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Biomedical subjects

M Poon

Publications and source records attributed to M Poon.

36 records · Page 2Linked to original sources
PubMed1996

Rapamycin inhibits vascular smooth muscle cell migration.

Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.

Administration, Oral↗
PubMed1996

Secretion of monocyte chemotactic activity by cultured rat aortic smooth muscle cells in response to PDGF is due predominantly to the induction of JE/MCP-1.

Inflammation is a critical feature of atherosclerosis and is characterized in part by the migration of circulating monocytes to the atherosclerotic plaque. These monocytes, together with macrophages, are a source of cytokines, growth factors, proteases, and procoagulants, which contribute to the progression of the atherosclerosis lesion. This study employed a modified Boyden chamber to examine the secretion of monocyte chemotactic activity by cultured rat aortic vascular smooth muscle cells in response to growth factors and cytokines. The induction of monocyte chemotactic activity showed a surprising specificity for platelet-derived growth factor-BB. This activity was blocked by actinomycin D and cycloheximide and thus required de novo transcription and protein synthesis. The ability to stimulate monocyte migration appeared to be solely due to the secretion of the monocyte chemoattractant protein JE/MCP-1 and was completely blocked by antisense oligonucleotides and antibodies to JE/MCP-1. The induction of chemotactic activity was also blocked by dexamethasone, an inhibitor of JE mRNA accumulation. This study suggests that the secretion of monocyte chemotactic activity by vascular smooth muscle cells is a highly regulatable and specific event and underscores the importance of JE/MCP-1 in the inflammatory response of the vessel wall.

Angiotensin II↗
PubMed1992

Congenital diaphragmatic hernia. Stabilization and repair on ECMO.

Availability of extracorporeal membrane oxygenation (ECMO) support and the potential advantages of delayed repair of congenital diaphragmatic hernia (CDH) have led several centers to delay CDH repair, using ECMO support if necessary. This study reviews the combined experience of five ECMO centers with infants who underwent stabilization with ECMO and repair of CDH while still on ECMO. All infants were symptomatic at birth, with a mean arterial oxygen pressure (PaO2) of 34 mmHg on institution of bypass despite maximal ventilatory support. A total of 42 infants were repaired on ECMO, with 18 (43%) surviving. Seven infants had total absence of the diaphragm, and 28 required a prosthetic patch to close the defect. Only five infants ever achieved a best postductal PaO2 over 100 mmHg before institution of ECMO. Prematurity was a significant risk factor, with no infants younger than 37 weeks of age surviving. Significant hemorrhage on bypass was also a hallmark of a poor outcome, with 10 of the 24 nonsurvivors requiring five thoracotomies and six laparotomies to control bleeding, whereas only one survivor required a thoracotomy to control bleeding. In follow-up, nine of the 18 survivors (50%) have developed recurrent herniation and seven (43%) have significant gastroesophageal reflux. Importantly, five of the 18 survivors were in the extremely high-risk group who never achieved a PaO2 over 100 mmHg or an arterial carbon dioxide pressure (PaCO2) less than 40 mmHg before the institution of ECMO. In conclusion, preoperative stabilization with ECMO and repair on bypass may allow some high-risk infants to survive. Surviving infants will require long-term follow-up because many will require secondary operations.

Extracorporeal Membrane Oxygenation↗
PubMed1992

JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells.

The early response to vascular injury is characterized by migration of inflammatory cells, including monocytes, and platelets to the damaged vessel wall. These inflammatory cells may serve as a source of growth factors and cytokines that stimulate vascular smooth muscle cell (VSMC) migration and proliferation associated with intimal hyperplasia. JE is a platelet-derived growth factor (PDGF)-inducible "early" gene that encodes a monocyte chemoattractant and, as such, could play an important role in inflammation. We now report that JE mRNA levels are increased in intact aorta after balloon injury. The time course of this increase, with maximal levels at 4 hours, is similar to that seen in PDGF-treated cultured rat aortic VSMCs. The accumulation of JE mRNA in cultured VSMCs is accompanied by a marked increase in the secretion of JE protein. The elevation of JE mRNA levels in VSMCs shows specificity for PDGF, because angiotensin II, alpha-thrombin, and epidermal growth factor fail to increase JE mRNA levels. In contrast to 3T3 fibroblasts, the accumulation of JE mRNA in VSMCs in response to PDGF is predominantly due to an increase in JE mRNA stability. The accumulation of JE mRNA in VSMCs stimulated by PDGF appears to occur via a novel pathway(s) independent of Ca2+ mobilization, Na(+)-H+ exchange, protein kinase C activation, or elevation in cAMP levels. These findings suggest that VSMCs may take part in the early inflammatory response after injury through the production of JE, a potent monocyte chemoattractant. Finally, our data suggest that JE may be a marker for PDGF-specific effects on VSMCs, both in vitro and in vivo. Thus, in addition to direct effects on VSMC growth and migration, PDGF may play a role in the early inflammatory response after vascular injury by inducing chemoattractants, such as that encoded by JE.

