Re: In search of the perfect SERM: beyond tamoxifen and raloxifene.
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Antineoplastic Agents, Hormonal↗
Biomedical subjects
G M Williams
Publications and source records attributed to G M Williams.
Faecal egg aggregation in humans infected with Schistosoma japonicum in China.
In this study we examine the variation in Schistosoma japonicum egg counts caused by differences in worm loads between individuals and the variability of egg counts within individuals with a given worm load. Six villages were selected from an area moderately endemic for Asian schistosomiasis in the Dongting Lake region (Hunan province), China. From a total population of 3451 individuals (53.8% male; x = 31 years), 163 subjects were identified as consistently stool egg-positive based on three successive positive Kato-Katz (KK) smears (41.67 mg/smear) obtained from one stool specimen. The distribution of eggs among individuals was found to be strongly aggregated (k = 0.27), but the distribution within the three smears was found to be only slightly aggregated (k = 2.59), indicating only minor clustering of eggs in stools. The relatively slight clustering of eggs within stool specimens suggests that a single KK smear may be quite adequate for detecting individuals moderately to heavily infected (> 100 eggs/g stool (epg)), as needed for a strategy of morbidity control. However, for estimating the true prevalence of infection in a community, or for obtaining an accurate estimate of egg excretion for research studies, multiple KK smears are warranted.
Animals↗
Rodent hepatocarcinogenic peroxisome proliferators induce proliferation of rat hepatocytes in primary mixed cultures with rat liver epithelial cells.
The effect of two members of the hypolipidemic medicine class of hepatocarcinogenic peroxisome proliferators on proliferation of hepatocytes in primary mixed cultures with liver epithelial cells was studied. Rat hepatocytes present in primary mixed cultures with rat liver epithelial cells were maintained for 3 months retaining their differentiated characteristics and proliferative potential. Hepatocyte clusters in mixed cultures stained positive for albumin, indicating that they retained some metabolic functions. Furthermore, in mixed cultures exposed to 0.2 mM clofibric acid or ciprofibrate for 3 months, hepatocytes were engaged in proliferation as shown by the expression of proliferating cell nuclear antigen (PCNA) and the presence of mitotic figures. This in vitro system could be useful to obtain more information about responses of liver cells during prolonged exposure to peroxisome proliferators.
Animals↗
Evaluation of possible genotoxic mechanisms for acrylonitrile tumorigenicity.
Acrylonitrile (ACN) exposure is associated with tumors in rat brain, Zymbal gland, and mammary gland. Adducts affecting base pairing were formed in isolated DNA exposed in vitro to the ACN metabolite cyanoethylene oxide (CNEO). DNA from liver, which is not a cancer target organ in ACN-exposed rats, contained low levels of 7-(2-oxoethyl)guanine, and adduct believed not to interfere with base pairing. No adducts have been detected in brain DNA from ACN-exposed rats, suggesting that brain tumors may have arisen by mechanisms other than ACN-DNA reactivity. Genotoxicity assays of ACN have indicated no particular carcinogenic mechanism. Positive reverse mutagenesis in Salmonella typhimurium HisG46 base substitution tester strains by ACN is attributable to CNEO. Other in vitro genotoxicity test assays of ACN have yielded mixed results, without consistent effect of metabolic activation. Some positive genotoxicity data for ACN appear to result from artifacts or from non-DNA-reactive mechanisms. In vivo micronucleus, chromosome aberration, and autoradiographic unscheduled DNA synthesis assays were negative for ACN. The comparative genotoxicity of vinyl chloride and ACN indicates that despite other similarities, they cause rodent tumors by different mechanisms. Also, they absence of ACN-DNA adduct formation in the rat brain suggests the operation of epigenetic mechanisms.
Acrylonitrile↗
Absence of DNA adduct formation by phenobarbital, polychlorinated biphenyls, and chlordane in mouse liver using the 32P-postlabeling assay.
