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Biomedical subjects

G M Williams

Publications and source records attributed to G M Williams.

At least 163 records · Page 9Linked to original sources
PubMed1996

A two-year dietary carcinogenicity study of the antiestrogen toremifene in Sprague-Dawley rats.

The carcinogenic potential of the nonsteroidal triphenylethylene antiestrogen toremifene (Fareston) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 and 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study weeks 1-16) or once every four weeks thereafter (study weeks 17-104). Blood samples were taken at weeks 34, 52 and 104 and the plasma concentrations of toremifene, as well as the two main metabolites (deaminohydroxy)toremifene and N-demethyltoremifene, were measured. All doses of toremifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced incidences of pituitary tumors. This was evident in all dose groups. Drug-related decrease of mammary tumors in females (at all doses) and testicular tumors in male rats (doses > or = 1.2 mg/kg/day) were also evident. The incidence of the preneoplastic foci of basophilic hepatocytes were significantly decreased in treated female groups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-related changes were observed in the genital organs, thyroid, spleen, mammary gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or reduced incidences of pituitary, mammary or testicular tumors. This study indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.

Aging↗
PubMed1995

Gastric emptying in acute overdose: a prospective randomised controlled trial.

OBJECTIVE: To test the hypothesis that administration of activated charcoal is as efficacious and safe as the combination regimen of gastric emptying plus charcoal in adults after acute oral overdose. DESIGN: Prospective randomised controlled trial, with subjects presenting on odd-numbered dates allocated to the emptied group (E), and those on even-numbered dates to the not-emptied group (NE). SETTING: Princess Alexandra Hospital, Brisbane (a tertiary referral hospital), which serves an adult urban community, between 4 January 1988 and 11 June 1990. SUBJECTS: Consecutive patients (13 years or older) who presented to the Emergency Department after ingesting an overdose of one or more compounds able to be adsorbed by activated charcoal. INTERVENTIONS: All patients received charcoal by the oral or nasogastric route. Those in the E group also had gastric emptying by ipecac-induced emesis or gastric lavage. OUTCOME MEASURES: Clinical course during the first six hours after treatment began, length of hospital stay, complications. RESULTS: 876 patients were eligible for the study. There were no significant differences between the E and NE groups in age and sex distribution, severity of the overdose or other characteristics, except the mean interval between presentation and administration of charcoal (91 min [SD, 52] for E group and 55 [SD, 41] for NE group; P = 0.0001). There were no significant differences between the E and NE groups in outcome, even when the groups were stratified for severity of the overdose or into subgroups that presented sooner or later than one hour after ingestion. CONCLUSIONS: Gastric emptying can be omitted from the treatment protocol for adults after acute oral overdose.

Adolescent↗
PubMed1995

Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma.

The possible influence of phenobarbital and phenytoin treatment on cancer risk was investigated in a case-control study nested in a cohort of 8004 epileptic patients in Denmark. Information on anticonvulsive treatments was abstracted for 95% of 60 patients with cancers of the liver and biliary tract or malignant lymphoma and for 94% of 171 cancer-free control patients. Use of anticonvulsive drugs was correlated with angiographic procedures that used Thorotrast, a well-known human liver carcinogen. After exclusion of study subjects exposed to Thorotrast, no association was seen between treatment with phenobarbital and cancer of the liver (odds ratio, 1.0; 95% confidence interval, 0.1-8.0) or biliary tract (odds ratio, 0.8; 95% confidence interval, 0.1-4.2). Furthermore, a histopathological evaluation of slides from 7 of 9 liver cancer patients not treated with Thorotrast revealed that 3 of the 4 cases of hepatocellular carcinoma involved cirrhosis of the liver, which suggested an etiological role for alcohol or viral hepatitis. A possible link was observed between use of phenytoin and risk for non-Hodgkin's lymphoma (1.8; 0.5-6.6), with a rising trend in risk with increasing dose. Our results suggest that the increased risk for cancers of the liver and biliary tract among Danish epileptic patients is likely to be due to Thorotrast administration and factors associated with cirrhosis of the liver rather than to anticonvulsive treatment.

Aged↗
PubMed1995

Benzoyl peroxide: an integrated human safety assessment for carcinogenicity.

