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1.
Oncogene ; 32(10): 1252-65, 2013 Mar 07.
Article in English | MEDLINE | ID: mdl-22580601

ABSTRACT

Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.


Subject(s)
Mutation , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Movement , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , HCT116 Cells , HT29 Cells , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Neoplasm Invasiveness , Phosphorylation , Signal Transduction , Transcription Factors/metabolism , Transfection , Tumor Suppressor Proteins/metabolism
2.
Respir Med ; 100(9): 1588-97, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16469490

ABSTRACT

INTRODUCTION: In vivo, the airway epithelium stretches and relaxes with each respiratory cycle, but little is known about the effect this pattern of elongation and relaxation has on bronchial epithelial cells. We have used a model of cell deformation to measure the effect of stretch on inflammatory cytokine release by the BEAS 2B cell line, and to examine the method of mechanotransduction in these cells. METHODS: BEAS 2B cells were cyclically stretched using the Flexercell system. IL-8 and RANTES protein and RNA levels were measured after different elongations, rates and duration of stretch. An inhibitor of Rho (Ras Homologous)-associated kinases was used, to assess the effect of blocking downstream of integrin signalling. Immunofluorescent staining of paxillin was used to study the effect of stretch on the distribution of focal contacts and the organisation of the actin cytoskeleton. RESULTS: IL-8 release by BEAS 2B cells was increased by cytokine stimulation and stretch, whereas RANTES levels in the cell supernatant decreased after stretch in a dose-, time- and rate-dependent manner. Thirty percent elongation at 20 cycles/min for 24h increased IL-8 levels by over 100% (P < 0.01). Blocking rho kinase using Y-27632 inhibited the effect of stretch on IL-8 release by the BEAS 2B cells. Immunofluorescent staining demonstrated that stretch caused dramatic disassembly of focal adhesions and resulted in the redistribution of paxillin to the peri-nuclear region. CONCLUSION: This study demonstrates a marked effect of stretch on bronchial epithelial cell function. We propose that stretch modulates epithelial cell function via the activation of rho kinases. The observation that stretch promotes focal adhesion disassembly suggests a mechanism whereby focal adhesion turnover (coordination of assembly and disassembly) is essential for mechanotransduction in bronchial epithelial cells.


Subject(s)
Bronchi/cytology , Chemokine CCL5/metabolism , Epithelial Cells/physiology , Interleukin-8/biosynthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mechanotransduction, Cellular , Protein Serine-Threonine Kinases/antagonists & inhibitors , Amides/pharmacology , Cell Line , Elasticity , Enzyme Inhibitors/pharmacology , Epithelial Cells/metabolism , Humans , Models, Biological , Paxillin/analysis , Pyridines/pharmacology , Stress, Mechanical , rho-Associated Kinases
3.
FEBS Lett ; 484(3): 179-83, 2000 Nov 10.
Article in English | MEDLINE | ID: mdl-11078874

ABSTRACT

Aggregation by immune complexes of receptors specific for the Fc region of IgG results in their internalisation and disposal by trafficking to lysosomes. We show here that internalisation of FcgammaRI by IFN-gamma treated U937 cells following receptor aggregation by cross-linking antibodies requires the activation of two distinct signalling pathways. The pathways were functionally dissected in streptolysin-O-permeabilised cells by capitalising on their relative dependence on active GTP binding proteins. One pathway required the presence of GTP-gammaS or active betagamma subunits, the other did not. Use of inhibitors revealed that the betagamma-independent pathway required activation of PI 3-kinases and was PKC-independent In contrast, the betagamma-dependent pathway involved activation of phospholipase C-beta and PKC, but was PI 3-kinase-independent. Both these pathways were found to be active in intact cells and are likely to determine receptor trafficking following internalisation.


