Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks.

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.

The effect of parathyroid hormone on osteogenesis is mediated partly by osteolectin.

We previously described a new osteogenic growth factor, osteolectin/Clec11a, which is required for the maintenance of skeletal bone mass during adulthood. Osteolectin binds to Integrin α11 (Itga11), promoting Wnt pathway activation and osteogenic differentiation by leptin receptor+ (LepR+) stromal cells in the bone marrow. Parathyroid hormone (PTH) and sclerostin inhibitor (SOSTi) are bone anabolic agents that are administered to patients with osteoporosis. Here we tested whether osteolectin mediates the effects of PTH or SOSTi on bone formation. We discovered that PTH promoted Osteolectin expression by bone marrow stromal cells within hours of administration and that PTH treatment increased serum osteolectin levels in mice and humans. Osteolectin deficiency in mice attenuated Wnt pathway activation by PTH in bone marrow stromal cells and reduced the osteogenic response to PTH in vitro and in vivo. In contrast, SOSTi did not affect serum osteolectin levels and osteolectin was not required for SOSTi-induced bone formation. Combined administration of osteolectin and PTH, but not osteolectin and SOSTi, additively increased bone volume. PTH thus promotes osteolectin expression and osteolectin mediates part of the effect of PTH on bone formation.

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas' disease and idiopathic dilated cardiomyopathy.

Chagas' disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.

Normal Hematopoiesis Is a Balancing Act of Self-Renewal and Regeneration.

The hematopoietic system is highly organized to maintain its functional integrity and to meet lifelong organismal demands. Hematopoietic stem cells (HSCs) must balance self-renewal with differentiation and the regeneration of the blood system. It is a complex balancing act between these competing HSC functions. Although highly quiescent at steady state, HSCs become activated in response to inflammatory cytokines and regenerative challenges. This activation phase leads to many intrinsic stresses such as replicative, metabolic, and oxidative stress, which can cause functional decline, impaired self-renewal, and exhaustion of HSCs. To cope with these insults, HSCs use both built-in and emergency-triggered stress-response mechanisms to maintain homeostasis and to defend against disease development. In this review, we discuss how the hematopoietic system operates in steady state and stress conditions, what strategies are used to maintain functional integrity, and how deregulation in the balance between self-renewal and regeneration can drive malignant transformation.

Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease.

BACKGROUND: Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects. METHODS: We studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs). We measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7 at baseline. RESULTS: BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1ß, IL-6 and CCL-3, of which high levels also preceded seroconversion. CONCLUSION: Relatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A distinct pattern of four inter correlating immune factors in the relatives preceded TPO-Ab seroconversion in the next 5 years.

Elevated levels of endothelial-derived microparticles, and serum CXCL9 and SCGF-ß are associated with unstable asymptomatic carotid plaques.

Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy. EMP/PMPs were quantified using flow cytometry. Bioplex assays profiled systemic inflammatory and bone-related proteins. Immunohistological analysis detailed the contribution of differentially-regulated systemic markers to plaque pathology. Alizarin red staining showed calcification. EMPs and PMPs were significantly higher in patients with carotid stenosis (≥ 70%) compared to controls, with no differences between asymptomatic vs symptomatic patients. Asymptomatic patients with unstable plaques exhibited higher levels of EMPs, CXCL9 and SCGF-ß compared to those with stable plaques. CXCL9, and SCGF-ß were detected within all plaques, suggesting a contribution to both localised and systemic inflammation. Osteopontin and osteoprotegerin were significantly elevated in the symptomatic vs asymptomatic group, while osteocalcin was higher in asymptomatic patients with stable plaque. All plaques exhibited calcification, which was significantly greater in asymptomatic patients. This may impact on plaque stability. These data could be important in identifying patients at most benefit from intervention.

Exploratory study for identifying systemic biomarkers that correlate with pain response in patients with intervertebral disc disorders.

