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Biomedical subjects

A G Wilson

Publications and source records attributed to A G Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Ethane sulfonate metabolite of alachlor: assessment of oncogenic potential based on metabolic and mechanistic considerations.

Chronic administration of alachlor has been shown to produce neoplastic responses in the nasal turbinate mucosa, glandular stomach mucosa, and thyroid follicular epithelium of rats. Subsequent studies have shown that specific metabolic activation of alachlor is required for nasal tumor formation, and that non-genotoxic, threshold-sensitive processes produce all three tumors. The herbicide alachlor is degraded in the soil by microbial action to the tertiary ethane sulfonate metabolite (ESA). The acute and subchronic toxicity of ESA is very low, and the metabolite did not produce developmental toxicity or genotoxicity. The studies described here were conducted to determine whether ESA shares a common mechanism of oncogenicity with alachlor in rats. Specifically, we studied ESA's pharmacokinetics and ability to produce changes that are causally associated with the oncogenicity of alachlor. These studies demonstrated that ESA was poorly absorbed and underwent minor metabolism, which contrasted with the significant absorption and substantial metabolism observed with alachlor. ESA was also excreted more quickly than alachlor and showed no evidence of accumulation in the nasal turbinates, a site of oncogenicity for alachlor in the rat. In addition, ESA did not elicit the characteristic preneoplastic changes observed in the development of alachlor-induced nasal, stomach, and thyroid tumors. The results of these studies support the conclusion that ESA does not share a common oncogenic mechanism with alachlor and would not be expected to produce the same oncogenic responses observed following chronic alachlor exposure in rats.

Acetamides↗
PubMed2000

Neoadjuvant hormone therapy and radical radiotherapy for localized prostate cancer: poorer biochemical outcome using flutamide alone.

Since a recent meta-analysis of non-steroidal anti-androgen therapy in metastatic prostate cancer concluded that survival was worse compared with medical or surgical androgen withdrawal, we analyzed our experience with flutamide monotherapy and other forms of neoadjuvant hormone therapy (NHT) prior to radiation therapy in clinically localized prostate cancer. A total of 45 patients received flutamide and 328 patients received other NHT. Flutamide patients had higher PSA levels at diagnosis and shorter duration of treatment, which could bias the results against flutamide monotherapy. Kaplan Meier analysis of PSA -- disease free survival showed significantly poorer outcome with flutamide monotherapy. Multivariate analysis supported this conclusion. Until equivalence to other forms of NHT is shown, we do not recommend flutamide monotherapy prior to radical radiation. A prospective randomized trial would be necessary to confirm this conclusion.

Adenocarcinoma↗
PubMed2000

Neoadjuvant hormone therapy and external beam radiation for localized prostate cancer: Vancouver Island Cancer Centre experience.

OBJECTIVES: To evaluate the effects of neo-adjuvant hormone therapy (NAHT) given prior to radiation in patients with clinically localized adenocarcinoma of the prostate. METHODS: Six hundred nine patients were treated between 1992 and 1997 with NAHT prior to radiation therapy. Clinical stage, presenting PSA and Gleason score were examined for influence on outcome. Time to post radiotherapy failure was defined from the first assessed PSA value over 4 microg/L at follow-up. Radiation therapy was confined to the prostate and seminal vesicles. Median follow-up was 2.6 years. RESULTS: PSA disease free survival (PDFS) decreased with increasing cancer risk factors (p <.0.0001). The overall duration of NAHT was significant with patients receiving >8 months having a lower failure rate than those on therapy for <3 months (p <0.0001). The PSA prior to starting radiation correlated with outcome, a PSA <=0.1 microg\L having a better PDFS than those with a PSA >=4 microg\L (P <0.0001). NAHT for >8 months gave improved PDFS in intermediate grade Gleason score 5-7, (n = 256, p <0.0001), high grade Gleason score 8-10 (n = 80, p =0.005), but not in low grade, Gleason score <=4. CONCLUSION: Neo-adjuvant hormone therapy for >8 months offers prolonged PSA disease free survival in patients with less well differentiated tumors, Gleason score >4. Clinical trials are required to confirm this.

