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The connection of renewable energy sources with significant nominal power (in the order of MW) to the medium-voltage distribution grid affects the operating conditions of that grid. Due to the increasing number of installed renewable energy sources and the limited transmission capacity of medium-voltage networks, the cooperation of these energy sources is becoming increasingly important. This article presents the results of a six-year study on a 2 MW wind power plant and a 1 MW photovoltaic power plant in the province of Warmia and Mazury, which are located a few kilometers away from each other. In this study, active energy, currents, voltages as well as active, reactive, and apparent power and higher harmonics of currents and voltages were measured. The obtained results show the parameters determining the power quality at different load levels. Long-term analysis of the operation of these power plants in terms of the generated electricity and active power transmitted to the power grid facilitated estimating the repeatability of active energy production and the active power generated in individual months of the year and times of day by a wind power plant and a photovoltaic power plant. It also allowed us to assess the options of cooperation between these energy sources. It is important, not only from a technical but also from an economic point of view, to determine the nominal power of individual power plants connected to the same connection point. Therefore, the cooperation of two such power plants with the same nominal power of 2 MW was analyzed and the economic losses caused by a reduction in electricity production resulting from connection capacity were estimated. [ABSTRACT FROM AUTHOR]

We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other. [ABSTRACT FROM AUTHOR]

A Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) case was maintained in remission with the use of chemo-immunotherapy. The latter involved sibling bone marrow transplant (BMT) (three procedures) followed by intravenous (IV) donor lymphocyte infusion (DLI). The third relapse responded to routine chemotherapy and again DLI was employed. During hematological and molecular remission verified at the level of iliac crest aspiration, extra-medullary relapse in the bones was apparent. A novel procedure of donor lymphocyte injection to the bone leukemic lesions was developed and employed. A dose of 106 donor lymphocytes/kg body weight (BW) of the recipient were each time injected to the plane of the right and left tibia, the head of the humerus, and the calcaneus, which resulted in healing of the destructive process. In consequence of this novel approach, in addition to the healing of bone lesions, an accumulation of cytotoxic activated T-cells in the marrow was documented, which was mirrored by an increase in the number of transcripts for interferon (IFN)- γ, interleukin (IL)-17, as well as ROR γt. The local administration of DLI directly to the leukemic lesions requires a lower dose that diminishes the toxicity due to the general immune system activation. [ABSTRACT FROM AUTHOR]

Abstract: Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen. [Copyright &y& Elsevier]

Acute graft-versus-host disease (aGvHD) is a major complication after hematopoietic stem cell transplantation (HSCT) and severity of aGvHD is associated with biological and genetic factors related to donors and recipients. Studies on inflammatory pathways involved in aGvHD have shown a significant impact of the gut microflora on aGvHD development giving increasing evidence in the understanding of the response of innate and adaptive immunity to microbial products. Cytokine deregulation may increase or reduce the risk of aGvHD. Damage of tissues affected by aGvHD reflects the immunological cascade of events in this disease. [ABSTRACT FROM AUTHOR]

This article presents a method for selecting the elements of a C-type filter working with a conventional LC-type filter for compensating reactive power and filtering out higher harmonics generated by arc furnaces and ladle furnaces. The study was conducted in a steel mill supplied by a 110 kV transmission system, where higher harmonic currents and nonlinear loads were measured. A series of computer simulations were performed under various operating conditions, and an algorithm for selecting the parameters of a third-order C-type filter (for suppressing the second harmonic) and two second-order LC-type filters (for suppressing the third harmonic) was proposed. The filtering system was tested in an arc furnace with the highest rated power, and harmonics in the current spectrum were evaluated. The results of the measurements were used to analyze the effectiveness of the compensation system comprising two passive C-type and LC-type filters at different system configurations. C-type filters significantly influenced current harmonics. The influence of the changes in the number of arc furnace transformers on the true Root Mean Square (RMS) of the currents injected into the 110 kV transmission system and on the voltages of the 110 kV busbars was discussed. [ABSTRACT FROM AUTHOR]

