The kinetics of hematopoietic niche cytokines and their influence on mobilization efficacy and timing in patients with hematological malignancies.

The bone marrow niche functions are modulated by complicated cytokines network. The aim of our study was to evaluate the levels of VCAM-1, VEGF, MMP-9 and SDF during mobilization of CD34+ cells in patients with hematological malignancies. Thirty four patients were enrolled to the study (19F, 15 M) at median age of 57 years. The group consisted of patients with multiple myeloma (26) and lymphoma (8). The mobilization procedures comprised chemotherapy and then G-CSF. Blood samples were collected before chemotherapy (N = 34) and on the day of the first apheresis (N = 26). Cytokines were evaluated with ELISA assay. We observed significant increase in VCAM-1 levels during mobilization. On contrary, VEGF and SDF levels decreased during mobilization procedure. The levels of MMP-9 were stable during mobilization. We divided patients according to baseline cytokines levels below and above median into "low" and "high" expressors. The group of VEGF "low" expressors had longer median time of G-CSF treatment before first apheresis than 'high' expressors. Baseline VEGF levels correlated adversely with duration of G-CSF treatment before first apheresis. Patients were also divided according to median cytokines levels at apheresis into "low" and "high" expressors. "High" VCAM-1 expressors had higher CD34+in peripheral blood as well as higher CD34+numbers collected during first apheresis than "low" expressors. In conclusion, the levels of niche cytokines change significantly during mobilization in patients with hematopoietic malignancies. Baseline VEGF can influence timing of mobilization. Higher VCAM-1 corresponds with higher mobilization efficacy.

Polymorphism of CD44 influences the efficacy of CD34(+) cells mobilization in patients with hematological malignancies.

In the last decade, peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous and allogeneic transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand-receptor interactions of adhesion molecules, such as SDF1/CXCR4, VLA4/VCAM-1, or CD44/osteopontin, play an important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. We enrolled 110 patients (60 females and 50 males) in the study. The median age of the patients was 55 (range, 22 to 69) years. The group consisted of patients with multiple myeloma (n = 74), non-Hodgkin lymphoma (n = 19), Hodgkin lymphoma (n = 15), or acute myeloid leukemia (n = 2). The mobilization procedures comprised chemotherapy and subsequent granulocyte-colony stimulating factor (G-CSF) at a dose of 10 µg/kg daily. The poor mobilizers group was defined according to Italian National Bone Marrow Transplant Registry criteria: patients with peak CD34(+) in the peripheral blood < 20/µL or total yield < 2 × 10(6) CD34(+) cells/kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N = 108) who achieved minimal threshold for collections (CD34(+) at least 10/µL) proceeded to apheresis. The median total yield of CD34(+) in this group was 5.6 × 10(6) cells/kg body weight, whereas the median number of cells collected during the first apheresis was 3.3 × 10(6) cells/kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for poor mobilizer. The group of poor mobilizers had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT versus TT P = .047). Patients homozygous for T allele had a lower total yield of CD34(+) cells/kg body weight than the group with allele C (median, 3.7 × 10(6)/kg versus 5.8 × 10(6)/kg; P = .019) and a lower number of CD34(+) cells gathered during first apheresis (.95 × 10(6)/kg versus 3.3 × 10(6)/kg, P = .04). Multivariate logistic regression analysis revealed that the CD44 TT genotype was the only factor associated with 5-fold higher risk of poor mobilization (P = .037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. In conclusion, our results indicate that among investigated single nucleotide polymorphisms (SNPs), only CD44 rs13347 has an impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting the poor mobilizers population who may benefit from newer modalities using adhesion molecules inhibitors.

The Clinical Outcome of Cardiac Rehabilitation in Coronary Artery Disease Patients with Regard to the Presence of Left Ventricular Systolic Dysfunction.

