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Biomedical subjects

P W Park

Publications and source records attributed to P W Park.

At least 19 recordsLinked to original sources
PubMed2006

Comparative pharmacokinetic and pharmacodynamic characteristics of amlodipine besylate and amlodipine nicotinate in healthy subjects.

BACKGROUND AND AIM: Amlodipine, a dihydropyridine calcium antagonist, is prescribed for the management of angina and hypertension, and is sold as amlodipine besylate. However, a new salt formulation, amlodipine nicotinate, has recently been developed. Here, we evaluated the comparative pharmacokinetic and pharmacodynamic characteristics of the nicotinate and besylate forms of amlodipine. SUBJECTS AND METHODS: A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. RESULTS: All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x h/ml and 3.87+/-1.04 ng/ml for the test formulation and 203.15+/-52.05 ng x h/ml and 4.01+/-0.60 ng/ml for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. CONCLUSION: The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.

Administration, Oral↗
PubMed2001

Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence.

Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abundant receptors/co-receptors of extracellular ligands, including many microbes. Their role in microbial infections is poorly defined, however, because no cell-surface HSPG has been clearly connected to the pathogenesis of a particular microbe. We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of syndecan-1-the predominant cell-surface HSPG of epithelia. Here we show that shedding of syndecan-1 is also activated by P. aeruginosa in vivo, and that the resulting syndecan-1 ectodomains enhance bacterial virulence in newborn mice. Newborn mice deficient in syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. Our findings uncover a pathogenetic mechanism in which a host response to tissue injury-syndecan-1 shedding-is exploited to enhance microbial virulence apparently by modulating host defences.

Animals↗
PubMed2001

Homologous monocuspid valve patch in right ventricular outflow tract reconstruction.

BACKGROUND: In the surgical repair of tetralogy of Fallot or pulmonary atresia, pulmonary regurgitation may be detrimental in the postoperative period. We have used homograft monocuspid valve patch to prevent pulmonary insufficiency. METHODS: From September 1996 to December 1998, twenty-five patients, 4 months to 8 years of age (median 10.1 months) had homograft monocuspid valve in the procedure of right ventricular outflow tract reconstruction. The function of the monocuspid valve was assessed by echocardiogram and graded as trivial to mild, mild to moderate, moderate, and severe. We evaluated the degree of pulmonary insufficiency before discharge, at 3-6 months, and at 12 months after the operation. RESULTS: There was one hospital death due to fulminate adeno viral pneumonia. On echocardiogram, 21 patients (88%, 21/24) had no significant pulmonary insufficiency. Only one patient (4.5%) showed a moderate degree of pulmonary insufficiency. At 3-6 months, seventeen of twenty-one (81%) patients had no significant pulmonary insufficiency. There were fourteen patients who had follow-up over 1 year, and no patients showed newly developed significant pulmonary insufficiency. CONCLUSIONS: We concluded that the homograft monocuspid valve patch for right ventricular outflow tract reconstruction has provided excellent early results for the prevention of pulmonary insufficiency. However these effects are limited in duration and further close follow-up should be needed.

Child↗
PubMed2000

Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase.

The syndecan family of four transmembrane heparan sulfate proteoglycans binds a variety of soluble and insoluble extracellular effectors. Syndecan extracellular domains (ectodomains) can be shed intact by proteolytic cleavage of their core proteins, yielding soluble proteoglycans that retain the binding properties of their cell surface precursors. Shedding is accelerated by PMA activation of protein kinase C, and by ligand activation of the thrombin (G-protein-coupled) and EGF (protein tyrosine kinase) receptors (Subramanian, S.V., M.L. Fitzgerald, and M. Bernfield. 1997. J. Biol. Chem. 272:14713-14720). Syndecan-1 and -4 ectodomains are found in acute dermal wound fluids, where they regulate growth factor activity (Kato, M., H. Wang, V. Kainulainen, M.L. Fitzgerald, S. Ledbetter, D.M. Ornitz, and M. Bernfield. 1998. Nat. Med. 4:691-697) and proteolytic balance (Kainulainen, V., H. Wang, C. Schick, and M. Bernfield. 1998. J. Biol. Chem. 273:11563-11569). However, little is known about how syndecan ectodomain shedding is regulated. To elucidate the mechanisms that regulate syndecan shedding, we analyzed several features of the process that sheds the syndecan-1 and -4 ectodomains. We find that shedding accelerated by various physiologic agents involves activation of distinct intracellular signaling pathways; and the proteolytic activity responsible for cleavage of syndecan core proteins, which is associated with the cell surface, can act on unstimulated adjacent cells, and is specifically inhibited by TIMP-3, a matrix-associated metalloproteinase inhibitor. In addition, we find that the syndecan-1 core protein is cleaved on the cell surface at a juxtamembrane site; and the proteolytic activity responsible for accelerated shedding differs from that involved in constitutive shedding of the syndecan ectodomains. These results demonstrate the existence of highly regulated mechanisms that can rapidly convert syndecans from cell surface receptors or coreceptors to soluble heparan sulfate proteoglycan effectors. Because the shed ectodomains are found and function in vivo, regulation of syndecan ectodomain shedding by physiological mediators indicates that shedding is a response to specific developmental and pathophysiological cues.