Adenocarcinoma↗
PubMed1999

A susceptibility region for myasthenia gravis extending into the HLA-class I sector telomeric to HLA-C.

We have analyzed a series of HLA region markers in 207 UK Caucasoids with early-onset myasthenia gravis (EOMG, onset before age 40), where there is a strong female bias. The well known associations with HLA-DR3 and -B8 have now proved to be significantly stronger in the 165 females than in the 42 males. In patients (of either sex) lacking -DR3, there was also a significant increase in HLA-DR2. Although the muscle weakness in EOMG is clearly mediated by autoantibodies, the associations are consistently stronger with HLA-B8 (in class I) than with HLADR3 (in class II), as confirmed here. We therefore typed 87-137 cases for polymorphisms at four loci in the intervening class III region, and also at three in the adjacent stretch of class I. At each locus, one allele tended to co-occur with HLA-B8 and showed strong and highly significant associations in the patients. There appeared to be a region of maximal susceptibility extending from HSP70 (in class III) past HLA-B and HLA-C at least 600 kb telomerically into the class I region, which is now being mapped in detail. Any candidate genes here that act shortly after puberty may allow more precise localization of susceptibility.

Adult↗
PubMed1999

An evaluation of the carcinogenic potential of the herbicide alachlor to man.

Chronic bioassays have revealed that alachlor caused nasal, thyroid, and stomach tumours in rats but was not carcinogenic in mice. Significant increases in thyroid and stomach tumours were observed only at doses that exceeded the maximum tolerated dose (MTD). While nasal tumours were found at doses below the MTD, they were small and benign in nature. This publication describes the work undertaken by Monsanto to understand the carcinogenic mode of action of alachlor in the rat and to investigate the relevance to humans. The genetic toxicity of alachlor has been investigated in an extensive battery of in vitro and in vivo test systems. In addition, target-specific mutagenicity tests, such as the COMET assay and DNA binding in nasal tissue, were carried out to investigate any possible in-situ genotoxic action. The weight-of-evidence analysis of all available data clearly demonstrates that alachlor exerts its carcinogenicity in the rat by non-genotoxic mechanisms. In the rat, alachlor is initially metabolised primarily in the liver through the P-450 pathway and by glutathione conjugation. The glutathione conjugates and their metabolites undergo enterohepatic circulation with further metabolism in the gastrointestinal tract, liver, and then nasal tissue where they can be converted to a diethyliminoquinone metabolite (DEIQ). This electrophilic species binds to the cysteine moiety of proteins leading to cell damage and increased cell turnover. When comparisons of in vitro nasal metabolic capability were made, the rat's capacity to form DEIQ from precursor metabolites was 38 times greater than for the mouse, 30-fold higher than monkey, and 751 times greater than that of humans. This data is consistent with the results of studies showing in vivo formation of DEIQ-protein adducts in the nasal tissue of rats but not mice or monkeys. The lack of DEIQ nasal adducts in mice is consistent with the lack of nasal tumours in that species. When the differences between rat and humans in the capacity for initial glutathione conjugation by the liver and nasal tissue are also taken into account, the rat is found to be even more susceptible to DEIQ formation than man. Based on this, it is clear that the potential for DEIQ formation and nasal tumour development in humans is negligible. The mechanism of stomach tumour formation has been studied in the rat. The results demonstrated that the mechanism is threshold-sensitive and involves a combination of regenerative cell proliferation and a gastrin-induced tropic effect on enterochromaffin-like (ECL) cells and stem cells of the mucosal epithelium. The absence of a carcinogenic effect in mice and of any preneoplastic effect in monkeys treated with very high doses is indicative ofthe species-specific aspect of this mechanism of action. The results of studies on thyroid tumour production indicate that alachlor is acting indirectly through the pituitary-thyroid axis by increasing the excretion of T4 by enhanced glucuronidation and subsequent biliary excretion. The increased excretion reduces plasma T4 levels and a feedback mechanism leads to increased synthesis of TSH by the pituitary. Chronic stimulation of the follicular epithelium of the thyroid by TSH produces hyperplasia and ultimately tumour formation. This non-genotoxic, threshold-based mechanism is well established and widely considered to be not relevant to humans. In this work, the modes of action for the three types of tumours elicited in the rat by alachlor were investigated. All are based on non-genotoxic, threshold-sensitive processes. From all the data presented it can be concluded that the tumours detected in the rat are not relevant to man and that alachlor presents no significant cancer risk to humans. This conclusion is supported by the lack of mortality and tumours in an epidemiology study of alachlor manufacturing workers.