Molecular events that drive disc damage and low back pain (LBP) may precede clinical manifestation of disease onset and can cause detrimental long-term effects such as disability. Biomarkers serve as objective molecular indicators of pathological processes. The goal of this study is to identify systemic biochemical factors as predictors of response to treatment of LBP with epidural steroid injection (ESI). Since inflammation plays a pivotal role in LBP, this pilot study investigates the effect of ESI on systemic levels of 48 inflammatory biochemical factors (cytokines, chemokines, and growth factors) and examines the relationship between biochemical factor levels and pain or disability in patients with disc herniation (DH), or other diagnoses (Other Dx) leading to low back pain, which included spinal stenosis (SS) and degenerative disc disease (DDD). Study participants (n = 16) were recruited from a back pain management practice. Pain numerical rating score (NRS), Oswestry Disability Index (ODI), and blood samples were collected pre- and at 7 to 10 days post-treatment. Blood samples were assayed for inflammatory mediators using commercial multiplex assays. Mediator levels were compared pre- and post-treatment to investigate the potential correlations between clinical and biochemical outcomes. Our results indicate that a single ESI significantly decreased systemic levels of SCGF-ß and IL-2. Improvement in pain in all subjects was correlated with changes in chemokines (MCP-1, MIG), hematopoietic progenitor factors (SCGF-ß), and factors that participate in angiogenesis/fibrosis (HGF), nociception (SCF, IFN-α2), and inflammation (IL-6, IL-10, IL-18, TRAIL). Levels of biochemical mediators varied based on diagnosis of LBP, and changes in pain responses and systemic mediators from pre- to post-treatment were dependent on the diagnosis cohort. In the DH cohort, levels of IL-17 and VEGF significantly decreased post-treatment. In the Other Dx cohort, levels of IL-2Rα, IL-3, and SCGF-ß significantly decreased post-treatment. In order to determine whether mediator changes were related to pain, correlations between change in pain scores and change in mediator levels were performed. Subjects with DH demonstrated a profile signature that implicated hematopoiesis factors (SCGF-ß, GM-CSF) in pain response, while subjects with Other Dx demonstrated a biomarker profile that implicated chemokines (MCP-1, MIG) and angiogenic factors (HGF, VEGF) in pain response. Our findings provide evidence that systemic biochemical factors in patients with LBP vary by diagnosis, and pain response to treatment is associated with a unique profile of biochemical responses in each diagnosis group. Future hypothesis-based studies with larger subject cohorts are warranted to confirm the findings of this pilot exploratory study.

Pilot study: elevated circulating levels of the proinflammatory cytokine macrophage migration inhibitory factor in patients with chronic spinal cord injury.

OBJECTIVE: To test the hypothesis that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is elevated in the circulation of patients with chronic spinal cord injury (SCI) relative to uninjured subjects, and secondarily to identify additional immune mediators that are elevated in subjects with chronic SCI. DESIGN: Prospective, observational pilot study. SETTING: Outpatient clinic of a department of physical medicine and rehabilitation and research institute in an academic medical center. PARTICIPANTS: Individuals with chronic (>1y from initial injury) SCI (n=22) and age- and sex-matched uninjured subjects (n=19). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma levels of MIF, as determined by a commercially available multiplex suspension immunoassay. The relationship between MIF levels and clinical/demographic variables was also examined. As a secondary outcome, we evaluated other cytokines, chemokines, and growth factors. RESULTS: Plasma MIF levels were significantly higher in subjects with chronic SCI than in control subjects (P<.001). Elevated MIF levels were not correlated significantly with any one clinical or demographic characteristic. Subjects with SCI also exhibited significantly higher plasma levels of monokine induced by interferon-gamma/chemokine C-X-C motif ligand 9 (P<.03), macrophage colony stimulating factor (P<.035), interleukin-3 (P<.044), and stem cell growth factor beta (SCGF-ß) (P<.016). Among subjects with SCI, the levels of SCGF-ß increased with the time from initial injury. CONCLUSIONS: These data confirm the hypothesis that MIF is elevated in subjects with chronic SCI and identify additional novel immune mediators that are also elevated in these subjects. This study suggests the importance of examining the potential functional roles of MIF and other immune factors in subjects with chronic SCI.

