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Biomedical subjects

A C Williams

Publications and source records attributed to A C Williams.

At least 73 records · Page 4Linked to original sources
PubMed2001

Cleft lip and palate care in the United Kingdom--the Clinical Standards Advisory Group (CSAG) Study. Part 3: speech outcomes.

OBJECTIVE: To summarize speech outcomes in children born with unilateral cleft lip and palate (UCLP) throughout the United Kingdom. DESIGN: Prospective descriptive study on a cross-sectional sample of children. PATIENTS/PARTICIPANTS: Data were collected for 238 5-year-olds (born between April 1, 1989, and March 31, 1991) and 218 12-year-olds (born between April 1, 1982, and March 31, 1984) with complete UCLP. MAIN OUTCOMES: Ratings of intelligibility, nasality, "speech cleft type characteristics" and speech therapy intervention. CONCLUSIONS: Nineteen percent of 5-year-olds and 4% of 12-year-olds were judged to be impossible to understand or just intelligible to strangers. Thirty-four percent of 5-year-olds and 17% of 12-year-olds had at least one serious error of consonant production. Eighteen percent of 5-year-olds and 12-year-olds had consistent hypernasality of mild, moderate, or severe degree. Approximately two-thirds of both age groups had undergone speech therapy.

Child↗
PubMed2001

Cleft lip and palate care in the United Kingdom--the Clinical Standards Advisory Group (CSAG) Study. Part 4: outcome comparisons, training, and conclusions.

OBJECTIVE: A critical appraisal of cleft care in the United Kingdom. DESIGN: Retrospective comparative study. SETTING: All National Health Service cleft centers in the United Kingdom. PATIENTS/PARTICIPANTS: Children born with unilateral complete clefts of the lip and palate between April 1, 1982, and March 31, 1984 (12-year-olds), and April 1, 1989, and March 31, 1991 (5-year-olds). Newly appointed and senior cleft clinicians. MAIN OUTCOME MEASURES: Skeletal pattern, dental arch relationship, success of alveolar bone grafting, dental health, facial appearance, oral health status, patient/parent satisfaction. CONCLUSIONS: This paper highlights the poor outcomes for the fragmented cleft care in the United Kingdom, compared with European centers. There is an urgent need for a review of structure, organization, and training.

Alveoloplasty↗
PubMed2001

The delivery of surgical cleft care in the United Kingdom.

BACKGROUND AND PURPOSE: A national survey of cleft teams was undertaken as part of the Clinical Standards Advisory Group investigation of the current status of cleft care in the United Kingdom (UK). METHODS: Fifty-seven cleft teams were identified, of which 90% responded to the survey. MAIN FINDINGS: Nine cleft teams had been established since 1992. Only one region, Northern Ireland, had a centralised cleft service and, despite 82% of teams having databases, only four were able to produce corroborated evidence of receiving at least 30 annual new referrals during 1995. There was a wide variation in the facilities provided by individual cleft teams--only six teams were able to provide all of the key facilities recommended by the Royal College of Surgeons Steering Group on cleft lip and palate. Facilities such as antenatal and neonatal counselling, protocols for record keeping and long-term treatment were similar for high and low volume teams. High volume teams were more likely to have established links with a full range of specialities including psychology, clinical genetics and paediatrics than low volume teams. CONCLUSION: A national survey of cleft services has demonstrated a need for reorganisation. This is now in process and once established will require continual monitoring and assessment.

Cleft Lip↗
PubMed2000

Skin delivery of oestradiol from lipid vesicles: importance of liposome structure.

The aim of this study was to investigate the importance of liposome structure in oestradiol skin delivery as a tool for understanding the delivery mechanism from lipid vesicles. Liposomes of phosphatidylcholine (PC) (1), PC, sodium cholate; 86:14 w/w (II), PC, Span 80; 86.7:13.3 w/w (III) and PC, oleic acid: 84:16 w/w (IV) with 1 mg/ml radiolabelled drug were prepared. Saturated radiolabelled oestradiol solutions containing the components of I-IV were separately prepared in 90% w/w propylene glycol in water. In addition, saturated solutions containing cholate, Span, oleic acid and ethanol at the same concentrations used in vesicles were formulated. Oestradiol permeation through human epidermis was studied. Formulations I-IV increased oestradiol flux by 8.6, 17, 17 and 13-fold when used as vesicles compared with control and by 2.9. 4.0, 4.7 and 6.9-fold when used in solution with drug. Testing individual components in solution, relative fluxes were 2.9, 0.87, 1.1, 2.9 and 1.1 for PC, cholate. Span, oleic acid and 7% ethanol, respectively. Accordingly, it is important to prepare phospholipids as vesicles for efficient oestradiol skin delivery even after inclusion of oleic acid. Penetration enhancement is not the main mechanism for improved flux. Liposome components in solution have additive effect with a possible synergism in some cases.