Animals↗
PubMed2000

Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa.

Microbial pathogens frequently take advantage of host systems for their pathogenesis. Shedding of cell surface molecules as soluble extracellular domains (ectodomains) is one of the host responses activated during tissue injury. In this study, we examined whether pathogenic bacteria can modulate shedding of syndecan-1, the predominant syndecan of host epithelia. Our studies found that overnight culture supernatants of Pseudomonas aeruginosa and Staphylococcus aureus enhanced the shedding of syndecan-1 ectodomains, whereas culture supernatants of several other Gram-negative and Gram-positive bacteria had only low levels of activity. Because supernatants from all tested strains of P. aeruginosa (n = 9) enhanced syndecan-1 shedding by more than 4-fold above control levels, we focused our attention on this Gram-negative bacterium. Culture supernatants of P. aeruginosa increased shedding of syndecan-1 in both a concentration- and time-dependent manner, and augmented shedding by various host cells. A 20-kDa shedding enhancer was partially purified from the supernatant through ammonium sulfate precipitation and gel chromatography, and identified by N-terminal sequencing as LasA, a known P. aeruginosa virulence factor. LasA was subsequently determined to be a syndecan-1 shedding enhancer from the findings that (i) immunodepletion of LasA from the partially purified sample resulted in abrogation of its activity to enhance shedding and (ii) purified LasA increased shedding in a concentration-dependent manner. Our results also indicated that LasA enhances syndecan-1 shedding by activation of the host cell's shedding mechanism and not by direct interaction with syndecan-1 ectodomains. Enhanced syndecan-1 shedding may be a means by which pathogenic bacteria take advantage of a host mechanism to promote their pathogenesis.

Bacterial Proteins↗
PubMed2000

Organo-axial volvulus of the stomach with diaphragmatic eventration.

Gastric volvulus occurs when the stomach rotates about its longitudinal axis (organo-axial volvulus), or about an axis joining the lesser and greater curvatures (mesentero-axial volvulus). Primary gastric volvulus, making up one third of cases, occurs when the stabilizing ligaments are too lax as a result of congenital or acquired causes. Secondary gastric volvulus, making up the remainder of cases, occurs in association with a paraesophageal hernia or other congenital or acquired diaphragmatic defects. While gastric volvulus may occur acutely, especially in children, it may not be clinically apparent and discovered incidentally. The authors present a case of chronic organo-axial volvulus of the stomach secondary to left hemidiaphragmatic eventration with a review of the relevant literature.

Adult↗
PubMed1999

Characterization of the elastin binding domain in the cell-surface 25-kDa elastin-binding protein of staphylococcus aureus (EbpS).

Our previous studies have established that a cell-surface 25-kDa elastin-binding protein of Staphylococcus aureus (EbpS) mediates binding of this pathogen to the extracellular matrix protein elastin. Results from binding assays examining the activity of various EbpS fragments suggested that the elastin recognition domain is contained within the first 59 amino acids. In this report, we have used functional analyses with synthetic peptides and recombinant truncated forms of EbpS to localize the elastin binding domain to a 21-amino acid region contained within residues 14-34 of EbpS. Further evidence for the importance of this domain was obtained by demonstrating that the inhibitory activity of anti-EbpS antibodies on staphylococcal elastin binding was neutralized when these antibodies were pre-absorbed with a truncated recombinant EbpS construct containing residues 1-34. Overlapping synthetic peptides corresponding to EbpS residues 14-36 were then generated and tested for elastin binding activity to define further the elastin binding domain, and results from these studies showed that sequences spanning amino acids Gln14-Asp23, Asp17-Asp23, and Thr18-Glu34 inhibit binding of Staphylococcus aureus to elastin. Our analyses indicate that the hexameric sequence Thr18-Asn-Ser-His-Gln-Asp23 is the minimal sequence common to all active synthetic peptides, proteolytic fragments, and recombinant constructs of EbpS. Furthermore, substitution of Asp23 with Asn abrogated the blocking activity of the synthetic peptides, demonstrating the requirement for a charged amino acid at this location. The composite data indicate that staphylococcal elastin binding is mediated by a discrete domain defined by short peptide sequences in the amino-terminal extracellular region of EbpS.