The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR.

Microcystins (MCs) cause normocytic anemia in patients in a hemodialysis unit in Caruaru, Brazil in 1996, but the underlying mechanisms are still unclear. In the present study, Balb/c mice were intraperitoneally injected with microcystin-LR (MC-LR) at the doses of 0.5, 2 and 8 µg/kg body weight (bw) every 48 h for 30 d. After the prolonged exposure of MC-LR, significant decreases of red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) were observed in 2 and 8 µg/kg bw groups, but erythrocyte mean corpuscular volume (MCV) showed no significant changes. Significantly elevated micronucleus frequency was observed in bone marrow cells (BMCs) in all MC-LR treatments. The proliferation of BMCs significantly declined in both 2 and 8 µg/kg bw groups. Serum levels of some hematopoietic growth factors significantly changed in 8 µg/kg bw group, mainly including granulocyte-macrophage (GM-CSF), erythropoietin (EPO), interleukin-3 (IL-3) and TNF-α. The transcriptional levels of these 4 genes in BMCs were also significantly changed in 8 µg/kg bw group. MC-LR exposure significantly increased the apoptosis rates in all MC-LR treatments. The present study indicates prolonged exposure of MC-LR induces normocytic anemia, and the disturbed hematopoietic growth factors and BMCs apoptosis are responsible for this normocytic anemia.

Prognostic value of circulating levels of stem cell growth factor beta (SCGF beta) in patients with Chagas' disease and idiopathic dilated cardiomyopathy.

Chagas' disease (CD) often leads to dilated cardiomyopathy (DCM), and during its chronic stage hematopoietic stem or progenitor cells are involved in its pathological process. However, it is not clear whether stem cell growth factor (SCGF) beta can be regulated in patients with CD and idiopathic DCM. In present study, we aim to investigate the plasma SCGF beta concentration and its correlation with echocardiographic parameters and clinical outcome. In this prospective cohort study, SCGF beta levels were quantified in patients with CD (n=94), DCM (n=48), and control healthy subjects (n=25). In comparison with healthy subjects, no statistical difference can be detected in NYHA classes I-II patients. However, SCGF beta was significantly increased in advanced heart failure patients (NYHA III-IV), compared to CD patients without heart failure. There was no group difference between CD and DCM. However, despite this significant increase in advanced heart failure patients, SCGF beta had no significant correlation with echocardiographic parameters, and it cannot be used as a prognostic marker for mortality and heart transplantation. To our best knowledge, this is the first report of SCGF beta in heart failure patients. Although it is significantly increased in advanced heart failure patients caused by CD or DCM, its prognostic value for end points is minor.

Interrelationship and expression profiling of cyclooxygenase and angiogenic factors in Indian patients with multiple myeloma.

Multiple myeloma (MM) is classically illustrated by a desynchronized cytokine system with rise in inflammatory cytokines. There are recent reports which emphasized the potential role of angiogenesis in the development of MM. Role of cyclooxygenase 2 (COX-2) is well documented in the pathogenesis of solid tumors, but little is known about its occurrence and function in hematologic neoplasms. Involvement of neoangiogenesis is reported in the progression of MM, and angiopoietins probably contribute to this progression by enhancing neovascularization. Circulatory and mRNA levels of angiogenic factors and cyclooxygenase were determined in 125 subjects (75 MM patients and 50 healthy controls) by using enzyme-linked immunosorbent assay and quantitative PCR. We observed significant increase for angiogenic factors (Ang-1, Ang-2, hepatocyte growth factor, and vascular endothelial growth factor) and cyclooxygenase at circulatory level, as well as at mRNA level, as compared to healthy controls except insignificant increase for Ang-1 at circulatory level. We have also observed the significant positive correlation of all angiogenic factors with cyclooxygenase. The strong association found between angiogenic factors and COX-2 in this study may lead to the development of combination therapeutic strategy to treat MM. Therefore, targeting COX-2 by using its effective inhibitors demonstrating antiangiogenic and antitumor effects could be used as a new therapeutic approach for treatment of MM.