This paper concerns the effects of electrodynamic forces that act on current paths that are part of high-grade industrial distribution switchgear. This work is composed of experimental and simulation sections. In the experimental section, the short-circuit tests are presented and the occurrence of electrodynamic forces are shown in a visible way. The formation of electrodynamic forces in the current circuits of electrical energy distribution systems is related to the flow of high currents, but mostly it is related to short-circuit currents. In order to highlight these phenomena, the detailed specification of the parameters during tests is displayed. In the simulation section, the physical phenomenon of electrodynamic forces is being captured by employing a detailed real-scale model of switchgear and current paths. Therefore, the authors proposed employment of the FEM (finite element method) in order to obtain values of electrodynamic forces acting on the current paths by executing the detailed 3D coupled simulation. The analysis of the results and aftermath effects of their interactions provided interesting conclusions that concerned the operation of such power distribution layouts in critical short-circuit conditions. [ABSTRACT FROM AUTHOR]

Introduction: Vascular endothelial growth factor (VEGF) is an angiogenic cytokine and a potential stimulator of permeability and lung neovascularization in asthmatics. It also plays an important role in the development of airway remodelling and in activation of many cells, including basophils. Aim: To reveal the possible role of VEGF in the activation of basophils in asthmatics - subgroups with and without irreversible bronchoconstriction. Protein CD203c on the basophils surface was used as the activation marker. To define the possible pathway of basophils VEGF-activation, the influence of a genetic factor (polymorphism del18/ins -2549 -2567 in the VEGF-promoter region) was also considered. Material and methods: Our study involved 82 patients with asthma (40 patients without and 42 patients with irreversible bronchoconstriction) and a group of 40 controls. The flow cytometric methods with anti-CD203c in the samples of basophils with increasing concentrations of VEGF was used for analysis of their activity. Genotyping for VEGF-promoter region was performed by PCR-based methods. Results: Patients with asthma and del/del genotype showed more significant differences in the basophils activation after stimulation with increasing concentrations of VEGF than asthmatics with ins/ins and ins/del genotype (p = 0.023) and controls with del/del genotype (p = 0.0006). Conclusions: Raised basophils VEGF-activation is characteristic for examined patients with asthma and might be associated with presence of polymorphism del18/ins -2549 -2567 in the VEGF-promoter region. Furthermore, it may contribute to the development of airways remodelling - this pathway has not been considered yet. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editors discuss various topics within the issue including genetic and non-genetic factors which affect the outcome of the hematopoietic stem cell transplantation (HSCT).

This paper focuses on determining the effects of short-circuit current values on the operation of high-voltage substations. The analyses performed focused on the dynamic and thermal effects on the short-circuit current for different input data configurations. The analyses of the dynamic effects of short-circuit current were performed in two ways. First, calculations were executed using the procedures contained in "IEC 60865-1:2012 Short-circuit currents, calculations of the effects of short-circuit currents. Part 1: Definitions and calculation methods". Analytic calculations were accomplished for different values of the initial three-phase short-circuit current, the type of short circuit, the static tension force of the conductors, the stiffness of the structure and the methods of attaching the lashing chains. Secondly, the same analysis was performed using PRIMTECH 3D software. The connections were modeled in computer software, for which the calculations were implemented according to normative recommendations. After obtaining the results, an analysis was performed using the model based on the input data. Performing the analysis in two ways made it possible to compare the results with each other and develop conclusions. An analysis of the thermal effects of the short-circuit current was also provided. The results of the calculations showed that the choice of conductor cross sections according to the value of the initial short-circuit current was correct. Particular attention has been paid to rigid conductors and flexible conductors, which are directly affected by the short circuit and have an impact on the selection of the complete equipment for the high-voltage switchgear. [ABSTRACT FROM AUTHOR]

