Biomedical subjects
Publications and source records attributed to L Samson.
Tracheal tumors are rare. They tend to be diagnosed late because of delayed specific symptoms. Of the nine patients studied, eight had primary tumors (squamous cell carcinoma) and one had a metastasis from a primary colon cancer. Most of these tumors could be seen on good quality chest radiographs. Linear tomograms and esophagograms were useful. Computed tomography tends to underestimate the size of the lesion.
Adhesive capsulitis of the shoulder is an idiopathic condition characterized clinically by pain and limitation of movement. The characteristic arthrographic features are those of limited capacity of the joint, pain during injection, and retracted recesses. Progressive distension of the capsule with 1% lidocaine and 40 mg of triamcinolone acetonide (Kenalog) is a recommended form of treatment for this condition. Twenty-five patients treated by this method were reviewed retrospectively. Eleven (44%) were completely relieved of their symptoms, 6 (24%) had a 50% improvement, and 8 (32%) had no relief. Patients with idiopathic adhesive capsulitis responded more favorably to the treatment than those with a traumatic etiology. The duration of symptoms had no correlation with the results of therapy. There were no complications from the treatment.
The in vivo removal of three different O-alkylated bases from DNA was measured in Escherichia coli. Using monoclonal antibodies specific for O6-methylguanine, O6-ethylguanine and O4-ethylthymine we have monitored the removal of these lesions from six different strains to assess the relative contributions of the adaptive response and of nucleotide excision repair. During the first hour after DNA alkylation, O6-methylguanine, O6-ethylguanine and O4-ethylthymine lesions were repaired almost exclusively by nucleotide excision, except when the adaptive response was being constitutively expressed. In wild-type E. coli the adaptive response began to contribute to O6-methylguanine repair about one hour after alkylation, the time required for the full induction of the ada DNA methyltransferase. In contrast, the adaptive response did not play such a large role in the repair of O6-ethylguanine and O4-ethylthymine in wild-type E. coli, presumably because DNA ethylation damage is a poor inducer of the adaptive response; possible reasons for this poor induction are discussed. The repair of all three O-alkylated lesions was virtually absent in ada- uvr- bacteria suggesting that no alternative pathway is available for their repair, at least during the first two hours after alkylation. When the repair of O-alkylated bases was compromised by an ada- or by a uvr- mutation, the bacteria became more sensitive to alkylation induced killing and mutation.
The Escherichia coli ada-alkB operon encodes a 39-kDa protein (Ada) that is a DNA-repair methyltransferase and a 27-kDa protein (AlkB) of unknown function. By DNA blot hybridization analysis we show that the alkylation-sensitive E. coli mutant BS23 [Sedgwick, B. & Lindahl, T. (1982) J. Mol. Biol. 154, 169-175] is a deletion mutant lacking the entire ada-alkB operon. Despite the absence of the ada gene and its product, the cells contain detectable levels of a DNA-repair methyltransferase activity. We conclude that the methyltransferase in BS23 cells is the product of a gene other than ada. A similar activity was detected in extracts of an ada-10::Tn10 insertion mutant of E. coli AB1157. This DNA methyltransferase has a molecular mass of about 19 kDa and transfers the methyl groups from O6-methylguanine and O4-methylthymine in DNA, but not those from methyl phosphotriester lesions. This enzyme was not induced by low doses of alkylating agent and is expressed at low levels in ada+ and a number of ada- E. coli strains.
L-Homocysteic acid (L-HCA) has been proposed as a natural transmitter at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor based on recent evidence that L-HCA occurs L-HCA occurs naturally in the mammalian CNS, is released from K+ stimulated brain slices in a calcium-dependent manner and may be contained in nerve terminals located in certain brain regions that have a high density of NMDA receptors. Here we report that L-HCA potently induces a pattern of cytopathology in the ex vivo chick retina which mimics the pattern of NMDA but not kainic acid (KA) neurotoxicity. We also show that known NMDA antagonists, including Mg++, D-aminophosphonopentanoate and certain anesthetics, analgesics, and sedative hypnotics block the neurotoxic actions of L-HCA in direct proportion to their efficacy in blocking NMDA neurotoxicity. While there is a perfect correspondence between agents that block NMDA and L-HCA neurotoxicity, only a few such agents are active against KA neurotoxicity. We find that 3H-Glu binding is inhibited more potently by L-HCA (Ki = 67 microM). Moreover the patterns with which L-HCA and NMDA displace 3H-Glu binding in autoradiograms appear essentially identical. These findings are consistent with the proposal that L-HCA is an endogenous ligand at NMDA receptors.
