Search PubMed⌕ Search

Biomedical subjects

G Thomas

Publications and source records attributed to G Thomas.

At least 577 records · Page 32Linked to original sources
PubMed1991

Pharmacokinetics of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.

It has been shown that patients with acute promyelocytic leukemia (AML3 subtype) treated with all-trans retinoic acid (all-trans RA), 45 mg/m2/day, achieve complete remission through differentiation of the leukemic clone to mature myeloid cells, which die spontaneously. The pharmacokinetics of all-trans RA given by mouth were studied in 15 AML3 patients. Blood samples were drawn for 24 h following a single oral dose of 45 mg/m2 and assayed for all-trans RA and 13-cis retinoic acid (13-cis RA) plasma concentrations by specific high-performance liquid chromatography. In one patient all-trans RA and 13-cis RA levels were below the detection limits at all times. In the other patients, the time to peak concentration of all-trans RA was between 60 and 210 min (median 90 min) after ingestion, with maximum concentrations between 0.03 and 2.5 micrograms/ml (median 0.4 micrograms/ml). These concentrations were within the in vitro differentiating concentration range of all-trans RA for these patients' cells. In nine patients, enterohepatic cycling was suggested by the presence on the concentration versus time curve of a secondary peak that occurred at meal times. The apparent plasma elimination half-life was between 16.8 and 77.4 min (median 30 min). Detectable plasma levels of 13-cis RA in 12 patients indicated in vivo isomerization of all-trans RA. Despite the high inter-individual variability of all-trans RA pharmacokinetics in these patients, high blast cell counts and failure to respond to differentiation treatment tended to be associated with low all-trans RA Cmax values and high clearance estimates.

Administration, Oral↗
PubMed1991

Epidemic dropsy in Andhra Pradesh due to contaminated ghee.

An outbreak of epidemic dropsy in Andhra Pradesh was studied during August to September 1987. Thirty cases from 6 families were identified and examined. Ghee and one oil sample were found to be contaminated with the toxic compound sanguinarine. The affected families had purchased ghee from one vendor. The epidemic ended after alerting the villagers of the contaminated ghee, and stopping its further use.

Alkaloids↗
PubMed1991

Superoxide production in the isolated rabbit aorta and the effect of alloxan, indomethacin and nitrovasodilators.

The purpose of this investigation was to develop a simple model to assess superoxide production from isolated vessels and to use this model to study the effects of various compounds on superoxide generation. The established method of cytochrome C reduction by superoxide was modified to measure superoxide production in vascular rings from rabbit aortae. The diabetogenic compound alloxan significantly increased superoxide production in a concentration-dependent manner. The nitrovasodilators nitroprusside and minoxidil exhibited contrasting effects. Nitroprusside inhibited alloxan-stimulated production of superoxide, but minoxidil had no effect, suggesting different mechanisms of action for these drugs. The cyclooxygenase inhibitor indomethacin had no effect on the production of superoxide stimulated by alloxan, demonstrating that superoxide production induced by this compound is not affected by mechanisms involving cyclooxygenase. These data demonstrate the use of a simple, rapid and inexpensive method for measuring superoxide produced by intact vessels. This may be useful in testing drugs exhibiting antioxidant and vasoactive properties. Finally, because superoxide is implicated in the destruction of endothelium-derived relaxing factor, and the presence of the vasodilator nitroprusside reduces superoxide production, it is concluded that some nitrovasodilators may have additional vascular effects through the suppression of superoxide formation.

Alloxan↗
PubMed1990

Three forms of phosphatase type 1 in Swiss 3T3 fibroblasts. Free catalytic subunit appears to mediate s6 dephosphorylation.

The major 40 S ribosomal protein S6 phosphatase in Swiss mouse 3T3 fibroblasts is a type 1 enzyme (Olivier, A. R., Ballou, L. M., and Thomas, G. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 4720-4724). Polyclonal antibodies were raised against a synthetic peptide containing the carboxyl-terminal 14 amino acids of the catalytic subunit of phosphatase 1 (PP-1C). Results from Western blot analysis and immunoprecipitation show that the peptide antiserum specifically recognizes PP-1C in cell extracts. Anion-exchange chromatography of cell extracts and Western blot analysis revealed three peaks of PP-1C termed A, B, and C. Peaks A and C are associated with the major type 1 S6 phosphatase activities, but peak B exhibits little activity. The phosphatase in peak A (Mr 39,000) appears to represent the free catalytic subunit, whereas the enzymes in peaks B and C display sizes of 68,000-140,000. Peak B contains two additional proteins of Mr 26,000 and 48,000 that co-immunoprecipitate with PP-1C, while peak C has a single additional protein of Mr 100,000. Fifteen min after serum withdrawal there is a 2-fold stimulation of S6 phosphatase activity in peak A that can be accounted for by an increase in the amount of PP-1C. The amount of PP-1C in the inactive peak B fraction also increases during this time and this increase is associated with changes in the phosphorylation state of the Mr 26,000 and 48,000 proteins. The results are discussed in relation to regulatory mechanisms which are thought to modulate the activity of type 1 phosphatase.