Mixed lymphocyte culture (MLC) response was measured with the use of Ki-67 monoclonal antibody and responding cells were verified by CD3 and CD56 surface markers staining. Stimulator cells were discriminated from responder cells on the basis of forward and side scatter. Allogeneic, but not autologous MLC had Ki-67+ responder cells in lymphocyte gate at the end of the culture. In allogeneic MLC T cells and natural killer (NK) cells were in a similar proportion Ki-67+ (mean ± SD: 59.25% ± 9.72% versus 61.75% ± 13.2%). Ki-67+ NK cells had higher CD56 mean fluorescence intensity than those lacking Ki-67 (745±357 versus 196±56 p < 0.0001). NK cells contribution to responding lymphocytes was positively correlated with the percentage of Ki67+ cells in NK population by the end of the culture (r = 0.74, p = 0.002). NK cells response in MLC increased upon supplementation of the culture medium with human recombintant interleukin-2 (IL-2). Responder cells from single individual were tested with 8 Bw4+ and 8 Bw4- as well as with 9 CNK1+ and 9 CNK1- stimulators. In IL-2 supplemented MLC killer inhibitory receptor expressing cells expanded when ligands for this receptor were absent in stimulating population. Consequently, stimulator cells lacking Bw4 promoted NKB1+ cells expansion (7.2% ± 3% versus 3.6% ± 1%, p = 0.0031), whereas HLA-C NK1 negative stimulators promoted CD158a+ cells expansion (9.6% ± 4.8% versus 6% ± 2.6%, p = 0.0385). [Copyright &y& Elsevier]

Network working conditions are influenced noticeably by the connection of renewable energy sources to distribution networks. This becomes more and more important due to the increase in renewable energy source penetration over the last few years. This in turn can lead to a mass effect. As a result, the classical open network model with simple unidirectional direction of energy flow has been replaced with an active model that includes many local energy sources. This paper deals with the analysis of long- and short-term changes in power and energy generated by three types of renewable energy sources with similar rated power and which operate in the same region (i.e., located no more than tens of kilometers away). The obtained results can be a starting point for a broader evaluation of the influence of renewable energy sources on power quality in power systems, which can be both positive (supply reliability) and negative (voltage fluctuations and higher harmonics in current and voltage waveforms). It is important not only to correctly place but also to assure the diversity of such sources as it has been confirmed by the source variability coefficient. The long-term analysis allows us also to estimate the annual repeatability of energy production and, furthermore, the profitability of investment in renewable sources in a given region. [ABSTRACT FROM AUTHOR]

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L ( p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency. [ABSTRACT FROM AUTHOR]

Background: Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. Methods: DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27-360 days (mean 126) after HSCT and from the donors shortly before the HSCT. Results: It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4x10-8 ) and predicted age (r = 0.97, p = 5x10-10 ) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 x 10-4 ). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 x10-4 ). This finding could not trivially be explained by shifts of the major cellular factions of blood. Conclusions: We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient's blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation from anti-cytomegalovirus immunoglobulin G (anti-CMV-IgG) positive donors facilitated immunological recovery post-transplant, which may indicate that chronic CMV infection has an effect on the immune system. This can be seen in the recipients after reconstitution with donor lymphocytes. We evaluated the composition of lymphocytes at hematologic recovery in 99 patients with hematologic malignancies post hematopoietic stem cell transplantation (HSCT). Anti-CMV-IgG seropositivity of the donor was associated with higher proportions of CD4+ (227.963 ± 304.858 × 106 vs. 102.050 ± 17.247 × 106 cells/L, p = 0.009) and CD4+CD25high (3.456 ± 0.436 × 106 vs. 1.589 ± 0.218 × 106 cells/L, p = 0.003) lymphocytes in the blood at hematologic recovery. The latter parameter exerted a diverse influence on the risk of acute graft-versus-host disease (GvHD) if low (1.483 ± 0.360 × 106 vs. 3.778 ± 0.484 × 106 cells/L, p < 0.001) and de novo chronic GvHD (cGvHD) if high (3.778 ± 0.780 × 106 vs. 2.042 ± 0.261 × 106 cells/L, p = 0.041). Higher values of CD4+ lymphocytes in patients who received transplants from anti-CMV-IgG-positive donors translated into a reduced demand for IgG support (23/63 vs. 19/33, p = 0.048), and these patients also exhibited reduced susceptibility to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and/or human herpes 6 virus (HHV6) infection/reactivation (12/50 vs. 21/47, p = 0.032). Finally, high levels (⩾0.4%) of CD4+CD25high lymphocytes were significantly associated with better post-transplant survival (56% vs. 38%, four-year survival, p = 0.040). Donors who experience CMV infection/reactivation provide the recipients with lymphocytes, which readily reinforce the recovery of the transplanted patients' immune system. [ABSTRACT FROM AUTHOR]

