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Biomedical subjects

D L Williams

Publications and source records attributed to D L Williams.

At least 163 records · Page 9Linked to original sources
PubMed1994

Characterization of rifampin-resistance in pathogenic mycobacteria.

The emergence of rifampin-resistant strains of pathogenic mycobacteria has threatened the usefulness of this drug in treating mycobacterial diseases. Critical to the treatment of individuals infected with resistant strains is the rapid identification of these strains directly from clinical specimens. It has been shown that resistance to rifampin in Mycobacterium tuberculosis and Mycobacterium leprae apparently involves mutations in the rpoB gene encoding the beta-subunit of the RNA polymerases of these species. DNA sequences were obtained from a 305-bp fragment of the rpoB gene from 110 rifampin-resistant and 10 rifampin-susceptible strains of M. tuberculosis from diverse geographical regions throughout the world. In 102 of 110 rifampin-resistant strains 16 mutations affecting 13 amino acids were observed. No mutations were observed in rifampin-susceptible strains. No association was found between particular mutations in the rpoB gene and drug susceptibility patterns of multidrug-resistant M. tuberculosis strains. Drug-resistant M. tuberculosis strains from the same outbreak and exhibiting the same IS6110 DNA fingerprint and drug susceptibility pattern contained the same mutation in the rpoB gene. However, mutations are not correlated with IS6110 profiling outside of epidemics. The evolution of rifampin resistance as a consequence of mutations in the rpoB gene was documented in a patient who developed rifampin resistance during the course of treatment. Rifampin-resistant strains of M. leprae, Mycobacterium avium, and Mycobacterium africanum contained mutations in the rpoB gene similar to that documented for M. tuberculosis. This information served as the basis for developing a rapid DNA diagnostic assay (PCR-heteroduplex formation) for the detection of rifampin susceptibility of M. tuberculosis.

Amino Acid Sequence↗
PubMed1994

Clinical trial of fusidic acid for lepromatous leprosy.

Fusidic acid was assessed for antileprosy activity in nine lepromatous leprosy patients. Patients received fusidic acid at either 500 mg/day for 12 weeks or 750 mg/day for 4 weeks followed by 500 mg/day for 8 weeks. All patients showed time-dependent clinical improvement and decreases in bacillary morphological index, radiorespirometric activity and PCR signal, and in serum phenolic glycolipid I. Fusidic acid appears to be a weakly bactericidal antileprosy agent which may have a role in the multidrug treatment of leprosy pending an evaluation of lepra-reaction-suppressive activity.

Adolescent↗
PubMed1994

Reactivation of apolipoprotein II gene transcription by cycloheximide reveals two steps in the deactivation of estrogen receptor-mediated transcription.

In this report, we describe apolipoprotein II (apoII) gene expression in cell lines derived by stable expression of the chicken estrogen receptor in LMH chicken hepatoma cells. In cell lines expressing high levels of receptor (LMH/2A), apoII gene expression is increased by estrogen 300-fold compared with levels in the receptor-deficient parent LMH line. LMH/2A cells show apoII mRNA induction and turnover kinetics similar to those in chicken liver. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin following estrogen withdrawal superinduces apoII mRNA without affecting apoII mRNA stability. Superinduction is due to an estrogen-independent reactivation of apoII gene transcription. The apoII gene can be reactivated by CHX for up to 24 h following hormone withdrawal, suggesting that the gene is in a repressed yet transcriptionally competent state. These results reveal two distinct events necessary for termination of estrogen receptor-mediated transcription. The first event, removal of hormone, is sufficient to stop transcription when translation is ongoing. The second event is revealed by the CHX-induced superinduction of apoII mRNA following hormone withdrawal. This superinduction suggests that deactivation of estrogen receptor-mediated transcription requires a labile protein. Furthermore, reactivation of apoII gene expression by CHX and estrogen is additive, suggesting that estrogen is unable to overcome repression completely. Thus, a labile protein may act to repress estrogen receptor-mediated transcription of the apoII gene.

