Biomedical subjects

M G Wong

Publications and source records attributed to M G Wong.

25 records · Page 2Linked to original sources

PubMed1990

Aspartate aminotransferase: investigation of the active sites.

An investigation of the crystal structure of cytosolic pig-heart aspartate aminotransferase (AAT, E.C.2.6.1.1) was carried out to determine the structural requirements for ligand recognition by the active site. Structural differences were observed between the two active sites of the AAT dimer. The natural ligand, L-aspartate, was docked into both active sites using various methods. However, due to structural differences, the ligand was able to form all the necessary interactions for initial binding in only one of the active sites. The program GRID (P.J. Goodford, J. Med. Chem. 1985, 28, 849-857) was used to predict favorable binding sites for the functional groups of the aspartate ligand. These binding sites corresponded to the position of the docked aspartate ligand, indicating that substrate recognition takes place before any major conformational changes occur within the enzyme.

Animals↗

PubMed1990

The "natural history" of segmental wall motion abnormalities in patients undergoing noncardiac surgery. S.P.I. Research Group.

Intraoperative segmental wall motion abnormalities (SWMA) detected by transesophageal echocardiography (TEE) are sensitive, but not always specific, markers of myocardial ischemia. To determine their incidence, characteristics, and relation to postoperative cardiac morbidity, we continuously recorded the left ventricular short-axis view and 12-lead ECG in 156 high-risk patients undergoing non-cardiac surgery. Monitoring was clinically blinded. Wall motion was scored at predefined clinical, hemodynamic, and ECG events and at periodic intervals (26 +/- 11 samples per patient). We detected 44 episodes of new or worsened SWMA in 32 patients (20%). The severity of most episodes was limited to severe hypokinesis (24/44, 55%) followed by akinesis (16/44, 36%) and dyskinesis (4/44, 9%). The remaining 124 patients had normal wall motion or only mild hypokinesis (56/156, 36%) or chronic SWMA (68/156, 44%). The incidence of new SWMA did not differ for patients with known coronary artery disease (CAD) and those with cardiac risk factors only (22% vs. 19%, P = not significant), although CAD patients had a significantly greater incidence of chronic SWMA (62% vs. 41%, P = 0.02). The incidence of new or worsened SWMA was significantly greater during aortic vascular surgery (38% vs. 17%, P = 0.05). Approximately 40% of all new TEE changes occurred in the absence of either an apparent clinical event or a significant change in systolic blood pressure or heart rate. Ten patients had new or worsened SWMA persisting until the end of surgery, 8 with new akinesis, only 1 developing myocardial infarction. The distribution of new or worsened SWMA and significant intraoperative ST-T changes (n = 19) in this cohort was discordant: temporal overlap between modalities was present in only 5 patients. Major cardiac complications occurred in 5 patients (3.2%), all of whom underwent peripheral vascularization. All patients with cardiac complications and new or worsened SWMA also had intraoperative or early postoperative ST-T changes. We conclude that: 1) continuous TEE recording with offline analysis in this high-risk group of patients revealed a relatively low incidence of new or worsened SWMA (20%), most episodes of which were characterized by severe hypokinesis (55%); 2) episodes were more common in patients undergoing aortic vascular surgery; 3) approximately 40% of episodes were unaccompanied by clinical events or significant hemodynamic changes; 4) episodes were poorly correlated with postoperative cardiac complications; and 5) the discordant relation between TEE and ECG changes observed here necessitates careful monitoring of the ECG when TEE is used clinically.

Aged↗

PubMed1988

Receptor site topographies for phencyclidine-like and sigma drugs: predictions from quantitative conformational, electrostatic potential, and radioreceptor analyses.

Computer-assisted molecular modelling techniques and electrostatic analyses of a wide range of phenycyclidine (PCP) and sigma ligands, in conjunction with radioreceptor studies, were used to determine the topographies of the PCP and sigma receptors. The PCP receptor model was defined using key molecules from the arylcyclohexylamine, benzomorphan, bridged benz[f]isoquinoline, and dibenzocycloalkenimine drug classes. Hypothetical receptor points (R1, R2) were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor, along with an additional receptor point (R3) representing a hydrogen bond between the nitrogen atom and the receptor. The superimposition of these key molecules gave the coordinates of the receptor points and nitrogen defining the primary PCP pharmacophore as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.66, -1.13, 0.00), and N (3.90, -1.46, -0.32). Additional analyses were used to describe secondary binding sites for an additional hydrogen bonding site and two lipophilic clefts. Similarly, the sigma receptor model was constructed from ligands of the benzomorphan, octahydrobenzo[f]quinoline, phenylpiperidine, and diphenylguanidine drug classes. Coordinates for the primary sigma pharmacophore are as follows: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (6.09, 2.09, 0.00), and N (4.9, -0.12, -1.25). Secondary binding sites for sigma ligands were proposed for the interaction of aromatic ring substituents and large N-substituted lipophilic groups with the receptor. The sigma receptor model differs from the PCP model in the position of nitrogen atom, direction of the nitrogen lone pair vector, and secondary sigma binding sites. This study has thus demonstrated that the differing quantitative structure-activity relationships of PCP and sigma ligands allow the definition of discrete receptors. These models may be used in conjunction with rational drug design techniques to design novel PCP and sigma ligands of high selectivity and potency.

