Main Clinical Use of Additive Manufacturing (Three-Dimensional Printing) in Finland Restricted to the Head and Neck Area in 2016-2017.

BACKGROUND AND AIMS: Additive manufacturing or three-dimensional printing is a novel production methodology for producing patient-specific models, medical aids, tools, and implants. However, the clinical impact of this technology is unknown. In this study, we sought to characterize the clinical adoption of medical additive manufacturing in Finland in 2016-2017. We focused on non-dental usage at university hospitals. MATERIALS AND METHODS: A questionnaire containing five questions was sent by email to all operative, radiologic, and oncologic departments of all university hospitals in Finland. Respondents who reported extensive use of medical additive manufacturing were contacted with additional, personalized questions. RESULTS: Of the 115 questionnaires sent, 58 received answers. Of the responders, 41% identified as non-users, including all general/gastrointestinal (GI) and vascular surgeons, urologists, and gynecologists; 23% identified as experimenters or previous users; and 36% identified as heavy users. Usage was concentrated around the head area by various specialties (neurosurgical, craniomaxillofacial, ear, nose and throat diseases (ENT), plastic surgery). Applications included repair of cranial vault defects and malformations, surgical oncology, trauma, and cleft palate reconstruction. Some routine usage was also reported in orthopedics. In addition to these patient-specific uses, we identified several off-the-shelf medical components that were produced by additive manufacturing, while some important patient-specific components were produced by traditional methodologies such as milling. CONCLUSION: During 2016-2017, medical additive manufacturing in Finland was routinely used at university hospitals for several applications in the head area. Outside of this area, usage was much less common. Future research should include all patient-specific products created by a computer-aided design/manufacture workflow from imaging data, instead of concentrating on the production methodology.

Plasma levels of hepatocyte growth factor and placental growth factor predict mortality in a general population: a prospective cohort study.

BACKGROUND: Circulating levels of growth factors involved in leucocyte production and angiogenesis could be indicative of underlying aberrations of tissue homeostasis and therefore be utilized as predictors of risk for all-cause cardiovascular disease (CVD) or cancer mortality. METHODS: Baseline plasma levels of a range of growth factors were measured in two cohorts of the population-based FINRISK study (1997 Discovery cohort, N = 8444, aged 25-74; 2002 Replication cohort, N = 2951, aged 51-74 years) using a multiplexed bead array methodology and ELISA. Participants were followed up by linking them to registry data. RESULTS: In the Discovery cohort (653 deaths; 216 CVD-related, 231 cancer-related), fully adjusted Cox proportional hazard regression models showed that increased plasma hepatocyte growth factor (HGF) and placental growth factor (PlGF) were associated with higher risk of 10-year mortality (HR, 1.29 [95% confidence interval (CI), 1.18-1.41] and HR, 1.23 [95% CI, 1.14-1.32], respectively). In the Replication cohort (259 deaths; 83 CVD-related, 90 cancer-related), baseline HGF levels also predicted all-cause mortality (HR, 1.2 [95% CI, 1.08-1.32]; PlGF data not available). By including HGF levels in a CVD mortality model, 9% of all CVD deaths were correctly reclassified in the Discovery cohort (categorical net reclassification improvement [NRI] for events, P = 4.0 × 10-4 ). Moreover, adding HGF to all-cause and CVD mortality models resulted in an overall clinical NRI of 0.10-0.18 in the Discovery cohort and meta-analyses (P < 0.05 for all tests). CONCLUSION: Blood levels of HGF and PlGF may serve as new biomarkers for predicting increased risk of death in the general population.

An autonomous lab on a chip for space flight calibration of gravity-induced transcellular calcium polarization in single-cell fern spores.

This report describes the development of lab-on-a-chip device designed to measure changes in cellular ion gradients that are induced by changes in gravitational (g) forces. The bioCD presented here detects differential calcium ion concentrations outside of individual cells. The device includes sufficient replicates for statistical analysis of the gradients around multiple single cells and around control wells that are empty or include dead cells. In the data presented, the degree of the cellular response correlates with the magnitude of the g-force applied via rotation of the bioCD. The experiments recorded the longest continuous observation of a cellular response to hypergravity made to date, and they demonstrate the potential utility of this device for assaying the threshold of cells' g-force responses in spaceflight conditions.

