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Biomedical subjects

S D Brown

Publications and source records attributed to S D Brown.

At least 73 records · Page 4Linked to original sources
PubMed1999

Effect of hypocapnea on CBF and extracellular intermediates of secondary brain injury.

We examined the metabolic response of the brain underlying subdural hematomas or surrounding contusions to hyperventilation and looked for evidence of ischemia. Twelve consecutive patients with severe traumatic brain injury (TBI) (GCS < 8) who required surgery for evacuation of subdural hematoma or hemorrhagic contusion were studied. At surgery, a microdialysis catheter was placed into the cortex in a gyrus adjacent to the contusion or underlying the subdural hematoma. A thermal diffusion flow probe was placed on the cortex directly above the dialysis catheter. On days 1 and 3 post injury, two trials of hyperventilation were performed which dropped the patients' pCO2 10 mm Hg for 30 minutes. Monitoring of CBF and collection of dialysis fluid continued throughout each hyperventilation trial. Data was analyzed for a three hour window surrounding each hyperventilation. Brief periods of hyperventilation did not cause a significant elevation of the extracellular lactate/pyruvate ratio or glutamate level in areas of the brain likely to be the most vulnerable to secondary injury. In spite of hyperventilation leading to a significant decline in local CBF in 20% of the trials, there was no evidence of ischemia or excitatory amino acid release associated with hyperventilation.

Brain↗
PubMed1999

Genetic mapping of the whirler mutation.

The whirler (wi) mutation on mouse Chromosome (Chr) 4 results in an autosomal recessive neuroepithelial deafness and vestibular dysfunction exhibited as a characteristic shaker-waltzer behavior (deafness, circling, and head-bobbing). We have constructed a genetic linkage map across the wi region in both an interspecific [(wi/wi x CAST/Ei)F1 x wi/wi] backcross (n = 817) and an intraspecific [(wi/wi x CBA/Ca)F1 x wi/wi)] backcross (n = 335). In the interspecific backcross, wi was found to be non-recombinant with Orm1, 0.12 cM distal of D4Mit87 and Ambp, and 0.12 cM proximal of CD301. In the intraspecific backcross, wi was found to be non-recombinant with Orm1 and D4Mit244, 0.3 cM distal of Mup1, and 0.6 cM proximal of Tnc. We also report a family from the interspecific backcross that shows evidence of multiple recombinations across the region of mouse Chr 4 around the wi locus. These rearrangements appear specific to both the region and the family.

Animals↗
PubMed1999

Large numbers of mice established by in vitro fertilization with cryopreserved spermatozoa: implications and applications for genetic resource banks, mutagenesis screens, and mouse backcrosses.

Recent advances in the methodologies for cryopreservation of mouse spermatozoa have opened up a number of opportunities for mouse geneticists. We have investigated various applications for this relatively new technology and have explored the potential of sperm freezing coupled with IVF for archiving, stock building, and the rapid establishment of backcrosses. Firstly, we investigated the use of sperm freezing for the archiving of (C3H/HeH x BALB/c)F(1) progeny from a large-scale mutagenesis program. We have demonstrated that it is possible to establish efficient, comprehensive, and deep archives and that potentially thousands of offspring can be derived from the frozen spermatozoa of a single mutant male mouse. Secondly, we examined the efficacy of sperm freezing for a number of other genotypes. For at least some genotypes, frozen spermatozoa can be utilized to rapidly build stock far more quickly than by conventional methods. Finally, we demonstrated that it is feasible to use frozen spermatozoa from the mouse mutant archive for the rapid generation of mutant backcross progeny.

Animals↗
PubMed1999

Antibacterial activity of moxifloxacin (Bay 12-8039) against aerobic clinical isolates, and provisional criteria for disk susceptibility tests.

