Family Physicians, General Practitioner, Internist
34 years of experience
Video profile
John Muir Medical Group
2700 Grant St
Ste 200
Concord, CA 94520
925-677-0500
Locations and availability (1)

Education ?

Medical School Score Rankings
Stanford University (1976)
  • Currently 4 of 4 apples
Top 25%

Affiliations ?

Dr. Owen is affiliated with 6 hospitals.

Hospital Affilations

Score

Rankings

  • John Muir Medical Center, Walnut Creek Campus
    1601 Ygnacio Valley Rd, Walnut Creek, CA 94598
    • Currently 4 of 4 crosses
    Top 25%
  • John Muir Medical Center, Concord Campus
    2540 East St, Concord, CA 94520
    • Currently 4 of 4 crosses
    Top 25%
  • Seton Medical Center
    1900 Sullivan Ave, Daly City, CA 94015
    • Currently 3 of 4 crosses
    Top 50%
  • Concord Campus
  • Seton Medical Center - Coastside
    600 Marine Blvd, Moss Beach, CA 94038
  • Mills Hospital
    100 S San Mateo Dr, San Mateo, CA 94401
  • Publications & Research

    Dr. Owen has contributed to 99 publications.
    Title Cd8+ T Cells Are Required for Inflammation and Destruction in Cigarette Smoke-induced Emphysema in Mice.
    Date July 2007
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Increased numbers of T lymphocytes are observed in the lungs of patients with chronic obstructive pulmonary disease, but their role in the disease process is not known. We investigated the role of CD8+ T cells in inflammatory cell recruitment and lung destruction in a cigarette smoke-induced murine model of emphysema. In contrast to wild-type C57BL/6J mice that displayed macrophage, lymphocyte, and neutrophil recruitment to the lung followed by emphysema in response to cigarette smoke, CD8+ T cell-deficient (CD8-/-) mice had a blunted inflammatory response and did not develop emphysema when exposed to long-term cigarette smoke. Further studies supported a pathogenetic pathway whereby the CD8+ T cell product, IFN-gamma-inducible protein-10, induces production of macrophage elastase (matrix metalloproteinase 12) that degrades elastin, both causing lung destruction directly and generating elastin fragments that serve as monocyte chemokines augmenting macrophage-mediated lung destruction. These studies demonstrate a requirement for CD8+ T cells for the development of cigarette smoke-induced emphysema and they provide a unifying pathway whereby CD8+ T cells are a central regulator of the inflammatory network in chronic obstructive pulmonary disease.

    Title The Sulfate Groups of Chondroitin Sulfate- and Heparan Sulfate-containing Proteoglycans in Neutrophil Plasma Membranes Are Novel Binding Sites for Human Leukocyte Elastase and Cathepsin G.
    Date June 2007
    Journal The Journal of Biological Chemistry
    Excerpt

    Human leukocyte elastase (HLE) and cathepsin G (CG) are expressed at high levels on the surface of activated human neutrophils (PMN) in catalytically active but inhibitor-resistant forms having the potential to contribute to tissue injury. Herein we have investigated the mechanisms by which HLE and CG bind to PMN plasma membranes. (125)I-Labeled HLE and CG bind to PMN at 0 degrees C in a saturable and reversible manner (K(D) = 5.38 and 4.36 x 10(-7) m and 11.5 and 8.1 x 10(6) binding sites/cell, respectively). Incubation of PMN with radiolabeled HLE and CG in the presence of a 200-fold molar excess of unlabeled HLE, CG, myeloperoxidase, lactoferrin, proteinase 3, phenylmethylsulfonyl fluoride (PMSF)-inactivated HLE, or PMSF-inactivated CG inhibited binding of radiolabeled ligands. This indicates that these PMN granule proteins share binding sites on PMN and that functional active sites of HLE and CG are not required for their binding to PMN. The sulfate groups of heparan sulfate- and chondroitin sulfate-containing proteoglycans are the PMN binding sites for HLE and CG since binding of HLE and CG to PMN was inhibited by incubating PMN with 1) trypsin, chondroitinase ABC, and heparitinases, but not other glycanases, and 2) purified chondroitin sulfates, heparan sulfate, and other sulfated molecules, but not with non-sulfated glycans. Thus, heparan sulfate- and chondroitin sulfate-containing proteoglycans are low affinity, high volume PMN surface binding sites for HLE and CG, which are well suited to bind high concentrations of active serine proteinases released from degranulating PMN.

    Title Induction of the Plasminogen Activator System by Mechanical Stimulation of Human Bronchial Epithelial Cells.
    Date January 2007
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Mechanical stimulation of the airway epithelium, as would occur during bronchoconstriction, is a potent stimulus and can activate profibrotic pathways. We used DNA microarray technology to examine gene expression in compressed normal human bronchial epithelial cells (NHBE). Compressive stress applied continuously over an 8-h period to NHBE cells led to the upregulation of several families of genes, including a family of plasminogen-related genes that were previously not known to be regulated in this system. Real-time PCR demonstrated a peak increase in gene expression of 8.0-fold for urokinase plasminogen activator (uPA), 16.2-fold for urokinase plasminogen activator receptor (uPAR), 4.2-fold for plasminogen activator inhibitor-1 (PAI-1), and 3.9-fold for tissue plasminogen activator (tPA). Compressive stress also increased uPA protein levels in the cell lysates (112.0 versus 82.0 ng/ml, P = 0.0004), and increased uPA (4.7 versus 3.3 ng/ml, P = 0.02), uPAR (1.3 versus 0.86 ng/ml, P = 0.007), and PAI-1 (50 versus 36 ng/ml, P = 0.006) protein levels in cell culture media. Functional studies demonstrated increased urokinase-dependent plasmin generation in compression-stimulated cells (0.0090 versus 0.0033 OD/min, P = 0.03). In addition, compression led to increased activation of matrix metalloproteinase (MMP)-9 and MMP-2 in a urokinase-dependent manner. In postmortem human lung tissue, we observed an increase in epithelial uPA and uPAR immunostaining in the airways of two patients who died in status asthmaticus compared with minimal immunoreactivity noted in airways from seven lung donors without asthma. Together these observations suggest an integrated response of airway epithelial cells to mechanical stimulation, acting through the plasminogen-activating system to modify the airway microenvironment.

    Title Double-incision Fasciotomy of the Leg for Decompression in Compartment Syndromes.
    Date September 2004
    Journal The Journal of Bone and Joint Surgery. American Volume
    Excerpt

    Surgical decompression remains the only effective treatment for the ischemia of the muscles and nerves of the leg that constitutes the principal defects in the compartment syndromes. Recently, partial fibulectomy has been proposed as a good way to decompress all four compartments instead of the older double incision. Both methods are effective in satisfactorily reducing intracompartmental pressures, as documented by our wick catheter measurements. However, the double-incision technique is easier, faster, safer, and is the treatment of choice when four-compartment decompressive fasciotomy is indicated.

