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T Chan

Publications and source records attributed to T Chan.

At least 19 recordsLinked to original sources
PubMed1992

4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor.

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4[[(phenylamino)carbonyl]amino]-1,2,3, 4-tetrahydroquinoline (35; IC50 = 7.4 nM vs [3H]glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent NMDA antagonists yet found. The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the alpha-amino acid center is required. The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial. Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group. The high affinity of trans-2-carboxy-5,7-dichloro-4-[1-(3-phenyl-2-oxoimidazolidinyl)]- 1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z conformer of the phenyl urea moiety in 35 is recognized by the receptor. Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor. The results allow the establishment of a three-dimensional pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.

Aminoquinolines↗
PubMed1992

Introduction of hydroxyl-bearing amino acids causes bathochromic spectral shifts in rhodopsin. Amino acid substitutions responsible for red-green color pigment spectral tuning.

Comparisons of the deduced amino acid sequences of eight primate photopigment genes led to the proposal that three amino acid substitutions produce the approximately 1,000 cm-1 difference in the absorption maxima of human red and green pigments (Neitz, M., Neitz, J., and Jacobs, G.H. (1991) Science 252, 971-974). We tested this proposal by mutating these three residues in rhodopsin and evaluating the effects on spectral properties. Nonpolar residues normally present in rhodopsin and in the green pigment were substituted by hydroxyl-bearing residues normally present in the red pigment. Two of these substitutions (Phe-261 to Tyr or Ala-269 to Thr) caused significant red shifts in the absorption maxima of the resulting mutant pigments. A third substitution (Ala-164 to Ser) caused only a slight effect. Combinations of substitutions caused additive shifts in absorption maxima. A double mutant (Phe-261 to Tyr/Ala-269 to Thr) displayed an absorption maximum that was red-shifted by 775 cm-1. Wavelength modulation in the visual pigments responsible for red-green color vision is likely to be governed by retinal-protein interactions involving primarily these two amino acid residues. Furthermore, interactions of hydroxyl-bearing amino acids with the chromophore may be a general mechanism of the opsin shift in visual pigments.

Amino Acid Sequence↗
PubMed1991

A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cis-diamminedichloroplatinum against human breast and ovarian tumor cell lines.

A monoclonal antibody (TAb 250) specific to an extracellular epitope of the c-erbB-2 protein (gp185) inhibited the in vitro proliferation of human breast tumor cell lines that overexpress c-erbB-2 in a dose-dependent manner. Treatment of cells with combinations of cis-diammedichloroplatinum (CDDP) and TAb 250 resulted in a significantly enhanced cytotoxic effect. This synergistic cytotoxicity was apparent over a wide range of antibody concentrations (200 pg/ml-100 micrograms/ml) including concentrations that showed no inhibitory effect alone. TAb 250 did not increase the cytotoxic effect of CDDP in a cell line exhibiting no detectable level of gp185. Athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of gp185 showed a greatly enhanced inhibition of tumor growth when treated with TAb 250 and CDDP compared to treatment with the antibody or CDDP alone. This effect was specific inasmuch as TAb 250 did not enhance the growth-inhibitory effect of CDDP on tumor xenografts which were not expressing gp185.

Animals↗
PubMed1991

Ocular manifestations in fetal alcohol syndrome.

Eight children with the fetal alcohol syndrome are described with ocular anomalies. They all had a strong history of maternal alcohol abuse throughout pregnancy, especially in the first trimester. All the children had eye abnormalities. These included external eye lesions, Peters' anomaly, lens opacification, ocular motility disorders, and optic nerve hypoplasia.

Child↗
PubMed1991

Intermittent downbeat nystagmus secondary to vermian arachnoid cyst with associated obstructive hydrocephalus.

A 27-year-old man presented with a history of dizziness and intermittent vertical oscillopsia after oblique extension of the head and neck, following a neck injury 2 years previously. He had no other symptoms of cerebellar or brainstem dysfunction. On examination, an intermittent downbeat nystagmus lasting about fifty seconds was elicited by head extension and rotation. Radiologic examination showed slight lateral instability of the odontoid on lateral rotation, and computed tomography brain scan with Iopamidol 300 (Niopam) contrast revealed a 5-cm vermian arachnoid cyst in the posterior fossa with obstructive hydrocephalus. Removal of the cyst cured the nystagmus.