Background: Despite the use of advanced treatment techniques, coronary artery disease (CAD) still remains the main cause of left ventricular (LV) dysfunction and heart failure. Participation in cardiac rehabilitation (CR) programs can lead to a number of beneficial effects, but some patients do not demonstrate the expected improvement. The aim of this study is to evaluate the impact of CR on changes in exercise capacity with regard to the presence of LV dysfunction. Methods: A group of 428 patients with CAD were consecutively admitted to an outpatient comprehensive cardiac rehabilitation program comprising 24 exercise sessions of interval training on cycle ergometers, three times a week for 45 min, and a health education. The patients were compared in two subgroups, i.e., with LV systolic dysfunction (LVEF < 50%, n = 175) and LVEF ≥ 50% (n = 253). Results: In the LVEF < 50% group, the exercise capacity improved by 1 ± 0.78 MET (median 1.15 MET), and 0.86 ± 0.77 MET (median 1.08 MET) in the LVEF ≥ 50% group. Women with LVEF < 50% demonstrated a significant increase in exercise capacity by 1.2 MET, while those with LVEF ≥ 50% did not display any such increase. All men, regardless of LVEF, exhibited a similar improvement in exercise capacity greater than 1 MET. Conclusions: An outpatient eight-week cardiac rehabilitation program based on 45 min aerobic interval training sessions three times a week appears less effective for women with CAD and EF ≥ 50%. In this group, the proposed training intervention is insufficient in improving exercise capacity to an extent that could indicate a reduction in mortality risk.

The kinetics and apoptotic profile of circulating endothelial cells in autologous hematopoietic stem cell transplantation in patients with lymphoproliferative disorders.

In neoplastic disorders, endothelial cells take part in tumor progression and also influence the recovery of hematopoiesis after high-dose chemotherapy. Measurements of circulating endothelial cells (CEC), their subsets and kinetics were taken in patients with lymphoid malignancies (37 multiple myeloma, ten lymphoma) during autologous hematopoietic stem cell transplantation (HSCT). CEC were evaluated by four-color flow cytometry at different time points. Additionally levels of angiopoietins 1 and 2 were evaluated by ELISA assay. The baseline number of CECs and their subsets in patients were higher than in the control group. The median CEC number dropped significantly after transplantation (from 9.5/µL to 6.2/µL, p < 0.001). Apoptosis of CECs 24 h after chemotherapy was enhanced in comparison to baseline values (median apoptotic CEC number 4.15/µL vs 3.1/µL; p < 0,001). The time for neutrophil engraftment was shorter for patients with a low apoptotic CEC count at baseline as compared to those with a high apoptotic CEC count (median time to engraftment 13 vs. 16 days respectively, p = 0.04). We observed an adverse correlation of progenitor CEC numbers measured 1 h after transplantation with the time to neutrophil engraftment (r = -0.49, p = 0.008). We also found a negative correlation between the number of CECs originating from microvessels measured 1 h after transplantation, and the time to neutrophil engraftment (r = -0.39, p = 0.04). Baseline angiopoietins 1 and 2 concentration did not influence the post-transplant regeneration time. CEC numbers significantly change during autologous HSCT. Our results suggest that progenitor CECs and CECs derived from microvessels both take part in successful engraftment.

Circulating endothelial cell kinetics and their potential predictive value during mobilization procedure.

