Estimating expected years of life lost of psychiatric disorders in Taiwan: A Nationwide cohort study.

OBJECTIVES: This study employed a national longitudinal cohort to assess expected years of life lost (EYLL) in newly diagnosed psychiatric patients. METHODS: Data from Taiwan's National Death Registry and Health Insurance Research Database were scrutinized to identify patients with various psychiatric disorders. Disorders were ranked hierarchically, and age groups were categorized as young, middle-aged, and older adults. We utilized the semiparametric survival extrapolation method to estimate life expectancy (LE) and EYLL. Modifying effect of comorbid conditions and socioeconomic characteristics were also explored. RESULTS: Among the 5,757,431 cases, young adults with dementia, alcohol use disorder, schizophrenia, and bipolar disorder experienced an excess of 15 years of EYLL. Middle-aged adults faced approximately 9 years or more of EYLL, while older adults had lower EYLL values. Comorbid conditions, low income levels, and living in rural areas were associated with higher EYLL. CONCLUSIONS: This study underscores the substantial EYLL among young adults with psychiatric disorders and the significant impact of specific disorders on EYLL. Early intervention, tailored support, and healthcare system readiness are imperative for improved outcomes. Resource allocation and targeted interventions focusing on early detection and comprehensive treatment can alleviate the economic burden.

Estimation of life expectancy and healthcare cost in rheumatoid arthritis patients with and without depression: a population-based retrospective cohort study.

Purpose: This study aimed to estimate the lifetime healthcare costs and loss of life expectancy (loss-of-LE) among patients with incident rheumatoid arthritis (RA) with and without depression. Methods: This 18 years longitudinal cohort study used data from Taiwan's National Health Insurance Research Database. In total, 43,311 patients with RA were included. Among them, 1,663 patients had depressive disorders in the year preceding the RA diagnosis. The survival function for patients with RA with or without depression was estimated and extrapolated over a lifetime using the rolling extrapolation algorithm. The loss-of-LE was calculated by comparing the sex, age, and calendar year-matched referents from vital statistics. The average monthly cost was calculated as the sum of the monthly costs for all patients divided by the number of surviving patients. Lifetime healthcare costs were estimated by multiplying the monthly average cost by the monthly survival probability. Results: The loss-of-LE for RA patients with and without depression was 5.60 years and 4.76 years, respectively. The lifetime costs of RA patients with and without depression were USD$ 90,346 and USD$ 92,239, respectively. However, the annual healthcare costs were USD$ 4,123 for RA patients with depression and USD$ 3,812 for RA patients without depression. Regardless of sex or age, RA patients with depression had higher annual healthcare costs than those without depression. Conclusion: Patients with RA and depression have a high loss-of-LE and high annual healthcare costs. Whether treating depression prolongs life expectancy and reduces healthcare costs warrants further investigation.

Lifetime risk, life expectancy, loss-of-life expectancy and lifetime healthcare expenditure for Stevens-Johnson syndrome/toxic epidermal necrolysis in Taiwan: follow-up of a nationwide cohort from 2008 to 2019.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) not only cause acute, devastating mucocutaneous reactions but also have long-lasting implications on survivors' lives. OBJECTIVES: To quantify the lifetime burden of SJS/TEN. METHODS: The cumulative incidence rate (CIR), life expectancy (LE), loss-of-life expectancy (LoLE) and lifetime healthcare expenditure (HE) for SJS/TEN were estimated over the period from 2008 to 2019 using data from the National Health Insurance Research Database of Taiwan and life tables of vital statistics. RESULTS: In this nationwide cohort of 6552 incident SJS/TEN cases, a trend towards a decrease in the CIR was observed between 2008 and 2019. Compared with the general population, patients with SJS/TEN experience a tremendous loss of 9.43 (1.06) [mean (SEM)] years of LE after diagnosis of SJS/TEN. Male patients with SJS/TEN had higher LoLE [10.74 (1.22) vs. 7.69 (1.43) years] and annual HE than females. Younger age at diagnosis of SJS/TEN was associated with longer LE but greater LoLE and higher lifetime HE. Patients with intensive care unit admission on diagnosis, malignancy, diabetes mellitus, end-stage renal disease and SJS/TEN-associated sequelae experienced substantially greater LoLE and HE per life year. CONCLUSIONS: Patients with SJS/TEN suffer substantial loss-of-LE and HE, particularly young patients, compared with the general population. These data provide a reference estimate of the lifetime burden of SJS/TEN to help health authorities evaluate the cost-effectiveness of future preventive and treatment strategies to minimize the burden of SJS/TEN.