Adult↗
PubMed1988

Pulmonary hypertension complicating portal hypertension: findings on chest radiographs.

Pulmonary hypertension is a rare but well-established complication of portal hypertension with a prevalence of 0.73% in one large autopsy series. In this report, we review the findings on chest radiographs in eight patients with this complication. Portal hypertension in these patients was evidenced by the presence of esophageal varices and/or ascites. The causes of portal hypertension were liver cirrhosis in seven patients and portal venous thrombosis in one patient. Pulmonary hypertension was established by right heart catheterization and pressure measurement. Qualitative assessment of the radiographs showed that four patients had the classic findings of pulmonary hypertension including prominent central pulmonary arteries and right ventricular enlargement, three had subtle abnormalities, and one had only cardiomegaly. Measurements of the width of the right descending pulmonary artery and the pulmonary lobar diameter/transverse thoracic diameter ratio were made in five of the patients in whom postero-anterior radiographs were available. The results confirmed our qualitative analysis, although they did not establish the diagnosis in borderline cases. We also observed that pulmonary vascular redistribution to the upper lobes was present in four patients, a finding that has been reported in patients with other causes of pulmonary hypertension. We conclude that the possibility of pulmonary hypertension should be raised in patients with portal hypertension, even when only subtle chest radiographic findings are present to suggest that diagnosis.

Adolescent↗
PubMed1987

Monoclonal antibodies to a brain dopamine binding protein: production, specificity, and immunohistochemistry.

A dopamine binding protein (DABP) has been purified from the rat brain synaptic membrane to homogeneity by affinity chromatography and gel electrophoresis. The monoclonal antibodies against the DABP were produced by the mouse-mouse hybridoma technique and characterized for their specificity to dopamine receptors by displacement of dopamine receptor binding. These monoclonal antibodies have been used to localize DABP in rat brain by immunohistochemistry. A specific linear structure of reaction product was seen in both caudate nucleus and cerebral cortex. This finding suggests that the DABP is present in the cerebral cortex and caudate nucleus as a membranous component of the neurons or their processes.

Animals↗
PubMed1987

Long-term treatment of hyperprolactinaemia with bromocriptine: effect of drug withdrawal.

Fifty-one patients with hyperprolactinaemia (23 with macroadenoma, 23 with microadenoma, and five with idiopathic hyperprolactinaemia) were treated with bromocriptine for 2-12 years (4.9 +/- 2.9 years, mean +/- SD). During therapy, the serum PRL levels were suppressed into the normal range in all but five patients. In these five patients, despite the high circulating PRL, gonadal function returned to normal in three, while in the other two gonadotrophin reserve was impaired even before therapy. Gel chromatography showed that one of these patients had a high proportion of a large molecular weight form of PRL. Twenty-four patients received bromocriptine as the sole method of treatment for over 2 years (3.4 +/- 2.3 years). In five out of the 24 subjects (21%), serum PRL remained normal with no clinical symptoms after prolonged drug withdrawal (1-4 years). Twenty-one patients received radiotherapy in conjunction with bromocriptine therapy. Of these 11 had prior surgery. After a follow-up of 6.0 +/- 3.0 years after radiotherapy, serum PRL remained within the normal range in 6 out of 21 subjects (29%), 1-4 years after bromocriptine withdrawal. One of the patients had impaired GH response to insulin hypoglycaemia developing after radiotherapy. We conclude that prolonged bromocriptine treatment is an effective treatment for prolactinomas.

Adenoma↗
PubMed1985

Skin graft rejection caused by the maternally transmitted antigen Mta.

Mta is a medial histocompatibility antigen of the mouse. It does not stimulate a primary mixed lymphocyte response and stimulates only a very weak secondary response. Primary skin grafts are rejected with a mean survival time of 59 days by Mta- NZB recipients, and 39 days by recipients of the C57BL/6 background. Rejection is accelerated in recipients primed against Mta with a skin graft or cells, especially when these differ by multiple minor histocompatibility antigens. Mta is determined by a maternally transmitted, extrachromosomal genetic element, so backcross mice reject skin from their inbred, homozygous paternal strain. Mta, therefore, constitutes a new exception to the classic laws of transplantation.