Aged↗
PubMed2000

Oestradiol skin delivery from ultradeformable liposomes: refinement of surfactant concentration.

The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and to evaluate Span 80 and Tween 80 as edge activators compared with sodium cholate. Vesicles containing phosphatidylcholine (PC) mixed with edge activators and oestradiol were prepared. Entrapment efficiency and vesicle size were determined. Interactions between activators and vesicles were investigated using differential scanning calorimetry. Transepidermal permeation of oestradiol from vesicles was studied compared to saturated aqueous control in vitro. The maximum flux (J(max)) and its time (T(max)) were calculated from the flux curves and skin deposition was assessed. The compositions of refined formulations were predicted, liposomes prepared, and tested against control. Entrapment efficiency depended on PC concentration with some contribution from sodium cholate and Tween 80. Vesicle sizes ranged from 124 to 135 nm. Edge activators interacted with lipid bilayers and disrupted packing. The refined edge activator concentrations in PC vesicles were 14.0, 13.3 and 15.5% w/w for sodium cholate, Span 80 and Tween 80, respectively; they increased J(max) by 18, 16 and 15-fold and skin deposition by 8, 7 and 8-fold compared with control. Ultradeformable vesicles thus improved skin delivery of oestradiol compared to control and Span 80 and Tween 80 were equivalent to sodium cholate as edge-activators.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Human brain cytochrome P450 1B1: immunohistochemical localization in human temporal lobe and induction by dimethylbenz(a)anthracene in astrocytoma cell line (MOG-G-CCM).

CYP1B1, a new member of human cytochrome P450 family 1, is involved in the xenobiotic detoxification metabolism and possibly activation of numerous procarcinogens and promutagens. Localization of CYP1B1 in human temporal lobe and its induction in astrocytoma cell line (MOG-G-CCM) by 7,12-dimethylbenz(a)anthracene (DMBA) was investigated using antibodies against human CYP1B1. A single band of approximately 58 kDa size in both human temporal lobe and in MOG-G-CCM was detected by Western blot analysis. Treatment of MOG-G-CCM cells with DMBA resulted in approximately 2.8-fold induction of CYP1B1. CYP1B1 immunoreactivity was detected at the blood-brain interface areas of the temporal lobe as evidenced by co-localization with CD34 antigen. These results suggest that this enzyme may be important in brain xenobiotic metabolism acting as an enzymatic barrier.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Increased p53-dependent apoptosis by the insulin-like growth factor binding protein IGFBP-3 in human colonic adenoma-derived cells.

We investigated the expression of insulin-like growth factor binding protein 3 (IGFBP-3) in normal human colonic epithelium and whether IGFBP-3 is involved in the induction of apoptosis in colonic epithelial cells. A gradient of IGFBP-3 protein expression was observed within the normal colonic crypt, and increased IGFBP-3 expression was coincident with the region of increased differentiation and apoptosis. Treatment of human colonic tumor cell lines with IGFBP-3 alone was shown to have no effect on growth. However, an increase in p53-dependent apoptosis was observed in the presence of 100 ng/ml IGFBP-3 24 h after the induction of DNA damage by gamma-irradiation. These results suggest that IGFBP-3 enhances the p53-dependent apoptotic response of colorectal cells to DNA damage.

Adenocarcinoma↗
PubMed2000

Development of an in vitro model for cysteine dioxygenase expression in the brain.