Subject(s)
Endocytosis/immunology , Interferon-gamma/pharmacology , Receptors, IgG/physiology , Signal Transduction/immunology , Bacterial Proteins , Cell Membrane Permeability , Cross-Linking Reagents , Endocytosis/drug effects , Enzyme Inhibitors/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Humans , Isoenzymes/metabolism , Kinetics , Naphthalenes/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phospholipase C beta , Protein Kinase C/metabolism , Receptors, IgG/drug effects , Signal Transduction/drug effects , Streptolysins , Type C Phospholipases/metabolism , U937 Cells
4.
Ann Thorac Surg ; 68(2): 780-4, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10475488

ABSTRACT

BACKGROUND: We are developing and testing a new ventricular assist device (VAD) to be powered by conditioned skeletal muscle. METHODS: To evaluate the VAD hardware and to develop a muscle training regimen, 8 calves have been used in studies in which the right latissimus dorsi muscle was employed. The experiments were carried out to an approximately 4-month duration. RESULTS: There was significant conversion of type II (fast twitch) to type I (slow twitch) muscle fibers. This did not correlate well, however, with device performance. The device stroke volumes ranged from approximately 17 to 90 cc. This variability of outcome occurred despite the fact that identical hardware, surgical procedures, and training regimens were employed. CONCLUSIONS: The results from the first eight studies lead us to speculate that perfusion may be important even when the muscle is working at pressures much lower than systemic blood pressure levels. In an attempt to augment tissue perfusion, we plan to investigate thermally induced angiogenesis as a possible mechanism for increasing blood flow to the tissue.


Subject(s)
Heart-Assist Devices , Muscle Contraction/physiology , Muscle, Skeletal/physiopathology , Animals , Cattle , Electric Stimulation , Equipment Design , Humans , Muscle, Skeletal/pathology , Stroke Volume
5.
J Cell Biol ; 143(7): 1981-95, 1998 Dec 28.
Article in English | MEDLINE | ID: mdl-9864369

ABSTRACT

Focal adhesion assembly and actin stress fiber formation were studied in serum-starved Swiss 3T3 fibroblasts permeabilized with streptolysin-O. Permeabilization in the presence of GTPgammaS stimulated rho-dependent formation of stress fibers, and the redistribution of vinculin and paxillin from a perinuclear location to focal adhesions. Addition of GTPgammaS at 8 min after permeabilization still induced paxillin recruitment to focal adhesion-like structures at the ends of stress fibers, but vinculin remained in the perinuclear region, indicating that the distributions of these two proteins are regulated by different mechanisms. Paxillin recruitment was largely rho-independent, but could be evoked using constitutively active Q71L ADP-ribosylation factor (ARF1), and blocked by NH2-terminally truncated Delta17ARF1. Moreover, leakage of endogenous ARF from cells was coincident with loss of GTPgammaS- induced redistribution of paxillin to focal adhesions, and the response was recovered by addition of ARF1. The ability of ARF1 to regulate paxillin recruitment to focal adhesions was confirmed by microinjection of Q71LARF1 and Delta17ARF1 into intact cells. Interestingly, these experiments showed that V14RhoA- induced assembly of actin stress fibers was potentiated by Q71LARF1. We conclude that rho and ARF1 activate complimentary pathways that together lead to the formation of paxillin-rich focal adhesions at the ends of prominent actin stress fibers.


Subject(s)
Cytoskeletal Proteins/metabolism , GTP-Binding Proteins/physiology , Intercellular Junctions/metabolism , Phosphoproteins/metabolism , 3T3 Cells/drug effects , 3T3 Cells/metabolism , 3T3 Cells/ultrastructure , ADP-Ribosylation Factor 1 , ADP-Ribosylation Factors , Actin Cytoskeleton/physiology , Animals , Bacterial Proteins , Biological Transport , Cell Membrane Permeability , Culture Media, Serum-Free , GTP-Binding Proteins/chemistry , GTP-Binding Proteins/genetics , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Mice , Microinjections , Paxillin , Recombinant Fusion Proteins/metabolism , Sequence Deletion , Streptolysins/pharmacology , rho GTP-Binding Proteins
6.
Immunology ; 94(1): 48-55, 1998 May.
Article in English | MEDLINE | ID: mdl-9708186

