The human CD40 gene lies within chromosome 20q deletions associated with myeloid malignancies

Deletions of chromosome 20q are associated with myeloid malignancies and have been previously shown to arise in a multipotent progenitor of both myeloid and B cells. However, B-cell differentiation from the abnormal progenitor was impaired. The CD40 antigen is a surface glycoprotein which is expressed in B cells and haemopoietic stem cells and is important for B-cell growth and development. Following the recent mapping of CD40 to chromosome 20q we sought to determine its position relative to 20q deletions. Analysis of lymphoblastoid cell lines carrying 20q deletions placed CD40 within a 19–21 cM interval which is almost coincidental with the common deleted region defined by previous analysis of patient samples. Our results raise the possibility that genetic alteration of this locus may contribute to the pathogenesis of myeloid disorders associated with 20q deletions.     

IGF-I and NGFβ enhance in vitro progressive motility and vitality of human spermatozoa

Purpose

Progressive motility (PM) and vitality are positively associated with fertilization ability of spermatozoa. Here, the effects of IGF-I and NGFβ on PM and vitality of human spermatozoa were investigated.

Methods

Forty-three volunteers gave semen samples after 2-3 days of sexual abstinence. Each sample was processed with density gradient centrifugation and sperm washing. The pellet was divided into 3 aliquots. An aliquot containing one million of progressively motile spermatozoa was incubated for an hour (37°C) in standard culture medium (control group), and two aliquots with the same number of progressively motile spermatozoa were incubated in medium supplemented with IGF-I or NGFβ. Two concentrations of IGF-I (100 ng/ml and 1000 ng/ml) and NGFβ (0,5 ng/ml and 5 ng/ml) were tested.

Results

Both growth factors significantly increased PM and vitality in comparison with control either at the low or the high concentration. IGF-I seemed to be more effective than NGFβ. The effects did not seem to be dose dependent with the exception of the effect of IGF-I on vitality.

Conclusions

The enhancement of PM and vitality of human spermatozoa by IGF-I and NGFβ opens new ways for the improvement of sperm processing. Further research is needed to determine the most effective concentrations.

     

Leukocyte integrin expression in patients undergoing cardiopulmonary bypass

BACKGROUND: The recruitment of leukocytes to vascular endothelium is controlled by adhesion events mediated through the beta2 integrins, whereas the response of extravasated leukocytes within the tissues is controlled through the beta1 integrins. Although cardiopulmonary bypass (CPB) has been shown to be associated with a systemic inflammatory response and elevated levels of beta2 integrins on leukocytes, its effect on the beta1 integrins is not known. This study investigated the effect of the protease inhibitor aprotinin on the expression of the beta1 and beta2 integrins on circulating leukocytes in patients undergoing CPB. METHODS: Patients undergoing primary elective coronary artery bypass grafting were randomized into full-dose aprotinin or placebo groups. Blood samples were obtained at nine time points preoperatively, intraoperatively, and up to 6 days postoperatively. The surface expression of the beta1 integrins VLA-1, -3, -4, -5, and -6 and of the beta2 integrins CD11a/CD18, CD11b/CD18, and CD11c/CD18 was measured by flow cytometry on gated neutrophil and monocyte subpopulations in whole blood. RESULTS: Expression of the beta1 integrins was not significantly altered during the study period and, therefore, aprotinin had no effect on the expression of these molecules. Of the beta2 integrins, CD11b/CD18 expression was significantly increased on neutrophils at 15 minutes after onset of CPB in the placebo group (p < 0.01) but not in the aprotinin group. CONCLUSIONS: This study showed that expression of the beta1 integrins on neutrophils and monocytes did not alter during the first 6 days after CPB. Expression of the beta2 integrin CD11b/CD18 increased significantly on neutrophils during CPB in control patients but not in patients treated with full-dose aprotinin.     

Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes

Studies of X chromosome inactivation patterns are central to many aspects of our understanding of the pathogenesis of haematological malignancies. In patients with myeloproliferative disorders and myelodysplastic syndromes the demonstration of skewed X inactivation patterns in multiple haemopoietic lineages has been taken to indicate a stem cell origin for these groups of diseases. However, stem cell depletion or selection pressures can also produce skewed X inactivation patterns and might increase with age. We have therefore used the HUMARA assay to study X inactivation patterns of elderly patients with myeloproliferative disorders together with an age-matched control group of normal elderly women.   A clonal pattern (clonal granulocytes and polyclonal T cells) was observed in 23.1% of normal women and 63.4% of patients with myeloproliferative disorders. This is the first report of X inactivation patterns in purified subpopulations of blood cells in normal elderly women. These results have three significant implications. Firstly, the finding of clonal granulocytes and polyclonal T cells in normal elderly women is likely to reflect age-related stem cell depletion or selection pressures. Secondly, the demonstration of clonal granulocytes and polyclonal T cells is not a useful diagnostic marker for myeloproliferative disorders or myelodysplastic syndromes in elderly women. Thirdly, our data raise the possibility that clonal blood cell patterns may precede rather than follow mutations which subsequently give rise to myelodysplastic or myeloproliferative phenotypes.     

Increased plasma adhesion molecule levels in patients with heart failure who have ischemic heart disease and dilated cardiomyopathy

BACKGROUND: Inflammatory mechanisms, including leukocyte activation, appear to play a pathogenetic role in the development of heart failure. Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) are important mediators of leukocyte adhesion to vascular endothelium. The plasma levels of the soluble form of these molecules may be elevated in chronic inflammation. METHODS AND RESULTS: We measured plasma VCAM-1 and ICAM-1 levels (in nanograms per milliliter) with the commercially available enzyme-linked immunosorbent assay method in 12 patients (9 male, 3 female, aged 64 +/- 8 years) with dilated cardiomyopathy and heart failure, in 23 patients (23 male, aged 65 +/- 9 years) with ischemic cardiomyopathy and heart failure, and in 11 healthy control subjects (8 male, 3 female, aged 49 +/- 14 years). Plasma ICAM-1 levels were higher both in patients with dilated cardiomyopathy (363 +/- 77 ng/mL, P <.05) (mean +/- SEM) and in those with ischemic heart disease (320 +/- 32 ng/mL, P <.05) than in control subjects (225 +/- 29 ng/mL). VCAM-1 levels were also higher in both groups with heart failure (664 +/- 73 ng/mL) than in control subjects (551 +/- 60 ng/mL). VCAM-1 levels were higher in patients with class IV compared with those with class II and III heart failure. CONCLUSIONS: Plasma adhesion molecule levels are increased in patients with heart failure and are unrelated to the presence or absence of angiographically demonstrable atherosclerotic coronary artery disease. The plasma level of VCAM-1 correlates with the severity of heart failure.     

Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells

Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line-only control. Furthermore, the combined co-culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM.     

Pregnancy and inflammatory bowel disease

Inflammatory bowel disease (IBD)--Crohn's disease, ulcerative colitis--affects frequently the women in their childbearing years with concerns about both on pregnancy and evolution of the IBD. Important issues concerning a pregnant woman with IBD include the effect of pregnancy on the disease, and, conversely, the effect of IBD on pregnancy and inheritance of IBD in the offspring. Adverse fetal outcomes are not increased when IBD is inactive; however, women with active disease incur a greater risk of premature birth. Most of women with active IBD at the time of contraception have continued or worsening disease activity during pregnancy. Most medications for IBD are safe during pregnancy, with notable exceptions. A key principle of management is that active disease, not therapy, poses the greatest risk to pregnancy.     

The angiogenetic effect of intramuscular administration of VEGF on muscle. The influence of exercise on angiogenesis

Although angiogenetic therapy using recombinant growth factors holds much hope for the treatment of ischemic diseases, there are still unanswered questions including the method, doses or duration of therapeutic approach. We evaluated the angiogenetic effects of vascular endothelial growth factor (VEGF) on rat heart and gastrocnemius muscles when this was administered intramuscularly and compared them to those obtained from rats, which exercised daily. CONCLUSION: Both daily swimming exercise and intramuscular administration of VEGF increased angiogenesis in rat heart, even though exercise alone was the only one that increased angiogenesis quite significantly. The combined protocol (administration of growth factor and exercise) led to an increase of angiogenesis in cardiac muscles. In contrast, there was no effect on the lateral gastrocnemius muscle either by VEGF or exercise, whereas these together induced angiogenesis locally at the site of injection.