Three-dimensional printing for restoration of the donor face: A new digital technique tested and used in the first facial allotransplantation patient in Finland.

BACKGROUND AND AIMS: Prosthetic mask restoration of the donor face is essential in current facial transplant protocols. The aim was to develop a new three-dimensional (3D) printing (additive manufacturing; AM) process for the production of a donor face mask that fulfilled the requirements for facial restoration after facial harvest. MATERIALS AND METHODS: A digital image of a single test person's face was obtained in a standardized setting and subjected to three different image processing techniques. These data were used for the 3D modeling and printing of a donor face mask. The process was also tested in a cadaver setting and ultimately used clinically in a donor patient after facial allograft harvest. RESULTS: and Conclusions: All the three developed and tested techniques enabled the 3D printing of a custom-made face mask in a timely manner that is almost an exact replica of the donor patient's face. This technique was successfully used in a facial allotransplantation donor patient.

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy.

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).

Inhibition of semicarbazide-sensitive amine oxidases decreases lymphocyte infiltration in the early phases of rat liver allograft rejection.

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation in vitro and in vivo. VAP-1 is also an ectoenzyme with semicarbazide-sensitive amine oxidase (SSAO) activity. In this study we investigated whether inhibition of SSAO influences the inflammatory infiltration in acute rat liver allograft rejection. BN recipients of DA liver allografts were treated with 50 mg/kg/d semicarbazide, an inhibitor of SSAO, or similar volumes of saline. 10 rats/group were followed for graft survival, and 10 rats/group were sacrificed on day 7 post-transplantation for histology and T-lymphocyte isolation. The area percentage of portal inflammatory infiltrates in the grafts was assessed from digital photomicrographs. The proportion of CD4-, CD8- and IL2-receptor positive lymphocytes in the graft was quantified with flow cytometry. On day 7, semicarbazide treatment significantly decreased the inflammatory infiltrate area in the grafts. CD4-, CD8- and IL2-receptor positive cells were equally affected. However, animal survival was not affected. Blockade of the enzymatic activity of VAP-1 has a significant effect on lymphocyte infiltration early in acute liver rejection. Later, activation of other adhesion pathways can by-pass the blockade caused by VAP-inhibition.

Vascular adhesion protein-1 (VAP-1) mediates lymphocyte-endothelial interactions in chronic kidney rejection.

The pathogenesis of chronic kidney rejection characterized by persistent low-level inflammation and intimal thickening of the arteries in the graft remains poorly understood. We studied whether two important endothelial adhesion molecules, vascular adhesion molecule-1 (VAP-1) and peripheral node addressin (PNAd), would contribute to the lymphocyte recruitment into the rejected organ. VAP-1 was found to be present both in the normal kidney and prominently also in the chronically rejected kidneys. In the kidney VAP-1 was a homodimeric sialoglycoprotein expressed in peritubular capillaries, but not on glomerular endothelium or on tubular cells. In contrast, PNAd was absent from all kidney samples, indicating that kidney inflammation differs from other sites of chronic inflammation. Blocking of VAP-1 with mAbs abolished > 50 % of lymphocyte binding to renal vessels in rejected kidney in in vitro adhesion assays. Levels of circulating soluble VAP-1 (sVAP-1) decreased back to normal levels in patients with well-functioning transplants. These results are the first evidence that VAP-1 is able to mediate leukocyte binding into a rejected organ. Thus, anti-adhesive therapies targeting VAP-1 may be useful in controlling chronic kidney graft rejection.

Distinct ligand binding properties of Mac-2-binding protein and mouse cyclophilin [correction of mousephilin] C-associated protein.

