Factors associated with smoking cessation in Chinese psychiatric professionals: A cross-sectional survey.

INTRODUCTION: Healthcare workers are integral to public smoking cessation; however, their own smoking behavior can create a significant obstacle to intervening in patients' cessation efforts. Conversely, their success in quitting can enhance their ability to support patients. Research on smoking behavior, particularly smoking cessation among Chinese psychiatric professionals is limited. This study addresses this gap by examining the factors associated with smoking cessation in this population, providing insights for targeted tobacco control policies. METHODS: A cross-sectional survey was conducted, targeting psychiatric professionals including psychiatrists and psychiatric nurses, in 41 tertiary psychiatric hospitals in China. From January to March 2021, a WeChat-based questionnaire was distributed to collect demographic, occupational, and health-behaviors (including smoking) data. Statistical analyses, including the chi-squared test and adjusted binary logistic regression analysis, were conducted to identify the factors associated with smoking cessation. RESULTS: Among the 12762 psychiatric professionals who participated in the survey, 11104 (87.0%) were non-smokers, 1196 (9.4%) were current smokers, and 462 (3.6%) were ex-smokers. Several factors were found to be associated with smoking cessation. Women had a higher prevalence of ex-smokers than men (AOR=1.88; 95% CI: 1.332-2.666, p<0.001). Compared to East China, the prevalence of ex-smokers among participants in Central and Northeast China was lower. Older age (≥50 years), higher level of education (Master's degree or higher), and non-drinkers, showed a higher likelihood of being ex-smokers. Notably, compared to current smokers, ex-smokers reported a lower prevalence of burnout (AOR=0.70; 95% CI: 0.552-0.892, p=0.004). CONCLUSIONS: Smoking cessation interventions or health promotion programs should also focus on gender, age, education level, region, alcohol use, and burnout to effectively address smoking cessation within this specific professional group.

Prevalence and associated factors of depression, anxiety and stress among clinical therapists in China in the context of early COVID-19 pandemic.

Objectives: To study the socio-demographic characteristics and the prevalence of depression, anxiety, and stress among clinical therapists in China during the early Coronavirus disease 2019 (COVID-19) pandemic and to identify associated factors. Method: This cross-sectional study was part of a multicenter, nationally representative survey conducted through WeChat from January 2021 to March 2021. Data, including socio-demographics, health-related behaviors, and information on whether they participated in the frontline work of treating COVID-19, were collected anonymously. Respondents also completed the Depression Anxiety Stress Scales-21 (DASS-21). Results: In total, 396 clinical therapists in the selected hospitals completed the questionnaires, with a response rate of 89.0%. Respondents were predominantly female (77.3%). About 6.6% of the participants were current tobacco users, and 20.7% had participated in the frontline work of treating COVID-19. Overall, 22.0%, 17.9%, and 8.8% of participants were classified as having clinically meaningful depression, anxiety, and stress, respectively, based on DASS-21 scores. Multiple logistic regression in Model 1 and Model 2 showed that depression, anxiety, and stress were associated with regular physical activity and frequent insomnia (all, p < 0.05). In anxiety model 2, the associated factors for anxiety during the pandemic were identified as education (master's degree or more, OR=0.520; 95% CI=0.283-0.955), marital status (single, OR=2.064; 95% CI=1.022-4.168), tobacco use (OR=4.265; 95% CI=1.352-13.454), regular physical activity (OR=0.357; 95% CI=0.192-0.663), frequent insomnia (OR=6.298; 95% CI =2.522-15.729), and participation in the frontline work of treating COVID-19 (OR=3.179; 95% CI=1.697-5.954). The COVID-19 epidemic did not significantly increase the depression and stress levels among clinical therapists, but it did significantly increase anxiety levels. Conclusion: During the COVID-19 pandemic, depression, anxiety and stress were relatively common among clinical therapists in China. Regular physical activity and good sleep were important protective factors against emotional problems. Therefore, encouraging regular physical activity and actively addressing clinical therapists' sleep problems is beneficial to improving the ability to cope with negative emotions. The COVID-19 epidemic significantly increased anxiety, and awareness and interventions should be recommended to reduce anxiety among clinical therapists during the COVID-19 pandemic.

The association between workload, alcohol use, and alcohol misuse among psychiatrists in China.

