PF-4var/CXCL4L1 Predicts Outcome in Stable Coronary Artery Disease Patients with Preserved Left Ventricular Function

Background: Platelet-derived chemokines are implicated in several aspects of vascular biology. However, for the chemokine platelet factor 4 variant (PF-4var/CXCL4L1), released by platelets during thrombosis and with different properties as compared to PF-4/CXCL4, its role in heart disease is not yet studied. We evaluated the determinants and prognostic value of the platelet-derived chemokines PF-4var, PF-4 and RANTES/CCL5 in patients with stable coronary artery disease (CAD). Methodology/Principal Findings: From 205 consecutive patients with stable CAD and preserved left ventricular (LV) function, blood samples were taken at inclusion and were analyzed for PF-4var, RANTES, platelet factor-4 and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were followed (median follow-up 2.5 years) for the combined endpoint of cardiac death, non-fatal acute myocardial infarction, stroke or hospitalization for heart failure. Independent determinants of PF-4var levels (median 10 ng/ml; interquartile range 8-16 ng/ml) were age, gender and circulating platelet number. Patients who experienced cardiac events (n = 20) during follow-up showed lower levels of PF-4var (8.5 [5.3-10] ng/ml versus 12 [8-16] ng/ml, p = 0.033). ROC analysis for events showed an area under the curve (AUC) of 0.82 (95% CI 0.73-0.90, p<0.001) for higher NT-proBNP levels and an AUC of 0.32 (95% CI 0.19-0.45, p = 0.009) for lower PF-4var levels. Cox proportional hazard analysis showed that PF-4var has an independent prognostic value on top of NT-proBNP. Conclusions: We conclude that low PF-4var/CXCL4L1 levels are associated with a poor outcome in patients with stable CAD and preserved LV function. This prognostic value is independent of NT-proBNP levels, suggesting that both neurohormonal and platelet-related factors determine outcome in these patients

Staphylococcus aureus enterotoxins induce IL-8 secretion by human nasal epithelial cells

BACKGROUND: Staphylococcus aureus produces a set of proteins which act both as superantigens and toxins. Although their mode of action as superantigens is well understood, little is known about their effects on airway epithelial cells. METHODS: To investigate this problem, primary nasal epithelial cells derived from normal and asthmatic subjects were stimulated with staphylococcal enterotoxin A and B (SEA and SEB) and secreted (supernatants) and cell-associated (cell lysates) IL-8, TNF-α, RANTES and eotaxin were determined by specific ELISAs. RESULTS: Non-toxic concentrations of SEA and SEB (0.01 μg/ml and 1.0 μg/ml) induced IL-8 secretion after 24 h of culture. Pre-treatment of the cells with IFN-γ (50 IU/ml) resulted in a further increase of IL-8 secretion. In cells from healthy donors pretreated with IFN-γ, SEA at 1.0 μg/ml induced release of 1009 pg/ml IL-8 (733.0–1216 pg/ml, median (range)) while in cells from asthmatic donors the same treatment induced significantly higher IL-8 secretion – 1550 pg/ml (1168.0–2000.0 pg/ml p = 0.04). Normal cells pre-treated with IFN-γ and then cultured with SEB at 1.0 μg/ml released 904.6 pg/ml IL-8 (666.5–1169.0 pg/ml). Cells from asthmatics treated in the same way produced significantly higher amounts of IL-8 – 1665.0 pg/ml (1168.0–2000.0 pg/ml, p = 0.01). Blocking antibodies to MHC class II molecules added to cultures stimulated with SEA and SEB, reduced IL-8 secretion by about 40% in IFN-γ unstimulated cultures and 75% in IFN-γ stimulated cultures. No secretion of TNF-α, RANTES and eotaxin was noted. CONCLUSION: Staphylococcal enterotoxins may have a role in the pathogenesis of asthma

Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia: Similar Efficacy of Non-Myeloablative and Myeloablative Conditioning; Long-Term Evaluation From the University of Minnesota.

Abstract Abstract 3385 Poster Board III-273 Allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is increasingly utilized. We retrospectively analyzed outcomes of HCT for 43 patients with CLL at the University of Minnesota from February 1985 through March 2009 using myeloablative (MA, n=19) (total body irradiation [TBI] 1320 cGY in 8 fractions and cyclophosphamide [Cy] 60 mg/kg x 2 days) and non-myeloablative (NMA, n=24) preparative regimens (fludarabine 40 mg/m2 × 5 days or cladribine 50 mg/m2 IV with TBI 200cGy in 1 fraction and either oral busulfan [Bu] 8 mg/kg divided every 6 hours over 2 days or Cy 50 mg/kg x1 day). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine (CSA) and methotrexate in most MA patients and CSA and mycophenolate mofetil (MMF) for all NMA patients. Median follow up for survivors was 3.3 years. Nine-two percent of NMA HCT took place after 2000 whereas only 26% of MA HCTs happened during this time. Most patients were male (15/19 MA, 20/24 NMA). Time from diagnosis to treatment was nearly twice as long in NMA vs. MA patients (median 72 vs. 39 months) with MA patients progressing through a median of 3 regimens (range, 1-5) and NMA 4 (1-7). Poor-risk cytogenetics (11q-, 17p-) were found in 5 MA and 10 NMA patients. Seven and 13 patients were fludarabine refractory in the MA and NMA groups, respectively. Eighteen patients in the MA group had matched related donors (MRD), while only 10 MRD were amongst the NMA patients. Umbilical cord blood stem cells were used in 12 NMA patients. Neutrophil recovery was slightly faster after NMA HCT vs. MA (median 12.5 vs. 18.5 days; p=0.14). Incidence of acute GVHD, grades II-IV, was similar (p=0.11) but grades III-IV at day 100 was more frequent in the NMA than the MA group (33% vs. 5%, p=0.04). The chronic GVHD incidence was 43% (95% CI, 18-68%) in MA and 29% in NMA (11-47%, p=0.08) patients. Transplant-related mortality (TRM) at 1 year was 42% (20-64) in the MA arm vs. 25% (8-42) (p=0.34) for the NMA group. Relapse rates at 3 years were higher in the NMA HCT group (MA 18% [0-36] vs. NMA 26% [8-44]). Three-year progression-free survival (PFS) was similar in MA (33% [13-55]) and NMA (39% [19-58]) patients (p=0.61). Overall survival at three years was also similar (MA 37%, [15-60] vs. NMA 52%, [30-70]) (p=0.28). While these data suggest that dose intensity may affect TRM and relapse, NMA HCT yields equivalent and encouraging PFS and OS as compared to MA HCT. Our results support further investigation of the role of allogeneic transplantation in the treatment of high risk and advanced CLL. Disclosures: No relevant conflicts of interest to declare. </jats:sec