Clonogenicity, gene expression and phenotype during neutrophil versus erythroid differentiation of cytokine-stimulated CD34 human marrow cells in vitro.

With the objective to correlate clonogenicity, gene expression and phenotype during differentiation, human bone marrow CD34+ cells were cultured in vitro to stimulate erythroid or neutrophil development, and sorted into five subpopulations according to their surface expression of CD15/CD33 and blood group antigen A/CD117 respectively. Sorted cells were cultured in methylcellulose and analysed by real-time reverse transcription polymerase chain reaction for expression of neutrophil and erythroid marker genes. Surface expression of CD15 coincided with restriction to neutrophil/monocyte differentiation and A antigen with restriction to erythroid differentiation. GATA-2 mRNA was down-regulated during both neutrophil and erythroid maturation, whereas GATA-1, SCL, ABO, erythropoietin receptor, Kell, glycophorin A, β-globin and α-haemoglobin stabilizing protein were up-regulated during erythroid differentiation and silenced during neutrophil differentiation. CCAAT/enhancer-binding protein (C/EBP)-α, PU.1, granulocyte colony-stimulating factor receptor, PR3, C/EBP-e and lactoferrin were sequentially expressed during neutrophil differentiation but rapidly down-regulated during the early erythroid stages. Nuclear factor erythroid-derived 2 (NF-E2) and glycophorin C were expressed both during neutrophil and erythroid differentiation. Our data support the notion of early expression of several lineage-associated genes prior to actual lineage commitment, defined by surface expression of CD15 and A antigen as markers for definitive neutrophil/monocyte and erythroid differentiation respectively. Previous findings, primarily from cell lines and mouse models, have been extended to adult human haematopoiesis

Decrease in sick leave among patients with rheumatoid arthritis in the first 12 months after start of treatment with tumour necrosis factor antagonists: a population-based controlled cohort study.

OBJECTIVE: /st> To investigate the effect of tumour necrosis factor (TNF) antagonist treatment of patients with rheumatoid arthritis (RA) on sick leave (SL) and disability pension (DP) in a population-based setting in southern Sweden. METHODS: /st> All patients with RA in the South Swedish Arthritis Treatment Group register living in the county of Skåne (population 1.2 million), who started their first treatment with a TNF antagonist between January 2004 and December 2007 and were 18-58 years at treatment start (n=365), were identified. For each patient with RA, four matched reference subjects from the general population were randomly selected. Data were linked to the Swedish Social Insurance Agency register and the point prevalence of SL and DP as well as days of SL and DP per month were calculated from 360 days before until 360 days after treatment start. RESULTS: /st> At treatment start 38.6% of the patients with RA were registered for SL. During the first 6 months this share dropped to 28.5% (decrease by 26.2%, p There was a marked decline in SL during the first 6 months of TNF antagonist treatment in patients with RA in southern Sweden, maintained throughout the first year, which was not offset by a corresponding increase in DP

The radical-binding lipocalin A1M binds to a Complex I subunit and protects mitochondrial structure and function.

Aims: During cell death, energy-consuming cell degradation and recycling programs are performed. Maintenance of energy-delivery during cell death is therefore crucial but the mechanisms to keep the mitochondrial functions intact during these processes are poorly understood. We have investigated the hypothesis that the heme- and radical-binding ubiquitous protein A1M (α1-microglobulin) is involved in protection of the mitochondria against oxidative insult during cell death. Results: Using blood cells, keratinocytes and liver cells, we show that A1M binds with high affinity to apoptosis-induced cells and is localized to mitochondria. The mitochondrial Complex I subunit NDUFAB1 was identified as a major molecular target of the A1M-binding. Furthermore, A1M was shown to inhibit the swelling of mitochondria, and to reverse the severely abrogated ATP-production of mitochondria when exposed to heme and ROS. Innovation: Import of the radical- and heme-binding protein A1M from the extracellular compartment confers protection of mitochondrial structure and function during cellular insult. Conclusion: A1M binds to a subunit of Complex I and has a role in assisting the mitochondria to maintain its energy delivery during cell death. A1M may also, at the same time, counteract and eliminate the ROS generated by the mitochondrial respiration to prevent oxidative damage to surrounding healthy tissue

Gene expression signatures in childhood acute leukemias are largely unique and distinct from those of normal tissues and other malignancies

