Summary.  Objectives: We explored the possibility that heme, an inflammatory mediator and a product of intravascular hemolysis in patients with hemolytic anemia including sickle cell disease, could modulate hemostasis by an effect on endothelial tissue factor (TF) expression. Methods: Levels of TF mRNA, protein and procoagulant activity were measured in heme‐treated endothelial cells. Results: Heme induces TF expression on the surface of both macrovascular and microvascular endothelial cells in a concentration‐dependent manner, with 12‐fold to 50‐fold induction being noted (enzyme‐linked immunosorbent assay) between 1 and 100 μm heme (P < 0.05). Complementary flow cytometry studies showed that the heme‐mediated endothelial TF expression was quantitatively similar to that of tumor necrosis factor‐alpha (TNF‐α). Heme also upregulated the expression of TF mRNA (8‐fold to 26‐fold), protein (20‐fold to 39‐fold) and procoagulant activity (5‐fold to 13‐fold) in endothelial cells in a time‐dependent manner. The time‐course of heme‐mediated TF antigen expression paralleled the induction of procoagulant activity, with antibody blocking studies demonstrating specificity for TF protein. Interleukin (IL)‐1α, and TNF‐α are not involved in mediating the heme effect, as antibodies against these cytokines and IL‐1‐receptor antagonist failed to block heme‐induced TF expression. Inhibition of heme‐induced TF mRNA expression by sulfasalazine and curcumin suggested that the transcription factor nuclear factor kappaB is involved in mediating heme‐induced TF expression in endothelial cells. Conclusions: Our results demonstrate that heme induces TF expression by directly activating endothelial cells, and that heme‐induced endothelial TF expression may provide a pathophysiologic link between the intravascular hemolytic milieu and the hemostatic perturbations previously noted in patients with hemolytic anemia including sickle cell disease.

SUMMARY BackgroundSerum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in various autoimmune and liver diseases.

The coexistence of HBsAg and anti-HBs is an atypical serological pattern in HBV infection. There is no epidemiological characteristics of this serological pattern in the community and there is controversy over the molecular mechanisms underlying this pattern. We investigated the epidemiological characteristics of the carriers with HBsAg and anti-HBs in a longitudinal community cohort study. The prevalence of this atypical serological pattern was 2.93% (122/4169) in HBsAg-positive populations. The prevalence progressively increased with age from 40 to 70 years old. The rate of HBeAg positive and detectable HBV DNA were both significantly higher in carriers with this pattern than in carriers who were HBsAg positive but anti-HBs negative (26/122 verse 598/4047, P = 0.046; 86/122 verse 275/529,P < 0.001). After 1 year of follow-up, 85.19% of the carriers still had coexistence HBsAg and anti-HBs, 14.81% of the carriers lost their anti-HBs. Viral sequencing showed that carriers with coexistence of HBsAg and anti-HBs had higher numbers of residue changes within the S gene than carriers who were HBsAg positive but anti-HBs negative (2.42 verse 1.33 changes per 100 residues, P < 0.05). Hence, the coexistence of HBsAg and anti-HBs is a unique serological pattern which may be associated with an increased risk of adverse clinical outcome and may be related to HBsAg immune variants which have genotypic heterogeneity.

The present results suggest that increased Cideb expression upon palmitate exposure may be involved in beta cell lipoapoptosis through its influence on conversion of FFAs to lipid esters in lipid droplets.

Infants infected with hepatitis B virus (HBV) face the risk of developing severe complications. Unfortunately, in spite of universal vaccination programmes, 5% or more of vaccinated newborns still do not achieve protective levels of anti-hepatitis B virus surface antigen titres (anti-HBs). The aim of this study was to use animal experiments and population-based research to determine whether maternal vaccination against HBV affects the outcome of neonatal vaccination. Six sows and 53 newborn piglets were used for this study and randomly assigned to the vaccination group (three 20 μg doses of recombinant HBV vaccine). All the piglets were followed up to 10 weeks of age, and peripheral blood was withdrawn for measurement of anti-HBs. A cross-sectional study was also conducted on 449 mothers with infants. A structured questionnaire was used to collect demographic, medical and maternal data, and their peripheral blood was collected for measurement of anti-HBs. The results of animal experiments demonstrated that nonvaccinated piglets born to vaccinated sows and nonvaccinated piglets born to nonvaccinated sows were negative for anti-HBs. Repeated measures analysis of variance showed that the titres of anti-HBs in vaccinated piglets born to vaccinated sows were significantly higher than in vaccinated piglets born to nonvaccinated sows (P < 0.05). In a population-based study, a cumulative logistic regression analysis showed that the strongest influences on neonatal anti-HBs titres were delay of the first vaccination dose [OR = 3.02(95% CI: 1.72-5.30)] and maternal anti-HBs titres [OR = 2.48(95% CI: 2.03-3.04)]. In conclusion, high maternal anti-HBs titres can enhance the response to HBV vaccination in infants.

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Psoriasis patients develop cardiovascular (CV) comorbidities that shorten their lifespan; why this occurs and whether treatment with current biologics improves these outcomes is unclear. KC-Tie2 mice develop psoriasiform skin inflammation with increases in IL-23/IL-17A and proinflammatory monocytes that precede the development of aortic vascular inflammation and shortened times to induced carotid artery thrombus formation (thrombosis). KC-Tie2 mice with skin disease were treated IP 1x/wk for 6wks with function-blocking antibodies (Abs) targeting murine IL-17A, IL-17F, IL-17RA, IL-12/23p40, IL-23p19 or isotype IgG (n¼9-21/grp) and thrombosis, skin inflammation and splenic immunocytes were examined. KC-Tie2 mice treated with Abs targeting IL-17A, IL-17RA, IL-12/23p40 and IL-23p19, but not IL-17F had significantly decreased acanthosis, cutaneous T and myeloid cell infiltrates, STAT3, S100A9, and TNFa (p<0.05 vs. IgG), consistent with observed efficacy (or lack thereof) of these biologic therapies in psoriasis patients. Improvement (increase) in thrombosis times was seen in mice with significantly improved skin inflammation and this corresponded with decreases in splenic proinflammatory CD11b + Ly6C hi monocytes. Notably, KC-Tie2 mice treated with IL-17F Abs also showed significantly improved thrombosis (p<0.05 vs. IgG), despite sustained skin inflammation and CD11b + Ly6C hi monocytosis. Further examination of splenic immunocytes identified reduced CD11b + Ly6G + neutrophils in all mice that showed improved thrombosis and this corresponded with decreases in cutaneous NF-kB (p<0.05 vs. IgG). Our data demonstrate that inhibiting IL-23/IL-17 cytokines associated with psoriasiform skin inflammation increases time to occlusive thrombosis and identifies a potential role for IL-17F in mediating CV outcomes. Moreover, splenic neutrophil number and skin NF-kB expression corresponded best with increased clotting times suggesting these may serve as surrogate measures of CV outcomes in psoriasis patients.