The Influence of Human Neutrophils on N-nitrosodimethylamine (NDMA) Synthesis

N-nitrozodimethyloamine (NDMA) is a carcinogenic compound that can be formed in vivo. NDMA is synthesized from precursors-amines and nitrosating agents. Nitrosating agents are formed through the reaction of oxide, reactive oxygen species and nitric oxide (NO). Human neutrophils (PMN) are an important source of the most reactive oxygen species as well as of the nitric oxide. The increase in oxygen metabolism of PMN can lead to the increase nitrosating agent and nitroso-forms. Inflammatory process is associated with locally decreased pH that may favor nitrosation reaction.

In the present study, we estimated the NDMA synthesis by LPS-stimulated PMN in the presence of the iNOS inhibitor – N-nitro-L-arginine methyl ester (L-NAME). In the nitrosation reaction dimethylamine (DMA) was used as substrat. The viability of the cells was measured by cytometric method. NDMA concentrations the culture media was measured by GCMS method. NO production was estimated by Griess's method. Expression of iNOS was determined by western blotting.

Results obtained showed that DMA nitrosation is most effective in pH between 3–4.5. Nonstimulated PMN produced lower concentrations of NO than LPS-stimulated cells (1.27 μg/cm³ and 1.57 μg/cm³, respectively). In the culture of nonstimulated PMN supplemented with DMA, there was NDMA (mean – 0.99 ng/cm³). In the culture of LPS-stimulated PMN in the presence of DMA, the concentration of NDMA was higher than in the culture of nonstimulated PMN (median – 1.45 ng/cm³). In the supernatants of cells incubated without DMA and with DMA, LPS and L-NAME, no NDMA was detected. These results indicate that PMN can be one of sources of nitrosating agents and can play a role in endogenous NDMA synthesis. Stimulation of PMN can lead to the increase of NDMA concentration following the increase of NO production. Different pathological conditions associated with PMN activation as well as the decreased pH may favor endogenous NDMA synthesis.     

Masowe badania molekularne dla identyfikacji dawców ze słabą ekspresją antygenu D

One of the basic rules of transfusion is to prevent alloimmunisation by highly immunogenic RhD antigen and not to transfuse RhD negative individuals with RhD positive blood. In some cases the expression of this antigen is so weak that it is undetectable in routine serological tests. The paper presents an algorithm for mass DNA testing with the purpose of identifying donors with low RhD expression. The screening is based on RHD gene detection (absent in RhD negative Caucasians) in DNA isolated from pools of 96 plasma samples from blood donors identified as RhD negative by the routine serological methods in Blood Transfusion Centers. Such procedure substantially reduces the costs. Plasma samples can be brought from the territory of the whole country, stored and accumulated for testing in one selected center. The cost would amount to approximately 25 PLN per donor. The test is performed once for each RhD negative individual. It is estimated that such persons will represent approximately 0.2% of RhD negative donors.     

Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

Pain associated with the musculoskeletal system in children from Warsaw schools

Objective

To assess the prevalence of pain in the musculoskeletal system and possible reasons for these complaints among early age children from Warsaw schools.

Material and methods

The study was conducted in 34 randomly selected primary schools in Warsaw in 2011. 2748 survey-questionnaires were given to parents or legal guardians by children. Of these, 1509 surveys were subject to a final analysis. The survey included 66 questions regarding, among other things, pain in the musculoskeletal system in children. Additionally, there were questions about possibly occurring diseases, any postural defects, significant obesity, as well as effects of these complaints on the child''s physical activity. Survey data regarded 6–7-year-old children.

Results

In the group of 1509 respondents, 242 children (16%) complained about pain in the musculoskeletal system. Pain was located most frequently in the knee joints, and more rarely in the spine and joints in the upper extremities. In the group of children who complained about pain, moderate physical activity was statistically significantly limited. According to parents, physicians did not diagnose any medical conditions in 106 children. Joint disease was diagnosed in 33 children. Postural defects were diagnosed in 589 children. In 123 children complaining about pain at least one postural defect was diagnosed. Such defects were diagnosed statistically significantly more rarely (p = 0.011) in 1234 children who did not complain about pain (460 children). Platypodia or other foot deformation was observed in 25% of these children, spinal curvature in 12%, abnormal knee joint position in 11% and uneven hip position in 2% children. Of note, 17% of all children were significantly overweight. In overweight children the prevalence of pain, especially in the knee joints and feet, was significantly higher.

Conclusions

This study aims to underline the problem of musculoskeletal pain in early-age children which limits their physical activity. Also the authors draw attention to the issue of postural defects in a large group of school children. This issue undoubtedly requires more attention and a plan how to create more effective methods of prevention.     

Human intrathymic lineage commitment is marked by differential CD7 expression: identification of CD7- lympho-myeloid thymic progenitors

The identity and lineage potential of the cells that initiate thymopoiesis remain controversial. The goal of these studies was to determine, at a clonal level, the immunophenotype and differentiation pathways of the earliest progenitors in human thymus. Although the majority of human CD34(+)lin(-) thymocytes express high levels of CD7, closer analysis reveals that a continuum of CD7 expression exists, and 1% to 2% of progenitors are CD7(-). CD34(+)lin(-) thymocytes were fractionated by CD7 expression and tested for lineage potential in B-lymphoid, T-lymphoid, and myeloid-erythroid conditions. Progressive restriction in lineage potential correlated with CD7 expression, that is, the CD7(hi) fraction produced T and NK cells but lacked B and myelo-erythroid potential, the CD7(int) (CD10(+)) fraction produced B, T, and NK cells, but lacked myelo-erythroid potential. The CD7(-) fraction produced all lymphoid and myelo-erythroid lineages and expressed HSC-associated genes. However, CD34(+)lin(-)CD7(-) thymocytes also expressed early T lymphoid genes Tdt, pTalpha, and IL-7Ralpha and lacked engraftment capacity, suggesting the signals that direct lymphoid commitment and corresponding loss of HSC function are rapidly initiated on arrival of HSC in the human thymus. Thus, differential levels of CD7 identify the progressive stages of lineage commitment in human thymus, initiated from a primitive CD7(-) lympho-myeloid thymic progenitor.