Animals↗
PubMed1990

Take it easy, friend.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Yeast KEX1 protease cleaves a prohormone processing intermediate in mammalian cells.

A vaccinia virus vector was used to express the yeast KEX1 gene, which encodes a prohormone carboxypeptidase specific for the removal of basic amino acids from prohormone processing intermediates, in mammalian cells. When produced in BSC-40 cells, Kex1p was localized to the perinuclear region and conferred a large increase in enzymatic activity characteristic of this carboxypeptidase. Expression of the KEX1 gene together with the yeast KEX2 gene, which encodes a prohormone endopeptidase specific for cleavage at pairs of basic amino acids, and the mouse proopiomelanocortin (mPOMC) cDNA in BSC-40 cells resulted in the full conversion of mPOMC to mature peptides including gamma-lipotropin. This in vivo processing of mPOMC to mature peptides by the KEX2/KEX1 gene products demonstrates a significant functional homology of the basic prohormone processing machinery in yeast and neuroendocrine cells.

Animals↗
PubMed1990

An in vivo characterization of the cleavage site specificity of the insulin cell prohormone processing enzymes.

Most peptide hormones and neurotransmitters are synthesized as larger precursor proteins, which are post-translationally processed to mature bioactive products. An early event in prohormone maturation is endoproteolytic cleavage, occurring usually at pairs of basic amino acids (e.g. Lys-Arg). Since many of the characteristics of a prohormone endoprotease are unknown, distinguishing these enzymes from other cellular proteases in vitro has been difficult. In this report, the substrate specificity of a model prohormone processing system, the insulinoma cell line Rin m5F, was characterized in vivo to establish a set of criteria by which putative proinsulin endoproteases may be assessed. To determine the role of composition of the paired basic amino acid site in directing cleavage, a series of mutant prohormones containing altered cleavage sites was constructed and expressed in Rin m5F cells. Proopiomelanocortin (POMC) was used as a substrate since this prohormone was previously shown to be processed by these cells. To control for positional effects, all four permutations of lysine and arginine (Lys-Arg, Arg-Arg, Arg-Lys, and Lys-Lys) were introduced at both the efficiently processed cleavage site separating the ACTH and beta-lipotropin (beta-LPH) domains of POMC and at the inefficiently processed site in the beta-endorphin sequence near the COOH-terminus of the precursor. His-Arg and Met-Arg sites were also introduced at the ACTH/beta-LPH junction to assess the requirement for paired lysines and arginines. Identification of POMC-derived peptides demonstrated efficient processing of Lys-Arg and inefficient processing of Lys-Lys and Arg-Lys sites at both positions in the prohormone. The Arg-Arg sequence, however, was processed in a position-dependent manner, being efficiently cleaved between ACTH and beta-LPH but only about 50% processed within beta-endorphin. His-Arg was not cleaved in Rin m5F cells, although surprisingly Met-Arg was partially processed. These results indicate a strict preference of the insulinoma prohormone endoprotease(s) for paired basic amino acids ending in arginine, but that processing efficiency of some sequences may be modulated by location within the precursor molecule.

Amino Acid Sequence↗
PubMed1990

Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy.

