Biomedical subjects

A C Williams

Publications and source records attributed to A C Williams.

At least 19 recordsLinked to original sources

PubMed2006

Insulin-like growth factor binding protein 3 (IGFBP-3) potentiates TRAIL-induced apoptosis of human colorectal carcinoma cells through inhibition of NF-kappaB.

There is growing evidence that the insulin-like growth factor-binding protein 3 (IGFBP-3) can have IGF-independent effects on cell growth. However, despite the fact that IGFBP-3 has been reported to be both antiproliferative and proapoptotic, the molecular mechanisms underlying the action of IGFBP-3 have not been elucidated. We report that although addition of IGFBP-3 (either synthetic or secreted protein) had no effect on cell survival, IGFBP-3 (100 ng/ml) significantly enhanced TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death in colonic carcinoma-derived cell lines (20-30% depending on cell line), whereas it had no effect on the survival of the TRAIL-resistant adenoma-derived cells. Both addition of IGFBP-3 protein to cell cultures or enforced expression of IGFBP-3 in the HT29 carcinoma cell line inhibited nuclear factor kappa B (NF-kappaB) activation in response to the induction of apoptosis by TRAIL. We propose that IGFBP-3 is a non-toxic NF-kappaB inhibitor, which could be used as an adjuvant in the treatment of colon cancer.

Adenoma↗

PubMed2006

Are the Peer Assessment Rating Index and the Index of Treatment Complexity, Outcome, and Need suitable measures for orthognathic outcomes?

The aim of this study was to determine which of two occlusal indices were the most appropriate for use in the assessment of orthognathic outcome. The indices used were the Peer Assessment Rating (PAR) Index and the Index of Treatment Complexity, Outcome, and Need (ICON). These indices were validated against the subjective assessments of treatment outcome and treatment improvement obtained from a panel of experienced orthodontic consultants. For the subjective assessment, intraexaminer agreement for ranking treatment outcome, from patient study models (30 models), was good. Interexaminer agreement for ranking treatment outcome, in the same way, was good or moderate. Intraexaminer agreement for ranking treatment improvement (30 start and finish pairs of models) was very good or good. Interexaminer agreement for ranking treatment improvement ranged from good to fair. All the patient study models were scored using PAR and ICON. The level of correlation between PAR and ICON scores of treatment outcome and the subjective ranking of treatment outcome was significant (P < 0.001). The level of correlation between PAR and ICON scores of treatment improvement and the subjective ranking of treatment improvement was also significant (P < 0.001). It is concluded that both PAR and ICON are suitable indices for assessing the clinical outcome of combined orthodontic treatment and orthognathic surgery.

Humans↗

PubMed2006

An investigation into the practice of tongue piercing in the South West of England.

OBJECTIVE: To investigate the prevalence and range of complications following tongue piercing. METHODS: A survey of individuals with tongue piercings ('piercees') and tongue piercers was undertaken in the South West of England. One hundred and twenty-three piercees completed a self-administered questionnaire and 22 piercers took part in an interviewer-led questionnaire. RESULTS: The mean age of an individual having a tongue piercing was 19 years old. Almost all the subjects reported problems following piercing; early problems were mainly due to tissue trauma, whereas later, ingestion of jewellery and tooth fracture were common events. A minority (7%) of piercees required the advice of a healthcare professional following tongue piercing. The majority of piercers reported adequate cross-infection measures and enquired about their clients' health prior to piercing. However, only one piercer was aware of the risk of bacterial endocarditis following tongue piercing. Most of the piercers reported that they would advise their clients to attend an Accident and Emergency department if a serious complication ensued. CONCLUSION: Tongue piercing may be associated with significant short-term and long-term morbidity, including tooth damage. Although the majority of piercers interviewed reported adequate cross-infection controls, knowledge of the medical risks associated with tongue piercing varied widely.

Adolescent↗

PubMed2006

A qualitative study to develop a tool to examine patients' perceptions of NHS orthodontic treatment.

