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Biomedical subjects

E Webb

Publications and source records attributed to E Webb.

At least 37 records · Page 2Linked to original sources
PubMed1983

Long-term experience with indapamide.

Indapamide, 2.5 mg administered once daily for periods up to 36 months, was found to be safe and effective for the long-term control of mild to moderate hypertension. The effects of hydrochlorothiazide, 50 mg, and indapamide, 2.5 mg, were studied in two randomized, double-blind, multicenter trials. Data from the two multicenter trials (20 study sites) were pooled for purposes of comparison. Significant reductions in systolic and diastolic blood pressure, with patients in both supine and standing positions, occurred in both groups within the first 8 weeks of treatment. This effect was maintained throughout the active treatment period. Success, as determined by the therapeutic success rate (percentage of patients with decreases of standing phase V diastolic blood pressure of at least 10 mm Hg or to below 90 mm Hg), occurred in 53% of the patients given hydrochlorothiazide and in 56% of the indapamide-treated patients. During the study period, the nature, frequency, and severity of adverse reactions were similar for both groups. There was no clinically significant difference between the treatment groups for the laboratory assessments. Patients who completed the multicenter trials were eligible for participation in an ongoing long-term extension study of the safety of indapamide. Data are available for periods up to 36 months and demonstrate neither augmentation of clinical or laboratory adverse effects nor any potentially harmful indicators that could be attributed to prolonged treatment.

Adult↗
PubMed1983

Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas.

Molecular cloning has recently established that the 15;12 chromosome translocations in murine plasmacytomas fuse DNA from chromosome 15 to the immunoglobulin heavy (H) chain locus, usually within the switch recombination region near the alpha constant region gene. We show here that the incoming DNA bears the cellular gene (c-myc) homologous to the oncogene (v-myc) of avian retrovirus MC29. In human Burkitt lymphomas bearing an 8;14 translocation, c-myc was also rearranged, apparently (in at least two cases) to an H chain switch recombination region (mu or alpha), and both products of a reciprocal chromosome exchange were detectable. Both the murine and human c-myc genes contain two exons homologous to v-myc, and additional 5' and 3' murine genomic segments (apparent exons) were defined by hybridization to c-myc mRNAs. In plasmacytomas, chromosome breakpoints fall near or within the 5' exon and apparently disrupt the normal c-myc transcriptional unit, because plasmacytoma c-myc mRNAs differ from the mRNA in lines without c-myc rearrangement. The translocated gene presumably has lost its normal 5' regulatory sequences and may well encode an altered myc polypeptide. We propose that altered expression of the c-myc gene, induced by translocation to an immunoglobulin locus, is a critical oncogenic event for these B lymphoid tumors. Two events may be required, because the plasmacytoma oncogene capable of transforming fibroblasts is not c-myc.

Animals↗
PubMed1983

Multi-centre clinical investigation of indapamide in the United States: a review.

Indapamide, a new indoline antihypertensive agent, has been the subject of a worldwide programme to develop this drug for general clinical use. The results are described of the multi-centre U.S. clinical programme demonstrating the effectiveness and tolerance of indapamide for the treatment of hypertension. All work was conducted under U.S. Federal Food and Drug Administration guidelines, and resulted recently in a New Drug Application. A total of 1891 subjects or patients participated in 27 separate studies conducted by 91 investigators. In controlled clinical trials comparing 2.5 mg indapamide once daily with 50 mg hydrochlorothiazide once daily for 40 weeks in patients with mild to moderate essential hypertension, indapamide produced a reduction of supine blood pressure of -9.5/-14.3 mmHg as compared with -7.6/-11.4 mmHg for hydrochlorothiazide. In combination with methyldopa, propranolol, clonidine, guanethidine and hydralazine, indapamide consistently produced a greater decrease in arterial pressure than did those agents given alone. Indapamide added to these step-care agents did not result in a meaningful increase in adverse reactions. Indapamide has been the subject of a long-term safety study in which over 100 hypertensive patients have been followed up for 2 years or longer. During this period of time, indapamide was well tolerated and remained effective. No biochemical, electrocardiographic or ophthalmological changes were associated with its use. Other studies with indapamide are discussed describing the systemic and renal haemodynamic effects, pharmacokinetic properties and special safety studies conducted with this agent. The use of indapamide in patients with hepatic or renal impairment is reviewed in detail.