Angiotensin II↗
PubMed1992

Induction of PDGF-responsive genes in vascular smooth muscle. Implications for the early response to vessel injury.

Arterial injury induces vascular smooth muscle cells (VSMC) to modulate from a quiescent to a proliferative state characterized by cell division, migration, and secretion of matrix. These changes have been implicated in the development of intimal hyperplasia after balloon angioplasty. The transition of VSMC to a proliferative state is preceded by the accumulation of platelets and leukocytes, which may release growth factors and cytokines at the site of injury. Platelet-derived growth factor (PDGF) is secreted by platelets and a variety of cellular elements associated with the vessel wall and, as a VSMC mitogen and chemoattractant, has been implicated in the pathogenesis of intimal hyperplasia. We have found that, in addition to its effects on VSMC growth and migration, PDGF induces the expression in VSMC of the JE and KC genes, which encode monocyte and neutrophil chemoattractants, respectively. The induction of JE and KC by PDGF in VSMC culture involves several distinct transmembrane signaling pathways. In addition to their induction in VSMC culture, JE and KC messenger RNA accumulates rapidly and transiently in adult rabbit aorta after balloon dilatation, suggesting a role for these chemoattractants in the early vascular response to injury in vivo. The VSMC may therefore play a dual role in vessel injury, both as a mediator of the inflammatory response through chemoattractant release and as an effector of the hyperplastic response through proliferation.

Animals↗
PubMed1991

In vivo and in vitro inhibition of JE gene expression by glucocorticoids.

Glucocorticoids are potent anti-inflammatory agents which affect cell growth and migration in a wide variety of systems and have profound effects on monocytes, decreasing their circulating number as well as inhibiting their accumulation at sites of inflammation and injury. Although the mechanisms by which glucocorticoids regulate gene induction have been established, the mechanisms by which they inhibit inflammation or cell growth and migration have yet to been determined. JE is one of the most abundant genes induced by platelet-derived growth factor (PDGF) in vitro and is also induced in vivo in response to ischemia or injury. JE encodes a low molecular weight glycoprotein that functions in part as a monocyte chemotactic factor and thus may be important in recruiting monocytes to sites of tissue injury and/or inflammation. We report that glucocorticoids block the induction of JE mRNA by serum or PDGF in cultured vascular smooth muscle cells. The effect of glucocorticoids appears largely due to destabilization of JE mRNA and has specificity for JE, in that other "early" PDGF-inducible genes are not inhibited by glucocorticoids. The effect of glucocorticoids also occurs in vivo: methyl prednisolone blocks the constitutive expression and inhibits the ischemia-induced elevation of JE mRNA levels in rat kidneys. The inhibition of JE mRNA accumulation by glucocorticoids may be related to the anti-inflammatory effects of these agents and defines JE as a member of what may be a group of PDGF-inducible genes that are responsive to corticosteroids.

Animals↗
PubMed1991

Expression of cytokine-like genes JE and KC is increased during renal ischemia.

Both mitogenic and inflammatory phenomena accompany the renal response to ischemic injury. Previous studies have shown that several nuclear-binding members of the immediate early genes are prominently expressed after renal ischemia and may underlie the mitogenic response to such injury. We now report on the expression of JE and KC, other growth-factor-responsive genes that code for small secreted glycoproteins with cytokine-like properties, which may play a role in inflammation. The expression of the immediate early genes JE and KC was determined in rat kidney tissue at varying time points after release of a 50-min period of bilateral renal hilar clamping. Relative levels of mRNA for JE and KC were analyzed by Northern blot analysis of cortical and outer stripe mRNA. KC mRNA rose rapidly to peak values at 1 h and returned toward low baseline levels by 24 h after release of the hilar clamp. By contrast, JE mRNA reached peak levels later and remained elevated for at least 96 h after ischemia. JE antigen was localized immunocytochemically to the apical regions of the cortical and medullary thick ascending limbs as well as in the lumen of the distal nephron in ischemic kidneys. Cells of the glomerulus and proximal tubules were negative for JE antigen. In contrast to the increase in JE and KC mRNA, steady-state levels of uromodulin (Tamm Horsfall) mRNA, a cytokine binding protein also made by the thick ascending limb, declined to virtually undetectable levels by 24 h after ischemia. Thus the increases in JE and KC are not generalized phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evoked potential tone-on-tone masking patterns in the chinchilla.

Tone-on-tone masking patterns were measured in the chinchilla using the auditory evoked response from the inferior colliculus. The masker was a 2 kHz continuous tone presented at one of five levels from 20 to 70 dB SPL. The evoked response was elicited with tone bursts presented over a wide range of frequencies. Masking was defined as the difference between evoked response thresholds measured in the presence of the masker versus quiet. At low masker levels, the masking profile was symmetrical and centered around 2 kHz. However, as masker level increased, masking spread toward the high frequencies. Furthermore, at masker levels above 50 dB SPL, a low-threshold notch occurred above the masker. The masking profiles obtained with the evoked response are in good agreement with those obtained psychophysically.

