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Biomedical subjects

C H Chang

Publications and source records attributed to C H Chang.

At least 145 records · Page 8Linked to original sources
PubMed1999

Thoracoscopic retrieval of foreign body after penetrating chest injury: report of two cases.

Video-assisted thoracic surgery has proved to be valuable in many settings in thoracic surgery. The use of video-assisted thoracic surgery in trauma has recently rapidly increased. It is useful in acute or delayed management of patients with blunt and penetrating chest trauma. It is safe for removal of clotted hemothorax, treatment of thoracic empyema, treatment of persistent pneumothorax, treatment of chylothorax, and for diagnosis of diaphragmatic injury. We report two cases using thoracoscopy to remove intrathoracic metal fragments and avert the need for thoracotomy. In the first patient, a metal fragment injury was sustained via a penetrating wound from the supraclavicular notch to the right upper lung. The metal fragment was retrieved and the lung was repaired thoracoscopically using conventional suturing techniques. A second patient sustained a broken pin injury to the left upper mediastinum via a low neck wound. The pin was successfully removed under videothoracoscopy. Both patients recovered uneventfully and had shortened hospital stays. We feel that thoracoscopy offers a therapeutic as well as diagnostic benefit in stable patients with penetrating chest trauma.

Adult↗
PubMed1999

Blunt trauma-induced internal thoracic artery injury: case report.

We report the case of a 54-year-old male motorcyclist with an apparent grade IV liver injury and life-threatening hemomediastinum and right hemothorax following blunt deceleration trauma. Massive hemothorax and an unstable hemodynamic status even under copious blood volume replacement made emergent surgical intervention mandatory. A midline laparotomy was performed at first to rule out abdominal bleeding accompanied by a diaphragmatic tear, but the procedure was soon converted to a thoracotomy after finding an intact diaphragm and persistent bleeding from the chest tube. An isolated internal thoracic artery (ITA) transection was identified. It was actively bleeding and causing a huge anterior mediastinal hematoma and had ruptured into the right pleural cavity. The bleeder was controlled with suture ligation and the hemodynamic status was soon stabilized. The patient recovered without significant sequelae. The rarity of this kind of presentation is discussed, including both the ITA injury mechanism and the problems posed in making an early and correct diagnosis.

Humans↗
PubMed1999

Modeling of occupant dynamics during automobile rear-end impacts.

Procedures for studying the dynamic response of the occupant within a rear-end impacted vehicle are presented. Most of the researches in the impact analysis were performed by experimental approach and this costs a lot of time and money. Especially, the repeatability is very hard to produce in a destructive condition. Most of all, the analytic parameters can be investigated are limited by the experimental approach. By using numerical techniques, this research employs Kane's equation and Huston's method to develop a simulated system with visual graphic output to observe the rear-end impact response. According to the simulated results, at a constant seatback angle the maximum acceleration values of head and chest increased with the increasing of impact velocity. Furthermore, at a constant impact velocity the relative rotation angle of a passenger's head to chest decreased with the increasing of initial seatback angle.

Acceleration↗
PubMed1998

Stimulation of membrane-bound guanylate cyclase activity by 17-beta estradiol.

Estrogen is known to exert both long-term genomic and short-term nongenomic actions. The long-term genomic actions of estrogen are mediated by the binding of estrogen to its cytoplasmic/nuclear receptor that subsequently triggers the transcription of target genes. In contrast, little is known about the molecular basis of the nongenomic actions of estrogen. We have found that 17-beta estradiol activates membrane-bound guanylate cyclase and enhances atrial natriuretic factor (ANF)-stimulated guanylate cyclase activity in PC12 cell membranes. Membrane-bound guanylate cyclase, GC-A, contains an extracellular ANF-binding domain and an intracellular kinase-like domain plus catalytic domain. The kinase-like domain plus the catalytic domain of guanylate cyclase (GC-kc) can be expressed in E. Coli and functionally renatured. 17-beta estradiol also activates the bacteria expressed GC-kc, indicating that 17-beta estradiol can directly interact with membrane-bound guanylate cyclase. These results demonstrate that 17-beta estradiol exerts a non-genomic action on membrane-bound guanylate cyclase.

Animals↗
PubMed1998

Oxidant stress impaired DNA-binding of estrogen receptor from human breast cancer.