ABSTRACT

The high-affinity receptor for immunoglobulin G (Fc gamma RI) plays a central role in the clearance of immune complexes by mediating their internalization and delivery to lysosomes. In monocytic U937 cells, receptor internalization is independent of tyrosine kinase activity. However, the tyrosine kinase inhibitor, genistein, prevents further progress of the receptor to lysosomes and traps it in a sub-plasma membrane early endosome. Similarly, Fc gamma RI expressed in COS cells is able to internalize immune complexes but is unable to translocate to lysosomes. This suggests that Fc gamma RI, whose cytoplasmic tail is devoid of known signalling motifs, must recruit tyrosine kinases via its gamma-chain to achieve lysosomal delivery. We show that a chimera of the extracellular domain of Fc gamma RI and the cytoplasmic tail of the gamma-chain is both internalized and efficiently trafficked to lysosomes. Our study suggests that a key function of the gamma-chain is recruitment of tyrosine kinases to initiate the intracellular signalling pathways required to target Fc gamma RI following immune complex aggregation to lysosomes and not to initiate endocytosis per se.


Subject(s)
Endosomes/immunology , Lysosomes/immunology , Protein-Tyrosine Kinases/immunology , Receptors, IgG/immunology , Antigen-Antibody Complex/metabolism , Endocytosis/drug effects , Genistein/pharmacology , Humans , Microscopy, Confocal , Protein-Tyrosine Kinases/antagonists & inhibitors , Tumor Cells, Cultured
7.
Mol Biol Cell ; 7(9): 1429-42, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8885237

ABSTRACT

In mast cells, activation of GTP-binding proteins induces centripetal reorganization of actin filaments. This effect is due to disassembly, relocalization, and polymerization of F-actin and is dependent on two small GTPases, Rac and Rho. Activities of Rac and Rho are also essential for the secretory function of mast cells. In response to GTP-gamma-S and/or calcium, only a proportion of permeabilized mast cells is capable of secretory response. Here, we have compared actin organization of secreting and nonsecreting cell populations. We show that the cytoskeletal and secretory responses are strongly correlated, indicating a common upstream regulator of the two functions. The secreting cell population preferentially displays both relocalization and polymerization of actin. However, when actin relocalization or polymerization is inhibited by phalloidin or cytochalasin, respectively, secretion is unaffected. Moreover, the ability of the constitutively active mutants of Rac and Rho to enhance secretion is also unaffected in the presence of cytochalasin. Therefore, Rac and Rho control these two functions by divergent, parallel signaling pathways. Cortical actin disassembly occurs in both secreting and nonsecreting populations and does not, by itself, induce exocytosis. A model for the control of exocytosis is proposed that includes at least four GTP-binding proteins and suggests the presence of both shared and divergent signaling pathways from Rac and Rho.


Subject(s)
Cytoskeleton/ultrastructure , Exocytosis/physiology , GTP-Binding Proteins/metabolism , Mast Cells/physiology , Proteins/metabolism , Actins/physiology , Animals , Boron Compounds , Cell Membrane Permeability , Cells, Cultured , Concanavalin A/metabolism , Cytochalasins/pharmacology , Cytoskeleton/metabolism , Exocytosis/drug effects , Flow Cytometry/methods , Fluorescein-5-isothiocyanate/analogs & derivatives , GTP-Binding Proteins/drug effects , GTPase-Activating Proteins , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Guanosine Diphosphate/analogs & derivatives , Guanosine Diphosphate/pharmacology , Mast Cells/metabolism , Mast Cells/ultrastructure , Microscopy, Confocal/methods , Proteins/drug effects , Rats , Staining and Labeling/methods , Thionucleotides/pharmacology , beta-N-Acetylhexosaminidases/metabolism , rac GTP-Binding Proteins , rho GTP-Binding Proteins , rhoA GTP-Binding Protein
8.
Biochem J ; 309 ( Pt 3): 725-9, 1995 Aug 01.
Article in English | MEDLINE | ID: mdl-7639685

