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Biomedical subjects

T Y Chen

Publications and source records attributed to T Y Chen.

At least 19 recordsLinked to original sources
PubMed1992

Pseudomonas exotoxin A-epidermal growth factor (EGF) mutant chimeric protein as an indicator for identifying amino acid residues important in EGF-receptor interaction.

Epidermal growth factor (EGF) was fused to the carboxyl end of a modified pseudomonas exotoxin A that has its toxin binding domain deleted. This chimeric toxin designated as PE(delta Ia)-EGF kills A431 cells through the EGF receptor-mediated pathway. In this study, we used a random mutagenesis approach to make point mutations on EGF, followed by replacing the wild type EGF in PE(delta Ia)-EGF with these EGF mutants. We have constructed 14 different PE(delta Ia)-EGFmutants, and examined their EGF receptor binding activity as well as their cytotoxicity to A431 cells. Our results showed that individual mutations of Val19 to Glu and Val34 to Asp in the EGF domain of PE(delta Ia)-EGFmutants resulted in an increase in the binding affinity to EGF receptor and cytotoxicity to A431 cells. On the other hand, individual mutations of His16 to Asp and Gly18 to Ala in the EGF domain of PE(delta Ia)-EGFmutants lead to a decrease in the binding affinity to EGF receptor and cytotoxicity to A431 cells. In addition, mutations of any of the cysteine residues of EGF in PE(delta Ia)-EGFmutants resulted in the loss of their binding activity to EGF receptor and a corresponding loss of their cytotoxicity. This study indicates that the cytotoxicity of PE(delta Ia)-EGFmutant to EGF receptor-bearing cells may be used as an indicator to screen mutations of EGF important in EGF-receptor interactions.

ADP Ribose Transferases↗
PubMed1992

Cytotoxic activity and production of toxic nitrogen oxides by macrophages treated with IFN-gamma and monoclonal antibodies against the 73-kDa lipopolysaccharide receptor.

The hamster IgM mAb 5D3 is specific for an 73-kDa LPS receptor on murine leukocytes. This mAb inhibits binding of radiolabeled LPS to splenocytes and acts as an agonist for induction of LPS-mediated changes in macrophage function. Resident peritoneal macrophages treated with IFN-gamma and mAb 5D3 developed potent cytotoxic activity against tumor cells. Cells treated with IFN-gamma or mAb 5D3 alone were inactive. Macrophage cytotoxic activity induced by IFN-gamma and mAb 5D3 was inhibited by NGMMLA and coincident with high levels of NO2-released into culture fluids. These data show that mAb 5D3 serves as an effective trigger signal for induction of cytotoxic activity with IFN-gamma-primed macrophages. Indeed, mAb 5D3 exactly mimicked the effects of LPS in these same systems. Unlike LPS, effects of mAb 5D3 on induction of macrophage cytotoxic activity and production of nitrogen oxides was abrogated after boiling, and not affected by addition of polymyxin B. The effects of LPS and mAb 5D3 as a trigger signal for IFN-gamma-primed macrophages were associated with production of TNF activity in culture fluids and inhibited by mAb against rTNF-alpha. Expression of class II MHC on macrophages induced by IFN-gamma treatment was suppressed by both LPS and mAb 5D3. These suppressive effects of LPS and mAb 5D3 were not affected by NGMMLA or mAb against rTNF-alpha. Finally, macrophages treated with LPS or mAb 5D3 before exposure to IFN-gamma and LPS or mAb 5D3 did not develop cytotoxic activity or high levels of NO2- in the culture fluids. These same cells developed both effector activities after addition of rTNF-alpha. These results in toto identify the 73-kDa protein as a receptor that mediates LPS-induced changes in macrophage effector function. The mAb 5D3 serves as a specific and defined reagent agonist for analysis of LPS receptor-linked change.

Animals↗
PubMed1992

Lipopolysaccharide receptors and signal transduction pathways in mononuclear phagocytes.

