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A Renwick

Publications and source records attributed to A Renwick.

At least 19 recordsLinked to original sources
PubMed2002

Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment.

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

Algorithms↗
PubMed2002

Economic, biological and policy constraints on the adoption of carbon farming in temperate regions.

In this paper the issues surrounding the potential role for agriculture in temperate climates in the mitigation of greenhouse gases are examined, with a particular focus on the constraints and limitations on the adoption of practices contributing to carbon sequestration. Other land uses have come under close scrutiny for their potential to act as carbon sinks and it is likely that soil sequestration may become a legitimate part of the 'Land-use, land-use change and forestry' mechanism. However, for this to occur, further developments in our understanding of the biological processes involved in soil-carbon sequestration are required.

Agriculture↗
PubMed2001

DNA dinucleotide evolution in humans: fitting theory to facts.

We examine length distributions of approximately 6000 human dinucleotide microsatellite loci, representing chromosomes 1-22, from the GDB database. Under the stepwise mutation model, results from theory and simulation are compared with the empirical data. In both constant and expanding population scenarios, a simple single-step model with parameters chosen to account for the observed variance of microsatellite lengths produces results inconsistent with the observed heterozygosity and the dispersion of length skewness. Complicating the model by allowing a variable mutation rate accounts for the homozygosity, and introducing a small probability of a large mutation step accounts for the dispersion in skewnesses. We discuss these results in light of the long-term evolution of microsatellites.

Chromosomes, Human↗
PubMed2001

Functional characterization of alpha1-adrenoceptor subtypes in human subcutaneous resistance arteries.

The functional characteristics of the alpha1-adrenoceptor subtypes in human resistance arteries are still not clear. We recently reported that the alpha1A-adrenoceptor predominantly mediates contraction to norepinephrine in human skeletal muscle resistance arteries. In this study we extended these investigations to human subcutaneous resistance arteries. Arterial segments were isolated from the inguinal subcutaneous fat and mounted on a small vessel wire myograph. Potencies of agonists and antagonists were examined. N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A-61603) was found to be 10- and 54-fold more potent than norepinephrine and phenylephrine, respectively. Brimonidine (UK 14304) evoked significantly smaller contractile responses than norepinephrine and phenylephrine, showing the presence of a small population of alpha2-adrenoceptors in these arteries, and this was confirmed by the studies with selective alpha1- and alpha2-adrenoceptor antagonists prazosin and (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3-methoxyl-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948). Prazosin, 5-methyl-urapidil, and 2-[2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB 4101) shifted the potency of norepinephrine concentration dependently giving pA2 values of 9.4, 8.9, and 10.1, respectively, showing the presence of the alpha1A-subtype in these arteries. Pretreatment with 1 and 10 microM chloroethylclonidine did not affect the potency of and maximum responses to norepinephrine, ruling out the presence of the alpha1B-subtype in these arteries. 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378, 10 and 100 nM) did not affect the potency of norepinephrine but a small shift was observed by 1 microM BMY 7378, giving a pK(B) value of 7.1, much less than that reported for the alpha1D-subtype. These results suggest the predominant involvement of alpha1A-adrenoceptor in the contractile responses to norepinephrine in these arteries. The physiological role of this subtype in the maintenance of peripheral arterial resistance is yet to be confirmed.

Adrenergic alpha-Agonists↗
PubMed2000

Evidence of a founder BRCA1 mutation in Scotland.

BRCA1 mutations have been identified in breast and ovarian cancer families from diverse ethnic backgrounds. We studied 17 different families with the BRCA1 2800delAA mutation; seven were ascertained in Scotland (Dundee, Edinburgh, Glasgow, St Andrews), five in Canada (Toronto, Victoria) and five in the United States (Chicago, Philadelphia, Seattle). Overall there was a clear preponderance of Scottish ancestry. Genotype analysis performed on key members from 17 families was consistent with a common haplotype, strongly suggesting a single ancestral origin. A possible link was established between two families by tracing their genealogies through the records of the Registrar General for Scotland. This is the first example of a BRCA1 mutation likely to be derived from a common founder in Scotland. Further studies will be necessary to estimate more accurately the population frequency of the BRCA1 2800delAA mutation among unselected cases of breast and ovarian cancer in Scotland and the UK.

Breast Neoplasms↗
PubMed2000

Chromosomal insertion of phenazine-1-carboxylic acid biosynthetic pathway enhances efficacy of damping-off disease control by Pseudomonas fluorescens.

A disarmed Tn5 vector (pUT::Ptac-phzABCDEFG) was used to introduce a single copy of the genes responsible for phenazine-1-carboxylic acid (PCA) biosynthesis into the chromosome of a plant-growth-promoting rhizobacterium Pseudomonas fluorescens. The PCA gene cluster was modified for expression under a constitutive Ptac promoter and lacked the phzIR regulators. PCA-producing variants significantly improved the ability of the wild-type P. fluorescens to reduce damping-off disease of pea seedlings caused by Pythium ultimum, even under conditions of heavy soil infestation. Under conditions of oxygen limitation that are typical of the rhizosphere, PCA production per cell in vitro was greater than that recorded in fast-growing, nutrient-rich cultures. Similarly, when the in vitro nutrient supply was limited, P fluorescens::phz variants that produced the most PCA effectively competed against P. ultimum by suppressing mycelial development. Soil-based bioassays confirmed that the level of PCA biosynthesis correlated directly with the efficacy of biological control and the persistence of inocula in soil microcosms. They also showed that soil pretreatment with bacteria provides a suitable method for plant protection by reducing infection, effectively decontaminating the soil. These data demonstrate that the insertion of a single chromosomal copy of the genes for a novel antifungal compound, PCA, enhances the ecological fitness of a natural isolate already adapted to the rhizosphere and capable of suppressing fungal disease.