Lifetime risk, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for psoriasis in Taiwan: a nationwide cohort followed from 2000 to 2017.

Background: Patients with psoriasis have a significant disease burden throughout the life course. Nevertheless, the lifetime risk and disease burden of psoriasis across the entire lifespan is rarely quantified in an easily understandable way. Objective: To estimate the cumulative incidence rate, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for incident psoriasis. Design and methods: Using real-world nationwide data from the National Health Insurance Research Database of Taiwan for 2000-2017, along with the life tables of vital statistics, we estimated cumulative incidence rate, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for those with psoriasis using a semi-parametric survival extrapolation method. Results: A total of 217,924 new psoriasis cases were identified. The lifetime risk of psoriasis in patients aged 18-80 for both sexes decreased in Taiwan with a cumulative incidence rate of 7.93% in 2000 to 3.25% in 2017. The mean (±standard error) life expectancy after diagnosis was 27.11 (± 1.15) and 27.14 (±1.17) years for patients with moderate-to-severe psoriasis and psoriatic arthritis, respectively. Patients with moderate-to-severe psoriasis and psoriatic arthritis had a mean (±standard error) loss-of-life expectancy of 6.41 (±1.16) and 6.48 (±1.17) due to psoriasis, respectively. Male patients have higher lifetime and annual lifetime healthcare expenditures than female. Mean life expectancy, loss-of-life expectancy, and lifetime cost were relatively higher for younger patients. Conclusion: Among psoriatic patients, patients with moderate-to-severe psoriasis and psoriatic arthritis had substantial years of life lost, particularly for younger patients. Our results provide a reliable estimation of lifetime disease burden, and these estimates will help health authorities in cost-effectiveness assessments of public health interventions and allocation of services resources to minimize loss-of-life expectancy, and lifetime healthcare expenditures in patients with psoriasis.

Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells.

BACKGROUND: The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy. METHODS: We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients. RESULTS: We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells. CONCLUSIONS: Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN. IMPACT: In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.

By-Products of the Black Soybean Sauce Manufacturing Process as Potential Antioxidant and Anti-Inflammatory Materials for Use as Functional Foods.

To assess the potential of by-products of the black bean fermented soybean sauce manufacturing process as new functional food materials, we prepared black bean steamed liquid lyophilized product (BBSLP) and analysed its antioxidant effects in vitro. RAW264.7 macrophages were cultured and treated with BBSLP for 24 h, and 1 µg/mL lipopolysaccharide (LPS) was then used for another 24 h to induce inflammation. The cellular antioxidant capacity and inflammatory response were then analysed. Activation of nuclear factor kappa B (NF-κB) signaling in RAW264.7 macrophages was also analysed. Results showed BBSLP had 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium (ABTS+) radical-scavenging abilities and reducing power in vitro. The levels of both reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) were reduced after RAW264.7 macrophages were treated with BBSLP after LPS induction. After RAW264.7 macrophage treatment with BBSLP and induction by LPS, the levels of inflammatory molecules, including nitric oxide (NO), prostaglandin E2 (PGE2), IL-1α, IL-6 and TNF-α, decreased. NF-κB signaling activity was inhibited by reductions in IκB phosphorylation and NF-κB DNA-binding activity after RAW264.7 macrophages were treated with BBSLP after LPS induction. In conclusion, BBSLP has antioxidant and anti-inflammatory capabilities and can be a supplement material for functional food.

Lipopolysaccharide stimulation test on cultured PBMCs assists the discrimination of cryopyrin-associated periodic syndrome from systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) and cryopyrin-associated periodic syndrome (CAPS) share many common manifestations. We aim to identify an applicable method to assist disease discrimination. Inflammatory cytokines were measured in the plasma of patients with CAPS, sJIA with persistent disease course and healthy controls. Supernatants collected from non-stimulated peripheral blood mononuclear cells (PBMCs) and those undergone inflammasome stimulation tests utilizing lipopolysaccharide (LPS) with and without adenosine triphosphate (ATP) were investigated. Inflammatory cytokines in patient plasma fail to differentiate sJIA from CAPS. PBMCs from sJIA secrets higher amount of IL-1ß and IL-18 while CAPS PBMCs produces more caspase-1 without stimulation. IL-1ß, IL-18, and caspase-1 were significantly elevated among CAPS PBMCs (all p < 0.05) upon LPS stimulation, but not when additional ATPs were provided. Levels of cytokines and PBMC responses to the stimulation assays were similar among all sJIA patients regardless of their history of macrophage activation syndrome. Unstimulated PBMC activities and the LPS inflammasome stimulation assay without exogenic ATPs can assist the differentiation of CAPS from sJIA with persistent disease course.

Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study.

BACKGROUND: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one-to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. RESULTS: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5). CONCLUSIONS: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.

Predictors of hepatitis B and C virus reactivation in patients with psoriasis treated with biologic agents: a 9-year multicenter cohort study.

BACKGROUND: The increasing use of biologics is accompanied by a risk of hepatitis B (HBV) and C virus (HCV) reactivation. OBJECTIVE: To determine the predictors of HBV and HCV reactivation in patients with psoriasis receiving biologics. METHODS: This study screened 2060 patients with psoriasis (3562 treatment episodes) who were taking biologics from 2009 to 2018. There were 359 patients with psoriasis with HBV (561 treatment episodes) and 61 with HCV infection (112 treatment episodes). RESULTS: During 8809 and 1522 person-months of follow-up, 88 treatment episodes for HBV involved HBV reactivation, and 14 episodes of HCV involved reactivation. The reactivation rate was significantly higher in treatment episodes of chronic HBV infection than in that of occult HBV (34.3% vs 3.2%, P = .001) and resolved HBV (34.3% vs 5.0%, P < .001). The multivariate analysis revealed that being hepatitis B surface antigen seropositive, being hepatitis B e-antigen seropositive, and tumor necrosis factor-α-inhibitor therapy were risk factors for HBV reactivation, whereas antiviral prophylaxis was effective in reducing the risk of HBV reactivation. No predictors were significantly associated with HCV reactivation. LIMITATIONS: Observational design and a lack of a comparison group. CONCLUSION: Patients with psoriasis on biologics have a risk of HBV and HCV reactivations, particularly those who are seropositive for hepatitis B surface antigen and hepatitis B e-antigen and undergoing tumor necrosis factor-α-inhibitor therapy.

Lifetime Risks, Life Expectancy, and Health Care Expenditures for Rheumatoid Arthritis: A Nationwide Cohort Followed Up From 2003 to 2016.

OBJECTIVE: This study was undertaken to estimate the cumulative incidence rate of rheumatoid arthritis (RA) in the Taiwanese population ages 16-84 years, and life expectancy, loss of life expectancy, and lifetime health care expenditures for incident RA in Taiwan after 2003, when biologics began to be prescribed. METHODS: We obtained all claims data for the period 1999 to 2016 from the National Health Insurance program of Taiwan, and validated the data against the Catastrophic Illness Registry to establish the study cohort. We estimated the survival function for RA and extrapolated to lifetime using a rolling-over algorithm. For every RA case, we simulated sex-, age-, and calendar year-matched referents from vital statistics and estimated their life expectancy. The difference between the life expectancy of the referent and the life expectancy of the RA patient was the loss of life expectancy for the RA patient. Average monthly health care expenditures were multiplied by the corresponding survival rates and summed up throughout the lifetime to calculate the lifetime health care expenditures. RESULTS: A total of 29,352 new RA cases were identified during 2003-2016. There was a decreasing trend in cumulative incidence rate in those ages 16-84 for both sexes. Mean life expectancy after diagnosis of RA was 26.3 years, and mean lifetime cost was $72,953. RA patients had a mean loss of life expectancy of 4.97 years. Women with RA survived 1-2 years longer than men with RA of the same age, which resulted in higher lifetime expenditures for the former. Since the life expectancy for women in Taiwan was 6-7 years higher than that for men, the loss of life expectancy for women with RA was higher than that for men with RA. Annual health care expenditures were similar for both sexes. CONCLUSION: Our findings indicate that since biologics became available, RA patients have lived longer and had higher lifetime expenditures, which should be monitored and evaluated for cost-effectiveness.

Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study

Abstract Background: Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). Methods: Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one- to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. Results: Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ∼ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5). Conclusions: Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.

