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Biomedical subjects

A E May

Publications and source records attributed to A E May.

At least 19 recordsLinked to original sources
PubMed2000

VLA-4 (alpha(4)beta(1)) engagement defines a novel activation pathway for beta(2) integrin-dependent leukocyte adhesion involving the urokinase receptor.

During acute inflammatory processes, beta(2) and beta(1) integrins sequentially mediate leukocyte recruitment into extravascular tissues. We studied the influence of VLA-4 (very late antigen-4) (alpha(4)beta(1)) engagement on beta(2) integrin activation-dependent cell-to-cell adhesion. Ligation of VLA-4 by the soluble chimera fusion product vascular cell adhesion molecule-1 (VCAM-1)-Fc or by 2 anti-CD29 (beta(1) chain) monoclonal antibodies (mAb) rapidly induced adhesion of myelomonocytic cells (HL60, U937) to human umbilical vein endothelial cells (HUVECs). Cell adhesion was mediated via beta(2) integrin (LFA-1 and Mac-1) activation: induced adhesion to HUVECs was inhibited by blocking mAbs anti-CD18 (70%-90%), anti-CD11a (50%-60%), or anti-CD11b (60%-70%). Adhesion to immobilized ligands of beta(2) integrins (intercellular adhesion molecule-1 [ICAM-1], fibrinogen, keyhole limpet hemocyanin) as well as to ICAM-1-transfected Chinese hamster ovary cells, but not to ligands of beta(1) integrins (VCAM-1, fibronectin, laminin, and collagen), was augmented. VCAM-1-Fc binding provoked the expression of the activation-dependent epitope CBRM1/5 of Mac-1 on leukocytes. Clustering of VLA-4 through dimeric VCAM-1-Fc was required for beta(2) integrin activation and induction of cell adhesion, whereas monovalent VCAM-1 or Fab fragments of anti-beta(1) integrin mAb were ineffective. Activation of beta(2) integrins by alpha(4)beta(1) integrin ligation (VCAM-1-Fc or anti-beta(1) mAb) required the presence of urokinase receptor (uPAR) on leukocytic cells, because the removal of uPAR from the cell surface by phosphatidylinositol-specific phospholipase C reduced cell adhesion to less than 40%. Adhesion was reconstituted when soluble recombinant uPAR was allowed to reassociate with the cells. Finally, VLA-4 engagement by VCAM-1-Fc or anti-beta(1) integrin mAb induced uPAR-dependent adhesion to immobilized vitronectin as well. These results elucidate a novel activation pathway of beta(2) integrin-dependent cell-to-cell adhesion that requires alpha(4)beta(1) integrin ligation for initiation and uPAR as activation transducer. (Blood. 2000;96:506-513)

Antibodies, Monoclonal↗
PubMed1999

Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and beta2-integrins.

The trace element Zinc (Zn2+) has been implicated as a mediator in host defense, yet the molecular basis for its extracellular functions remains obscure. Here, we demonstrate that Zn2+ can induce the adhesion of myelomonocytic cells to the endothelium, as well as to the provisional matrix proteins vitronectin (VN) and fibrinogen (FBG), which are pivotal steps for the recruitment of leukocytes into inflamed/injured tissue. Physiologic concentrations of Zn2+ increased the urokinase receptor (uPAR)-mediated adhesion of myelomonocytic cells to VN, whereas other divalent cations had smaller effects. Zn2+-induced cell adhesion to VN was abolished by cation chelators such as 1-10-phenanthroline, as well as by plasminogen activator inhibitor-1 (PAI-1) and a monoclonal antibody (MoAb) against uPAR. These characteristics could be recapitulated with a uPAR-transfected cell line emphasizing the specificity of this receptor system for Zn2+-dependent cell adhesion. Like urokinase (uPA), Zn2+ increased the binding of radiolabeled VN to uPAR-expressing cells, as well as the interaction of VN with immobilized uPAR in an isolated system. Moreover, Zn2+ enhanced leukocytic cell adhesion to FBG and endothelial cell monolayers by activating beta2-integrins. Instead of the direct beta2-integrin activation through the divalent cation binding site, Zn2+-induced integrin activation was mediated via uPAR, a crucial regulator of this system. The present study uncovers for the first time Zn2+-mediated cell adhesion mechanisms that may play a crucial role in modulating leukocyte adhesion to vessel wall components.