Amino Acid Sequence↗
PubMed1999

Functions of cell surface heparan sulfate proteoglycans.

The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

Animals↗
PubMed1998

Video-assisted thoracic surgery as a primary therapy for primary spontaneous pneumothorax. Decision making by the guideline of high-resolution computed tomography.

BACKGROUND: Because blebs are confirmed in most of the patients undergoing thoracotomy, identification of blebs by high-resolution computed tomography (HRCT) can be proposed as a surgical indication in primary spontaneous pneumothorax (PSP). If an apical bleb is identified, we treat the patient by video-assisted thoracic surgery (VATS). METHODS: From May 1995 to September 1997, 61 patients (21.9 +/- 4.6 years) were seen for initial episodes of PSP. Only seven showed bullae on simple chest radiography. However, by HRCT, 48 had sizable blebs (>5 mm), and 45 were treated surgically by VATS. RESULTS: The mean duration of chest tube use after surgery was 3.2 +/- 1.9 days, and the mean hospital stay was 4.5 +/- 1.9 days. Only one recurrence developed 5 weeks after VATS. CONCLUSIONS: Our protocol is effective in controlling an initial episode of PSP. It shortens the observation time before definitive surgical treatment, shortens the hospital stay, and decreases the likelihood of recurrence.

Adolescent↗
PubMed1998

MR imaging of non-visualized pulmonary arteries at angiography in patients with congenital heart disease.

The aim of this study was to evaluate whether MR could depict pulmonary arterial anatomy in more detail than routine angiography in patients with congenital interruption or acquired occlusion of the left pulmonary artery or pulmonary atresia. This study included 10 patients with tetralogy of Fallot (n=6) or pulmonary atresia with ventricular septal defect (n=3) or aorticopulmonary window (n=1) diagnosed by cardiac angiography and MR. Surgical confirmation was made in seven patients. Interruption of the proximal left pulmonary artery, diagnosed at the time of evaluation, was found in seven patients and acquired obstruction of the hilar pulmonary artery (PA) was found in two at cardiac angiography. In the remaining one patient with pulmonary atresia and an occluded palliative shunt, the central PA was not visualized at angiography. MR showed 3-6 mm-sized hilar PAs in five and a central PA in a patient with pulmonary atresia. In 4 of 6 (67%) surgically-proven patients with congenital or acquired left PA obstruction, the status of the PA distal to the obstruction was correctly diagnosed with MR. In conclusion, MR is an effective modality in depicting sizable PAs when routine angiography fails to visualize the PA anatomy.

Adolescent↗
PubMed1997

Cardiac tamponade due to a rupture of the coronary arteriovenous aneurysm--a case report.

We experienced an unusual case of cardiac tamponde caused by a rupture of the coronary arteriovenous aneurysm in a 54-year-old woman. The patient was suffered from sudden chest pain and syncope, and was initially managed by pericardiocentesis following an echocardiogram which revealed a massive pericardial effusion with signs of cardiac tamponade. She was referred to our hospital under the impression of aortic dissection with cardiac tamponade. She underwent an emergency operation and was found to have a 2 x 2 cm sized bleeding cystic mass protruding from the proximal anterior descending coronary artery. The aneurysm was excised and the openings connected with the coronary artery and right ventricular outflow tract were closed with sutures from the inside of aneurysm. Subsequent coronary arteriography supported the diagnosis.

Aortic Rupture↗
PubMed1996

Molecular cloning and expression of the gene for elastin-binding protein (ebpS) in Staphylococcus aureus.