The In Vivo Radiosensitizing Effect of Magnolol on Tumor Growth of Hepatocellular Carcinoma.

BACKGROUND/AIM: Radiation (RT) induced ERK/NF-κB in hepatocellular carcinoma (HCC) has been reported in our previous works; it weakens the toxicity of RT or triggers a radioresistance effect. Thus, combining RT with a suitable NF-κB inhibitor may sensitize HCC to RT. Magnolol, a bioactive compound, was known to have anti-inflammatory and anti-tumor functions. Here, we aimed to investigate whether magnolol may enhance anti-HCC efficacy of RT in vivo. MATERIALS AND METHODS: We established a Hep3B bearing mouse to evaluate the efficacy of the combination treatment of magnolol and RT. RESULTS: Most significantly, tumor volume and tumor weight inhibition was found in the combination group. Tumor immunohistochemistry staining also illustrated the suppression of RT-induced ERK/NF-κB-related proteins expression by magnolol. In addition, intrinsic apoptosis-related proteins, such as caspase-3 and -9, were markedly increased in the combination group. CONCLUSION: Magnolol may effectively enhance anti-HCC ability of RT by downregulating the expression of ERK/NF-κB-related proteins and increasing the expression of apoptosis-related proteins.

Infection risk in patients undergoing treatment for inflammatory arthritis: non-biologics versus biologics.

Introduction: Despite the therapeutic effectiveness of biologics targeting immune cells or cytokines in patients with inflammatory arthritis, which reflects their pathogenic roles, an increased infection risk is observed in those undergoing biological treatment. However, there are limited data regarding the comparison of infection risks in inflammatory arthritis patients treated with non-biologics (csDMARDs), biologics (bDMARDs), including tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors, or targeted synthetic (ts)DMARDs.Areas covered: Through a review of English-language literature as of 30 June 2019, we focus on the existing evidence on the risk of infections caused by bacteria, Mycobacterium tuberculosis, and hepatitis virus in inflammatory arthritis patients undergoing treatment with csDMARDs, bDMARDs, or tsDMARDs.Expert opinion: While the risks of bacterial and mycobacterial infection are increased in arthritis patients treated with csDMARDs, the risks are further higher in those receiving bDMARDs therapy, particularly TNF inhibitors. Regarding HBV infection, antiviral therapy may effectively prevent HBV reactivation in patients receiving bDMARDs, especially rituximab. However, more data are needed to establish effective preventive strategies for HBsAg-negative/HBcAb-positive patients. It seems safe to use cyclosporine and TNF inhibitors in patients with HCV infection, while those undergoing rituximab therapies should be frequently monitored for HCV activity.Abbreviations: ABT: abatacept; ADA: adalimumab; AS: ankylosing spondylitis; bDMARDs: biologic disease-modifying anti-rheumatic drugs; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: corticosteroids; CsA: cyclosporine A; csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs; CZP: certolizumab; DAAs: direct-acting antiviral agents; DM: diabetes mellitus; DOT: directly observed therapy; EIN: Emerging Infections Network; ETN: etanercept; GOL: golimumab; GPRD: General Practice Research Database; HBV: hepatitis B virus; HBVr: HBV reactivation; HBsAg+: HBsAg-positive; HBsAg-/anti-HBc+: HBsAg-negative anti-HBc antibodies-positive; HCV: hepatitis C virus; HCQ: hydroxychloroquine: IFX: infliximab; IL-6: interleukin-6; JAK: Janus kinase; LEF: leflunomide; LTBI: latent tuberculosis infection; mAb: monoclonal antibody; MTX: methotrexate; OR: odds ratio; PsA: psoriatic arthritis; PMS: post-marketing surveillance; RA: rheumatoid arthritis; TNF: tumor necrosis factor; TNFi: tumor necrosis factor inhibitor; SCK: secukinumab; SSZ: sulfasalazine; TOZ: tocilizumab; RCT: randomized controlled trial; RR: relative risk; RTX: rituximab; 3HP: 3-month once-weekly isoniazid plus rifapentine; TB: tuberculosis; tsDMARDs: targeted synthetic disease-modifying anti-rheumatic drugs; UTK: ustekinumab; WHO: World Health Organization.

Recruitment of CCR6+ Foxp3+ regulatory gastric infiltrating lymphocytes in Helicobacter pylori gastritis.

