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Biomedical subjects

A C Williams

Publications and source records attributed to A C Williams.

At least 127 records · Page 7Linked to original sources
PubMed1996

Chromosomal localisation of genes coding for human and mouse liver cytosolic cysteine dioxygenase.

A panel of 22 hybrids was tested for the presence of the gene coding for human cysteine dioxygenase (CDO) by using human specific oligonucleotide primers in the polymerase chain reaction. Detection of human CDO completely correlated with the presence of human chromosome 5. A human total genome cosmid library was screened with a PCR product from the coding region of human CDO cDNA and the two positive clones identified were used in fluorescent in situ hybridisation (FISH) analysis on metaphase chromosome spreads. Fluorescent signals were seen on chromosome 5q22-23. Interspecific backcross mapping in the mouse indicated that Cdo, the mouse homologue of CDO, is situated in the central region of mouse chromosome 18 which shares a region of homology with human chromosome 5.

Animals↗
PubMed1996

Permeation characteristics of 8-methoxypsoralen through human skin; relevance to clinical treatment.

The permeation characteristics through human skin of 8-methoxypsoralen (8-MOP) and its physical attributes were investigated. The log octanol/water partition coefficient and saturated aqueous solubility of 8-MOP at 32 degrees C were 1-98 and 55.8 micrograms mL-1 respectively, 8-MOP showed Fickian diffusion, with its flux being linearly related to the concentration of drug in the donor solution. The permeability coefficient of 8-MOP through human skin from different concentrations of aqueous solutions and a 2.6 micrograms mL-1 bath lotion (as used in clinics) were statistically identical with mean values of 1.76 +/- 0.12 x 10(-2) and 1.70 +/- 0.32 x 10(-2) cm h-1 respectively (P > or = 0.05). An ethanol/water (1:1 w/v) receptor solution did not improve the clearance of 8-MOP from the dermis when compared with an aqueous vehicle. Complete removal of the stratum corneum by tape stripping from full-thickness membranes produced a threefold increase in the flux of 8-MOP thus suggesting that the main barrier to 8-MOP permeation resides in the stratum corneum although the aqueous epidermal and dermal tissue provide a significant resistance to transdermal drug permeation. The equilibrium uptake of 8-MOP into psoriatic plaques and the 8-MOP aqueous plaque partition coefficient were found to be more than twofold greater than for normal stratum corneum. The absorption of 8-MOP from the total applied topical dose (396 mg) was assessed as approximately 0.25% and only 2.5% of an oral dose, a significant reduction in the possible toxic hazard. The peak concentration of 8-MOP permeating through the skin was observed at about 35 min after limited exposure for 15 min. Our results suggest that following a 15 min bath in the drug solution, there may be a need for an interval of about 20 min before patients are irradiated to ensure the optimization of photosensitizer with UVA irradiation (PUVA) therapy. Alternatively, UV irradiation could be applied at a lower flux over a longer time.

Chemical Phenomena↗
PubMed1996

Complete structural characterisation of the human aryl hydrocarbon receptor gene.

Aims-To clone and characterise the complete structural gene for the human aryl hydrocarbon receptor (AhR). This gene, located on chromosome 7, encodes a cytosolic receptor protein which, upon activation by various xenobiotic ligands, translocates to the nucleus, where it acts as a specific transcription factor.Methods-Primers, based on the AhR cDNA sequence, were used in conjunction with recently developed long range PCR techniques to amplify contiguous sections of the cognate gene. The amplicons produced were then cloned and characterised. A cDNA probe was also used to screen a human P1 library.Results-Using the cDNA primers, DNA fragments which mapped the entire coding region of the gene were amplified and cloned. All but one of these fragments were amplified directly from human genomic DNA. The remaining fragment was amplified using DNA prepared from a P1 clone as the PCR template. This P1 clone, obtained by screening a human P1 library, also contained the entire Ah locus. Characterisation of amplified and cloned DNA fragments provided sufficient information for the construction of a complete structural map of the gene. This also included 150 base pairs of nucleotide sequence data at all intronic termini.Conclusions-These data indicate that the human AhR gene is about 50 kilobases long and contains 11 exons. The overall intron/exon structure of the human gene is homologous to that of the previously characterised mouse gene; however, it is probably some 20 kilobases larger. These results demonstrate the need for further characterisation and provide the data to facilitate this.