There is little question but that bacterial lipopolysaccharides (LPS) remain one of the most potent stimuli which can affect macrophage activation. Although the precise biochemical mechanisms responsible for this remain to be fully defined, there is now evidence accumulating from a number of laboratories that functional receptors for these bacterial products do exist and may contribute to the initial triggering event. Unfortunately, there is currently no consensus as to which of the candidate receptors identified to date serves as the primary binding target for LPS, and it is possible that the difference in macrophage cell types, LPS probes, and detection systems will all influence the nature of the binding. At the present time, therefore, macromolecules of 96-kDa, 95-kDa (adhesion beta chain), 80-kDa, 65-kDa, and 55-kDa may be considered as possible LPS targets. With the exception of the 96-kDa protein identified by Hampton and his co-workers, there exists some experimental evidence for a functional role for each of the molecules so far identified. It is apparent that the molecular cloning and sequencing and subsequent biochemical characterization of these LPS receptors will be required to determine unequivocally their role in LPS-mediated triggering events. Such information will be invaluable in sorting out the relevant biochemical second signals involved in macrophage activation. Although much new information has recently been accumulated on potential signaling pathways for LPS, the definitive events remain far from unequivocally established. In view of the obvious importance of LPS-macrophage interactions in the overall capacity of the mammalian host to respond appropriately to the potentially hostile prokaryotic environment, a precise delineation of LPS-mediated macrophage activation is critical to our understanding of this important inflammatory mediator cell.

Animals↗
PubMed1992

Comparison of haloperidol and reduced haloperidol plasma levels in four different ethnic populations.

1. Plasma haloperidol and reduced haloperidol concentration were measured in four ethnic populations. 2. Plasma samples were obtained under steady-state conditions and obtained 10-12 hours post bedtime dose and prior to the morning dose. 3. Haloperidol and reduced haloperidol plasma levels were assayed by radioimmunoassay and liquid chromatography. 4. A wide interpatient variability between haloperidol dose and plasma concentration was observed for each ethnic group. 5. The Chinese group differed from the other ethnic populations. 6. A nonlinear relationship was observed between haloperidol and reduced haloperidol plasma levels in each ethnic group. Further, the relationship of haloperidol to reduced haloperidol plasma levels differed for each ethnic group. These results suggest that various ethnic groups could metabolize haloperidol and reduced haloperidol differently.

Black or African American↗
PubMed1992

Tumor necrosis factor-alpha gene expression in the tissues of normal mice.

Although TNF-alpha is traditionally associated with macrophage activation during neoplasia and acute inflammation, recent Northern blot hybridization studies indicate that gene expression occurs in the absence of pathology. In order to identify the cellular sources of endogenous message and protein, normal mouse tissues were tested for TNF-alpha mRNA using in situ hybridization and for the corresponding protein by immunocytochemistry. Unexpectedly, specific TNF-alpha message was readily detected in hepatocytes, kidney tubule epithelial cells, various populations of spleen cells and neurons. TNF-alpha protein was present in the same liver and kidney cells as those that contained TNF-alpha mRNA, was low in spleen cells, and was absent in neurons. These results suggest that cells other than macrophages are the major sources of TNF-alpha gene products in normal tissues, indicate that regulation is accomplished by more than one mechanism, and are consistent with the postulate that products of this gene contribute to normal physiological processes.

Animals↗
PubMed1992

Evidence for lipopolysaccharide binding in human granulosa-luteal cells.

We investigated whether human granulosa-luteal (GL) cells exhibited lipopolysaccharide (LPS)-binding protein, and the response of follicular aspirate cells to LPS in vitro. Follicular aspirates taken from a human in-vitro fertilization and gamete intra-fallopian-tube transfer programme were subjected to Percoll gradients in order to isolate an enriched population of GL cells. GL cells exhibited specific LPS-binding protein, detected by autoradiography of the cellular lysate on SDS-PAGE after the cells were specifically labelled with a radioiodinated, photoactivable and reducible LPS derivative. LPS binding to the cells was also detected by the appearance of immunofluorescence associated with the cellular membrane when incubated with a fluorescent conjugated LPS receptor antibody. Ninety-four per cent of the cells exhibiting immunofluorescent LPS-binding protein were also positive for the steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase, as detected by cytochemistry. In order to detect a response to LPS, the enriched population of GL cells were cultured in vitro in the presence or absence of LPS; after 16 h of culture, tumour necrosis factor-alpha (TNF) mRNA was detected by reverse transcription-polymerase chain reaction and Southern blot analysis of the amplified cDNA. The expression of TNF mRNA was enhanced when the cells were cultured in the presence of LPS, which also significantly enhanced TNF secretion into the media during the 16-h period. These results reveal that GL cells exhibit LPS-binding protein and thus increased TNF secretion occurs in response to LPS in follicular aspirate cells. The source of ovarian TNF may be leukocytes, macrophages and/or GL cells.

3-Hydroxysteroid Dehydrogenases↗
PubMed1991

Dose-dependent reduced haloperidol/haloperidol ratios in schizophrenic patients.