Human Mac-2-binding protein (Mac-2-BP) is a secreted glycoprotein that is widely expressed. It binds to the human macrophage-associated lectin Mac-2 and has been suggested to have a role in host defence. Mouse cyclophilin C-associated protein (mCyCAP) is also a secreted glycoprotein that binds with high affinity to cyclophilin C in the absence of the immunosuppressive drug cyclosporin A. The two proteins share a similar domain structure and considerable sequence identity, including a highly conserved scavenger receptor cysteine-rich domain, and both of them exert their function within the immune system. To elucidate whether these molecules are also functional homologues, we compared their ligand binding properties using cell lines which express Mac-2-BP or mCyCAP as well as transfected cell lines stably expressing mCyCAP or a mutant version lacking the scavenger domain. These experiments show that Mac-2-BP is unable to bind to either human or mouse cyclophilin C and thatmCyCAP cannot bind to Mac-2. The scavenger domain is not required for the interaction between mCyCAP and cyclophilin C. We conclude that these proteins may be part of a larger family of proteins of immunological importance in which closer functional homologues might exists.

Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium.

Continuous lymphocyte recirculation between blood and lymphoid tissues forms a basis for the function of the immune system. Lymphocyte entrance from the blood into the tissues has been thoroughly characterized, but mechanisms controlling lymphocyte exit from the lymphoid tissues via efferent lymphatics have remained virtually unknown. In this work we have identified mannose receptor (MR) on human lymphatic endothelium and demonstrate its involvement in binding of lymphocytes to lymphatic vessels. We also show that the binding requires L-selectin, and L-selectin and MR form a receptor-ligand pair. On the other hand, L-selectin binds to peripheral lymph node addressins (PNAds) on high endothelial venules (HEVs) that are sites where lymphocytes enter the lymphatic organs. Interestingly, MR is absent from HEVs and PNAds from lymphatic endothelium. Thus, lymphocyte L-selectin uses distinct ligand molecules to mediate binding at sites of lymphocyte entrance and exit within lymph nodes. Taken together, interaction between L-selectin and MR is the first molecularly defined mechanism mediating lymphocyte binding to lymphatic endothelium.

Immune cell trafficking in uterus and early life is dominated by the mucosal addressin MAdCAM-1 in humans.

BACKGROUND & AIMS: In adults, binding of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) to lymphocyte alpha4beta7 integrin directs cell trafficking to gut, whereas interaction of peripheral node addressins (PNAd) with lymphocyte L-selectin targets immune cells to peripheral lymph nodes (PLNs). Because nothing is known about these addressins during human development, we studied the expression and function of MAdCAM-1 (and PNAd for comparison) in fetuses and children. METHODS: Series of human tissue samples obtained from fetuses (7-40 weeks), children (2 months-7 years), and adults were immunostained with monoclonal antibodies. The function of the addressins and their lymphocyte counter-receptors was tested in in vitro binding assays on fetal and adult tissues. RESULTS: Unlike in adults, MAdCAM-1 is widely expressed from embryonic week 7 onwards, and it only gradually becomes polarized to mucosal vessels after birth. In utero MAdCAM-1 functionally governs lymphocyte adhesion to vessels both in the gut and PLNs by binding to alpha4beta7 integrin. The later induction of PNAd gradually starts to dominate the binding of lymphocytes to PLNs during childhood. CONCLUSIONS: There are striking age-dependent switches and species-specific variation in the molecular mechanisms of lymphocyte migration. In utero and during early childhood, the mucosal addressin MAdCAM-1 plays a dominant role in lymphocyte-endothelial cell adhesion at mucosal and nonmucosal sites.

Cell surface monoamine oxidases: enzymes in search of a function.

Ectoenzymes with a catalytically active domain outside the cell surface have the potential to regulate multiple biological processes. A distinct class of copper-containing semicarbazide-sensitive monoamine oxidases, expressed on the cell surface and in soluble forms, oxidatively deaminate primary amines. Via transient covalent enzyme-substrate intermediates, this reaction results in production of aldehydes, hydrogen peroxide and ammonium, which are all biologically active substances. The physiological functions of these enzymes have remained unknown, although they have been suggested to be involved in the metabolism of biogenic amines. Recently, new roles have been proposed for these enzymes in regulation of glucose uptake and, even more surprisingly, in leukocyte-endothelial cell interactions. The emerging functions of ectoenzymes in signalling and cell-cell adhesion suggest a novel mode of molecular control of these complex processes.