OBJECTIVE: To identify issues of importance to adolescent patients surrounding the delivery of orthodontic treatment under the National Health Service (NHS), which can form the basis of a tool to examine patients' perceptions of NHS orthodontic treatment. DESIGN: Study using qualitative research methods. SETTING: Patients were recruited from the orthodontic departments at Derriford Hospital and Bristol Dental Hospital, and from Specialist Orthodontic Practices in Plymouth and Solihull. SUBJECTS: A rolling sample of patients from a list of orthodontic patients under treatment at each site was selected. Twenty-six patients took part in five focus group meetings. Three patients took part in semi-structured telephone interviews. METHODS: Participants were invited to participate in either a focus group meeting or a telephone interview. The transcripts of these meetings were analysed by two researchers working independently. Issues of importance to patients regarding the delivery of orthodontic treatment under the NHS were identified. RESULTS: The issues identified included being treated with respect by the clinician and being included in discussions about treatment. Participants tended to rely on their peers for advice about what to expect from treatment. The patients also discussed the benefits to them of undergoing orthodontic treatment. These included an improved appearance and increased self-confidence. CONCLUSION: This qualitative research has identified issues that are important to adolescent orthodontic patients. These issues will be used to form the basis of a patient-centred measure for auditing patients' perceptions of orthodontic treatment under the NHS.

Adolescent↗

PubMed2006

Permeation of bioactive constituents from Arnica montana preparations through human skin in-vitro.

This study investigated and characterised transdermal permeation of bioactive agents from a topically applied Arnica montana tincture. Permeation experiments conducted over 48 h used polydimethylsiloxane (silastic) and human epidermal membranes mounted in Franz-type diffusion cells with a methanol-water (50:50 v/v) receptor fluid. A commercially available tincture of A. montana L. derived from dried Spanish flower heads was a donor solution. Further donor solutions prepared from this stock tincture concentrated the tincture constituents 1, 2 and 10 fold and its sesquiterpene lactones 10 fold. Permeants were assayed using a high-performance liquid chromatography method. Five components permeated through silastic membranes providing peaks with relative retention factors to an internal standard (santonin) of 0.28, 1.18, 1.45, 1.98 and 2.76, respectively. No permeant was detected within 12 h of applying the Arnica tincture onto human epidermal membranes. However, after 12 h, the first two of these components were detected. These were shown by Zimmermann reagent reaction to be sesquiterpene lactones and liquid chromatography/diode array detection/mass spectrometry indicated that these two permeants were 11,13-dihydrohelenalin (DH) analogues (methacrylate and tiglate esters). The same two components were also detected within 3 h of topical application of the 10-fold concentrated tincture and the concentrated sesquiterpene lactone extract.

Administration, Topical↗

PubMed2005

The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2.

BACKGROUND AND AIMS: Cyclooxygenase 2 (COX-2) is upregulated in most colorectal cancers and is responsible for metabolism of the endogenous cannabinoid, anandamide, into prostaglandin-ethanolamides (PG-EAs). The aims of this study were to determine whether anandamide and PG-EAs induce cell death in colorectal carcinoma (CRC) cells, and whether high levels of COX-2 in CRC cells could be utilised for their specific targeting for cell death by anandamide. METHODS: We determined the effect of anandamide on human CRC cell growth by measuring cell growth and cell death, whether this was dependent on COX-2 protein expression or enzyme activity, and the potential involvement of PG-EAs in induction of cell death. RESULTS: Anandamide inhibited the growth of CRC cell lines HT29 and HCA7/C29 (moderate and high COX-2 expressors, respectively) but had little effect on the very low COX-2 expressing CRC cell line, SW480. Induction of cell death in HT29 and HCA7/C29 cell lines was partially rescued by the COX-2 selective inhibitor NS398. Cell death induced by anandamide was neither apoptosis nor necrosis. Furthermore, inhibition of fatty acid amide hydrolase potentiated the non-apoptotic cell death, indicating that anandamide induced cell death was mediated via metabolism of anandamide by COX-2, rather than its degradation into arachidonic acid and ethanolamine. Interestingly, both PGE2-EA and PGD2-EA induced classical apoptosis. CONCLUSIONS: These findings suggest anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the eradication of tumour cells that have become resistant to apoptosis.