OBJECTIVE: Circulating endothelial cells (CECs) in patients with hematological malignancies are assessed as a noninvasive marker of angiogenesis. The aim of this study was to evaluate the numbers of CECs and their subsets during mobilization of hematopoietic stem cells. PATIENTS AND METHODS: Thirty-eight patients were enrolled to the study (19 females and 19 males) at median age of 56.5 years. The group consisted of patients with multiple myeloma (26), lymphoma (10), and acute myeloid leukemia (2). Blood samples were collected before chemotherapy (0), 1 day after chemotherapy (Cht+1), on the day G-CSF commenced (G0), after 1 day of G-CSF (G+1), and on the day of the first apheresis. CECs were evaluated by four-color flow cytometry. Circulating progenitor cells were defined as CD45-/CD34+/CD31+/CD133+. Apoptotic CECs (ApoCECs) were defined as CD146+/AnnexinV+. RESULTS: Median (Me) CECs number was 10.5/µl and it decreased after chemotherapy (Me = 8.3/µl, P < 0.001 when compared with baseline). Based on the number of aphereses needed to obtain 2 × 10(6)/kg CD34+ cells, patients were divided into "highly efficient" (one apheresis) and "poorly efficient" mobilizers (two or more aphereses). Median ApoCEC at Day G+1 was lower in highly efficient than in poorly efficient mobilizers (Me = 3.1/µl vs. Me = 5.1/µl, P = 0.02). ApoCEC at Day G+1 correlated with the number of aphereses (r = 0.48, P = 0.03). In multivariate analysis, ApoCEC at Day G+1 was an independent factor for successful mobilization during one apheresis. CONCLUSIONS: CECs and their subsets change significantly during mobilization of HSCs. ApoCECs measured at the time of G-CSF commencement can predict the efficacy of HSC collection.

Clinical Outcomes of Cardiac Rehabilitation in Women with Coronary Artery Disease-Differences in Comparison with Men.

This study evaluated the clinical outcomes of cardiac rehabilitation (CR) in women with coronary artery disease (CAD) in comparison to men. Methods: Patients after acute coronary syndrome or after revascularization procedures (106 women, 180 men) were consecutively admitted to a comprehensive outpatient CR program, comprising of 45-min ergometer interval training three times a week for eight weeks. The training intensity was determined on the basis of training heart rate, calculated following an exercise test. Patients were divided into subgroups according to age (≤55, >55 years), BMI (<25, ≥25 kg/m2), left ventricular ejection fraction (LVEF; ≤40%, 41−49%, ≥50%), and number of affected coronary vessels. Results: After eight weeks, exercise capacity increased significantly by 0.6 ± 0.77 MET (women) and by 1.0 ± 0.74 MET (men). The greatest benefit was observed in men, women under 55 years, women with LVEF 41−49%, and women with single-vessel CAD. An outpatient CR program appears less beneficial for women, especially those over 55 years, with two or three coronary vessels affected with atherosclerosis or with LVEF > 50%. In women with CAD, eight weeks of 45-min interval training, with sessions three times a week, is insufficient to improve exercise capacity to an extent that is considered a predictor of mortality risk reduction.

The influence of cardiac rehabilitation on heart rate variability indices in men with type 2 diabetes and coronary artery disease.

METHOD: The study population included 141 male CAD patients prospectively and consecutively admitted to an outpatient comprehensive CR program. Twenty-seven patients with type-2 diabetes were compared with 114 males without diabetes. The participants performed a 45-min cycle ergometer interval training alternating 4-min workload and a 2-min active restitution three times a week for 8 weeks. The training intensity was adjusted so that the patient's heart rate achieved the training heart rate calculated according to the Karvonen formula. At the baseline and after 8 weeks, all the patients underwent the HRV assessment. RESULTS: HRV indices in the patients with diabetes were significantly lower as compared to the patients without diabetes in SDNN, TP, LF parameters, both at the baseline and after 8 weeks of CR. After 8 weeks of CR, a significant improvement of TP, SDNN, pNN50% and HF occurred in the patients without diabetes, whereas in the patients with diabetes only HF component improved significantly. CONCLUSIONS: As regards HRV indices, CR seems to be less effective in patients with CAD and type-2 diabetes.

The Influence of Comprehensive Cardiac Rehabilitation on Heart Rate Variability Indices after CABG is More Effective than after PCI.