Animals↗
PubMed1993

Characterization of cloned human endothelin receptors.

Two subtypes of human endothelin receptors, ETA and ETB, have been cloned and stably expressed in Chinese Hamster Ovary cells. These receptors have been characterized by [125I]-endothelin-1 binding and phosphatidyl inositol hydrolysis using the potent peptidyl ETA antagonists BQ-123 and BQ-153, as well as the potent ETB agonist, sarafotoxin S6c. In binding studies, Ki values for BQ-123 and BQ-153 are 17 nM and 13 nM for ETA compared to 11,100 nM and 7200 nM for ETB. Conversely, Ki values for sarafotoxin S6c are 2800 nM for ETA and 0.29 nM for ETB. Endothelin-1 stimulates phosphatidyl inositol hydrolysis in cells expressing either ETA or ETB with EC50 values of 0.2-0.3 nM, while sarafotoxin S6c stimulates phosphatidyl inositol hydrolysis only in ETB expressing cells with an EC50 value of 0.2 nM, consistent with the binding data. Comparison of binding data for the cloned and expressed human receptors with binding data for receptors obtained from human tissues indicates the cloned and expressed receptors are essentially indistinguishable from the naturally occurring receptors.

Animals↗
PubMed1993

A comparative approach to anterior segment dysgenesis.

The role of animal models in our developing understanding of anterior segment dysgenesis is outlined. Research in avian models shows the importance of the neural crest in the development of the anterior segment and the failure of terms such as anterior segment cleavage adequately to describe the embryology of this area. Study of the anatomical differences between the anterior segment of the primate and that of the sub-primate mammal explains the differences seen in the dysplastic changes occurring in the iridocorneal angle in man and those occurring in sub-primate mammals such as the rabbit or the dog. Such work gives an improved understanding of congenital lesions seen ophthalmologically in man as well as those encountered in veterinary ophthalmology.

Animals↗
PubMed1993

Ambient noise levels in audiometric test rooms used for clinical audiometry.

Recently, the American National Standards Institute (ANSI) has specified (ANSI S3.1-1991) maximum permissible ambient noise levels (MPANLs) allowed in an audiometric test room that would produce negligible masking of pure tones presented down to O-dB HL for two test conditions (ears covered, ears not covered) and three test frequency ranges (125-8000 Hz, 250-8000 Hz, 500-8000 Hz). In the present study, octave band ambient noise sound pressure levels were measured in 136 audiometric test rooms used for clinical audiometry and compared with the ANSI octave band MPANLs for each test condition and frequency range. For the ears covered condition, about 50% of the rooms were in compliance (passed) with the MPANLs for the 125-8000 Hz and 250-8000 Hz range and 82% for the 500-8000 Hz range. For the ears not covered condition, only about 14% of the rooms passed for the 125-8000 Hz and 250-8000 Hz range and 37% passed for the 500-8000 Hz range. The primary cause of the low pass rate for each test condition and frequency range was attributed to low frequency (125-500 Hz) ambient noise presumably from the ventilation system.

Audiometry↗
PubMed1993

An investigation into the effect of cimetidine pre-treatment on raft formation of an anti-reflux agent.

It is now becoming common practice to co-administer H2-receptor antagonists and anti-reflux agents in the treatment of reflux oesophagitis. The mechanism by which anti-reflux agents achieve flotation requires a small amount of gastric acid to be present in the stomach. This study investigated whether an anti-reflux agent would remain effective after the decrease in acid secretion produced by a typical clinical dosage regimen of cimetidine (400 mg q.d.s., 7 days). Gastric distribution and residence of a meal and an anti-reflux agent were assessed in 12 normal subjects using gamma scintigraphy. The area under the gastric and fundal emptying curves demonstrated that Liquid Gaviscon (sodium alginate compound) had a significantly greater gastric residence than the meal, both during the control period and after cimetidine pretreatment, and that the majority of the Gaviscon was located in the fundus. The distribution of Gaviscon into the fundus was not affected by cimetidine pretreatment. Cimetidine pre-treatment slightly, but not significantly, increased the time for half the meal and the Gaviscon to empty from the stomach. The results suggest that the mechanism of action of Liquid Gaviscon is not compromised by concurrent H2-antagonist therapy.