Mer- human cells, which lack O6-methylguanine DNA methyltransferase activity, are extremely sensitive to alkylation induced killing, mutation and sister chromatid exchange. We have analyzed a Mer+, a Mer-, and a Mer- revertant HeLa cell line and found that the methyltransferase deficiency correlates with increased levels of mutation and sister chromatid exchange, but does not correlate with increased killing of Mer- HeLa cells by alkylating agents. Furthermore, we show that HeLa Mer- cells repair N-3-methylguanine and N-3-methyladenine just as efficiently as HeLa Mer+ cells.
For evaluation of the clinical usefulness of CT of the thorax in workers exposed to silica, 58 workers with long-term exposure to silica in the granite and foundry industries of the Eastern Townships of Quebec were examined. CT scans were compared with standard posteroanterior chest radiographs by using the International Labour Office 1980 grading system for silicosis. Six areas of the lung in each patient were assessed by both techniques for profusion (number) of opacities (small nodules), coalescence, and the presence of large opacities. CT scans and chest radiographs yielded similar average scores for detection of opacities. CT identified significantly more coalescence and large opacities in patients with simple silicosis. In patients with complicated silicosis, CT results were comparable with those of chest radiographs. CT of the thorax in workers exposed to silica does not identify more patients with minimal parenchymal disease, but it does detect earlier changes of coalescence.
Various agents were tested for their ability to antagonize the acute excitotoxic action of N-methyl-DL-aspartate (NMA) and kainic acid (KA) on neurons in the in vitro chick embryo retina. The following compounds (in order of descending potencies) were effective in completely blocking the neurotoxic activity of NMA: phencyclidine, ketamine, (+/-)-SKF 10,047, pentazocine, D-aminophosphonovalerate, D-amino-phosphonoheptanoate, D-alpha-aminoadipate, OH-quinoxaline carboxylate, kynurenate, (+/-)-cis-2,3-piperidine dicarboxylate, secobarbital, amobarbital and pentobarbital. The latter 6 agents also protected against KA toxicity but complete protection was observed only from relatively high concentrations. At 20 mM, Mg2+ blocked NMA toxicity but at concentrations up to 30 mM did not block KA toxicity. Compounds that failed to block either NMA or KA toxicity include D- and L-aminophosphonobutyrate, L-glutamic acid diethyl ester, xanthurenate, GABA and taurine. The chick embryo retina is a useful preparation for identifying agents that have either excitotoxic or anti-excitotoxic activity.
When the chick embryo retina is incubated in balanced salt solution containing glutamate (Glu) in 1 mM concentration, a neurodegenerative reaction occurs within 30 min. Here we report that the neurotoxic action of Glu on retinal neurons is dependent on the presence of Na+ and Cl-, but not Ca2+, in the incubation medium. Also, we report that depolarizing concentrations of K+ can induce a severe cytotoxic reaction in chick retina which, like the depolarization-linked neurotoxicity of Glu, is a Cl- dependent phenomenon.
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The ada-alkB operon protects Escherichia coli against the effects of many alkylating agents. We have subcloned it into the pSV2 mammalian expression vector to yield pSV2ada-alkB, and this plasmid has been introduced into Mer- HeLa S3 cells, which are extremely sensitive to killing and induction of sister chromatid exchange by alkylating agents. One transformant (the S3-9 cell line) has several integrated copies of pSV2ada-alkB and was found to express a very high level of the ada gene product, the 39-kDa O6-methylguanine-DNA methyltransferase. S3-9 cells were found to have become resistant to killing and induction of sister chromatid exchange by two alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine and N,N'-bis(2-chloroethyl)-N-nitro-sourea. This shows that bacterial DNA alkylation-repair genes are able to suppress the alkylation-repair defects in human Mer- cells.
