Effects of active and latent H. pylori infection coupled with chronic alcohol ingestion on cytokine profiles and markers of oxidative balance in men seropositive for H. pylori CagA Ab: An observational study.

This study aimed to explore the effects of active and latent Helicobacter pylori infection coupled with alcohol consumption on cytokine profiles and markers of oxidative balance in men seropositive for H. pylori CagA Ab.The 100 male subjects were divided into groups with active H. pylori infection and H. pylori CagA Ab coupled with chronic alcohol ingestion (group A, n = 38), latent H. pylori infection with H. pylori CagA Ab coupled with chronic alcohol ingestion (group B, n = 30), and latent H. pylori infection with H. pylori CagA Ab without chronic alcohol ingestion (group C, n = 32).No differences in serum levels of CRP, IL-10, ADP, E-selectin, MDA, or SOD were detected between the 3 groups or between any 2 groups (all P > .05). The serum IL-6 and TNF-α concentrations in groups A and B were significantly lower than those in group C (P = .004, P = .005, P = .009, and P = .023). However, there were no differences in serum IL-6 and TNF-α between group A and group B (all P > .05).In conclusion, active or latent H. pylori infection coupled with chronic alcohol ingestion may decrease certain cytokines, that is, IL-6 and TNF-α, in men with H. pylori CagA Ab seropositivity. However, there was no difference in the detected cytokine profile between active and latent H. pylori infection coupled with chronic alcohol ingestion, and no changes were detected in markers of oxidative balance in men with H. pylori CagA Ab.

Association between circulating inflammatory molecules and alcoholic liver disease in men.

The association between alcoholic liver disease (ALD) and the inflammatory response remains controversial. The aim of this study was to explore this association between ALD and inflammation. We enrolled 214 male participants, who were divided into three age-matched groups: ALD (n = 135), chronic alcohol ingestion without ALD (non-ALD; n = 42), and control (n = 37). The BMI was significantly higher in the ALD group than in the non-ALD and control groups (all P = 0.000). Further, the constituent ratio of the liver inflammatory level was significantly higher in the ALD group than in the non-ALD and control groups (P = 0.002 and P = 0.000, respectively). In addition, the median serum ALT, AST, and GGT levels were significantly higher in the ALD group than in the control group (P = 0.023, P = 0.008, and P = 0.000, respectively); these levels were also significantly higher in the ALD group than in the non-ALD group (P = 0.013, P = 0.010, and P = 0.000, respectively). The median serum CRP level was significantly higher in the ALD group than in the non-ALD and control groups (P = 0.006 and P = 0.000, respectively). Further, the median serum TNF-α level was significantly lower in the ALD group than in the non-ALD and control groups (P = 0.004 and P = 0.000, respectively). The median serum sOX40L and HSP70 levels were significantly lower in the ALD group than in the control group (P = 0.008 and P = 0.018, respectively). In addition, the ALT, AST, and GGT levels were positively correlated with the CRP level (r = 0.211, P = 0.002; r = 0.220, P = 0.001 and r = 0.295, P = 0.000, respectively), and the GGT level was negatively correlated with the TNF-α (r = -0.225, P = 0.001), sOX40L (r = -0.165, P = 0.016), and HSP70 levels (r = -0.178, P = 0.009). Further, the Cr level was negatively correlated with the IL-10 level (r = -0.166, P = 0.015). Logistic regression analysis verified that the BMI (OR  =  1.637, 95%CI: 1.374-1.951, P  =  0.000) and GGT level were significantly higher (OR  =  1.039, 95%CI: 1.020-1.059, P  =  0.000) and that the TNF-α (OR  =  0.998, 95%CI: 0.996-1.000, P  =  0.030) and HSP70 levels were significantly lower (OR  =  1.017, 95%CI: 1.003-1.031, P  =  0.029) in the ALD group than in the non-ALD group. Further, the moderate-to-severe ALD patients had a significantly higher serum CRP level (Or =   1.349, 95%CI: 1.066-1.702, P  =  0.013) and significantly lower HSP60 (OR  =  0.965, 95%CI: 0.938-0.993, P  =  0.014) and HSP70 levels (OR  =  0.978, 95%CI: 0.962-0.995, P  =  0.010) than the mild ALD patients. These results suggest that ALD patients may present with obesity, liver damage, and an imbalanced inflammatory immune response, mainly manifesting as decreased levels of immune inflammatory cytokines. In addition, they suggest that certain liver and kidney function parameters and ALD severity are either positively or negatively correlated with certain inflammatory cytokines. Hence, ALD patients may be at increased risks of obesity- and inflammation-related diseases. Accordingly, to control the inflammatory response, preventative measures for patients with this disease should include weight control and protection of liver and kidney function.