Moxifloxacin (Bay 12-8039), ciprofloxacin, and levofloxacin were compared in vitro against 1074 clinical isolates gathered from different medical centers throughout North America during the winter months of 1997. Moxifloxacin E tests and broth microdilution tests gave comparable results. Moxifloxacin was particularly potent against respiratory pathogens such as Haemophilus influenzae and Streptococcus pneumoniae. Ciprofloxacin was the most potent study drug against the family of Enterobacteriaceae and Pseudomonas spp. For tests of 5 microg moxifloxacin disks, zone size criteria of < or = 17 mm for resistant (MIC > or = 8 microg/ml) and > or = 21 mm for susceptible (MIC < or = 2 microg/ml) are provisionally proposed for use while clinical trials are under way.

Anti-Infective Agents↗
PubMed1999

In vitro activity of trovafloxacin against ciprofloxacin-susceptible and -resistant clinical bacterial isolates and assessment of the trovafloxacin disk test.

A total of 4241 consecutive clinical bacterial isolates from 10 North American medical centers were tested for susceptibility to trovafloxacin. Trovafloxacin was significantly more active than ciprofloxacin against Gram-positive bacteria, Acinetobacter spp., and Stenotrophomonas maltophilia, and resistance to trovafloxacin occurred in these groups only among isolates with high-level resistance (MIC > or = 16 micrograms/mL) to ciprofloxacin. With other species, the two drugs had comparable activity. Concerns about staphylococci and Pseudomonas aeruginosa with trovafloxacin MICs of 2.0 micrograms/mL (the upper end of the susceptible category) are discussed. Results of trovafloxacin disk diffusion test on more than 3200 nonfastidious isolates supported the FDA-approved zone size interpretive criteria when the MIC breakpoint of < or = 2.0 micrograms/mL is used to define the trovafloxacin-susceptible category.

Anti-Infective Agents↗
PubMed1999

A YAC-based physical map of the mouse genome.

A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research. Indeed, the construction of a mouse physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project. Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map provides a comprehensive framework for mouse genomic studies.

Animals↗
PubMed1999

The gene mutated in bare patches and striated mice encodes a novel 3beta-hydroxysteroid dehydrogenase.

X-linked dominant disorders that are exclusively lethal prenatally in hemizygous males have been described in human and mouse. None of the genes responsible has been isolated in either species. The bare patches (Bpa) and striated (Str) mouse mutations were originally identified in female offspring of X-irradiated males. Subsequently, additional independent alleles were described. We have previously mapped these X-linked dominant, male-lethal mutations to an overlapping region of 600 kb that is homologous to human Xq28 (ref. 4) and identified several candidate genes in this interval. Here we report mutations in one of these genes, Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein, in two independent Bpa and three independent Str alleles. Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis. Our results demonstrate that Bpa and Str are allelic mutations and identify the first mammalian locus associated with an X-linked dominant, male-lethal phenotype. They also expand the spectrum of phenotypes associated with abnormalities of cholesterol metabolism.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Fosfomycin tromethamine susceptibility of outpatient urine isolates of Escherichia coli and Enterococcus faecalis from ten North American medical centres by three methods.

One hundred percent of 1097 Escherichia coli and 97.5% of 157 Enterococcus faecalis isolates from outpatient urine specimens at ten North American medical centres were susceptible to fosfomycin tromethamine. The Etest MICs correlated well with those of agar dilution. Disc diffusion zone diameters correlated well with MICs and supported the previously proposed zone diameter breakpoints for fosfomycin.

Anti-Bacterial Agents↗
PubMed1999

In-vitro antimicrobial activity of a carbapenem, MK-0826 (L-749,345) and provisional interpretive criteria for disc tests.

The in-vitro activity of MK-0826, a new oral carbapenem, was compared with that of imipenem by broth microdilution susceptibility tests against 545 bacterial isolates. MK-0826 had significantly greater activity against Enterobacteriaceae and poorer activity against Pseudomonas aeruginosa and many gram-positive species. MK-0826 disc diffusion tests were also performed according to the NCCLS procedure and tentative interpretive criteria were determined for possible susceptible MIC breakpoints of < or = 4.0 and < or = 2.0 mg/L.