Antihypertensive Agents↗
PubMed1982

Transcriptionally active DNA region that rearranges frequently in murine lymphoid tumors.

A DNA region not associated with conventional immunoglobulin gene rearrangement is rearranged in many lymphoid tumors. This region, designated here as lymphoid rearranging (LyR) DNA, was cloned from plasmacytoma J558 in which it had recombined 5' to a constant (C) region of the alpha heavy (H) chain gene, C alpha, within a switch (S) region, S alpha, involved in the switching of CH genes. Sequence determination established that LyR DNA had recombined within a S alpha recombination unit. LyR DNA does not originate from the H chain locus, and discordance between LyR DNA and CH copy number in certain lines suggests that LyR DNA probably derives from another chromosome. LyR DNA rearrangement is a characteristic of tumors of mature B cells; it was detected in 24 of 28 plasmacytomas and B-cell lymphomas, usually as LyR-S alpha, but not in 11 Abelson retrovirus-induced lymphomas of B-cell precursors nor detectably in normal B cells. In contrast, rearrangement was observed in only 3 of 18 T-cell lymphomas, and none of seven nonlymphoid lines. Most tumor lines (49 of 52), whether lymphoid or not, contained a low level of polyadenylylated LyR transcript(s), but several new RNA species with differences in their 5' regions appeared in B-cell lines in which LyR DNA was rearranged, suggesting that rearrangement may activate a new promoter or mode of splicing. The results suggest that the LyR-S alpha rearrangement represents a translocation to chromosome 12 that alters expression of LyR-encoded genes; hence, it may have participated in lymphoid tumor oncogenesis.

Animals↗
PubMed1981

Recombination events near the immunoglobulin Cmu gene join variable and constant region genes, switch heavy-chain expression, or inactivate the locus.

Immunoglobulin heavy-chain expression is initiated by recombination between a variable region (VH) gene and one of several joining region (JH) genes located near the mu constant region (Cmu) gene, and the active VH gene can subsequently switch to another CH gene. That the general mechanism for CH switching involves recombination between sites within the JH-Cmu intervening sequence and the 5' flanking region of another CH gene is supported here by Southern blot hybridization analysis of eight IgG- and IgA-secreting plasmacytomas. An alternative model requiring successive VH linkage to similar JH clusters near each CH gene is shown to be very unlikely since the mouse genome appears to contain only one complement of the JH locus and no JH gene was detectable within large cloned sequences flanking germline C gamma 3 and C gamma 1 genes. Thus, VH-JH joining and CH switching are mediated by separate regions of "the joining-switch" or J-S element. In each plasmacytoma examined, the J-S element had undergone recombination within both the JH locus and the switch region and was shown to be linked to the functional CH gene in an IgG3, and IgG1, and three IgA secretors. Both JH joining and CH switching occurred by deletion of DNA. Switch recombination occurred at more than one site within the J-S element in different lines, even for recombination with the same CH gene. Significantly, although heavy-chain expression is restricted to one allele ("allelic exclusion"), all rearranged in each plasmacytoma. Some rearrangements were aberrant, involving, for example, deletion of all JH genes from the allele. Hence, an error-prone recombination machinery may account for allelic exclusion in many plasmacytomas.

Animals↗
PubMed1980

Cloned embryonic DNA sequences flanking the mouse immunoglobulin C gamma 3 and C gamma 1 genes.

To investigate the DNA surrounding genes for immunoglobulin heavy chain constant (CH) regions, we have isolated two clones bearing a C gamma 3 gene and two bearing a C gamma 1 gene from a library of mouse embryo DNA fragments. The C gamma 3 clones span 8.6 kilobase pairs (kb) on the 5' side of the gene and 6.7 kb on its 3' side, while the C gamma 1 clones together span 13 kb of 5' flanking sequence and 2.5 kb of 3' flanking sequence. Restriction mapping of the C gamma 3 gene indicates that intervening sequences divide the gene into segments of domain size, as in other CH genes. Hybridization of clone fragments to restriction digests of mouse DNA indicates that both the C gamma 1 and C gamma 3 genes probably occur as single copies in the genome. Moreover, the entire cloned sequences on the 5' side of both genes appear to be unique in the genome, indicating that no large common sequences flank CH genes. Restriction data suggest that the C gamma 3 gene is 37-40 kb 5' to the C gamma 1 gene.