Risk Factors Associated With Increased Carotid Intima-Media Thickness in a Male Population With Chronic Alcohol Consumption: A Prospective Observational Study.

Previous studies have reported a relationship between alcohol consumption and carotid intima-media thickness (CIMT). However, the exact associations between different severities of CIMT and dyslipidemia, dyslipoproteinemia, inflammatory immune markers, and oxidative markers associated with chronic alcohol consumption remain unknown. The aim of this study was to explore whether there are associations between different severities of CIMT and dyslipidemia, dyslipoproteinemia, inflammatory immune markers, and oxidative markers associated with chronic alcohol consumption. We enrolled 173 males with chronic alcohol consumption and categorized them into 2 groups: 104 chronic alcohol consumers with normal CIMT (group A) and 69 chronic alcohol consumers with increased CIMT (group B). Nonparametric statistics showed that age, body mass index (BMI), and serum TC, TG, Apo A1, and ApoB levels were significantly higher in group B than in group A (P = 0.002, 0.019, 0.021, 0.023, 0.001, and 0.001, respectively). Additionally, tumor necrosis factor alpha (TNFα) and HSP70 serum levels were significantly lower in group B than in group A (P = 0.023 and 0.017, respectively). A binary logistic regression analysis showed that age (OR: 1.077, 95% CI: 1.024-1.13, P = 0.004), ApoB (OR: 6.828, 95% CI: 1.506-30.956, P = 0.013), and TNF-α (OR: 0.999, 95% CI: 0.998-1.00) were independent risk factors associated with CIMT. The present study demonstrated that age, ApoB, and TNFα are independent risk factors associated with CIMT. Thus, older subjects with increased serum ApoB levels are more likely to present with increased CIMT, suggesting that age and ApoB promote such thickening and that TNFα downregulation might play a protective role against the progression of subclinical atherosclerosis in subjects with chronic alcohol consumption.

PRISMA-Compliant Article: Clinical Characteristics and Factors Influencing Prognosis of Patients With Hepatoid Adenocarcinoma of the Stomach in China.

Most previous studies have been single case reports, and studies with large samples are presently lacking. In addition, no studies have investigated the associations between the clinical characteristics and prognosis of hepatoid adenocarcinoma of the stomach (HAS). The aim of this study was to explore the associations of different clinical characteristics with the ages, serum alpha-fetoprotein (AFP) levels, and survival times of HAS patients. The present study was conducted using the CBM disc, HowNet, Wanfang and VIP data resource systems, and PubMed. According to the PRISMA Flow Diagram, certain case reports from the same center, those that did not provide patient age or sex, and those that did not report serum AFP levels or AFP immunohistochemistry results were excluded. A total of 131 relevant articles, including 124 case reports, 5 reviews, and 2 postgraduate Master's theses, were reported in the above-mentioned five databases. We applied inclusion criteria to case reports on the clinical characteristics and prognosis of HAS, which resulted in the ultimate inclusion of 180 patients from 62 case reports for statistical analyses. The main finding was that the age of the men was significantly higher than that of the women (P = 0.004). In addition, the serum AFP levels of the participants with antral disease were significantly higher than those with nonantral disease (P = 0.001). The median serum AFP levels and survival times significantly differed among the patients with the three lesion types (P = 0.001 and 0.019, respectively). The serum AFP levels of the participants with ulcerative-upheaval-type tumors and purely ulcerative tumors were significantly higher than those with upheaval-type tumors (P = 0.000 and 0.017, respectively). In addition, the serum AFP levels of the participants with ulcerative-upheaval-type tumors were significantly higher than those with ulcerative-type tumors (P = 0.019), and their survival time was also significantly higher (P = 0.000). The serum AFP levels of the participants without metastasis or liver metastasis were significantly lower than those with metastasis or liver metastasis (P = 0.000 and 0.000, respectively), and their survival time was significantly longer (P = 0.000 and 0.001, respectively). Finally, the survival time of the participants treated with surgery was significantly longer than those treated using nonsurgical methods (P = 0.046). However, survival analysis revealed that the survival time was only significantly associated with the presence of metastasis (P = 0.002) and liver metastasis (P = 0.036). The main limitations of this study are as follows: it was a retrospective analysis of published case reports, the clinical data were incomplete, and the cases included in subgroup analyses were different. Our study results have demonstrated that the prognosis of HAS patients is poor. In addition, the survival time is significantly negatively correlated with the presence of metastasis and liver metastasis.

