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S M Brown

Publications and source records attributed to S M Brown.

At least 55 records · Page 3Linked to original sources
PubMed1999

BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer.

The frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-based case-control-family study. Cases were women living in Melbourne or Sydney, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched for age, randomly selected from electoral rolls. Full manual sequencing of the coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a first- or second-degree relative. All detected variants were tested in a random sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast cancer, but did not carry the mutation. The proportion of Australian women with breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% CI 0.3-12.6%). Seven rare variants were also detected, but for none was there evidence of a strong effect on breast cancer susceptibility. Therefore, on a population basis, rare variants are likely to contribute little to breast cancer incidence.

Adult↗
PubMed1999

Snapping up SNPs.

Explore the source record for details and available documents.

Databases, Factual↗
PubMed1998

A technique for repair of iridodialysis in children.

Iridodialysis can occur with blunt or penetrating trauma or inadvertently during intraocular surgery. A small dialysis may not need treatment. A larger iridodialysis that causes polycoria and diplopia, or a grossly eccentric pupil, needs to be reapproximated. A number of surgical techniques for repair, using double-armed polypropylene suture, have been reported. The suture is either left external on the surface of the sclera with the knot buried, covered with a triangular scleral flap, or retrieved with special forceps and buried in a scleral "groove." These techniques have also been used to allow posterior fixation of intraocular lens implants in the absence of capsular support; a complication of this approach is suture erosion through sclera, conjunctiva, or both. The pediatric sclera is softer and more elastic than adult sclera, and surgical repairs must last for decades. Concern about late suture erosion, and a desire for minimal scleral manipulation, led me to develop a simple technique for iridodialysis repair using a scleral tunnel incision and double-armed 10-0 polypropylene suture.

Accidents↗
PubMed1998

Selective astrocytic transgene expression in vitro and in vivo from the GFAP promoter in a HSV RL1 null mutant vector--potential glioblastoma targeting.

Due to the lack of any effective therapy, novel approaches are currently being explored for the treatment of primary brain tumours. It has previously been demonstrated that variants of HSV-1 which are deleted in the RL1 gene and fail to produce the virulence factor ICP34.5 are potential candidates for tumour therapy. The RL1 variant 1716 replicates selectively within tumour cells and has the potential to deliver a therapeutic or tumour killing gene directly to the site of tumour growth. As many intracerebral tumours are glial and predominantly astrocytic in origin, we have evaluated the ability of 1716 to deliver a reporter gene specifically to astrocytes in vivo and in vitro using a 2.2 kb fragment which controls expression of the glial fibrillary acidic protein (GFAP), an astrocyte specific protein. Two 1716 variants, 1774 and 1775, were constructed which contain the GFAP-promoter element linked to the E. coli beta-galactosidase gene, inserted into the HSV-1 UL43 and US5 loci, respectively. In primary cultures, human primary tumour cell lines and established tumour cell lines in vitro, 1774 and 1775 gave high levels of expression of beta-galactosidase specifically in astrocytes. In vivo following intracerebral inoculation, both viruses demonstrated high levels of beta-galactosidase expression predominantly in astrocytes. These results indicate that the GFAP promoter element could be used for efficient and selective transgene delivery to human gliomas.

Animals↗
PubMed1998

High efficiency gene transfer to the central nervous system of rodents and primates using herpes virus vectors lacking functional ICP27 and ICP34.5.

The safe and efficient use of herpes simplex virus (HSV)-based vectors to deliver genes of potentially therapeutic benefit to the central nervous system will require their effective disablement by the inactivation of viral genes required for lytic growth. Here we report that viruses lacking functional genes for ICP27 (which is required for growth in all cell types) and ICP34.5 (which is required for growth in nondividing cell types) can deliver a marker gene to both the rodent and primate CNS with high efficiency whilst producing relatively minimal damage and having no effect on sodium currents in dorsal root ganglion neurons. Such viruses paradoxically deliver genes at much higher efficiency than the less disabled single mutant lacking ICP34.5 alone and also, as expected, produce less damage in vivo. Moreover, unlike the single mutant lacking ICP27 the double mutant viruses cannot revert to wild-type by acquistion of complimenting gene sequences during growth of virus stocks in vitro on dividing cells expressing ICP27 since artificial expression of ICP34.5 in these cells is not required. Such ICP27-; ICP34.5- viruses thus offer a platform for the development of vectors which are sufficiently safe for ultimate use in human gene therapy.

Animals↗
PubMed1998

Amyloid beta protein (A beta) deposition in dementia with Lewy bodies: predominance of A beta 42(43) and paucity of A beta 40 compared with sporadic Alzheimer's disease.

Amyloid beta protein (A-beta) deposition was investigated by quantitative immunohistochemistry in 13 cases of dementia with Lewy bodies (DLB) and compared with that in a series of age, gender and ApoE genotype matched cases of Alzheimer's disease (AD). In DLB the predominant A-beta peptide species deposited was A-beta-42(43) and this was similar in amount to that in AD. By contrast, A-beta(40) deposition was sparse in DLB and was lower than that in AD as was the total A-beta (A-beta-40 + A-beta-42(43) deposition. These data reinforce the viewpoint that in all disorders in which A-beta deposition is characteristics, the initial and predominant peptide species deposited is the longer form, A-beta-42(43). The density of Lewy bodies (LB) in DLB was unrelated to the extent of A-beta deposition, although those cases possessing one or more copies of the apolipoprotein E E4 allele had a higher LB density than those without an E4 allele. This suggests that the apolipoprotein E E4 isoform might facilitate, though not necessarily trigger, the formation of LB in susceptible individuals.

Aged↗
PubMed1998

Histopathological responses in the CNS following inoculation with a non-neurovirulent mutant (1716) of herpes simplex virus type 1 (HSV 1): relevance for gene and cancer therapy.