Animals↗

PubMed1988

Structure activity relationships of anxiolytics.

Several strikingly different classes of compound bind at the benzodiazepine receptor and exhibit an anxiolytic profile. The conformational preferences of these compounds were ascertained by a variety of techniques. Their electrostatic features were also studied. The combined information has been utilised in the development of a receptor model for the binding site.

Anti-Anxiety Agents↗

PubMed1988

Intraoperative myocardial ischemia: localization by continuous 12-lead electrocardiography.

Based primarily on results obtained during exercise treadmill testing, electrocardiographic (ECG) leads II and V5 are the suggested optimal leads for detecting intraoperative myocardial ischemia. However, these recommendations have not been validated in this setting using all 12 ECG leads. Accordingly, the authors studied 105 patients with known or suspected coronary artery disease (CAD) undergoing noncardiac surgery with general anesthesia by continuously recording the 12-lead ECG intraoperatively in all patients. The average duration of monitoring was 8.2 +/- 2.7 h (mean +/- SD). Ischemic episodes (i.e., greater than or equal to 1-mm horizontal or downsloping ST depression, greater than or equal to 1.5-mm slowly upsloping ST depression or greater than or equal to 1.5-mm ST elevation in a non-Q wave lead) occurred in 25 patients (24%). Out of 51 ischemic episodes, 45 involved ST depression alone, and the remaining six involved both ST depression and elevation. ST segment changes occurred in a single lead only in 14 episodes, while multiple leads were involved in 37 episodes. Lead sensitivity was estimated assuming that all ST segment changes were true positive responses. Sensitivity using a single lead was greatest in V5 (75%) and V4 (61%), and intermediate in II, V3, and V6 (33%, 24%, and 37%, respectively). The remaining seven leads demonstrated very low sensitivity (2-14%) or exhibited no ischemic changes (I and a VL). Combining leads V4 and V5 increased sensitivity to 90%, while the standard clinical combination, II and V5, was only 80% sensitive. Sensitivity increased to 96% by combining II, V4, and V5. The further addition of V2 and V3 (five leads) increased sensitivity to 100%. This study confirms previous recommendations for the routine use of a V5 lead (either uni- or bipolar) in all patients at risk for ischemia. V4 is more sensitive than lead II, and should be considered as a second choice. However, lead II, superior for detection of atrial dysrhythmias, is more easily obtained with conventional monitors. The use of all three would appear to be the optimal arrangement for most clinical needs, and is recommended if the clinician has the capability.

Aged↗

PubMed1986

Conformational analysis of clinically active anticonvulsant drugs.

A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.

Anticonvulsants↗

PubMedDate not supplied

Invasion by cultured human follicular thyroid cancer correlates with increased beta 1 integrins and production of proteases.

A recognized model of tumor invasion requires cells to adhere to epithelial basement membrane and extracellular matrix components triggering release of proteases thus allowing cancer cells to invade the substrate. This adhesion is mediated by beta 1 integrins, a family of receptors to substrates such as collagen, laminin, and fibronectin. In order to study tumor invasion in follicular thyroid cancer (FTC), we used cell lines derived from a single patient's FTC primary tumor (FTC-133), neck lymph node metastases (FTC-236), and lung metastases (FTC-238). In vitro invasion as determined by the ability of the tumor cells to penetrate Matrigel was assessed by scanning electron microscopy. FTC-133 did not invade, FTC-236 was moderately invasive, and FTC-238 was highly invasive. Immunoprecipation with a monoclonal antibody to beta 1 integrin subunits and SDS-PAGE showed increased synthesis and flow cytometry showed increased expression of this subunit in FTC-236 and FTC-238 compared to FTC-133. Proteolytic activity was assessed by gelatin zymography. FTC-238 cell extract and conditioned media exhibited a more complex array of proteases consistent with activated type I collagenase and stromelysin compared to the less invasive clones, however 72 and 92 kd gelatinases consistent with type IV collagenases were present in the conditioned media from all three lines. In conclusion, in vitro invasion parallels in vivo metastasis by the source cells in the FTC-133/236/238 cell-lines. The ability to invade basement membrane preparation correlates with increased synthesis and expression of beta 1 integrins and activation of tumor proteases.

Adenocarcinoma↗