Influence of H. pylori CagA Coupled with Alcohol Consumption on Cytokine Profiles in Men.

The aim of this study was to evaluate the effect of Helicobacter pylori (H pylori) cytotoxin-associated gene A (CagA) coupled with chronic alcohol ingestion on cytokine profiles.A total of 215 male subjects were divided into the following 4 groups: 130 alcohol H pylori CagA-negative consumers (CagA-) (group A), 50 alcohol H pylori CagA-positive consumers (CagA+) (group B), 24 nonalcohol H pylori CagA-negative consumers (group C), and 11 nonalcohol H pylori CagA-positive consumers (group D). The serum CagA, C-reactive protein (CRP), interleukin (IL)-6, IL-10, E-selectin, adiponectin (ADP), and tumor necrosis factor-α (TNF-α) levels were measured through enzyme-linked immunosorbent assays (ELISAs).After adjusting for age and mean alcohol drinking history, a multivariable linear regression analysis revealed that the mean daily alcohol consumption, IL-6, TNF-α, and ADP levels were significantly increased with increases in the serum CagA concentrations (P = 0.008, P = 0.000, P = 0.000, and P = 0.006, respectively). The serum IL-6 and IL-10 levels of group A were significantly lower than those of group B (all P = 0.000). Furthermore, the serum IL-6 and IL-10 levels of groups A and C were significantly lower than those of group D (all P = 0.000), and the serum IL-6 and IL-10 levels of group C were significantly lower than those of group B (all P = 0.000). The serum ADP and E-selectin levels of groups B and D were significantly higher than those of group A (P = 0.000). The serum ADP levels of group B were significantly higher than those of group C (P = 0.000), and the serum ADP and E-selectin levels of group C were significantly lower than those of group D (P = 0.000 and P = 0.005, respectively). Finally, the serum TNF-α levels of groups B, C, and D were significantly higher than those of group A (all P = 0.000), and the serum TNF-α levels of group C were significantly higher than those of group D (P = 0.005).In conclusion, H pylori CagA may result in significantly higher levels of several inflammatory markers in both alcohol consumers and nonalcohol consumers. However, chronic alcohol ingestion coupled with H pylori CagA positivity does not result in significant changes in cytokine profiles.

Causes of Thickening of Carotid Intima-Media Thickness in Patients With Alcoholic Liver Disease: A Prospective Observational Study.