Full-length (67 kDa) immunoreactive estrogen receptor (ER) extracted from a third of untreated ER-positive primary breast tumors appears unable to bind to its cognate estrogen response element (ERE). We have observed partial reversibility of this ER DNA-binding defect upon treatment of these tumor extracts with excess thiol reducing agent (DTT), suggesting that ER DNA-binding is subject to redox modulation as is reported for other zinc-finger proteins and transcriptional activators. Treatment of recombinant ER DNA-binding domain (ER-DBD) or ER-enriched extracts from CHO(ER) and MCF-7 cells with thiol-reacting oxidants (diamide, iodosobenzoate, H2O2) or alkylator (iodoacetamide) produces a dose-dependent loss in ER DNA-binding capacity. Thiol-specific oxidative loss in ER DNA-binding is fully reversible by DTT reduction, unlike the defect caused by thiol-specific alkylation. Circular dichroism spectrometry shows that both forms of treatment substantially modify ER secondary structure, inducing loss of alpha-helical content within the ER-DBD that is reversible after thiol oxidation but not after thiol alkylation. Oxidant (H2O2, menadione) exposure of cultured CHO(ER) or MCF-7 cells impairs the ability of endogenous ER to bind DNA and transactivate an ER-responsive reporter gene (ERE-tk-CAT), demonstrating that extracellular redox stress can modulate intracellular ER function. Since these thiol-specific oxidant and alkylator treatments have no significant effect on either recombinant ER ligand-binding or intracellular immunoreactive ER content, our findings suggest that DNA-binding and transactivation are the most sensitive intracellular ER functions impaired by oxidant stress in some ER-positive human breast tumors.

Alkylating Agents↗
PubMed1998

Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities.

The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.

Amino Acid Substitution↗
PubMed1998

Enantiomeric inhibitors of cholesterol esterase and acetylcholinesterase.

Enantiomers of N-methyl-N,alpha-methylbenzylbutyramide (1), 1-butyl-3-methyl-3'-alpha-methylbenzylurea (2), 1,2,3, 4-tetrahydro-1-naphthyl-N-butylcarbamate (3), 1,1'-bi-2-naphthyl-2, 2'-di-N-butylcarbamate (4), 1, 1'-bi-2-naphthyl-2-ol-2'-N-butylcarbamate (5), and 1, 1'-bi-2-naphthyl-2-butyrate-2'-N-butylcarbamate (6) are inhibitors of porcine pancreatic cholesterol esterase-catalyzed hydrolysis of 4-nitrophenyl butyrate and of electric eel acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine in the presence of 5,5'-dithiobis-2-nitrobenzoate. For competitive inhibitors, values of the inhibition constant (Ki) and the enantiomeric ratio (Ecomp.) are investigated. For active site-directed irreversible inhibitors, values of the inhibition constant (Ki), the carbamylation constant (k2), the bimolecular rate constant (ki), and the enantiomeric ratio (E) are investigated. Toward both enzymes, compounds 1 are poor competitive inhibitors (Ki=102-104 microM) but have good enantioselectivities (Ecomp.=10-50, the preference for R). R-2 and S-2 are competitive inhibitors of acetylcholinesterase with Ki=26 and 80 microM, respectively (the preference for R) but are active site-directed irreversible inhibitors of cholesterol esterase with ki=4 and 16 M-1 sec-1, respectively (the preference for S). For those competitive inhibitions, both leaving group hydrophilic and hydrophobic binding sites of cholesterol esterase or both anionic substrate binding site and peripheral anionic binding site of acetylcholinesterase bind to N,N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors and the enzyme does not catalyze the hydrolysis of these inhibitors. The opposite stereopreference (S) for the inhibition of cholesterol esterase by compounds 2 may be due to the fact that N, N-methyl-alpha-methylbenzyl disubstituted amide parts of these inhibitors bind to the alkyl chain binding site of the enzyme. Compounds 3-6 are active site-directed irreversible inhibitors of cholesterol esterase (ki=1-13000 M-1 s-1) and peripheral anionic binding site-directed irreversible inhibitors of acetylcholinesterase (ki=1.7-1300 M-1 s-1). Compounds 3 have low enantioselectivities (E=1.3-1.4) for both enzymes. The stereopreference for atropisomers 4 and 6 is S-form toward both enzymes (E=2-30) and is identical to that of cholesterol esterase-catalyzed hydrolysis of 1,1'-bi-2-naphthyl-2,2'-diacylate. This stereopreference (S) may be due to the fact that the butyryl group or one of two butylcarbamate groups of S-atropisomers binds more effectively to the leaving group hydrophobic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase than that of R-atropisomers. The opposite stereopreference (R) for atropisomers 5 toward both enzymes may be due to a favorable interaction between the hydroxyl group of the inhibitors and the leaving group hydrophilic binding site of cholesterol esterase or the peripheral anionic binding site of acetylcholinesterase.

