Biomedical subjects
Publications and source records attributed to S D Brown.
A new triazole derivative (voriconazole or UK-109,496) and fluconazole were tested against 249 isolates of Candida spp. representing six species. Voriconazole was 10 to 100 times more potent than fluconazole. Strains with decreased susceptibility to fluconazole were inhibited by relatively low concentrations of voriconazole.
A simple disk diffusion test was defined for quick determination of the susceptibility of Candida species to fluconazole. The standard macrotube dilution reference method, the fluconazole E test, and a 25-microgram fluconazole disk test were all performed with each of 250 Candida species selected to provide a broad range of fluconazole MICs. All three methods were in excellent agreement. On RPMI 1640-glucose agar, isolates with inhibition zone diameters of > or = 19 mm were all susceptible (MIC, < or = 8.0 micrograms/ml) by the E test and 94% were susceptible by the macrotube method. Strains with smaller zones were either resistant, intermediate (dose-dependent susceptibility), or susceptible by the reference methods. The disk test did not adequately separate fully resistant strains from those with dose-dependent susceptibility: additional quantitative tests are needed for the few strains that are not unequivocally susceptible by the disk method.
There is sufficient information in the clinical literature to support the prognostic utility of gastric tonometry. Gastric tonometry measures increases in mucosal PCO2, a very useful physiologic signal. This information helps clinicians judge the state of energy balance in a tissue that is exquisitely sensitive to alterations in perfusion and oxygenation. Furthermore, the information obtained with gastric tonometry comes at relatively low cost and with minimal risk to the patient. At present, gastric tonometry has the drawback of being a relatively cumbersome technique that is labor intensive and prone to errors. New technological advances should improve both the ease of use and the timeliness of the information, and minimize measurement errors.
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Genetic deafness is common, affecting about 1 in 2,000 births. Many of these show primary abnormalities of the sensory neuroepithelia of the inner ear, as do several hearing-impaired mouse mutants, suggesting that genes involved in sensory transduction could be affected. Here we report the identification of one such gene, the mouse shaker-1 (sh1) gene. Shaker-1 homozygotes show hyperactivity, head-tossing and circling due to vestibular dysfunction, together with typical neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti. The sh1 gene encodes an unconventional myosin molecule of the type VII family. Three mutations are described, two mis-sense mutations and a splice acceptor site mutation, all in the region encoding the myosin head. The myosin type VII molecule encoded by sh1 is the first molecule to be identified that is known, by virtue of its mutations, to be involved in auditory transduction.
The ky mouse mutant, kyphoscoliosis, exhibits a degenerative muscle disease resulting in chronic deformation of the spinal column. Using an interspecific backcross segregating the ky mutation, we have mapped the ky locus to a small region of mouse chromosome 9. ky is nonrecombinant with the microsatellites D9Mit24 and D9Mit169 and lies in a conserved linkage group that encompasses human chromosome 3. s-Laminin (LAMS) and the gene for dystrophin-associated glycoprotein 1 (DAG1), which map to human chromosome 3, are both recombinant with ky, ruling them out as candidates.
DNA methylation at the promoter region of X-linked genes is associated with the maintenance of X inactivation in mammals. One of the methylated DNA binding proteins, MECP2, that binds to methylated bases in DNA is encoded by a gene (Mecp2) located on the mouse X Chromosome (Chr). To determine whether this gene was expressed from the inactive X Chr, and X-autosome translocation (T(X;16)16H) system in which expression from the Mecp2 allele on the inactive X Chr could be assayed was used. Results from these experiments indicate that Mecp2 is subject to X inactivation in mouse.
In vitro susceptibility tests were performed with 350 selected strains of Streptococcus pneumoniae to evaluate disk diffusion tests with 30 micrograms and 1 microgram cefotaxime disks. Zones were compared to MICs of cefotaxime with and without its desacetyl metabolite. Cefotaxime was two to eight times more active than desacetyl cefotaxime, but the two compounds were additive when combined in vitro. For 30 micrograms disks, zone size breakpoints were < or = 27 mm, 28-30 mm and > or = 31 mm for resistant, intermediate and susceptible, respectively. For 1 microgram disks, those zone size criteria were reduced to < or = 13 mm, 14-16 mm and > or = 17 mm. The 30 micrograms disk that is currently available for testing other species can be used for testing pneumococci; however, the 1 microgram disk has some important advantages.