Plasma haloperidol (HAL) and reduced HAL (RHAL) concentrations were measured in 113 Chinese schizophrenic patients. Daily doses of HAL ranged from 8 to 65 mg. Samples were obtained under steady-state conditions and drawn 10-12 hours after the bedtime dose and before the morning dose. In all, 313 blood samples were collected. Multiple samples were obtained at the same doses in 63 patients and at two or three different doses in 31 patients. HAL and RHAL concentrations were assayed by high performance liquid chromatography. Interpatient variation in plasma HAL levels at a given dosage was up to sixfold. However, there was a high positive correlation between plasma levels and daily dosages with the equation of HAL plasma level (ng/ml) = 0.88 x dosage (mg/day) -0.56 or 46.0 x dosage (mg/day/kg) + 0.28. The expected values are about 15-55% higher than those obtained from non-Chinese patients as reported in the literature. The RHAL/HAL ratios were dose-dependent. The greater the dose used, the higher the ratio. An upper therapeutic limit of plasma HAL level is suggested to be 25 ng/ml, which can be achieved at dosages about 30 mg/day in most Chinese patients. Based upon the dose-dependent increase in RHAL/HAL ratios, the importance of RHAL in determining the therapeutic benefit of HAL treatment is discussed.

Adolescent↗
PubMed1991

Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.

Nitric oxide (NO) has recently been discovered to be an important endothelium-derived relaxing factor and produces profound relaxation of vascular smooth muscle. To learn if NO could be a potent and selective pulmonary vasodilator, NO was inhaled by 16 awake lambs in an attempt to reduce the increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) induced by either the infusion of an exogenous pulmonary vasoconstrictor (the thromboxane analog U46619) or the endogenous release of thromboxane that occurs during the neutralization of heparin anticoagulation by protamine sulfate. Inhaling greater than or equal to 40 ppm of NO during a continuous U46619 infusion returned the PAP to a normal value, without affecting systemic blood pressure or vascular resistance. Pretreatment with the cyclooxygenase inhibitor indomethacin before infusing U46619 did not reduce the pulmonary vasodilatory effect of inhaled NO, and we conclude that the dilatory effect of NO on the lung's circulation is independent of cyclooxygenase products such as prostacyclin. Continuously inhaling NO at 180 ppm did not significantly reduce the mean peak thromboxane B2 concentration at 1 min after protamine injection; however, the mean values of pulmonary hypertension and vasoconstriction at 1 min were markedly reduced below the levels in untreated heparin-protamine reactions. Breathing NO at lower concentrations (40-80 ppm) did not decrease the mean peak PAP and PVR at 1 min after protamine but decreased the PAP and PVR values at 2, 3, and 5 min below those of control heparin-protamine reactions. Intravenous infusion of nitroprusside completely prevented the transient increase of PAP and PVR during the heparin-protamine reaction; however, marked concomitant systemic vasodilation occurred. Inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during the heparin-protamine reaction in lambs and can do so without causing systemic vasodilation.

Animals↗
PubMed1991

Effects of continuous graded total parenteral nutrition on feeding indexes and metabolic concomitants in rats.

The influence of graded amounts of total parenteral nutrition (TPN) on food intake and feeding indexes was investigated in 90 rats housed in Automated Computerized Rat Eater Meter metabolic cages with free access to water and chow. When food intake was stable after catheter placement, 10 control rats continued with the 3 ml/h normal saline used for catheter patency, whereas study rats were given graded TPN continuously for 3 days, amounting to the equivalent of 26% (TPN-26), 53% (TPN-53), 81% (TPN-81), or 114% (TPN-114) of their daily caloric needs. TPN consisted of glucose, fat, and amino acids in the caloric ratio of 50:30:20. In study rats, the graded TPN depressed food intake, meal number, meal size, and eventually food consumption rate, meal sniffs, and intermeal sniffs in a dose- and time-dependent manner. During graded TPN, rats decreased total food intake by eating fewer, smaller, shorter meals at a decreasing consumption rate; sniffing activities were correspondingly curtailed. Stopping TPN led to normalization of feeding indexes. Blood glucose did not change while plasma insulin rose with graded TPN. A decrease in hepatic glycogen and an increase in hepatic triglycerides occurred. Plasma valine, phenylalanine, and methionine rose in a TPN dose-dependent manner. TPN-26 and TPN-53 significantly decreased whole brain amino acids; with TPN-114 no change occurred. Brain influx of tryptophan remained unchanged, but a progressive decrease in brain influx of tyrosine occurred. Whole brain dopamine and serotonin were depressed with TPN-26 and TPN-81 but were normal with TPN-114.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Double uterus with an obstructed hemivagina and ipsilateral renal agenesis: report of 5 cases and a review of the literature.

