Biomedical subjects

T C Chan

Publications and source records attributed to T C Chan.

At least 55 records · Page 3Linked to original sources

PubMed1995

Formic acid skin burns resulting in systemic toxicity.

Systemic toxicity developed in a 3-year-old girl burned by formic acid over 35% of her total body surface area. The patient presented with profound metabolic acidosis and a serum formate level of 400 micrograms/mL, the highest reported in the literature for poisoning by any route. The patient was successfully treated with hemodialysis, IV bicarbonate, and supportive measures. Reports of formic acid skin burns and systemic toxicity are limited. We discuss the pathophysiology and treatment of these cases.

Acidosis↗

PubMed1995

The effect of density and diameter on haptic perception of rod length.

Three experiments on the effect of density and diameter on haptic perception of rod length are reported. In Experiment 1, the subjects wielded visually occluded rods of different densities. Perceived length was found to be affected by the density of the rod regardless of the actual length. In Experiment 2, three aluminum rods of different lengths with handles of four different diameters were wielded. Perceived length of the rod was found to be shorter as the diameter of the handle with which it was wielded increased. A diameter-length illusion was thereby produced. In Experiment 3, visually occluded rods of different diameters but of the same moment of inertia about the x-axis were wielded with the right hand, and tubes of different diameters were felt with the left hand. The subjects were instructed that their right hand was grasping a handle, and that the actual diameter of the rod could be felt with the left hand. Rods were perceived to be shorter if a larger diameter was felt with the left hand. The results showed that perceived length is not just a function of actual rod length, and that is not accounted for by inertia only. The results are discussed in terms of the nature of invariants and the effect of knowledge on perception.

Humans↗

PubMed1995

Effectiveness of a dot-blot immunoassay of anti-Rickettsia tsutsugamushi antibodies for serologic analysis of scrub typhus.

We compared a commercially available dot-blot immunoassay system with the indirect immunofluorescence assay (IFA) in tests of known negative and known positive sera from scrub typhus cases. Using a panel of 100 sera from patients with various rickettsial and nonrickettsial infections, we observed that the IFA was 99% specific and the dipstick assay was 98% specific. In tests of 91 sera (30 negative and 61 positive for scrub typhus antibodies) from a study of febrile patients in Malaysia, using the standard of an IFA titer < 1:64 as negative, an IFA titer > 1:128 as positive, and an IFA titer = 1:64 as either positive or negative (supported by clinical records), dipsticks were 83% specific and 90% sensitive. The quantitative correlation of the dipsticks to IFA titers was confirmed by significant differences in geometric means of inverse IFA titers corresponding to the number of positive dipstick spots (no dots = 8.5, one dot = 43.3, two dots = 206.7, and three dots = 676.9). The assay would enable physicians and public health workers who deal with patients to quickly diagnose and appropriately treat most cases of the disease, especially in areas of high prevalence where the proportion of false-positive results to true-positive results would be low.

Antibodies, Bacterial↗

PubMed1995

Evaluation of in vitro cytotoxicity of nonsteroidal anti-inflammatory drugs against canine tumor cells.

Piroxicam and other nonsteroidal anti-inflammatory drugs (NSAID) have antitumor activity against naturally acquired cancer in dogs and human beings, and against experimentally induced tumors in rodents. We are investigating potential mechanisms of NSAID antitumor activity. The direct cytotoxicity of piroxicam indomethacin, and aspirin against 4 canine tumor cell lines (transitional cell carcinoma, squamous cell carcinoma, melanoma, and soft tissue sarcoma) was determined in short-term growth rate assays and in clonogenic assays. Piroxicam was evaluated alone and in combination with the lipoxygenase inhibitor zileuton, and in combination with the chemotherapeutic agents cisplatin and carboplatin. The 50% inhibitory concentrations (IC50) against melanoma cells in short-term growth rate assays were: 530 microM piroxicam, 180 microM indomethacin, and greater than 1 mM aspirin. These IC50 values were over 10 times greater than serum concentrations of these drugs that could safely be achieved in vivo. The IC50 of zileuton combined with piroxicam (280 microM) was not different from the IC50 of zileuton alone (230 microM; ANOVA P = 0.47) in melanoma cells. Similarly, addition of piroxicam did not alter the IC50 of either cisplatin (1.6 microM) or carboplatin (6.1 microM). These results suggest that NSAID, at serum concentrations achievable in vivo, do not have direct cytotoxicity against canine tumor cells tested. It is unlikely that the in vivo antitumor activity of NSAID is attributable to a direct cytotoxic effect.