Animals↗
PubMed1979

Rate of metabolism of norethisterone in women from different populations.

The rate of metabolism of orally administered norethisterone was compared in fourteen centres by measuring plasma levels of the steroid by radioimmunoassay at varying times after oral administration of a 1 mg dose. The inter-centre differences were of the same order as the intra-centre differences. Variations in metabolism appeared not to be due to variations in body size.

Adult↗
PubMed1979

Radioimmunoassay of free thyroxine with prebound anti-T4 microcapsules.

Free thyroxine (FT4) may be one of the active throid hormones in contact with target end organs. It is unaffected by alterations in serum protein levels. In most cases, measurement of FT4 reflects an individual's true thyroid function or dysfunction. Previous FT4 assay techniques have been difficult, tedious, indirect, and inaccurate. A rapid, simple, and accurate radioimmunoassay for FT4 has been developed using microencapsulated rabbit anti-T4 antiserum to which I-125 T4 tracer of high specific activity has been complexed. Addition of FT4 standards or unknown samples displaces a proportional amount of I-125 T4 from antibody. Protein-bound T4 is excluded from the reaction by short incubation time and spatial configurations. Specimens representing known thyroid dysfunction were tested using the above procedure. The normal range of FT4 was 0.8-2.4 ng/dl. The mean FT4 for the hyperthyroid group was 6.92 +/- 1.38 (range 4.4-9.6) ng/dl. The mean FT4 for the hypothyroid group was 0.43 +/- 0.37 (range 0.1-1.3) ng/dl, and in pregnancy the mean FT4 was 1.64 +/- 0.44 (range of 1.0-2.2) ng/dl (1).

Animals↗
PubMed1978

Some properties of the specific androgen-binding activities in cultured human genital skin fibroblasts.

Specific 5 alpha-dihydrotestosterone (DHT)-binding activity in the cytosol (C) and 0.4 M KCl-extractable nuclear fraction (N) of cultured human fibroblast cell strains developed from preputial (n = 12) and labium majus (n = 12) skin were analyzed by gel exclusion chromatography, sucrose gradient sedimentation, and thermostability. Both fractions had activities that were excluded from Sephacryl S-200 columns; another component (mol wt, 20,000) was present in the N fraction. The C was more thermostable than a homologous N activity, and addition to the former of KCl to 0.4 M had no effect. There was large, overlapping variation in thermostability of the C and N activities among strains from either site, sister strains developed from a single skin biopsy, and even among serial subcultures within a strain; likewise, the variable sedimentability of the C (4-7S) and N (3.2-5.9S) activities prevented their consistent discrimination. Each type of variation occurred despite excellent intraexperimental replication. The thermostability of a given N activity varied directly with its sedimentation coefficient. By cluster analysis, the data relating thermostability of a given N activity with the percentage of 0.4 M KCl-resistant nuclear activity segregated into two populations; within each population these two measurements were related inversely. We suggest that these coordinate behaviors of the N activity reflect intrinsic properties of the androgen-receptor system in normal genital skin fibroblasts which may be useful for defining qualitative aberrations of the system in receptor-positive forms of congenital androgen insensitivity.

Adolescent↗
PubMed1977

The relationship between surface potentials and the number of active motor units.

One of the assumptions inherent in a technique recently devised for enumerating motor units in human muscles is that the surface potentials from active motor units summate in a linear fashion. We present an electrical model of a muscle which predicts that a linear relationship between the number of active units and the electrical response recorded at the surface overlying the muscle would not be expected. The extent of the non-linearity, and hence the error in the calculation of the number of motor units in a given muscle, depends upon the ratio between the mean conductance of the motor units themselves and that of the external conduction pathway through which the electrical signal is fed (Gu/Ge). The extent of non-linearity is assessed experimentally in human hypothenar muscles using a "collision" technique. The average underestimate introduced into the calculation of the number of motor units in this particular case was concluded to be 26%. The value of Gu/Ge derived from these experiments, in 2 subjects, was checked by simulating an intramuscular action potential and determining the attenuation at the surface. The 2 independently obtained values were sufficiently close to suggest that the model may be a valid one. We conclude that caution should be employed in the interpretation of experiments which purport to determine the number of motor units in a muscle by means of surface recordings.

Adult↗