Adrenocortical carcinoma is a rare tumor, and only limited information is available about its natural history and the effects of therapy. We studied 105 patients (75 female and 30 male; mean age, 46 years) with adrenocortical carcinoma who were referred to us between 1963 and 1987. The average duration of symptoms before diagnosis was 8.7 months. At the time of diagnosis, 68 percent of the patients had endocrine symptoms, and 30 percent had distant metastases. Hormonal studies showed that 79 percent of the tumors were functional. Eighty patients underwent surgery, and 59 also received the adrenal cytotoxic agent mitotane. The median disease-free interval after surgery was 12.1 months (range, 1 to 175). Tumor dissemination occurred in 82 percent of the patients, most commonly to the lung, liver, and adjacent organs. The median survival time was 14.5 months (range, less than 1 to 175), and the five-year survival was 22 percent. Age over 40 years and the presence of metastases at the time of diagnosis were the only factors recognized as indicating a poor prognosis. Mitotane controlled hormonal secretion in 75 percent of the patients. Eight mitotane-treated patients had partial tumor regression, but the drug did not have a significant effect on survival. We conclude that adrenocortical carcinoma carries a poor prognosis. Mitotane therapy may offer transient benefits, particularly in controlling endocrine symptoms.

Adrenal Cortex Hormones↗
PubMed1990

Effect of N alpha-benzoyl-L-arginine ethyl ester on coronary perfusion pressure in isolated guinea pig heart.

N alpha-Benzoyl-L-arginine ethyl ester (BAEE) when compared to L-arginine significantly decreased coronary perfusion pressure of isolated guinea pig heart in a dose dependent and reproducible manner. This effect of BAEE was antagonized by haemoglobin and N-monomethyl L-arginine, both inhibitors of endothelium dependent relaxation. These results support the notion that the mechanism of relaxation elicited by BAEE is due to the generation endothelium dependent relaxing factor (EDRF) like agents.

Animals↗
PubMed1990

Simultaneous monitoring of P53 protein and DNA content of colorectal adenocarcinomas by flow cytometry.

The p53 transformation-related gene is located on 17p, a chromosomal segment frequently under-represented in colorectal adenocarcinoma karyotypes. We have developed a flow cytometric method for detection of its gene product on isolated nuclei by indirect immunofluorescence. Criteria for defining the presence of p53 were established, using parameters related to the difference of fluorescence obtained by incubating nuclei with a specific monoclonal antibody (MAB) versus isotypic control. This method allowed simultaneous quantitation of p53 and DNA in tumor nuclei to be made. Twenty-two of the 41 tumors analyzed (54%) were found to overexpress p53 when compared to 13 normal mucosa specimens. Repeated preparations from different fragments of the same tumor gave reproducible results for the 21 cases tested. p53 was detected in a higher proportion of disseminated tumors (64%) compared to localized disease (39%), but the difference did not reach statistical significance (chi 2 = 2.4, p greater than 0.10). Tumors containing aneuploid cell subpopulations were also more frequently positive (65%) than diploid ones (20%), the difference being significant (Fisher's exact test, p less than 0.03). This dual parameter flow cytometric method, evaluating both DNA ploidy and p53 expression, may prove useful in identifying different biological subgroups of colorectal cancer.

Adenocarcinoma↗
PubMed1990

Inactivation of pyruvate decarboxylase by 3-hydroxypyruvate.

Pyruvate decarboxylase from Zymomonas mobilis is inhibited by 3-hydroxypyruvate, which can also act as a poor substrate. While catalysing the decarboxylation of this alternative substrate, the enzyme undergoes a progressive but partial inactivation over several hours. The extent of inactivation depends upon the pH and upon the concentration of 3-hydroxypyruvate. After partial inactivation and removal of unchanged 3-hydroxypyruvate, enzymic activity recovers slowly. We suggest that inactivation results from accumulation of enzyme-bound glycollaldehyde, which is relatively stable, possibly because it is dehydrated to form an acetyl group.

Binding, Competitive↗
PubMed1990

Effect of adenotonsillectomy on nocturnal hypoxaemia, sleep disturbance, and symptoms in snoring children.

61 snoring children selected for adenotonsillectomy, mainly for recurrent tonsillitis, were compared with a matched group of 31 healthy children for symptoms of sleep apnoea, extent of sleep hypoxaemia, and amount of sleep disturbance. The studies were repeated six months postoperatively, and after six months in the healthy children. Preoperatively, 61% of the children had degrees of sleep hypoxaemia above normal and 65% had abnormally disturbed sleep. A questionnaire administered to the parents about their children showed abnormal patterns of answers about sleep problems daytime sleepiness, hyperactivity, aggression, learning difficulties, restless sleep, and odd sleeping positions. After adenotonsillectomy, the abnormal hypoxaemia, excessive sleep disturbance, and multiple symptoms almost resolved; a growth spurt also occurred.

Adenoidectomy↗
PubMed1990

Identification of a chromosome 18q gene that is altered in colorectal cancers.

Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

Alleles↗