Interactions between staphylococci and components of the extracellular matrix mediate attachment of the bacteria to host tissues and organs and define an important mechanism leading to colonization, invasion, and formation of metastatic abscesses. We have previously demonstrated a specific binding interaction between Staphylococcus aureus and elastin, one of the major protein components of the extracellular matrix. Available evidence suggests that this association is mediated by a 25-kDa elastin-binding protein on the surface of S. aureus (EbpS). To study the molecular structure and function of EbpS, the gene encoding EbpS was cloned, sequenced, and expressed in Escherichia coli. DNA sequence data indicate that the ebpS open reading frame consists of 606 base pairs and encodes a novel polypeptide with a predicted molecular mass of 23,345 daltons and pI of 4.9. A polyclonal antibody raised against recombinant EbpS interacted with the native 25-kDa cell surface EbpS and inhibited staphylococcal elastin binding. Furthermore, recombinant EbpS bound specifically to immobilized elastin and inhibited binding of S. aureus to elastin. A degradation product of recombinant EbpS lacking the first 59 amino acids of the molecule and a C-terminal fragment of CNBr-cleaved recombinant EbpS, however, did not interact with elastin. Together, these results confirm that EbpS is the cell surface molecule mediating binding of S. aureus to elastin. The inability of truncated forms of recombinant EbpS to bind to elastin suggests that the elastin binding site in EbpS is contained in the first 59 amino acids of the molecule.

Amino Acid Sequence↗
PubMed1996

Stereospecific analysis of triacylglycerols rich in long-chain polyunsaturated fatty acids.

Six oils of marine, algal, and microbial origin were analyzed for stereospecific distribution of component fatty acids. The general procedure involved preparation of sn-1,2-(2,3)-diacylglycerols by partial deacylation with ethylmagnesium bromide or pancreatic lipase, separation of X-1,3- and sn-1,2(2,3)-diacylglycerols by borate thin-layer chromatography, resolution of the sn-1,2- and sn-2,3-enantiomers by chiral phase high-performance liquid chromatography following preparation of dinitrophenylurethane derivatives, and determination of the fatty acid composition by gas chromatography. Unexpected complications arose during a stereospecific analysis of triacylglycerols containing over 33% of either 20:4 or 22:6 fatty acids. The sn-1,2(2,3)-diacylglycerols made up of two long-chain polyunsaturated acids migrated with the X-1,3-diacylglycerols and required separate chiral phase resolution. Furthermore, the enzymatic method yielded sn-1,2(2,3)-diacylglycerols, overrepresenting the polyenoic species due to their relative resistance to lipolysis, but prolonged digestion yielded correct composition for the 2-monoacylglycerols. The final positional distribution of the fatty acids was established by pooling and normalizing the data from subfractions obtained by normal- and chiral-phase separation of diacylglycerols. The molecular species of X-1,3-, sn-1,2- and sn-2,3-diacylglycerol dinitrophenylurethanes were identified by chiral-phase liquid chromatography/mass spectrometry with electrospray ionization, which demonstrated a preferential association of the paired long-chain acids with the sn-1,2- and sn-2,3-diacylglycerol isomers.

Chromatography, Gas↗
PubMed1996

Lysozyme binds to elastin and protects elastin from elastase-mediated degradation.

Lysozyme has been shown to be associated with damaged elastic fibers in many tissues and organs. To better characterize this interaction, binding of lysozyme to elastin was studied using solution-based binding assays. Under physiologic conditions, radio-labeled lysozyme bound specifically to elastin in a time- and concentration-dependent manner. Binding was reversible and was inhibited by unlabeled human and hen lysozyme but not by other proteins. Lysozyme had no elastolytic activity as assessed by a standard tritium-release assay, but, importantly, prevented the proteolytic degradation of elastin by human leukocyte elastase, pancreatic elastase, thermolysin, and Pseudomonas elastase. A striking feature of lysozyme's anti-elastase activity was that it did not function in the classical sense of inhibiting directly the enzymatic activity of the protease. Instead, by binding to elastin, lysozyme prevented the protease from interacting with the elastin substrate in ways that normally favor proteolysis. These results show that lysozyme binds to the elastin component of elastic fibers and that this interaction has important biological consequences for elastic fiber degradation. By preventing degradation of elastin, lysozyme can function as an important natural inhibitor that exerts a protective effect on elastic fibers at sites of tissue injury.

Elastin↗
PubMed1995

The mitogenic effects of the B beta chain of fibrinogen are mediated through cell surface calreticulin.