    Title Membrane-bound Matrix Metalloproteinase-8 on Activated Polymorphonuclear Cells is a Potent, Tissue Inhibitor of Metalloproteinase-resistant Collagenase and Serpinase.
    Date September 2004
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Little is known about the cell biology or the biologic roles of polymorphonuclear cell (PMN)-derived matrix metalloproteinase-8 (MMP-8). When activated with proinflammatory mediators, human PMN release only approximately 15-20% of their content of MMP-8 ( approximately 60 ng/10(6) cells) exclusively as latent pro-MMP-8. However, activated PMN incubated on type I collagen are associated with pericellular collagenase activity even when bathed in serum. PMN pericellular collagenase activity is attributable to membrane-bound MMP-8 because: 1) MMP-8 is expressed in an inducible manner in both pro- and active forms on the surface of human PMN; 2) studies of activated PMN from mice genetically deficient in MMP-8 (MMP-8(-/-)) vs wild-type (WT) mice show that membrane-bound MMP-8 accounts for 92% of the MMP-mediated, PMN surface type I collagenase activity; and 3) human membrane-bound MMP-8 on PMN cleaves types I and II collagens, and alpha(1)-proteinase inhibitor, but is substantially resistant to inhibition by tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Binding of MMP-8 to the PMN surface promotes its stability because soluble MMP-8 has t(1/2) = 7.5 h at 37 degrees C, but membrane-bound MMP-8 retains >80% of its activity after incubation at 37 degrees C for 18 h. Studies of MMP-8(-/-) vs WT mice given intratracheal LPS demonstrate that 24 h after intratracheal LPS, MMP-8(-/-) mice have 2-fold greater accumulation of PMN in the alveolar space than WT mice. Thus, MMP-8 has an unexpected, anti-inflammatory role during acute lung injury in mice. TIMP-resistant, active MMP-8 expressed on the surface of activated PMN is likely to be an important form of MMP-8, regulating lung inflammation and collagen turnover in vivo.

    Title Inducible Expression of Tissue Inhibitor of Metalloproteinases-resistant Matrix Metalloproteinase-9 on the Cell Surface of Neutrophils.
    Date October 2003
    Journal American Journal of Respiratory Cell and Molecular Biology
    Excerpt

    Matrix metalloproteinase (MMP)-9 secreted by activated polymorphonuclear neutrophils (PMN) may play roles in mediating lung injury by degrading extracellular matrix proteins. However, the mechanisms by which MMP-9 retains activity in the presence of tissue inhibitors of metalloproteinases (TIMPs) are not known. We show that MMP-9 is also expressed on the cell surface of PMN, and proinflammatory mediators induce up to 10-fold increases in cell surface expression of MMP-9. Stimulated human PMN express active forms of cell surface MMP, which cleave the MMP substrate, McaPLGLDpaAR. Loss-of-function studies employing PMN from mice genetically deficient in MMP-9 (MMP-9-/-) demonstrate that membrane-bound MMP-9 contributes substantially to MMP-mediated surface-bound cleavage of McaPLGLDpaAR (approximately 50%) and gelatin (approximately 70%) by stimulated PMN. Like soluble MMP-9, membrane-bound MMP-9 cleaves McaPLGLDpaAR (Kcat/KM = 82,000 M-1s-1), gelatin, type IV collagen, elastin, and alpha1-proteinase inhibitor. However, in contrast to soluble MMP-9, membrane-bound MMP-9 is substantially resistant to inhibition by TIMPs. The IC50 for inhibition of membrane-bound MMP-9 by TIMP-1 and TIMP-2 are approximately 21-fold and approximately 68-fold higher, respectively, than those for inhibition of soluble MMP-9. The binding of MMP-9 to the plasma membrane of PMN enables it to evade inhibition by TIMPs, and thereby may alter the pericellular proteolytic balance in favor of extracellular matrix degradation. Membrane-bound MMP-9 on PMN may play pathogenetic roles in inflammatory lung diseases.

    Title Neutrophil Elastase in Human Atherosclerotic Plaques: Production by Macrophages.
    Date June 2003
    Journal Circulation
    Excerpt

    BACKGROUND: Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. METHODS AND RESULTS: Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma. CONCLUSIONS: These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

    Title Adam-33 Surfaces As an Asthma Gene.
    Date September 2002
    Journal The New England Journal of Medicine
    Title Bioactive Proteinase 3 on the Cell Surface of Human Neutrophils: Quantification, Catalytic Activity, and Susceptibility to Inhibition.
    Date October 2000
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Although proteinase 3 (PR3) is known to have the potential to promote inflammation and injure tissues, the biologic forms and function of PR3 in polymorphonuclear neutrophils (PMN) from healthy donors have received little attention. In this paper, we show that PMN contain 3.24 +/- SD 0.24 pg of PR3 per cell, and that the mean concentration of PR3 in azurophil granules of PMN is 13.4 mM. Low levels of PR3 are detectable on the cell surface of unstimulated PMN. Exposure of PMN to cytokines or chemoattractants alone induces modest (1.5- to 2.5-fold) increases in cell surface-bound PR3. In contrast, brief priming of PMN with cytokines, followed by activation with a chemoattractant, induces rapid and persistent, 5- to 6-fold increases in cell surface expression of PR3, while causing minimal free release of PR3. Membrane-bound PR3 on PMN is catalytically active against Boc-Alanine-Alanine-Norvaline-thiobenzyl ester and fibronectin, but in marked contrast to soluble PR3, membrane-bound PR3 is resistant to inhibition by physiologic proteinase inhibitors. PR3 appears to bind to the cell surface of PMN via a charge-dependent mechanism because exposure of fixed, activated PMN to solutions having increasing ionic strength results in elution of PR3, HLE, and CG, and there is a direct relationship between their order of elution and their isoelectric points. These data indicate that rapidly inducible PR3 expressed on the cell surface of PMN is an important bioactive form of the proteinase. If PR3 expression on the cell surface of PMN is dysregulated, it is well equipped to amplify tissue injury directly, and also indirectly via the generation of autoantibodies.

    Title Leukocyte Proteinases in Wound Healing: Roles in Physiologic and Pathologic Processes.
    Date March 2000
    Journal Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society
    Excerpt

    Leukocytes express a number of proteinases which play critical roles in physiologic processes during wound healing. However, if the activity of these proteinases is uncontrolled, they can contribute to devastating tissue injury that can affect most organ systems. Until recently, little was known about the mechanisms by which leukocytes retain the activity of their proteinases within the extracellular space which contains highly effective proteinase inhibitors. Studies of the cell biology of leukocyte proteinases have begun to identify the mechanisms by which proteinases can circumvent the effects of physiologic proteinase inhibitors. Herein, we will review the cell biology of leukocyte proteinases, and we will discuss the mechanisms by which leukocyte proteinases can contribute to physiologic processes occurring during wound healing, as well as their roles in pathologic processes.