Aim: Survey alcohol use and workload among Chinese psychiatrists and explore their associations. Methods: We conducted an online questionnaire among psychiatrists working in large psychiatric institutions across the country. We collected data including demographic factors, alcohol use, and workload. Alcohol use was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C), and workload-related questions included working hours, night shifts, and caseloads. Results: In total, 3,549 psychiatrists completed the survey. Nearly half (47.6%) reported alcohol use, and the percentage of alcohol use in males (74.1%) was significantly higher than in females. 8.1% exceeded the AUDIT-C cutoff scores for probable alcohol misuse (19.6%in males and 2.6%in females). AUDIT-C scores were significantly correlated with working hours per week (p = 0.017) and the number of outpatient visits per week (p = 0.006). Regressional analysis showed that alcohol use was significantly associated with the following factors: longer working hours (Working more than 44 h/week, OR = 1.315), having an administrative position (OR = 1.352), being male (OR = 6.856), being single (OR = 1.601), being divorced or widowed (OR = 1.888), smoking (OR = 2.219), working in the West (OR = 1.511) or the Northeast (OR = 2.440). Regressional analysis showed that alcohol misuse was significantly associated with the following factors: fewer night shifts (Three to four night shifts/month, OR = 1.460; No more than 2 night shifts/month, OR = 1.864), being male (OR = 4.007), working in the Northeast (OR = 1.683), smoking (OR = 2.219), frequent insomnia (OR = 1.678). Conclusion: Nearly half of the psychiatrists in China reported alcohol use and 8.1% had probable AUD. Alcohol consumption is significantly associated with several workload-related factors, such as long working hours, heavy caseload, and administrative duties. Alcohol misuse was inversely associated with the number of night shifts per month. While the direction of causality is unclear, our findings may help identify vulnerable professional groups and develop more targeted interventions to improve healthcare professionals' well-being.

Immune-inflammatory responses and pulmonary embolism in Catatonia: A report of two cases.

Venous thromboembolism (VTE) comprises pulmonary embolism (PE) and deep vein thrombosis (DVT). PE, as the most severe manifestation of VTE, can cause increased mortality in patients with mental disorders. Here we describe two cases of young male patients with catatonia who developed PE and DVT during their hospital stay. We also discuss the possible pathogenesis, with a focus on immune and inflammatory mechanisms.

Alcohol misuse, health-related behaviors, and burnout among clinical therapists in China during the early Covid-19 pandemic: A Nationwide survey.

Objectives: This study aimed to assess the extent of alcohol use and misuse among clinical therapists working in psychiatric hospitals in China during the early COVID-19 Pandemic, and to identify associated factors. Methods: An anonymous nationwide survey was conducted in 41 tertiary psychiatric hospitals. We collected demographic data as well as alcohol use using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and burnout using the Maslach Burnout Inventory Human Services Survey. Results: In total, 396 clinical therapists completed the survey, representing 89.0% of all potential participants we targeted. The mean age of participants was 33.8 years old, and more than three-quarters (77.5%) were female. Nearly two-fifths (39.1%) self-reported as current alcohol users. The overall prevalence of alcohol misuse was 6.6%. Nearly one-fifth (19.9%) reported symptoms of burnout with high emotional exhaustion in 46 (11.6%), and high depersonalization in 61 (15.4%). Multiple logistic regression showed alcohol use was associated with male gender (OR = 4.392; 95% CI =2.443-7.894), single marital status (OR = 1.652; 95% CI =0.970-2.814), smoking habit (OR = 3.847; 95%CI =1.160-12.758) and regular exercise (OR = 2.719; 95%CI =1.490-4.963). Alcohol misuse was associated with male gender (OR = 3.367; 95% CI =1.174-9.655), a lower education level (OR = 3.788; 95%CI =1.009-14.224), smoking habit (OR = 4.626; 95%CI =1.277-16.754) and high burnout (depersonalization, OR = 4.848; 95%CI =1.433-16.406). Conclusion: During the COVID-19 pandemic, clinical therapists' alcohol consumption did not increase significantly. Male gender, cigarette smoking, and burnout are associated with an increased risk of alcohol misuse among clinical therapists. Targeted intervention is needed when developing strategies to reduce alcohol misuse and improve clinical therapists' wellness and mental health.

Gender differences in the association between lifestyle behaviors and mental health among psychiatrists in China.