We have previously shown that soluble partially degraded fibrin(ogen) remains in solution after fibrin clot formation and is a potent fibroblast mitogen (Gray, A.J., Bishop, J.E., Reeves J.T., Mecham, R.P., and Laurent, G.J. (1995) Am. J. Cell Mol. Biol. 12, 684-690). Mitogenic sites within the fibrin(ogen) molecule are located on the A alpha and B beta chains of the protein (Gray, A.J., Bishop, J. E., Reeves, J.T., and Laurent, G.J. (1993) J. Cell Sci. 104, 409-413). However, receptor pathways through which mitogenic effects are mediated are unknown. The present study sought to determine the nature of fibrin(ogen) receptors expressed on human fibroblasts which interact with the fibrinogen B beta chain. Receptor complexes were isolated from 125I-surface-labeled fibroblasts and purified on a fibrinogen B beta chain affinity column. Subsequent high performance liquid chromatography and SDS-polyacrylamide gel electrophoresis analysis indicated fibrinogen B beta chain bound specifically to a 60-kDa surface protein. Sequence analysis of the amino terminus of this protein indicated 100% homology to human calreticulin. Immunoprecipitation experiments employing a polyclonal anti-calreticulin antibody provided further evidence that the 60-kDa protein isolated in this study was calreticulin. Further, polyclonal antibodies to human calreticulin significantly inhibited the mitogenic activity of fibrinogen B beta chain on human fibroblasts. The present study has shown that cell surface calreticulin binds to the B beta chain of fibrinogen mediating its mitogenic activity.

Amino Acid Sequence↗
PubMed1995

Binding and degradation of elastin by the staphylolytic enzyme lysostaphin.

Lysostaphin is a bacterial zinc metalloproteinase that degrades staphylococcal cell wall peptidoglycans. We have shown that lysostaphin also binds tightly to elastin and contains elastolytic activity. The objective of this investigation was to further characterize the biochemical mechanism of elastolysis by lysostaphin. Binding of lysostaphin to elastin was demonstrated with elastin peptide affinity chromatography. Elastolysis by lysostaphin was studied using a tritium release assay with tritium borohydride-reduced elastin as substrate. Proteolysis of elastin by lysostaphin was maximal at neutral to slightly basic pH and proceeded linearly for 10 hr before reaching saturation. The elastolytic activity was not affected by inhibitors of cysteine or serine proteinases, but was inhibited by o-phenanthroline, EDTA, and by the addition of exogenous zinc. Inhibition by zinc was not due to an alteration in enzyme-ligand interaction since zinc-containing buffers did not impair the ability of lysostaphin to bind elastin. Lysostaphin elastolysis was not inhibited by trypsin treatment of the enzyme, which has been shown to inactivate the enzyme's staphylolytic properties. It is therefore concluded that: (1) lysostaphin binds and degrades elastin; (2) the elastolytic activity of lysostaphin is distinct from its staphylolytic activity; (3) sequence similarities with matrix metalloproteinases suggest the Ala-Ala-Thr-His-Glu sequence in the amino terminus of lysostaphin to be involved in elastin degradation; (4) our studies are important in establishing that metalloproteinases from staphylococci can participate in elastin degradation.

Amino Acid Sequence↗
PubMed1994

Isolated left main coronary ostial stenosis: intraoperative transesophageal echocardiography during surgical angioplasty.

OBJECTIVE: We hypothesized that transesophageal echocardiography could be used to image the repair of a left ostium or main coronary artery following surgical angioplasty. METHODS AND RESULTS: Six patients, all women, were found to have isolated left main coronary ostial stenosis. We performed preoperative transesophageal echocardiography (TEE) in three and intraoperative TEE in four of six patients. Their mean age was 48 years. They presented with severe angina (Class III or IV) with a short duration (6.8 +/- 7.8 months). They had a low incidence of risk factors while histopathologic examinations showed typical atherosclerosis in all four patients. Preoperative two-dimensional echocardiography demonstrated left main coronary ostial stenosis in three patients. We clearly observed the patency of the pericardial or saphenous venous patch with basal short-axis scan on two-dimensional and color Doppler echocardiography in all four patients after weaning them from cardiopulmonary bypass and finished operation without complications. CONCLUSIONS: Our study shows that TEE can be used to image the repair of a left ostium or main coronary artery following surgical angioplasty and provide the surgeon with the required information about the adequacy of the repair.

Coronary Disease↗