Background: CXCR4 chemokine receptor is constitutively expressed on normal and malignant B lymphocytes derived from patients with B-cell lymphoproliferative disorders and has a significant role in cell migration to lymph nodes and bone marrow. Non-Hodgkin's lymphomas (NHL) constitute a heterogeneous group of lymphoproliferative diseases, which can localize not only to lymph nodes, but also can migrate to peripheral blood and metastase to other organs, including bone marrow. Aim: The purpose of this study was to determine CXCR4 gene expression in peripheral blood and bone marrow of NHL patients before and after treatment. Methods: Samples of lymphoma lymph nodes, peripheral blood and bone marrow aspirates of patients with B-cell NHL were taken at diagnosis and after chemotherapy. Gene expression was determined by the reverse transcription (RT)-polymerase chain reaction method. Expression was estimated from 0 AU (no amplificate signal) to 3 AU (maximal amplificate signal). Results: No significant difference in the level of CXCR4 expression was found in reactive lymph nodes compared to lymphoma samples We observed high level of CXCR4 expression in most patients before treatment: in bone marrow: 3 AU-10 pts, 2 AU–8 pts, 1 AU–2 pts. In peripheral blood: 3 AU–14 pts, 2 AU–4 pts, 1 AU–1 pts, 0 AU–1 pts. After chemotherapy, significant decrease in CXCR4 expression was observed. Bone marrow: 3 AU–5 pts, 2 AU–7 pts, 1 AU–5 pts, 0 AU–3 pts (p = 0.03). Peripheral blood: 3 AU–2 pts, 2 AU–6 pts, 1 AU–10 pts, 0 AU–2 pts (p = 0.0002). There was a good response to treatment in patients with significant decrease of CXCR4 expression in the bone marrow after treatment with 10-fold lower risk of death (p = 0.03). Conclusions: Decrease in CXCR4 expression in the bone marrow of NHL patients after chemotherapy may be a good prognostic factor. [ABSTRACT FROM AUTHOR]

Abstract: Peripheral blood mobilized by cytokines (i.e. granulocyte colony stimulating factor, G-CSF) and chemotherapy has become a major source of hematopoietic stem and progenitor cells for transplantation (PBPCT). In this study the effect of the G-CSF receptor (CSF3R) gene polymorphism was investigated. The presence of the CSF3R variant (T allele, rs3917924) was related to CD34+ mobilization yield and the pace of granulocyte recovery after autologous PBPCT. The mobilization yield was higher in patients lacking the CSF3R variant (OR=4.756, p =0.046) and those with multiple myeloma (OR=10.534, p =0.019). The pace of granulocyte recovery was found to be associated with the CSF3R polymorphism and was significantly slower in patients carrying the CSF3R-T variant than in CC homozygotes (median of 17 vs. 13days, p <0.001). This association was confirmed (OR=4.445, p =0.014) by multiple regression analysis considering patient age and sex, the number of transplanted CD34+ cells, diagnosis and CSF3R polymorphism. These results imply that CSF3R gene polymorphism plays a significant role in PBPCT. [Copyright &y& Elsevier]

