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D J Davies

Publications and source records attributed to D J Davies.

At least 19 recordsLinked to original sources
PubMed2004

Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies.

Assessment of percutaneous absorption in vitro provides key information when predicting dermal absorption in vivo. Confirmation of skin membrane integrity is an essential component of the in vitro method, as described in test guideline OECD 428. Historically, assessment of the membrane's permeability to tritiated water (T2O) and the generation of a permeability coefficient (Kp) were used to confirm that the skin membrane was intact prior to application of the test penetrant. Measuring electrical resistance (ER) across the membrane is a simpler, quicker, safer and more cost effective method. To investigate the robustness of the ER integrity measure, the Kp values for T2O for a range of human and animal skin membranes were compared with corresponding ER data. Overall, for human, rat, pig, mouse, rabbit and guinea pig skin, the ER data gave a good inverse association with the corresponding Kp values; the higher the Kp the lower the ER values. In addition, the distribution across a large dataset for individual skin samples was similar for Kp and ER, allowing a cut-off value for ER to be established for each skin type. Based on CTL's (Syngenta Central Toxicology Laboratory) standard static diffusion cells and databridge, we propose that intact skin should have an ER equal to or above (in kOmega): human (10), mouse (5) guinea pig (5), pig (4) rat (3), and rabbit (0.8). We conclude that measurement of ER across in vitro skin membranes provides a robust measurement of skin barrier integrity and is an appropriate alternative to Kp for T2O in order to identify intact membranes that have acceptable permeability characteristics for in vitro percutaneous absorption studies.

Administration, Topical↗
PubMed2004

Canadian Total Diet Study in 1998: pesticide levels in foods from Whitehorse, Yukon, Canada, and corresponding dietary intake estimates.

The Canadian Total Diet Study is a national survey to determine the level of chemical contaminants in the Canadian food supply. Food samples were collected from Whitehorse, Yukon, supermarkets as part of the study in 1998. Whitehorse was chosen as a sampling centre, despite its small population (n = 19,000), to determine if residue levels were different in foods available in northern communities relative to levels observed in previous studies in the more populated south. Foods were prepared as for consumption before pesticide residue analysis. Residue levels observed in most foods were similar to levels observed in samples from previous surveys from southern Canadian cities. Malathion and DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), a transformation product of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl(ethane), were the two most frequently detected compounds (26.4 and 25.8%, respectively). The majority of pesticides, however, had a detection frequency of < 5%. In general, pesticides in food composites were well below maximum residue limits established in the Canadian Food and Drug Regulations. Chlorpropham and captan had the highest dietary intakes (2.16 and 1.94 micrograms (kg body weight-day)-1, respectively), based on the results from Whitehorse. No dietary intakes above the acceptable daily intakes, however, were observed for any of the 39 pesticides investigated in any age-sex category, where an acceptable daily intake has been proposed.

Adolescent↗
PubMed2000

Effect of melatonin agonists and antagonists on horizontal cell spinule formation and dopamine release in a fish retina.

The crucian carp retina was used to study the effects of the melatonin antagonist p697 (N-pentanoyl 2-benzyltryptamine) and the melatonin agonists [+]- and [-]-AMMTC (N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazol e) on horizontal cell spinule formation, an indicator of the state of retinal adaptation. DH97 was capable of both counteracting dark-adaptive spinule degradation and inducing light-adaptive spinule formation at the beginning of the dark phase. Addition of dopamine receptor blockers opposed the action of DH97 on spinules, with SCH 23930, a D1 dopamine receptor antagonist, being more effective than the D2 receptor antagonist sulpiride. DH97 induced a twofold increase in dopamine release. We conclude that melatonin acts as a dark signal within the teleost retina by inhibiting the dopaminergic system. In accordance with this, both enantiomers of AMMTC prevented light-induced spinule formation, and reduced dopamine release to below dark-adaptive baseline levels. We suggest that the suppression of spinule formation by AMMTC may be due to either a direct inhibitory interaction between the melatonin agonist and horizontal cell dopamine D1 receptors, or an inhibitory effect on the activity of the dopamine-releasing interplexiform cells.