Acoustics↗
PubMed1988

In vitro susceptibility of Cryptococcus neoformans isolates from patients with acquired immunodeficiency syndrome.

Cryptococcus neoformans strains from 26 individual patients with acquired immunodeficiency syndrome (AIDS) and three isolates from patients without AIDS were tested for their susceptibility to amphotericin B, flucytosine, ketoconazole, and miconazole nitrate. Ninety percent of the C neoformans isolates from patients with AIDS were inhibited by drug concentrations within achievable serum levels. The minimum fungicidal concentration of the four tested antifungal agents, however, exceeded obtainable cerebrospinal fluid levels.

Acquired Immunodeficiency Syndrome↗
PubMed1978

Neuronal generation of the leech swimming movement.

The swimming movement of the leech is produced by an ensemble of bilaterally symmetric, rhythmically active pairs of motor neurons present in each segmental ganglion of the ventral nerve cord. These motor neurons innervate the longitudinal muscles in dorsal or ventral sectors of the segmental body wall. Their duty cycles are phase-locked in a manner such that the dorsal and ventral body wall sectors of any given segment undergo an antiphasic contractile rhythm and that the contractile rhythms of different segments form a rostrocaudal phase progression. This activity rhythm is imposed on the motor neurons by a central swim oscillator, of which four bilaterally symmetric pairs of interneurons present in each segmental ganglion appear to constitute the major component. These interneurons are linked intra- and intersegmentally via inhibitory connections to form a segmentally iterated and inter-segmentally concatenated cyclic neuronal network. The network appears to owe its oscillatory activity pattern to the mechanism of recurrent cyclic inhibition.

Action Potentials↗
PubMed1978

Neuronal control of swimming in the medicinal leech. IV. Identification of a network of oscillatory interneurones.

Four oscillatory interneurones that appear to be the principal components of the central swim oscillator of Hirudo medicinalis have been identified on each side of the segmental ganglia of the ventral nerve cord. During 'swimming' episodes of an isolated nerve cord preparation each interneurone undergoes a polarization rhythm that is phase-locked with the impulse burst rhythm of the motor neurones known to drive the swimming movement. Passage of current into any of the interneurones can shift the phase of the swim rhythm. One of the interneurones projects its axon rearward to posterior ganglia and the other three project their axons frontward to anterior ganglia. The oscillatory interneurones are connected both intra- and interganglionically to form a topologically complex intersegmental network of concatenated ring circuits that possess the feature of recurrent cyclic inhibition. Theoretical analysis and electronic analogue models show that the network is inherently oscillatory and can produce both a cycle period and intra- and intersegmental phase relations of its elements that are appropriate for generating the body wave of the swimming movement.

Animals↗
PubMed1978

Neuronal control of swimming in the medicinal leech. V. Connexions between the oscillatory interneurones and the motor neurones.

A network of intra- and intersegmental synaptic connexions has been identified in the ventral nerve cord of the leech that links the set of oscillatory interneurones of the central swim oscillator to the motor neurones commanding the swimming rhythm. Excitatory connexions lead from oscillatory interneurones to both excitatory and inhibitory motor neurones, whereas inhibitory connexions lead from oscillatory interneurones to only the inhibitory motor neurones. Connexions leading from a motor neurone back to the oscillatory interneurones were found in only one exceptional case, an inhibitory motor neurone previously known to have access to the central swim oscillator. This network of identified connexions can account reasonably well for the mechanism by which the oscillatory interneurones drive their follower motor neurones into the phasic activity pattern characteristic of the swimming movement.

Action Potentials↗
PubMed1976

An oscillatory neuronal circuit generating a locomotory rhythm.

A quartet of interconnected interneurons whose periodic activity appears to generate the traveling body wave of the swimming leech has been identified on each side of segmental ganglia of the ventral nerve cord of Hirudo medicinalis. Theoretical analysis and electronic analog models of the identified intra- and interganglionic synaptic connections of the segmentally iterated interneurons showed that they form an oscillatory network with cycle period and intra-and intersegmental phase relations appropriate for the swimming movement.

Animals↗
PubMed1976

Studies on the blood clotting and fibrinolytic system in the plasma from a sei (baleen) whale.

Blood clotting and fibrinolytic systems were studied in the plasma of a sei whale (Balaenoptera borealis). The sei whale belongs to the suborder baleen whales of the order Cetacea. Whale plasma had a greatly prolonged kaolin-activated partial thromboplastin time and was deficient in Hageman factor (factor XII), Fletcher factor (a plasma prekallikrein), and PTA (factor XI). All other clotting factor activities were present in amounts comparable to that of normal human plasma. Whale plasminogen was activated by human urokinase, but not by streptokinase. Whale plasma contained inhibitory activities against thrombin, activated Stuart factor, activated PTA, activated Fletcher factor, and plasmin.

Animals↗