Perinatal immunoproteins predict the risk of cerebral palsy in preterm children.

OBJECTIVE: To investigate whether blood cytokines during the perinatal period predict the risk of cerebral palsy (CP) in preterm infants. METHODS: This prospective cohort study comprised 169 children born before 32 weeks of gestation. Cord blood was drawn at birth, and 109 cytokines were analyzed using microarrays. Eleven cytokines were further measured from both cord and peripheral blood on days 1 and 7. Cerebral palsy was confirmed at 5 years of age. RESULTS: Cerebral palsy was diagnosed in 19 children. Five clusters of cord blood cytokines were scored using factor analysis. According to logistic regression analysis, the scores of factors 1 and 2 independently predicted the risk of CP. These cytokines included several growth factors and chemokines, and they all tended to be higher in children with CP than in children without CP. Inflammatory cytokine levels were associated with CP risk on days 1 and 7 after birth. CONCLUSION: The high blood concentrations of various cytokines during the perinatal period may relate to CP, and these cytokines may influence the pathways leading to early insult in the central nervous system. The risk profile of inflammatory cytokines is different at birth than during the first week after birth.

Leukemoid reaction in malignant bone tumor patients - a retrospective, single-institution study.

BACKGROUND: To the Authors' knowledge, the literature regarding leukemoid reaction in patients with malignant bone tumor is sparse, and most of patients with leukemoid reaction have poor prognosis. AIM: To study the leukemoid reaction in malignant bone tumor patients. MATERIALS AND METHODS: A total of 105 consecutive malignant bone tumor patients with a white blood cell count > 50,000/microL were retrospectively identified over a 4-years period (2007-2010). Those patients without a secondary cause of their leukocytosis were defined as having a paraneoplastic leukemoid reaction. RESULTS: Three etiologies of the leukocytosis were found in those 105 patients: the major one was paraneoplastic leukemoid reaction which accounted for 56%; the second one was hematopoietic growth factors defect accounting for 30%; 14% patients were caused by infection and Tumor bone marrow involvement. The patients diagnosed with a paraneoplastic leukemoid reaction typically had neutrophil predominance (94.8%) and radiographic evidence of metastatic diseases (78%). They were clinically stable, but had a poor prognosis. 95% either died or were discharged to hospice within 12 weeks of their initial extreme leukocyte count. Both of the 2 (2%) patients who survived over 12 weeks received effective antineoplastic therapy. CONCLUSIONS: Patients with typical paraneoplastic leukemoid reaction were clinically stable despite having large tumor burdens. However, clinical outcomes were poor unless receiving an effective antineoplastic treatment.

Hematopoietic cytokines as tumor markers in gynecological malignancies: a multivariate analysis with ROC curve in endometrial cancer patients.

Hematopoietic cytokines have been implicated in the pathogenesis of malignant diseases. This study compared the diagnostic utility of hematopoietic growth factors with commonly accepted tumor marker (CA 125) in the early stages (I and II) of endometrial cancer (EC) patients (65) in relation to the control groups: uterine myoma patients (40) and healthy subjects (45). The pretreatment plasma levels of interleukin 3, stem cell factor, granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor, and macrophage-colony stimulating factor (M-CSF) were determined by the use of immunoenzyme assay, and those of CA 125 were determined by chemiluminescent microparticle immunoassay. Our results have demonstrated significant differences in the concentration of cytokines and CA 125 between the groups of EC patients, uterine myoma patients, and the healthy controls. M-CSF has demonstrated equal to CA 125 or higher values of the diagnostic sensitivity, the predictive values of positive and negative test results, and the area under the receiver-operating characteristics curve in the tested groups. These findings suggest the usefulness of M-CSF in the diagnosis of EC and uterine myomas.

Serum hematopoietic growth factors as diagnostic and prognostic markers of acute renal allograft rejection: a potential role for serum stem cell factor.