ABSTRACT

The whole-cell patch-clamp technique was used to study the effect of primaquine, an inhibitor of vesicular transport, on the calcium-release-activated current (Icrac) in rat megakaryocytes. Addition of primaquine, before emptying of internal Ca2+ stores by ionomycin, prevented the development of Icrac, with a half-maximal concentration of near 100 microM. Maximal inhibition (> or = 83%) was observed at 0.6-1 mM primaquine. At 1 mM, chloroquine, a related compound which is less effective at blocking vesicular secretion, had no effect on Icrac. Primaquine (0.8 mM) added after sustained activation of Icrac caused a gradual block of current, with maximal inhibition of 50% observed after 2-3 min. At 1 mM, internal guanosine 5'-[gamma-thio]triphosphate reduced Icrac by 65 +/- 13%. Neither 1 mM GTP nor 2 mM guanosine 5'-[beta-thio]diphosphate had any significant effect on Icrac. The recognized role of GTPases in the regulation of vesicular trafficking, together with block of Icrac activation by primaquine, provide evidence that the channels carrying Icrac may be stored in a vesicular membrane compartment and transferred to the plasma membrane following store depletion.


Subject(s)
Calcium Channel Blockers/pharmacology , Megakaryocytes/drug effects , Primaquine/pharmacology , Animals , Biological Transport , Calcium/metabolism , Ionomycin/pharmacology , Male , Megakaryocytes/metabolism , Patch-Clamp Techniques , Rats , Rats, Wistar
9.
J Cell Sci ; 108 ( Pt 2): 657-66, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7769009

ABSTRACT

Permeabilised rat mast cells were exposed to gelsolin and its N-terminal half (S1-3), proteins that sever actin filaments in a calcium-dependent and independent manner, respectively. Gelsolin and S1-3 induced a decrease in cellular F-actin content and an increase in the extent of the secretory response. The calcium sensitivities of both these effects were consistent with the differential calcium requirements of the two proteins. Segment 1 (S1), which binds G-actin and caps filaments but does not sever them, did not show these effects. Thus, secretion of mast cells is promoted as a consequence of the severing activity of exogenous gelsolin or S1-3. Most of the endogenous gelsolin remained within permeabilised, washed mast cells and its distribution in resting state was predominantly cortical. Addition of calcium in the absence of MgATP did not reduce the F-actin content; by contrast, calcium with MgATP induced F-actin loss that was unaffected by the presence of anti-gelsolin. Because this antibody inhibits the severing activity of gelsolin, these results indicate that in permeabilised mast cells the severing activity of the remaining endogenous gelsolin is not involved in cortical actin filaments disassembly. Upon exposure to GTP-gamma-S in the absence of calcium, the content of cortical gelsolin was reduced. This parallels our previous observation of a GTP-gamma-S induced reduction of cortical actin filaments followed by their relocation to the cell's interior (Norman et al. (1994) J. Cell Biol. 126, 1005-1015) and suggests that actin redistribution may be a consequence of dissociation of gelsolin caps brought about by activation of a GTP-binding protein.


Subject(s)
Gelsolin/pharmacology , Gelsolin/physiology , Mast Cells/drug effects , Actins/metabolism , Animals , Cell Degranulation , Cells, Cultured , Kinetics , Male , Mast Cells/metabolism , Mast Cells/physiology , Rats , Rats, Sprague-Dawley
10.
Curr Biol ; 5(1): 68-73, 1995 Jan 01.
Article in English | MEDLINE | ID: mdl-7697350

ABSTRACT

BACKGROUND: Regulated secretion by mast cells is known to be controlled by GTP-binding proteins, but the proteins involved have not been identified. Rac and Rho, two small GTPases related to the oncoprotein Ras, mediate transmission of signals from cell-surface receptors to the actin cytoskeleton. In rat mast cells, both Rac and Rho participate in effecting the centripetal redistribution of filamentous actin that is observed after stimulation of the cells. Rho is responsible for polymerization of actin filaments in the cell interior, whereas Rac is required for the entrapment in the interior of filaments released from the cortex. Such cytoskeletal changes could be important in control of the exocytotic process, so we examined whether Rac and Rho also play a role in regulated secretion by mast cells. RESULTS: We show that the constitutively active mutant proteins, V14RhoA and V12Rac1, enhance regulated secretion from permeabilized mast cells by increasing the proportion of cells that are competent to respond to stimulation. In addition, inhibition of endogenous Rac and Rho activity using inhibitors, N17Rac1 and C3 transferase, respectively, reduces the secretory response of mast cells to stimuli. CONCLUSION: These results provide direct evidence that, in mast cells, both Rac and Rho are components of the signalling pathway that leads to secretion.