Adaptation, Ocular↗
PubMed1998

Mapping the melatonin receptor. 5. Melatonin agonists and antagonists derived from tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles and hexahydrocyclohept[b]indoles.

Tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles, and hexahydrocyclohept[b]indoles have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was compared in a radioligand binding assay using chicken brain membranes and agonist and antagonist potency measured in clonal Xenopus laevis melanophore cells. Comparison of the N-acyl-3-amino-6-methoxytetrahydrocarbazoles (2) with N-acyl-4-(aminomethyl)-6-methoxy-9-methyltetrahydrocarbazoles (9) showed that the latter have much higher binding affinities for the chicken brain receptor. Comparison of N-acyl-1-(aminomethyl)-7-methoxy-4-methyltetrahydrocyclopent[b]ind oles (10), 6-methoxytetrahydrocarbazoles (9), and N-acyl-10-(aminomethyl)-2-methoxy-5-methylhexahydrocyclohept[b]ind oles (11) showed that the tetrahydrocarbazoles had the highest binding affinity with the cyclohept[b]indoles and the cyclopent[b]indoles having rather lower affinities. All of these observations are in agreement with our postulated model of melatonin orientation at the binding pocket in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group, as is shown in the X-ray crystallographic structure of 9m and in the energy-minimized computed structures. Separation of the enantiomers of members from each of these three systems was accomplished by chiral HPLC. It was found that in all cases the (-)-enantiomer had a higher binding affinity than the (+)-enantiomer. An X-ray crystallographic analysis of the two enantiomers of 9a showed that the (+)-enantiomer had the (R) absolute stereochemistry. Since the sign of the Cotton curves, determined from circular dichroism studies, was the same for all (+)-enantiomers, it is assumed that the absolute stereochemistry at these centers is identical. In the Xenopus melanophore assay, the tetrahydrocarbazoles 2 (R = H) were mainly weak antagonists, while those with R = OMe were agonists. The biological behavior of the tetrahydrocarbazoles 9 (R = H) depended on R1, some being agonists and some antagonists, whereas those with R = OMe were generally agonists. Variation of the R and R1 groups in compounds of type 9 produced both agonists and antagonists. The tetrahydrocylopentaindoles 10 had similar biological properties to the corresponding analogues of 9, but the hexahydrocycloheptaindoles 11 showed a much greater propensity to be antagonists. In all cases the (S)-enantiomers were found to be more potent agonists than the (R)-enantiomers.

Animals↗
PubMed1998

Biological indicators for steam sterilization: characterization of a rapid biological indicator utilizing Bacillus stearothermophilus spore-associated alpha-glucosidase enzyme.

The alpha-glucosidase enzyme was isolated from vegetative cells and spores of Bacillus stearothermophilus, ATCC 7953. Spore-associated enzyme had a molecular weight of approximately 92,700, a temperature optimum of 60 degrees C, and a pH optimum of 7.0-7.5. The enzyme in crude aqueous spore extract was stable for 30 min up to a temperature of 65 degrees C, above which the enzyme was rapidly denatured. The optimal pH for stability of the enzyme was approximately 7.2. The alpha-glucosidase in crude vegetative cell extract had similar characteristics to the spore-associated enzyme but its molecular weight was 86,700. The vegetative cell and spore-associated enzymes were cross-reactive. The enzymes are postulated to derive from a single gene product, which undergoes modification to produce the spore-associated form. The location of alpha-glucosidase in the spore coats (outside the spore protoplast) is consistent with the location of most enzymes involved in activation, germination and outgrowth.

Animals↗
PubMed1998

Residues of polychlorinated biphenyls (PCB) in fatty foods of the Canadian diet.

Market basket samples representative of food from six Canadian cities were surveyed from 1992 to 1996. Fifty composites of fatty foods, prepared for consumption were analysed for 40 PCB congeners by gas chromatography-mass spectrometry. Fish and butter contained the highest total PCB concentrations, while milk and infant foods contained the lowest. The dairy and meat composites were major contributors to the total PCB intake of 5.7 ng/kg/day, and to the TEQ (2,3,7,8-tetrachloro-p-dibenzodioxin equivalent) intake of 0.11 pg/kg/day. The pattern of congeners was similar for the different food groups with the exception of fish, which contained less tri- and tetra-chlorinated biphenyls and more of the hexachlorinated congener No. 153.

