Biomedical subjects

T Lai

Publications and source records attributed to T Lai.

40 records · Page 3Linked to original sources

PubMedDate not supplied

Inhibition of protein synthesis, pulmonary localization and pulmonary tumour formation by drug-treated tumour cells as a means of predicting their chemosensitivity.

Mouse mammary carcinoma cells were exposed in vitro to increasing concentrations of doxorubicin hydrochloride [adriamycin (ADR)] or 5-fluorouracil (5-FU). Uptake of [75Se]selenomethionine (75SeM) in a methionine-deficient medium measured the resulting inhibition of protein synthesis by the tumour cells. This was compared with the ability of the 75SeM labelled tumour cells to localize in mouse lungs and to form pulmonary tumours following intravenous (i.v.) injection into isogenic hosts. These parameters were also related to the ability of the drugs to inhibit pulmonary tumour formation in vivo when injected into mice which had received tumour cells i.v. Results from five different tumours were pooled for analysis. At the highest drug concentration (10 micrograms/ml ADR, 100 micrograms/ml 5-FU) inhibition of protein synthesis was significantly related to the in vivo action of the drugs in limiting formation of pulmonary tumors (P less than 0.02 using the rank difference coefficient). There was also a direct relationship between pulmonary localization of tumour cells following exposure to drugs, their ability to form tumour nodules (P less than 0.025) and the in vivo action of the drugs in inhibiting tumour formation (P less than 0.05). Thus inhibition of protein synthesis in vitro and pulmonary localization following i.v. injection may be of value in predicting the in vivo effect of cytotoxic drugs.

Animals↗

PubMedDate not supplied

Impact of delayed reperfusion of myocardial hibernation on myocardial ultrastructure and function and their recoveries after reperfusion in a pig model of myocardial hibernation.

UNLABELLED: This study examined the effect of delayed reperfusion of myocardial hibernation from 24 hours to 7 days on myocardial ultrastructural and functional changes and their recoveries after reperfusion. BACKGROUND: We have previously shown in pigs that after reperfusion the functional and structural alterations in short-term myocardial hibernation which was reperfused in 24 hours can recover in 7 days. The effect of delayed reperfusion of hibernating myocardium on the extent and severity of cellular and extracellular structural changes of hibernating myocardium, and their recoveries after reperfusion is not known. METHODS AND RESULTS: A severe LAD stenosis was created in 27 pigs, reducing resting flow by 30-40% immediately after placement of the stenosis and producing acute ischemia as evidenced by regional lactate production, a decrease in regional coronary venous pH, reduced regional wall thickening (from 38.5 +/- 5.1% to 10.4 +/- 8.0%) and a 33% reduction of regional oxygen consumption. The stenosis was maintained either for 24 hours in 9 pigs (group 1) with LAD flow of 0.65 +/- 0.13 ml/min/g (38% reduction), or for 7 days in 17 pigs (group 2) with LAD flow of 0.67 +/- 0.14 ml/min/g (36% reduction). There were no differences (p = NS) in the reduction of wall thickening, rate-pressure product, lactate production, or regional oxygen consumption between group 1 and group 2. Quantitative morphometric evaluation of the ultrastructure on electromicrographs revealed a greater decrease in sarcomere volume and a higher incidence of myocytes with reduced sarcomere volume in 7-day than in 24-hour hibernating regions (53 +/- 19% versus 33 +/- 14%, p < 0.05). Patchy myocardial necrosis with replacement fibrosis was common, but 6 of the 18 pigs had no myocardial necrosis or replacement fibrosis in the 7-day hibernating group, and 4 of 9 pigs had no patchy myocyte necrosis in the 24 hour hibernating group. In 6 pigs in group 1 in which the stenosis was then released and hibernating myocardium reperfused in 24 hours, regional wall thickening recovered to 30 +/- 6% (p = NS compared to baseline) after one week of reperfusion. In 12 pigs in group 2 in which the stenosis was released and hibernating myocardium reperfused in 7 days, regional wall thickening recovered slowly, from 10.1 +/- 7.2% to 18.1 +/- 8.3% at one week (n = 5) and to 28.0 +/- 3.6% at 3-4 weeks of reperfusion (n = 7, p < 0.05 compared to baseline). Similarly, the sarcomere volume or myofilament recovered significantly (p < 0.01) and was not different compared to the normal region (p = NS) in the 24-hour hibernating region of group 1, but the recovery was much slower and was incomplete at 4 weeks (p < 0.01) compared to baseline in the 7-day hibernating region of group 2. Recovery of regional wall thickening correlated with ultrstructural recovery (p < 0.01). By multivariate stepwise regression analysis, the degree of LAD flow reduction, the extent of fibrosis, and myofilament loss were independent predictors of the extent of functional recovery. CONCLUSIONS: In a porcine model of myocardial hibernation with myocardial hypoperfusion, systolic dysfunction, and metabolic adaptations, a longer period of myocardial hibernation with delayed reperfusion was associated with more severe abnormalities of myocytes. an increasing interstitial fibrosis, and more protracted myofibrillar and functional recoveries after reperfusion. The extent of functional recovery is related to the degree of coronary flow reduction, the severity of the ultrastructural changes, and the extent of interstitial fibrosis.