Vascular adhesion protein 1 mediates binding of immunotherapeutic effector cells to tumor endothelium.

Tumor-infiltrating lymphocytes (TIL) can be used as an immunotherapeutic tool to treat cancer. Success of this therapy depends on the homing and killing capacity of in vitro-activated and -expanded TIL. Vascular adhesion protein 1 (VAP-1) is an endothelial molecule that mediates binding of lymphocytes to vessels of inflamed tissue. Here, we studied whether VAP-1 is involved in binding of TIL, lymphokine-activated killer (LAK) cells, and NK cells to vasculature of the cancer tissue. We demonstrated that VAP-1 is expressed on the endothelium of cancer vasculature. The intensity and number of positive vessels varied greatly between the individual specimens, but it did not correlate with the histological grade of the cancer. Using an in vitro adhesion assay we showed that VAP-1 mediates adhesion of TIL, LAK, and NK cells to cancer vasculature. Treatment of the tumor sections with anti-VAP-1 Abs diminished the number of adhesive cells by 60%. When binding of different effector cell types was compared, it was evident that different cancer tissues supported the adhesion of TIL to a variable extent and LAK cells were more adhesive than TIL and NK cells to tumor vasculature. These data suggest that VAP-1 is an important interplayer in the antitumor response. Thus, by up-regulating the expression of VAP-1 in tumor vasculature, it can be possible to improve the effectiveness of TIL therapy.

A cell surface amine oxidase directly controls lymphocyte migration.

Lymphocytes leave the blood using a sequential adhesion cascade. Vascular adhesion molecule-1 (VAP-1) is a surface-expressed endothelial glycoprotein, which belongs to a distinct subgroup of monoamine oxidases. We show here that catalytic activity of VAP-1 on primary endothelial cells directly regulates lymphocyte rolling under defined laminar shear. VAP-1 seems to bind to a primary amino group presented on the lymphocyte surface and oxidatively deaminate it in a reaction, which results in the formation of a transient covalent bond between the two cell types. Instead, soluble reaction products (aldehydes and hydrogen peroxide) are not needed for the VAP-1-dependent rolling. Enzymatic regulation of lymphocyte adhesion to endothelium provides a previously unrecognized rapid way of controlling the extravasation process.

Human leukocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules.

Reactive arthritis can be triggered by inflammatory bowel diseases. We hypothesized that migration of mucosal immune cells from inflamed gut to joints could contribute to the development of reactive arthritis. Here we isolated gut-derived leukocytes from patients with Crohn's disease and ulcerative colitis. Using function-blocking mAbs and in vitro frozen section adhesion assays we studied whether these cells bind to synovial vessels and which molecules mediate the interaction. The results showed that mucosal leukocytes from inflammatory bowel diseased gut bind well to venules in synovial membrane. Small intestinal lymphocytes adhered to synovial vessels using multiple homing receptors and their corresponding endothelial ligands (CD18-ICAM-1, alpha(4)beta(7)/alpha(4)beta(1)-integrin-VCAM-1, L-selectin-peripheral lymph node addressins, and CD44). Of these, only ICAM-1 significantly supported binding of immunoblasts. In contrast, P-selectin glycoprotein ligand-1-P-selectin interaction accounted for practically all synovial adherence of mucosal macrophages. In addition, blocking of vascular adhesion protein-1 significantly inhibited binding of all these leukocyte subsets to joint vessels. We conclude that different leukocyte populations derived from inflamed gut bind avidly to synovial vessels using distinct repertoire of adhesion molecules, suggesting that their recirculation may contribute to the development of reactive arthritis in inflammatory bowel diseases.

VAP-1: an adhesin and an enzyme.