The aim of this study was to evaluate the influence of cardiac rehabilitation (CR) on heart rate variability (HRV) indices in men with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). The study population consisted of 131 male patients with CAD prospectively and consecutively admitted to CR after PCI n = 72, or CABG n = 59. Participants performed cycle ergometer interval training for 45 min three times a week for 8 weeks. At baseline and after 8 weeks, all patients underwent the HRV assessment. HRV indices in CAGB survivals were significantly lower in comparison to PCI patients at baseline. Significant increases were seen for SDNN, rMSSD, and HF in the CABG group and only in HF component in PCI group after 8 weeks of CR. Eight weeks of CR seems to be more effective in CABG patients than patients after PCI.

Characterization of 2-methylglyceric acid oligomers in secondary organic aerosol formed from the photooxidation of isoprene using trimethylsilylation and gas chromatography/ion trap mass spectrometry.

In the present work, we have characterized in detail the chemical structures of secondary organic aerosol (SOA) components that were generated in a smog chamber and result from the photooxidation of isoprene under high-NO(x) conditions typical for a polluted atmosphere. Isoprene high-NO(x) SOA contains 2-methylglyceric acid (2-MG) and oligoester derivatives thereof. Trimethylsilylation, in combination with capillary gas chromatography (GC)/ion trap mass spectrometry (MS) and detailed interpretation of the MS data, allowed structural characterization the polar oxygenated compounds present in isoprene SOA up to 2-MG trimers. GC separation was achieved between 2-MG linear and branched dimers or trimers, as well as between the 2-MG linear dimer and isomeric mono-acetate derivatives thereof. The electron ionization (EI) spectra of the trimethylsilyl derivatives contain a wealth of structural information, including information about the molecular weight (MW), oligoester linkages, terminal carboxylic and hydroxymethyl groups, and esterification sites. Only part of this information can be achieved with a soft ionization technique such as electrospray (ESI) in combination with collision-induced dissociation (CID). The methane chemical ionization (CI) data were used to obtain supporting MW information. Interesting EI spectral differences were observed between the trimethylsilyl derivatives of 2-MG linear and branched dimers or trimers and between 2-MG linear dimer mono-acetate isomers.

Blood Pressure Response to Submaximal Exercise Test in Adults.

Background. The assessment of blood pressure (BP) response during exercise test is an important diagnostic instrument in cardiovascular system evaluation. The study aim was to determine normal values of BP response to submaximal, multistage exercise test in healthy adults with regard to their age, gender, and workload. Materials and Methods. The study was conducted in randomly selected normotensive subjects (n = 1015), 512 females and 498 males, aged 18-64 years (mean age 42.1 ± 12.7 years) divided into five age groups. All subjects were clinically healthy with no chronic diseases diagnosed. Exercise stress tests were performed using Monark bicycle ergometer until a minimum of 85% of physical capacity was reached. BP was measured at rest and at peak of each exercise test stage. Results. The relations between BP, age, and workload during exercise test were determined by linear regression analysis and can be illustrated by the equations: systolic BP (mmHg) = 0.346 × load (W) + 135.76 for males and systolic BP (mmHg) = 0.103 × load (W) + 155.72 for females. Conclusions. Systolic BP increases significantly and proportionally to workload increase during exercise test in healthy adults. The relation can be described by linear equation which can be useful in diagnostics of cardiovascular diseases.

Blood pressure response to exercise in young athletes aged 10 to 18 years.