Subject(s)
GTP Phosphohydrolases/physiology , GTP-Binding Proteins/physiology , Mast Cells/metabolism , Animals , Calcium/metabolism , Cell Degranulation , Exocytosis/physiology , In Vitro Techniques , Mast Cells/cytology , Rats , rac GTP-Binding Proteins , rhoA GTP-Binding Protein
11.
J Biol Chem ; 269(39): 24396-402, 1994 Sep 30.
Article in English | MEDLINE | ID: mdl-7929100

ABSTRACT

Cross-linking of leukocyte Fc receptors specific for IgG (Fc gamma Rs) by multivalent IgG complexes triggers a wide range of immune functions. Many of these responses can also be stimulated in vitro using anti-Fc gamma R monoclonal antibody-containing complexes. This observation has suggested that cross-linking is the key event and that binding of IgG, which in itself does not elicit a response, is functionally passive. However, in this study we show that binding of monomeric IgG to the human high affinity receptor, Fc gamma RI, is itself sufficient to permit the receptor to enter an internalization-recycling pathway, which has a small intracellular pool. Unoccupied Fc gamma RI is not internalized and recycled in this manner. This finding may be explained by the previous observation that there is a physical association between Fc gamma RI and the cytoskeletal component, actin-binding protein (non-muscle filamin; ABP-280), which is disrupted upon IgG binding. Thus, in the absence of IgG, Fc gamma RI may be physically excluded from the endocytic pathway by tethering to the cytoskeleton. The role of cross-linking is to divert Fc gamma RI-IgG complexes from the recycling pathway, causing their retention and subsequent degradation within the cell. In contrast to Fc gamma RII-mediated endocytosis, intracellular accumulation of cross-linked Fc gamma RI-IgG complexes is not sensitive to inhibition by genistein, suggesting that the process is independent of tyrosine kinase activity.


Subject(s)
Endocytosis , Immunoglobulin G/metabolism , Receptors, IgG/metabolism , Antigen-Antibody Complex , Cell Membrane/metabolism , Humans , Microscopy, Electron , Primaquine/pharmacology , Protein Binding , Protein-Tyrosine Kinases/metabolism , Receptors, IgG/drug effects , Tumor Cells, Cultured
12.
J Cell Biol ; 126(4): 1005-15, 1994 Aug.
Article in English | MEDLINE | ID: mdl-8051203

ABSTRACT

Rat peritoneal mast cells, both intact and permeabilized, have been used widely as model secretory cells. GTP-binding proteins and calcium play a major role in controlling their secretory response. Here we have examined changes in the organization of actin filaments in intact mast cells after activation by compound 48/80, and in permeabilized cells after direct activation of GTP-binding proteins by GTP-gamma-S. In both cases, a centripetal redistribution of cellular F-actin was observed: the content of F-actin was reduced in the cortical region and increased in the cell interior. The overall F-actin content was increased. Using permeabilized cells, we show that AIF4-, an activator of heterotrimeric G proteins, induces the disassembly of F-actin at the cortex, while the appearance of actin filaments in the interior of the cell is dependent on two small GTPases, rho and rac. Rho was found to be responsible for de novo actin polymerization, presumably from a membrane-bound monomeric pool, while rac was required for an entrapment of the released cortical filaments. Thus, a heterotrimeric G-protein and the small GTPases, rho and rac, participate in affecting the changes in the actin cytoskeleton observed after activation of mast cells.