Several studies have reported the relationship between alcoholic liver disease (ALD) and carotid intima-media thickness (CIMT). Few studies, however, have investigated the causes of CIMT thickening in patients with ALD. The authors explored the causes of CIMT thickening in patients with ALD. The authors enrolled 152 patients who were stratified into groups: nonthickening CIMT with ALD (group A); thickening CIMT with ALD (group B); nonthickening CIMT without ALD (group C); and thickening CIMT without ALD (group D). The CIMT was significantly different between patients with and without ALD (χ 2= 3.875, P = 0.049). The patients in groups A, B, and C were significantly younger than group D (P = 0.001, 0.036, and 0.001, respectively). The body mass indexes (BMI) in groups A and B were significantly higher than in group C (P = 0.000 and 0.007, respectively). The blood glucose levels in groups B and D were significantly higher than in group C (P = 0.016 and 0.018, respectively). The blood uric acid levels in group B were significantly higher than in groups A, C, and D (P = 0.009, 0.000, and 0.003, respectively). The blood uric acid in group A was significantly higher than in group C (P = 0.002). The serum total cholesterol (TC) levels of patients in group B were significantly higher than in groups A and C (P = 0.027 and 0.000, respectively) and the serum TC level in group A was significantly higher than in group C (P = 0.048). The serum triglyceride (TG) levels in groups A and B were significantly higher than in group C (P = 0.027 and 0.000, respectively). The serum of very low-density lipoprotein (VLDL) levels in group B were significantly higher than in group C (P = 0.000). Although a comparison of the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) serum levels among the 4 groups indicated no changes. The serum LDL levels in group B were significantly higher than in group A (P = 0.008). No significant differences were observed among the groups with respect to serum homocysteine, C-reactive protein (CRP), interleukin-6 (IL-6), malondialdehyde (MDA), superoxide dismutase (SOD), soluble OX40 ligand (sOX40L), or heat shock protein (HSP) 60 or 70. Alcoholic liver disease may result in CIMT thickening. Carotid intima-media thickness is associated with age and metabolic factors in patients with ALD. In addition, ALD might promote the premature occurrence of CIMT thickening. The thickening of carotid artery intima thickness, however, is not associated with cytokine profiles, oxidative balance, or immune responses in patients with ALD.

Effect of H. pylori Infection on Cytokine Profiles and Oxidative Balance in Subjects with Chronic Alcohol Ingestion.

Different amounts of ingested alcohol can have distinct effects on the human body. However, there is limited research on chronic alcohol consumption with Helicobacter pylori infection. We sought to investigate the relationship between the cytokine profile, oxidative balance and H. pylori infection in subjects with chronic alcohol consumption. A total of 142 subjects were divided into three groups: 59 subjects with chronic alcohol ingestion and H. pylori infection (group A); 53 subjects with chronic alcohol ingestion without H. pylori infection (group B); and 30 control subjects (group C). The serum levels of CagA, interleukin (IL)-10, E-selectin, TNF-α, malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured by enzyme-linked immunosorbent assay (ELISA). We found that the ages and serum H. pylori CagA levels among the three groups, as well as both the mean drinking age and the mean daily alcohol consumption between groups A and B, were matched and comparable. Comparing the BMIs among the three groups, the BMI differences were found to be statistically significant (F=3.921, P<0.05). Compared with group C, the BMIs in groups A and B were significantly higher (P<0.001 and P<0.01, respectively); however, the BMI differences between group A and group B were not statistically significant (P>0.05). Additionally, no differences in the serum CagA levels were found in comparisons among the groups (all P>0.05). The serum IL-10 and E-selectin levels in group A were significantly lower than those in group B (serum IL-10: P<0.05; E-selectin: P<0.05). The serum IL-10 in group A was significantly higher than that in group C (P<0.01); the serum E-selectin levels in group A did not significantly differ compared with those in group C (P>0.05). Furthermore, the serum IL-10 and E-selectin levels in group B were significantly higher than those in group C (serum IL-10: P<0.001; E-selectin: P<0.05); however, the serum TNF-α levels did not differ among groups (all P>0.05). Although the serum levels of MDA and SOD in groups A and B were slightly lower than those in group C, there were no significant differences among groups (all P>0.05). In conclusion, we believe that H. pylori infection might cause a significant inhibition of certain cytokine profiles in subjects with chronic alcohol ingestion. Moreover, chronically ingested alcohol may exert an adjusted inflammatory effect, but there was no association between H. pylori infection, chronic alcohol consumption and oxidative balance.

Changes in tumor necrosis factor-α, heat shock protein 70, malondialdehyde, and superoxide dismutase in patients with different severities of alcoholic fatty liver disease: a prospective observational study.