Antibodies, Monoclonal↗
PubMed1999

The dual role of the urokinase receptor system in pericellular proteolysis and cell adhesion: implications for cardiovascular function.

Cell-cell and cell-matrix interactions are key events in morphogenetic processes during development and tissue remodelling. In the vascular system, overexpression of adhesion receptors such as integrins, protease (receptors) or dysregulation of adhesive interactions are directly related to the pathophysiology of cardiovascular diseases (atherosclerosis, restenosis, thrombosis) or angiogenesis-driven tumor progression. Protease cascades such as the plasminogen activation system exhibit a dual role in cell invasion by promoting pericellular proteolysis as well as by regulating cell adhesion and migration in a non-proteolytic fashion. In both these mechanisms, the urokinase receptor (uPAR) plays a central role and may become engaged in complexes with beta1-, beta2-, and beta3-integrins. This article will focus on the molecular and functional interactions between the uPAR system and vascular integrins and discuss implications for cardiovascular function.

Animals↗
PubMed1999

Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers.

Circulating monocytes and T lymphocytes extravasate through the endothelium at sites of developing atheromatous lesions, where they tend to accumulate and mediate the progression of the disease. We have previously demonstrated the presence of an enzymatically degraded, nonoxidized form of LDL (E-LDL) in early human fatty streaks, which possesses major biological properties of an atherogenic lipoprotein. The effects of E-LDL on human endothelial cells have now been studied with respect to adhesion and transmigration of monocytes and T lymphocytes. E-LDL induced a rapid and dose-dependent selective adhesion of monocytes and T lymphocytes to endothelial cell monolayers within 30 minutes of incubation. Maximal increases in the number of adherent monocytes (8-fold) and of adherent T lymphocytes (4-fold) were observed after treatment with 50 microg/mL E-LDL. E-LDL was more active than oxidized LDL (ox-LDL), whereas native LDL produced only minor adhesive effects. Both E-LDL and ox-LDL enhanced transmigration of monocytes and of T lymphocytes through endothelial monolayers. Again, E-LDL was more potent than ox-LDL, inducing transmigration to a similar extent as N-formyl-Met-Leu-Phe. In endothelial cells, E-LDL stimulated upregulation of intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cells adhesion molecule-1 (PECAM-1), P-selectin, and E-selectin with distinct kinetics. Analyses with blocking antibodies indicated that ICAM-1 and P-selectin together mediated approximately 70% of cell adhesion, whereas blocking of PECAM-1 had no effect on adhesion but reduced transmigration to less than 50% of controls. E-LDL also upregulated expression of ICAM-1 in human aortic smooth muscle cells, and this correlated with increased adhesion of T lymphocytes. E-LDL is thus able to promote the selective adhesion of monocytes and T lymphocytes to the endothelium, stimulate transmigration of these cells, and foster their retention in the vessel wall by increasing their adherence to smooth muscle cells. These findings underline the potential significance of E-LDL in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed1999

The relevance of blood cell-vessel wall adhesive interactions for vascular thrombotic disease.

Activation and signaling of circulating blood and vessel wall cells, as well as their direct adhesive interactions, are critical for the regulation of vascular homeostasis related to vasomotor responses, inflammation, hemostasis, and wound repair. Under conditions of stress, inflammation, or infection the targeting and anchoring of leukocytic cells to the vascular endothelium is mediated by specific pairs of adhesion receptors and their counter-ligands that may induce juxtacrine signaling resulting in the expression of prothrombotic agonists such as tissue factor. Concomitant action of inflammatory cytokines may down-regulate thromboprotective mechanisms of the endothelium. Through similar intercellular interactions, the platelets recruited to these inflamed sites may aggregate and modulate leukocyte function. In addition, leukocytes can influence coagulation by their ability to produce pro- and anticoagulant factors as well as by providing specific receptors (such as Mac-1 or EPR-1) that serve as direct molecular links between inflammation and hemostasis. The initiation and amplification of blood clotting reactions on the leukocyte surface has consequences on other vascular cell functions and involves (cytokine) activation and signaling pathways that contribute to pathophysiological aspects of inflammatory responses. As a consequence, the diverse cell-to-cell interactions, as well as different inflammatory mediators or bidirectional signaling pathways, appear to be promising targets for the treatment of thrombotic complications in the context of inflammation-dependent vascular diseases.