INTRODUCTION: Mental health symptoms are common among health professionals and the influence of lifestyle behaviors on psychiatrists' mental health is insufficiently understood. Based on a nationwide sample, we aimed to survey the lifestyle behaviors and mental health status among psychiatrists, and to identify the co-occurrence and gender differences in lifestyle behaviors. METHODS: Data were collected through an anonymous questionnaire among psychiatrists in China. Depression, Anxiety and Stress Scale - 21 (DASS-21) was used to evaluate mental health symptoms. Latent class analysis (LCA) was used to explore the co-occurrence of lifestyle behaviors. The multivariate logistic regression model was used to examine the effects of demographic and lifestyle factors. RESULTS: 4520 psychiatrists were included in the analysis with 11.5 % of them reporting smoking, 10 % reporting alcohol misuse, 35.2 % reporting physical inactivity, and 23.1 % reporting insomnia. The prevalence of depression, anxiety and stress symptoms were 29.2 %, 34.5 %, and 12.2 %, respectively. Significant gender differences were found in smoking (P < 0.001), alcohol misuse (P < 0.001), and physical inactivity (P < 0.001), but not in insomnia. Based on these four high-risk health behaviors above, three lifestyle behavior clusters with huge gender differences were identified through the LCA. Accordingly, the unhealthy lifestyle classes, though defined differently for males and females, were significantly associated with depression, anxiety, and stress. CONCLUSIONS: The co-occurrence and significant gender differences in multiple lifestyle behaviors exist in this group, highlighting the need for gender-specific comprehensive interventions against mental health symptoms and the urgency of promoting their well-being.

Alcohol Use and Misuse Among Chinese Psychiatrists During the Early COVID-19 Pandemic.

Aim: Survey alcohol use and misuse among Chinese psychiatrists during the Coronavirus diseases 2019 (COVID-19) pandemic. Methods: We conducted a large-scale, nationwide online survey of psychiatrists regarding their alcohol use during the pandemic. The Alcohol Use Disorder Identification Test-Concise (AUDIT-C) was used to assess alcohol use and misuse. Results: Of 3,815 psychiatrists who completed the survey, alcohol use and misus were 47.5% and 8.2%, respectively, and both were significantly higher in males. The majority (59%) reported no change in alcohol use during the pandemic, one-third (34.5%) reported a decrease, and 6.5% reported an increase. Alcohol misuse was associated with middle-age (OR = 1.418), male sex (OR = 5.089), Northeast China (OR = 1.507), cigarette-smoking (OR = 2.335), insomnia (OR = 1.660), and regular exercise (OR = 1.488). A master's degree (OR = 0.714) and confidence in clinical work (OR = 0.610) were associated with less alcohol misuse. Those who reported a decrease in alcohol use during the pandemic were more likely to be male (OR = 2.011), located in Northeast China (OR = 1.994), and feel confident in their clinical work (OR = 1.624). Increased alcohol use was significantly associated with insomnia (OR = 3.139). Conclusions: During the COVID-19 pandemic, alcohol use and misuse among Chinese psychiatrists declined. While males were more likely to misuse alcohol, they were also more likely to have reduced their intake. Age, location, and lifestyle factors also predicted alcohol use and misuse. Further examination of specific factors that reduced alcohol use and misuse may help guide public health efforts to sustain the lower rates beyond the pandemic.

Patterns of antipsychotic prescriptions in patients with schizophrenia in China: A national survey.

INTRODUCTION: To investigate the patterns and correlates of antipsychotic prescriptions among recently discharged inpatients with schizophrenia in China. METHODS: The study included discharged patients from 41 tertiary psychiatric hospitals in 29 provinces between March 19-30, 2019. A total of 1032 inpatients with schizophrenia were included. Socio-demographic and clinical data were retrieved from medical records upon discharge. RESULTS: Patients received a total of 13 unique antipsychotic medications, which included 9 s-generation antipsychotics (SGAs) and 4 first-generation antipsychotics (FGAs). The utilization rates of SGAs and FGAs were 98.8 % and 6.1 % respectively. The three most commonly antipsychotic medications were risperidone (35.1 %), olanzapine (31.3 %), and clozapine (24.6 %). The mean chlorpromazine equivalent dose was 452.12 ± 230.74 mg/day. The utilization rate of mood stabilizers was 18.9 %, 8.8 % for antidepressants, 20.3 % for sleep improvers, and 9.9 % for anticholinergics. More than two fifths patients (43.1 %) received two or more antipsychotic medications. Predictors of antipsychotic polypharmacy included younger age, residing in Central or West China, a longer duration of illness, a history of prior hospitalizations, and having agitated behavior during the hospitalization. CONCLUSION: Antipsychotic polypharmacy in China is common on inpatients settings. The proportion of antipsychotic polypharmacy in China is higher than in many other countries, despite limited data to support the efficacy of many combinations. Clozapine remains one of most commonly prescribed antipsychotics in China, either as a monotherapy or combination therapy.