Animals↗

PubMed1994

Validity of cephalometric landmarks. An experimental study on human skulls.

Cephalometric landmark validity (the difference between the estimated landmark and the true landmark) has surprisingly not previously been comprehensively evaluated, and no previous study has examined the validity of cephalometric angles and distances. The aim of this study was to investigate the validity of 15 commonly used skeletal and dental cephalometric landmarks, and the subsequent effects on 17 angles and distances. Small steel balls were glued on to 30 Chinese dry skulls to represent the true anatomical landmarks. The skulls were mounted in a purpose-designed skull holder and two cephalograms recorded of each skull, one with and one without the steel balls on the landmarks. Validity was expressed as the difference in the measurements between the assessments made with and without the steel ball markers. Measurements were made relative to X and Y co-ordinates which were constructed from reference points (steel balls) glued intracranially to the skulls. Seven out of the 10 skeletal landmarks and all five dental landmarks, were found to be non-valid along the X or the Y axes (P < 0.05). The standard deviations of the validity errors were large, being 1.0-2.5 mm, along at least one axis, for eight of the skeletal landmarks and three of the dental landmarks. Four of the cephalometric angles (SNA, SN/MnP, MxP/MnP, and LI/MnP) and three of the distances (N-Me, MxP-Me, and lower incisor edge to APg) were also found to be invalid (P < 0.05). The validity errors were greater for angles involving dental landmarks and for angles dependent on four landmarks compared to those dependent on three. The standard deviations of the validity errors for the skeletal angles ranged from 0.9 to 1.8 degrees, except for ANB (0.4 degrees), and for the dental angles from 3.2 to 5.8 degrees.

Adult↗

PubMed1994

Detection and characterization of Rickettsia tsutsugamushi (Rickettsiales: Rickettsiaceae) in infected Leptotrombidium (Leptotrombidium) fletcheri chiggers (Acari: Trombiculidae) with the polymerase chain reaction.

We developed a method for detecting and characterizing the DNA of Rickettsia tsutsugamushi in chiggers (larval trombiculid mites) by polymerase chain reaction (PCR). Three procedures for extracting DNA from frozen chiggers were compared by evaluating the yield of PCR amplicand obtained with nine oligonucleotide primer pairs derived from the rickettsial 22 kD, 47 kD, groESL, 56 kD, and 110 kD antigen genes. Although extracts and primer pairs differed in amplification efficiency, R. tsutsugamushi DNA was successfully detected in extracts of colonized infected Leptotrombidium (Leptotrombidium) fletcheri (Wormersley & Heaslip) chiggers and in uninfected chigger extracts seeded with known amounts of Karp-strain rickettsiae. The 22 kD gene restriction fragment length polymorphisms (RFLP) observed in PCR amplicands from five rickettsial isolates obtained from the infected chigger colony over a 26-yr period were identical to those of PCR amplicands derived directly from infected chiggers taken from the same colony. This suggests that stable transmission of R. tsutsugamushi occurs in mites (62 generations), and isolates encompass the full genetic heterogeneity found in the chigger. PCR/RFLP analysis is an important new tool for investigating the complex epidemiology of scrub typhus rickettsiae in their mite vectors.

Animals↗

PubMed1994

Haptic perception of partial-rod lengths with the rod held stationary or wielded.

