Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Locally Transplanted CD34+ Bone Marrow-Derived Cells Contribute to Vascular Healing After Vascular Injury.

INTRODUCTION: Vascular progenitor cells contribute to repair of injured vasculature. In this study, we aimed to investigate the role of bone marrow-derived cells in the intimal formation after arterial injury. METHODS AND RESULTS: Balloon injury of the femoral artery of wild-type mice was followed by local delivery of bone marrow-derived cells from GFP transgenic mice. The arteries were collected 1, 4, 7, and 14 days after injury and studied for morphology, localization, and phenotypes of delivered cells. Bone marrow-derived cells were present in the intima only at the early stages of arterial injury and expressed endothelial progenitor cell markers (CD31, CD34, and VEGFR-2). In the areas where intima was thicker, bone marrow-derived cells differentiated to intimal smooth muscle cells but they did not fuse with intimal cells. Delivery of CD34+ cells contributed to a 1.5-fold inhibition of intimal hyperplasia. CONCLUSION: Bone marrow-derived endothelial cells differentiated but did not fuse with vascular smooth muscle cells at the early stages of intimal formation and contributed to intimal hyperplasia.

Effect of interaction between anionic surfactants and poly(piperazine-amide) nanofiltration membranes used for chromium(III) recovery from saline solution.

The effect of the anionic surfactant on the permeation properties of the nanofiltration (NF) membranes used for chromium(III) recovery from saline solution at low pH have been presented in this paper. The membrane surface layer performance periodically modified by sodium dodecyl sulphate (SDS) solution has been studied with measurements of zeta potential, atomic force microscopy (AFM) and permeability coefficient of tested membranes. It was found that the membrane surface layer modification by SDS caused a substantial reduction in the possibility of separation of loose NF membrane characterized by a high density of positively charged groups activating under the effect of the low pH of the saline solutions (HL membrane). On the other hand, in the case of dense NF membranes characterized by a strong negatively charged surface (DL membrane) constituting used the SDS improves the separation of chloride and chromium(III) ions. In this case, the surfactant solution also provides a high membrane permeability coefficient behavior over a long period of use. DL membrane modification by SDS allowed both to retain the stable membrane working for a long period and to limit the frequency of the chemical cleaning of this membrane.

Heart failure and Alzheimer's disease.

It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.

C/EBPß expression is an independent predictor of overall survival in breast cancer patients by MHCII/CD4-dependent mechanism of metastasis formation.

CCAAT-enhancer binding protein ß (C/EBPß) is a transcription factor that has a critical role in mammary gland development and breast cancer progression. Loss of C/EBPß increases metastatic dissemination of mouse mammary tumor cells. However, the mechanism by which C/EBPß expression affects metastasis formation remains unknown. This study aims at determining the relationship between C/EBPß and survival of breast cancer patients, and elucidating C/EBPß's link with metastasis formation. C/EBPß expression was evaluated in 137 cases of human breast cancer, and the correlation with overall survival was estimated by Kaplan-Meier analysis. Additionally, the mouse 4T1 tumor model was used for in vivo studies. Decreased C/EBPß expression was found to be associated with shorter overall survival of breast cancer patients. In the murine 4T1 model, loss of C/EBPß affects tumor growth, morphology and promotes metastatic spread to the lungs. Immunohistochemical analyses showed that C/EBPß inhibition leads to increased major histocompatibility complex II (MHCII) expression, followed by the accumulation of CD45-, CD3- and CD4-positive (CD4+) lymphocytes in the tumors. Inflammation involvement in C/EBPß-mediated metastasis formation was confirmed by DNA microarray and by experiments on CD4+ cell-deprived nude mice. Additionally, anti-CD3 and anti-CD4 treatments of C/EBPß-silenced tumor-bearing mice resulted in reverting the C/EBPß effect on tumor growth and metastasis. Altogether, C/EBPß is a predictor of overall survival in breast cancer patients, and affects tumor growth, morphology and lung metastasis formation in murine 4T1 model. The mechanism of metastasis formation involves immunologic response depending on C/EBPß-mediated activation of MHCII and accumulation of CD4+ lymphocytes in the tumor.

Supported liquid membrane system for Cr(III) separation from Cr(III)/Cr(VI) mixtures.

