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Biomedical subjects

A C Williams

Publications and source records attributed to A C Williams.

At least 109 records · Page 6Linked to original sources
PubMed1997

The effect of different TP53 mutations on the chromosomal stability of a human colonic adenoma derived cell line with endogenous wild type TP53 activity, before and after DNA damage.

We examined the effect of loss of wild type TP53 activity on the chromosomal stability of a human colonic adenoma derived cell line (designated AA/Cl) by studying transfected variants which express different TP53 mutations. Using gross chromosomal aberrations as a measure of instability, we studied metaphase spreads of a vector control cell line (AA/PCMV) and variants expressing the 143(Val-Ala) mutation, which retain endogenous wild type TP53 activity, or the 273(Arg-His) TP53 mutation, which acts as a dominant negative. It was found that the proportion of cells with more than 4% aberrations was significantly greater in the AA/273p53/B cell line (an approximate 5-Fold increase) than in the vector control or the AA/143p53/A cell line. To investigate whether loss of TP53 dependent checkpoints also predisposed the cells to accumulate persistent chromosomal aberrations after DNA damage, cells were exposed to 5 Gy gamma radiation. Regardless of TP53 status, cells with radiation induced chromosomal damage were eliminated through a TP53 independent mechanism, suggesting that loss of TP53 activity did not permit the survival of these cells. In contrast, when exposed to low level gamma radiation (0.2 Gy), decreased wild type TP53 function and/or expression of mutant TP53 protein led to increased radioresistance (both in the non-dominant as well as the dominant mutant expressing cell lines). These findings suggest that loss of TP53 activity and/or acquisition of specific TP53 mutations can increase chromosomal instability and resistance to low level DNA damage in human colonic adenoma cells. This study emphasises the different biological consequences of individual TP53 mutations on the genotype of premalignant colorectal epithelial cells and subsequent implications for tumorigenic progression.

Adenoma↗
PubMed1997

Chronic low back pain: predictions of pain and relationship to anxiety and avoidance.

The present study examined the discrepancy between prediction and experience of pain in 20 chronic low back pain (CLBP) patients undertaking a series of standard physical exercises. Subjects gave ratings of predicted pain and anxiety before each exercise and a rating of the pain experienced during the exercise. Contrary to prediction, the majority of CLBP patients predicted less pain than they subsequently experienced. Moreover, multiple regression analysis showed that, in these patients, the greater the discrepancy between predicted and experienced pain the greater the increase in pain predicted for the subsequent exercise. Anxiety was greater the higher the level of pain predicted, although it was not significantly related to the amount of pain experienced on the previous exercise or to the discrepancy between predicted and experienced pain. However, the discrepancy between predicted and experienced pain was found to be related to subsequent physical performance whereas the other variables were not; the more that pain exceeded expectations on the first exercise the less patients performed on the subsequent exercises. The results of this study are compared with those of previous studies and the implications of the findings to the maintenance of CLBP are discussed.

Adult↗
PubMed1997

Patients' and professionals' understandings of the causes of chronic pain: blame, responsibility and identity protection.

A social constructionist analysis of how sense is made of the causes of chronic pain is reported. It is recognised that there is a multiplicity of stories available in any culture from which understanding can be reached. Q-factor analysis is used within a critical framework as Q-methodology. Sixty chronic pain patients and pain professionals completed the sorting procedure. Four factors were derived that account for the causes of chronic pain. These are reported as the patients' account, the professionals' account, the scientists account and the alternative practitioner's account. Common to all four accounts are the themes of responsibility, blame and the need to protect identity. It is argued that in all accounts responsibility is repositioned away from the sufferer or the healer. In all of the accounts blame is resisted or deflected away from individual ownership. Finally, it is argued that when pain is no longer useful as a symptom, identity is challenged, weakened and at risk for both chronic pain patients and pain professionals. Implications of this study for chronic pain research and treatment are discussed.

Adult↗
PubMed1997

Platelet sulphotransferase activity, plasma sulphate levels and sulphation capacity in patients with migraine and tension headache.