Eighty-six patients suffering from hematological malignancies, immunodeficiencies, and aplastic anemias received alloHSCT from unrelated donors. Donors were selected from the BMDWfiles and further matching was performed according to the confirmatory typing procedure with the use of PCR SSP and that based on sequencing. The time from the clinical request of the donor search to the final decision of clinicians accepting the donor was from 0.3 to 17.8 months (median 1.6). Matching was analyzed at the allele level, and 50, 27, and 9 donor-recipient pairs were 10/10 matched, mismatched in one ormore alleles, respectively. In an univariate analysis we found better survival if patients were transplanted: (i) from donors matched 10/10 (P = 0.025), (ii) not from female donor to male recipient (P = 0.037), (iii) in female donation from those with ⩽1 pregnancy than multiparous (P = 0.075). Notably, it became apparent that duration of the confirmatory typing process affected the survival (HR = 1.138, P = 0.013). In multivariate analysis only the level of matching and the duration of the matching procedure significantly affected the survival. In conclusion, the duration of the matching procedure in addition to the level of matching should be considered as an independent risk factor of survival. [ABSTRACT FROM AUTHOR]

Although anti-human leukocyte antigen antibodies (anti-HLA Abs) are important factors responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complications, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been finally defined. Enormous polymorphism of HLA-genes, their immunogenicity and heterogeneity of antibodies, as well as the growing number of allo-HSCTs from partially HLA-mismatched donors, increase the probability that anti-HLA antibodies could be important factors responsible for the treatment outcomes. We have examined the incidence of anti-HLA antibodies in a group of 30 allo-HSCT recipients from HLA-mismatched unrelated donors. Anti-HLA Abs were identified in sera collected before and after allo-HSCT.We have used automated Dyna Chip assay utilizing microchips bearing purified class I and II HLA antigens for detection of anti-HLA Abs. We have detected anit-HLA antibodies against HLA-A, B, C, DR, DQ and DP, but no donor or recipient-specific anti-HLA Abs were detected in the studied group. The preliminary results indicate that anti-HLA antibodies are present before and after allo-HSCT in HLA-mismatched recipients. [ABSTRACT FROM AUTHOR]

CMV donor/recipient serostatus was analyzed in 200 patients allografted in our institution from unrelated (122 patients) donors and 78 sibling donors in the years 2002-2011 in relation to posttransplant complications. On a group basis independently of the CMV serostatus of donor-recipient pairs sibling transplantations and those from unrelated donors that matched 10/10 at allele level had a similar rate of CMV reactivation (17/78 versus 19/71, P = ns). The rate of CMV reactivation/infection was higher in patients grafted from donors accepted at the lower level of matching than 10/10 (18/38 versus 36/149, P = 0.008). The incidence of a GvHD followed frequencies of CMVreactivation in the tested groups, being 40/156 and 25/44 in patients grafted fromsibling or unrelated donors that 10/10 matched and in those grafted from donors taht HLA mismatched, respectively (P = 0.001). Regarding the rate of reactivation in both groups seropositive patients receiving a transplant from seronegative donors had more frequently CMV reactivation as compared to those with another donor-recipient matching CMV serostatus constellation (22/43 versus 32/143, P = 0 < 0.001). Multivariate analysis revealed that seropositivity of recipients with concomitant seronegativity of donors plays an independent role in the CMV reactivation/infection (OR = 2.669, P = 0.037; OR = 5.322, P = 0.078; OR = 23.034, P = 0.023 for optimally matched and mismatched patients and the whole group of patients, resp.). [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4+ lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 105 peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with ≥ 100 CMV copies/105 cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/105 cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with ≥ 100 CMV copies/105 cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4+ lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4+ lymphocytes (0.62 vs 0.21, P = .001; mean ± SEM, 4422 ± 1667 vs 937 ± 662 CMV copies/105 cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 ± 1699 vs 950±591 CMV copies/105 cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4+ lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor–recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies. [Copyright &y& Elsevier]

The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid ( n = 459) and lymphoblastic ( n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 ± 2%, 19 ± 2%, and 23 ± 2%, respectively. The cumulative incidence of NRM decreased from 22 ± 2% for patients treated between 1990 and 2002 to 15 ± 3% for transplantations performed between 2003 and 2006 ( p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous. [ABSTRACT FROM AUTHOR]