Acetylcholinesterase↗
PubMed1998

Arachidonic acid mediates angiotensin II effects on p21ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway.

In kidney epithelial cells, an angiotensin II (Ang II) type 2 receptor subtype (AT2) is linked to a membrane-associated phospholipase A2 (PLA2) and the mitogen-activated protein kinase (MAPK) superfamily. However, the intervening steps in this linkage have not been determined. The aim of this study was to determine whether arachidonic acid mediates Ang II's effect on p21ras and if so, to ascertain the signaling mechanism(s). We observed that Ang II activated p21ras and that mepacrine, a phospholipase A2 inhibitor, blocked this effect. This activation was also inhibited by PD123319, an AT2 receptor antagonist but not by losartan, an AT1 receptor antagonist. Furthermore, Ang II caused rapid tyrosine phosphorylation of Shc and its association with Grb2. Arachidonic acid and linoleic acid mimicked Ang II-induced tyrosine phosphorylation of Shc and activation of p21ras. Moreover, Ang II and arachidonic acid induced an association between p21ras and Shc. We demonstrate that arachidonic acid mediates linkage of a G protein-coupled receptor to p21ras via Shc tyrosine phosphorylation and association with Grb2/Sos. These observations have important implications for other G protein-coupled receptors linked to a variety of phospholipases.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Cyclic HIV protease inhibitors: design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency.

Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HIVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.

Administration, Oral↗
PubMed1998

Predictors of systemic embolism in patients with mitral stenosis. A prospective study.

BACKGROUND: Most studies of the predictors of systemic embolism in patients with mitral stenosis have been retrospective. OBJECTIVE: To prospectively study factors associated with systemic embolism in mitral stenosis. DESIGN: Prospective cohort study. SETTING: University-affiliated medical institution with 3000 beds. PATIENTS: 534 consecutive patients with a mitral valve area of 2.0 cm2 or less; 132 patients were in sinus rhythm, and 402 were in atrial fibrillation. MEASUREMENTS: Nine clinical and 10 echocardiographic variables were assessed for prediction of systemic embolism over a mean (+/- SD) follow-up of 36.9 +/- 22.5 months. Diagnosis of systemic embolism was based on symptoms and signs (sudden onset of peripheral arterial ischemic or neurologic manifestations without prodromes) and on findings on computed tomography, angiography, and surgery. RESULTS: For patients in sinus rhythm, age (relative risk [RR], 1.12 [95% CI, 1.04 to 1.21]), the presence of a left atrial thrombus (RR, 37.1 [CI, 2.82 to 487.8]), mitral valve area (RR, 16.9 [CI, 1.53 to 187.0]), and the presence of significant aortic regurgitation (RR, 22.4 [CI, 2.72 to 184.8]) were positively associated with embolism. For patients in atrial fibrillation, previous embolism (RR, 3.11 [CI, 1.66 to 5.85]) was positively associated with embolism; percutaneous balloon mitral commissurotomy (RR, 0.37 [CI, 0.18 to 0.79]) was a negative predictor. CONCLUSIONS: It may be prudent to give anticoagulants not only to patients in atrial fibrillation and patients with previous systemic embolism but also to those showing a left atrial thrombus or significant aortic regurgitation on echocardiography. Early percutaneous balloon mitral commissurotomy may also help prevent systemic embolism in patients with mitral stenosis.

Adult↗
PubMed1998

Molecular recognition of cyclic urea HIV-1 protease inhibitors.