Activity of both the M- and P-forms of sulphotransferase (ST) was measured in platelets from patients with migraine, tension headache and controls. Mean PST values were 0.065 +/- 0.023 and 0.057 +/- 0.052 nmol/mg protein/min for migraine patients with and without aura. The corresponding values for tension headache and controls were 0.122 +/- 0.059 and 0.127 +/- 0.093 nmol/mg protein/min respectively (p < 0.05). Mean MST values were not different for any of the groups, and MST and PST activities measured in two patients during a migraine attack were not significantly altered from baseline levels. Mean plasma inorganic sulphate concentrations and paracetamol metabolites were not significantly different in any of the groups studied. The results suggest that PST activity may be a factor in the aetiology of migraine.

Acetaminophen↗
PubMed1997

An intercomparison of methods for the determination of ochratoxin A in pig kidney.

The preparation of two pig kidney materials is described, together with a report on the results of an intercomparison study of methods to determine ochratoxin A levels in these materials. The materials were prepared, and the intercomparison study carried out within the European Commission. Measurements and Testing Programme, which is the successor of the Community Bureau of Reference (BCR). The materials were prepared from blank and naturally-contaminated pig kidneys and were freeze-dried. Details are given on the freeze-drying and packaging procedure, and the checks to ensure homogeneity and stability of the freeze-dried materials. The intercomparison study involved 20 European laboratories, which analysed the naturally-contaminated (freeze-dried) sample (ochratoxin A content approximately 10 micrograms/ kg based on fresh weight) and the 'blank' sample (ochratoxin A content < 0.6 microgram/kg based on fresh weight) using a variety of procedures for extraction and clean-up. All laboratories used HPLC as the determinative step. Recoveries were found to range from 43 to 128%. The study highlighted problems with recovery of spiked ochratoxin A from freeze-dried pig kidney material. There is a clear need to improve analytical performance, particularly with respect to the extraction efficiency from this type of matrix.

Animals↗
PubMed1997

Ochratoxin A in wheat: certification of two reference materials.

The preparation of two wheat reference materials and the certification of their ochratoxin A content is described. The materials were prepared and certified within the European Commission. Measurements and Testing Programme (M&T). The first and second phases of this project, two intercomparisons of procedures for the determination of ochratoxin A in wheat, at levels of approximately 13 micrograms/kg, and 7 micrograms/kg, respectively have already been reported. This paper describes the work carried out in certification of the ochratoxin A content (mass fraction) of two wheat reference materials: a blank wheat CRM 471, and a contaminated wheat, CRM 472. These materials were prepared for use in the second intercomparison referred to above and reported previously. Reference material CRM 472 was prepared from naturally-contaminated wheat blended with the blank wheat (CRM 471). Details are given of the milling, blending and packaging procedure, and the checks to ensure homogeneity and stability of the material. The certification exercise was carried out by 15 laboratories using a variety of extraction and clean-up procedures, and the certified ochratoxin A content (mass fraction) of CRM 471 was < 0.6 microgram/kg. The value for CRM 472 was 8.2 micrograms/kg with an uncertainty of 1.0 microgram/kg.

Calibration↗
PubMed1997

Human cysteine dioxygenase type I (CDO-I; EC 1.13.11.20): 5' flanking region and intron-exon structure of the gene.

AIM: The elucidation of the structure of the 5' flanking region and the exonic organisation of the human cysteine dioxygenase type I gene. METHODS: Material for sequence studies was generated by polymerase chain reaction (PCR) methods using human genomic DNA, a cosmid clone containing the entire gene, and a commercial gene walking kit. RESULTS AND CONCLUSIONS: The gene was found to be--12 kb in length and made up of five exons (418, 78, 155, 170, and 731 base pairs, respectively). The immediate 5' flanking region did not contain the canonical TATAA box. One DNA source (Clontech promoter finder kit) contained a liver specific nuclear factor response element approximately 550 base pairs from the transcription start site, whereas a second source did not. This and other cis acting factors in the 5' flanking region were identified by computer analysis. The physiological significance of such elements requires detailed experimental evaluation.

Base Sequence↗
PubMed1997

Characterization of frozen glucose solutions.