The hypocholesterolemic agent 3 beta-(2-diethylaminoethoxy)androst-5-en-17-one . HCl (U18666A) is known to induce experimental epilepsy. The possibility that this drug interferes with cholesteryl ester formation in glioblastoma cells was examined. The incorporation of radioactive oleic acid into cellular cholesteryl ester was drastically and specifically inhibited by U18666A. The inhibitory effect of U18666A persisted in different oleic acid concentrations. Kinetic studies revealed the rapidity of U18666A action. U18666A was found to be ineffective in inhibiting acyl-CoA:cholesterol acyltransferase activity when it was added directly to the cell homogenates. In contrast, the acyltransferase activity was greatly diminished in homogenates derived from U18666A-treated cells. Thus, U18666A appeared to block cellular cholesteryl ester biosynthesis by indirectly inactivating acyl-CoA:cholesterol acyltransferase activity in a cell-dependent manner. The potent inhibition of cholesteryl ester formation by U18666A represents one unique aspect of the drug which might contribute to its ability to induce chronic epileptiform activity.
The perturbation of cellular cholesteryl ester biosynthesis in glioblastoma C-6 cells by lidocaine was investigated. Lidocaine specifically inhibited the incorporation of radioactive oleic acid into cellular cholesteryl ester but had no significant effect on the incorporation of oleic acid into phosphatidylcholine. Oxygenated cholesterol-enhanced cholesteryl ester formation was less sensitive to lidocaine inhibition. Several other local anesthetics were compared. Lidocaine altered cholesteryl ester formation in time- and dose-dependent manners. Lidocaine was a powerful inhibitor initially and its potency declined with time. Lidocaine was capable of directly inhibiting acyl-CoA:cholesterol acyltransferase (ACAT) activity in broken cell homogenates. The lidocaine-mediated inhibition of cellular cholesteryl ester formation triggered an enhanced intracellular ACAT activity that was not fully expressed in the presence of lidocaine. The activation of ACAT activity by lidocaine might represent a compensatory mechanism by which the inhibitory effect of lidocaine was partially overcome with time.
Several authors have recently proposed that excessive calcium (Ca++) influx into postsynaptic cells may be the mechanism by which excitotoxins such as glutamate (Glu), N-methylaspartate (NMA) and kainic acid (KA) cause neuronal necrosis. Here we have undertaken both in vivo and in vitro studies to explore this hypothesis. Our findings indicate that Ca++ does accumulate selectively in neural elements undergoing degeneration in the in vivo mouse hypothalamus following subcutaneous administration of NMA. However, pretreatment with the putative Ca++ channel blocker nimodipine resulted in augmentation rather than suppression of the toxic action of NMA and Glu on the mouse hypothalamus and eliminating Ca++ from the incubation medium did not interfere with the toxic action of Glu, NMA or KA on the chick embryo retina in vitro. We conclude, therefore, that Ca++ influx is an unlikely explanation for excitotoxin-induced degeneration of retinal or hypothalamic neurons.
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SV40 and pBR322 DNAs damaged by ultraviolet light were cleaved abnormally by several restriction enzymes because of damage to pyrimidines in the recognition sequences. The use of a tandemly duplicated plasmid provided a particularly sensitive target molecule for detecting pyrimidine dimers and other possible photoproducts. The relative efficiency with which cleavage was blocked (HindIII greater than TaqI greater than EcoRI greater than BamI greater than SalI much greater than Hha I, Hae III) corresponds approximately to the relative frequency of pyrimidine dimer formation in the recognition sequences, but at a slightly higher frequency in potential sites for the non-cyclobutane T-C product. The pyrimidine dimers appear to have a range of influence that extends 1 to 3 basepairs along the DNA molecule. These effects provide clues to the way DNA damage from mutagens and carcinogens can interfere with specific enzyme-DNA interactions.
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