As long as the threat of human immunodeficiency virus (HIV) protease drug resistance still exists, there will be a need for more potent antiretroviral agents. We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit. The structures reveal that the preorganized, C2 symmetric scaffolds of the inhibitors are anchored in the active site of the protease by six hydrogen bonds and that their P1 and P2 substituents participate in extensive van der Waals interactions and hydrogen bonds. Because all of our inhibitors possess benzyl groups at P1 and P1', their relative binding affinities are modulated by the extent of their P2 interactions, e.g. XK216, the least potent inhibitor (Ki (inhibition constant) = 4.70 nM), possesses the smallest P2 and the lowest number of P2-S2 interactions; whereas SD146, the most potent inhibitor (Ki = 0.02 nM), contains a benzimidazolylbenzamide at P2 and participates in fourteen hydrogen bonds and approximately 200 van der Waals interactions. This analysis identifies the strongest interactions between the protease and the inhibitors, suggests ways to improve potency by building into the S2 subsite, and reveals how conformational changes and unique features of the viral protease increase the binding affinity of HIV protease inhibitors.

Anti-HIV Agents↗
PubMed1998

Advanced field-measurement method with three orthogonal Hall probes for an elliptically polarizing undulator.

A three-orthogonal-Hall-probe assembly with an 'on the fly' mapping method has been developed to characterize an elliptically polarizing undulator (EPU). The underlying design concept is that it can measure the three real field components without any field correction under a reliable and synchronization measurement method. Therefore, the relative central position shift, orthogonal angle and the planar Hall effect error between the three Hall probes should be calibrated and readjusted. Experimental results demonstrate that this method can yield an r.m.s. reproducibility of 10 G cm for the three field components and 2 G for the peak field strength. Under precision conditions this system can completely measure the three on-axis field components within 2 min for a 4 m-long EPU.

Journal Article↗
PubMed1998

Effects of magnets with non-unit magnetic permeability on an elliptically polarizing undulator.

This study employs the three-dimensional magnetostatic code TOSCA to assess numerically the effects of NdFeB magnets with non-unit magnetic permeability on an elliptically polarizing undulator. A reduction of a few percent of the on-axis magnetic field strength is predicted. In addition, a deviation of +/-100 G cm uncompensated dipole steering is predicted in a phase shift of 180 degrees for the elliptically polarizing undulator EPU5.6 (having a period length of 56 mm) at the minimum gap of 18 mm, which is related primarily to the configuration of the device end scheme. Results presented herein demonstrate that implementing an active compensation mechanism is a prerequisite for minimizing the orbit distortion during phase-shift adjustment, particularly for operating such a polarizing undulator in a third-generation machine having a median energy similar to that of the 1.5 GeV storage ring at SRRC.

Journal Article↗
PubMed1998

An SRRC elliptically polarizing undulator prototype to examine mechanical design feasibility and magnetic field performance.

In this work, a 1 m long Sasaki-type elliptically polarizing undulator (EPU) prototype with 5.6 cm period length is used to examine the mechanical design feasibility as well as magnetic field performance. The magnetic field characteristics of the EPU5.6 prototype at various phase shifts and gap motion are described. The field errors from mechanical tolerances, magnet block errors, end field effects and phase/gap motion effects are analysed. The procedures related to correcting the field with the block position tuning, iron shimming and the trim blocks at both ends are outlined.

Journal Article↗
PubMed1998

Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies.

Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information.

Anti-HIV Agents↗
PubMed1998

Potent cyclic urea HIV protease inhibitors with 3-aminoindazole P2/P2' groups.

Cyclic ureas containing 3-aminoindazole P2/P2' groups are extremely potent inhibitors of HIV protease. The parent 3-aminoindazole 6 showed a Ki < 0.01 nM but poor translation of enzyme activity to antiviral activity was observed. A series of 3-alkylaminoindazoles revealed that translation improved with increasing lipophilicity. An X-ray crystal structure of 6 bound to HIV protease was obtained.

Crystallography, X-Ray↗
PubMed1998

FACT, a factor that facilitates transcript elongation through nucleosomes.

The requirements for transcriptional activation by RNA polymerase II were examined using chromatin templates assembled in vitro and a transcription system composed of the human general transcription factors and RNA polymerase II. Activator-induced, energy-dependent chromatin remodeling promoted efficient preinitiation complex formation and transcription initiation, but was not sufficient for productive transcription. Polymerases that initiated transcription on remodeled chromatin templates encountered a block to transcription proximal to the promoter. Entry into productive transcription required an accessory factor present in HeLa cell nuclear extract, FACT (facilitates chromatin transcription), which we have purified. FACT acts subsequent to transcription initiation to release RNA polymerase II from a nucleosome-induced block to productive transcription. The biochemical properties and polypeptide composition of FACT suggest that it is a novel protein factor that facilitates transcript elongation through nucleosomes.

Adenosine Triphosphate↗