Phenobarbital (PB), polychlorinated biphenyls (PCBs), and chlordane (CLD) increase liver tumor incidences in rodents, and all are tumor promoters. Most indirect tests for DNA reactivity, including mutagenicity and chromosomal damage, have been negative with these agents. Consequently, the modes of action for tumorigenesis by these compounds are not believed to involve direct DNA reactivity; however, only limited information from direct tests is available for the lack of DNA adduct formation. PB, PCBs, and CLD were tested for DNA adduct formation in the liver of male and female B6C3F1 mice after either single or 2-week dietary exposures. Single gavage dose levels were as follows: PB, 200 mg/kg; PCBs, 50 mg/kg; and CLD, 50 mg/kg. Dietary dose levels were as follows: PB, 1000 ppm; PCBs, 200 ppm and CLD, 200 ppm. Animals were killed 24 h following the end of test-substance administration. DNA was extracted from the liver, and DNA adduct concentrations were enriched using either 1-butanol extraction of adducted nucleotides or nuclease P1 digestion of unadducted nucleotides. Using this protocol, none of the three test compounds produced DNA adducts detected by 32P-postlabeling. Similar negative results were obtained for DNA from the livers of both male and female mice receiving either single or 2-week exposures. The two positive controls, benzidine for the 1-butanol extraction procedure and 2-acetylaminofluorene for the nuclease P1 procedure, showed the expected patterns of DNA adducts. These results support the conclusion that the carcinogenicity of PB, PCBs, and CLD in experimental animals is not the result of direct DNA reactivity, but involves epigenetic mechanisms.
2-Acetylaminofluorene↗
Effect of rodent hepatocarcinogenic peroxisome proliferators on fatty acyl-CoA oxidase, DNA synthesis, and apoptosis in cultured human and rat hepatocytes.
The effects of the rodent hepatocarcinogens clofibric acid and diprofibrate on the activity of the peroxisomal fatty acyl-CoA oxidase, DNA synthesis, and apoptosis were compared in cultured rat and human hepatocytes. Rat hepatocytes expressed a 10-fold greater level of the peroxisomal fatty acyl-CoA oxidase compared to human hepatocytes. At the highest concentration (1.0 mM), both drugs induced a two- to threefold increase in this enzyme activity in both rat and human hepatocytes. Ciprofibrate (0.1 and 0.2 mM) caused a twofold increase in DNA synthesis in rat hepatocytes, whereas clofibric acid had no effect on DNA synthesis in these cells. In contrast, increasing concentrations of both clofibric acid and ciprofibrate produced inhibition of DNA synthesis in human hepatocytes. By using the terminal transferase dUTP-biotin nick end labeling technique, it was observed that 0.1 and 0.2 mM clofibric acid and ciprofibrate suppressed transforming growth factor-beta (TGF beta)-induced apoptosis by 50% in rat hepatocytes, but they had no effect on TGF beta-induced apoptosis in human hepatocytes. Although clofibric acid and ciprofibrate diminished TGF beta-induced apoptosis, they had no effect on the basal apoptotic levels in the rat hepatocyte cultures. However, both drugs significantly increased the percent of apoptotic cells in the human hepatocyte cultures. It is concluded that primary rat and human hepatocyte cultures respond differently to peroxisome proliferators. The differences in effects on DNA synthesis and apoptosis support the hypothesis that human liver cells are refractory to peroxisome proliferator-induced hepatocarcinogenesis.
Acyl-CoA Oxidase↗
Nonlinearities in 2-acetylaminofluorene exposure responses for genotoxic and epigenetic effects leading to initiation of carcinogenesis in rat liver.