Maldevelopment of the Müllerian duct system can result in various uterine, vaginal, and renal abnormalities. Complete or partial absence of Müllerian duct fusion and/or canalization results in a septate, bicornuate or didelphys uterus with various types of hemivaginal obstruction. In addition, unilateral renal agenesis is a common association. Five patients with uterine anomalies and an obstructed hemivagina are described according to the complete or incomplete obstruction between the double vagina and uterus. Early and accurate diagnosis is important, but difficult, due to the variable clinical pictures. Sonographic evaluation can provide valuable diagnostic information. Early diagnosis and excision of the obstructed vaginal septum can completely relieve the symptoms and prevent further sequelae.

Abnormalities, Multiple↗
PubMed1991

Ethnic comparison of haloperidol and reduced haloperidol plasma levels: Taiwan Chinese versus American non-Chinese.

Steady-state haloperidol (HAL) and reduced HAL (RHAL) plasma levels were measured in Chinese and non-Chinese schizophrenic patients. The patients (n = 38) were matched according to age (+/- 1 yr) and by HAL dose. In general, Chinese patients had higher mean plasma HAL levels and lower RHAL/HAL ratios compared to non-Chinese patients (23.6 +/- 14.9 ng/ml versus 17.1 +/- 10.1 ng/ml, p less than 0.05; 0.52 +/- 0.44 versus 0.82 +/- 0.62, p less than 0.05). Six groups were formed according to HAL dose (number per group): 10 mg/day (6); 20 (11); 30 (11); 40 (4); 50 (3); and 60 (3). No significant differences were found in age, weight and dose/weight. In each dose group, HAL plasma levels were generally higher in the Chinese patients than in the non-Chinese patients, though significance was only detected in the 30 mg group (26.1 +/- 7.0 ng/ml versus 18.5 +/- 5.1 ng/ml, p = 0.035) and a slight trend in the 40 mg group (36.0 +/- 15.0 ng/ml versus 23.5 +/- 10.4 ng/ml, p = 0.074). RHAL/HAL ratios were generally lower in the Chinese patients than in the non-Chinese patients, with a strong trend toward the significance level in the 20 mg and 30 mg groups (0.22 +/- 0.13 versus 0.58 +/- 0.57, p = 0.066 and 0.43 +/- 0.26 versus 0.71 +/- 0.34, p = 0.062). This study further suggests the possibility of different metabolic rates between Chinese and non-Chinese patients. Possible differences in the enzyme systems which relate to the metabolism of HAL and RHAL between Chinese and non-Chinese populations are discussed.

Adult↗
PubMed1991

[Unilateral thalamic tumor with atrophy of ipsilateral cortical cortex: report of a case].

Ipsilateral brain atrophy is rare in neoplastic lesions of the brain, but it has been reported in patients with a thalamic tumor. We report a Chinese boy who presented with a right focal motor seizure and right side weakness at the age of six and half years when an electroencephalogram (EEG) showed focal epileptic discharges over the left hemisphere, but computed tomography (CT) of the brain failed to reveal a definite mass lesion. The weakness became gradually worse. On admission at age 8, follow-up CT scan revealed a huge tumor (5 x 5 x 7 cm) compressing the third and lateral ventricles with mixed densities in the left thalamus and centrum semiovale. The scan after contrast infusion showed a marked enhancement of the tumor. Instead of peri-mass edema surrounding the tumor, the overlying cerebral tissue showed atrophy of the ipsilateral cortical layer. He received subtotal resection of the tumor. The pathology proved to be germinoma. A test of tumor markers revealed a high human chorionic gonadotrophin level in the blood and cerebrospinal fluid. A short course of radiotherapy and chemotherapy was given after surgery. He has been well for the past two years.

Atrophy↗
PubMed1990

Generation and characterization of hamster-mouse hybridomas secreting monoclonal antibodies with specificity for lipopolysaccharide receptor.