Alcohol Use Among Mental Health Professionals in China: A Nationwide Cross-sectional Survey.

AIM: To survey the use of alcohol, and its correlates by mental health professions in China, a nation where there is rapid increase in alcohol consumption and problems. METHODS: As a part of a large-scale, nation-wide online survey of healthcare professionals, we collected demographic variables and other health-related variables anonymously. The Alcohol Use Disorder Identification Test-Concise (AUDIT-C) was used to collect data on alcohol use. RESULTS: 13,980 mental health professionals completed the survey (4382 doctors, 9339 nurses and 259 clinical psychologists), representing 64% of the total targeted. Respondents were predominantly female (75.1%). Alcohol consumption was reported by 41.8% of participants (by 53.9% of doctors, 36.2% of nurses and 40.5% of clinical psychologists). Based on the cut-off scores of the AUDIT-C (≥3 for women and ≥4 for men), 7.5% were classified as probable alcohol misusers in the past year, and the rates were 10.2% in doctors, 6.3% in nurses and 5.8% in clinical psychologists. Multiple logistic regression showed that male sex (OR = 3.772; CI = 3.206-4.439), being a doctor (OR = 1.259; CI = 1.052-1.506), being divorced or widowed (OR = 1.979; CI = 1.467-2.666), having an associate degree or less (OR = 1.809; CI = 1.040-3.147), working in Northeast China (OR = 1.538; CI = 1.281-1.848) and the habit of smoking (OR = 3.345; CI = 2.280-3.967) were significantly associated with alcohol misuse. CONCLUSIONS: Alcohol use and misuse were relatively common among mental health professionals in China, and male sex, being a doctor, with lower education, working in Northeast China and cigarette smoking were significant associations. Awareness and interventions are recommended to promote healthier use of alcohol in this professional group, especially among risk subgroups.

Cigarette Smoking, Health-Related Behaviors, and Burnout Among Mental Health Professionals in China: A Nationwide Survey.

OBJECTIVES: Mental health professionals (MHPs) play an important role in treating patients with nicotine addiction. However, data on MHPs' cigarette smoking habits are scarce. This survey aimed to collect such data and to examine the correlates of smoking among MHPs working in China. METHODS: A cross-sectional survey was conducted in all 41 provincial, tertiary psychiatric hospitals, and MHPs from these hospitals were targeted. An anonymous questionnaire was designed to collect socio-demographic and occupational factors, and the Maslach Burnout Inventory-Human Service Survey was used to assess burnout. Data about smoking and other health behaviors were also collected. RESULTS: In total, 13,614 MHPs were included in the analysis. The overall rate of current smoking was 8.6% (31.3% in males, and 1.1% in females). A substantial proportion (28.0%) of life-time smokers had abstained for more than 3 months. Those who were male (OR=37.73), older (OR=1.02), divorced or widowed (OR=1.72), working in West (OR=1.45), and Northeast China (OR=1.65), were nurses (OR=1.44), had a high income (OR=1.31), experienced burnout (OR=1.29), frequent insomnia (OR=1.39), and used alcohol (OR=2.76) were significantly more likely to be smokers, while those who had a higher level of education (OR=0.67, 0.47, and 0.43 for college, master, and doctorate degrees, respectively), and exercised regularly (OR=0.73) were significantly less likely to be smokers. CONCLUSION: Although lower than that of the general population in China, smoking is still relatively high among MPHs. Efforts to lower smoking rates among MHPs in China should continue and should incorporate strategies that target burnout, sleep, alcohol use, exercise and other factors associated with smoking.

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview.

