstrated to activate the synoviolin promoter via association with GABPalpha in rheumatoid synovial cells. In addition, further activation was observed with ILF-2 and GABPbeta, previously reported interactants of ILF-3 and GABPalpha, respectively. Moreover, ILF-3-knockdown experiments showed reduced expression of the synoviolin gene. CONCLUSION: Our findings indicate that ILF-3, which has been known to regulate IL-2 expression in T cells, up-regulates synoviolin expression with GABPalpha in rheumatoid synovial cells. ILF-3 might be a target for RA treatment through its effect on IL-2 in T cells and synoviolin in rheumatoid synovial cells.

Increased prevalence of group A ß-hemolytic streptococcus among an ethnic population in Kyrgyzstan detected by the rapid antigen detection test.

The incidence of rheumatic fever (RF) has markedly increased in the last 10 years in Kyrgyzstan. Therefore, investigating the prevalence of group A ß-hemolytic streptococcus (GABHS), which is the cause of RF, in the Kyrgyzstan population is crucial. We studied 189 subjects: 59 children [29 with RF and/or rheumatic heart disease (RHD)] and 130 adults (15 with RHD). The average age of the subjects was 41.0±10.0 years (range 8 months to 72 years). A general clinical examination and medical history including eating habits was carried out. The prevalence of GABHS was tested using the highly sensitive rapid antigen detection test (RADT) to detect the outcrop of streptococcus antigen in smears taken from the mucosal surface of the tonsils or the back of the throat. GABHS antigen was positive in 70 of a total 189 subjects [37.0%; 22/59 children (37.2%), 48/130 adults (36.9%)]. In patients with RF/RHD (n=44), GABHS was positive in 14 subjects [31.8%; 8/29 children (27.6%), 6/15 adults (40.0%)]. Thirty-two subjects with RF/RHD had frequent episodes of tonsillopharyngitis. In subjects without RF/RHD (n=145), GABHS was positive in 56 subjects [38.6%; 14/30 children (46.6%), 42/115 adults (36.5%)]. Thirty of these subjects had frequent episodes of tonsillopharyngitis. Of the 130 adults, the most-consumed dairy products included yoghurt (n=115; 88.4%), milk kasha (n=75; 57.7%) and milk (n=40; 30.7%). Of the 115 subjects in the yoghurt-consuming group, 44 (38.2%) had positive results for GABHS. In the non-yoghurt-consuming group, 4/15 subjects (26.6%) had positive results for GABHS. Using RADT for GABHS, a high prevalence of GABHS antigen was detected not only in patients with RF/RHD, but also in the healthy population (without RF/RHD). The low GABHS prevalence in children with RF/RHD (27.6%) was probably due to corresponding antibiotic therapy. In conclusion, the high prevalence of GABHS is one of the main reasons for the rapid increase in RF/RHD in Kyrgyzstan, and RADT would be an effective tool for its detection.