Amidohydrolases↗

PubMed2005

Drug interaction and location in liposomes: correlation with polar surface areas.

An important step in liposome characterization is to determine the location of a drug within the liposome. This work thus investigated the interaction of dipalmitoylphosphatidylcholine liposomes with drugs of varied water solubility, polar surface area (PSA) and partition coefficient using high sensitivity differential scanning calorimetry. Lipophilic estradiol (ES) interacted strongest with the acyl chains of the lipid membrane, followed by the somewhat polar 5-fluorouracil (5-FU). Strongly hydrophilic mannitol (MAN) showed no evidence of interaction but water soluble polymers inulin (IN) and an antisense oligonucleotide (OLG), which have very high PSAs, interacted with the lipid head groups. Accordingly, the drugs could be classified as: hydrophilic ones situated in the aqueous core and which may interact with the head groups; those located at the water-bilayer interface with some degree of penetration into the lipid bilayer; those lipophilic drugs constrained within the bilayer.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells.

BAG-1 is an anti-apoptotic protein that is frequently deregulated in a variety of malignancies including colorectal cancer. There are three isoforms: BAG-1L is located in the nucleus, BAG-1M and BAG-1S are located both in the nucleus and the cytoplasm. In colon cancer, the expression of nuclear BAG-1 is associated with poorer prognosis and is potentially a useful predictive factor for distant metastasis. However, the function of BAG-1 in colonic epithelial cells has not been studied. Having previously shown a predominant nuclear localisation of BAG-1 in adenoma-derived cell lines, we wanted to determine the function of nuclear BAG-1 in these non-tumourigenic cells, to identify whether nuclear BAG-1 was implicated in tumour progression in the colon. In the current report we established that nuclear BAG-1 inhibits apoptosis in a colorectal adenoma-derived cell line. We demonstrate that apoptosis induced by gamma-radiation or the vitamin D analogue EB1089 in the non-tumourigenic human colorectal adenoma-derived S/RG/C2 cell line, was preceded by a decrease in nuclear and an increase in cytoplasmic BAG-1 expression. This change in subcellular localisation of BAG-1 was due to the redistribution of the BAG-1M isoform. In addition, we have shown that the maintenance of high nuclear BAG-1 through enforced expression of the nuclear localised BAG-1L isoform enhanced cellular survival after gamma-radiation or exposure to EB1089. Furthermore the expression of cytoplasmic BAG-1S isoform fused with a nuclear localisation signal protected against gamma-radiation induced apoptosis. This demonstrates that nuclear localisation of the BAG-1 protein confers a survival advantage in colorectal adenoma-derived cells and that nuclear BAG-1 could potentially be an important survival factor in colorectal carcinogenesis.

Adenoma↗

PubMed2005

Nicotinamide homeostasis: a xenobiotic pathway that is key to development and degenerative diseases.