Subject(s)
Actin Cytoskeleton/physiology , Actins/metabolism , GTP-Binding Proteins/metabolism , Mast Cells/physiology , Actin Cytoskeleton/ultrastructure , Actins/ultrastructure , Adenosine Diphosphate Ribose/metabolism , Aluminum Compounds/pharmacology , Animals , Cell Membrane Permeability , Cells, Cultured , Fluorides/pharmacology , Kinetics , Macromolecular Substances , Mast Cells/cytology , Mast Cells/drug effects , Rats , p-Methoxy-N-methylphenethylamine/pharmacology
13.
J Neuroendocrinol ; 4(4): 401-9, 1992 Aug.
Article in English | MEDLINE | ID: mdl-21554623

ABSTRACT

The effects of glucocorticoids and corticotrophin-releasing factor (CRF) on the release of various molecular forms of adrenocorticotrophic hormone (ACTH) have been investigated in primary cultures of rat anterior pituitary. The rat cells responded to a 30 min challenge with CRF by secreting increased amounts of ACTH, as assessed both by bioassay, using rat adrenocortical cells, and by radioimmunoassay. Inclusion of a synthetic glucocorticoid, such as dexamethasone (DEX), in the incubation for 5 min prior to, and during the CRF challenge, had no effect on the response as measured by radioimmunoassay. Bioassay, however, indicated profound suppression of the response to CRF. This discrepancy between ACTH immuno- and bioactivity was investigated by fractionating the immunoreactive ACTH species using high-performance liquid chromatography. The lower molecular weight (<15kd) forms (ACTH(1-39) , phosphorylated ACTH(1-39) and glycosylated ACTH(1±39) ) were separated from higher molecular weight (>15kd) forms (i.e. ACTH biosynthetic intermediate and proopiomelanocortin) using C-18 Sep-Pak. The lower molecular weight molecules were further resolved into glycosylated and non-glycosylated ACTH, using an acetonitrile gradient high-performance liquid chromatography with trifluoroacetic acid as an ion-pairer. Neither the proportion of low molecular weight forms of ACTH, nor that of glycosylated ACTH(1-39) secreted in response to CRF, were affected by DEX. Further fractionation of non-glycosylated ACTH, also using acetonitrile gradient high-performance liquid chromatography but with heptafluorobutyric acid as the ion-pairer, yielded peaks corresponding to phosphorylated and non-phosphorylated ACTH(1-39) . DEX significantly increased the proportion of phosphorylated ACTH secreted in response to CRF by 18%. An additional effect of DEX was revealed when Sep-Pak extracts were treated with alkaline phosphatase, prior to analysis. After dephosphorylation, it became clear that the peptides released by CRF-stimulated cells were different if DEX was present in the medium. The peptide released in the presence of DEX (ACTH-S) had a slightly, but consistently, different retention time on high-performance liquid chromatography and very little biological activity. Antibody cross-reactivity studies suggested that ACTH-S was modified in the 1-24 region of the peptide. It is concluded that challenge of anterior pituitary cells in primary culture with CRF, following 5 min previous exposure to DEX, results in a molecular change. The consequence of this is that ACTH immunoreactivity is released, but the molecule has reduced biological activity. This may be part of the mechanism by which fast feedback inhibition of ACTH secretion is effected.

14.
J Ky Med Assoc ; 89(6): 274-6, 1991 Jun.
Article in English | MEDLINE | ID: mdl-1856586

ABSTRACT

Infection is the most dreaded complication associated with implantation of a prosthetic arterial graft. The reported incidence of primary graft infection varies from 1.3% to 6.0%, with a mortality rate from this complication as high as 75%. Although remote bypass followed by complete removal of the infected prosthesis has proven to be a satisfactory method of treatment, in certain instances remote bypass alone is not feasible and other modes of surgical treatment must be employed. Such conservative methods of management of infected aorto-iliac-femoral prosthesis sometimes irradicate infection. The only certain cure, however, is obtained by totally removing the graft. And the success of extra-anatomic axillofemoral techniques has led to its extended use. The addition of a cross-limb on an axillo-unilateral femoral graft to form an axillobilateral femoral graft was described by Sauvage and Wood, reasoning that the higher flow rate in the axillary limb of the axillobilateral femoral graft would result in an improved patency rate compared with that of axillounilateral femoral grafts. Additionally, both medial (obturator foramen) and lateral extra-anatomic remote bypass of infected femoral prosthesis have been used, successfully. The current case illustrates the complexity of management, once sepsis occurs. It further focuses on groin, retroperitoneal and bilateral axillo-femoral tract infection with prolonged (apparently innocuous) graft exposure and finally points out the utility of the ascending aorta as an alternative extra-anatomic inlet to perfuse the lower extremities.