Animals↗
PubMed1998

Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo.

The urokinase receptor (CD87; uPAR) is found in close association with beta 2 integrins on leukocytes. We studied the functional consequence of this association for leukocyte adhesion and migration. In vivo, the beta 2 integrin-dependent recruitment of leukocytes to the inflamed peritoneum of uPAR-deficient mice was significantly reduced as compared with wild-type animals. In vitro, beta 2 integrin-mediated adhesion of leukocytes to endothelium was lost upon removal of uPAR from the leukocyte surface by phosphatidyl-inositol-specific phospholipase C. Leukocyte adhesion was reconstituted when soluble intact uPAR, but not a truncated form lacking the uPA-binding domain, was allowed to reassociate with the cell surface. uPAR ligation with a monoclonal antibody induced adhesion of monocytic cells and neutrophils to vascular endothelium by six- to eightfold, whereas ligation with inactivated uPA significantly reduced cell-to-cell adhesion irrespective of the beta 2 integrin-stimulating pathway. These data indicate that beta 2 integrin-mediated leukocyte-endothelial cell interactions and recruitment to inflamed areas require the presence of uPAR and define a new phenotype for uPAR-deficient mice. Moreover, uPAR ligation differentially modulates leukocyte adhesion to endothelium and provides novel targets for therapeutic strategies in inflammation-related vascular pathologies.

Animals↗
PubMed1998

The effects of pain and its management on mother and fetus.

Childbirth is frequently accompanied by pain. For religious, cultural and philosophical reasons many groups have sought to prevent treatment of pain. Pain may have adverse effects on the mother and fetus. The psychological effects of severe pain should not be overlooked particularly where it is associated with an adverse fetal or maternal outcome. There are a number of different forms of pain relief in labour with differing side-effects and efficacies. The controversy concerning medical management of women in labour has been used to dissuade women from requesting pain relief. This debate has encouraged the use of a patient-centred philosophy of care that encourages the patient to retain control. However, good pain relief may allow the women to retain control if administered in a sensitive manner. The ideal analgesic in labour is discussed. Recent and future developments of analgesia in childbirth are discussed with respect to this.

Acupuncture Analgesia↗
PubMed1998

Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation.

Lipodermatosclerosis refers to skin induration of the lower extremities and is associated with patients preceding venous ulcerations. To better understand the pathogenesis of ulcer formation we investigated the expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in lipodermatosclerosis. By preparing biopsies from healthy skin and liposclerotic lesions, MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were analyzed by using reverse transcriptase-polymerase chain reaction, western blot, zymography, hydrolysis of [3H]labeled collagens, and immunohistochemistry. Our investigations provide evidence that mRNA and protein expression of MMP-1, MMP-2, and TIMP-1 were significantly increased in lipodermatosclerosis, whereas the total amount of MMP-9 and TIMP-2 mRNA and protein was not altered. Western blot of liposclerotic lesions revealed an inactive proMMP-1-TIMP-1 complex, whereas MMP-2 was prominent as an active 66 kDa band. Increased proteolytic activity of MMP-2 could be proven in lesional in comparison with healthy skin by zymography and [3H] collagen degradation. Increased diffuse staining was found for MMP-1 in the epidermis and dermis in comparison with controls. In lipodermatosclerosis, MMP-2 was predominantly localized in the basal and suprabasal layers of the epidermis, in perivascular regions, and in the reticular part of the dermis. Furthermore, MMP-2 was imbalanced by locally reduced expression of TIMP-2 in the basement membrane zone of lesional skin. Our findings indicate lipodermatosclerosis to be characterized by elevated matrix turnover.

Collagen↗
PubMed1997

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation.