Three experiments on the haptic perception of partial-rod lengths are reported. The rods were gripped between the two ends and held horizontal. The subjects held the rods stationary; the distribution of mass of the segment in front of the hand was fixed, while the distribution of mass of the segment behind the hand was varied. Perceived forward length was found to be significantly affected by the distribution of mass of the backward segment. Similar results were obtained when the rods were wielded. The results indicated that partial-rod lengths are specified by functions of mechanical perturbations acting on the hand, and not by the breaking up of the first moment of mass or the moment of inertia of the rod by attention as suggested previously by others. The results are also discussed with respect to invariant detection and attention.

Adult↗

PubMed1993

Permeation and metabolism of anti-HIV and endogenous nucleosides in human immune effector cells.

Numerous anti-HIV drugs are synthetic analogs of endogenous nucleosides. Therefore it is of interest to see if a facilitated nucleoside transport system exists to mediate their uptake into human immune effector cells that are known HIV targets. Nucleoside permeation and metabolism in lymphocytes, macrophages and bone marrow cells isolated from healthy human volunteers were studied, using uridine as the prototype endogenous nucleoside. There are saturable broad specificity nucleoside transport systems in all three cell types, all of which were inhibited by dipyridamole. The Vmax and Km values for uridine transport were 0.05 +/- 0.01 pmol/sec/10(6) cells and 18.4 +/- 4.2 microM, respectively, for lymphocytes, 0.04 +/- 0.01 pmol/sec/10(6) cells and 25.3 +/- 6.6 microM, respectively, for macrophages, and 0.03 +/- 0.01 pmol/sec/10(6) cells and 90.2 +/- 10.1 microM, respectively, for bone marrow mononuclear cells. Anti-HIV dideoxynucleosides such as azidothymidine (AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyinosine (DDI), 2',3'-dideoxyadenosine (DDA), and 2',3'-dideoxythymidine (DDT) are not substrates of this nucleotide transport system; hence, little or no drug accumulated inside the cells after 60 sec. Equilibration of cells with uridine or dideoxynucleosides for 2 hr resulted in high levels of cellular uridine and DDA, low levels of cellular AZT, but undetectable levels of the other analogs in all three cell types. Active metabolite levels in lymphocytes as assayed by HPLC correlated with the drug permeation results. Our data demonstrated that DDC, DDI, and DDT are not substrates for the nucleoside transporter and cannot diffuse readily across the cell membrane of human immune effector cells. Future anti-HIV drug development efforts should consider drugs that are substrates of the nucleotide transporter to ensure rapid and complete uptake into target cells.

Biological Transport↗

PubMed1993

Selective inhibition of the growth of ras-transformed human bronchial epithelial cells by emodin, a protein-tyrosine kinase inhibitor.

Emodin (3-methyl-1,6,8-trihydroxyanthraquinone), a naturally occurring protein-tyrosine kinase inhibitor, selectively blocked the growth of v-ras-transformed human bronchial epithelial cells. Half-maximal inhibition of cell growth occurred at a concentration of 4 micrograms/ml. In contrast, emodin at a concentration of 100 micrograms/ml had little effect on the growth of normal human bronchial epithelial cells. Cell cycle analyses indicated that treatment with emodin arrested the v-ras-transformed cells in the G2/M phase of their cell cycle. Immunoblotting experiments using anti-phosphotyrosine antibodies indicated that ras-transformed cells, as compared to their normal counterparts, exhibited elevated levels of phosphotyrosine-containing proteins. Treatment with emodin resulted in a decrease in intracellular protein-tyrosine phosphorylation. These results suggest that compounds that inhibit the ras-dependent elevation in the level of tyrosine phosphorylated proteins may prove to be useful chemotherapeutic agents and may exhibit selective cytotoxicity against cancer cells with an activated ras oncogene.

Bronchi↗

PubMed1993

Epidermal growth factor induces terminal differentiation in human epidermoid carcinoma cells.