The development of an in vitro model for cysteine dioxygenase (CDO) expression in the brain would provide a useful model for determining the mechanisms for the regulation of CDO expression that does not involve the use of animals. Here we demonstrate the screening and characterization of a cell line that expresses CDO, the primary metabolizing enzyme of cysteine and the regulatory point of sulfate production. A panel of four commercially available tumor-derived human brain cell lines, each representing one major class of brain cell, were screened using western blotting and activity assay for cysteine dioxygenase expression. One cell line, TE 671 (human medulloblastoma) was found to express both a protein of approximately 70 kDa and CDO activity. Nuclease protection assay (NPA) of mRNA isolated from TE 671 showed the expression of a CDO mRNA. Reverse transcription-polymerase chain reaction of this mRNA and sequencing of the cDNA obtained showed that this was indeed CDO. Treatment of TE 671 cells with cysteine resulted in the upregulation of CDO mRNA, whereas treatment with tumor necrosis factor alpha resulted in the downregulation of CDO mRNA, as evidenced using NPA. The characterization of an in vitro model for CDO expression provides a useful tool for the investigation of this important enzyme, which may have an etiological role in the pathogenesis of Parkinson's disease.

Animals↗
PubMed2000

The role of entacapone in the management of Parkinson's disease.

Catechol-O-methyltransferase (COMT) inhibition is an important advance in the treatment of Parkinson's disease. This consensus statement provides guidelines for the optimal use of the only currently available COMT inhibitor, entacapone (Comtess, Orion Pharma (UK) Ltd, Newbury, Berkshire).

Antiparkinson Agents↗
PubMed2000

Dentoalveolar relations in children born with a unilateral cleft lip and palate (UCLP) in Western Australia.

OBJECTIVE: Our objective was to evaluate complete unilateral cleft lip and palate repair outcome in the Cleft Unit in Perth, Western Australia, by assessment of dentoalveolar relationships. DESIGN: This is a retrospective study. SETTING: Our subjects were individuals under the care of the cleft team in Perth, Western Australia. PARTICIPANTS: All patients with unilateral cleft lip and palate and available 6-year casts who had been born since January 1, 1985, were identified from the cleft unit's database. The nature of the cleft was verified by examination of birth study models and photographs. A total of 54 such patients were identified. MAIN OUTCOME MEASURES: Main outcome measures were identified through dental arch relationship grading of study models using the 5 Year Old Study Model Index. RESULTS: Interexaminer and intraexaminer agreement kappa statistics revealed good to very good agreement using this index. The results indicate that the surgical outcome was graded as excellent, good, or fair for 77% of patients and poor or very poor for 23% of patients. CONCLUSIONS: The results of the Western Australia study compare favorably to the overall U.K. outcome (the Clinical Standards Advisory Group study) but unfavorably to the results of some European centers, such as Oslo.

Child↗
PubMed1999

Influence of surgeon's experience on speech outcome in cleft lip and palate.

Relation between the number of cases treated and outcome, particularly in low-incidence anomalies, are difficult to identify and rectify. We show clear advantages in speech outcomes for children born with a cleft lip and palate who are operated on by surgeons who do large numbers of these procedures.

Child↗
PubMed1999

A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism.

OBJECTIVE: To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS: A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS: We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS: This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

Aged↗
PubMed1999

Protein conformational stability in the hydrofluoroalkane propellants tetrafluoroethane and heptafluoropropane analysed by Fourier transform Raman spectroscopy.

Due to the inherent structural instability of proteins, development of chlorofluorocarbon (CFC) free metered dose inhalers (MDIs) containing these biomolecules is beset with numerous challenges. In assessing the conformation of proteins in any medium, both secondary and tertiary structures need to be elucidated. This study uses Fourier transform (FT-) Raman spectroscopy to probe protein conformational stability in hydrofluoroalkane (HFA) propellants. Assignments of molecular modes for lysozyme as a solid and in aqueous solution, and for the first time, HFAs tetrafluoroethane (HFA 134a) and heptafluoropropane (HFA 227) are given. The Raman spectra provided molecular structural information on the peptide backbone, disulfide bonds and C-C stretching vibrations of hen egg lysozyme, enabling the secondary conformation of protein in HFA propellants to be determined; structural integrity of this robust model protein was maintained in both propellants. These results demonstrate that FT-Raman may be a useful tool for the optimisation of protein MDI formulations.

Drug Stability↗
PubMed1999

An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis.