Acetamides↗
PubMed1997

Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.

Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.

Cell Line↗
PubMed1997

Mechanism of thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats.

Chronic administration of thiazopyr in the diet at dose levels of 1000 and 3000 ppm, but not 100 ppm, has demonstrated an increase in thyroid follicular cell tumors in male Sprague-Dawley rats. In the studies reported here we have evaluated the mechanism of thiazopyr-induced thyroid tumors by studying the effect of thiazopyr on a number of endpoints that indicate hypothalamic-pituitary-thyroid homeostasis. At a dose level of 3000 ppm, thiazopyr caused a marked depression in circulating levels of T4 as soon as 7 days after commencement of treatment. Concurrent with this decrease in T4 was an increase in TSH levels, an increase in thyroid and liver weights, a three- to sixfold increase in hepatic T4-uridine diphosphate glucuronosyl transferase (UDPGT) activity, and increases in thyroid follicular cell hypertrophy and hyperplasia. Dose-related changes associated with thiazopyr treatment were significant increases in liver weight, thyroid weight, and hepatic T4-UDPGT activity at high doses. Increased levels of serum TSH, T3, and rT3, decreased levels of T4, and an increased incidence of thyroid follicular cell hypertrophy and hyperplasia were observed 56 days after the initiation of 3000 ppm thiazopyr. All the changes, except thyroid weight, were partially or completely reversible upon removal of thiazopyr from the diet. Increased thyroid T4 elimination, primarily via increased hepatic conjugation by T4-UDPGT, resulting in decreased serum T4, appeared to be responsible for the increased TSH levels. The sustained increase in TSH by thiazopyr appears responsible for the stimulation of the thyroid follicular cells resulting in follicular cell hypertrophy, hyperplasia, and ultimately neoplasia. In summary, evidence is presented for a hormonally mediated, threshold-dependent process for the development of thyroid follicular cell tumors from high-dose thiazopyr administration in male rats. This mechanism is not considered to be relevant to humans, since the thyroid of humans is much less sensitive to this pathogenic phenomenon than rodents.

Adenoma↗
PubMed1996

TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype.

Celiac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF-alpha, which encodes the cytokine tumor necrosis factor-alpha which has a broad range of pro-inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF-alpha could be important in the pathogenesis of MHC-associated immune disorders. A TNF-alpha variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC-linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLA A1-B8-DR3-DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE +/- 0.0490) in CD, compared to 0.1635 (+/- 0.0362) in a control sample (p < 10(-6)). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA-DQB1*0201 (frequency = 0.7791 +/- 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.

Alleles↗
PubMed1996

Mode of action of thyroid tumor formation in the male Long-Evans rat administered high doses of alachlor.

Chronic administration of alachlor in the diet at a level of 126 mg/kg/day has previously been shown to cause an increase in benign thyroid follicular cell tumors in male Long-Evans rats. Studies were conducted to elucidate the mechanism of the alachlor-induced thyroid tumors in the male rat by evaluating changes in parameters that are collectively associated with a hormonally mediated mode of action for thyroid neoplasia. Male Long-Evans rats were administered 126 mg alachlor/kg body wt/day via the diet for up to 120 days. One group of animals was removed from alachlor-treated diet after 60 days and received untreated diet for an additional 60 days. Liver and thyroid weights and serum levels of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH), as well as hepatic uridine diphosphate glucuronosyl transferase (UDPGT) activity, were determined at 7, 14, 28, 60, and 120 days of treatment. Liver and thyroid weights, hepatic UDPGT activity, and circulating levels of TSH were significantly increased in animals administered alachlor. These increases were seen as early as 7 days after alachlor administration. Circulating levels of T4 in alachlor-treated animals were significantly decreased compared with controls at 7 days, but had returned to control levels by 60 days. T3 levels were elevated at all time points except at 28 days. The changes in TSH and T3 levels, hepatic UDPGT activity, and liver weights were all reversible on elimination of alachlor from the diet. Thyroid weights did not completely return to control levels after removal of alachlor from the diet, although some recovery was evident. The results of this study clearly suggest that alachlor-induced thyroid neoplasia, observed in previous chronic bioassays with alachlor, was associated with increases in circulating TSH levels. Increased metabolism of T4 via hepatic enzymatic conjugation (i.e., T4-UDPGT) appeared to be responsible for the increased TSH levels. These effects were shown to be reversible on cessation of exposure to alachlor. In summary, evidence is presented for a hormonally mediated process for the development of thyroid follicular cell tumors.