Reducing sugars may be used as additives in freeze-dried formulations. The purpose of this study is to examine the effect of freezing on nonequilibrated glucose solutions using FT-Raman spectroscopy. The methods used solutions freshly prepared from either alpha- or beta-crystalline glucose, frozen at different time intervals after dissolution. Solutions frozen immediately after dissolution showed peaks in the anomeric region of the spectrum characteristic of those observed for the parent crystalline form. No change occurred in these spectra after 24 hr in the frozen state. Solutions prepared from either alpha- or beta-crystalline glucose and left for 24 hr at room temperature before freezing showed the presence of both anomers. The glass transition temperature of maximally freeze-concentrated solutions of beta-glucose, frozen immediately after dissolution, was found to be approximately 3 degrees C lower than for solutions prepared from alpha-glucose. Freezing appears to halt the interconversion of glucose anomers, enabling the formation of predominantly alpha- or beta-frozen solutions which exhibit different properties. Freezing of nonequilibrated solutions of reducing sugars may lead to variation in the properties of freeze-dried formulations.

Calorimetry, Differential Scanning↗
PubMed1997

Reactive oxygen species in human sperm suspensions: production by leukocytes and the generation of NADPH to protect sperm against their effects.

In men from couples consulting for infertility, 72% of washed sperm preparations produced detectable amounts of reactive oxygen species (ROS) compared to only 25% of preparations from a population of fertile donors. High ROS production was associated with oligozoospermia and poor sperm function. The rate of ROS production was closely correlated with the concentration of leukocytes (r = 0.826) and the degrees of stimulation by N-formyl-methionyl-leucyl-phenyl alanine (NFMLP) and by phorbol 12-myristate 13 acetate (PMA) were similar (r = 0.923). The removal of leukocytes with 'Dynabeads' either abolished or substantially decreased ROS production but in a few cases ROS production that could be stimulated by PMA but not NFMLP was observed in leukocyte-free preparations. When sperm preparations which produced ROS were incubated under 95% O2 there was a rapid 40% decrease in the number of sperm that could be stimulated to acrosome react although the acrosome reaction was unaffected by incubation under 95% N2 for up to 6 h. The harmful effect of oxygen was not seen in preparations that produced no ROS and could be prevented by removing leukocytes from the suspension or by adding superoxide dismutase and catalase. We conclude that leukocytes are the predominant source of ROS in human sperm preparations and that the ROS they produce are harmful to sperm. On the other hand these data confirm that highly purified sperm can produce ROS albeit in smaller amounts. We have demonstrated that flux through the pentose phosphate pathway (PPP) in purified sperm preparations increases in response to oxidative stress. This is required to make reduced glutathione available for glutathione peroxidase and we suggest that measurement of PPP flux provides an index of the capacity of glutathione peroxidase to protect sperm against oxidation.

Humans↗
PubMed1997

Systematic review of outpatient services for chronic pain control.