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Discrimination of three synthetic versions of a/ra-la/ speech continuum was studied in two species of birds. The stimuli used in these experiments were identical to those used in a previous study of speech perception by humans [Best et al., Percept. Psychophys. 45, 237-250 (1989)]. Budgerigars and zebra finches were trained using operant conditioning and tested on three different series of acoustic stimuli: three-formant synthetic speech, sinewave versions of those tokens, and isolated F3 tones from the sinewave speech. Both species showed enhanced discrimination performance near the /l/-/r/ boundary in the full-formant speech continuum, whereas for the F3 continuum, neither species showed a peak near this boundary. These results are similar to human discrimination of the same continua. Budgerigars also showed a peak in discrimination of the sinewave analog continuum paralleling that for full-formant syllables, similar to humans who are induced to perceive sinewave speech as speech. Zebra finches, by contrast, showed a relatively flat function mirroring their performance for F3 sinewaves, similar to humans who are induced to perceive sinewave speech as nonspeech. These data provide new evidence of species similarities and differences in the discrimination of speech and speechlike sounds. These data also strengthen and refine previous findings on the sensitivities of the vertebrate auditory system to the acoustic distinctions between speech sound categories.
The in vitro activities of four extended-spectrum cephalosporins and benzyl penicillin were evaluated against 698 clinical isolates of Streptococcus pneumoniae, including 130 (19%) penicillin-intermediate and 84 (12%) penicillin-resistant strains. Cefotaxime and ceftriaxone were essentially identical in their antipneumococcal activities: both were active against penicillin-susceptible strains and most penicillin-intermediate strains. Cefpirome was twice as potent as cefotaxime and ceftriaxone against penicillin-resistant strains. Ceftazidime was 8- to 16-fold less active than cefotaxime and ceftriaxone against S. pneumoniae in vitro, and thus, its spectrum included only penicillin-susceptible strains.
Since 1980, at North London Blood Transfusion Centre 61 (14%) of a total of 442 hepatitis B surface antigen (HBsAg) positive carriers have been hepatitis B e antigen (HBeAg) positive by radioimmunoassay at the time of detection, with 353 (80%) anti-HBe positive. We have undertaken long-term follow-up of infectivity markers in 285 of these 442 HBsAg carriers detected by routine screening. Donors undergoing acute HBV infection were excluded from the analysis. The donor follow-up times ranged from 1.2 to 13.5 years. Regular follow-up samples were obtained and examined for HBsAg, HBeAg, anti-HBe, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Thirty-five (12.3%) of the 285 carriers were HBeAg-positive when first detected. Eight of these 35 developed anti-HBe during follow-up. At no time did any carrier revert from anti-HBe to HBeAg. When these data were subjected to a Kaplan--Meier analysis an estimated lower quartile time to seroconversion of 3.83 years, and a median seroconversion time of 8.25 years were predicted. This corresponds to a mean rate of 6.5% per annum for the first 25% to seroconvert, and 5.7 for the next 25%.
The whirler mouse harbors an autosomal recessive mutation on mouse chromosome 4 that causes deafness and vestibular dysfunction in the adult that is manifested as head-bobbing and circling behavior. Although there is no obvious human homologue for this mutation as yet, whirler is a potential mouse model for human autosomal recessive deafness. Many genetic markers for this region of mouse chromosome 4 are now available, and we have used these to construct genetic linkage maps in both inter- and intraspecific backcrosses as the first step toward the cloning of the whirler gene. A total of 19 loci were analyzed in these crosses, giving the following gene orders: interspecific cross, centromere-(D4Mit5, D4Mit38)-D4Mit6-(Lv, Tzn, D4Mit44)-wi-Hxb-(D4Mit25, D4Nds9)-(D4Mit7, D4Ler2)-b-D4Mit45-(D4Wsm1, D4Mit27b)-(D4Rck65, D4Mit15), and intraspecific cross, centromere-(Mup-1, wi, Hxb)-b-D4Wsm1. This analysis has positioned the wi locus in the interval between the genes for delta-aminolevulinate dehydratase (Lv) and hexabrachion (Hxb). The human homologues of these genes, ALAD and HXB, both lie on human chromosome 9q32-q34. We therefore predict that a human homologue of the wi gene, involved in autosomal recessive deafness, lies in this region of conserved homology on 9q32-q34.
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