Topical benzoyl peroxide has been used in the treatment of acne for over 30 years, with no reports of adverse effects that could be related to skin carcinogenesis. Two case-control epidemiological studies have found a lack of association between the specific use of benzoyl peroxide and skin cancer. In addition to these findings in humans, 23 carcinogenicity studies in rodents with benzoyl peroxide, including 16 employing topical application, have yielded negative results. An increase in skin carcinomas was reported in 1 study in which benzoyl peroxide in acetone was applied to the skin of SENCAR mice for a 1-year period; however, this study did not employ adequate control groups to fully understand the unusual findings, and the results were inconsistent with those of 6 other similar studies. While benzoyl peroxide is not a complete carcinogen in animals and has weak or no mutagenic potential, it has been found to be a tumor promoter in mouse skin using experimental two-stage models of carcinogenesis. Consistently positive results have been obtained in tumor promotion studies in which SENCAR mice were exposed to initiating doses of potent experimental carcinogens followed by promotion with benzoyl peroxide in acetone. Negative results have been obtained in similar studies with commercial formulations. However, the results of promotion studies with benzoyl peroxide do not carry significant weight for human safety assessment as evidenced by (i) the absence of demonstrated carcinogenicity in humans of a number of rodent tumor promoters despite long-term human exposure; (ii) the observation that tumor promotion in mouse skin occurs only under specific experimental conditions and predominantly in highly sensitive strains; (iii) clinical use scenarios markedly different from the conditions resulting in tumor promotion in mouse skin; and (iv) the significant physiological differences between mouse and human skin. Thus, to date, available scientific evidence does not allow the results of these rodent promotion studies to be meaningfully applied to human safety assessment. As such, significant scientific progress must be made before human safety estimations can be derived from rodent promotion data.(ABSTRACT TRUNCATED AT 400 WORDS)

Acne Vulgaris↗
PubMed1995

Analysis of studies related to tumorigenicity induced by hydroquinone.

Hydroquinone (HQ) produced renal adenomas in male F344 rats, and these tumors appeared to arise from areas of spontaneous progressive nephropathy; the nephropathy itself has been found to be enhanced by HQ. Other neoplasms were not confirmed to be causally related to HQ among the reported bioassays. In the male F344 rat, HQ administered alone was not DNA reactive. HQ produced enhanced proliferation of renal tubular epithelium, presumably through toxicity involving glutathione conjugate formation. In the kidney, bone marrow, and other tissues, HQ may induce toxicity by redox cycling and lipid peroxidation. In bone marrow, HQ may produce microtubulin dysfunction, which is a plausible explanation for positive cytogenetic tests, the only consistently positive genotoxicity effect reported for HQ. Although HQ is a metabolic product of benzene, several lines of evidence suggest that the effects of HQ exposure are significantly different from those of benzene. Based upon the plausible mechanisms by which HQ may produce kidney tumors in male rats, we have concluded that occupational exposure levels of HQ are not predicted to be a cancer risk for humans.

Adenoma↗
PubMed1995

Correlation of relaxometry and histopathology: the transplantable human glioblastoma SF295 grown in athymic nude mice.

Human glioblastomas of the brain are characterized by a wide range of proton relaxation rates in vitro (1/T1 and 1/T2) and heterogeneous appearance in magnetic resonance imaging. It was previously found that their 1/T1 values vary widely at magnetic field strengths much below imaging fields, even at the same water content. In the present study, we measure 1/T1 at different magnetic field strengths (NMRD profile) for a specific transplantable, human glioblastoma (SF295), grown subcutaneously in athymic nude mice, to search for histologic characteristics that might correlate with the variability of 1/T1 at low fields (1/T1L). Using a field-cycling relaxometer, NMRD profiles were obtained for 32 fresh, histologically characterized, tumor specimens, 7 to 24 days post implantation of cryopreserved SF295 fragments. Tumor volume, dry weight, and pH of specimens were determined, the extent of hemorrhage and necrosis rated, and specimen location within the tumor recorded. A statistically significant increase in the average 1/T1 was found with increasing level of necrosis at 0.0024 T and below, possibly reflecting progressive protein aggregation in samples with up to 40% necrosis. This correlation was not significant at imaging fields. Although pH was increased in central necrosis, neither pH, dry weight, sample location, nor fresh hemorrhage could explain the changes in 1/T1L. The variability of 1/T1L among SF295 samples is much reduced compared to that of fresh surgical specimens of human glioblastomas of the brain. The heterogeneous appearance of glioblastomas in MRI may have a histologic correlate which reflects molecular changes involved with induction of cell death and necrosis. Further investigations may identify the factors responsible for affecting 1/T1L (hypoxia, radiation, chemotherapy).

Animals↗
PubMed1995

Carotid Dacron patch angioplasty: immediate and long-term results of a prospective series.