Journal Article↗
PubMed1996

Consultant orthodontic services for cleft patients in England and Wales.

A postal questionnaire survey of consultant orthodontists in England and Wales was undertaken as part of a national audit of the care of children born with cleft lip/and or cleft palate. A 100% response rate was achieved. The majority of respondents stated that they provide orthodontic treatment for cleft patients but only 78% of these attend multi-disciplinary cleft clinics. Consultant orthodontists provide treatment not only in the form of appliances for patients born with clefts but are also involved in the counselling of parents and coordination of regional data bases. Only 24% of hospital orthodontists are involved in the provision of presurgical appliances for cleft babies on a regular basis. The lack of rationalisation of orthodontic services and a low uptake of standardised record keeping protocols for cleft patients by consultant orthodontists gives cause for concern.

Child↗
PubMed1996

Minimum standards for the management of cleft lip and palate: efforts to close the audit loop. Royal College of Surgeons of England.

Intercentre audit in the late 1980s revealed poorer outcomes for facial growth for British patients with cleft lip and palate than equivalent patients in northern Europe. A subsequent survey of the surgical practices in England and Wales, under the auspices of the Surgical Audit and Epidemiology Unit, revealed the widespread involvement of low-volume operators in cleft care, a tendency for low-volume operators to have an incomplete network of associated professionals, and non-standardised record keeping protocols. Recommendations for minimum standards of care for children born with cleft lip and palate were produced by a multidisciplinary steering group. A further investigation is planned to determine their validity and to provide a baseline for future audit cycles.

Cleft Lip↗
PubMed1995

Sucrose reduces the efficiency of protein denaturation by a chaotropic agent.

Sugars and polyols are used to stabilize proteins. The degree of stabilization conferred on a model protein by sucrose was calculated in terms of the free energy of folding. Phosphoglycerate kinase (PGK) was denatured by guanidine hydrochloride (GuHCl) in different sucrose concentrations. The linear extrapolation method [1,2] was used to calculate the free energy of folding in the absence of denaturant. Although sucrose increased the concentration of GuHCl required to unfold the protein, the free energy of folding in water was unchanged. In order to probe the nature of the stabilizing effect of sucrose, an FT-Raman spectroscopic study of denaturant-polyol systems was undertaken. Investigations of interactions between GuHCl, urea or formamide and polyhydric compounds, revealed no evidence for hydrogen bonding or dipole-dipole associations. Polyhydric compounds caused minor changes in denaturant spectra although the converse was not observed. The structure of deuterated water changed on addition of denaturants. For non-ionic denaturants, addition of polyhydric solutes countered this change in water structure. Thus polyhydric compounds oppose the effect of denaturants on water structure. The observed increase in GuHCl concentration required to unfold PGK in the presence of sucrose may be attributed to this property of sucrose.

Formamides↗
PubMed1995

Mutant p53 is not fully dominant over endogenous wild type p53 in a colorectal adenoma cell line as demonstrated by induction of MDM2 protein and retention of a p53 dependent G1 arrest after gamma irradiation.

To determine whether a single mutational event in one p53 gene is sufficient to confer a significant growth advantage on a colonic epithelial cell, the 143(Ala) p53 mutation was previously expressed in the human colonic adenoma derived cell line AA/C1 (which is wild type for p53) and shown to have no effect on it's in vitro or in vivo growth characteristics. In this investigation, by expressing the 175(His), 248(Trp) or 273(His) mutations in the same AA/C1 cell line, we have shown that this failure to affect the growth of the cells was not mutant specific. We have also demonstrated, using induction of MDM2 protein and the ability of the cells to undergo a p53 dependent G1 arrest, that the 143(Ala), 175(His) or 248(Trp) transfected cells retain functional endogenous wild type p53 activity, and suggest that these p53 mutations would not have a fully dominant negative mode of action in vivo. In contrast, one of the two AA/C1 cell lines transfected with the 273(His) mutation did fail to cell cycle arrest after gamma irradiation, indicating that this mutation can act as a dominant negative. However even loss of wild type p53 function in this cell line was insufficient to directly effect the growth rate of the AA/C1 cells, suggesting that acquisition of the 273(His) mutation may contribute to malignant progression through genomic instability (by inhibiting the G1 arrest) and that other mutations are required before outgrowth of the cell population containing the p53 mutation.