This paper presents the results of analyses of the chromium(III) transport process from mixtures of Cr(III)/Cr(VI) ions using supported liquid membranes (SLM), in which dinonylnaphthalene sulfonic acid (DNNSA) and di(2-ethylhexyl) phosphoric acid (D2EHPA) were used as carriers. In both cases the membrane worked as a selective barrier for Cr(VI) ions. The increase in both the time of Cr(VI) ions-carrier interaction and the Cr(VI) concentration in the feed phase negatively influenced the Cr(III) separation. The polarizing layer consisting of Cr(VI) ions prevents the access of Cr(III) ions to the inter phase surface and leads to the deactivation of the carrier, which is the result of the strong oxidation properties of Cr(VI) ions. These factors meant that, in the case of the membrane with DNNSA, the membrane could not be used for the effective separation of Cr(III) from the Cr(III)/Cr(VI) mixture. On the other hand, the membrane with D2EHPA can be used for fast and efficient transport of Cr(III) ions, but only for strictly defined process parameters, i.e. where the level of chromium(VI) concentration is below 10(-3)M and with intensive feed phase mixing.

MiR-155-mediated loss of C/EBPß shifts the TGF-ß response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.

During breast cancer progression, transforming growth factor-beta (TGF-ß) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPß), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-ß-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBPß was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBPß potentiated the TGF-ß response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-ß. Furthermore, loss of C/EBPß enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBPß promoted the TGF-ß response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBPß as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBPß as a mechanism, which promotes breast cancer progression by shifting the TGF-ß response from growth inhibition to EMT, invasion and metastasis.

Significance of cytomegalovirus infection in the failure of native arteriovenous fistula.

High cytomegalovirus (CMV) IgG levels have been identified as a risk factor for arteriovenous fistula (AVF) failure. None of the 68 patents in our study were CMV IgM positive, although 96% were CMV IgG positive. CMV antigens were detected in the radial artery or cephalic vein of 46% of patients who received an AVF. The presence of CMV antigens or high serum CMV IgG levels had no prognostic value for AVF failure.

Application of nanofiltration for chromium concentration in the tannery wastewater.

The article presents results of investigation concerning an influence of tannery wastewater composition on chromium(III) concentration in the wastewaters during the nanofiltration process (NF). The effectiveness of this process strongly depends on mutual relation between chloride and sulfate ions concentration in tannery wastewater. For this reason, the optimum composition of the tannery wastewater should consist chloride/sulfate ions ratio close to 1. Moreover, an influence of transmembrane pressure (TMP) and the "ageing" of chromium tannery wastewater on the efficiency of the process has been investigated. Optimal range of TMP equal to 14-16 bar has been assumed for the process. It is necessary to point out that the optimum transmembrane pressure can be changed in the case of the membranes with different permeation properties. "Ageing" of the tannery wastewater reduces only a little an efficiency of the process. Experimental results demonstrated that the NF process could be successfully used for the concentration of chromium in the tannery wastewater with high permeate flux, selectivity and performance stability.

Exercise in patients with intermittent claudication elicits signs of inflammation and angiogenesis.

OBJECTIVES: Previous studies have demonstrated elevation of systemic levels of inflammatory cytokines after treadmill exercise in patients with intermittent claudication (IC), but it is unknown if growth factor expression also is stimulated. The aim of this study was to assess whether physical exercise-induced ischemia elicits an inflammatory response and increase in local and systemic vascular growth factor expression in patients with IC. METHODS: Nineteen patients with IC had plasma concentrations of inflammatory markers (IL-6, TNF-alpha, hs-CRP) and vascular growth factors (VEGF and FGF-2) measured before and at four time points after a treadmill exercise test. In 10 patients a gastrocnemius muscle biopsy was obtained to measure VEGF and FGF-2 mRNA. Plasma concentrations of vWF were also measured. Five patients who underwent the treadmill test without experiencing calf pain were enrolled as controls. RESULTS: Plasma concentrations of IL-6 increased after exercise (p=0.004), while TNF-alpha and hs-CRP were unchanged (p=0.191 and p=0.709, respectively). Plasma concentrations of VEGF were similar (p=0.151) at the different time points after exercise but FGF-2 levels decreased (p=0.013). In biopsies after treadmill testing VEGF-A mRNA was increased (p=0.043), but no change was observed for FGF-2 (p=0.456). CONCLUSION: Exercise in IC triggers an inflammatory response as exemplified by elevated concentrations of IL-6. After exercise-induced pain, VEGF mRNA in calf muscle is increased. Therefore, it is plausible that angiogenesis is stimulated by exercise in IC.

Overexpression of CD39/nucleoside triphosphate diphosphohydrolase-1 decreases smooth muscle cell proliferation and prevents neointima formation after angioplasty.