OBJECTIVES: Hematopoietic growth factors (HGFs) are proliferative and chemotactic agents for hematopoietic stem cells, although their functions on renal transplantation are rarely reported. This study aimed to investigate the association of HGFs with acute T cell-mediated renal rejection. EXPERIMENTAL DESIGN: A cytokine bead array was used to analyze 10 HGFs in the sera of 32 patients with acute T cell-mediated renal allograft rejection before and during rejection and after rejection reversal. Stable renal allograft recipients (n=38) were also investigated. RESULTS: Serum levels of stem cell factor (SCF), IL-3, flt3 ligand, G-CSF, M-CSF and GM-CSF were elevated during episodes of rejection compared with before and after rejection. Serum concentrations of SCF, G-CSF, flt3 ligand and IL-3 were significantly higher than in the absence of rejection. Moreover, serum SCF levels were significantly higher in patients before rejection versus stable controls. CONCLUSIONS: HGFs are reported to be involved in acute T cell-mediated renal allograft rejection. A direct correlation was observed between SCF levels and the occurrence of acute renal allograft rejection which may represent an effective diagnostic and predictive biomarker for acute cellular renal allograft rejection.

Modulation of the blood-stimulating effect of immobilized granulocyte colony-stimulating factor by immobilized hyaluronidase.

We evaluated whether immobilized hyaluronidase can modify the hematotropic effect of immobilized granulocyte CSF (G-CSF). The preparation of immobilized hyaluronidase (50 arb. units per mouse) potentiated the specific effect of immobilized G-CSF on granulomonocytopoiesis. The preparation was shown to facilitate the indirect effect of immobilized G-CSF on hemopoiesis (stimulation of the erythroid and lymphoid hemopoietic stems). These changes were accompanied by an increase in functional activity of hemopoietic precursor cells, secretion of humoral factors by bone marrow myelokaryocytes, and concentration of hemopoietins in the serum.

[The plasma levels and diagnostic utility of selected hematopoietic growth factors in endometrial cancer patients and with myoma uteri]. / Ocena stezenia i przydatnosci diagnostycznej wybranych cytokin hematopoetycznych w osoczu chorych na raka endometrium i ze zmianami lagodnymi (miesniakami) macicy.

UNLABELLED: Hematopoietic growth factors (HGFs) are involved in the regulation of growth hematopoietic cells. Some clinical investigations have shown an autologous production of HGFs in various human cell lines in vitro and by tumour cells in vivo, for example in endometrial cancer. THE AIM OF THE STUDY: To evaluate the plasma levels and diagnostics utility of selected HGFs, such as SCF M-CSF, G-CSF in endometrial cancer patients and with myoma uteri. MATERIAL AND METHODS: We have investigated the plasma levels of HGFs and tumor marker like CA 125 in patients with endometrial cancer (55 women), with myoma uteri (30 patients) and in 30 healthy subjects. HGFs were determined using enzyme-linked immunosorbent assay (ELISA), CA 125 was measured by chemiluminescence immunoassay (CMIA). RESULTS: SCF and M-CSF similarly to CA 125 plasma levels were significantly higher in endometrial cancer patients comparing to the healthy subjects. Furthermore M-CSF was significantly higher in endometrial cancer comparing to the myoma patients. The diagnostic sensitivity of M-CSF was high and slightly lower than CA 125 (51% and 60% respectively). The combined use of all tested cytokines resulted in the increased sensitivity range, especially with marker CA 125 (84%). Diagnostic specificities were high and equal for all tested cytokines and for CA 125(93%). Positive predictive values (PPV) were high for all tested parameters, and negative predictive values (NPV) were higher enough to exclude endometrial cancer. CONCLUSIONS: Our study suggest that tested cytokines (HGFs) can be clinically useful in diagnostic of endometrial cancer patients. M-CSF can be clinically useful in differentiation of endometrial cancer and myoma uteri. Furthermore SCF and M-CSF showed usefulness in primary diagnostic of cancer uteri, especially with CA 125.