Acetamides↗
PubMed1996

Is the metacarpal index useful in the diagnosis of Marfan syndrome?

AIM: This study was undertaken to analyse the importance of the Metacarpal Index (MCI) in making the diagnosis of Marfan syndrome. PATIENTS AND METHODS: The characteristics of 42 patients with Marfan syndrome as defined by strict criteria were analysed. Fifty-one consecutive accident and emergency patients comprised the control group for the MCI measurements. RESULTS: Using MCI alone four (7.8%) of controls had an abnormal MCI, and seven (16.6%) of Marfan patients were normal. Thirty-two (76%) of Marfan patients had an abnormal MCI and three (13.4%) were equivocal. Using other skeletal parameters (upper segment to lower segment ratio, arm span 3 cm or more greater than height, or palate, pectus or scoliosis deformity) 40 (95%) of the Marfan group had an abnormality. Other parameters: 18 (43%) in the Marfan group gave a history of retinal detachment or ectopia lentis. Echocardiographic measurements showed aortic root dilatation in 29 (69%) and in 21 (50%) mitral valve prolapse was found; 37 (88%) had one or other cardiac abnormality. Using all parameters excluding MCI: All the patients would still have fulfilled the diagnostic criteria for the diagnosis of Marfan syndrome. CONCLUSION: The role of the MCI, a radiation dependent and time consuming measurement, is probably insignificant in diagnosis of the majority of Marfan patients. Combined with clinical measurements, an echocardiogram is probably the single most useful investigation, aiding both diagnosis and management.

Adult↗
PubMed1996

Ultrasound features of folded lung.

The ultrasound features of folded lung (rounded atelectasis) have not been described previously. The US findings of folded lung in fourteen patients and correlation with computed tomography are presented. The principal US findings were a pleurally based 'mass' and thickening of the adjacent pleura and extrapleural fat. A highly echogenic line extending from the pleural surface into the mass was seen in 12 patients (86%). We believe this finding corresponds to the scarred invaginated pleura as demonstrated in pathological studies of this condition.

Aged↗
PubMed1996

Effect of a patient's sex on the timing of thrombolytic therapy.

STUDY OBJECTIVE: We sought to determine whether a patient's sex independently influences the interval from emergency department arrival to the initiation of thrombolytic therapy in acute myocardial infarction (AMI). METHODS: We conducted a retrospective cohort study in two suburban EDs, one at a 929-bed tertiary care teaching hospital and the other at a 189-bed community hospital. Only patients found to be having an ST-segment-elevated AMI on their first ECG who were treated with a thrombolytic agent in the ED were eligible. We excluded patients who arrived at the ED after cardiac arrest or with a known AMI. We used as the main outcome measure the interval from ED arrival to initiation of thrombolytic therapy. Secondary outcome variables included time elapsed before ECG, interval between ECG and treatment, and 1-year mortality. RESULTS: Entry criteria were satisfied by 328 patients. The 88 women experienced a mean 23-minute delay to treatment initiation compared with men (P < .01). This observation is not accounted for by age, race, time of day, medical history, sex of the physician, type of thrombolytic agent, hospital, or triage category. The longest delays were found in women treated by female physicians, although female physicians also waited longer than male physicians to administer thrombolytic therapy to men. The mean time elapsed before the first ECG was also 6 minutes longer for women (P < .01) Women had an increased 1-year mortality rate that was fully explained by their advanced age at the time of AMI. CONCLUSION: We infer that a patient's sex may play a significant role in the observed delay in treatment for women. Our data, coupled with previously published work, strongly suggest a systematic negative effect for women in their interaction with the health care system during AMI. We suggest that variables other than systems issues affect the time elapsed before thrombolytic therapy.