As tumours are known to acidify their microenvironment and fluctuations in lumenal pH have been reported in a number of colonic disease conditions, we investigated whether loss of p53 function, commonly associated with the adenoma to carcinoma transition in human colorectal epithelium, was implicated in the cellular response to changes in extracellular pH. Human colonic adenoma and carcinoma derived cell lines were incubated at an initial pH range of 5.5-8.0 and the attached cell yield and apoptotic cell yield determined after 4 days. Exposure of all cell lines to an acidic growth environment was associated with a G1 arrest, down regulation of the retinoblastoma protein (pRb) protein and switch to the hypophosphorylated form of the protein, and increased expression of the p21 protein. However, induction of apoptosis, associated with increased p53 protein expression but not with changes in Bcl-2 expression, was only detected in the adenoma derived BH/C1 and AA/C1 cell lines which express wild type p53 activity. Furthermore, this induction of apoptosis was inhibited in the transfected cell line AA/273p53/B, in which the wild type p53 function has been abrogated. These results suggest that acidification of the microenvironment would provide a selective growth advantage for cells that have lost wild type p53 function, leading to clonal expansion of aberrant cell populations.

Acids↗
PubMed1999

Solubility parameters as predictors of miscibility in solid dispersions.

This paper reports interactions and possible incompatibilities in solid dispersions of hydrophobic drugs with hydrophilic carriers, with solubility parameters employed as a means of interpreting results. Systems containing ibuprofen (IB) and xylitol (XYL) in varying proportions and systems of IB with other sugars and a sugar polymer were produced using solvent evaporation and fusion methods. Additionally, bridging agents were employed with IB/XYL systems to facilitate the production of a solid dispersion. Results show that IB formed no interactions with any of the sugar carriers but interacted with all the bridging agents studied. The bridging agents were immiscible with XYL in the liquid state. Results of other reported drug/carrier systems and those from the systems studied in this paper were interpreted using Hildebrand solubility parameters. A trend between differences in drug/carrier solubility parameters and immiscibility was identified with incompatibilities evidence when large solubility parameter differences exist between drug and carrier. It was concluded that Hildebrand parameters give an indication of possible incompatibilities between drugs and carriers in solid dispersions, but that the use of partial solubility parameters may provide a more accurate prediction of interactions in and between materials and could provide more accurate indications of potential incompatibilities.

Analgesics, Non-Narcotic↗
PubMed1999

Plasma membrane phospholipid integrity and orientation during hypoxic and toxic proximal tubular attack.

BACKGROUND: Acute cell injury can activate intracellular phospholipase A2 (PLA2) and can inhibit plasma membrane aminophospholipid translocase(s). The latter maintains inner/outer plasma membrane phospholipid (PL) asymmetry. The mechanistic importance of PLA2-mediated PL breakdown and possible PL redistribution ("flip flop") to lethal tubule injury has not been well defined. This study was performed to help clarify these issues. METHODS: Proximal tubule segments (PTS) from normal CD-1 mice were subjected to either 30 minutes of hypoxia, Ca2+ ionophore (50 microM A23187), or oxidant attack (50 microM Fe). Lethal cell injury [the percentage of lactate dehydrogenase (LDH) release], plasma membrane PL expression [two-dimensional thin layer chromatography (TLC)], and free fatty acid (FFA) levels were then assessed. "Flip flop" was gauged by preferential decrements in phosphatidylserine (PS) versus phosphatidylcholine (PC; PS/PC ratios) in response to extracellular (Naja) PLA2 exposure. RESULTS: Hypoxia induced approximately 60% LDH release, but no PL losses were observed. FFA increments suggested, at most 3% or less PL hydrolysis. Naja PLA2 reduced PLs in hypoxic tubules, but paradoxically, mild cytoprotection resulted. In contrast to hypoxia, Ca2+ ionophore and Fe each induced significant PL losses (6 to 15%) despite minimal FFA accumulation or cell death (26 to 27% LDH release). Arachidonic acid markedly inhibited PLA2 activity, potentially explaining an inverse correlation (r = -0.91) between tubule FFA accumulation and PL decrements. No evidence for plasma membrane "flip flop" was observed. In vivo ischemia reperfusion and oxidant injury (myohemoglobinuria) induced 0 and 24% cortical PL depletion, respectively, validating these in vitro data. CONCLUSIONS: (a) Plasma membrane PLs are well preserved during acute hypoxic/ischemic injury, possibly because FFA accumulation (caused by mitochondrial inhibition) creates a negative feedback loop, inhibiting intracellular PLA2. (b) Exogenous PLA2 induces PL losses during hypoxia, but decreased cell injury can result. Together these findings suggest that PL loss may not be essential to hypoxic cell death. (c) Oxidant/Ca2+ overload injury induces early PL losses, perhaps facilitated by ongoing mitochondrial FFA metabolism, and (d) membrane "flip flop" does not appear to be an immediate mediator of acute necrotic tubular cell death.

Animals↗