    Title Extracellular Proteolysis: New Paradigms for an Old Paradox.
    Date October 1999
    Journal The Journal of Laboratory and Clinical Medicine
    Title Quantum Proteolysis by Neutrophils: Implications for Pulmonary Emphysema in Alpha 1-antitrypsin Deficiency.
    Date August 1999
    Journal The Journal of Clinical Investigation
    Excerpt

    Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in alpha 1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.

    Title Interaction Between Leukocyte Elastase and Elastin: Quantitative and Catalytic Analyses.
    Date May 1999
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Solubilization of elastin by human leukocyte elastase (HLE) cannot be analyzed by conventional kinetic methods because the biologically relevant substrate is insoluble and the concentration of enzyme-substrate complex has no physical meaning. We now report quantitative measurements of the binding and catalytic interaction between HLE and elastin permitted by analogy to receptor-ligand systems. Our results indicated that a limited and relatively constant number of enzyme binding sites were available on elastin, and that new sites became accessible as catalysis proceeded. The activation energies and solvent deuterium isotope effects were similar for catalysis of elastin and a soluble peptide substrate by HLE, yet the turnover number for HLE digestion of elastin was 200-2000-fold lower than that of HLE acting on soluble peptide substrates. Analysis of the binding of HLE to elastin at 0 degrees C, in the absence of significant catalytic activity, demonstrated two classes of binding sites (Kd=9.3x10(-9) M and 2.5x10(-7) M). The higher affinity sites accounted for only 6% of the total HLE binding capacity, but essentially all of the catalytic activity, and dissociation of HLE from these sites was minimal. Our studies suggest that interaction of HLE with elastin in vivo may be very persistent and permit progressive solubilization of this structurally important extracellular matrix component.

    Title The Cell Biology of Leukocyte-mediated Proteolysis.
    Date March 1999
    Journal Journal of Leukocyte Biology
    Excerpt

    Leukocyte-derived proteinases have the capacity to degrade every component of the extracellular matrix, and thereby play fundamental roles in physiological processes. However, if the activity of these proteinases is uncontrolled or dysregulated, they have the capacity to contribute to tissue injury that potentially affects every organ in the body. Although there is a substantial literature on structure and activity of these proteinases when they are free in solution, until recently there has been little information about the cell biology of proteinases and their inhibitors. Recent studies, however, have identified several mechanisms by which inflammatory cells can degrade extracellular proteins in a milieu that contains high-affinity proteinase inhibitors.

    Title Angiotensin Ii Generation at the Cell Surface of Activated Neutrophils: Novel Cathepsin G-mediated Catalytic Activity That is Resistant to Inhibition.
    Date May 1998
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Human neutrophils express inducible, catalytically active cathepsin G on their cell surface. Herein, we report that membrane-bound cathepsin G on intact neutrophils has potent angiotensin II-generating activity. Membrane-bound cathepsin G on activated neutrophils 1) converts both human angiotensin I and angiotensinogen to angiotensin II; 2) expresses angiotensin II-generating activity equivalent to 8.6 +/- 2.3 (+/-SD) x 10(-18) mol of free cathepsin G (5.2 +/- 1.4 x 10(6) molecules)/cell; and 3) has similar high affinity for angiotensin I compared with free cathepsin G (Km = 5.9 x 10(-4) and 4.6 x 10(-4) M; k(cat) = 4.0 and 2.0/s, respectively). In marked contrast to soluble cathepsin G, membrane-bound enzyme was substantially resistant to inhibition by plasma proteinase inhibitors and converted angiotensin I to angiotensin II even in undiluted plasma. There was a striking inverse relationship between inhibitor size and its effectiveness against membrane-bound cathepsin G activity. Alpha1-antichymotrypsin was a markedly ineffective inhibitor of membrane-bound enzyme (IC50 = 2.18 microM and 1.38 nM when tested against 1 nM membrane-bound and free cathepsin G, respectively). These data indicate that membrane-bound cathepsin G expressed on neutrophils is an inducible and mobile angiotensin II-generating system that may exert potent local vasoactive and chemoattractant properties at sites of inflammation.

    Title Cytokines Regulate Membrane-bound Leukocyte Elastase on Neutrophils: a Novel Mechanism for Effector Activity.
    Date April 1997
    Journal The American Journal of Physiology
    Excerpt

    Membrane-bound leukocyte elastase activity on neutrophils may have potent proinflammatory effects. Herein, we report the effects of tumor necrosis factor-alpha (TNF-alpha), platelet-activating factor (PAF), N-formyl-leucyl-methionyl-phenylalanine (fMLP), and interleukin-8 (IL-8) on membrane-bound elastase expression. TNF-alpha or PAF alone induced only approximately two- to threefold increases in membrane-bound elastase but exhibited marked dose- and time-dependent priming effects for subsequent stimulation with fMLP or IL-8 (up to 20-fold increases in membrane-bound human leukocyte elastase compared with unstimulated cells). Optimally PAF-primed and fMLP-stimulated cells expressed 1.105 +/- 0.25 (SD) x 10(-17) mol [6.65 +/- 1.51 (SD) x 10(6) molecules] membrane-bound elastase activity/cell or approximately 12% of the content of unstimulated cells. Elastase binds to the cell surface by a charge-dependent mechanism since 1) incubation of cells with cationic molecules abrogated agonist-induced upregulation of membrane-bound elastase and 2) elastase was progressively eluted from the cell surface by solutions with increasing ionic strength. Thus interactions between proinflammatory mediators strikingly upregulate membrane-bound elastase on neutrophils, which may promote inflammatory responses and/or contribute to tissue injury.

    Title Neutrophil Proteinases and Matrix Degradation. The Cell Biology of Pericellular Proteolysis.
    Date December 1996
    Journal Seminars in Cell Biology
    Excerpt

    Neutrophil proteinases have the capacity to degrade almost every component of the extracellular matrix. In marked contrast to the wealth of available data about the structure and activity of these proteinases when they are free in solution, there has been relatively little information about the mechanisms by which neutrophils use and control their proteolytic enzymes in an extracellular milieu that is replete with proteinase inhibitors. However, recent data have provided insights into several mechanisms that permit these enzymes to evade inhibition: (1) compartmentalization; (2) localized inactivation of proteinase inhibitors; (3) tight binding of enzymes to substrates; and (4) binding of proteinases to the neutrophil's cell surface.

