Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils

In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca⁺² chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.     

Reciprocal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemias: Review of 5,654 patients with an evaluable karyotype

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent. © 2013 Wiley Periodicals, Inc.     

Ultrasound-detected joint inflammation and B cell count: related variables for rituximab-treated RA patients?

This cross-sectional observational study aimed to explore the relationship between B cell count and ultrasound (US)-detected synovitis, in patients with rheumatoid arthritis treated with rituximab. Thirty-seven consecutive RA patients treated with RTX were recruited for the study. The patients underwent clinical [i.e., Disease Activity Score 28 joints (DAS28)], laboratory, and US assessment of 12 joints. Each joint was semiquantitatively (0–3) scored on B-mode and power Doppler mode. The scores were summed, and a global index was created for BM (BMS) and PD scores (PDI) synovitis. BM subclinical synovitis was evident in all patients, with PD synovial signal detected in 16 patients (43.2 %). No correlation was found between DAS28 and US scores. B cells were detected in 27 (72.9 %) patients, but there was no association in the mean B cell count and disease activity as measured by DAS28 (DAS28 < 2.6 = 34.53, DAS28 > 2.6 = 49.45, p = 0.52) and PDI score (PDI < 1 = 49.48, PDI > 1 = 35.44, p = 0.54). There was no correlation between the B cell count and DAS28, BMS, and PDI (r = 0.020, p = 0.907; r = ?0.151, p = 0.371; r = ?0.099, p = 0.558, respectively). In RTX-treated RA patients, no relationship could be established between US-detected synovitis and peripheral blood B cell count.     

Objectively-measured and self-reported physical activity and fitness in relation to inflammatory markers in European adolescents: the HELENA Study

ObjectiveAtherogenesis involves an inflammatory process that occurs early in life even though clinical symptoms are not observed until adulthood. Two important protective factors for low-grade inflammation may be physical activity (PA) and fitness. We examined the independent associations of objective and subjective measurements of PA and fitness with low-grade inflammation in European adolescents.MethodsA total of 1045 adolescents, aged from 12.5 to 17.5 years old from 10 European cities, were selected from the HELENA-Cross-Sectional Study. Objectively-measured and self-reported PA variables were obtained by accelerometry and the International PA Questionnaire for Adolescents, respectively. Overall, cardiorespiratory, muscular and motor fitness variables were assessed by standardized field-based fitness tests and the International Fitness Scale. C-reactive protein (CRP), complement factors 3 (C3) and 4 (C4), interleukin-6 and TNF-α inflammatory markers were measured.ResultsObjectively-measured vigorous PA was inversely associated with C3 (β = ?0.094, P = 0.021) but it did not remain significant after any objective fitness indicator was included in the model. Other objectively measured or self-reported assessments of PA were not significantly associated with inflammatory markers. All objective measures of fitness were inversely associated with CRP, C3 and C4, whereas only self-reported motor fitness remained significantly associated with C3, C4 and TNF-α. All these observations were independent of age, sex, city and body mass index or waist circumference.ConclusionHigh PA in adolescence may play an indirect role on lessening low-grade inflammation through improvements in fitness.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.     

Effect of Avocado Soybean Unsaponifiables on Insulin Secretion and Insulin Sensitivity in Patients with Obesity

AimTo evaluate the effect of avocado soybean unsaponifiables (ASU) on insulin secretion and insulin sensitivity in patients with obesity.MethodsA randomized, double-blind, placebo-controlled, clinical trial was carried out in 14 obese adult volunteers. After random allocation of the intervention, 7 patients received 300 mg of ASU or placebo during a fasting state for 3 months. A metabolic profile including IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels was carried out prior to the intervention. A hyperglycemic-hyperinsulinemic clamp technique was used to assess insulin secretion and insulin sensitivity phases. Mann-Whitney U test and Wilcoxon test were performed for statistical analyses. The study was approved by the local ethics committee of our institution.ResultsAt baseline, both groups were similar according to clinical and laboratory characteristics. There was no significant difference in insulin secretion and insulin sensitivity with ASU.ConclusionsASU administration for 3 months did not modify insulin secretion and insulin sensitivity in patients with obesity.Key Words: Avocado soybean unsaponifiables, Insulin secretion, Insulin sensitivity, Obesity     

Fragment length analysis screening for detection of CEBPA mutations in intermediate-risk karyotype acute myeloid leukemia

During last years, molecular markers have been increased as prognostic factors routinely screened in acute myeloid leukemia (AML). Recently, an increasing interest has been reported in introducing to clinical practice screening for mutations in the CCAAT/enhancer-binding protein ?? (CEBPA) gene in AML, as it seems to be a good prognostic factor. However, there is no reliable established method for assessing CEBPA mutations during the diagnostic work-up of AMLs. We describe here a straightforward and reliable fragment analysis method based in PCR capillary electrophoresis (PCR-CE) for screening of CEBPA mutations; moreover, we present the results obtained in 151 intermediate-risk karyotype AML patients (aged 16?C80?years). The method gave a specificity of 100% and sensitivity of 93% with a lower detection limit of 1?C5% for CEBPA mutations. The series found 19 mutations and four polymorphisms in 12 patients, seven of whom (58%) presented two mutations. The overall frequency of CEBPA mutations in AML was 8% (n?=?12). CEBPA mutations showed no coincidence with FLT3-ITD or NPM1 mutations. CEBPA mutation predicted better disease-free survival in the group of patients without FLT3-ITD, NPM, or both genes mutated (HR 3.6, IC 95%; 1.0?C13.2, p?=?0.05) and better overall survival in patients younger than 65 of this group without molecular markers (HR 4.0, IC 95%; 1.0?C17.4, p?=?0.05). In conclusion, the fragment analysis method based in PCR-CE is a rapid, specific, and sensitive method for CEBPA mutation screening and our results confirm that CEBPA mutations can identify a subgroup of patients with favorable prognosis in AML with intermediate-risk karyotype.     

Assessing the validity of an ELISA test for the serological diagnosis of human fascioliasis in different epidemiological situations

Objectives To improve the diagnosis of human fascioliasis caused by Fasciola hepatica and Fasciola gigantica, we evaluated the diagnostic accuracy of an enzyme‐linked immunosorbent assay (ELISA), with Fasciola antigen from the adult liver fluke, for the detection of IgG against fascioliasis in human sera. Methods The sera of 54 fascioliasis cases, originating from three endemic areas, were used in this evaluation: (i) a hyperendemic F. hepatica area where humans usually shed a great number of parasite eggs in faeces (11 sera); (ii) an epidemic F. hepatica area where humans usually shed small amounts of parasite eggs (24 sera) and (iii) an overlap area of both Fasciola species and where human shedding of parasite eggs in faeces is usually scarce or non‐existent (19 sera). One hundred and sixty‐eight patients with other parasitic infections and 89 healthy controls were also analysed. Results The respective sensitivity and specificity of this assay were 95.3% (95% confidence intervals, 82.9–99.2%) and 95.7% (95% confidence intervals, 92.3–97.5%). No correlation between egg output and the OD450 values of the F. hepatica IgG ELISA test was observed. Conclusions This test could be used both as an individual serodiagnostic test for human fascioliasis when backed up by a compatible clinical history together with a second diagnostic technique for other cross‐reactive helminth infections, and in large‐scale epidemiological studies of human fascioliasis worldwide.