Bacteria, Aerobic↗
PubMed1999

In vitro activities of SCH27899 alone and in combination with 17 other antimicrobial agents.

SCH27899, an everninomicin antibiotic, was tested for its in vitro activity against 718 bacterial isolates representing 27 species. The Enterobacteriaceae and nonenteric gram-negative bacilli were resistant to > or = 8.0 microg/ml, but all others were inhibited by < or = 1.0 microg/ml. When tested in combination with 17 other antimicrobial agents against 110 strains, SCH27899 demonstrated no significant antagonism or synergy. Consequently, combination therapy is not contraindicated.

Aminoglycosides↗
PubMed1999

ENU mutagenesis and the search for deafness genes.

The availability of mouse mutant models for known human deafness loci is limited. Moreover, it is unlikely that the current mouse archives hold mutants for the full panoply of genes involved in auditory system development and transduction. A large-scale ENU mutagenesis is currently underway to increase significantly the number of mouse deafness mutants available, employing specific screens for both deafness and balance defects. In the MRC Harwell screen, 13 mice have been identified so far with deafness, a balance defect or both. Mutagenized mice from the programme are also being used to search for modifiers of a known deafness gene, myosin VIIA (mutated in the Shaker 1 mutant mouse). The progress and encouraging results of the programme indicate that the combination of ENU mutagenesis and effective phenotype screens will lead to a significant contribution to the understanding of the genes and mechanisms involved in hereditary deafness.

Animals↗
PubMed1998

A STS content physical and transcription map across the ky, kyphoscoliosis, nonrecombinant region.

The ky mouse mutant exhibits a degenerative muscle disease resulting in chronic deformation of the spinal column. Following a previous report describing the mapping of the ky locus to a small region of mouse chromosome 9 (Skynner et al., 1995, Genomics 25, 207-213), we have now undertaken a positional cloning approach to identify candidate genes for ky. A YAC/BAC contig encompassing the ky locus was constructed comprising 48 YAC clones and 48 newly generated STSs. The results from the combined physical and genetic analyses showed that only two overlapping BAC clones, which together do not exceed 260 kb, span the ky nonrecombinant region. A combination of gene hunting methods on the critical BACs has led to the identification of seven coding fragments, which have been tested for expression. The expression analysis and the position of the coding fragments on the contig suggest their grouping in at least four transcription units. One of these transcription units is expressed exclusively in skeletal muscle, making it a suitable candidate for this muscle defect in the ky mouse.

Animals↗
PubMed1998

Cloning of a novel member of the low-density lipoprotein receptor family.

A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus IDDM4 on chromosome 11q13. Based on its chromosomal position, this gene is a candidate for conferring susceptibility to diabetes. The gene, termed low-density lipoprotein receptor related protein 5 (LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family. These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain. The encoded protein has a unique organization of EGF and LDLR repeats; therefore, LRP5 likely represents a new category of the LDLR family. Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation.

Amino Acid Sequence↗
PubMed1998

Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family.

A novel member of the low density lipoprotein receptor (LDLR) gene family has been identified and characterized. This gene, termed LDL receptor-related protein 6 (LRP6), encodes a transmembrane protein which has 71% identity and is structurally similar to the protein encoded by LRP5, a proposed candidate gene for type 1 diabetes located on human chromosome 11q13. LRP6 maps to human chromosome 12p11-p13. Mouse Lrp6 encodes a protein that has 98% identity to human LRP6 and maps to chromosome 6. Unlike other members of the LDLR family, LRP6 and LRP5 display a unique pattern of four epidermal growth factor (EGF) and three LDLR repeats in the extracellular domain. The cytoplasmic domain of LRP6 is not similar to other members of the LDLR family, while comparison with LRP5 reveals proline-rich motifs that may mediate protein-protein interactions. Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family.

Amino Acid Sequence↗