AIM OF REPORT. This report reviews the evidence about the effectiveness of treatments for chronic pain. While treatment of chronic pain is usually seen as an integrated service, this report concentrates on the individual interventions that constitute the service. HOW THE RESEARCH WAS CONDUCTED. Searches of databases and journals identified over 15,000 randomised studies with pain as an outcome, and many more which were not randomised. Over 150 systematic reviews relevant to chronic pain treatment were identified and their quality assessed using a simple scoring system. Systematic reviews conducted for this report were based mainly on randomised trials. The number needed to treat (NNT) was chosen as the output for the report. NNTs of 2-4 indicate effective treatments. Because NNT is treatment-specific it overcomes problems associated with highly variable placebo or control event rates in pain trials. Such variability is predominantly due to the limited numbers of patients in the clinical trials. Dichotomous outcome measures are important in synthesising information from many studies, and in deriving NNTs. Methods have been developed which allow mean information on pain relief and intensity to be converted reliably into the simple dichotomous outcome of at least 50% pain relief. RESEARCH FINDINGS. PHYSICAL INTERVENTIONS. Transcutaneous electrical nerve stimulation (TENS) has been shown not to be effective in postoperative and labour pain. In chronic pain, there is evidence that TENS effectiveness increases slowly, and that large doses need to be used. There is lack of evidence for the effectiveness of TENS in chronic pain. There is a lack of evidence for the effectiveness of relaxation. Intravenous systemic regional blockade with guanethidine has been shown to be without effect. Epidural corticosteroids are effective in the short term for back pain and sciatica. Injections of corticosteroids in or around shoulder joints for shoulder pain have been shown not to be effective. There is a lack of evidence supporting spinal cord stimulators. Case series are of poor quality and do not provide evidence of effectiveness, although at least 50% pain relief at 5 years is reported in over 50% of patients. PHARMACOLOGICAL INTERVENTIONS. Minor analgesics are important in chronic pain. NNTs were calculated for analgesics given orally for moderate or severe acute postoperative pain. The NNTs found ranged from 17 (poor) for codeine, 60 mg, to 2.5 (good) for ibuprofen, 400 mg. Anticonvulsant and antidepressant drugs are prescribed for neuropathic pains like diabetic neuropathy. NNTs are of the order of 2.5, showing them to be effective treatments. However, there are too few studies with too few patients to determine which is the best drug. Minor adverse events are common, and major adverse events occur in about 1 in 20 patients. There are no studies comparing antidepressants and anticonvulsants directly. Systemic local anaesthetic-type drugs have been shown to be effective in nerve injury pain but there is little or no evidence to support their use in migraine or cancer-related pain. Topical NSAIDs (for example, gels, creams) are effective in rheumatological conditions with an overall NNT of 3. There are too few studies to determine which is the best agent. Topical NSAIDs have few adverse events; most importantly they are without the major gastrointestinal adverse events found with oral NSAIDs, which might make them an important choice for some patients with peripheral arthritis. (ABSTRACT TRUNCATED)

Ambulatory Care↗
PubMed1997

Inhibition of radiation-induced G2 delay potentiates cell death by apoptosis and/or the induction of giant cells in colorectal tumor cells with disrupted p53 function.

We have previously identified a p53-independent apoptotic response that is delayed until 48-72 h after irradiation of colorectal adenoma and carcinoma cells. Because the delay appears to be in part due to a transient G2 cell cycle arrest, the importance of this checkpoint in the mechanism of ionizing radiation (IR)-induced death of colorectal tumor cells was investigated. An adenoma cell line with (282Arg-->Trp) mutant p53 (S/RG/C2) and a carcinoma cell line (PC/JW/FI) lacking p53 protein treated with 5 Gy IR in the presence of 1.5 mm caffeine (CAF) reduced IR-induced G2 arrest and increased the level of apoptosis (1.5-1.6-fold) 24 h after treatment. Increased IR apoptotic cell death with CAF significantly reduced IR cell survival over a 7-day period in S/RG/C2 and PC/JW/FI. To investigate whether CAF radiosensitization correlated with lack of wild-type (wt) p53, we studied transfected derivatives of an adenoma-derived cell line (PC/AA/C1), in which the endogenous wt p53 activity was disrupted by the expression of a dominant negative (273Arg-->His) p53 mutant protein (designated AA/273p53/B). This p53-defective cell line was also radiosensitized by CAF, whereas the vector control (AA/PCMV/D), which retained wt p53 activity, was not. In addition, as with the S/RG/C2 and PC/JW/FI cell lines, the 7-day IR cell survival was reduced significantly in AA/273p53/B compared with the vector control cell line. This suggests that radiosensitization by CAF and increased cell death is dependent on loss of wt p53 function. Interestingly, radiosensitization of the AA/273p53/B cell line was not associated with accelerated apoptosis but correlated with increased polyploid giant cells, which have been associated with disruption of cell cycle checkpoints and genomic instability. These results demonstrate that G2 checkpoint inhibition with CAF leads to preferential IR cell killing in cell lines in which wt p53 is inactivated and that this increased cell killing is not necessarily dependent on increased IR-induced apoptosis.

Adenoma↗
PubMed1996

Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D.