    Title Inducible Binding of Bioactive Cathepsin G to the Cell Surface of Neutrophils. A Novel Mechanism for Mediating Extracellular Catalytic Activity of Cathepsin G.
    Date January 1996
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Catalytically active cathepsin G that is bound to the cell surface of human neutrophils may play a variety of roles in normal neutrophil biology and in pathobiology associated with inflammation. In this study, we describe expression of neutrophil cell surface-bound cathepsin G in response to TNF-alpha and platelet-activating factor (PAF) under conditions in which minimal free release of cathepsin G is detected. TNF-alpha and PAF alone induced modest (two- to threefold) increases in cell surface-bound cathepsin G, but exhibited a marked dose- and time-dependent priming effect for subsequent chemoattractant-induced responses (up to 15- to 25-fold increases in cell surface expression). When optimally primed (TNF-alpha, 100 U/ml, or PAF, 10(-9) M), neutrophils expressed five- to sixfold more cell surface-bound cathepsin G, in comparison with cells exposed to FMLP alone. Priming responses were more rapid with PAF (15 s to 5 min) than with TNF-alpha (1 to 60 min). Optimally primed and FMLP-stimulated neutrophils express approximately 160 ng of catalytically active cathepsin G per 10(6) cells, which represents approximately 11% of the cellular content of unstimulated cells. Cathepsin G binds to the cell surface by a charge-dependent mechanism since: 1) incubation of cells with highly positively charged molecules abrogated agonist-induced up-regulation of the cell surface expression of cathepsin G and 2) cathepsin G was eluted from the cell surface by high concentrations of NaCl. These data indicate that interactions between biologically relevant pro-inflammatory cytokines and chemoattractants serve to markedly up-regulate cell surface-bound cathepsin G. The focused catalytic activity of cell surface-bound cathepsin G may alter endothelial and epithelial barriers, promote thrombogenesis, injure extracellular matrix, and/or facilitate directed migration of neutrophils during inflammation.

    Title Cell Surface-bound Elastase and Cathepsin G on Human Neutrophils: a Novel, Non-oxidative Mechanism by Which Neutrophils Focus and Preserve Catalytic Activity of Serine Proteinases.
    Date December 1995
    Journal The Journal of Cell Biology
    Excerpt

    Serine proteinases of human polymorphonuclear neutrophils play an important role in neutrophil-mediated proteolytic events; however, the non-oxidative mechanisms by which the cells can degrade extracellular matrix in the presence of proteinase inhibitors have not been elucidated. Herein, we provide the first report that human neutrophils express persistently active cell surface-bound human leukocyte elastase and cathepsin G on their cell surface. Unstimulated neutrophils have minimal cell surface expression of these enzymes; however, phorbol ester induces a 30-fold increase. While exposure of neutrophils to chemoattractants (fMLP and C5a) stimulates modest (two- to threefold) increases in cell surface expression of serine proteinases, priming with concentrations of lipopolysaccharide as low as 100 fg/ml leads to striking (up to 10-fold) increase in chemoattractant-induced cell surface expression, even in the presence of serum proteins. LPS-primed and fMLP-stimulated neutrophils have approximately 100 ng of cell surface human leukocyte elastase activity per 10(6) cells. Cell surface-bound human leukocyte elastase is catalytically active, yet is remarkably resistant to inhibition by naturally occurring proteinase inhibitors. These data indicate that binding of serine proteinases to the cell surface focuses and preserves their catalytic activity, even in the presence of proteinase inhibitors. Upregulated expression of persistently active cell surface-bound serine proteinases on activated neutrophils provides a novel mechanism to facilitate their egress from the vasculature, penetration of tissue barriers, and recruitment into sites of inflammation. Dysregulation of the cell surface expression of these enzymes has the potential to cause tissue destruction during inflammation.

    Title A Discrete Subpopulation of Human Monocytes Expresses a Neutrophil-like Proinflammatory (p) Phenotype.
    Date January 1995
    Journal The American Journal of Physiology
    Excerpt

    We have demonstrated that a discrete and naturally occurring subpopulation of human monocytes expresses a neutrophil-like proinflammatory (P) phenotype. P monocytes constitute 20-30% of the circulating monocyte pool and are characterized by 1) avid adherence to extracellular matrix through high-level cell-surface expression of alpha 5-, beta 1-, and beta 2-integrins; 2) high capacity to produce reactive oxygen species; 3) high content of serine proteinases and alpha 1-proteinase inhibitor; and 4) proteolytic activity against a soluble peptide human leukocyte elastase substrate, [3H]elastin, and solid-phase fibronectin, even in the presence of proteinase inhibitors. However, P monocytes express little or no cell-surface HLA-DR antigen, suggesting that they are unable to participate in specific immune responses. In contrast, the remainder of circulating monocytes have a low proinflammatory potential but contain the population of monocytes with high-level expression of HLA-DR antigen. P monocytes can readily be separated from the remainder of monocytes on the basis of 1) their capacity to adhere to fibronectin; and 2) their absent expression of HLA-DR antigen when flow cytometry or immunomagnetic beads are used. Our data indicate that, when recruited to sites of inflammation, P monocytes can either promote resolution of inflammation or contribute to tissue injury.

    Title Monocytes Recruited to Sites of Inflammation Express a Distinctive Proinflammatory (p) Phenotype.
    Date January 1995
    Journal The American Journal of Physiology
    Excerpt

    Only a minor proportion of monocytes responds to chemoattractants. To test the possibility that chemoattractant-responsive monocytes have distinctive functional characteristics, we enriched or depleted monocyte preparations for cells having a proinflammatory (P) phenotype and tested their responses to biologically relevant chemoattractants. We prepared monocyte subpopulations by one of three independent techniques to minimize the chances of artifacts: 1) depletion of P monocytes by adherence to fibronectin; 2) enrichment for P monocytes by negative selection for HLA-DR antigen; and 3) flow cytometric sorting. We measured responsiveness of monocyte subpopulations to N-formyl-Met-Leu-Phe, C5a, zymosan-activated serum, and monocyte chemoattractant protein-1 by three parameters: 1) polarization, 2) actin polymerization, and 3) directed migration. With each chemoattractant and each parameter, there was a striking direct relationship between the responsiveness of the monocyte preparations and their content of P monocytes. Our data indicate that the capacity of monocytes to be recruited rapidly from the vasculature into sites of inflammation is a property of a subpopulation of monocytes with a distinctive, neutrophil-like proinflammatory phenotype.

    Title Monocyte Adherence to Fibronectin: Role of Cd11/cd18 Integrins and Relationship to Other Monocyte Functions.
    Date May 1992
    Journal Journal of Leukocyte Biology
    Excerpt

    Adherence of monocytes to extracellular matrix components is critical for their accumulation at sites of infection. To gain insight into the factors that regulate monocyte recruitment, we have studied monocyte adherence with regard to the regulatory effects of bacterial lipopolysaccharide (LPS) and the mechanisms involved; moreover, we have contrasted the phenotypes of adherent and nonadherent cells. Our results show that only a minor subpopulation of monocytes (20-25%) adhere spontaneously to fibronectin and that LPS stimulated a threefold increase in the proportion of adherent cells. Basal adherence and LPS-stimulated adherence of monocytes to fibronectin were substantially mediated by CD11/CD18 integrins. Further studies revealed that spontaneously adherent monocytes were 14-fold more actively phagocytic, released 1.6-fold more superoxide anion, and contained 20-fold more peroxidase activity than nonadherent cells, whereas LPS-adherent cells had an intermediate phenotype. These results indicate that LPS may enhance the accumulation of monocytes with an antimicrobial phenotype and thereby promote resolution of tissue infection.