The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126, 0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsulfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione S-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure group, only one adenoma occurred at 36 weeks in 17 rats, while in the low exposure group, no liver tumor occurred in 23 rats. Thus, these findings document nonlinearities for some of the effects of AAF, with supralinear effects at the high exposure for cell proliferation and induction of HAF, and a no-observed-effect level for induction of promotable liver neoplasms at the lowest cumulative exposure of 0.126 mmol/kg, in spite of the formation of DNA adducts. We conclude that the effects of this DNA-reactive hepatocarcinogen leading to initiation exhibit nonlinearities and possible thresholds.
2-Acetylaminofluorene↗
Formation of 8-oxodeoxyguanosine in brain DNA of rats exposed to acrylonitrile.
Acrylonitrile (ACN) produces tumors in rats, particularly gliomas of the brain, but tests for genotoxicity have yielded mixed results and no ACN-DNA adducts have been identified in the brain. To examine the possibility that ACN-related brain tumors were not a consequence of binding of ACN to brain DNA, experiments were conducted to investigate possible epigenetic mechanisms. Male Sprague-Dawley rats were exposed to 0, 3, 30, and 300 ppm ACN in drinking water for 21 days, a range that includes doses associated with brain tumorigenesis. In the 30 and 300 ppm ACN groups, 8-oxodeoxyguanosine (8-oxodG) levels were two fold greater than in the controls. Measures of glutathione levels, glutathione peroxidase and catalase were not significantly changed, but cyst(e)ine was somewhat increased. No changes were found in brain cytochrome oxidase activity, which indicates a lack of metabolic hypoxia. Also, no effects on thiobarbituric acid reactive substances were found, indicating a lack of lipid peroxidation. In an additional experiment, male Sprague-Dawley rats were exposed to 0 or 100 ppm ACN in drinking water for 94 days; interim sacrifices were conducted at 3, 10, and 31 days. Levels of brain nuclear DNA 8-oxodG were significantly increased in ACN-exposed rats compared with controls. Another group of animals were given weekly i.v. injections of 5 mg/kg methylnitrosurea and no increases in 8-oxodG were found. These studies suggest the possibility that ACN-induced tumors may be produced by a mode of action involving 8-oxodG. The formation of 8-oxodG is not understood, but does not appear to involve lipid peroxidation or disruption of antioxidant defenses.
8-Hydroxy-2'-Deoxyguanosine↗
HLA class II antigens are associated with resistance or susceptibility to hepatosplenic disease in a Chinese population infected with Schistosoma japonicum.
The major histocompatibility Class II alleles of 108 individuals living in an area endemic for schistosomiasis japonica in China were determined to identify possible immunogenetic associations with advanced schistosomiasis. Two alleles, HLA-DRB1*1202 (P = 0.002) and HLA-DQA*0601 (P = 0.001) were strongly associated with resistance to advanced disease. In contrast, HLA-DQB1*05031 (P = 0.02) was associated with susceptibility to advanced schistosomiasis. The remaining alleles showed no association with advanced disease. Allele DRB1*1202 co-occurred with allele DQA1*0601; therefore, their independent protective effects could not be ascertained. In contrast, alleles DQA1*0601 and DQB1*05031 never co-occurred and had opposite and significant effects on the occurrence of disease.
Alleles↗
A study of the degradation of phenoxyacid herbicides at different sites in a limestone aquifer.
The biodegradation of three phenoxyalkanoic acid herbicides, viz. MCPA, dichlorprop and mecoprop, under aerobic and anaerobic conditions was investigated using microcosm techniques. The field studies were conducted in a limestone aquifer that had suffered contamination from leaking landfill sites in which phenoxyalkanoic acid herbicides (mostly mecoprop) had undergone disposal. The results from in situ field and laboratory microcosms indicated that under microbially active aerobic conditions the biotransformation of all three herbicides was rapid and that lag phases were short. Under fully aerobic conditions the concentration of each of the three herbicides was reduced from 2,000 micrograms/l to below the detection limit (approx. 10 micrograms/l) of the HPLC system, used for their analysis, within 14 days. However, under microbially active anaerobic conditions no degradation of the herbicides could be discerned over the 100-200 day duration of the experiments. This finding has significant implications for the disposal of phenoxyalkanoic acid herbicides particularly in situations where any resulting leachate may find its way into underlying water resources.