BACKGROUND: Monocyte activation induces different procoagulant and proadhesive inflammatory responses and thus may play a role in thrombotic complications after coronary interventions. Monocyte-platelet interaction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulation therapy on monocyte-platelet interaction and monocyte function after intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successful coronary stenting, monocyte-platelet conjugates and monocyte function were assessed by flow cytometric detection of GPIIb/IIIa (CD41) on monocytes and by monocyte surface exposure of Mac-1 (CD11b/CD18) and L-selectin (CD62L). Twenty patients receiving combined antiplatelet therapy (ticlopidine, aspirin) were compared to 20 patients with standard anticoagulation (phenprocoumon, overlapping heparin, aspirin). Before stenting, monocyte-platelet conjugates and Mac-1 surface expression in both groups were significantly increased, while L-selectin was significantly diminished. Anticoagulation did not change these variables significantly during the subsequent 12 days. In contrast, antiplatelet therapy reduced platelet-monocyte conjugates by 46 +/- 9.3% (mean +/- SEM, P = 0.0019) within 4 days, which was associated with a decrease in Mac-1 expression (28 +/- 6.7%, P = 0.0013) and an increase in L-selectin (56 +/- 15.0%, P = 0.0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy, but not anticoagulation, causes reduction of monocyte-platelet interaction, which is associated with monocyte deactivation. This may contribute to a decreased risk for thrombotic events.

Adult↗
PubMed1997

A survey of how British obstetric anaesthetists test regional anaesthesia before caesarean section.

We surveyed members of the Obstetric Anaesthetists Association asking how they tested regional blocks prior to Caesarean section. A large proportion of these anaesthetists appear to test their blocks inadequately. Temperature sensation was the most common sensory modality tested (64%) and 79% of those who tested for temperature sensation used an ethyl chloride spray.

Anesthesia, Conduction↗
PubMed1997

Molecular crosstalk between adhesion receptors and proteolytic cascades in vascular remodelling.

The multifunctionality of adhesion receptor ligands as well as the promiscuous nature of vascular integrins and nonintegrin-dependent adhesive interactions allow ligand-receptor binding of variable strength. The cooperation with pericellular proteolysis cascades is required for vascular remodelling during angiogenesis, atherogenesis or inflammatory processes. In particular, integrin-dependent cell contact, spreading and (trans-)migration can be modulated by ECM-associated PAI-1 and uPA-receptor driven reactions that are intimately linked to the invasive potential of cells. Recently, mechanisms of molecular crosstalk between these receptor systems have been recognized: (a) uPA-receptor may directly interact with beta 1- and beta 2-integrins on circulating blood cells; (b) av beta 3-integrin-directly binds to a matrix metalloproteinase; (c) uPA and PAI-1 balance the high affinity binding of vitronectin to uPA-receptor; (d) vitronectin-dependent cell adhesion and migration involving alpha v-integrins or uPA-receptor are blocked by active PAI-1 independent of its role as protease inhibitor. These results are compatible with vascular injury studies in uPA- and PAI-1 knock-out mice and provide new targets for the treatment of diseases associated with imbalanced vascular remodelling.

Animals↗
PubMed1993

Long-term backache after extradural or general anaesthesia for manual removal of placenta: preliminary report.

A questionnaire designed to investigate the incidence of newly acquired, long-term backache was sent to women who had previously undergone manual removal of the placenta during a 12-month period in one maternity hospital. There was a significantly greater incidence of long-term backache in patients who had extradural anaesthesia specifically for manual removal of the placenta compared with patients receiving a general anaesthetic for the same procedure. The results of this retrospective study in a small population warrant examination in a large, prospective, controlled investigation.

Anesthesia, Epidural↗
PubMed1990

A comparison of the effects of alfentanil/droperidol or fentanyl/droperidol on intra-ocular pressure.

The influence of two intravenous sedative regimens on intra-ocular pressure was investigated in conjunction with retrobulbar local anaesthesia. Forty patients were allocated randomly to either group A (alfentanil and droperidol) or group F (fentanyl and droperidol). Measurements of intra-ocular pressure, arterial pressure and oxygen saturation were made before operation, after premedication, after intravenous sedation and after surgery. Paco2 was also measured before and after operation. Each sedation technique caused a similar reduction in intra-ocular pressure. There was less effect on Paco2 and oxygenation in group A.

Aged↗