    Title Increased Adherence of Monocytes to Fibronectin in Bronchiectasis. Regulatory Effects of Bacterial Lipopolysaccharide and Role of Cd11/cd18 Integrins.
    Date April 1992
    Journal The American Review of Respiratory Disease
    Excerpt

    Regulated adherence of monocytes to extracellular matrix is a prerequisite for accumulation of mononuclear phagocytes during pulmonary infection and inflammation. We have obtained monocytes from patients with an inflammatory lung disease (bronchiectasis) and from control subjects and have compared their adherence to fibronectin. Spontaneous adherence of monocytes from the control subjects was 20 +/- 2%, whereas that of patients' cells was markedly higher and correlated with the severity of airway inflammation: 65 +/- 5% and 40 +/- 8% in patients with purulent and mucoid sputum, respectively. Endotoxin and cytokines from areas of airway disease are likely to be responsible for the observed monocyte activation, since: (1) endotoxin was detectable in all of the patients but in none of the control subjects; (2) LPS produced a dose-related increase in adherence of normal monocytes in vitro (maximal 65 +/- 2% adherence at 1 microgram/ml of LPS); (3) recombinant cytokines and LPS produced additive effects on monocyte adherence in vitro. The adherence of the patients' monocytes to fibronectin was substantially mediated by CD11/CD18 integrins, via both RGD-dependent and RGD-independent mechanisms. These data indicate that signals arising from foci of infection and inflammation can influence the adherence of monocytes, and they are likely to be determinants of the accumulation of mononuclear phagocytes in the lungs of patients with bronchiectasis.

    Title Role of the Liver in Metabolism of Dl-norepinephrine-14c.
    Date March 1990
    Journal The American Journal of Physiology
    Title Kappa Delta Award Paper. Tissue Fluid Pressures: from Basic Research Tools to Clinical Applications.
    Date November 1989
    Journal Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society
    Excerpt

    The two basic research tools developed to measure tissue fluid pressure (wick catheter) and osmotic pressure (colloid osmometer) have undergone extensive validation and refinement over the past 20 years. Using these techniques, basic science investigations were undertaken of edema in Amazon reptiles, pressure-volume relations in animals and plants, adaptive physiology of Antarctic penguins and fishes, edema in spawning salmon, tissue fluid balance in humans under normal conditions and during simulated weightlessness, and orthostatic adaptation in a mammal with high and variable blood pressures--the giraffe. Following and sometimes paralleling this basic research have been several clinical applications related to use of our colloid osmometer and wick technique. Applications of the osmometer have included insights into (a) reduced osmotic pressure of sickle-cell hemoglobin with deoxygenation and (b) reduced swelling pressure of human nucleus pulposus with hydration or certain enzymes. Clinical uses of the wick technique have included (a) improvement of diagnosis and treatment of acute and chronic compartment syndromes, (b) elucidation of tissue pressure thresholds for neuromuscular dysfunction, and (c) development of a better tourniquet design for orthopaedics. This article demonstrates that basic research tools open up areas of basic, applied, and clinical research.

    Title Evaluation of Preoperative Hematology-coagulation Screening in Liver Transplantation.
    Date April 1989
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    We retrospectively reviewed the results of preoperative hematology-coagulation studies in 66 patients who underwent orthotopic liver transplantation-24 with the primary diagnosis of chronic active hepatitis (CAH), 22 with primary sclerosing cholangitis (PSC), and 20 with primary biliary cirrhosis (PBC). The mean prothrombin time was above normal in all three diagnostic groups, patients with CAH having the highest values. The mean activated partial thromboplastin time was normal in patients with PSC or PBC but elevated in those with CAH. Fibrinogen levels were above normal in patients with PBC but decreased in 1 patient (5%) with PSC and 10 (42%) with CAH. Mean platelet counts were below normal in 68% and 55% of patients with PSC and PBC, respectively, but in 96% of those with CAH. The mean Ivy bleeding time was normal in patients with PSC or PBC but prolonged in those with CAH. Patients with PSC or PBC had normal mean activity levels of factors II, V, VII, IX, and X, whereas those with CAH had below normal mean values for factors II and VII. The antithrombin III activity level was normal in patients with PSC or PBC but reduced in those with CAH. Thus, patients with CAH have a greater derangement in results of clotting studies in comparison with those who have PSC or PBC, but the use of blood did not differ among the three diagnostic groups.

    Title Hemostatic Evaluation of Patients Undergoing Liver Transplantation.
    Date September 1987
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    A detailed coagulation and thromboelastographic study was done on the first 50 liver transplantation procedures performed at the Mayo Clinic between March 1985 and June 1986. Most of the patients suffered from primary sclerosing cholangitis, primary biliary cirrhosis, or chronic active hepatitis. Seven patients required a second liver transplantation, and six patients died, none intraoperatively. Most of the patients had distorted hemostatic mechanisms preoperatively, as would be expected because the liver generates most of the clotting factors. The outstanding exception was factor VIII, which was usually in the high-normal range or even more elevated. Substantial deterioration of coagulation factors occurred regularly during reperfusion of the donor liver. In some instances, this trend was corrected within 1 hour, but platelet counts continued to decrease, and some coagulation factors rebounded only partially. Because thromboelastographic tracings are quickly available to the liver transplant team and because they tend to forewarn of impending hemostatic problems, we believe that thromboelastography is a reasonably effective procedure for monitoring coagulation during liver transplantation.

    Title Prothrombin, Thrombin and Prothrombin Fragments in Plasma of Normal Individuals and of Patients with Laboratory Evidence of Disseminated Intravascular Coagulation.
    Date March 1980
    Journal Thrombosis Research
    Title The Turnover in Normal Dogs of Prothrombin and Its Fragments; Effect of Induced Intravascular Coagulation.
    Date January 1980
    Journal Thrombosis and Haemostasis
    Excerpt

    When 125I-labeled canine prothrombin was given to normal adult dogs intravenously, it was calculated that 240% of the plasma prothrombin crossed the capillary barrier per day, 410% of the interstitial prothrombin returned to the blood stream daily, and 79% of the plasmatic prothrombin was catabolized per day. These data are in close agreement with those observed for bovine prothrombin in calves by Takeda (1970). When derived from normal dog prothrombin, prethrombin-1 is a mixture of 2 polypeptides, one larger than the other, and both present in about equal amounts. The longer peptide, "prethrombin-1-long," was catabolized twice as fast as prothrombin, and the shorter, "prethrombin-1-short," 4 times faster. Prothrombin fragment-1 was catabolized by the normal dog still more rapidly. The catabolism of prothrombin was not accelerated in 3 dogs receiving continuous infusions of a thromboplastic emulsion of dog brain. Nor was the level of prothrombin in their plasma remarkably altered.