Adenoma↗
PubMed1995

The 'Iceman': molecular structure of 5200-year-old skin characterised by Raman spectroscopy and electron microscopy.

The molecular state of about 5200-year-old skin from the so-called 'Iceman' (Similaun man or Otzi) has been characterised using Fourier transform Raman spectroscopy, and has been compared with that of contemporary man. Contemporary skin was also freeze-dried (to mimic the conditions under which the ancient skin was preserved) and its molecular structure was compared with that of Iceman skin. The results showed that the proteinaceous moiety of the ancient skin had degraded considerably and, although olefinic bonds had probably oxidised, the lipoidal component was largely unaltered. Electron microscopical comparisons of Iceman and contemporary skin showed that the gross structure of Iceman skin had survived essentially intact for five millennia.

Animals↗
PubMed1995

An allelic association study of monoamine oxidase B in Parkinson's disease.

A single-stranded conformational polymorphism in the monoamine oxidase B gene was shown to be A or G, 36 bases upstream from the intron 13-exon 14 boundary. An allelic association study revealed no statistically significant associations between this single-base polymorphism and Parkinson's disease, unlike the results of a previous study.

Adult↗
PubMed1995

Toxicity of sulphur-containing compounds to neuronal cell lines.

Cysteine and its metabolites cysteine sulphinic acid (CSA) and taurine (TA) were shown to be toxic to human and rat neuronal cell lines. However, the mechanisms of action of CSA and TA appeared to be different. As MND/ALS patients have high plasma and CSF cysteine levels, they may have increased levels of neurotoxins in vivo, since cysteine was more toxic than CSA in the assay system used. Cysteic acid, homocysteic acid, BMAA and BOAA were also toxic to the cell lines used.

Animals↗
PubMed1995

Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action.

The effects of propylene glycol/water co-solvent systems and terpene penetration enhancers (1,8-cineole, menthone, (+)-limonene and nerolidol) on the absorption rate of the model hydrophilic permeant, 5-fluorouracil, were investigated using excised human skin. Similar fluxes for 5-fluorouracil were obtained from saturated enhancer-free co-solvent systems. Co-application of each terpene with the drug, both at saturation, in propylene glycol co-solvent systems increased drug flux significantly. Terpene activity depended on the propylene glycol content in the vehicles. Maximum fluxes were obtained from formulations containing the terpenes in 80% propylene glycol systems (highest concentration used), which when normalized to the flux from the pure vehicles yielded enhancement ratios of about 24, 21, 4 and 18, with 1,8-cineole, menthone, (+)-limonene and nerolidol, respectively. Combining the permeation studies with differential scanning calorimetry (DSC) and partitioning experiments revealed that increased lipid disruption is probably an important mechanism involved in the enhancing ability of formulations containing 1,8-cineole, menthone and nerolidol. This was clearly demonstrated by applying thermodynamic principles to interpret DSC results. This approach has indicated that these terpenes are probably able to disrupt stratum corneum lipids at physiological temperature as manifested by reductions in the entropy changes associated with the lipid-related transitions, particularly T2, the first major lipid transition. Additionally, increased drug partitioning contributed to the effect of the high propylene glycol content formulations. (+)-Limonene, as interpreted from DSC results, produced a freezing point-depression effect on stratum corneum lipids, suggesting little interaction with lipids at skin temperature; its small enhancement effect may involve phase separation of the oil in stratum corneum lipids. Terpenes in co-solvent systems such as propylene glycol/water at appropriate propylene glycol content might thus be useful vehicles for the delivery of drugs from topical formulations.