DNA Transposable Elements↗
PubMed1999

Ecological basis for biocontrol of damping-off disease by pseudomonas fluorescens 54/96

Pseudomonas fluorescens 54/96, originally isolated from the rhizosphere of sugar beet, has been shown to be commercially effective in field trials for the suppression of a number of fungal diseases of seedlings. In vitro and microcosm-based assays revealed that both the timing and method of application of bacteria were important for effective control of Pythium ultimum, the causative agent of damping-off disease. Following transposon mutagenesis (Tn5lac), mutants deficient for the suppression of Pythium ultimum infections of peas were isolated. Three major classes of insertional mutants of Ps. fluorescens 54/96 were identified which either inhibited sporulation, reduced mycelial growth or affected the regulation of bacterial metabolic activity. Evaluation of the metabolic capability of pathogen and antagonist revealed evidence for direct competition, as both the fungus and bacterium had similar sole carbon source nutrient utilization profiles. Further comparisons of the activity of the transposon mutants indicated that although the mechanisms of disease control were multifactorial, the most significant factor was the prevention of rapid spore germination in the presence of pea seeds.

Journal Article↗
PubMed1998

Boron tolerable intake: re-evaluation of toxicokinetics for data-derived uncertainty factors.

Boron, which is ubiquitous in the environment, causes developmental and reproductive effects in experimental animals. This observation has led to efforts to establish a Tolerable Intake value for boron. Although risk assessors agree on the use of fetal weight decreases observed in rats as an appropriate critical effect, consensus on the adequacy of toxicokinetic data as a basis for replacement of default uncertainty factors remains to be reached. A critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values. The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3- to 4-fold higher in rats than in humans and data on dynamic differences--in order to modify the default value--are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Additional studies to investigate the toxicokinetics of boron in rats would be useful to provide a stronger basis for replacement of default uncertainty factors for interspecies variation.

Animals↗
PubMed1998

A single amino-acid substitution in the iron-sulphur protein subunit of succinate dehydrogenase determines resistance to carboxin in Mycosphaerella graminicola.

A gene encoding the iron-sulphur protein (Ip) subunit of succinate dehydrogenase (Sdh, EC 1.3.99.1) from Mycosphaerella graminicola (Septoria tritici) has been cloned andsequenced. The deduced amino-acid sequence exhibited a high degree of homology to Ip subunits of Sdh from other organisms; three cysteine-rich clusters associated with the iron-sulphur centres involved in electron transport were particularly conserved. Expression studies using a synthetic green fluorescent protein (SGFP) expression vector demonstrated that the cloned DNA also contained a functional promoter region and confirmed that the deduced initiation codon could act as a translational start site. Mutants resistant to the fungicide carboxin (Cbx), a known inhibitor of Sdh, were found to contain a single amino-acid substitution in the third cysteine-rich domain of the Ip protein. These mutations resulted in the conversion of a highly conserved His residue, located in a region of the protein associated with the [3Fe-4 S] high-potential non-heme iron sulphur-redox (S3) centre, to either Tyr or Leu. AnIp gene containing the His -> Tyr mutation was constructed and shown to confer Cbx resistance following co-transformation into the Cbx-sensitive wild-type strain. This confirmed that the mutation identified by sequence analysis was responsible for determining Cbx resistance.

Alleles↗
PubMed1997

CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein.

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.

Adolescent↗
PubMed1993

Induction of cytochrome P-450-dependent enzyme activities in cultured rat liver slices.

Precision-cut liver slices were prepared from male Sprague-Dawley rats with a Krumdieck tissue slicer and cultured in RPMI 1640 medium for up to 72 hr. After 48 hr, cytochrome P-450 content in the slices declined to 36% of levels present in freshly cut rat liver slices. The addition of either beta-naphthoflavone (BNF) or Aroclor 1254 (ARO) partially prevented the loss of cytochrome P-450. Culture of liver slices with phenobarbitone (PB), BNF and ARO resulted in the induction of 7-ethoxycoumarin O-deethylase, 7-benzoxyresorufin O-debenzylase and 7-ethoxyresorufin O-deethylase activities. Generally, the induction of mixed-function oxidase enzymes was greater in 72- than in 48-hr cultured slices, and at the concentrations examined ARO produced a greater stimulation of enzyme activities than did either PB or BNF. These results demonstrate that rat liver slices may be maintained in culture for up to 72 hr, and that they respond in a similar manner to rat primary hepatocyte cultures to some inducers of xenobiotic metabolism. Precision-cut liver slices may therefore be a useful alternative in vitro system to hepatocyte cultures for screening compounds for effects on mixed-function oxidases and for assessing species differences in response.

Animals↗