Chronic idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder that is characterized by increased platelet destruction and is believed to be autoantibody mediated. In this study, CD3+ T cells from ITP patients had increased expression of genes involved in cell-mediated cytotoxicity. In addition, cytotoxic cell-mediated lysis of autologous platelets was shown in active ITP. Our data suggest that T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP.

Key Points• Patients up to age 70 years with CML treated within a decentralized health care setting had a relative survival close to 1.0. • Sokal, but not EUTOS, score at diagnosis predicted overall and relative survival in a population-based cohort of patients with CML.Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (<70 years) and 79% for older (>80 years) patients during [2007][2008][2009]. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival. (Blood. 2013;122(7):1284-1292

SummaryTo study the effects of standardized mental stress (arithmetic and the Stroop color word test) on plasma coagulation and fibrinolysis, blood samples were obtained before, during, and after 20 minutes of mental stress from 10 healthy, non-smoking young males aged 22 to 30 years. Reactions were compared with those observed during physical exercise and infusion of adrenaline. Both von Willebrand factor antigen and factor VIII coagulant activity increased significantly in response to mental stress (95 ± 28 vs 123 + 56%; p <0.05 and 125 ±54 vs 217 ± 170%; p <0.05, respectively). There was also a significant increase of factor VII coagulant activity (86 ± 31 vs 108 + 51%; p <0.05). Furthermore, mental stress caused an activation of the fibrinolytic system with an elevation of tissue plasminogen activator activity and tissue plasminogen activator antigen (0.80 ± 0.48 vs 1.23 ± 0.96 IU/ml; p = 0.076 and 4.38 ± 1.87 vs 5.78 ± 2.58 IU/ml; p <0.01). Fibrinogen concentration increased during stress (1.95 ± 0.29 vs 2.11 ± 0.27 g/1; p <0.05). Similar but more pronounced responses were observed during exercise and adrenaline infusion. Parallel to the increases in coagulation and fibrinolytic factors there were significant increases in heart rate, and systolic and diastolic blood pressure. It is concluded that mental stress has significant effects on plasma coagulation and fibrinolysis, and that it could thus affect important risk factors for cardiovascular disease.

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34CD38) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.

In idiopathic thrombocytopenic purpura (ITP), platelets are destroyed in the spleen, liver, and bone marrow (BM) by autoantibodies and cytotoxic T cells. In a DNA microarray screen of peripheral blood T cells, we found that VLA-4, CX3CR1, and CXCR4, involved in T-cell homing, had increased expression in ITP patients compared with controls. However, we only found increased protein expression of VLA-4 on T cells from peripheral blood by flow cytometry. To address a possible recruitment of T cells into the organs involved in platelet destruction, we analyzed T cells in BM. In BM, T-cell surface expression of VLA-4 and CX3CR1 was increased in ITP patients compared with controls. Furthermore, the number of CD3 ؉ T cells in BM, but not in blood, was increased in ITP patients compared with controls. This finding was confirmed by immunohistochemistry of BM biopsies. The number of regulatory T cells (CD4 IntroductionIdiopathic thrombocytopenic purpura (ITP) is an autoimmune disease where platelets are destroyed prematurely, mainly in the spleen, liver, and bone marrow. Besides the well-known autoantibody-mediated destruction of platelets in the reticuloendothelial systems, 1-4 several T-cell abnormalities have been identified in ITP. CD4 ϩ T-helper cells from ITP patients have been shown to secrete interleukin 2 (IL-2) upon stimulation with autologous platelets. 5,6 Clonal expansion of CD4 ϩ T-helper cells has also been reported, 7 and it has been shown that T cells from ITP patients can proliferate in vitro by GPIIb/IIIa stimulation. 8,9 We have previously demonstrated that platelets in ITP can be destroyed directly by CD8 ϩ T cell-mediated cytotoxicity, 10 and that activation-induced cell death (AICD) of T cells is impaired. 11 A CD8 ϩ T cell-mediated platelet lysis in ITP has also been reported by Zhang and coworkers. 12 We and others have shown that ITP during active phase is associated with a Th1 cytokine profile, 13,14 that is, secretion of interferon gamma (IFN-␥) and tumor necrosis factor alpha (TNF-␣), whereas remission is associated with an elevated level of transforming growth factor beta 1 (TGF-␤1), 14,15 that is, a Th3 profile.Recent studies of immune responses have revealed that cells respond to an activation signal with waves of coordinated gene expression that can be monitored by global expression profiling using DNA microarray technology. 16 The components of these responses are probably the key to understanding the specific mechanisms that lead to phenotypic differentiation. In the present study, we analyzed genes and proteins involved in T-cell trafficking, using DNA microarray technology and flow cytometry in chronic ITP patients. Methods SubjectsIn this study, a total of 26 chronic ITP patients were identified from our roster of ITP patients. All patients were treated at the Hematology Section at Sahlgrenska University Hospital in Gothenburg, Sweden. Besides a thorough history and physical examination, a bone marrow examination on biopsy and/or aspiration material was performed in all patients at pr...

No abstract

BackgroundMicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.MethodsHeparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells. MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).ResultsWe identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls. By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS. The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.ConclusionThese findings indicate that microRNA may be important regulatory molecules in T-cells in MS.

Previous studies have suggested that adherence to imatinib therapy can be an obstacle among patients with chronic myeloid leukemia (CML). We studied adherence to imatinib therapy among CML patients treated at the Sahlgrenska University Hospital. We identified all CML patients that were alive at the 1st of January 2010 (n = 70). Nineteen patients were excluded due to a history of allogenic hematopoietic stem cell transplantation, and nine were excluded due to treatment with other tyrosine kinase inhibitors. Thirty-eight out of 42 patients (90%) treated with imatinib accepted inclusion in the study. The patients were interviewed in a structured way, and adherence was evaluated in a standardized way using the nine-item Morisky Medication Adherence Scale that ranges from 1 to 13. A Morisky score ≤10 indicates nonadherence and ≥11 indicates adherence. In addition, predefined follow-up questions were asked to identify factors known to influence adherence to therapy. In contrast to previous studies, our patients showed good adherence to imatinib therapy with a mean Morisky score of 12.3 out of 13 (range, 9-13). The interviews revealed factors known to predict adherence to therapy, namely being well informed and having frequent contact with a single hematologist. Furthermore, the patients had easy access to the treating clinic and felt that they took part in decisions concerning their disease and treatment. We show that adherence to imatinib can be very good in CML patients, and we suggest that simple measures such as increased patient information and continuity of care will increase adherence in patients with CML.