Biomedical subjects
Publications and source records attributed to B Singer.
The effects of attention and reading tests on the EEG and the H reflex were studied in a patient affected by primary reading epilepsy. During the attention tests, EEG was normal while H reflex was facilitated. On the contrary, during reading tests, EEG showed typical epileptic seizures while at the same time, the H reflex was depressed.
Upon ethyl nitrosourea treatment of RNA of tobacco mosaic virus, up to four phosphodiester groups may be alkylated per molecule without chain breakage, as shown be sucrose gradient centrifugation. This indicates that ribophosphotriesters are quite stable. However, when this alkylation reaction is of longer duration and 6 to 10 triesters are formed, then an average of 1 to 2 breaks occurs and little or no intact RNA can be isolated. Methyl nitrosourea is less effective in forming triesters (about 25% of total alkyl groups compared to about 65% for ethyl nitrosourea), and a greater number of alkyl groups can, therefore, be introduced before breaks occur. Diethyl sulfate and dimethyl sulfate, which alkylate almost only the bases of nucleic acids, do not cause significant degradation of RNA of tobacco mosaic virus, even when as many as 70 alkyl groups are bound. All types of alkylation cause similar losses in viral infectivity at low levels of alkylation. Thus, an average of two chemical events leads to one lethal event, regardless of the nature of the alkylating reaction, which, for example, is with dimethyl sulfate about 65% on the N-7 guanine while with ethyl nitrosourea it is about 65% on phosphodiesters. It is thus concluded that all alkyl groups, whether on the base or on the phosphate, have the same potential to cause inactivation and that inactivation of RNA can result from phosphotriester formation per se.
1 Isolated renal cortical cells of the cat have been demonstrated to produce renin on incubation in vitro. After 2 h of incubation, without added agonist, the total amount of renin in the flask increased by a mean of 27.2 percent. The increase in renin content of the incubation flask was found to be present in the medium. 2 Noradrenaline (1.18 times 10-minus 4M) and adrenaline (1.09 times 10-minus 4M) added to the incubation medium stimulated renin production by 45 and 34% respectively, compared with the incubated controls. Most of the increase in renin production was present in the incubation medium. 3 Isoprenaline did not stimulate renin production. However, when added to the incubation medium at a concentration of 0.72 times 10-minus 4M there was a significant decrease in the cellular content and a significant increase in the medium content of renin. This increase was at least as great as that observed with adrenaline and noradrenaline. 4 Salbutamol had an effect similar to isoprenaline, i.e. it induced the release of renin into the medium without affecting production. In this respect it was about a third as potent as isoprenaline.
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Two alkylation products implicated in initiation of carcinogenesis are O6-alkylguanine (m6G) and O4-alkylthymine (m4T). We have used site-specific insertion of these derivatives into oligonucleotides and measured the kinetic constants of various pairings, using both prokaryotic and eukaryotic polymerases for replication. Preliminary data are also reported for another carcinogen product, N2,3-ethenodeoxyguanosine ( epsilon G). The immediate neighbor bases play an important role in determining the frequency of specific changed basepairing and subsequent elongation of the annealed primer. However, both m4T and m6G prefer to form a type of G.T pairing which would lead to the transitions: G.C----A.T or T.A----C.G. The enzymes were the Klenow fragment of E. coli DNA polymerase I (Kf), engineered 3'----5' exonuclease-free Kf (exo-free Kf), polymerase alpha-primase complex from Drosophila melanogaster or calf thymus, and human immunodeficient virus-I reverse transcriptase (HIV-I RT). All enzymes led to approximately the same frequency of transitions. It is postulated that the mutation frequency at a given site is primarily a function of the structure of the sequence around the target site.
A hybrid transmission/genetics model for the development of resistance by Plasmodium falciparum to anti-malarial drugs is set forth. Field data on pyrimethamine resistance are used to calibrate and test the model. Simulated consequences of different drug dosage and population coverage strategies are presented to illustrate an ethical dilemma. A strategy of maximally effective treatment for all infected individuals in the short term can be deleterious--in terms of rapid development of drug resistance--for a community in the longer term.