Antineoplastic Agents↗
PubMed1995

Attrition from a pain management programme.

Drop-out from treatment and attrition from follow-up present problems for generalizing results from pain management programmes. Predictors of drop-out and of attrition were sought from a range of psychological and physical variables. Of 239 patients admitted to an in-patient pain management programme, 24 (10 percent) dropped out, 12 (5 percent) did not attend one month follow-up and 65 (26 percent) did not attend six month follow-up. Comparisons were made of personal, medical, psychological, physical and pain measures, taken before admission, on discharge and at one month follow-up. Drop-out was best predicted by the combination of low self-efficacy and poor physical performance. Before treatment, future non-attenders at six month follow-up reported more distress due to pain and more frequent catastrophic thinking. Although they improved during treatment, at one month follow-up future non-attenders at six month follow-up scored significantly worse on almost all physical and psychological measures. Frequency of catastrophic thoughts at one month follow-up was the best predictor of attrition at six month follow-up.

Adult↗
PubMed1995

Hormonal regulation of circulating insulin-like growth factor-binding protein-1 phosphorylation status.

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) normally circulates as a single, highly phosphorylated species. However, IGFBP-1 phosphorylation status can be altered, such as in pregnancy where non- and lesser phosphorylated isoforms are also present. We have examined how hormonal regulators of circulating IGFBP-1 influence its phosphorylation status and, hence, its ability to modulate IGF activity. In response to insulin-induced hypoglycemia (0.2 U/kg, iv), an increase in the highly phosphorylated isoform was observed after 5 h [16 (range, 11.5-35.5) to 77 (range, 63-250) microgram/L; 4.8-fold increase; P = 0.009], but no non- or lesser phosphorylated variants could be detected. Glucagon (1 mg, sc), increased IGFBP-1 from 27 (range, 13-36.5) to 112 (range, 100.5-129) micrograms/L (4.1-fold increase; P = 0.009) after 90 min despite preceding insulin concentrations of more than 500 pmol/L, but again the IGFBP-1 remained in the highly phosphorylated form. Regulation of IGFBP-1 phosphorylation by sex steroids was studied by comparing women receiving a combined oral contraceptive with women on no medication. Although plasma IGFBP-1 levels were significantly elevated in the treatment group [120 (range, 97.5-237.5) vs. 52 (range, 38-70) micrograms/L; P < 0.004], there was no difference in the form of IGFBP-1 present. The acute effect of somatostatin (500 micrograms/h) on IGFBP-1 phosphorylation status was also studied. Somatostatin only increased the phosphoform characteristic of normal subjects; the appearance of non- or lesser phosphorylated variants was not induced. The effect of rhIGF-I (80 or 120 micrograms, sc) on plasma IGFBP-1 was studied in three subjects with Laron's syndrome. A transient increase in the highly phosphorylated isoform of IGFBP-1 was noted; there was no rise in the non- and lesser phosphorylated isoforms also found in the plasma of Laron's syndrome subjects. These data suggest that only the highly phosphorylated species of IGFBP-1 is under hormonal control; regulation of the non- and lesser phosphorylated variants remains to be determined.

Adult↗
PubMed1994

Human cysteine dioxygenase type I: primary structure derived from base sequencing of cDNA.

The base sequence of cDNA encoding the complete human liver cysteine dioxygenase type I (CDO-I; EC 1.13.11.20) message, and the derived amino-acid sequence are reported. CDO-I is encoded on a single mRNA species (approx. 1.5 kb). Human CDO-I clones were identified by screening a liver cDNA library, and inserts were isolated and sequenced. In addition, human liver total RNA was reverse-transcribed and CDO-I cDNA amplified by PCR using a modified poly-T primer and specific CDO-I primers to give a second source of sequencing template. The CDO-I message encodes a 200 amino-acid residue protein, the sequence of which has greater than 90% homology with the equivalent rat enzyme. The message was not expressed in a human hepatoma cell line (Hep G2).

Amino Acid Sequence↗