Monkeys and man are very closely related genetically. Yet intellectually there are big differences and they suffer from a broad range of different diseases. For example, monkeys do not get Parkinson's or Alzheimer's disease. The former is surprising given that both get parkinsonism from MPTP poisoning and the latter initially less surprising as the cortex predominantly affected in Alzheimer's never developed as fully in the monkey. Man is an omnivore whilst other primates are predominantly herbivores. The one primate who was almost wholly carnivorous was Neanderthal man who became extinct. Red meat has a high content of Nicotinamide, Choline, and methyl donors. The enzyme NNMT converts nicotinamide to N-methyl-nicotinamide using SAM as the methyl donor. It is not present to any degree in herbivores. It has recently been shown to be present in human brain and up regulated in Parkinson's disease. Omnivores presumably need it for nicotinamide homeostasis but the production of N-methyl-nicotinamide will also be beneficial as it will reduce the export of Choline from neurones. Both will aid brain growth and development. However, as N-methyl-nicotinamide resembles MPTP it could cause parkinsonism later in life for man but not monkeys as they would be predicted not to have as much NNMT. Humans with a diet low in Nicotinamide,Choline or methyl donors early in life and low enzyme activity may be prone to Alzheimer's as their brain and therefore its reserves may never have developed as fully. The possession of NNMT plus a diet rich in Nicotinamide, Choline and methyl providers may explain many of the advantages but also the disadvantages of the human condition. One prediction is that a diet rich in these micronutrients whilst young will improve brain development and reduce the risk of Alzheimer's but that a lower dose later in life will reduce the risk of Parkinsonism. A second prediction is that it will become clear that dietary factors including vitamins are signalers and at the head of vital biochemical pathways. A time point will be reached when errors emerge that could not be deleted by evolutionary pressures. Finding and rectifying them will be the key to preventing many common diseases.

Animals↗

PubMed2005

Prospects in NSAID-derived chemoprevention of colorectal cancer.

There is strong evidence for an important role for increased COX (cyclo-oxygenase)-2 expression and PG (prostaglandin) E2 production in colorectal tumorigenesis. PGE(2) acts through four E-prostanoid receptors (EP1-4). COX-2 has therefore become a target for the potential chemoprevention and therapy of colorectal cancer. However, any therapeutic/preventive strategy has the potential to have an impact on physiological processes and hence result in side effects. General COX (COX-1 and -2) inhibition by traditional NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin, although chemopreventive, has some side effects, as do some conventional COX-2-selective NSAIDs. As PGE2 is thought to be the major PG species responsible for promoting colorectal tumorigenesis, research is being directed to a number of protein targets downstream of COX-2 that might allow the selective inhibition of the tumour-promoting activities of PGE2, while minimizing the associated adverse events. The PGE synthases and E-prostanoid receptors (EP1-4) have therefore recently attracted considerable interest as potential novel targets for the prevention/therapy of colorectal cancer. Selective (and possibly combinatorial) inhibition of the synthesis and signalling of those PGs most highly associated with colorectal tumorigenesis may have some advantages over COX-2-selective inhibitors.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2005

The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival.

Although the retinoblastoma susceptibility gene RB1 is inactivated in a wide variety of human cancers, the retinoblastoma protein (Rb) has been shown to be overexpressed in colon cancers, which is linked to the anti-apoptotic function of the protein. However, the mechanisms by which Rb regulates apoptosis are yet to be fully elucidated. We have established that Rb interacts with the anti-apoptotic BAG-1 (Bcl-2 associated athanogene-1) protein, and that a decrease in nuclear localization of BAG-1 is detectable when the interaction between Rb and BAG-1 is disrupted by expression of the E7 viral oncoprotein. Interestingly, although reported as deregulated in colorectal cancers, we have found that BAG-1 expression is also altered in small adenomas, where its localization was found to be predominantly nuclear. In addition, we have established that maintenance of high nuclear BAG-1 in vitro increases the resistance of adenoma-derived cells to gamma-radiation-induced apoptosis. Our work suggests a novel function for Rb, involving modulation of the subcellular localization of BAG-1. We have found predominant nuclear BAG-1 localization in small adenomas, and suggest that BAG-1 may promote colorectal tumour cell survival by making colonic epithelial cells less sensitive to DNA damage.

Adenoma↗

PubMed2005

Cannabinoids and cancer: potential for colorectal cancer therapy.