Previous studies have reported that the proliferation of A431 cells, a human squamous cell carcinoma cell line, was stimulated by picomolar epidermal growth factor (EGF) but inhibited by nanomolar EGF. This biphasic dose-response phenomenon is not observed in normal human epithelial cells where nanomolar EGF is usually mitogenic. We have examined the effects of inhibitory and stimulatory concentrations of EGF on the growth and differentiation of A431 cells. In the presence of 100 pM EGF, A431 cells showed a mild increase in growth rate (129% of control) compared to cells grown in the absence of EGF. At 10 nM EGF, growth inhibition to 63% of control was observed. EGF at 10 nM stimulates a twofold increase both in cornified envelope formation and in epidermal transglutaminase activity, suggesting that high concentrations of EGF induce terminal differentiation in A431 cells. Mitogenic concentrations of EGF (100 pM) had no significant effect on these differentiation markers. Chronic exposure of A431 cells to 20 or 50 nM EGF resulted in EGF-resistant A431 variants that are neither growth arrested nor induced to terminally differentiate by 10 nM EGF. Removal of EGF from the growth medium of the EGF-resistant cells resulted in the reversion of these cells back to the wild-type A431 biphasic response pattern within 2 weeks. Our results suggest that A431 cells have the capacity to non-mutatively alter their response pattern to EGF in vitro to maintain themselves in a state of optimum proliferation and away from terminal differentiation.

Binding Sites↗

PubMed1993

Measurement of NK activity in effector cells purified from canine peripheral lymphocytes.

Natural killer (NK) cells spontaneously lyse a variety of tumor cells in vitro, and are believed to play an important role in host resistance to tumor growth and metastasis in vivo. As part of our work in comparative oncology, we have designed and validated a canine NK cell assay. Of several lymphocyte isolation techniques evaluated, sedimentation of whole blood through a two-step Ficoll/Hypaque gradient (sp. gr. 1.066/1.119) followed by plastic adherence of monocytes resulted in the most pure lymphocyte population (> 95% lymphocytes). Of four cell lines evaluated as targets in the NK assay, a canine thyroid adenocarcinoma (CTAC) cell line was determined to be most sensitive, and a lymphoblastoid (CT45-S) cell line was determined to be most resistant to NK lysis. A 15 h effector-target incubation period using these targets resulted in reproducible measurement of cell specific lytic activity. Passage of canine lymphocytes through nylon wool columns did not result in a significant increase in NK activity. A final sedimentation of purified lymphocytes through a 45/50% Percoll gradient concentrated NK activity into a single band of lymphocytes. Lymphocytes forming conjugates with CTAC target cells were 5.5-6.5 microns in diameter, and were characterized by a reniform nucleus and varying numbers of electron-dense cytoplasmic granules.

Animals↗

PubMed1993

Effect of head posture on cephalometric sagittal angular measures.

The definitions of cephalometric landmarks include relative terms that are dependent on the orientation of the head (e.g., lowest, most posterior) and head orientation differ widely during cephalometry (e.g., Frankfort plane horizontal, natural head posture). The purpose of this study was to quantify the effect of head posture changes on the commonly used sagittal angular measures SNA, SNB, and SNPogonion (SNPg). The sample comprised 30 Chinese skulls. Cephalograms were taken in a purpose designed skull holder with the Frankfort plane horizontal and at +10 degrees, +20 degrees, +30 degrees, -10 degrees, -20 degrees, and -30 degrees. A geometric grid was used to locate the deepest landmarks, and the landmarks were digitized followed by computer superimposition on the S-N line. To compare the values of the SNA, SNB, and SNPg angles in the different head postures, t tests were used. Head (skull) posture changes produced significant effects on the cephalometric values even at +/- 10 degrees of tilting. Overall, the angles were underestimated by approximately 1 degrees. In general, the angular differences and their standard deviations increased as the skull rotation increased with most of the differences for the SNB and the SNPg angles being clinically significant and also statistically significant at the 0.1% level. It was concluded that head posture needs to be standardized during cephalometry. Changes in posture significantly affect the location of some landmarks and the subsequent data obtained.