The purpose of the present study was to determine the acute clinical results associated with the performance of Dacron patch angioplasty during carotid endarterectomy, and to define the incidence of residual and recurrent carotid stenoses in patched arteries. Some 115 consecutive patients (mean age 68.0 years) underwent 119 primary carotid endarterectomy procedures in which the arteriotomy was repaired with a Dacron patch. The patients underwent duplex/occulopneumoplethysmography evaluation at 6 months after surgery, and annually thereafter. There was one (0.8%) operative death and two (1.7%) perioperative strokes. There were no immediate postoperative carotid thromboses. There were no wound or patch infections acutely, or in long-term follow-up. Thirteen patients (11%) were lost to follow-up; hence 106 arteries in 102 patients were followed for 1-65 (mean 17.8) months, including 66 arteries (62%) that have undergone serial OPG/duplex evaluation. The incidence of residual stenoses (within 3 months) was 4.5%, and that of recurrent stenoses 4.8%. The results of the study show Dacron carotid patch angioplasty to be associated with excellent clinical results, with a relatively low incidence of residual/recurrent carotid stenoses.

Aged↗
PubMed1995

Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor.

Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and female rats was atrophy of the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscopic lesions, it is concluded that the macroscopic stomach tumors associated with the dietary administration of butachlor are poorly differentiated gastric carcinoids, in some cases admixed with a non-neuroendocrine epithelial element. Fundic ECL and stem cells are known to be under the trophic influence of gastrin, which is apparently responsible for the induction of the tumors associated with butachlor administration. Gastric tumor development involving gastrin is recognized as a secondary, hormonal mechanism of carcinogenesis, demonstrating a dose-threshold phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetanilides↗
PubMed1995

A study of the mechanism of butachlor-associated gastric neoplasms in Sprague-Dawley rats.

Long term administration of butachlor to Sprague-Dawley rats in a previous bioassay, resulted in the induction of gastric neoplasms which occurred only in the highest dose group (3000 ppm in the diet), primarily in females and specifically in the fundic region. The tumors were a composite of highly undifferentiated enterochromaffin-like (ECL) cells and mucus producing cells with morphologic characteristics unlike those previously described in the rat stomach. Mucosal atrophy of marked intensity was a consistent feature of the gastric mucosa in animals from the highest dose group. An additional long term study was conducted in female Sprague-Dawley rats at dietary levels of 0, 100, 1000 and 3000 ppm to explore the mechanism(s) involved in the formation of these neoplasms. Cell proliferation was evaluated in both fundic and pyloric regions of the stomachs of rats at multiple time periods from 14 days to 26 months. Mucosal thickness was determined in the fundic region at the same time intervals as were used for cell proliferation studies. Gastric pH and gastric acid production were measured after approximately 21 months of exposure. Serum gastrin levels were analyzed at 14, 60, and 120 days and at 6, 18 and 20 months. Cholecystokinin (CCK)/gastrin receptor binding studies were conducted on samples of four tumors and pooled fundic mucosa from five animals in the control group. Cell proliferation was increased in both the neck and base regions of the fundic mucosa at nearly all time points measured from 14 days to 26 months. The magnitude of the changes in the base region were substantially greater than those in the neck region. Fundic mucosal thickness was decreased beginning at the 30-day time point and continued at all intervals, being less than one half that of controls at 20 and 26 months. Gastric pH in rats from the highest dose was elevated to nearly twice control levels at 21 months. Gastric acid secretion was dramatically decreased in animals from the 3000 ppm group and was moderately decreased in the 1000 ppm group at 21 months. Hypergastrinemia was observed at the 3000 ppm level only, beginning at 120 days with progression to extremely high levels by 18 months. CCK/gastrin receptor binding was demonstrated in all tumors studied, at levels comparable to or higher than that of the pooled control sample. All changes involved only the fundic region, the site of tumor formation. Tumors occurred only in animals from the 3000 ppm level, the only level at which hypergastrinemia occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetanilides↗
PubMed1995

Social and biological risk factors for mild and borderline impairment of language comprehension in a cohort of five-year-old children.

Biological risk factors during intra-uterine life, delivery and the neonatal period, and measures of social adversity during pregnancy, were studied as predictors of a 'mildly impaired' (50 to 74) or 'borderline' (75 to 84) score on the Peabody Picture Vocabulary Test (PPVT) at aged five years in 3906 children. Biological risk factors in pregnancy were associated with neither PPVT outcome. Gestation of < 36 weeks, > 3 minutes to establishment of respiration and admission to intensive care were associated with a lower PPVT score indicating mild impairment, though only in the unadjusted analyses. A five minute Apgar score of < 5 and male sex were related to borderline scores, though only the latter remained significant after statistical allowance for possible confounding. In contrast, almost all measures of social adversity were related to both PPVT outcomes even after statistical adjustment for the influence of other factors.

Apgar Score↗
PubMed1995

The influence of anesthetic method on infrainguinal bypass graft patency: a closer look.