Irreversible airflow obstruction may develop in some cases of asthma even in absence of known risk factors such as smoking and environmental insults and despite implementing apparently appropriate therapy. This implies that genetic factors may significantly contribute to determining the severity in the course of the disease. The published reports on genetic predisposition to irreversible bronchoconstriction in asthma, however, are relatively scarce, and disregard its potential association with transforming growth factor (TGF)-β1 gene polymorphism despite established role that TGF-β1 plays in airway remodelling. We tested TGF-β1 single-nucleotide polymorphisms (SNPs) at position +869 of codon 10 (leucine or proline) and position +915 of codon 25 (arginine or proline) for association with irreversible bronchoconstriction in a case–control study involving 110 patients with asthma and 109 controls. Multivariate logistic regression analysis revealed that genotype G/G at codon 25 was significantly associated with irreversible bronchoconstriction in asthmatics (odds ratio = 4.44; 95% confidence interval: 1.00–19.61; P = 0.05), but only after adjustment for gender, disease duration and smoking index. The influence of SNPs at codon 10 on irreversible airway obstruction was not significant. Our results suggest that presence of SNP (+915G/G) at codon 25 in TGF-β1 gene may predispose to the development of irreversible bronchoconstriction in asthmatic patients, but only when coincident with the male gender, habitual smoking and relevant duration of the disease. [ABSTRACT FROM AUTHOR]

The treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4-2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17–60 years), 116 patients were suitable for analysis. MRD level ≥0·1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population ( P < 0·0001), as well as in the standard risk (SR, P = 0·0003) and high-risk ( P = 0·008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0·1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects ( P = 0·001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL. [ABSTRACT FROM AUTHOR]

The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carbo- platin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m2, paclitaxël at 175 mg/m2, and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% Cl = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% Cl = 67% to 87%] and n = 48 [68%, 95% Cl = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High- ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade 2 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High- ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold. [ABSTRACT FROM AUTHOR]

Abstract: Non-Hodgkin''s lymphomas (NHL) constitute a heterogenous group of mainly B-cell lymphoproliferative diseases with different patterns of clinical behaviour. Biological mechanisms leading to development of NHL are not clearly understood. Transforming growth factor-beta1 (TGF-β1) influences B cell growth and development. The present study aimed to determine whether there is an association between the polymorphic features located within the TGF-β1 gene in NHL patients and progression of the disease. Two single nucleotide polymorphisms at positions 869 T/C (Leu10Pro) and 915 G/C (Arg25Pro) in the precursor region of the TGF-β1 gene were determined in 55 NHL patients and 50 healthy individuals by PCR-SSP technique using commercial primers. In univariate analysis the presence of TGF-β1 high producer genotypes (T/T G/G or T/C G/G) was found to significantly associate with an increased number of extranodal sites (11/30 vs 3/25, p =0.035 for two or more extranodal sites in patients having or lacking the TGF-β1 high producer genotype, respectively). TGF-β1 high producer genotype together with other clinical and biological factors (patient sex and age, stage and aggressiveness of the disease, presence of B symptoms, serum LDH level) were subjected to multivariate logistic regression analyses for the number of extranodal sites. Multivariate analysis confirmed the role of TGF-β1 high producer genotype as a risk factor of NHL manifestation in two or more extranodal sites (OR=7.217, p =0.043) in addition to histological aggressiveness of the disease (OR=4.302, p =0.057). TGF-β1 gene polymorphisms were found to associate with the course of the disease in NHL patients. TGF-β1 high producer genotype appeared as an independent risk factor of extranodal manifestation of the disease. [Copyright &y& Elsevier]