Alginates↗
PubMed1993

Homologs of Mycobacterium leprae 18-kilodalton and Mycobacterium tuberculosis 19-kilodalton antigens in other mycobacteria.

Most of the antigens of Mycobacterium leprae and M. tuberculosis that have been identified are members of stress protein families, which are highly conserved throughout many diverse species. Of the M. leprae and M. tuberculosis antigens identified by monoclonal antibodies, all except the 18-kDa M. leprae antigen and the 19-kDa M. tuberculosis antigen are strongly cross-reaction between these two species and are coded within very similar genes. Studies of T cell reactivity against mycobacterial antigens have indicated that M. tuberculosis bears epitopes that are cross-reactive with the M. leprae 18-kDa antigen, but attempts to identify an 18-kDa antigen-like protein or protein coding sequence in M. tuberculosis have been unsuccessful. We have used a combination of low-stringency DNA hybridization and polymerase chain reaction techniques to identify, isolate, and sequence genes from M. avium and M. intracellulare that are very similar to the 18-kDa antigen gene of M. leprae and others that are homologs of the 19-kDa antigen gene of M. tuberculosis. Unlike M. leprae, which contains a single 18-kDa antigen gene, M. avium and M. intracellulare each have two 18-kDa antigen coding sequences. Although the M. leprae, M. avium, and M. intracellulare 18-kDa antigen genes are all very similar to one another, as are the M. tuberculosis, M. avium, and M. intracellulare 19-kDa antigen genes, we have been unable to detect any 18-kDa antigen-like coding sequences in DNA from M. tuberculosis.

Amino Acid Sequence↗
PubMed1993

Easily unwound DNA sequences and hairpin structures in the Epstein-Barr virus origin of plasmid replication.

The Epstein-Barr virus (EBV) origin of plasmid replication (oriP) includes two known cis-acting components, the dyad symmetry region and the family of repeats. We used P1 nuclease, a single-strand-specific endonuclease, to probe EBV oriP for DNA sequences that are intrinsically easy to unwind on a negatively supercoiled plasmid. Selective nuclease hypersensitivity was detected in the family of repeats on an oriP-containing plasmid and in the dyad symmetry region on a plasmid that lacks the family of repeats, indicating that the DNA in both cis-acting components is intrinsically easy to unwind. The hierarchy of nuclease hypersensitivity indicates that the family of repeats is more easily unwound than the dyad symmetry region, consistent with the hierarchy of helical stability predicted by computer analysis of the DNA sequence. A specific subset of the family of repeats is nuclease hypersensitive, and the DNA structure deduced from nucleotide-level analysis of the P1 nuclease nicks is a cruciform near a single-stranded bubble. The dyad symmetry region unwinds to form a broad single-stranded bubble containing hairpins in the 65-bp dyad sequence. We propose that the intrinsic ease of unwinding the dyad symmetry region, the actual origin of DNA replication, is an important component in the mechanism of initiation.

Base Sequence↗
PubMed1993

Use of beta-lactam/beta-lactamase-inhibitor combinations as antimycobacterial agents.