Subject(s)
Aortic Aneurysm/surgery , Blood Vessel Prosthesis , Surgical Wound Infection/etiology , Aged , Aorta, Abdominal/surgery , Cellulitis/etiology , Femoral Artery/surgery , Humans , Male , Reoperation
15.
J Ky Med Assoc ; 89(5): 213-7, 1991 May.
Article in English | MEDLINE | ID: mdl-2066652

ABSTRACT

Acute mycotic aneurysms of the ascending aorta following aortocoronary bypass are exceedingly rare. To our knowledge, there have been few reports of successful management. The central location of this lesion places it apart from acute or chronic mycotic aneurysms in general and enhances its lethality. The availability of ascending and arch aortography, computerized chest tomography and the techniques of peripheral cardiopulmonary bypass, deep hypothermia and reversible circulatory arrest for prolonged periods of time permit successful management. The purpose of this report is to (1) illustrate such a problem; (2) describe its successful management; (3) review the etiology of mycotic aneurysms, historically and contemporarily; and (4) to differentiate early, acute mycotic aneurysms of the ascending aorta following aortocoronary bypass (usually lethal) from similar late chronic processes (readily reparable).


Subject(s)
Aneurysm, Infected/surgery , Aortic Aneurysm/surgery , Coronary Artery Bypass/adverse effects , Acute Disease , Aneurysm, Infected/diagnostic imaging , Aneurysm, Infected/etiology , Aortic Aneurysm/diagnostic imaging , Aortic Aneurysm/etiology , Female , Humans , Middle Aged , Tomography, X-Ray Computed
17.
J Ky Med Assoc ; 89(3): 118-20, 1991 Mar.
Article in English | MEDLINE | ID: mdl-1827489

ABSTRACT

Laser/balloon thermal angioplasty has proven to be a valuable adjunct in our management of peripheral vascular disease. The initial trials have produced a 77% success rate, a 3% incidence of complications, and no morbidity. Patient acceptance has been high and the return to prior activities in less than 1 week is an appreciated advantage. Laser/balloon angioplasty expands the armamentarium of the vascular surgeon and makes possible broader applications of standard vascular surgical techniques.


Subject(s)
Angioplasty, Balloon , Angioplasty, Laser , Intermittent Claudication/therapy , Aged , Female , Femoral Artery , Humans , Iliac Artery , Intermittent Claudication/surgery , Male , Middle Aged , Popliteal Artery
20.
J Immunol Methods ; 127(2): 255-62, 1990 Mar 09.
Article in English | MEDLINE | ID: mdl-2313103

ABSTRACT

A new, specific and sensitive radioimmunoassay, using a polyclonal antiserum raised in rabbits, is described for quantitating plasma thymulin. As little as 300 fg thymulin can be measured in one assay tube. The method has been used to measure thymulin in human blood (umbilical vessel blood, 2191 +/- 123 fg/ml; children and adults up to the age of 20 years, 1499 +/- 119 fg/ml; and adults between 21-65 years, 371 +/- 18 fg/ml). There is a highly significant decrease within these three groups (P less than 0.001 by one way analysis of variance). Also plasma thymulin levels were determined in rats (601 +/- 127 fg/ml) and in pooled plasma samples from mice (638 +/- 56 fg/ml). No thymulin was detected in plasma obtained from nude rats, nude mice and thymectomised mice. These results show that the radioimmunoassay described here is a useful quantitative tool for measuring plasma thymulin that will have applications in basic, applied and clinical research.


Subject(s)
Thymic Factor, Circulating/analysis , Thymus Hormones/analysis , Animals , Chromatography, High Pressure Liquid , Female , Humans , Male , Mice , Mice, Inbred C57BL , Rabbits , Radioimmunoassay , Rats , Rats, Inbred Strains , Thymic Factor, Circulating/immunology , Thymic Factor, Circulating/isolation & purification
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