Animals↗

PubMedDate not supplied

Reversibility and pathohistological basis of left ventricular remodeling in hibernating myocardium.

The phenomenon of left ventricular (LV) remodeling with dilatation, wall thinning, and increased muscle mass has previously been reported in pigs with 7-day myocardial hibernation. This study investigated cellular and extracellular basis and reversibility of the structural LV remodeling with hibernating myocardium. Five groups of pigs were included: Group A: 7-day myocardial hibernation with a fixed coronary stenosis; Group B: 7-day hibernation with subsequent 3-week reperfusion by release of the stenosis; Group C: control group with sham operation; Group D: 24-hour myocardial hibernation to define structural mechanism of initial wall thinning in the hibernating region without confounding factors of cell loss or hypertrophy, Group E: 4-week myocardial hibernation to exclude the possibility of spontaneous regression of LV remodeling with hibernation. LAD flow decreased by 38+/-12% (p<0.01) with a significant decrease in systolic wall thickening at 7 days of hibernation with severe coronary stenosis (Group A). End-diastolic wall thickness decreased by 19% (p<0.01) accompanied by a decrease in myocyte number across the wall (44%) and in myocyte density (24%), a significant increase in myocyte width (17%), a mild increase in interstitial tissues in hibernating region, and significant increases in LV diastolic volume and in LV mass at 7 days. After reperfusion (Group B), LV volume decreased, LV ejection fraction improved, and myocyte hypertrophy regressed with a decreased LV mass index without a significant change in interstitial tissue. LV remodeling progressed with further increases in LV volume, mass, and interstitial fibrosis in 4-week hibernation. In pigs undergoing 24 hours of myocardial hibernation (Group D), end-diastolic LV wall thickness decreased significantly in the hibernating region with a proportional decrease in the transmural myocyte number but without changes in myocyte width, myocyte density, or interstitial tissues. Therefore, progressive gross LV remodeling associated with hibernating myocardium is accompanied by increasing myocyte hypertrophy and interstitial fibrosis. In hibernating myocardial region, wall thinning is proportional to a decreased myocyte number across the LV wall, indicating slippage of myocytes as a preponderant mechanism for the wall thinning. Myocyte hypertrophy develops within 7 days in hibernating myocardium, causing an increase in LV mass. These changes are partially reversible after reperfusion.

Animals↗

PubMedDate not supplied

Thimerosal increases the responsiveness of the calcium receptor in human parathyroid and rMTC6-23 cells.

Parathyroid cells express a plasma membrane calcium receptor (CaR), which is stimulated by a rise in extracellular calcium concentration ([Ca2+]ext). A decreased sensitivity to [Ca2+]ext occurs in adenomatous parathyroid cells in patients with primary hyperparathyroidism, but the underlying functional mechanism is not yet fully understood. This study explored whether CaR responsiveness is influenced by increasing the affinity of IP3 receptors--a major signalling component of other G-protein-coupled receptors. The sulphydryl reagent thimerosal was used to increase the responsiveness of IP3-receptors. Quantitative fluorescence microscopy in Fura-2-loaded cells was used to investigate the effects of thimerosal on the cytoplasmic calcium concentrations ([Ca2+]i) in human parathyroid cells and to compare its effects in a rat medullary thyroid carcinoma cell line (rMTC6-23) also expressing CaR. During incubation in Ca(2+)-free medium, thimerosal 5 microM induced a rapid sustained rise in [Ca2+]i in human parathyroid cells and no further [Ca2+]i increase appeared in response to the CaR agonist Gd3+ (100 microM). Thimerosal 1 microM induced only slow and minimal changes of basal [Ca2+]i and allowed a rapid response to Gd3+ 20 nM (a concentration without effect in control cells). The slope of the thimerosal-induced [Ca2+]i responses was steeper following exposure to CaR agonists. In the presence of 1 mM [Ca2+]ext, thimerosal (0.5 microM) induced a sharp increase in [Ca2+]i to a peak (within 60 s), followed either by return to basal [Ca2+]i or by a plateau of slightly higher amplitude. Similar results were obtained using rMTC6-23 cells. Thimerosal increases the responsiveness to CaR agonists through modulation of the sensitivity of the IP3 receptor in both parathyroid and rMTC6-23 cells.

Adenoma↗