Despite extensive research into the biology of CRC (colorectal cancer), and recent advances in surgical techniques and chemotherapy, CRC continues to be a major cause of death throughout the world. Therefore it is important to develop novel chemopreventive/chemotherapeutic agents for CRC. Cannabinoids are a class of compounds that are currently used in the treatment of chemotherapy-induced nausea and vomiting, and in the stimulation of appetite. However, there is accumulating evidence that they could also be useful for the inhibition of tumour cell growth by modulating key survival signalling pathways. The chemotherapeutic potential for plant-derived and endogenous cannabinoids in CRC therapy is reviewed.

Antiemetics↗

PubMed2005

Parkinson's disease: the first common neurological disease due to auto-intoxication?

Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.

Brain↗

PubMed2005

Patients' motivations for treatment and their experiences of orthodontic preparation for orthognathic surgery.

OBJECTIVE: To determine patients' motivations for undergoing orthognathic surgery and their experiences of the orthodontic aspects of this treatment. DESIGN: Retrospective questionnaire survey using a patient-centred measure. SETTING: Thirteen National Health Service (NHS) hospital orthodontic departments. SUBJECTS: Three-hundred-and-twenty-six patients (58% response rate) who underwent orthognathic surgery during the period 1 January 1995 to 30 September 2001 completed a questionnaire. MAIN OUTCOME MEASURES: Motivations for treatment and perception of information about treatment and experiences of orthodontic treatment. RESULTS: Major motivations for treatment were to have straight teeth (80%), to prevent future dental problems (69%) and to improve self-confidence (68%). Females sought treatment to improve self-confidence and their smile. Males wanted treatment to improve their social life. Most of these issues had improved following surgery. Most (94%) respondents felt well-informed about their orthodontics. However, 36% wore braces for longer than they expected. Males and younger patients knew less about the duration of treatment than other groups. Fifty-eight per cent of subjects found their braces difficult to clean and 9% reported that they were very painful. Older patients experienced fewer problems wearing braces than younger patients. CONCLUSIONS: Improving dental appearance and preventing future dental problems are major motivators for orthognathic patients. Although patients felt well informed about what to expect from their orthodontic treatment, a significant proportion, particularly younger patients and males, were surprised at the length of treatment and the need to wear retainers. This suggests that orthognathic patients might benefit from better information regarding the orthodontic aspects of their care.

Adolescent↗

PubMed2005

Practical aspects to undertaking research in the primary care setting: experience from two studies.

AIMS: To discuss the practical aspects of conducting research in a primary care setting, from the perspectives of the practitioner and the research team. METHODS: Various issues are discussed, including the relevance of research questions being generated in this setting, the advantages to both parties and the processes involved in conducting a study in specialist practice. This paper describes two recent studies (a randomized clinical trial and a qualitative study) conducted within specialist practice, to illustrate some of the potential difficulties. CONCLUSIONS: The success of conducting a study in primary care is determined by a variety of factors, including an interested specialist practitioner, motivated staff in a well-organized practice and the close support of an academic-based research team.

Communication↗

PubMed2004

Research in primary dental care. Part 7: writing up your research.

Writing up your research for publication is an important part of the research process, since it is through publication in all its forms that the wider community becomes aware of your contribution to knowledge. How the research is written up will depend to a large degree on your target audience; in this final paper we discuss writing up your research for members of your practice, funders of your research, and for publication in academic journals.

Dental Care↗

PubMed2004

Research in primary dental care Part 6: Data analysis.

The analysis of data from a research project seeks to answer the research question which the investigators set at the outset of the study. This article provides information on data analysis for both quantitative and qualitative data, always referring the reader back to their initial research question. Advice is also given on software which can be used for the analysis of data. A guide is provided to the choice of appropriate statistics for studies involving quantitative data.

Data Interpretation, Statistical↗

PubMed2004

Research in primary dental care. Part 5: devising a proposal, obtaining funding and ethical considerations.

In previous articles, we have considered how to formulate a research question and choose an appropriate methodological approach to answer that question, including the use of evidence-based research instruments or measurement scales. In this article, we put this information together in the form of a research proposal and consider how to obtain funding for the research project, as well as fulfil ethical requirements.

Confidentiality↗