Since 1997, studies have found that Asians need lower clozapine doses than Caucasians. Caucasians with average clozapine metabolism may need from 300 to 600 mg/day to reach the therapeutic range (350 ng/ml). Thus, serum clozapine concentration-to-dose (C/D) ratios typically range between 0.60 (male smokers) and 1.20 (female non-smokers). A 2019 systematic review of clozapine levels demonstrated weighted mean C/D ratios of 1.57 in 876 East Asians and 1.07 in 1147 Caucasians (P < .001). In Asian countries, average clozapine doses are lower than 300 mg/day. After sex and smoking stratification in 5 Asian samples with clozapine concentrations, the clozapine dose required to reach 350 ng/ml in female non-smokers ranged from 145 to 189 mg/day and in male smokers, from 259 to 294 mg/day. Thus, in Asian patients with average metabolism (with no inducers other than smoking, with no inhibitors, and in the absence of extreme obesity), the dose needed for clinical response may range between 150 mg/day for female non-smokers to 300 mg/day for male smokers. Clozapine levels may help personalize dosing in clozapine poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Asian PMs may need very low doses (50-150 mg/day) to obtain therapeutic concentrations. About 10% (range 2-13%) of Asians are genetic PM cases. Other PMs are patients taking CYP1A2 inhibitors such as fluvoxamine, oral contraceptives, and valproate. Temporary clozapine PM status may occur during severe systemic infections/inflammations with fever and C-reactive protein (CRP) elevations. Asian UMs include patients taking potent inducers such as phenytoin, and rarely, valproate.

Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression.

IL-6 binds to the IL-6R α-chain (IL-6Rα) and signals via the signal transducer gp130. Recently, IL-6 was found to also bind to the cell surface glycoprotein CD5, which would then engage gp130 in the absence of IL-6Rα. However, the biological relevance of this alternative pathway is under debate. In this study, we developed a mouse model, in which murine IL-6 is overexpressed in a CD11c-Cre-dependent manner. Transgenic mice developed a lethal immune dysregulation syndrome with increased numbers of Ly-6G+ neutrophils and Ly-6Chi monocytes/macrophages. IL-6 overexpression promoted activation of CD4+ T cells while suppressing CD5+ B-1a cell development. However, additional ablation of IL-6Rα protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6Rα-deficient mice without IL-6 overexpression. Mechanistically, IL-6Rα deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Rα is the only biologically relevant receptor for IL-6 in mice.

Efficacy and Safety of ECT for Behavioral and Psychological Symptoms of Dementia (BPSD): A Retrospective Chart Review.

OBJECTIVE: Much of the functional disturbance in patients with dementia reflects the presence of noncognitive behavioral and psychological symptoms of dementia (BPSD). Agitation is among the most distressing symptoms for patients, clinicians, and caregivers. Currently no pharmacotherapy has clearly been shown to be of value for this condition. This study used a chart review method to examine the safety and efficacy of electroconvulsive therapy (ECT) for patients with dementia receiving ECT for agitation. METHODS: A retrospective chart review was conducted of patients with dementia presenting with symptoms of aggression or agitation and who received ECT treatments. Aggression and agitation were measured by pre- and post-ECT Pittsburg Agitation Scale (PAS) scores. Detailed history of the use of psychotropic medications as well as other clinically relevant variables was analyzed. FINDINGS: Sixty elderly patients (45 women and 15 men, 75% female, mean age 77.5 ± 8.0 years) were included in the analysis. Most patients were treatment resistant to multiple psychotropic medications prior to ECT (mean number 6.1±1.5). The baseline PAS total was 9.3 ± 3.7 and it decreased significantly after three (2.5±2.8) and six (1.5±2.3) ECT treatments. No significant ECT-related medical complications were observed except transient confusion. A decrease in the number of psychotropics prescribed along with an increase in the GAF score was observed after the ECT treatment course. CONCLUSION: ECT was safe in this sample of patients who had co-morbid medical conditions. ECT was associated with the following observations: 1) a reduction in agitation; 2) a reduction in psychotropic polypharmacy; and 3) an improvement in global functioning level. Further research evaluating the effects of ECT in the setting of dementia is warranted.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13.

PURPOSE/BACKGROUND: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). FINDINGS/RESULTS: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. IMPLICATIONS/CONCLUSIONS: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis.