The relationships among inflammation, oxidative balance, and the severity of alcoholic fatty liver disease (AFLD) remain unknown. The aim of this study is to explore the relationships among tumor necrosis factor alpha (TNF-α), heat shock protein 70 (HSP70), malondialdehyde (MDA), superoxide dismutase (SOD), and the severity of AFLD.From January 2012 to December 2013, 162 participants were enrolled in this study and divided into 4 groups: 44 cases of mild AFLD (group A), 55 cases of moderate-to-severe AFLD (group B), 44 cases of alcohol consumption without AFLD (group C), and 20 cases of no alcohol consumption without AFLD (group D). A cross-sectional study was conducted by detecting the serum levels of TNF-α, HSP70, MDA, and SOD by enzyme-linked immunosorbent assay.The median serum levels of TNF-α and HSP70 among the 4 groups were statistically significant (P = 0.000 and 0.001, respectively). The median serum levels of TNF-α in groups A and B were significantly lower than in group C (P = 0.002 and 0.000, respectively), and the median serum level of TNF-α in group B was significantly lower than in group D (P = 0.023). In addition, the median serum level of HSP70 in group B was significantly lower than in groups A and C (P = 0.002 and 0.000, respectively), and the median serum level of HSP70 in group C was significantly higher than in group D (P = 0.044). However, the median serum level of MDA in group B was significantly lower than only group C (P = 0.008).Chronic alcohol ingestion without AFLD may result in a significant increase in the circulation of certain inflammatory markers; the severity of AFLD is associated with circulating inflammatory markers, and moderate-to-severe AFLD may result in a more significant reduction of these markers. However, moderate-to-severe AFLD may also result in a significant downregulation of oxidative stress products.

Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial.

BACKGROUND: Acute gout is an intensely painful, inflammatory arthritis. Although the non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for this condition, the efficacy is based on only a few studies, particularly in China. We tried to assess the safety and efficacy of etoricoxib in the treatment of acute gouty arthritis in China. METHODS: A randomized, double-blind, active comparator study was conducted at 10 sites in China. Patients (n = 178; ≥ 18 years of age) with acute gouty attack (< 48 hours) were treated for 5 days with etoricoxib (120 mg/d; n = 89) or indometacin (75 mg twice daily; n = 89). The primary efficacy end point was self-assessed pain in the affected joint (0-4 point Likert scale) from days 2 - 5. Secondary end points included investigator assessments of tenderness and swelling, patient/ investigator global assessments of response to therapy, and patients discontinuing treatment. Safety was assessed by adverse events (AEs). RESULTS: Etoricoxib and indometacin had comparable primary and secondary end points. Mean change difference from baseline from days 2 - 5 was 0.03 (95% confidence interval (CI) -0.19 to 0.25; P = 0.6364), which fell within the prespecified comparative bounds of -0.5 to 0.5. No severe AEs were associated with etoricoxib use. Non-severe AEs were mainly digestive and general, and most (73.7%) were mild, although they caused withdrawal of two subjects in the etoricoxib group, due to bilateral renal calculi and uronephrosis of the left kidney (unrelated to etoricoxib) and fever and chills (potentially etoricoxib-related). Overall, AEs were similar, although the absolute number of AEs in the etoricoxib group (n = 31) was less than the indometacin group (n = 34). CONCLUSIONS: Etoricoxib (120 mg once daily) is effective in treating acute gout, is generally safe and well-tolerated, and is comparable in efficacy to indometacin (75 mg twice daily).

Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate.

OBJECTIVE: To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks. RESULTS: After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups. CONCLUSION: Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.

A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) and methotrexate in treatment of patients with active rheumatoid arthritis in China.

The objective of this study is to evaluate the efficacy and safety of rhTNFR:Fc: a recombinant tumor necrosis factor receptor:Fc fusion protein compared with methotrexate (MTX) in patients with rheumatoid arthritis in China. We treated 238 patients with active rheumatoid arthritis with either twice weekly subcutaneous injection rhTNFR:Fc (25 mg) or weekly oral MTX (mean 15 mg per week) for 24 weeks (registration number: 2003L01264). Clinical responses were defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology (ACR-N). As compared with MTX-treated patients, more patients who received rhTNFR:Fc had ACR20 improvement in disease activity during the first 2 weeks (P < 0.05). Similarly, more patients treated with rhTNFR:Fc having ACR20, ACR50, ACR70 improvement in disease activity during 8 weeks (P < 0.05). At the end of 12-week treatment, patients received rhTNFR:Fc also had significant improvement at ACR20 (P < 0.05). Compared with oral MTX, patients received rhTNFR:Fc also had significant improvement at ACR70 at the end of 24 weeks treatment (P < 0.05). In conclusion, compared with oral MTX subcutaneous injection, rhTNFR:Fc acted more rapidly to release symptoms and signs of active RA in Chinese patients, and well tolerated in patients with rheumatoid arthritis in China.