Experiments are described for the partial purification of the 80-kDa LPS binding protein expressed on macrophages and lymphocytes. This partially purified Ag was used to immunize adult Armenian hamsters and splenocytes from immunized animals were fused with murine myeloma cell lines. Hybridoma cell culture supernatants containing mAb were screened by ELISA for positive binding to the immunizing Ag, murine splenocytes and the murine 70Z/3 pre B cell and for an absence of binding to sheep E. Positive clones were further screened for reciprocal competitive binding with LPS on spleen cells and ability to modulate B lymphocyte mitogenic activity. Two hybridoma cell lines secreting IgM monoclonals, termed mAb3D7 and mAb5D3, were identified that satisfied all of the selection criteria. These hybridoma cell lines were subcloned and expanded. Binding of one (mAb3D7) was abrogated by treatment of Ag with mild periodate; binding of the second (mAb5D3) was destroyed by digestion of Ag with proteinase K. Binding specificity for mAb5D3 has been confirmed by ELISA using highly purified 80-kDa protein. These mAb have been of value in establishing that the 80-kDa LPS binding protein previously identified may serve as a specific functional receptor for LPS.

Animals↗
PubMed1990

Induction of macrophage-mediated tumor cytotoxicity by a hamster monoclonal antibody with specificity for lipopolysaccharide receptor.

Experiments have been carried out to assess the immunostimulatory activity of a hamster IgM mAb (mAb5D3) with specificity for an 80-kDa LPS-binding protein expressed on murine macrophages and monocytes. The addition of mAb5D3 to cultures of murine bone marrow-derived macrophages activated these cells to become tumoricidal for mastocytoma cells in vitro. The activity of mAb5D3 was enhanced in the presence of IFN-gamma. Neither mAb5D3 nor LPS were able to activate macrophages from the LPS-hyporesponsive C3H/HeJ mouse, although these cells responded normally to heat-killed Listeria monocytogenes. The results of several experiments establish that the observed LPS-like activity of mAb5D3 was not due to contaminating endotoxin: 1) the activity of mAb5D3 but not LPS was heat labile at 100 degrees C; 2) the activity of LPS but not mAb5D3, was inhibited by addition of polymyxin B; and 3) quantitative estimates of endotoxin contamination by Limulus amoebocyte lysate reactivity. These experiments thus demonstrate that mAb5D3 can serve as an agonist for LPS-dependent macrophage responses and, when considered with those of our companion paper showing specificity of mAb5D3 for the 80-kDa LPS-binding protein, provide strong support for the concept that the 80-kDa LPS-binding protein previously identified serves as a functional receptor for LPS on murine macrophages.

Animals↗
PubMed1990

Plasma catecholamine metabolites in schizophrenics: evidence for the two-subtype concept.

Plasma homovanillic acid (pHVA) and plasma methoxyhydroxyphenyl glycol (pMHPG), as well as plasma haloperidol, were measured in 33 schizophrenic patients before and during 6 weeks of haloperidol treatment. Good responders had higher baseline pHVA values compared with poor responders (17.4 +/- 8.8 ng/ml, n = 22 versus 11.4 +/- 5.0 ng/ml, n = 11, p less than 0.05). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Differential pHVA changes during treatment were also found between good and poor responders. Within the good responder group, a significant decline in pHVA over time was found. By contrast, pHVA showed a transient increase in the poor responder group. Plasma MHPG changes showed a similar pattern during treatment in good responders, although no significant differences in baseline values were found between the good (n = 13) and poor (n = 9) responders, and pMHPG showed no change during treatment in poor responders. Significant correlations between baseline pHVA and pMHPG values were found in 22 patients. Good responders and poor responders did not differ significantly in terms of age, duration of illness, severity of presenting symptoms, haloperidol dose, or plasma drug concentration. Two hypothetical subtypes of schizophrenia and both dopamine and norepinephrine systems involved in schizophrenic psychopathology are proposed.

Adult↗
PubMed1990

Liver biochemical and histological changes with graded amounts of total parenteral nutrition.

We sought to determine whether an excess in energy intake as total parenteral nutrition would result in liver biochemical and histological changes in the presence of a functional gastrointestinal tract. Three groups of rats were given amounts of total parenteral nutrition that provided either 25% (total parenteral nutrition-25), 100% (total parenteral nutrition-100), or 200% (total parenteral nutrition-200) of a rat's energy requirements. Rat chow and water were available ad libitum. Food intake decreased in proportion to the amount of total parenteral nutrition infused; it ceased with total parenteral nutrition-200. Liver glycogen and triglyceride concentrations were higher with high energy intake (total parenteral nutrition-100 and total parenteral nutrition-200), while total liver nitrogen concentrations remained unchanged. No cholestasis, inflammation, or fibrosis was seen histologically. Fatty vacuoles were increased with total parenteral nutrition (more so with total parenteral nutrition-200) but a prompt return to normal liver features was observed after cessation of total parenteral nutrition and the resumption of normal food intake.

Animals↗