Animals↗
PubMed1997

Studies on the vasoconstrictor action of melatonin and putative melatonin receptor ligands in the tail artery of juvenile Wistar rats.

1. In this study we compared the vasoconstrictor activity of melatonin in rat isolated tail artery using two different recording systems, the Halpern pressure myograph and the Halpern-Mulvany wire myograph, with the view to determining a reliable method for obtaining pharmacological data on vascular melatonin receptors. In addition, we characterized the melatonin receptor in this preparation, using analogues of melatonin, and examined the activity of various naphthalenic derivatives with biological activity in non-vascular models of melatonin receptors. 2. Using the Halpern pressure myograph, cumulative addition of melatonin (0.1 nM to 1 microM) produced direct vasoconstriction (19.3+/-6.4% reduction in lumen diameter, n=5) in five of 11 pressurized segments, with pEC50 of 9.14+/-0.17. Similarly, non-cumulative application of melatonin caused vasoconstriction (19.7+/-4.6% reduction in lumen diameter, n=7) in seven of 20 preparations examined with pEC50 of 8.74+/-0.26. The selective alpha2-adrenoceptor agonist, UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate), produced vasoconstriction in all 'melatonin-insensitive' preparations. 3. Melatonin (0.1 nM to 1 microM) failed to elicit isometric contractions of tail artery segments in the Halpern wire myograph, but produced concentration-dependent potentiation of electrically-evoked, isometric contractions (maximum effect of 150-200% enhancement) when applied either noncumulatively (seven of seven preparations) or cumulatively (four of seven preparations). The pEC50 value of melatonin (non-cumulative) was 8.50+/-0.10 (n=7) which was not different from that obtained in the pressure myograph. All further experiments were conducted using a non-cumulative protocol against electrically-evoked, isometric contractions. 4. Based on the pEC50 values for the melatonin analogues examined, the pharmacological profile for the enhancement of electrically-evoked contractions was 2-iodomelatonin > 6-chloromelatonin > or = (-)-AMMTC > or = S21634 > or = melatonin > or = S20098 > S20242 > or = S20304 > 6-hydroxymelatonin > S20932 > (+)-AMMTC > N-acetyl-5-HT. Our data suggests the vascular receptor belongs to the MEL1-like subtype. All the indole-based analogues of melatonin, 2-iodomelatonin, (-)-AMMTC, (+)-AMMTC, S20932, 6-chloromelatonin, 6-hydroxymelatonin and N-acetyl-5-HT, behaved as full agonists. All the naphthalenic derivatives examined, S21634, S20098, S20242 and S20304 behaved as partial agonists relative to melatonin. 5. The naphthalenic-based antagonists, S20928 and S20929, did not modify electrically-evoked, isometric contractions of the tail artery, but produced a parallel, rightward displacement of the melatonin concentration-response curve. Based upon the effect of 1 microM S20928 and S20929, the estimated pK(B) values for these antagonists were 7.18+/-0.25 (n=4) and 7.17+/-0.25 (n=5), respectively. 6. We demonstrated that enhancement of electrically-evoked, isometric contractions of the rat isolated tail artery (using the Halpern-Mulvany wire myograph) is a simple and reproducible model for assessing the activity of putative agonists, partial agonists and antagonists at vascular melatonin receptors. Pharmacological characterization of the receptor suggests the presence of a MEL1-like subtype.

Animals↗
PubMed1996

Biological indicators for low temperature steam and formaldehyde sterilization: investigation of the effect of change in temperature and formaldehyde concentration on spores of Bacillus stearothermophilus NCIMB 8224.

Five strains of Bacillus stearothermophilus have been studied to identify a spore strain to be used as a biological indicator organism for low temperature steam and formaldehyde sterilization. Three strains gave poor reproducibility of batch size and growth index and were discarded. The other two strains gave good reproducibility with a high growth index and gave rise to linear survivor curves when exposed to 5% aqueous formaldehyde. However, only NCIMB 8224 sporulates on a simpler medium and as it was the most resistant to formaldehyde, it was further studied. Tests were carried out in a modified miniclave and factors studied included temperature of the steam and formaldehyde concentration. All studies confirmed the suitability of this strain as a biological indicator organism.