[The predictive factors and unfavourable prognostic factors of interstitial lung disease in patients with polymyositis/dermatomyositis].

OBJECTIVE: To analyze the predictive factors and the unfavourable prognostic factors of interstitial lung disease (ILD) in patients with polymyositis (PM)/dermatomyositis (DM). METHODS: The clinical data were collected from 87 inpatients with DM or PM, who were admitted to Shanghai Changhai Hospital from January 1997 to November 2006. The patients were divided into an ILD group and a non-ILD group. The clinical feature, incidence and prognosis of ILD were retrospectively analyzed. The clinical and laboratory data were analyzed by using the SPSS 13.0 software. The t-test and rank-sum test were used, depending on the measurement data. The enumeration data were analyzed with chi-square test. Logistic regression and Kaplan-Meier survival curve were used to analyze the correlative and prognostic factors of interstitial lung disease (ILD) in patients with PM/DM. RESULTS: The incidence and mortality of ILD in PM/DM patients were 46% (40/87) and 40% (16/40), respectively. Compared with the non-ILD group, the age in the ILD group was markedly older [(54 +/- 13) years vs (45 +/- 18) years], and the percentages of fever (21/40 vs 7/47, chi2 = 14.00, P < 0.01), dysphagia (16/40 vs 8/47, chi2 = 5.71, P < 0.05), arthralgia (26/40 vs 9/47, chi2 = 18.89, P<0.01), Gottron's rash (14/40 vs 2/47, chi2 = 13.61, P <0.01) and heart impairment (26/40 vs 14/47, chi2 = 10.28, P <0.01) were significantly higher in the ILD group. The levels ofLDH [(472 +/- 285) IU vs (310 +/- 238) IU, t =2.86, P<0.01], ESR [(44 +/- 24) mm/1 h vs (26 +/- 24) mm/l h, t = 3.19, P <0.01] and immunoglobulin G [(18 +/- 9) g/L vs (14 +/- 5) g/L, t = 2.31, P <0.05] were statistically different between the two groups. By multivariate nonparametric logistic regression analysis, Gottron's rash, arthralgia, fever, and > or = 40 years of age were identified as predictors with relative risk ratio of 12.048, 7.812, 6.329 and 5.236 respectively. The unfavourable prognostic factors of ILD were Gottron' s rash (chi2 = 5.35, P <0.05), cardiac impairment (chi2 = 5.68, P < 0.05) and pulmonary fibrosis (chi2 = 5.42, P <0.05) by survival analysis. CONCLUSION: The occurrence of ILD in PM/ DM patients was closely correlated to Gottron's rash, age > or = 40 years, arthralgia and fever. Gottron's rash, heart impairment and pulmonary fibrosis were poor prognosis factors of PM/DM patients complicated with ILD.

TLR9/TLR7-triggered downregulation of BDCA2 expression on human plasmacytoid dendritic cells from healthy individuals and lupus patients.