Hemopoietic and angiogenetic progenitors in healthy athletes: different responses to endurance and maximal exercise.

The effects of endurance or maximal exercise on mobilization of bone marrow-derived hemopoietic and angiogenetic progenitors in healthy subjects are poorly defined. In 10 healthy amateur runners, we collected venous blood before, at the end of, and the day after a marathon race (n = 9), and before and at the end of a 1.5-km field test (n = 8), and measured hemopoietic and angiogenetic progenitors by flow cytometry and culture assays, as well as plasma or serum concentrations of several cytokines/growth factors. After the marathon, CD34(+) cells were unchanged, whereas clonogenetic assays showed decreased number of colonies for both erythropoietic (BFU-E) and granulocyte-monocyte (CFU-GM) series, returning to baseline the morning post-race. Conversely, CD34(+) cells, BFU-E, and CFU-GM increased after the field test. Angiogenetic progenitors, assessed as CD34(+)KDR(+) and CD133(+)VE-cadherin(+) cells or as adherent cells in culture expressing endothelial markers, increased after both endurance and maximal exercise but showed a different pattern between protocols. Interleukin-6 increased more after the marathon than after the field test, whereas hepatocyte growth factor and stem cell factor increased similarly in both protocols. Plasma levels of angiopoietin (Ang) 1 and 2 increased after both types of exercise, whereas the Ang-1-to-Ang-2 ratio or vascular endothelial growth factor-A were little affected. These data suggest that circulating hemopoietic progenitors may be utilized in peripheral tissues during prolonged endurance exercise. Endothelial progenitor mobilization after exercise in healthy trained subjects appears modulated by the type of exercise. Exercise-induced increase in growth factors suggests a physiological trophic effect of exercise on the bone marrow.

[The plasma levels and diagnostic utility of selected hematopoietic growth factors (HGFs) in breast cancer patients]. / Ocena stezen i przydatnosci diagnostycznej wybranych cytokin hematopoetycznych (HGFs) w osoczu pacjentek z rakiem piersi.

BACKGROUND: Hematopoietic growth factors (HGFs) are involved in the regulation of hematopoietic cells growth. Few clinical investigations have shown their autologous production both in vitro by human cell lines and in vivo by tumors, for example in breast cancer. We have investigated the plasma levels of selected cytokines (M-CSF, G-CSF, GM-CSF) and commonly accepted tumor marker (CA 15-3) before treatment of breast cancer patients in relation to the healthy controls. Additionally, the diagnostic criteria: sensitivity, specificity, the predictive value of positive and negative results were defined. MATERIAL AND METHODS: Tested group--80 patients with breast cancer, control group--20 healthy women. M-CSF, G-CSF and GM-CSF were determined using ELISA method, CA 15-3--was measured by chemiluminescence immunoassay--CMIA (ABBOTT). RESULTS: Median values of HGFs and CA 15-3 plasma levels were significantly higher in breast cancer patients comparing to the control group. The diagnostic sensitivity of M-CSF was higher than CA 15-3 (59% and 44% respectively), and for the other tested cytokines. The combined analysis of all tested cytokines resulted also in the increased sensitivity range (81%), especially with CA 15-3 (91%). The diagnostic specificities were higher for M-CSF and CA 15-3 (equal 95%) and for other tested cytokines (equal 90%). Positive predictive values (PPV) were high for all tested parameters, and negative predictive values (NPV) were higher to exclude breast cancer. CONCLUSIONS: This study suggests that tested cytokines can be clinically useful in diagnostics of breast cancer patients, especially with CA 15-3, but further investigation and confirmation by a prospective study are necessary.

Abnormal hematological indices in cirrhosis.

Abnormalities in hematological indices are frequently encountered in cirrhosis. Multiple causes contribute to the occurrence of hematological abnormalities. Recent studies suggest that the presence of hematological cytopenias is associated with a poor prognosis in cirrhosis. The present article reviews the pathogenesis, incidence, prevalence, clinical significance and treatment of abnormal hematological indices in cirrhosis.