The aim of the study was to determine arterial blood pressure response to exercise in young athletes. The study group comprised 711 young athletes (457 boys, 254 girls) aged 10 to 18 years (mean 13.41 ± 3.12 years) who had been training for an average of 7.62 ± 4.2 h per week for an average of 4.01 ± 2.5 years. Participants with elevated arterial blood pressure above the 90th percentile at rest were excluded from investigation. A symptom-limited, multistage exercise test to exhaustion was performed using a Monark cycle ergometer. Arterial blood pressure was measured with an aneroid manometer in the third minute of each stage of the test. Mean systolic arterial blood pressure during peak exercise was significantly higher in boys than in girls: 183.21 ± 27.97 mm Hg and 170.97 ± 21.4 mm Hg, respectively (p = 0.03). Multivariate linear regression analysis showed that age and workload had significant effects on arterial blood pressure during the test. Systolic arterial blood pressure during the exercise can be described with the following equations: boys, SBPex (mm Hg) = -1.92 × age (years) + 0.55 × workload (W) + 120.84; girls, SBPex (mm Hg) = -0.88 × age (years) + 0.48 × workload (W) + 111.22. The study results describe reference values of arterial blood pressure during the exercise test. The presented equations and figures can help to assess whether the arterial blood pressure at each stage of the exercise test exceeds the normal range or not.

Angiopoietins in haematopoietic stem cell mobilisation in patients with haematological malignancies.

BACKGROUND: The bone marrow niche contains different types of cells including osteoblasts and endothelial progenitors, all of which interact and take part in the process of mobilisation. The aim of our study was to evaluate the levels of cytokines (osteopontin and angiopoietins 1 and 2) active in the bone marrow niche during the mobilisation of haematopoietic stem cells for autologous transplantation. MATERIALS AND METHODS: Forty-eight patients (24 females, 24 males), median age 56.5 years, entered the study. The group consisted of patients with multiple myeloma (n=34), lymphoma (n=13) and acute myeloid leukaemia (n=1). Blood samples were collected before chemotherapy and on the day of the first apheresis. Cytokines were evaluated by enzyme-linked immunosorbent assays. Additionally, circulating endothelial cells were assessed by flow cytometry. RESULTS: The median concentration of angiopoietin 1 at the time of apheresis was lower than that at baseline (2.7 vs 7.8 ng/mL, p<0.001). In contrast, the median level of angiopoietin 2 increased during the mobilisation procedure (3.6 vs 2.8 ng/mL, p=0.001). The patients were divided according to the number of days of granulocyte colony-stimulating factor treatment before the first apheresis into "early" (median) mobilisers. The group of "early mobilisers" had higher baseline angiopoietin 1 levels (median=11.6 ng/mL) than those of the "late mobilisers" (median=6.0 ng/mL, p=0.05). An adverse correlation was observed between duration of granulocyte colony-stimulating factor treatment and baseline angiopoietin 1 level. Baseline angiopoietin 1 levels correlated with numbers of circulating endothelial cells. Low angiopoietin 2 level increased the chance of poor mobilisation. CONCLUSIONS: The angiogenic processes can influence the timing of mobilisation. Angiopoietins 1 and 2 need further evaluation in the context of mobilisation.

Health-related quality of life in patients with coronary heart disease after residential vs ambulatory cardiac rehabilitation.

BACKGROUND: The aim of this study was to evaluate the influence of residential (RCR) vs ambulatory (ACR) cardiac rehabilitation (CR) on health-related quality of life (QOL) connected with changes in exercise capacity of patients with coronary heart disease (CHD). METHODS AND RESULTS: The 562 patients with CHD were studied: 313 participants in RCR and 249 participants in ACR. The examination was performed at the beginning of CR and after 8 weeks. QOL was assessed using the EuroQuol 5D (EQ-5D) and SF36 questionnaires. Exercise testing was performed with evaluation of workload during the last stage of the test and rate of perceived exertion intensity. In the first examination, patients from both groups did not differ significantly. After 8 weeks, a similar improvement in QOL was observed in both settings of CR according to EQ-5D and SF36 results. Health status was improved by 11.1% in the RCR group and by 10.4% in the ACR group. Last workload's intensity increased significantly by 32.1% in the RCR group and by 38.1% in the ACR group. The rate of perceived exertion intensity did not change despite the bigger workloads during the exercise test. CONCLUSIONS: Comprehensive CR improves health-related QOL and exercise capacity without differences between residential and ambulatory models.