Plasmacytoid dendritic cells (pDCs) can produce a large amount of interferon-alpha (IFN-alpha) upon exposure to TLR9 or TLR7 agonists. Human pDCs have been shown to play an important role in the pathogenesis of systemic lupus erythematosus (SLE) through increased production of IFN-alpha. So, how to negatively regulate activation of pDCs and how to evaluate the activation of pDC in SLE patients attract much attention. BDCA2 is selectively expressed on human pDCs, acting as a hallmark of human pDCs. In this study, we showed that BDCA2 expression on pDCs decreased along maturation of pDCs, and TLR7 or TLR9 agonists could further significantly downregulate pDCs to express BDCA2, suggesting that the activated pDCs exhibit decreased expression of BDCA2. Functionally, BDCA2 ligation significantly inhibited upregulation of CD40, CD86 and CCR7 expression, IFN-alpha, IFN-beta and IL-6 production by pDCs stimulated with CpG ODN. Moreover, BDCA2 ligation suppressed CpG ODN-activated pDCs to mediate Th1 response, including T cell proliferation, IFN-gamma production, and CD4(+)CCR5(+)Th1 development, confirming that BDCA2 is a negative regulator of TLR9-dependent activation of human pDCs. BDCA2 expression on pDCs from SLE patients decreased significantly but IFN-alpha production of these patients increased markedly as compared to that from healthy donors. Therefore, these results suggest that downregulation of BDCA2 expression on pDCs may reflect the activation of pDCs accumulated in SLE patients, and may be one marker for indication of the disease activity of SLE patients.

Safety and efficacy of T-614 in the treatment of patients with active rheumatoid arthritis: a double blind, randomized, placebo-controlled and multicenter trial.

BACKGROUND: A novel anti-rheumatic drug, T-614, has been shown to have an anti-inflammatory effect and to improve abnormal immunological findings in rheumatoid arthritis (RA). To assess the safety and efficacy of T-614 versus placebo in patients with active RA we conducted a 24-week clinical study in 280 Chinese patients. METHODS: In a multicenter, randomized, double blind, placebo controlled study, 280 patients were randomly assigned to receive placebo (n = 95) or T-614 at 50 mg (n = 93) or 25 mg (n = 92) daily. Active disease was defined by 4 of the following 5 criteria: >or= 5 tender joints, >or= 3 swollen joints, morning stiffness lasting for >or= 60 minutes, and Westergren erythrocyte sedimentation rate (ESR) >or= 28 mm/h, the assessment of pain at the rest by patient as moderate or severe. Clinical and laboratory parameters were analyzed at baseline, 2, 4, 6, 12, 18 and 24 weeks. The primary efficacy variable at week 24 was the American College of Rheumatology (ACR) response rate using the intent-to-treat population. RESULTS: The ACR response rate was significantly higher in the T-614 treatment group compared with the placebo group within 8 weeks after the initiation of treatment. After 24 weeks, the 25 mg/d and 50 mg/d dosage groups and the placebo group showed 39.13%, 61.29% and 24.21% in ACR20 and 23.91%, 31.18% and 7.37% in ACR50, respectively. A time-response in ACR response was observed, with clear superiority for the 25 mg/d and 50 mg/d dosage groups compared to placebo (P < 0.0001), and the 50 mg/d dose compared to the 25 mg/d dose (P < 0.05) when using the ACR response analyses after 24 weeks. ESR and c-reactive protein (CRP) were significantly different in the treatment groups after 24 weeks. The incidence of adverse events (AEs) was not significantly higher with T-614 than with placebo, but upper abdominal discomfort, leucopenia, elevated serum alanine aminotransferase (sALT), skin rash and/or pruritus were more common in the 50 mg and 25 mg dosage groups. CONCLUSION: T-614, a new slow-acting drug, is effective in treatment of rheumatoid arthritis and is well tolerated.

Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors.

Smad4 is the common mediator of transforming growth factor-beta (TGF-beta) superfamily signaling, which functions in diverse developmental processes in mammals. To study the role of Smad4 in skin development, a keratinocyte-specific null mutant of Smad4 (Smad4(co/co);K5-Cre) was generated in mice using the Cre-loxP system. The Smad4-mutant mice exhibited progressive alopecia as a result of the mutant hair follicles failing to undergo programmed regression. Sonic hedgehog (Shh) was only detected in Smad4-mutant hair follicles at the catagen stage. Seventy percent of Smad4(co/co); K5-Cre mice developed spontaneous tumors within 12 months of birth. c-Myc and cyclin D1 were up-regulated whereas p21 and p27 expressions were decreased, which correlated with the epidermal hyperplasia in Smad4 mutants. Interestingly, coordinated deletion of the Smad4 and PTEN genes resulted in accelerated hair loss and skin tumor formation, suggesting that Smad4 and PTEN act synergistically to regulate epidermal proliferation and differentiation. All of our data indicate that Smad4 is essential for catagen induction and acts as a critical suppressor in skin tumorigenesis.