The synthesis of a new modified etheno-2'-deoxyguanosine is reported. N2,3-Ethenodeoxy-guanosine (epsilon dGuo) is a product in double-stranded DNA treated with the carcinogen vinyl chloride in vivo or its metabolite chloroacetaldehyde in vitro. The lability of its glycosyl bond has, however, interfered with its isolation from DNA. The synthesis, starting with O6-benzyl-2'-deoxyguanosine 5'-phosphate, reacted with bromoacetaldehyde, could only be accomplished in slightly alkaline media, which prevented significant loss of the sugar. The 5'-phosphate also decreased the lability of the glycosyl bond. The resulting compound, when deprotected, was converted to N2,3-ethenodeoxyguanosine 5'-triphosphate, as well as the corresponding nucleoside. Fluorescence, UV, and 1H NMR data were consistent with the assigned structures and almost identical with those of the previously synthesized much more stable ribo analogues [Kuśmierek et al. (1987) J. Org. Chem. 52, 2374-2378]. A systematic study of the pH-dependent glycosyl bond cleavage gave a t1/2, 37 degrees C, pH 6, of approximately 3.5 h for the nucleoside and 7-10 h for the nucleotides. Comparison, under the same conditions, of stability of the glycosyl bond in poly(dG,epsilon dG-dC) showed an increased stability of 2 orders of magnitude, t1/2 = approximately 600 h. The rate of sugar loss was, in all cases, greatly decreased at higher pH's, over the range of pH 5-9. These stability data indicate that when slightly alkaline conditions can be used, studies on incorporation of epsilon dGuo into polymers for in vitro mutagenesis studies are possible.
A method is described for preparing 3',5'-bisphosphates of labile deoxynucleosides. Under strictly anhydrous conditions, pyrophosphoryl tetrakistriazole apparently forms a ring structure bridging the 3'- and 5'-hydroxyl groups of deoxynucleosides, since upon the addition of water the ring opens and the 3',5'-bisphosphate is formed. Due to the presence of triethylamine no acid is generated at any time so that the entire procedure is in neutral solution. The bisphosphates of N2,3-ethenodeoxyguanosine, O2-ethyldeoxythymidine, and O4-methyldeoxythymidine, all of which are acid-labile, were prepared in good yield without degradation. Other modified bisphosphates prepared include O6-benzyldeoxyguanosine and 1,N6-ethenodeoxyadenosine, as well as those of unmodified deoxyguanosine and thymidine. Characterization was by 31P NMR and UV spectroscopy. Both 5'p(dT)p3' and 5'p(dG)p3' were substrates for RNA ligase, further proving the structure of the phosphorylated compounds.
1,N2-Etheno-2'-deoxyguanosine (1,N2-epsilon dGuo), not previously reported as a product of chloroacetaldehyde (CAA) reaction, has been synthesized and characterized. Reaction of deoxyguanosine with CAA in dimethylformamide in the presence of K2CO3 led to preparation of pure 1,N2-epsilon dGuo with 55% yield. pKa values are 2.2 and 9.2. The anionic form of the compound exhibits weak but defined fluorescence; the intensity is similar to that of N2,3-etheno-2'-deoxyguanosine (N2,3-epsilon dGuo) at neutrality. The stability of the glycosyl bond of 1,N2-epsilon dGuo (t1/2 = 2.3 h at 37 degrees C, pH 1) is 10-fold greater than of unmodified deoxyguanosine and at least one thousand-fold greater than of isomeric N2,3-epsilon dGuo. Reaction of CAA with model polynucleotides indicates that hydrogen bonding of guanine residues in the double-stranded structures is, as expected, an important factor in the formation of 1,N2-ethenoguanine. In contrast, the formation of isomeric N2,3-ethenoguanine is relatively independent of whether the DNA is single- or double-stranded. In salmon sperm DNA, reacted with CAA at neutrality, the formation of 1,N2-ethenoguanine could be demonstrated. However, we find the efficiency of formation of this adduct in double-stranded DNA to be lower than that of all other etheno derivatives.
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Five patients, four of them with severe or severe generalized myasthenia gravis, were treated by long term orally administrated prednisolone, with following results: one complete remission and two almost complete remissions (in three aged fernale patients), two substantial improvements (one in a male patient, one in a young adult female patient, both thymectomized). The least favourable result was observed in the male patient. Positive results of such treatment were similarly reported by several authors (with an average of 70% complete or almost complete remission, 20% substantial improvement, 7% moderate improvement). These results appear qualitatively superior to those obtained with ACTH, and may be long-lasting. Treatment with prednisolone may be applied to any form of myasthenia gravis, particularly those which do not react to anticholinesterasic agents in moderate dosages. At onset of treatment, patients should be under care of a reanimation unit. Dosage is initially high (60--100 mg daily, secondarily on alternate days), and should be reduced very slowly, once a definite improvement is achieved. The duration of this treatment depends upon the results obtained: it should not last under one year. Associated treatment with anticholinesterasic agents remains disputable, whereas associated thymectomy seems to provide best results.
Four patients with abnormal movements were treated with tiapridal. Very good results were obtained in a case of buccofacial dyskinesia associated with an extrapyramidal syndrome and dementia, and in another patient with middle-of-the-dose dyskinesias induced by L-dopa treatment for Parkinson's disease. No effect was observed, however in a case of beginning of the dose dyskinesias, and the extrapyramidal symptoms increased in severity. A dopadecarboxylase-inhibitor was associated with the L-dopa treatment in these three cases. In the fourth case, there was an increase in the spasms of the medial part of the face.
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