Biomedical subjects
Publications and source records attributed to T R Jones.
A case is reported of a congenital aneurysm of the brachial artery in a 9-month-old boy. The lesion was excised and the artery reconstructed with an end-to-end anastomosis. Review of the English language literature showed that brachial artery aneurysms in children usually occur in association with arteritis, connective tissue disorder, or a syndrome of multiple aneurysms of unknown origin.
1. Responses of antigen-challenged isolated trachea from sensitized guinea-pigs were pharmacologically characterized by use of some novel inhibitors and antagonists of arachidonic acid metabolites. 2. The cyclo-oxygenase inhibitor, indomethacin, prolonged without altering the maximum response to antigen in the absence of the anti-muscarinic agent, atropine, and/or the H1-receptor blocker, mepyramine. In the presence of mepyramine, indomethacin both prolonged and increased the magnitude of the response. The selective (SQ-29548) and non-selective (L-640,035) thromboxane A2 (TXA2) antagonist and the TXA2 synthetase inhibitor, OKY-046, were essentially inactive. 3. Two novel inhibitors of 5-lipoxygenase product formation, AA-861 and L-651,896 produced complete inhibition of the response to antigen on tissues treated with atropine and mepyramine, with or without indomethacin. 4. Equimolar concentrations of the leukotriene D4 (LTD4) receptor antagonists LY-171883 greater than L-649,923 greater than or equal to L-648,051 greater than or equal to FPL-55712 blocked part of the response to antigen on tissues treated with atropine, mepyramine and indomethacin. All compounds tended to block a larger component of the response in the absence of indomethacin. A similar tendency was observed with the potent phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) but not the less potent phosphodiesterase inhibitor theophylline. 5. These results are consistent with the hypothesis that 5-lipoxygenase products acting on LTD4 receptors play only a minor role in the mediation of the contraction of guinea-pig trachea to antigen challenge. The nature of the residual contractile mediator is unknown; however, it can be completely blocked by the 5-lipoxygenase inhibitors AA-861 and L-651,896 and non-selectively blocked by the phosphodiesterase inhibitor, IBMX and non-selective LTD4 receptor antagonists, such as LY-171883.
The pharmacological actions of three leukotriene D4 (LTD4) receptor antagonists, FPL-55712, L-648,051, and L-649,923, and a novel inhibitor of leukotriene biosynthesis, L-651,896, have been investigated on isolated human tracheal smooth muscle. In the order of potency L-648,051 greater than FPL-55712 greater than L-649,923, these agents antagonized contractions to LTD4 and produced parallel rightward shifts in the dose-response curves. Mean -log KB values against LTD4 were 6.9 +/- 0.1, 6.5 +/- 0.3, and 6.0 +/- 0.1 for L-648,051, FPL-55712, and L-649,923, respectively. FPL-55712 also antagonized contractions to LTC4 (-log KB value, 6.4 +/- 0.3) and this activity was not decreased by the gamma-glutamyl transpeptidase inhibitor, L-serine borate. In the presence of 1 x 10(-7) M atropine, 7 x 10(-6) M mepyramine, and 1.4 x 10(-6) M indomethacin, L-648,051 at 2 x 10(-5) and 2 x 10(-6) M produced complete and partial blockade, respectively, of the contraction to goat anti-IgE. L-649,923 and FPL-55712 produced partial but significant inhibition at 2 x 10(-5) M, whereas the 5-lipoxygenase inhibitor, L-651,896, produced almost complete inhibition at 3.5 and 35 x 10(-6) M. L-Serine borate (15 mM) did not alter the the activity of FPL-55712 versus anti-IgE. These findings indicate that LTD4 receptors mediate contraction of human trachea to exogenously applied and endogenously (anti-IgE) released leukotrienes. LTD4 antagonists, such as L-648,051, may be useful in assessing the role of leukotrienes in respiratory disease.
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L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) has been studied in vitro on the guinea-pig tracheal chain, pulmonary artery and thoracic aorta ring and shown to be a potent, competitive antagonist of contractions induced by the prostaglandin endoperoxide analogue, U-44069 (pA2 values 8.0, 8.4 and 8.0 respectively). Selectivity on the guinea-pig trachea was indicated by non-competitive antagonism of contractions induced by prostaglandin D2 and minimal activity against contractions induced by leukotriene D4, prostaglandin F2 alpha, serotonin, histamine and acetylcholine. L-655,240 was a potent inhibitor of the aggregation of washed human platelets induced by U-44069 (IC50 value 7 X 10(-9) M) and inhibited aggregation of human platelet rich plasma induced by U-44069, U-46619, thromboxane A2 and collagen but not ADP or platelet activating factor. In vivo i.v. L-655,240 administered to guinea-pigs inhibited bronchoconstriction induced by i.v. U-44069 and arachidonic acid (ED50 values 0.09 and 0.23 mg kg-1) but not histamine, acetylcholine or serotonin. When administered to rhesus monkeys (3 and 10 mg/kg p.o.), L-655,240 inhibited ex vivo platelet aggregation induced by U-44069 but not ADP. It is concluded that L-655,240 is a potent, selective, orally active thromboxane/prostaglandin endoperoxide antagonist.