Asian People↗

PubMed1992

The readers' NIH.

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Financing, Government↗

PubMed1992

Synergism between dipyridamole and cisplatin in human ovarian carcinoma cells in vitro.

Dipyridamole (DPM), a nucleoside membrane transport inhibitor, enhanced the cytotoxicity of cisplatin (DDP) for human ovarian carcinoma 2008 cells by a factor of 4.7 +/- 0.4-fold (mean +/- SD) and for the 10-fold DDP-resistant 2008/C13*5.25 subline by a factor of 5.8 +/- 2.7-fold. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM enhancement of DDP cytotoxicity was schedule dependent; it was greatest when cells were exposed to DPM continuously during and following a 1-h exposure to DDP and less pronounced when DPM exposure was limited to pretreatment or concurrent treatment only. DPM increased DDP uptake in a concentration-dependent manner as measured with both [195mPt]-DDP and the DDP analogue [3H]-cis-dichloro(ethylenediamine) platinum. Nitrobenzylthioinosine, another nucleoside membrane transport inhibitor, did not enhance DDP cytotoxicity or uptake at concentrations that produced equivalent degrees of inhibition of [3H]uridine uptake. DPM did not interact synergistically through an increase in cellular cyclic AMP levels. DPM did not increase trypan blue or propidium iodide uptake, or change cell size, indicating that it did not nonspecifically increase membrane permeability. We conclude that DPM interacts synergistically with DDP and that, while an increase in DDP uptake is one component of the mechanism of this interaction, there are additional components since maximal effect was observed only with prolonged DDP exposure.

Carcinoma↗

PubMed1992

Phase I trial of piroxicam in 62 dogs bearing naturally occurring tumors.

Piroxicam, a nonsteroidal antiinflammatory drug, was given to 62 dogs bearing naturally occurring tumors in a phase I clinical trial. Dose escalation was performed, with oral doses ranging from 0.5 mg/kg every 48 h (q48h) to 1.5 mg/kg q48h being tested. Dose-limiting gastrointestinal irritation/ulceration occurred in all four animals that received 1.5 mg/kg q48h. The maximum tolerated dose was 1 mg/kg q48h. Subclinical renal papillary necrosis occurred in two dogs (initial dosages, 1 and 1.5 mg/kg q48h, respectively). Following dose escalation, an additional group of dogs was treated with 0.3 mg/kg piroxicam q24h per os, the accepted canine dosage prior to this trial. Inclusion of this treatment group enabled evaluation of the toxicity of and tumor response to a daily dosage regimen. No complete remissions occurred in this trial. Partial remission was documented in three of ten dogs exhibiting transitional-cell carcinoma, in three of five animals bearing squamous-cell carcinoma, in one of three dogs displaying mammary adenocarcinoma, and in the one dog that exhibited a transmissible venereal tumor. The results of this study support the additional evaluation of piroxicam in a phase II clinical trial in dogs bearing naturally occurring tumors.

Animals↗

PubMed1992

Mechanism-based model for tumor drug resistance.