Data Interpretation, Statistical↗
PubMed1995

Radioligand binding affinity and biological activity of the enantiomers of a chiral melatonin analogue.

Melatonin, a hormone secreted by the pineal gland, can act on the central circadian oscillator in the suprachiasmatic nucleus of the hypothalamus. It has been proposed that melatonin or its analogues may be useful in restoring disturbed circadian rhythms in jet-lag, shift-work and some blind subjects, and as sleep-promoting agents. In the present study, the (-)- and (+)-enantiomers of N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazole (AMMTC) were separated and tested. The affinity of the enantiomers at the specific 2-[125I]iodomelatonin binding site in chick brain membranes was compared in competition assays, and their biological activity in a specific melatonin receptor bioassay, aggregation of pigment granules in Xenopus laevis melanophores. The (-)-enantiomer of AMMTC was 130-fold and 230-fold more potent than the (+)-enantiomer in competition radioligand binding assays and melanophores, respectively. Both enantiomers are melatonin receptor agonists; (-)-AMMTC is slightly more potent than melatonin itself. As the tetrahydrocarbazole nucleus holds the C-3 amido side-chain of AMMTC in a restricted conformation, the analogues will be useful in modelling the melatonin receptor binding site.

Animals↗
PubMed1995

Welsh water should reinstate fluoridation on Anglesey.

In 1992, Welsh Water withdrew the successful water fluoridation scheme on Anglesey. Despite evidence of the benefits of water fluoridation and the rise in number of children with tooth decay since the scheme's withdrawal, Welsh Water is still not prepared to re-establish the scheme.

Child, Preschool↗
PubMed1995

Evidence of photoenzymatic repair due to the phrA gene in a phrB mutant of Escherichia coli K-12.

The role of the phrA gene in the genetic control of photoreactivation in Escherichia coli has been a matter of some controversy. It has been proposed that the gene has no significant physiological role in photoreactivation. However, we have previously sequenced a restriction fragment thought to contain the phrA gene and shown it to contain a putative gene. When this gene, termed the putative phrA gene, was transformed into a phrAphrB mutant, a photoreactivable response above that of the phrAphrB mutant was observed. It has been suggested that the photorepair seen in phrB mutants is due to Type III photoreactivation, which is independent of temperature and fluence rate effects. Here we have shown that the photorecovery associated with the phrA gene is dependent on both temperature and fluence rate. This suggests that the photorecovery is not due to Type III photoreactivation but to an enzymatic reaction caused by an unknown photoactive protein, the phrA gene product, which acts on lesions other than pyrimidine dimers, possibly pyrimidine (6-4) pyrimidone photoproducts. We therefore propose that the phrA gene be reaccepted and its role in photoreactivation in Escherichia coli acknowledged.

ATP-Binding Cassette Transporters↗
PubMed1995

Biological indicators for low temperature steam and formaldehyde sterilization: the effect of defined media on sporulation, growth index and formaldehyde resistance of spores of Bacillus stearothermophilus strains.

Preliminary screening was carried out on spores of 29 strains of Bacillus stearothermophilus to determine their potential as biological indicator organisms for low temperature steam and formaldehyde sterilization. Each strain was sporulated on four chemically defined media. Fourteen strains produced satisfactory sporulation on one or more of the media but there was considerable variation in the extent of sporulation. The growth index of the spores, which was dependent on both the strain of organism and the sporulation medium, ranged from 1% to 90%. The spores were appraised on the basis of their resistance to inactivation by 0.5% w/v formaldehyde in aqueous solution at 70 degrees C. The survivor curves obtained could be characterized into five types on the basis of the shape of the curve. Only five strains of Bacillus stearothermophilus produced spores with the characteristics of high resistance, linear semi-logarithmic survivor curve and high growth index that would be required of a potential biological indicator organism.