    Title Intramuscular Pressures with Limb Compression Clarification of the Pathogenesis of the Drug-induced Muscle-compartment Syndrome.
    Date June 1979
    Journal The New England Journal of Medicine
    Excerpt

    To study muscle necrosis due to prolonged limb compression, we measured intramuscular pressure by inserting wick catheters into 10 volar forearms and 10 anterior tibial compartments of adult volunteers. We then placed the subjects in positions in which victims of drug overdose are commonly found. Intramuscular pressures in the area of direct compression on hard surfaces ranged from 26 to 240 mm Hg, and averaged 101 mm Hg. Most remarkable was a mean pressure of 180 mm Hg on compression of the forearm by the rib cage. These pressures are sufficient to cause muscle and capillary ischemia and necrosis by local obstruction of the circulation. This local injury by limb compression may produce edema sufficient to start compartment tamponade and consequent muscle-compartment and crush syndromes.

    Title Acute Compartment Syndromes: Diagnosis and Treatment with the Aid of the Wick Catheter.
    Date February 1979
    Journal The Journal of Bone and Joint Surgery. American Volume
    Excerpt

    Intracompartmental pressures were measured by the wick catheter technique in sixty-five compartments of twenty-seven patients who were clinically suspected of having acute compartment syndromes. A pressure of thirty millimeters of mercury or more was used as an indication for decompressive fasciotomy. The range of normal pressure was from zero to eight millimeters of mercury. Eleven of these patients were diagnosed as actually having compartment syndromes and in these patients, twenty-seven compartments were decompressed. Only two patients had significant sequelae. In the sixteen patients (thirty-eight compartments) whose pressures remained less than thirty millimeters of mercury, fasciotomy was withheld and compartment syndrome sequelae did not develop in any patient. Intraoperatively the wick catheter was used continuously in eight patients to document the effectiveness of decompression. Fasciotomy consistently restored pressures to normal except in the buttock and deltoid compartments, where epimysiotomy was required to supplement the fasciotomy. Continuous intraoperative monitoring of pressure by the wick catheter technique allowed us to select the few cases in which primary closure of wounds was appropriate and to decide which patients were best treated with secondary closure.

    Title Acute Exertional Superficial Posterior Compartment Syndrome.
    Date December 1978
    Journal The American Journal of Sports Medicine
    Excerpt

    This case report of an acute exertional compartment syndrome involving predominantly the superficial posterior compartment emphasizes several important facts: (1) The subacute recurring syndromes, if left untreated, may develop into an acute syndrome. (2) The diagnostic findings separating the acute syndrome from the chronic forms are marked pain with passive stretch of the involved muscles, paresis, and sensory deficit.8,12,15, (3) In the acute form, immediate fasciotomy is mandatory and often results in full recovery. (4) All four major compartments of the leg are susceptible to chronic or acute compartment syndromes initiated by exertion. These compartments can be decompressed as necessary through a limited skin incision as recently reported.11 (5) The need for an easily obtainable and reproducible method for measuring intracompartment pressures (e.g., the wick catheter technique) is indicated.

    Title Gluteal Compartment Syndromes: a Report of Three Cases and Management Utilizing the Wick Catheter.
    Date October 1978
    Journal Clinical Orthopaedics and Related Research
    Excerpt

    Contusion or prolonged compression of the buttock produced severe local injury in 3 cases. Rhabdomyolysis with acute renal failure occurred in 2 of these cases, and one of them had an associated sciatic nerve palsy. The affected muscles included the gluteus maximus, gluteus medius, and the tensor fascia latae. Clinically and experimentally, these muscles were shown to be functionally enclosed within separate compartments like the peripheral limb muscles. Prompt decompression in the two cases with pressures exceeding 30 mm Hg resulted in muscle and nerve recovery.

    Title Fluid Balance Within the Canine Anterolateral Compartment and Its Relationship to Compartment Syndromes.
    Date September 1978
    Journal The Journal of Bone and Joint Surgery. American Volume
    Excerpt

    Fluid homeostasis within muscle compartments is maintained by four pressures: capillary blood pressure, capillary blood oncotic pressure, tissue-fluid pressure, and tissue fluid oncotic pressure. As determined in the canine anterolateral compartment, capillary blood pressure is 25 +/- 3 millimeters of mercury; capillary blood oncotic pressure, 26 +/- 3 millimeters of mercury, tissue-pbessure, -2 +/- 2 millimeters of mercury; and tissue-fluid oncotic pressure, 11 +/- 1 millimeters of mercury. The wick technique allows direct measurement of tissue-fluid pressure in skeletal muscle and, with minor modifications, is adapted to collect microsamples of interstitial fluid for determinations of tissue-fluid oncotic pressure. The wick technique detects very slight fluctuations in intracompartmental pressure such as light finger compression, injection of small volumes of fluid, and even pulsation due to adjacent arterial pressure. Adjacent muscle compartments may contain different tissue-fluid pressure due to impermeable osseofascial barriers. Our results obtained in canine muscle compartments pressurized by infusion of autologous plasma suggest that risks of muscle damage are significant at intracompartmental pressures greater than thirty millimeters of mercury.

    Title Resistance to Arteriosclerosis in Pigs with Von Willebrand's Disease. Spontaneous and High Cholesterol Diet-induced Arteriosclerosis.
    Date June 1978
    Journal The Journal of Clinical Investigation
    Excerpt

    The aortas of 11 pigs (aged 1-3 yr) with homozygous von Willebrand's disease (vWd) were compared with those of 11 normal pigs of the same ages. Six of the controls exhibited multiple arteriosclerotic plaques with intimal thickening of 63-130 mum. In contrast, none of the pigs with vWd had multiple plaques, and only one had a lesion >2 mm in diameter. In a subsequent study, 3-mo-old pigs (11 controls and 7 with homozygous vWd) were placed on a 2% cholesterol diet for up to 6 mo. All of the controls developed arteriosclerotic plaques in the aorta, and in nine of the controls, at least 13% of the entire surface was involved. Intimal thickness ranged up to 390 mum. In contrast, four of the pigs with vWd did not develop such lesions, two developed arteriosclerotic lesions affecting 6 and 7% of the aortic surface, and the seventh had 13% of the aortic surface involved. Most of the pigs with vWd, however, developed flat fatty lesions in contrast to the normal pigs whether on the normal or the high cholesterol diet. There was blue staining of the flat fatty lesions when two pigs with vWd were injected with Evans blue dye antemortem. By electron microscopy, severe endothelial damage was apparent, but there was no intimal proliferation. The coincidence of the impaired platelet-arterial wall interaction and lack of arteriosclerosis in this bleeding disease is discussed.

    Title Hepatic Subcellular Distribution of Copper in Primary Biliary Cirrhosis. Comparison with Other Hyperhepatocupric States and Review of the Literature.
    Date May 1978
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Fibrinolytic Degradation Products in Urine of Anticoagulated Transplant Patients.
    Date April 1978
    Journal European Urology
    Excerpt

    A study of the level of urinary fibrinolytic split products in 14 renal transplant patients who received oral anticoagulants postoperatively revealed a tendency toward increased levels of fibrinolytic split products that were temporally related to graft rejection. The amount of fibrinolytic split products in the urine was positively related to the severity of rejection as well as to the final status of the allograft. Thus, the urinary level of fibrinolytic split products, as determined by the latex-coated particle test, can be used as an indicator of the course of warfarin-anticoagulated patients after renal allografting.