The development of tumor resistance to cytotoxic agents has important implications in the treatment of cancer. If supported by experimental data, mathematical models of resistance can provide useful information on the underlying mechanisms and aid in the design of therapeutic regimens. We report on the development of a model of tumor-growth kinetics based on the assumption that the rates of cell growth in a tumor are normally distributed. We further assumed that the growth rate of each cell is proportional to its rate of total pyrimidine synthesis (de novo plus salvage). Using an ovarian carcinoma cell line (2008) and resistant variants selected for chronic exposure to a pyrimidine antimetabolite, N-phosphonacetyl-L-aspartate (PALA), we derived a simple and specific analytical form describing the growth curves generated in 72 h growth assays. The model assumes that the rate of de novo pyrimidine synthesis, denoted alpha, is shifted down by an amount proportional to the log10 PALA concentration and that cells whose rate of pyrimidine synthesis falls below a critical level, denoted alpha 0, can no longer grow. This is described by the equation: Probability (growth) = probability (alpha 0 less than alpha-constant x log10 [PALA]). This model predicts that when growth curves are plotted on probit paper, they will produce straight lines. This prediction is in agreement with the data we obtained for the 2008 cells. Another prediction of this model is that the same probit plots for the resistant variants should shift to the right in a parallel fashion. Probit plots of the dose-response data obtained for each resistant 2008 line following chronic exposure to PALA again confirmed this prediction. Correlation of the rightward shift of dose responses to uridine transport (r = 0.99) also suggests that salvage metabolism plays a key role in tumor-cell resistance to PALA. Furthermore, the slope of the regression lines enables the detection of synergy such as that observed between dipyridamole and PALA. Although the rate-normal model was used to study the rate of salvage metabolism in PALA resistance in the present study, it may be widely applicable to modeling of other resistance mechanisms such as gene amplification of target enzymes.

Animals↗

PubMed1992

Antiviral nucleoside toxicity in canine bone marrow progenitor cells and its relationship to drug permeation.

The most promising nucleoside analogs that are currently undergoing preclinical and clinical testing for anti-HIV activity belong to the dideoxynucleoside group. We have studied the toxicity of 3'-azido,3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC), and 2',3'-dideoxyinosine (DDI) in canine bone marrow progenitor cells in culture. AZT potently inhibited both canine CFU-GM and CFU-E with IC50 values of 2 and 8 mumol/l respectively, while DDC was relatively non-toxic to either progenitor with IC50 of > 200 mumol/l and 80 mumol/l respectively. DDI was mildly toxic to the bone marrow progenitors, with IC50 values of 62 mumol/l for CFU-GM and 70 mumol/l for CFU-E. Dipyridamole, a nucleoside transport inhibitor, did not influence the toxicity of these dideoxynucleosides in either progenitor at concentrations up to 10 mumol/l. Using uridine as the prototype endogenous nucleoside, we have demonstrated that there is a saturable "zero-trans" nucleoside transport system in canine bone marrow mononuclear cells, which is completely inhibited by 1 mumol/l dipyridamole (Ki = 0.02 mumol/l). None of the dideoxynucleosides appeared to be a substrate for this transport system, and dipyridamole did not alter their influx. Permeation of radiolabeled AZT into bone marrow mononuclear cells was slow and non-saturable, while the permeation of DDI was even slower. DDC did not permeate bone marrow cells well, with very little cell accumulation even after 2 hours of equilibration. Our toxicity data from canine bone marrow progenitor cells paralleled the clinical hematotoxicity profiles of these dideoxynucleosides in AIDS patients and suggest that the myelotoxicity of a nucleoside analog is related to its ability to permeate the progenitor cells in question. Canine bone marrow progenitor cultures may serve well as an in vitro model for drug hematotoxicity studies.

Animals↗

PubMed1991

Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs.

Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m2 ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1 +/- 4.5 min and the mean elimination half-life was 69 +/- 28 min. The mean plasma clearance was 227 +/- 125 ml min-1 m-2. The peak concentration of ara-C in the CSF was 29 +/- 11 microM, which occurred at 57 +/- 13 min after the ara-C bolus. The CSF elimination half-life was 113 +/- 26 min. During a 12-h infusion of ara-C (50 mg m-2 h-1), the plasma steady-state concentration was 14.1 +/- 4.2 microM, the CSF steady-state concentration was 8.3 +/- 1.1 microM, and the CSF: plasma ratio was 0.62 +/- 0.14. The plasma elimination half-life was 64 +/- 19 min and the plasma clearance was 214 +/- 69 ml min-1 m-2. The CSF elimination half-life was 165 +/- 28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.

Animals↗