Mycobacterium tuberculosis and Mycobacterium leprae develop resistance against the drugs used to treat tuberculosis and leprosy, respectively. Now multidrug-resistant tuberculosis is spreading in many countries, especially with the emergence of AIDS. Multidrug treatment is being promoted at present to eradicate leprosy. Since M. leprae may also become multidrug-resistant, new approaches have to be adopted for controlling mycobacterial diseases. Mycobacteria usually synthesize beta-lactamase and are insensitive to beta-lactam antibiotics. M. tuberculosis contains a constitutive beta-lactamase; de-repression of beta-lactamase has been reported in M. leprae. Three different beta-lactam/beta-lactamase-inhibitor combinations (ampicillin/sulbactam, amoxicillin/clavulanate and piperacillin/tazobactam) were used to suppress the growth of several strains of mycobacteria (including M. tuberculosis H37Rv) in vitro. Ampicillin/sulbactam is a potent bactericidal agent against M. leprae multiplying in mouse foot pads. In the present work, ampicillin/sulbactam showed higher activity than the other drug combinations. The beta-lactam/beta-lactamase inhibitors are likely to be effective as rational therapeutic agents against mycobacterial infections.

Amoxicillin↗
PubMed1993

Effects of background noise on earphone thresholds.

Real-ear attenuation at threshold (REAT) and monaural pure-tone thresholds were determined for normally hearing adults using a supra-aural, Audiocup, and insert earphone. The thresholds were obtained in quiet and in background noises approximating the maximum permissible ambient noise levels (MPANLs) allowed in an audiometric test room specified by ANSI S3.1-1991 and OSHA (1983). The supra-aural REAT was less than the Audiocup, which was less than the insert earphone. The mean threshold shifts were negligible regardless of earphone type in the ANSI noise and for the insert earphone in the OSHA noise. Thresholds can be obtained down to 0 dB HL in ANSI 1991 MPANLs using a supra-aural, Audiocup, or insert earphone and in OSHA MPANLs using an insert earphone. However, the OSHA MPANLs are too high and the REAT is too low for a supra-aural earphone and Audiocup for testing down to 0 dB HL.

Adolescent↗
PubMed1992

Development of a water-soluble, sulfated (1-->3)-beta-D-glucan biological response modifier derived from Saccharomyces cerevisiae.

This report describes a method for the solubilization of micro-particulate (1-->3)-beta-D-glucan. Insoluble glucan is dissolved in methyl sulfoxide and urea (8 M) and partially sulfated at 100 degrees. The resulting water-soluble product is called glucan sulfate. The conversion rate is 98%, and the preparation is endotoxin free as determined by the Limulus lysate procedure. Glucan sulfate is composed of 34.06% C, 6.15% H, 50.30% O, 5.69% S and 3.23% N, and has a repeating unit empirical formula of (C6H10O5)8.3 SO3NH4+.4 H2O, suggesting that, on the average, a sulfate group is substituted on every third glucose subunit along the polymer. Molecular weight averages, polydispersity, and intrinsic viscosity were determined by aqueous high-performance size-exclusion chromatography (HPSEC). Two polymer peaks were resolved. Peak 1 (Mw = 1.25 x 10(6) g/mol) represents < 1% of the total polymer mass. Peak 2 (Mw = 1.45 x 10(4) g/mol) comprises > 99% of polymers. 13C NMR spectroscopy confirmed the beta-(1-->3) interchain linkage. In solution, glucan sulfate polymers self-associate in a triple helix. Glucan sulfate stimulates murine bone marrow proliferation following intravenous administration. The ability to prepare a immunologically active, water-soluble (1-->3)-beta-D-glucan preparation will greatly enhance the clinical utility of this class of compounds.

Animals↗
PubMed1992

A pilot study of dried blood spot testing for HIV antibody in neonates.

An unlinked anonymous HIV antibody study of neonates, using surplus dried blood spots on Guthrie cards, was introduced as a means of estimating the prevalence of HIV infection in childbearing women. From March 1990 to February 1992, blood spots from 14,520 infants were tested for anti-HIV, using an HIV IgG antibody capture particle-adherence test; only one sample gave a confirmed positive reaction. This type of study involves no interference in routine care and can be operated without difficulty in a district general hospital setting where neonatal metabolic screening is performed.

AIDS Serodiagnosis↗