BACKGROUND: Growing evidence implicates the involvement of extracellular nucleotides in the regulation of platelet, leukocyte, endothelial cell (EC) and vascular smooth muscle cell (VSMC) phenotype and function. Within the quiescent vasculature, extracellular nucleotides are rapidly hydrolyzed by CD39, the dominant endothelial nucleoside triphosphate diphosphohydrolase (NTPDase-1). However, vascular CD39/NTPDase-1 activity is lost in EC activated by oxidative stress or proinflammatory mediators, and upon denudation of the endothelium following balloon injury. The consequent increase in extracellular nucleotide concentrations triggers signaling events leading to prothrombotic responses and increased VSMC proliferation. OBJECTIVES: To investigate the effect of overexpressed CD39/NTPDase-1 in injured aorta. METHODS: Using adenoviral-mediated gene transfer we expressed CD39/NTPDase-1 in mechanically denudated rat aortas. We measured intima formation by morphometry and VSMC proliferation by the [(3)H]-thymidine incorporation assay. RESULTS: Targeted expression of CD39 in injured vessels increased NTPDase activity (from 2.91 +/- 0.31 to 22.07 +/- 6.7 nmols Pi mg(-1) protein, 4 days after exposure to the adenovirus) and prevented the formation of neointima. The thickness of the intimal layer in injured aortas exposed to Ad-CD39 was 26.2 +/- 3.9 microm vs. 51.8 +/- 6.1 microm and 64.4 +/- 22.2 microm (P < 0.001) in vessels treated with Ad-beta-gal and saline, respectively. Moreover, targeted expression of CD39/NTPDase-1 caused a 70% (P < 0.01) decrease in proliferation of VSMC isolated from transduced rat aortas as compared with VSMC derived from control vessels. CONCLUSIONS: The presented data suggest that increasing CD39/NTPDase-1 activity in VSMC could represent a novel therapeutic approach for the prevention of stenosis associated with angioplasty and other occlusive vascular diseases.

Fucoidan inhibits smooth muscle cell proliferation and reduces mitogen-activated protein kinase activity.

OBJECTIVES AND DESIGN: fucoidan has previously been shown to inhibit the proliferation of arterial smooth muscle cells both in animal models and in vitro. However, the mechanisms behind the anti-proliferative effects of this polysulfated polysaccharide are not known in detail. Here, the inhibitory effect of fucoidan on rat aortic smooth muscle cell proliferation was examined and compared with the effects of heparin after stimulation with fetal calf serum, platelet-derived growth factor BB, basic fibroblast growth factor, heparin-binding epidermal growth factor, and angiotensin II. MATERIALS AND METHODS: the cultures were analysed with respect to cell proliferation and DNA synthesis by cell counting and measurement of(3)H-thymidine incorporation. Phosphorylation of mitogen-activated protein kinase and nuclear translocation of phosphorylated mitogen-activated protein kinase were studied by immunoblotting and immunocytochemistry. RESULTS: fucoidan was shown to be a more potent inhibitor of smooth muscle cell proliferation than heparin. Fucoidan also reduced growth factor-induced activation of mitogen-activated protein kinase and prevented nuclear translocation of phosphorylated mitogen-activated protein kinase. CONCLUSION: fucoidan is a more potent anti-proliferative polysulphated polysaccharide than heparin and may mediate its effects through inhibition of the mitogen-activated protein kinase pathway in a similar manner as heparin.

Donor DNA can be detected in recipient tissues during rejection of allograft.

The main source of donor DNA in recipients of allograft are "passenger" cells. It is claimed that they are responsible for the posttransplantation microchimerism and prolongation of allograft survival. We have observed that besides cellular microchimerism, donor DNA can be found in the recipient tissues at the time of rejection of the allograft. In this study, we provide evidence for the presence in the recipient of both DNA in "passenger cells" and free DNA in tissues at the terminal stage of rejection. Male BN (RT1 n) rat heart or skin was transplanted to female LEW (RT1 l) rats followed by a vascularized bone marrow in a hindlimb transplant. In another group, heart and skin were transplanted followed by immediate i.v. infusion of donor-type bone marrow cells. CsA was given in a dose of 17 mg/kg body weight for 30 days, then the rats were followed up until day 100 unless rejection occurred earlier. LEW blood, spleen, mesenteric node and bone marrow cells were stained with moAb OX27 specific for BN but not LEW. Genomic male DNA was isolated and amplified with SRY oligonucleotide. At day 30 and day 100 cellular microchimerism was detected in blood, spleen, nodes and bone marrow cells. Donor DNA was detected in recipient skin, liver and heart extracts, as well as lymphoid organs, at the time of rejection of allograft, but not when the rats were maintained on CsA. Taken together, donor DNAwas detected in recipient tissues at the time of heart or skin rejection. It appeared to be released from cells of rejecting grafts and not from "passenger" cells, representing only a minor cellular mass compared with the graft.