Recent studies have shown that interferon- γ gene ( IFNG) polymorphism constitutes a risk factor for acute and chronic graft- versus-host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (HSCT). Patients with IFNG 3/3 have been found to be more prone to GvHD. This rather puzzling result, as 3/3 genotype is associated with a decreased IFN- γ production, was investigated in the present study in the context of Epstein–Barr virus (EBV) reactivation. Microsatellite polymorphism (CA) n within the first intron of IFNG gene was assessed in 83 HSCT recipients and related to EBV load. Quantification of EBV copies was performed by a real-time polymerase chain reaction in peripheral blood cells taken from the patients 2–3 months after HSCT. It was found, that patients having IFNG 3/3 genotype presented with a high number of EBV copies (over 10/105 blood cells) when compared with the recipients with other IFNG genotypes (10/14 vs. 17/69, P < 0·001). This association was independent of recipient's age, underlying disease, conditioning regimen, type of donor, source of stem cells or pretransplant donor and recipient EBV serological status. Thus IFNG 3/3 genotype, known to be associated with a decreased IFN- γ production, appeared as a factor significantly contributing to the risk of EBV reactivation after allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to determine existing associations between single nucleotide polymorphisms within the promoters of interleukin (IL)-6 (-174 G/C) and IL-10 (-1082 G/A, -819 C/T, -592 C/A) genes and the outcome of allogeneic sibling hematopoietic stem cell transplantation. Ninety-three recipients and 74 donors were typed for IL-6 and IL-10 alleles by polymerase chain reaction-sequence specific primer. Then, IL-6 activity in patient serum and the concentration of C-reactive protein were analyzed at various times after transplantation in relation to transplant complications and IL-6 genotype. IL-6 activity in serum was significantly higher in patients who died as a result of toxic complications and after the 6 weeks after transplantation in patients with severe acute graft-versus-host disease (aGVHD). Recipient IL-6 G genotype was associated with increased IL-6 activity and C-reactive protein production. In univariate analyses, recipient IL-6 G and donor IL-6 GG associated or tended to associate with increased risk for aGVHD. In contrast, recipient IL-10 GCC/GCC and donor IL-10 ACC decreased the risk of aGVHD. IL-6 and IL-10 polymorphic features, together with other factors known to affect the risk of aGVHD, were also subjected to multivariate analyses. These analyses confirmed the independent contribution of recipient IL-10 GCC/GCC (odds ratio = 0.085, p = 0.046) and donor IL-6 GG (odds ratio = 3.934, p = 0.034) genotypes to the risk of aGVHD. [Copyright &y& Elsevier]

Abstract: Multiple myeloma (MM) is a plasma cell malignancy characterised by bone marrow infiltration and the presence of a monoclonal protein in serum and/or urine. Interleukin-6 (IL-6) has been identified as one of the most important cytokines that contributes to myeloma cell survival and proliferation. Recent investigations suggest involvement of another cytokine, IL-10, in the activation of MM cells. The present study aimed to determine whether there is an association between the polymorphic features located within the promoter regions of IL-6 and IL-10 genes and progression the disease. IL-6 (-174 G/C) and IL-10 (-1082 A/G, -819 C/T, -592 A/C) promoter single nucleotide polymorphisms (SNPs) were determined by PCR-SSP technique using commercial primers. Our single centre results were compared with the data from literature and combined in cumulative analysis employing the Mantel-Haenszel method. In univariate analysis, only IL-10 ACC genotype tended to prevail in our (Polish) group of patients. None of IL-6 genotypes or IL-10 (-1082) alleles was found to associate with MM disease either in our single centre or in cumulative study. Among patients who died within 36 months of diagnosis, a significant prevalence (P < 0.05) of IL-6 heterozygous cases as opposed to IL-6 homozygotes was observed. IL-6 and IL-10 promoter gene polymorphisms were not found to associate with the susceptibility to the development of MM. However, the IL-6 polymorphic features appeared as factors that might affect the survival of MM patients. The latter observation warrants further study. [Copyright &y& Elsevier]

In the present study, short tandem repeats (STR) polymorphism within the first intron of IFN-gamma gene in connection with HLA-DRB1*03 specificities was analysed in 43 sarcoidosis patients, 14 of which presented with Lo¨fgren’s syndrome (LS). Four out of 5 known IFN-gamma alleles with 12–15 CA repeats, respectively were detected in sarcoidosis patients. IFN-gamma 3,3 homozygosity was found to constitute a risk factor associating with LS manifestation (0.50 versus 0.19, OD=4.18, P=0.014). As expected, DRB1*03 prevailed in LS cases (9/14 versus 7/29, P=0.014 LS versus non-LS cases and 9/14 versus 35/162, OD=6.20, P=0.001, LS patients versus controls). However, we also showed the presence of a combined association between DRB1*03 and IFN-gamma 3,3 in sarcoidosis (P=0.017) and LS patients (P=0.001). [Copyright &y& Elsevier]