Culture Media↗
PubMed1995

Evaluation of the prevalence of drug and alcohol abuse in motor vehicle trauma in south western Sydney.

This study estimated prospectively the prevalence of high drug and alcohol levels in road trauma cases who met the criteria for activation of the Liverpool Hospital's trauma team. Urine analysis of road trauma victims between October 1992 and October 1993 was undertaken for drug and alcohol estimation. A total of 164 drivers were studied. A urine alcohol concentration (UAC) exceeding 0.08 g/dL was detected in 27 drivers (16.5%). Cannabinoids were detected in the urine of 25 drivers (15.2%), in 17 the concentrations exceeded 400 ng/mL. In one instance amphetamine, cocaine and heroin were detected in the same injured driver. Combined use of alcohol with some other drugs was detected in only four drivers. Alcohol and cannabinoid levels were prevalent in the urine of injured drivers in this study, particularly in young males who remain over-represented in the group of injured drivers. In the population surveyed other drugs were rarely detected. The role of cannabinoids in road trauma and the use of cannabinoids in young male drivers will however need to be monitored more extensively.

Accidents, Traffic↗
PubMed1994

Anti-neutrophil cytoplasmic antibodies (ANCA): their detection and significance: report from workshops.

Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes that are found mainly within the azurophil or primary granules of neutrophils. There are 3 types of ANCA that can be distinguished by the patterns they produce by indirect immunofluorescence when tested on normal ethanol-fixed neutrophils. Diffuse fine granular cytoplasmic fluorescence (cANCA) is typically found in Wegener's granulomatosis, in some cases of microscopic polyarteritis and Churg Strauss syndrome, and in some cases of crescentic and segmental necrotising glomerulonephritis, but it is rare in other conditions. The target antigen is usually proteinase 3. Perinuclear fluorescence (pANCA) is found in many cases of microscopic polyarteritis and in other cases of crescentic and segmental necrotising glomerulonephritis. These antibodies are often directed against myeloperoxidase but other targets include elastase, cathepsin G, lactoferrin, lysozyme and beta-glucuronidase. The third group designated "atypical" ANCA includes neutrophil nuclear fluorescence and some unusual cytoplasmic patterns, and while a few of the target antigens are shared with pANCA, the others have not been identified. Sera that produce a pANCA or atypical ANCA pattern on alcohol-fixed neutrophils result in cytoplasmic fluorescence when formalin acetone fixation is used. pANCA or atypical ANCA occur in about 2/3 of all individuals with ulcerative colitis or primary sclerosing cholangitis, and they are found in a third of patients with Crohn's disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Intractable leg ulceration caused by cutaneous cholesterol embolism.

OBJECTIVE: To present a case of chronic intractable leg ulceration caused by cholesterol crystal embolism. CLINICAL FEATURES: A 76-year-old Caucasian male with a history of ischaemic heart disease had repeated hospital admissions for diagnosis and treatment of recurrent leg ulceration of more than three years' duration. INTERVENTION AND OUTCOME: Definitive diagnosis was made after the third biopsy when the specimen obtained included subcutaneous arteries. Complete healing occurred within three weeks of excision and a skin graft, and subsequent treatment which included systemic steroids. CONCLUSION: Cholesterol crystal embolism is probably an underdiagnosed cause of intractable leg ulceration and can be identified by a biopsy specimen which includes vessels in subcutaneous fat. Systemic steroids may be helpful in its treatment.

Aged↗
PubMed1990

Lead intake and blood lead in two-year-old U.K. urban children.

A comprehensive study of a group of 2-year-old urban children (n = 97), designed to provide quantitative information simultaneously for lead intakes via all identified pathways, has been carried out in Birmingham (U.K.). Results showed that for children whose blood levels and exposure to environmental lead were within the normal range for the U.K., blood lead concentration was significantly related to a combination of house dust lead loading and an overall rate of touching objects, to water lead concentration and to the parents' smoking habits. On the basis of assumptions used by the Royal Commission on Environmental Pollution (RCEP), the estimated average total uptake of lead was 36 micrograms day-1; of this, 97% was from ingestion from dust, food and water and only 3% from inhalation.

Air Pollutants↗