Thirty-one percent of a group of 49 hospitalized patients or laboratory workers in Guyana showed positive intradermal paracoccidioidin tests in the presence of negative histoplasmin reactions. In 2 patients (4%), the intradermal reactions to paracoccidioidin were greater than 10 mm in diameter. The prevalence of positive reactors in a selected population suggests that paracoccidioidomycosis may be endemic in Guyana although no clinical case has been reported from the country. A further survey in a larger, unselected population would lead to a clearer understanding of the problem.
A small DNA fragment containing the simple sequence [GGC]10 from the long repeat of herpes simplex virus type 1 (HSV-1) DNA hybridized to cellular DNA and polyadenylated RNA from different mammalian species. The number and intensity of blot hybridization signals were increased in human compared with rodent and simian nucleic acids. The hybridization was blocked specifically by human 28S ribosomal DNA, which shares only the GGC repeats with the herpes simplex virus DNA. These data indicate that GGC repeats were common components of cellular DNA and were expressed in mRNA. Blot hybridization analysis of viral RNA from the HSV-1 gene regions encompassing the GGC repeats revealed abundant stable mRNAs from portions of the virus genome not previously analyzed in detail and indicated that the viral GGC sequence was not expressed in stable cytoplasmic mRNA.
The antagonist activity of three leukotriene D4 (LTD4) receptor antagonists and a number of bronchodilators was determined against LTC4-induced contractions of guinea-pig isolated tracheal chains in the absence and presence of the gamma-glutamyltranspeptidase inhibitor, L-serine borate (SB). The LTD4 receptor antagonists FPL-55712, L-649,923 and L-648,051 effectively antagonized LTC4 responses in the absence of SB but were ineffective in the presence of 15 and/or 45 mM SB. Salbutamol greater than isobutylmethylxanthine (IBMX) greater than dibutyryl cyclic AMP greater than aminophylline greater than nifedipine antagonized contractions to LTC4 in the absence of SB. In contrast, in the presence of SB the antagonist activity of all of these agents except nifedipine was significantly reduced. The antagonist activity of the Ca2+ entry blocker, nifedipine, was similar in the absence and presence of SB. Salbutamol and IBMX were potent functional antagonists of LTE4-induced contractions both in the absence and presence of SB. These results are consistent with the hypothesis that there are contractile LTC4 receptor mechanisms in guinea-pig trachea which are unmasked by SB and are not blocked by LTD4 receptor antagonists and which are less effectively down modulated by cyclic AMP-dependent bronchodilators.
Expression of the c-myc gene can be controlled by transcriptional or posttranscriptional mechanisms (or both), depending on the cell type and the growth conditions. An important mechanism of posttranscriptional regulation is modulation of cytoplasmic c-myc mRNA stability; normal human and murine c-myc mRNAs have cytoplasmic half-lives of 30 min or less. To elucidate the c-myc sequences which impart this unusually high rate of cytoplasmic transcript turnover, we have constructed various deletion and hybrid c-myc genes and analyzed the cytoplasmic stability of the mRNAs produced from them in stably transfected murine fibroblasts. The results indicate that sequences contained within the 5' and 3' ends of the c-myc transcript can affect cytoplasmic stability. Specifically, the 3' untranslated sequences of c-myc exon 3 are required for, but do not ensure, a high rate of transcript turnover in the cytoplasm. Exon 2 coding sequences do not seem to be involved, and exon 1 sequences at the 5' end of the transcript have only a small effect on cytoplasmic transcript stability. The sequences that are primarily responsible for the short c-myc RNA half-life were localized to a region of 140 bases in the 3' untranslated region.
We reviewed retrospectively our experience with the transcutaneous placement of 77 double-lumen hemodialysis catheters in the jugular or subclavian veins in 65 patients. The catheters remained in place for an average of 20.7 days. Three unrelated deaths occurred within 30 days of insertion. Post-insertion chest roentgenograms were made on all patients. One pneumothorax and one misplacement into the carotid artery were noted. Five patients developed blood-culture-substantiated sepsis that required hospitalization. Deep-vein thrombosis occurred in one patient and subclavian-vein stenosis was found in two other patients. Various mechanical difficulties such as kinking, cracking, and thrombosis were encountered. The use of this catheter provides immediate access for hemodialysis with a minimum of complications. However, its disadvantages include its length, tendency to kink, and the requirement for a separate venous cannula to be used with each hemodialysis.