Although several studies have demonstrated a reduced incidence of postoperative deep venous thrombosis among patients who receive regional anesthesia, the influence of anesthetic method on early arterial bypass graft patency has not been well studied. The records of 78 consecutive patients undergoing elective femoro-popliteal (FP) or femoro-tibial (FT) bypass grafts, and who were randomized to receive general anesthesia and postoperative patient-controlled intravenous narcotic analgesia (GEN, n = 41), or epidural anesthesia and postoperative continuous epidural analgesia (EPI, n = 37), were retrospectively reviewed. The two groups were evenly matched with respect to demographic characteristics, risk factors, and vascular variables. There was one death in each group, yielding an operative mortality of 2.6 per cent, and leaving 76 patients available for further analysis. Graft occlusion occurred in 11 (14.5%) cases within the first 7 postoperative days, including 9 (22.5%) GEN and 2 (5.6%) EPI patients (P < 0.05). There were two (4.4%) FP occlusions, including two (8.7%) GEN and 0(0%) EPI cases; there were nine FT occlusions, including seven (41.2%) GEN and two (14.3%) EPI cases. Graft occlusion occurred in 11 (17.1%) of the 64 limb salvage cases, including nine (27.3%) GEN and two (6.5%) EPI cases (P < 0.05), and in seven (12.7%) of 55 greater saphenous vein grafts, including six (22.2%) GEN and 1 (3.6%) EPI cases (P < 0.05). By multivariate analysis, FT grafts, preoperative plasminogen activator inhibitor-1 (PAI-1) levels, and GEN were predictive of early graft occlusion (P < 0.05). Furthermore, the levels of circulating PAI-1 were higher 24 hours postoperatively among patients in the GEN group (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The STL1 gene of Saccharomyces cerevisiae is predicted to encode a sugar transporter-like protein.

A gene has been cloned from the yeast Saccharomyces cerevisiae which, on the basis of the deduced translation product, encodes a sugar transporter-like protein. This gene, STL1, was identified as an open reading frame (ORF) closely linked to the cinnamic-acid-resistance gene POF1 on chromosome IV. The putative translation product of STL1 (STL1) contains 536 amino acids, with a M(r) of 60,507. Hydropathy analysis of STL1 suggests that it contains the twelve transmembrane (TM) domains characteristic of a family of sugar transporters from S. cerevisiae and other organisms. STL1 displays greatest homology (28% identity) to the products of the yeast HXT2 (hexose transporter) and GAL2 (galactose transporter) genes. Disruption of STL1 had no detectable effect on yeast growth on glucose, galactose, mannose, maltose or glycerol as sole carbon source. The transport function of the gene product remains unknown at present.

Amino Acid Sequence↗
PubMed1994

Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen.

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.

Animals↗
PubMed1994

Genotoxicity and carcinogenicity in rats and mice of 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7- one: an intestinal bacterial metabolite of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline.

BACKGROUND: Compounds formed on the surface of fried or grilled meat and fish may be associated with increased risk of colon cancer. Normal intestinal bacteria can convert one of these compounds, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), to the 7-hydroxy metabolite, 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7-o ne (7-OHIQ), a direct-acting mutagen. PURPOSE: We studied the genotoxicity and carcinogenicity of 7-OHIQ to determine if it is responsible for the colon-specific activity of IQ. METHODS: The effects of pure, synthetic 7-OHIQ on DNA were evaluated in the Ames Salmonella typhimurium TA98 test, with and without an induced rat liver S9 fraction, and in the Williams DNA repair test using freshly explanted rat hepatocytes. 7-OHIQ was also subjected to an in vivo bioassay for 21 months by long-term intrarectal infusion in male F344 rats, using IQ and N-nitrosomethylurea (NMU) given intrarectally as positive tumor-producing controls. The standard NIH-07 rodent diet was supplemented with 15% corn oil to maximize any effect of the infused materials on the colon. A parallel bioassay involved intraperitoneal injection of 7-OHIQ in newborn mice, followed by dietary administration from week 11 to week 67. Again, IQ and NMU were used as positive controls. RESULTS: We confirmed that 7-OHIQ is a direct-acting mutagen in the Ames test, with added S9 liver fraction giving higher mutagenicity. 7-OHIQ was negative in the Williams test, whereas IQ was positive. 7-OHIQ did not induce colon cancer in rats, and in the newborn mouse test it produced only a low incidence of liver neoplasms. CONCLUSIONS: 7-OHIQ is not genotoxic, for to be so classified it must be definitely positive in both the Ames and Williams tests; moreover, it is not carcinogenic, in marked contrast to IQ and NMU.

Animals↗