Arteriosclerosis in rat aortic allografts: early changes in endothelial integrity and smooth muscle phenotype.

BACKGROUND: Transplant arteriosclerosis remains a limiting factor for the long-term survival of transplanted organs and effective treatment is lacking. A rat model of aortic allografts was used to analyze this process by electron microscopy and further characterize the phenotypic properties of the cells involved. METHODS: A segment of abdominal aorta was transplanted orthotopically from Fischer to Lewis rats. The animals were killed 1-12 weeks after the operation (four to six rats/group), and the grafts were removed and processed for microscopy. RESULTS: The first changes (1 week) included detachment of endothelial cells, adhesion of degranulating platelets to the subendothelial matrix, and modification of smooth muscle cells in the media. The latter process was distinguished by loss of myofilaments and formation of a prominent endoplasmic reticulum and Golgi complex (shift from contractile to synthetic phenotype). Subsequently, modified smooth muscle cells invaded the intima. In parallel, lymphocytes and monocytes/macrophages infiltrated the intima and adventitia. The neointima grew in size by cell proliferation and production of extracellular matrix (4-8 weeks). Smooth muscle cells and monocytes/macrophages in the neointima and media were also noted to accumulate cytoplasmic lipid droplets and eventually turn into foam cells and die. Within the lipid-rich cell remnants, calcification occurred. Finally (12 weeks), the growth in mass of the intimal lesions ceased and in some places reformation of an endothelial lining was detected. Few viable smooth muscle cells remained in the media and the inflammatory infiltrate in the adventitia was reduced. CONCLUSIONS: These observations highlight the importance of early changes in endothelial integrity and smooth muscle phenotype in the development of allograft vascular disease and form the basis for a partly modified model of the cellular mechanisms in this process.

DNA from rejecting allografts can be detected in recipient nonlymphoid tissues.

The main source of donor DNA in recipients of allograft are "passenger" cells. They are claimed to be responsible for the posttransplantation microchimerism and prolongation of allograft survival. We have noticed that beside of the cellular microchimerism, donor DNA can be found in the recipient tissues at the time of rejection of allograft. In this study we provide evidence for presence in the recipient of both, DNA in "passenger cells" and free DNA in tissues at terminal stage of rejection. Male BN (RTIn) rat heart or skin were transplanted to female LEW (RTII) rats followed by a vascularized bone marrow in hind-limb transplant. CsA was given in a dose of 17mg/kg b.w. for 30 days, then rats were followed until day 100 unless rejection occurred earlier. LEW blood, spleen, mesenteric node and bone marrow cells were stained with moAb OX27 specific for BN but not LEW. Genomic male DNA was isolated and amplified with SRY oligonucleotide. At day 30 and 100 cellular microchimerism was detected in blood, spleen, nodes and bone marrow cells. Donor DNA was detected in recipient skin, liver and heart extracts, beside of lymphoid organs, at the time of rejection of allograft but not when rats were maintained on CsA. Taken together, donor DNA can be detected in recipient tissues at the time of heart or skin rejection. It seems to be released from cells of rejecting grafts and not from "passenger" cells representing only a minor cellular mass compared with the graft.

Tolerance induction following allogeneic vascularized bone marrow transplantation--the possible role of microchimerism.

We have noticed that bone marrow transplanted in a vascularized limb graft, providing a continuous supply of donor bone marrow cells (BMC), may prolong the survival time of a skin graft from the same donor. The question arises whether the microchimerism raised plays a role in the prolonged survival of skin allografts. The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMTx) concomitantly with the rejection process of transplanted skin. Brown Norway (BN) rats served as donors and Lewis rats as recipients of VBMTx and free skin flap allografts. A hind limb was transplanted, followed by a full-thickness skin graft on the dorsum. Cellular microchimerism was investigated in recipients of VBMTx and skin grafts in blood, spleen, mesenteric lymph node, and bone marrow with the monoclonal antibody OX27 directed against MHC class I polymorphic RT1 on BN cells and quantitatively analyzed in a FACStar. In the VBMTx group, the free skin flap survived 70 days after weaning off cyclosporine A (CsA). An intravenous infusion of BMC in suspension equivalent to that grafted in the hind limb did not prolong skin graft survival after cessation of CsA therapy. Donor-derived cells could be detected in VBMTx recipients as long 70 days after weaning off CsA but not in recipients of i.v. suspension BMC grafting.