<p>Abstract</p> <p>Background</p> <p>Childhood leukemia is characterized by the presence of balanced chromosomal translocations or by other structural or numerical chromosomal changes. It is well know that leukemias with specific molecular abnormalities display profoundly different global gene expression profiles. However, it is largely unknown whether such subtype-specific leukemic signatures are unique or if they are active also in non-hematopoietic normal tissues or in other human cancer types.</p> <p>Methods</p> <p>Using gene set enrichment analysis, we systematically explored whether the transcriptional programs in childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) were significantly similar to those in different flow-sorted subpopulations of normal hematopoietic cells (n = 8), normal non-hematopoietic tissues (n = 22) or human cancer tissues (n = 13).</p> <p>Results</p> <p>This study revealed that e.g., the t(12;21) [<it>ETV6-RUNX1</it>] subtype of ALL and the t(15;17) [<it>PML-RARA</it>] subtype of AML had transcriptional programs similar to those in normal Pro-B cells and promyelocytes, respectively. Moreover, the 11q23/<it>MLL </it>subtype of ALL showed similarities with non-hematopoietic tissues. Strikingly however, most of the transcriptional programs in the other leukemic subtypes lacked significant similarity to ~100 gene sets derived from normal and malignant tissues.</p> <p>Conclusions</p> <p>This study demonstrates, for the first time, that the expression profiles of childhood leukemia are largely unique, with limited similarities to transcriptional programs active in normal hematopoietic cells, non-hematopoietic normal tissues or the most common forms of human cancer. In addition to providing important pathogenetic insights, these findings should facilitate the identification of candidate genes or transcriptional programs that can be used as unique targets in leukemia.</p

Patient-reported outcomes in axial spondyloarthritis and psoriatic arthritis patients treated with secukinumab for 24 months in daily clinical practice

On behalf of the EuroSpA Scientific Committee, the authors acknowledge Novartis Pharma AG for supporting the EuroSpA collaboration.Peer reviewe

Network-Based Positioning Using Last Visited Cells Report

The positioning performance with the LVC (Last Visited Cells) report is evaluated and compared with extended reports with signal strength data. The LVC report contains cell identities and time spent in the last cells listened to. This is an off-line data source and the purpose of the positioning is to extract information about users’ whereabouts, which for example can be used to optimize the cellular network or vehicular traffic. The positioning evaluation is done in Matlab with a log-distance model, a fingerprinting algorithm, and a new LVC specific algorithm. A particle filter and a particle smoother is used to process simulated LVC reports and extended reports with different amount of information. The results are compared and evaluated with regard to the positioning accuracy and the information density of the reports

Network-Based Positioning Using Last Visited Cells Report

The positioning performance with the LVC (Last Visited Cells) report is evaluated and compared with extended reports with signal strength data. The LVC report contains cell identities and time spent in the last cells listened to. This is an off-line data source and the purpose of the positioning is to extract information about users’ whereabouts, which for example can be used to optimize the cellular network or vehicular traffic. The positioning evaluation is done in Matlab with a log-distance model, a fingerprinting algorithm, and a new LVC specific algorithm. A particle filter and a particle smoother is used to process simulated LVC reports and extended reports with different amount of information. The results are compared and evaluated with regard to the positioning accuracy and the information density of the reports

Anti-TNF therapy in rheumatoid arthritis. Effects on and predictors of work disability

Objectives: To study: (I) work-loss seen as sick leave and disability pension before and after the start of first anti-TNF therapy in Swedish regional and national RA cohorts; (II) baseline predictors of a good future work prognosis at diagnosis and after anti-TNF start with a special focus on the impact of the disease activity level and the disease duration at treatment start. Methods: RA patients were identified in the regional biologics register in Southern Sweden, SSATG, the national register over RA patients, SRQ, and the national biologics register, ARTIS, and linkage was performed to the Social Insurance Agency Register for day-level data on sick leave and disability pension. The development of these work-loss measures over selected time-periods after diagnosis and after anti-TNF start were then computed for patients and, in relevant cases, for matched reference subjects from the general population. Predictors were assessed by linear and logistic regression analysis as well as with survival analysis including Cox regression. Results: From start of the first anti-TNF therapy until 6 months after, a reduction in sick leave of almost 30% was seen in working-age RA patients. This was not due to secular trends and only to some extent offset by an increase in disability pension. Regarding cumulative 3-year work-loss after RA diagnosis, the most important predictor of a favorable prognosis was the baseline work ability level, but low HAQ-values, low values of the more subjective DAS28 components (VAS pain, VAS global and tender joint count) and high education level were also predictors of less future work-loss. We also reported that after first anti-TNF start no difference in the decline of work-loss over 5 years between patients with high vs. moderate disease activity (~40% in both groups) was seen. Furthermore, for patients lacking work ability at anti-TNF start, we could show that the chance of regaining all or some of it during 3 years of follow-up was 35% if they started treatment within 5 years of symptom onset, and less than half of that for later treatment starts. This effect seemed to be channeled through the impact of disease duration on disability pension status. Conclusion: Anti-TNF therapy seems to lower monthly work-loss levels during the first treatment year and a continuous decline is also seen over 5 years with no difference between patients starting treatment with high vs. moderate disease activity. Out of patients lacking work ability at anti-TNF start, those with less than 5 years disease duration are more likely to get it back. Thus, anti-TNF therapy seems to add positive outcomes for work ability to its favorable clinical effects in RA patients