Biomedical subjects
Publications and source records attributed to T Chan.
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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.
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.
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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.
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.
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.
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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.
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.
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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.
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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.
Two chondroitin lyases were isolated from the colon anaerobe Bacteroides thetaiotaomicron. Both enzymes had similar molecular weights (104,000 and 108,000) and similar isoelectric points (8.0 and 7.9, respectively). Both enzymes were active against chondroitin sulfates A, B, and C and unsulfated polysaccharides, such as chondroitin and hyaluronic acid, although one of the enzymes was twice as active against chondroitin as the other enzyme. Both had similar Km values for chondroitin sulfates A and C (40 to 70 micrograms/ml) and for chondroitin (300 to 400 micrograms/ml). Neither enzyme could degrade the highly sulfated mucopolysaccharide heparin, but heparin was a potent inhibitor of the activity of both enzymes. Although enzymes I and II were similar in many respects, a comparison of peptides resulting from partial digestion with N-chlorosuccinimide or papain demonstrated that the two proteins are not related.
Single-cell microscopic immunodiffusion assays were used to determine the cellular mechanisms that regulate fetal hemoglobin (HbF) levels in cultures of primitive and late erythroid precursors obtained from human adult bone marrow. Two variables--the percentage of cells containing HbF (F cells) and the picograms (pg) of HbF/F cell--were assayed in cells derived from erythroid colony-forming units (CFU-E) and from erythroid burst-forming units (BFU-E) at 7 and 14 days in culture, respectively. The percentage of F cells among all nucleated cells from CFU-E-derived colonies (29.4% +/- 12.5%, mean +/- SD) was not significantly different (p = 0.2) from the percentage of F cells from BFU-E-derived bursts (37.3% +/- 10.1%). Serial daily assays of all cells in cultures on days 3 through 7 and on day 14 revealed a marked increase in F cells between days 4 and 6 in culture. The average amount of HbF/F cell was less in CFU-E-derived F cells than in BFU-E-derived cells (3.5 +/- 0.3 pg versus 6.2 +/- 3.3 pg; p less than 0.01), while adult hemoglobin (HbA) levels in CFU-E-and BFU-E-derived cells remained comparable (19.9 +/- 2.2 pg versus 21.9 +/- 5.3 pg, p = 0.3). These findings indicate that F cell number in culture is not significantly influenced by the relative maturity of the erythroid precursors from which the cells are derived. Differences in the levels of HbF between CFU-E-and BFU-E-derived cells are due to differences in the amount of HbF per F cell, not F cell number.
An ultrasonic pachometer was used to measure the central, mid-peripheral, and peripheral thickness in 17 locations across the corneas of 12 adult New Zealand Albino rabbit eyes. The mean thickness at each location was entered into a microcomputer to generate a three-dimensional plot of corneal thickness. The rabbit cornea was found to have uniform thickness, with an average thickness variation of only 7 micrometers across the cornea. The average central corneal thickness was 407 +/- 20 micrometers. The three-dimensional representation of corneal thickness was useful in monitoring the surgical effects of cataract extraction and postoperative healing in rabbits. The ultrasonic pachometer was found to be well suited to animal studies. This study indicated that the velocity of sound in rabbit corneal tissue was approximately 1,580 m/sec.