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The simple sequence GGC was tandemly repeated in herpes simplex virus type 1 DNA and human 28S rDNA and its mature 28 S rRNA transcript. The sequence homology was responsible for the observed hybridization between the two DNAs under high stringency blot hybridization conditions.
Addition of aluminum to the culture medium of Nakano mouse lens epithelial (NMLE) cells and Swiss 3T3K cells induced both 3H-thymidine incorporation and mitosis. This is in contrast to other metal ions such as vanadium, which, at concentrations high enough to increase 3H-thymidine incorporation, actually inhibits mitosis (Jones and Reid, J Cell Physiol 121:199, 1984). Aluminum concentrations between 20 microM and 50 microM were most effective. The 3T3 cells respond to aluminum with a 7.6-fold increase, and NMLE cells respond with a 21-fold increase in 3H-thymidine incorporation. DNA synthesis in NMLE cells was also found to be synergistically stimulated by aluminum and low concentrations of insulin (4.5 X 10(-8) M). A 3.25-hr incubation with 50 microM aluminum was sufficient to induce 50% of maximum 3H-thymidine incorporation during the 40-hr assay. Aluminum-stimulated 3H-thymidine incorporation is inhibited by hydroxyurea, and aluminum causes an increase in cell number. Also, by sedimentation equilibrium analysis of the product of aluminum-stimulated DNA synthesis it was found that a single copy of DNA was synthesized following addition of aluminum to quiescent cells. These facts indicate that aluminum induces both S-phase DNA synthesis and mitosis. However, only 48% of the NMLE cells found to be labeled with DNA went on to divide. In contrast, although only a small percentage of 3T3 cells were found to be labeled after aluminum treatment, all of these cells appeared to go through mitosis.
Glucocorticoid-receptor complexes in rat thymus cytosol were characterized by gel-filtration and ion-exchange chromatography and by other procedures. Two forms of non-transformed complex were identified at low ionic strength in the presence of molybdate, with Stokes radii of approx. 8 and 6 nm. The 8 nm molybdate-stabilized form could be converted to the 6 nm form by chromatography on Sephacryl S-300 or Lipidex 1000 or by incubation with charcoal or phospholipase C, but not by chromatography on Sephadex G-25. The dissociation rate of the complex was reduced by treatment with charcoal or Lipidex 1000, but none of the treatments caused transformation to a DNA-binding form. Transformation of the complex, by exposure to elevated temperature or ionic strength in the absence of molybdate, resulted in the appearance of a different 6 nm form, distinguished by an increased affinity for DNA-cellulose and a reduced affinity for DEAE-cellulose. These results suggest that receptor transformation is preceded by structural changes associated with the loss of a lipid factor from the complex. Non-polar steroid antagonists, and lipophilic compounds such as phenothiazines, were found to bind to secondary, hydrophobic sites on the receptor and to exert allosteric effects on the primary steroid-binding site; these and other observations emphasize the importance of hydrophobic interactions as determinants of the structure and properties of glucocorticoid receptors.
A short segment of the herpes simplex virus (HSV) DNA proximal IRL region hybridized to two doublet bands of EcoRI-digested human cellular DNA. The hybridization was abolished neither by increasing stringency conditions nor by inclusion of guanine-rich DNA in the hybridization mixture. Thus, the hybridization appeared to represent authentic base sequence homology between HSV DNA and middle repetitive human DNA.
Four new analogues of the antifolate N10-propargyl-5,8-dideazafolic acid were prepared that were substituted in the benzoyl ring. The 2'-chloro and 2'-methyl analogues were prepared from the appropriately substituted p-nitrobenzoic acids. The route to the 3'-chloro and 3',5'-dichloro analogues was by chlorination of diethyl N10-propargyl-5,8-dideazafolate and diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate, respectively, using sulfuryl chloride. The compounds were tested for their inhibition of purified L1210 thymidylate synthase (TS), for their inhibition of purified L1210 dihydrofolate reductase (DHFR), and for their inhibition of the growth of L1210 cells in culture. The 2'-chloro substituent reduced the TS inhibition by twofold and the 2'-methyl substituent reduced it by 20-fold; the 3'-chloro and 3',5'-dichloro derivatives were very poor inhibitors. The substituents only slightly affected the DHFR inhibition. None of the compounds improved upon N10-propargyl-5,8-dideazafolic acid in inhibiting the growth of L1210 cells in culture.