Leukocyte extravasation from the blood into tissues is of paramount importance for normal immunosurveillance and in mounting adequate inflammatory responses. Multiple traditional adhesion molecules and chemoattractants on leukocytes and endothelial cells are involved in the emigration process. Vascular adhesion protein 1 (VAP-1) is a nonclassical inflammation-inducible endothelial molecule involved in leukocyte-subtype-specific rolling under physiological shear. Molecularly, VAP-1 belongs to a special class of cell surface amino oxidases. The enzymatic reaction itself and the biologically active end products can potentially regulate the adhesive status of the vessel wall. Thus, VAP-1 is an ectoenzyme that has inter-related adhesive and enzymatic functions in regulating physiological trafficking and inflammation.

Vascular adhesion protein 1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo.

Granulocyte extravasation from the blood into tissues is a prerequisite for a proper inflammatory response. It is regulated by a multistep adhesion cascade consisting of successive contacts between leukocyte surface receptors and their endothelial ligands on vessels. Vascular adhesion protein 1 (VAP-1) is an endothelial surface glycoprotein with two functions. It is an enzyme (monoamine oxidase) and an adhesion molecule for lymphocytes. Its function in binding of granulocytes or in leukocyte trafficking into sites of inflammation in vivo has remained unknown. Here we show that treatment of rabbits with anti-VAP-1 monoclonal antibodies abrogates approximately 70% of granulocyte extravasation into a site of an experimental inflammation. Using intravital microscopy, VAP-1 blockade is shown to increase the velocity of the rolling granulocytes and the frequency of their jerky skippings during the rolling. In addition, the number of firmly bound leukocytes decreased by 44% when VAP-1 was rendered nonfunctional. Our results suggest that VAP-1 functions as a molecular brake early in the adhesion cascade and consequently decreases the firm adherence; it may also directly influence the transmigration step. These data elucidate a new interplayer in the granulocyte extravasation process and provide a novel physiological function for a member of the monoamine oxidase family.

Circulating soluble vascular adhesion protein 1 accounts for the increased serum monoamine oxidase activity in chronic liver disease.

BACKGROUND & AIMS: Vascular adhesion protein 1 (VAP-1) is an endothelial glycoprotein that supports adhesion of lymphocytes to hepatic endothelium and has sequence homology with semicarbazide-sensitive amine oxidases (SSAOs). We investigated whether soluble VAP-1 (sVAP-1) displays SSAO activity and thereby accounts for increased monoamine oxidase activity in the serum of patients with liver diseases. METHODS: sVAP-1 concentration and SSAO activity were measured in peripheral, hepatic, and portal blood and in bile from patients with liver disease and in peripheral blood of control subjects, using enzyme-linked immunosorbent assay and enzymatic assays. RESULTS: sVAP-1 concentration (mean [+/-SE], 143. 67 [34.97-92.67] ng/mL) and SSAO activity (18.8 [12.0-24.6] nmol. mL(-1). h(-1)) were significantly increased in chronic liver diseases compared with healthy controls (87.1 [53.5-127] ng/mL [P<0.001] and 10.7 [6.5-12.7] nmol. mL(-1) x h(-1) [P<0.05]) but not in massive necrosis caused by paracetamol poisoning (109 [80.3-140] ng/mL and 8.9 [5.7-12.3] nmol. mL(-1) x h(-1)). sVAP-1 correlated with serum transaminase and bilirubin but not with creatinine. In 5 paired samples, sVAP-1 concentration was higher in hepatic (median, 113 [range, 53-122]) than in portal vein (102 [42-109]; 2P<0.05), and was not detected in bile. There was a highly significant correlation between serum sVAP-1 and SSAO activity in normal subjects, patients with acute liver failure, and those with chronic liver disease (r = 0.895; P<0.001). When serum was depleted of sVAP-1 by immunoaffinity chromatography, SSAO activity was eliminated. CONCLUSIONS: sVAP-1 levels are increased in chronic liver disease, and sVAP-1 is likely derived from the liver. Serum sVAP-1 displays SSAO activity and accounts for most of the monoamine oxidase activity in human serum.

Induction of vascular adhesion protein-1 during liver allograft rejection and concomitant cytomegalovirus infection in rats.