The RL1 gene of herpes simplex virus (HSV) encodes a polypeptide, ICP34.5 which is a specific virulence determinant. RL1 null mutants fail to replicate in both the PNS and CNS and are incapable of causing encephalitis. Additionally, RL1 null mutants have the capacity to replicate in actively dividing cells but fail to replicate in growth arrested or terminally differentiated cells. This selective replication phenotype has highlighted their use as both tumour killing agents and gene delivery vehicles particularly to the nervous system. Before their full potential can be assessed, however, it is necessary to determine the pathological and immune responses induced following direct intracerebral inoculation. Fourteen mice were injected in the left cerebral hemisphere with a high dose of the HSV-1, RL1 null mutant 1716. At regular time intervals up to 28 days, the mice were killed and the distribution of virus antigen, histopathological changes and immune responses in the CNS determined by H & E staining and immunohistochemistry. Control mice were injected with either wild type HSV-1 or buffer. At early times post-inoculation with 1716, there is a low grade meningoencephalitis with a limited inflammatory response. This is accompanied by virus antigen expression confined to the site of inoculation. By 28 days the CNS is histopathologically normal; virus antigen and immune responses are no longer detectable. These findings demonstrate that infection of the CNS by RL1 null mutants of HSV results in a finite, self-limiting response and highlights their potential for therapeutic use.

Animals↗
PubMed1998

Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal meninges of monkeys and pigs.

BACKGROUND: Acetylcholinesterase inhibition at the spinal level has been shown to produce a potent antinociceptive effect. However, the site of cholinesterase inhibition is unknown. To determine whether the spinal meninges participate in acetylcholine metabolism, the spinal meninges of monkeys and pigs were assayed for cholinesterase activity. METHODS: Spinal cord, dura mater, and arachnoid mater specimens from anesthetized pigs and monkeys were mechanically homogenized and cholinesterase activity was determined quantitatively using a commercially available colorimetric assay. The ability of neostigmine to inhibit cholinesterase activity in vitro was also measured. Finally, the reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify the cholinesterase metabolizing enzymes expressed by the spinal meninges. RESULTS: All spinal cord and meningeal specimens showed cholinesterase activity. In pigs, the dura mater showed less enzyme activity (36 +/- 17.7 U/mg protein) than the arachnoid mater (73.4 +/- 30.3 U/mg protein; P < 0.05), and the arachnoid mater showed less activity than the spinal cord (131.3 +/- 55.2 U/mg protein; P < 0.05). In monkeys, the dura mater again showed less cholinesterase activity (45.8 +/- 20.1 U/mg protein; P < 0.05), whereas cholinesterase activity in the arachnoid mater (90.3 +/- 45.9 U/mg protein) and spinal cord specimens (101.9 +/- 37.5 U/mg protein) were not significantly different. There were no significant species-related differences in cholinesterase activity. Neostigmine inhibited cholinesterase activity in a log-dose-dependent manner. The RT-PCR identified mRNA for acetylcholinesterase and butyrylcholinesterase in monkey pia-arachnoid mater. CONCLUSIONS: These data show that the spinal meninges express acetylcholinesterase and butyrylcholinesterase; for monkeys, although not pigs, the level of cholinesterase activity is comparable with that found in the spinal cord. This finding suggests that the meninges may be an important site for acetylcholine metabolism and may play a role in the analgesic effect produced by intrathecally administered cholinesterase inhibitors.

Acetylcholinesterase↗
PubMed1998

Overexpression of 20-oxidase confers a gibberellin-overproduction phenotype in Arabidopsis.

In the gibberellin (GA) biosynthesis pathway, 20-oxidase catalyzes the oxidation and elimination of carbon-20 to give rise to C19-GAs. All bioactive GAs are C19-GAs. We have overexpressed a cDNA encoding 20-oxidase isolated from Arabidopsis seedlings in transgenic Arabidopsis plants. These transgenic plants display a phenotype that may be attributed to the overproduction of GA. The phenotype includes a longer hypocotyl, lighter-green leaves, increased stem elongation, earlier flowering, and decreased seed dormancy. However, the fertility of the transgenic plants is not affected. Increased levels of endogenous GA1, GA9, and GA20 were detected in seedlings of the transgenic line examined. GA4, which is thought to be the predominantly active GA in Arabidopsis, was not present at increased levels in this line. These results suggest that the overexpression of this 20-oxidase increases the levels of some endogenous GAs in transgenic seedlings, which causes the GA-overproduction phenotype.

Arabidopsis↗
PubMed1997

An equine herpesvirus-1 gene 71 deletant is attenuated and elicits a protective immune response in mice.

The pathogenesis of pulmonary infection and the immune response following intranasal inoculation of mice with two equine herpesvirus type 1 (EHV-1) deletion mutants have been assessed. The mutants, ED71 and ED75, have deletions in genes 71 (EUS4) and 75 (10K), respectively. Deletions were replaced by the Escherichia coli lacZ gene driven by the simian virus 40 (SV40) early promoter. It has previously been shown that the protein products of genes 71 and 75 are dispensable in vitro but that removal of gene 71 results in a defect in virus maturation and capsid envelopment which impairs the ability of mutant virus to spread via release and readsorption. This study demonstrated that the 192-kDa gene 71 product is required for full expression of virulence in mice, whereas the putative 10-kDa product of gene 75 has minimal effect. Both mutants exhibited the same tissue and cytotropism as wild-type EHV-1 and induced both humoral and cell-mediated immune responses indistinguishable from those induced by the parental strain. Irrespective of the reduced pathogenicity of the gene 71 mutant, infected mice were protected against a challenge with wild-type EHV-1. These findings highlight the potential of ED71 as a vaccine candidate.

Animals↗