The aim of our study was to identify changes in secreted procathepsin B levels in a model of the human colorectal adenoma to carcinoma sequence and to determine the factors required for its extracellular activation. Conversion of the non-tumorigenic adenoma-derived cell line PC/AA to a highly tumorigenic phenotype (designated AA/CI/SB10/M) was associated with an 8-fold increase in the presence of the proform of cathepsin B in 24 hr conditioned serum-free medium (SFM). In addition, mature enzyme was only detected in the cell lines of this model with increased malignant potential. This is in agreement with the findings of a previous study, in which mature cathepsin B was only present in the 24 hr conditioned SFM of cancer-derived cell lines and not in SFM from adenoma-derived cell lines. Having demonstrated a reduction in the pH of conditioned medium from cell lines with increased malignant potential, we used a range of specific proteinase inhibitors to show that an aspartyl proteinase was involved in the initial activation of procathepsin B. Consistent with this finding, we subsequently demonstrated an increased secretion of the aspartyl proteinase cathepsin D in the medium of the AA/CI/SB10/M adenocarcinoma cells compared with the non-tumorigenic AA/Cl cell line. Therefore, the presence of mature cathpsin B in the conditioned medium of the more malignant cell lines coincided with a reduction in pH and an increase in the amount of cathepsin D secreted. Data from the human colorectal derived adenoma to carcinoma sequence indicate that an in vivo mechanism may exist that, dependent on the simultaneous presence of both a tumour-generated acidic extracellular environment and an elevated secretion of procathepsin D, could result in the activation of latent procathepsin outside the cell.

Adenocarcinoma↗
PubMed1996

Idiopathic dysautonomia treated with intravenous gammaglobulin.

BACKGROUND: A previously healthy 23-year-old man presented with a short history of abdominal pain and diarrhoea followed by blurred vision, severe postural hypotension, reduced sweating and unremitting fever. METHODS: Examination revealed fixed dilated pupils, impaired sweating and postural hypotension. Clinical and neurophysiological examination showed no motor or sensory deficit. A diagnosis of idiopathic autonomic neuropathy was made. He became gravely ill with profound life-threatening hypotension and a prolonged ileus. FINDINGS: Within 36 h of receiving intravenous gammaglobulin (IVGG) his pupillary areflexia and severe hypotension resolved. 2 weeks later the autonomic failure recurred but again responded to treatment with IVGG. IVGG is a recognised treatment for Guillain-Barré syndrome. INTERPRETATION: This case report demonstrates that IVGG is also effective in the rare pure dysautonomic variant.

Adult↗
PubMed1996

The surgical care of cleft lip and palate patients in England and Wales.

The results of a postal survey in 1992 of surgeons in England and Wales undertaking primary repairs for babies born with cleft lip and palate are presented. 64 plastic surgeons undertaking primary cleft repairs were identified. The majority of cleft surgeons were low volume operators undertaking 10 or less lip repairs annually. Low volume operators were less likely to attend joint disciplinary clinics than high volume operators and those that did attended clinics with fewer specialities represented. None of the low volume operators collected standardised records for their patients. The recommendations of the Royal College of Surgeons of England for centralisation of cleft care in England and Wales on a regional basis and a minimum case-load per surgeon of 30 new cases per year are discussed.

Child, Preschool↗
PubMed1996

Characterization of dihydrates prepared from carbamazepine polymorphs.

To clarify earlier literature suggesting its existence in more than one solid form, carbamazepine dihydrate was prepared from individual anhydrous carbamazepine polymorphs I and III. The resultant materials were characterized by thermal and spectroscopic techniques, including variable-temperature Fourier transform (FT) Raman spectroscopy. On thermal dehydration, the carbamazepine dihydrates formed different anhydrous polymorphs depending on both starting material and dehydration conditions. Under conditions where liberated hydrate water cannot readily escape from around the sample, the dihydrate originating from polymorph III reverted to polymorph III, but under conditions of lower humidity/moisture, this dihydrate reverted to polymorph I. The dihydrate originating from polymorph I reverted to polymorph I irrespective of dehydration conditions. These observations could be due to a trace amount of nonhydrated original polymorph existing in the dihydrate phase that acts as a seed to regenerate the original polymorph under conditions where liberated hydrate water cannot readily escape from around the sample during dehydration. No evidence was generated that supported the existence of true polymorphs of carbamazepine dihydrate.

Calorimetry, Differential Scanning↗