Helicobacter pylori (H. pylori) infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. Increased T-cell infiltration is found at sites of H. pylori infection. The CCR6+ subset of CD4+ regulatory T cells (Tregs), a newly characterized subset of Tregs, has been reported to contribute to local immune inhibition. However, whether CCR6+ Tregs are present in H. pylori gastritis, and what their relationship is to disease prognosis, remains to be elucidated. In this study, gastric infiltrating lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed. We found that in gastric infiltrating lymphocytes, CCR6+  CD4+  CD25high Tregs, which express high levels of CD45RO, are positively associated with more severe inflammation in gastric mucosa during H. pylori infection. Furthermore, the frequency of CCR6+ Tregs in gastric infiltrating lymphocytes, but not CCR6- Tregs, is significantly increased in inflamed gastric tissues, which is inversely correlated with significantly lower expression of IFN-γ+  CD8+ T cells. We also found that the frequency of CCR6+ Tregs is positively correlated with the frequency of CD4+  IFN-γ+ T cells. In addition, the frequency of CCR6+ Tregs, but not that of CCR6- Tregs, is significantly correlated with increased inflammation in H. pylori gastritis. This study demonstrates that immunosuppression in H. pylori gastritis might be related to the activity of CCR6+ Tregs, which could influence disease prognosis.

GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells.

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells. Reducing this resistance might shed light on the treatment of human gastric adenocarcinoma. In this study, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors can restore TRAIL responsiveness in gastric adenocarcinoma cells. The effect of two GSK-3 inhibitors, SB-415286, and LiCl, on apoptosis signaling of TRAIL in human gastric adenocarcinoma cell lines and primary gastric epithelial cells was analyzed. Both inhibitors can sensitize gastric adenocarcinoma cells, but not primary gastric epithelial cells, to TRAIL-induced apoptosis by increasing caspase-8 activity and its downstream signal transmission. Adding p53 siRNA can downregulate GSK-3 inhibitor-related sensitization to TRAIL-induced apoptosis and caspase-3 activity. GSK-3 inhibitors strongly activate the phosphorylation of JNK. Inhibition of JNK leads to earlier and more intense apoptosis, showing that the activation of JNK may provide anti-apoptotic equilibrium of pro-apoptotic cells. Our observations indicate that GSK-3 inhibitors can sentize AGS gastric adenocarcinoma cells to TRAIL-induced apoptosis. Therefore, in certain types of gastric adenocarcinoma, GSK-3 inhibitor might enhance the antitumor activity of TRAIL and mightbe a promising candidate for the treatment of certain types of gastric adenocarcinoma.

Changes in hepatitis B virus surface antibody titer and risk of hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients undergoing biologic therapy for rheumatic diseases: a prospective cohort study.

BACKGROUND: Our aim was to investigate dynamic changes in hepatitis B virus (HBV) surface antibody (HBsAb) titer and the associated risk of HBV reactivation and clinical course in patients with HBV surface antigen negative/core antibody positive (HBsAg-/HBcAb+) serostatus during antirheumatic therapy with biologic agents. METHODS: In a prospective study from January 2013 to June 2017, we monitored the HBV serostatus of HBsAg-/HBcAb+ patients undergoing biologic therapy for rheumatic diseases. From HBsAb titers at baseline and subsequent time points, we calculated the person-years (PY) contributed by patients with different HBsAb levels: < 10 mIU/mL (negative); 10-100 mIU/mL (low); and > 100 mIU/mL (high). We analyzed the incidence of detectable HBV DNA and HBV reactivation in each group, and documented the clinical courses of patients. RESULTS: Among 380 participants, 83 (21.8%) had baseline HBsAb < 10 mIU/mL, 156 (41.1%) HBsAb 10-100 mIU/mL, and 141 (37.1%) HBsAb > 100 mIU/mL. Total PY at study end were 169.3 PY from the HBsAb-negative group, 362.7 PY from the low-titer group, and 285.8 PY from the high-titer group. Seventeen patients had detectable HBV DNA, with respective incidence rates in negative, low- and high-titer groups of 4.7/100 PY, 2.5/100 PY, and 0/100 PY. Two HBsAb-negative patients subsequently developed HBV reactivation, an incidence of 1.2/100 PY. CONCLUSIONS: The risk of HBV reactivation varied with HBsAb titer, which changed during biologic therapy. Neither HBV DNA nor reactivation were detected in patients with HBsAb > 100 mIU/mL, whereas HBV DNA without reactivation occurred periodically in patients with HBsAb 10-100 mIU/mL; HBsAb-negative serostatus was associated with a risk of HBV reactivation.