Animals↗
PubMed1976

General and specific effects of amino acid starvation on the formation of undermodified Escherichia coli phenylalanine tRNA.

The heterogeneity of undermodified phenylalanine tRNA produced in relaxed control E. coli during amino acid starvation was investigated. Examination of the RPC-5 elution profiles of tRNAPhe prepared from non-starved cells and cells starved of a variety of amino acids, including some known to be involved in the formation of modified bases revealed that: (1) only one species of fully modified tRNAPhe appears to occur in cells grown in enriched medium; (2) at least two chromatographically unique isoacceptor species are observed in addition to the normal tRNAPhe in starved cells; (3) the unique, undermodified species of tRNAPhe from leucine-starved cells, known to be deficient in dihydrouridine, pseudouridine, 2-thiomethyl-N6-(delta2-isopentenyl) adenosine and 3-(3-amino-3-carboxypropyl) uridine, co-elute with the unique species produced in cells starved of histidine or arginine or treated with puromycin or chloramphenicol; (4) additional unique species of tRNAPhe can be detected in methyl- and sulfur-deficient tRNA from methionine- and cysteine-starved cells; (5) analysis of phenoxyacetylated tRNA revealed that the chromatographically unique and normal species from starved cells contain subspecies deficient in 3-(3-amino-3-carboxypropyl) uridine; and (6) using phenoxyacetylation as a means of effecting the resolution of undermodified subspecies, a total of at least ten chromatographically unique subspecies of rRNAPhe were detected in an organism that appears to posses only one gene for tRNAPhe. Taken together, the results support the view that there are both general and specific effects of amino acid starvation on the post-transcriptional modification of tRNA.

Amino Acids↗
PubMed1976

Unique phenylalanine transfer ribonucleic acids in relaxed control Escherichia coli: genetic origin and some functional properties.

Inhibition of protein synthesis in relaxed control E. coli results in the formation of chromatographically unique isoacceptor species of phenylalanine tRNA. The genetic origin and some functional properties of the major unique species of tRNA (Phe) produced during leucine starvation were investigated. RNA:DNA hybridization analyses revealed that the normally occurring and major unique species of tRNA (Phe) are generated from DNA sequences which are identical or closely related and that there may be only one such sequence in the E. coli chromosome. Results from 32P pulse-chase experiments revealed that the unique tRNA (Phe) can be converted to a chromatographically normal form upon resumption of cell growth in fully supplemented medium. These findings, taken with earlier results which indicate that the unique species is not derived from preexisting, normally occurring species, indicate that the unique tRNA(Phe) is a modification-deficient form of the normal species. Comparative studies of the unique and normal phenylalanine tRNAs revealed that the unique species is aminoacylated at a much lower rate than the normal species and is only about 60% as efficient in a tRNA-dependent, poly(U)-directed protein synthesizing system.

Binding Sites↗
PubMed1975

Fractionation and characterization of surface antigens from group A Neisseria meningitidis.

Group A meningococcal surface components were first subjected to fractionation with a mixture of chloroform-methanol. Sodium dodecyl sulfate-acrylamide gel electrophoresis of the aqueous phase containing 30 to 40% of the original material revealed only two polypeptide components and a slowly migrating carbohydrate component. The soluble fraction of the interphase was found to contain most of the bacterial surface proteins and the chloroform-methanol phase essentially all of the lipid components. The components of the aqueous phase were further fractionated by use of the hydrophobic affinity column, 4-phenylbutylamino-Sepharose and gradient elution with NaCl to yield fractions I and II. Fraction II was further separated into a minor and a major component (IIb) with Sepharose G-200. Fraction I contained the group A polysaccharide in ionic linkages with a minor polypeptide component (6%). It elicited bactericidal antibodies in rabbits and protected mice against homologous challenge, whereas the polysaccharide alone was non-immunogenic in these animals. Fraction IIb was a polysaccharide-polypeptide complex with unknown linkages; it induced a low concentration of rabbit antibodies that were bactericidal to group A and C meningococci. Mice vaccinated with fraction IIb were most resistant to homologous challenge and the resistance was also extended to challenges with group B and C cells. Fractions I and IIb appeared to be useful alternatives to the currently employed group-specific polysaccharide vaccines for the protection against drug-resistant meningococci. A simplified procedure for the preparation of group-specific polysaccharide was presented.

Amino Acids↗