Expression and function of inducible costimulator on peripheral blood T cells in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the role of inducible costimulator (ICOS) in the pathogenesis of SLE, we assessed its expression on peripheral blood CD4 and CD8 T cells and functional roles in patients with systemic lupus erythematosus (SLE). METHODS: Expression of ICOS on peripheral blood CD4 and CD8 T cells and ICOS ligand (ICOSL) on peripheral blood CD19 B cells from patients with SLE, patients with rheumatoid arthritis (RA) and healthy volunteers were determined by two-colour flow cytometry. The functional costimulatory effects of ICOS on peripheral blood mononuclear cells (PBMC) were assessed by T-cell proliferative responses, cytokines, anti-double-stranded DNA (anti-dsDNA) antibody and total IgG production. RESULTS: Peripheral blood CD4 and CD8 T cells expressing ICOS were significantly increased in patients with SLE compared with patients with RA and healthy subjects. Peripheral blood CD19 B cells expressing ICOSL in SLE were markedly reduced compared with RA. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher than those of anti-CD3/hamster IgG (HIgG) in healthy subjects, but not in patients with SLE. Anti-CD3/ICOS-stimulated SLE PBMC secreted similar levels of IL-10 and IFN-gamma but a significantly lower level of IL-2 than healthy PBMC. Anti-CD3/ICOS-mediated costimulation significantly enhanced the production of anti-dsDNA antibodies and total IgG in patients with SLE. CONCLUSION: Hyperexpression of ICOS on peripheral blood CD4 and CD8 T cells from patients with SLE contributed to the dysregulated T-cell proliferation, T-cell activation and pathogenic autoantibody production, which showed that the abnormality of ICOS costimulation may play an immunopathological role(s) in the pathogenesis of SLE.

[Expression and clinical significance of inducible co-stimulator on peripheral blood T lymphocyte subsets in patients with systemic lupus erythematosus].

OBJECTIVE: To investigate the expression of inducible co-stimulator (ICOS) and other immunological molecules on peripheral blood T lymphocyte subsets in patients with systemic lupus erythematosus (SLE) and to find out the relationship with disease-activity, disease-stage and the contents of anti-dsDNA antibody and immunoglobulin in serum so as to pave the way for further studying the possibly immunologically pathological role of ICOS in SLE. METHODS: Peripheral blood samples were collected from 51 patients with SLE, 3 males and 22 females. Three-color flow cytometry was used to detect the levels of ICOS, CD45RO, CD45RA, and HLA-DR expression on the peripheral blood T lymphocytes subsets. The results were analyzed along with the disease-activity, disease-stage, contents of anti-dsDNA antibody and immunoglobulin in serum. Thirty healthy subjects were used as controls. RESULTS: Compared with the healthy subjects the level of ICOS expression on the peripheral blood CD4+ and CD8+ T cells in the patients with SLE during active- and stable-stages were significantly increased (all P < 0.05), but there was no significant difference between the last two group patients (P > or = 0.05); In the same patients, the level of ICOS expression on the peripheral blood CD4+, CD8+, CD45RO+, CD4+CD45RO+ and CD8+CD45RO+ cells in active-stage were significantly increased compared with those in stable-stage (P <0.05); The level of ICOS expression on the peripheral blood CD45RO+ cells in the untreated primary patients was higher than those with disease-relapse (P <0.05); The levels of ICOS expression on the peripheral blood CD45RO+ and CD4+CD45RO+ cells were significantly increased in the patients with serum anti-dsDNA antibody(+) and the patients with aberrantly high content of immunoglobulin compared with those of the patients with serum anti-dsDNA antibody(-) and the patients with normal content of immunoglobulin, respectively (all P < 0.05). CONCLUSION: ICOS is aberrantly highly expressed on certain peripheral blood T lymphocyte subsets in patients with SLE, which is related to disease-activity, disease-stage and the contents of serum anti-dsDNA antibody and immunoglobulin, thus ICOS may play a role in SLE pathogenesis.