Aged↗
PubMed1996

Promoter region polymorphism in the human TNF-alpha gene is not associated with lichen sclerosus.

The pathogenesis of lichen sclerosus remains unknown. However, it has been frequently associated clinically with autoimmunity. The MHC haplotype A1, B8, DR3 is associated with many autoimmune conditions and has also been associated with the uncommon allele of the tumour necrosis factor (TNF-alpha) promoter polymorphism. This allele is also associated with higher production of TNF in vivo and in vitro, and thus it has been speculated that it is the TNF-alpha gene which underlies the genetic association of many diseases with the autoimmune haplotype. There have been many reports of HLA associations with lichen scleroses, but these have not been concordant. We therefore decided to analyse the TNF-alpha polymorphism in patients with lichen scleroses to determine if TNF-alpha was likely to play a role in susceptibility or severity of lichen scleroses. No association between alleles of the TNF-alpha polymorphism and lichen scleroses was found.

Alleles↗
PubMed1996

Evaluation of the potential carcinogenicity and genetic toxicity to humans of the herbicide acetochlor.

Comprehensive toxicological studies of the herbicide acetochlor are presented and discussed. Although it gave a negative profile of responses in the many toxicity tests conducted there were some findings that prompted further investigation. First, although non-mutagenic in the Salmonella assay, acetochlor was clastogenic to mammalian cells treated in vitro. This clastogenic potential was not expressed in vivo in four rodent cytogenetic assays (bone marrow and germ cells). Second, although acetochlor gave a negative response in rat liver UDS assays when tested at the acute MTD, gavage administration of a single, supra-MTD dose (2000 mg/kg) gave a weak positive assay response. This dose-level (2000 mg/kg) was necrotic to the liver, depressed hepatic glutathione levels by up to approximately 80%, altered the metabolism of acetochlor, and was associated with up to 33% lethality. In contrast, reference liver genotoxins such as DMN, DMH and 2AAF were shown to elicit UDS in the absence of such effects, and at approximately 400 x lower dose-levels. Finally, microscopic nasal polypoid adenomas were induced in the rat when acetochlor was administered for two years at the maximum tolerated dose (MTD). The tumours were not life-threatening, they did not metastasize, and no DNA damage was induced in the nasal cells of rats maintained on a diet containing the MTD of acetochlor for either 1 or 18 weeks (comet assay). In order to probe the mechanism of action of these high dose toxicities a series of chemical and genetic toxicity studies was conducted on acetochlor and a range of structural analogues. These revealed the chloroacetyl substructure to be the clastogenic species in vitro. Although relatively inert, this substituent is preferentially reactive to sulphydryl groupings, most evidently, to glutathione (GSH). Similar chemical reactivity and clastogenicity in vitro was observed for two related chemicals bearing a chloroacetyl group, both of which have been defined as non-carcinogens in studies reported by the US.NTP. These collective observations indicate that the source of the clastogenicity of acetochlor in vitro is also the source of its rapid detoxification in the rat in vivo, via reaction with GSH. Metabolic studies of acetochlor are described which reveal the formation of a series of GSH-associated biliary metabolites in the rat that were not produced in the mouse. The metabolism of acetochlor in the rat changes with increasing dose-levels, probably because of depletion of hepatic GSH. It is most likely that a rat-specific metabolite is responsible for the rat nasal tumours observed uniquely at elevated dose-levels. The absence of genetic toxicity to the nasal epithelium of rats exposed acutely or subchronically to acetochlor favours a non-genotoxic mechanism for the induction of these adenomas. The observation of a time- and dose-related increase in S-phase cells in the nasal epithelium is consistent with this conclusion. Despite some confusion caused by the early use of perilethal gavage administrations of acetochlor to rodents, and supra-MTD dietary concentrations in some of the chronic studies, the available MTD data are consistent with acetochlor not posing a genetic or carcinogenic hazard to humans.

Adenomatous Polyps↗