    Title Prothrombin Quick. A Newly Identified Dysprothrombinemia.
    Date April 1978
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    The rarest of reported inherited plasmatic coagulopathies involve prothrombin. Only 10 families with significant reductions of this plasma protein (hypoprothrombinemia) have been observed. Even fewer, six families, have been found to have a functionally abnormal prothrombin (dysprothrombinemia) in their blood. An as yet undefined prothrombin abnormally has been recognized in eight other families. One of the first patients previously identified by Quick and his associates as having a defect in her plasma prothrombin has been shown to have about half the normal amount of prothrombin antigen but virtually no prothrombic function. We propose that this dysprothrombin be designated prothrombin Quick. An additional patient also first described by Quick was found to be truly hypoprothrombinemic--that is, to lack both functional and antigenic prothrombin. Briefly summarized are the other five families with dysprothrombinemia, nine with hypoprothrombinemia, and the eight in whom the defect has not been classified.

    Title Tissue Fluid States in Compartment Syndromes.
    Date February 1978
    Journal Bibliotheca Anatomica
    Title Interstitial Fluid Pressure in Muscle and Compartment Syndromes in Man.
    Date October 1977
    Journal Microvascular Research
    Title Exertional Anterolateral-compartment Syndrome. Case Report with Fascial Defect, Muscle Herniation, and Superficial Peroneal-nerve Entrapment.
    Date May 1977
    Journal The Journal of Bone and Joint Surgery. American Volume
    Title The Wick Catheter Technique for Measurement of Intramuscular Pressure. A New Research and Clinical Tool.
    Date December 1976
    Journal The Journal of Bone and Joint Surgery. American Volume
    Excerpt

    The wick catheter technique was developed in 1968 for measurement of subcutaneous pressure and has been modified for easy intramuscular insertion and continuous recording of interstitial fluid pressure in animals and humans. Studies in dogs of the anterolateral compartment of the leg in simulation of the compartment syndrome showed the technique to be accurate and reproducible. The wick catheter technique is capable of important clinical applications in the diagnosis and treatment of acute and chronic compartment syndromes.

    Title Liver Transplantation in Pigs with Von Willebrand's Disease.
    Date April 1976
    Journal British Journal of Haematology
    Excerpt

    Nine pigs with von Willebrand's disease (vWd pigs) received normal auxiliary livers; in the immediate postoperative period, three pigs died, three survived from 3 days to 3 weeks, and three were killed 5-13 weeks postoperatively. There was an increase in factor VIII (up to 90 u/dl) but with a type of factor VIII that was more labile than normal and that decreased after 2 weeks, probably as a result of liver rejection. There was a slight increase in the levels of the ristocetin-Willebrand factor postoperatively (up to 11%) but this activity was undetectable after 2 weeks. There was no correction of the abnormal bleeding time and platelet retention. When a vWd liver was transplanted orthotopically into a normal pig, the factor-VIII coagulant activity and the ristocetin-Willebrand factor remained normal. The abnormality in porcine von Willebrand's disease is only partially corrected by liver transplantation, which suggests that there also is extrahepatic synthesis of the missing or abnormal plasmatic activity or activities.

    Title The Spectrum of Von Willebrand's Disease Revisited.
    Date April 1976
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    We have examined nine patients with presumed von Willebrand's disease who present the spectrum of that disorder. Two had findings that would be accepted generally as diagnostic of von Willebrand's disease, and seven had variations of the usual pattern. The commonest variation was the combination of borderline and variable levels of coagulant Factor VIII, commensurate levels of Factor VIII-related antigen, and low levels of ristocetin-Willebrand factor.

    Title Proceedings: Studies on Platelet Factor 4 Like Activity in Atherosclerosis Susceptible and Resistant Pigeons.
    Date February 1976
    Journal Thrombosis Et Diathesis Haemorrhagica
    Title Effect of Dietary D-penicillamine on Metabolism of Copper in the Rat.
    Date September 1975
    Journal The American Journal of Physiology
    Excerpt

    When normal rats were put on a diet containing d-penicillamine equivalent to a dosage of about 1.75 g/day in a 70-kg man, there was a prompt, marked decrease in biliary excretion of copper and of radiocopper after its intravenous administration. Urinary copper increased as tissue copper levels decreased; this decrease was most pronounced in bone marrow, kidney, lung, and spleen. Plasma copper increased and p-phenylendiamine oxidase activity increased. Fecal copper decreased modestly, which was probably attributable to decreases in food intake and biliary copper. Copper-toxic rats, already hypercupriuric, excreted more urinary copper when given d-penicillamine.

    Title Effect of Induced Chronic Intravascular Coagulation on Plasminogen Activator in Dogs.
    Date June 1975
    Journal Thrombosis Et Diathesis Haemorrhagica
    Excerpt

    Plasminogen activator activity in blood vessels of various organs was determined in three untreated (control) male dogs and in two male dogs that received a continous infusion of canine brain thromboplastic emulsion for 2 weeks. Activator was measured by the speed and degree of lysis of fibrin films that were overlaid with slices of tissue. Depletion of vascular plasminogen activator occurred in the vena cava of treated dogs at the site of the tip of the catheter, which was surrounded by a clot. A decrease of activator was found in most organs and particularly in certain endocrine organs (thyroid, pituitary, and testis). Of organs that normally contained the most activator, the greatest depletion was found in the skin, lung, and penis. The wide variation of plasminogen activator activity in organs of normal dogs is described.