BACKGROUND & AIMS: The CYLD lysine 63 deubiquitinase gene (CYLD) encodes tumor suppressor protein that is mutated in familial cylindromatosus, and variants have been associated with Crohn disease (CD). Splice forms of CYLD that lack exons 7 and 8 regulate transcription factors and functions of immune cells. We examined the expression of splice forms of CYLD in colon tissues from patients with CD and their effects in mice. METHODS: We performed immunohistochemical analyses of colon tissues from patients with untreated CD and patients without inflammatory bowel diseases (controls). We obtained mice that expressed splice forms of CYLD (sCYLD mice) without or with SMAD7 (sCYLD/SMAD7 mice) from transgenes and CYLD-knockout mice (with or without transgenic expression of SMAD7) and performed endoscopic analyses. Colitis was induced in Rag1-/- mice by transfer of CD4+ CD62L+ T cells from C57/Bl6 or transgenic mice. T cells were isolated from mice and analyzed by flow cytometry and quantitative real-time polymerase chain reaction and intestinal tissues were analyzed by histology and immunohistochemistry. CYLD forms were expressed in mouse embryonic fibroblasts, primary T cells, and HEK293T cells, which were analyzed by immunoblot, mobility shift, and immunoprecipitation assays. RESULTS: The colonic lamina propria from patients with CD was infiltrated by T cells and had higher levels of sCYLD (but not full-length CYLD) and SMAD7 than tissues from controls. Incubation of mouse embryonic fibroblasts and T cells with transforming growth factor ß increased their production of sCYLD and decreased full-length CYLD. Transgenic expression of sCYLD and SMAD7 in T cells prevented the differentiation of regulatory T cells and T-helper type 17 cells and increased the differentiation of T-helper type 1 cells. The same effects were observed in colon tissues from sCYLD/SMAD7 mice but not in those from CYLD-knockout SMAD7 mice. The sCYLD mice had significant increases in the numbers of T-helper type 1 cells and CD44high CD62Llow memory-effector CD4+ T cells in the spleen and mesenteric lymph nodes compared with wild-type mice; sCYLD/SMAD7 mice had even larger increases. The sCYLD/SMAD7 mice spontaneously developed severe colitis, with infiltration of the colon by dendritic cells, neutrophils, macrophages, and CD4+ T cells and increased levels of Ifng, Il6, Il12a, Il23a, and Tnf mRNAs. Co-transfer of regulatory T cells from wild-type, but not from sCYLD/SMAD7, mice prevented the induction of colitis in Rag1-/- mice by CD4+ T cells. We found increased levels of poly-ubiquitinated SMAD7 in sCYLD CD4+ T cells. CYLD formed a nuclear complex with SMAD3, whereas sCYLD recruited SMAD7 to the nucleus, which inhibited the expression of genes regulated by SMAD3 and SMAD4. We found that sCYLD mediated lysine 63-linked ubiquitination of SMAD7. The sCYLD-SMAD7 complex inhibited transforming growth factor ß signaling in CD4+ T cells. CONCLUSIONS: Levels of the spliced form of CYLD are increased in colon tissues from patients with CD. sCYLD mediates ubiquitination and nuclear translocation of SMAD7 and thereby decreases transforming growth factor ß signaling in T cells. This prevents immune regulatory mechanisms and leads to colitis in mice.

NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling.

NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.

Impact of childhood trauma on sensorimotor gating in Chinese patients with chronic schizophrenia.

We investigated the relationship between childhood trauma (CT) and sensorimotor gating in Chinese patients diagnosed with chronic schizophrenia. Seventy-five patients were assessed with the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and then the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS PPI) and the perceived spatial co-location PPI (PSC PPI or classical PPI) were applied to test sensorimotor gating. Startling stimuli (90 dB) were presented either alone or preceded by discrete prepulse stimuli of 4 dB in a background 60-dB noise level. Associations between CT and various PPI paradigms were statistically analyzed. Univariate analysis revealed the absence of a significant correlation between CT and PPI paradigms (p > 0.05). However, multiple linear regression analyses revealed that sexual abuse and the positive and negative syndrome scale (PANSS) score were negatively correlated with PSS PPI (p = 0.029 and 0.008, respectively). On the other hand, female sex and history of smoking were positively correlated with PSS PPI (p = 0.044 and 0.043, respectively). In conclusion, the results of this study suggest that CT can be a predisposing factor that affects sensorimotor gating in schizophrenia patients.

IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal.

Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα-/- as well as in macrophage-specific IL-4Rα-/- (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. RESEARCH IN CONTEXT: Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression.

Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis.

Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αß T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis.

Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.

The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis. However the molecular mechanisms regulating HSC dormancy remain poorly understood. Here we show that cylindromatosis (CYLD), a tumor suppressor gene and negative regulator of NF-κB signaling with deubiquitinase activity, is highly expressed in label-retaining dormant HSCs (dHSCs). Moreover, Cre-mediated conditional elimination of the catalytic domain of CYLD induced dHSCs to exit quiescence and abrogated their repopulation and self-renewal potential. This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor-associated factor 2). HSCs expressing a mutant CYLD with an intact catalytic domain, but unable to bind TRAF2, showed the same HSC phenotype. Unexpectedly, the robust cycling of HSCs lacking functional CYLD-TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway. Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.