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule controlling lymphocyte recirculation through high endothelial venules of the lymph nodes. It has also been shown to be induced and to mediate lymphocyte adhesion at sites of inflammation. We studied the expression of VAP-1 and two other inducible adhesion molecules ICAM-1 and VCAM-1 in our experimental model of rat liver allograft rejection and, in addition, the effect of concomitant rat cytomegalovirus (RCMV) infection on this expression. Expression of VAP-1, ICAM-1, and VCAM-1 was studied in rat liver allografts with or without RCMV infection, isografts, and normal rat liver. Immunoperoxidase technique and monoclonal antibodies including a novel anti-VAP-1 reagent were used. VAP-1 expression was induced by acute rejection in sinusoids, hepatocytes, and also in bile ducts, when compared to the isografts or normal liver, where only blood vessels were consistently positive. Sinusoidal and hepatocyte expression of VAP-1 was prolonged by the presence of RCMV. ICAM-1 and VCAM-1 expression was also induced by acute rejection. However, RCMV increased sinusoidal VCAM-1 expression compared to uninfected grafts. The present experimental study shows that VAP-1 is up-regulated in acute rejection of liver allografts, and that this up-regulation is prolonged by RCMV infection.

Expression of alpha4-integrins on human neutrophils.

alpha4 Integrins are important adhesion molecules mediating binding of lymphocytes, monocytes, and eosinophils to multiple cellular and extracellular ligands. Mature neutrophils have been recently suggested to express alpha4-integrins as well. We studied whether human neutrophils can synthesize alpha4-integrins upon activation in vitro or in vivo. Two anti-alpha4 mAbs, but not multiple subclass-matched non-binding controls, reacted with granulocytes in an inducer and time-dependent manner. Nevertheless, staining with Ig subclass-specific second-stage reagents surprisingly revealed that commercial anti-alpha4 mAbs contain two distinct Igs, the alpha4-specific IgG1 and an IgG2a of an unknown specificity. We showed that in vitro inductions used by us and others only induce the binding of nonspecific IgG2a from the commercial HP2/1 to activated neutrophils. By reverse-transcriptase polymerase chain reaction, alpha4 mRNA was not detectable in purified neutrophils. Our results show that alpha4 integrin protein and mRNA are absent from normal and stimulated human neutrophils.

Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans.

OBJECTIVES: The expression of endothelial adhesion molecules and their functional significance in leukocyte adhesion to human myocardial blood vessels in acute myocardial infarction (AMI) were studied. BACKGROUND: Leukocyte extravasation, mediated by specific adhesion molecules, exacerbates tissue injury after restoration of blood supply to an ischemic tissue. Experimental myocardial reperfusion injury can be alleviated with antibodies that block the function of adhesion molecules involved in leukocyte emigration, but the relevant molecules remain poorly characterized in human AMI. METHODS: Semiquantitative immunohistochemistry and in vitro adhesion assays were used to study the expression and granulocyte binding abilities of different endothelial adhesion molecules in human AMI. Changes in the molecular nature of vascular adhesion protein-1 (VAP-1) were evaluated using immunoblotting. RESULTS: Certain endothelial adhesion molecules (intercellular adhesion molecule [ICAM-2], CD31 and CD73) were expressed in myocardial blood vessels homogeneously in normal and ischemic hearts, whereas others (E-selectin and peripheral lymph node addressin) were completely absent from all specimens. The synthesis of ICAM-1 was locally, and that of P-selectin regionally, upregulated in the infarcted hearts when compared with nonischemic controls. Vascular adhesion protein-1 showed ventricular preponderance in expression and alterations in posttranslational modifications during ischemia-reperfusion. Importantly, P-selectin, ICAM-1 and VAP-1 mediated granulocyte binding to blood vessels in the ischemic human heart. CONCLUSIONS: Human P-selectin, ICAM-1 and VAP-1 appear to be the most promising targets when antiadhesive interventions preventing leukocyte-mediated tissue destruction after myocardial ischemia are planned.