    Title Blood Coagulation Studies in Patients with Cancer.
    Date December 1974
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Effect of Surgical Operations on Certain Tests Used to Diagnose Intravascular Coagulation and Fibrinolysis.
    Date December 1974
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Eller's Remarkable Experiment.
    Date November 1974
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Temporal Disorganization and Delusional-like Ideation. Processes Induced by Hashish and Alcohol.
    Date July 1974
    Journal Archives of General Psychiatry
    Title Tests of Hemostasis in Swine: Normal Values and Values in Pigs Affected with Von Willebrand's Disease.
    Date January 1974
    Journal American Journal of Veterinary Research
    Title Von Willebrand's Disease in Pregnancy.
    Date August 1973
    Journal Obstetrics and Gynecology
    Title Quantitation of Platelet Aggregation in Myeloproliferative Disorders.
    Date June 1972
    Journal American Journal of Clinical Pathology
    Title Chronic Intravascular Coagulation in Dogs.
    Date February 1972
    Journal The Journal of Laboratory and Clinical Medicine
    Title Studies of Diabetic Instability. I. Immunoassay of Human Insulin in Plasma Containing Antibodies to Pork and Beef Insulin.
    Date February 1972
    Journal Metabolism: Clinical and Experimental
    Title Prothrombin Utilization in Congenital Coagulation Deficiency States.
    Date November 1971
    Journal Thrombosis Et Diathesis Haemorrhagica
    Title Paradoxic Changes in Platelets and Fibrinogen in Chronically Induced Intravascular Coagulation.
    Date October 1971
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Assay for Fibrinolytic Split Products: Comparison of Staphylococcal Clumping and Hemagglutination-inhibition Tests.
    Date September 1971
    Journal The Journal of Laboratory and Clinical Medicine
    Title Bleeding from Standardized Skin Punctures: Automated Technic for Recording Time, Intensity, and Pattern of Bleeding.
    Date August 1971
    Journal American Journal of Clinical Pathology
    Title Prevention of Experimental Arterial Thrombosis and Platelet Adhesiveness by 2,6-bis-(diethanolamino)-4-piperidinopyrimido-[5,4-d]-pyrimidine (rna 233).
    Date January 1971
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Effects of Monoamine Oxidase Inhibitors, Glyceryl Gualacolate, and Ethanol on Experimental Arterial Thrombosis.
    Date November 1970
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Intravascular Coagulation-fibrinolysis (icf) Syndrome and Malignancy: Historical Review and Report of Two Cases with Metastatic Carcinoid and with Acute Myelomonocytic Leukemia.
    Date October 1970
    Journal Thrombosis Et Diathesis Haemorrhagica. Supplementum
    Title Intravascular Coagulation in Systemic Amyloidosis.
    Date September 1970
    Journal Thrombosis Et Diathesis Haemorrhagica. Supplementum
    Title Intravascular Coagulation and Hemangiomata.
    Date August 1970
    Journal Thrombosis Et Diathesis Haemorrhagica. Supplementum
    Title Chronic Intravascular Coagulation (ifc) Syndrome.
    Date August 1970
    Journal Thrombosis Et Diathesis Haemorrhagica. Supplementum
    Title Experimental Arterial Thrombosis: Description of a Method.
    Date June 1970
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Antihemophilic Factor 8 in Hemophilia. Use of Concentrates to Permit Major Surgery.
    Date April 1970
    Journal Jama : the Journal of the American Medical Association
    Title Inhibition of Arterial Thrombosis and Platelet Adhesiveness in the Rat by Intravenous 2,4,6-trimorpholinopyrimido-(5,4-d)-pyrimidine (ra 433).
    Date March 1970
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Citrate Stabilization of Chromatographically Purified Factor 8.
    Date January 1970
    Journal Blood
    Title Cell-culture Synthesis of a Factor Viii-like Activity.
    Date December 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Platelet Adhesiveness in Von Willebrand's Disease.
    Date September 1969
    Journal American Journal of Clinical Pathology
    Title A Test of Platelet Adhesiveness.
    Date August 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Development of the Present Concept of Hemophilia.
    Date May 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Synthesis of Antihemophilic Factor (factor Viii) by Leukocytes: Preliminary Report.
    Date April 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Rapid Sensitive Method for Measuring Fibrinogen Split-products in Human Serum.
    Date March 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Metabolism of Butyl 4-hydroxy-3,5-diiodobenzoate (bhdb), a Thyroxine Analogue.
    Date September 1968
    Journal Endocrinology
    Title Release of Vitamin K-dependent Coagulation Factors by Isolated Perfused Rat Liver.
    Date July 1968
    Journal The American Journal of Physiology
    Title Von Willebrand Disease "stimulating Factor" in Porcine Plasma.
    Date June 1968
    Journal The American Journal of Physiology
    Title Hypercoagulability Associated with Chronic Ulcerative Colitis: Changes in Blood Coagulation Factors.
    Date April 1968
    Journal Gastroenterology
    Title Agglutinating Factors Eluted from Erythrocytes of Patients with Rheumatoid Arthritis and Patients with Acquired Hemolytic Anemia.
    Date March 1968
    Journal Acta Rheumatologica Scandinavica
    Title The Spectrum of Von Willebrand's Disease.
    Date February 1968
    Journal Thrombosis Et Diathesis Haemorrhagica
    Title Effect of Bypass Surgery on Coagulation-sensitive Clotting Factors.
    Date December 1967
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Effect of Monoamine Oxidase Inhibition on Biliary Excretion of Metabolites of Norepinephrine by Isolated Rat Liver.
    Date September 1967
    Journal The Journal of Pharmacology and Experimental Therapeutics
    Title Disappearance Rates of Coagulation Factors: Transfusion Studies in Factor-deficient Patients.
    Date July 1967
    Journal Transfusion
    Title Effect of Thyroid Hormones on Metabolism of D,l-norepinephrine by Isolated Rat Liver.
    Date June 1967
    Journal Endocrinology
    Title Quantitative Thin-layer Chromatography of Chenodeoxycholic Acid and Deoxycholic Acid in Human Duodenal Contents.
    Date May 1967
    Journal Journal of Chromatography
    Title Pool Size and Turnover of Bile Acids in Six Hypercholesteremic Patients with and Without Administration of Nicotinic Acid.
    Date May 1967
    Journal The Journal of Laboratory and Clinical Medicine
    Title Agglutinins Eluted from Erythrocytes of Rheumatoid Patients.
    Date February 1967
    Journal Arthritis and Rheumatism
    Title In Vitro Blood Cell Uptake of Radioactive Norepinephrine: Experience in Pheochromocytoma and Idiopathic Orthostatic Hypotension.
    Date February 1967
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title A Mathematical Model for Copper Metabolism and Its Relation to Wilson's Disease.
    Date January 1967
    Journal The American Journal of Physiology
    Title Effect of Nicotinic Acid on Pool Size and Turnover of Taurocholic Acid in Normal and Hypothyroid Dogs.
    Date December 1966
    Journal Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (new York, N.y.)
    Title The Distribution and Excretion of Tritiated Substances in Experimental Animals Following the Administration of Digoxin-3h.
    Date October 1966
    Journal The Journal of Laboratory and Clinical Medicine
    Title Quantitative Thin-layer Chromatography of Free and Conjugated Cholic Acid in Human Bile and Duodenal Contents.
    Date October 1966
    Journal Journal of Chromatography
    Title Mechanism and Management of Intravascular Thrombosis.
    Date March 1966
    Journal Minnesota Medicine
    Title The Effect of Certain Hemostatic Agents and the Local Use of Diluted Epinephrine on Bleeding During Oral Surgical Procedures.
    Date March 1966
    Journal Oral Surgery, Oral Medicine, and Oral Pathology
    Title Standardization of Platelets in the Thromboplastin Generation Test.
    Date February 1966
    Journal American Journal of Clinical Pathology
    Title Anticoagulant Malingerers (the "dicumarol-eaters").
    Date December 1965
    Journal The American Journal of Medicine
    Title Quantum Proteolysis by Neutrophils : Implications for Pulmonary Emphysema in Alpha(1)-antitrypsin Deficiency
    Date
    Journal Chest

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