Isosteviol Derivative Inhibits Osteoclast Differentiation and Ameliorates Ovariectomy-Induced Osteoporosis.

NC-8 (ent-16-oxobeyeran-19-N-methylureido) is an isosteviol-derived analogue with multiple biological effects, including anti-inflammation and anti-bacterial activities and inhibition of HBV viral surface antigen gene expression. In this study, we explored the effects of NC-8 on the formation of osteoclasts from RAW 264.7 cells. We found that NC-8 exerts the novel effect of inhibiting osteoclast-like cell formation. Our experiments showed that RANKL-induced ERK, p38, and JNK phosphorylation were inhibited by NC-8. An ovariectomy-induced osteoporosis animal model was used to examine the protective effects of oral treatment with NC-8. Serum analysis was used to examine markers of osteoblasts, osteoclasts, and renal and hepatic function in rats. Micro CT scanning and histological analysis were used to measure bone loss in ovariectomized rats. Oral administration of NC-8 effectively decreased excess bone resorption and significantly antagonized trabecular bone loss in ovariectomized rats. Serum analysis of C-terminal telopeptide of type-I collagen, an osteoclast marker, also showed that NC-8 administration inhibited excess bone resorption. Furthermore, serum analysis showed that renal and liver function were not affected by these doses of NC-8 during long-term treatment. Our results demonstrate that NC-8 inhibits osteoclast differentiation and effectively ameliorates ovariectomy-induced osteoporosis.

A paeonol derivative, YPH-PA3 promotes the differentiation of monocyte/macrophage lineage precursor cells into osteoblasts and enhances their autophagy.

Previous studies have indicated that paeonol inhibits RANKL-induced osteoclastogenesis by inhibiting the ERK, p38, and NF-κB pathway. We modified paeonol to form a new compound, YPH-PA3, and found that it promoted osteoclastogenesis rather than inhibited it the way paeonol does. The aim of this study is to investigate the mechanisms involved in YPH-PA3-promoted osteoclastogenesis. YPH-PA3-promoted differentiation of RAW264.7 cells (human monocytes) into osteoclasts is activated through ERK/p38/JNK phosphorylation, affecting c-FOS, NF-κB, and NFATc2. Real-time quantitative PCR and western blot revealed an increased expression of autophagy-related markers during YPH-PA3-induced osteoclastogenesis. We also demonstrated the relationship between p62/LC3 localization and F-actin ring formation by double-labeling immunofluorescence. Knockdown of p62 small-interfering RNA (siRNA) attenuated YPH-PA3-induced expression of autophagy-related genes. Our study results indicated that p62 may play a role in YPH-PA3-induced autophagy and osteoclastogenesis, which may help to develop a novel therapeutic strategy against osteoclastogenesis-related diseases.

Interleukin-32 plays an essential role in human calcified aortic valve cells.

Interleukin-32 (IL-32) is an inflammatory cytokine produced mainly by T, natural killer, and epithelial cells. Previous studies on IL-32 have primarily investigated its proinflammatory properties. The IL-32 also has been described as an activator of the p38 mitogen-activated protein kinase (MAPK) and NF-κB, and induces several cytokines. In this study, we hypothesized that the inflammatory regulators NF-κB, MAP kinase, STAT1, and STAT3 are associated with the expression of the IL-32 protein in human calcified aortic valve cells. This study comprised aortic valve sclerotic patients and control group patients without calcified aortic valve. Increased IL-32 expression in calcified aortic valvular tissue was shown by immunohistochemical staining and western blotting. There was an increase in NF-κB p65 level, p-ERK, p-JNK, and p-p38 MAPK activation underlying IL-32 expression in the study. The level of p-STAT3 but not p-STAT1 was found to be increased in calcified aortic valve tissue. In cultured primary human aortic valve interstitial cells, inhibition of NF-κB or MAPK kinase pathways results in a decrease of IL-32 expression. Treatment of recombinant IL-32 induced the levels of TNF-α, IL-6, IL-1ß, and IL-8. Our findings demonstrate that IL-32 may be an important pro-inflammatory molecule involved in calcific aortic valve disease.