Abstract: Objectives : The aim of this study was to assess the suitability of a technique based on counter-flow centrifugal elutriation (CCE), which should allow one to enrich chronic myeloid leukemia (CML) patients' unstimulated native leukapheresis product (nLP) in CD34 + HLADR – cells and BCR-ABL negative cells. Methods : Six newly diagnosed CML patients were subjected to leukapheresis, and the products were subfractionated with the use of CCE. nLP and all fractions were studied for the presence of CD34 + cells and a proportion of BCR-ABL fluorescence in situ hybridization (FISH) + cells. Results : CCE fractions with a high flow rate contained the highest proportion of CD34 + cells [mean (SEM) 6.89% (3.88)]. However, CD34 + cells present in low-rate CCE fractions showed a higher proportion of HLADR – [49.6% (13.5 in 70 mL min -1 ) and 21.5% (11.6 in 110 mL min -1 )] than those in 170 mL min -1 [3.2% (2.5)] and ‘rotor off’[3.4% (1.9)]. This was associated with lower proportions of BCR-ABL FISH + [8.1% (4.8) and 1.9 (1.7)] and smaller BCR-ABL to ABL transcript ratios [0.58 ( 17 ) and 0.26 (0.08) in 70 and 110 mL min -1 ] fractions as compared to 140 and 170 mL min -1 fractions [21.6% (5.2) and 31.6% (15.3) for BCR-ABL FISH + cells and 0.75 (0.16) and 0.90 (0.24) for BCR - ABL / ABL ]. Fractions with the lowest proportions of BCR - ABL -positive cells and the lowest BCR - ABL / ABL transcript ratios (110 mL min -1 ) contained from 1.3 × 10 6 to 82.7 × 10 6 (median: 3.97 × 10 6 ) CD34 + cells. Conclusions : In the present study we have shown that CCE may be used effectively to obtain nLP fractions enriched in normal hematopoietic progenitors. [ABSTRACT FROM AUTHOR]

Cytokine storm described in patients after allogeneic haematopoietic stem cell transplantation (alloHSCT) is associated with the appearance of CD14 + HLADR - in the blood. To study the role of CD14 + HLADR - cells 223 patients after alloHSCT followed from 1 month to 15 years. The methods used included flow cytometry for blood cells profiling, nucleic acid tests for viral reactivation, and physician care according to the Polish and international guidelines. We found that CD14 + HLADR - peak values determined during the first 60 post-transplant days were higher in the patients who died than in those who survived in this time interval (mean ± SEM: 3.78 ± 0.67% vs 2.38 ± 0.65%, p < 0.001). Receiver operating characteristic (ROC) analysis showed that CD14 + HLADR - cells level in the blood at cut-off point at 0.71% discriminated the patients as to survival; the patients above the threshold had poorer survival (Kaplan-Meier curve covering 15-year observation) than those below (0.19 vs 0.46, p < 0.001). Infections prevailed other causes of death in the high blood CD14 + HLADR - group (0.61 vs 0.38, p = 0.057). ROC analysis defined the CD4+ blood level at 17.70% as not significantly associated with survival. Multivariate analysis revealed that CD14 + HLADR - cells (HR = 3.47, p < 0.001) and the presence of acute graft-versus-host disease (aGvHD) grade ≥ 3 (HR = 3.82, p = 0.005) adversely impacted the survival. CD14 + HLADR - cells can serve as a biomarker for the risk of fatal complications frequently associated with infections. • Overwhelming inflammation contributes to the pathomechanism of complications after alloHSCT. • CD14 + HLADR-cells appear in the blood of alloHSCT patients experiencing overproduction of cytokines. • The presence of CD14 + HLADR- cells is predictive of unfavourable post-transplant course. • The patients they died post-transplant have higher levels of CD14 + HLADR- cells than those who survived. • The cells, if increase may rise alert witnessing immunosuppression and in consequence heralding infectious complications. [ABSTRACT FROM AUTHOR]