2,4-Dichlorophenoxyacetic Acid↗
Short- and intermediate-term carcinogenicity testing--a review. Part 1: the prototypes mouse skin tumour assay and rat liver focus assay.
Carcinogenicity testing is by far the most expensive and time-consuming study type of toxicology. For many years, the lifetime exposure with the maximum tolerated dose in two rodent species has been the gold standard of carcinogenicity testing of pharmaceuticals. Major change was introduced by the Fourth International Conference on Harmonization in July 1997; a chronic rodent bioassay in one species and a short-term carcinogenicity assay are regarded as sufficient for registration. Such requirements provide the opportunity to redirect the vast resources previously spent on the lifetime study in the second species. Numerous experimental protocols for short- and intermediate-term carcinogenicity testing in many target tissues have been available for years. The first part of this review describes the basic principles of short- and intermediate-term carcinogenicity testing using the examples of the widely used mouse skin tumour assay and the rat liver foci assay. In the context of these experimental models, the discrimination and quantification of initiating and promoting activity and the use of preneoplastic lesions as endpoints in carcinogenicity testing are described. The review includes the limitations of the models with regard to the extrapolation from effects observed in animal experiments to a potential exposure of humans.
Age Factors↗
Short- and intermediate-term carcinogenicity testing--a review. Part 2: available experimental models.
Numerous experimental protocols for short- and intermediate-term carcinogenicity assays have been available for many years. This paper surveys various of these test systems in rodents, fish species, non-vertebrates and avian embryos in ovo. The mouse skin tumour assay and the rat liver foci assay were used to introduce the basic concepts of short- and intermediate-term carcinogenicity testing in the previous part of the review. The focus of this second part of the review is on rodent assays for carcinogenicity testing in the lung, kidney, urinary bladder, pancreas, stomach, oral cavity, small intestine, colon, and on the possibility to combine several target organs in multi-organ models. The potential use of various fish species, non-vertebrates and hatching eggs for carcinogenicity testing is outlined and the advantages and limitations are discussed. This review also presents the problem of validation of any carcinogenicity test system and proposes a strategy for contemporary safety assessment of chemicals with regard to the detection and evaluation of carcinogenicity.
Animals↗
Surgical repair of ruptured abdominal aortic aneurysms in the state of Maryland: factors influencing outcome among 527 recent cases.
PURPOSE: Abdominal aortic aneurysm (AAA) rupture has been historically associated with high operative mortality rates. In this community-based, cross-sectional study, we examined factors influencing outcome after operations performed for ruptured AAA (rAAA). METHODS: An analysis of a state database identified 3820 patients who underwent AAA repair between 1990 and 1995, including 527 (13.8%) who had an operation for an rAAA. Demographic variables examined included patient age, gender, race, associated comorbidity rates, operative surgeon experience with rAAA, and annual hospital rAAA and total AAA operative volumes. Outcomes measured included operative mortality rates, hospital length of stay, and charges. RESULTS: Operative mortality rates increased significantly with advancing age (P < 0.0001) but were not related to gender (P = 0.474) or race (p = 0.598) and were significantly lower among patients with hypertension (P = 0.006) or pulmonary disease (P = 0.045). There was no relationship between hospital rAAA or total AAA volume and rAAA repair mortality rate, although high-volume surgeons (i.e., performing more than 10 rAAA repairs) had decreased mortality rates and hospital charges compared with other surgeons. Hospital lengths of stay and charges increased with age among survivors, but not nonsurvivors, of rAAA repair. Despite a stable incidence of rAAA repairs during the study interval and no significant change in the mean age of patients undergoing operation or the percentage of operations performed by high-volume surgeons, the statewide mortality rate declined from 59.3% to 43.2% (P = 0.039). CONCLUSION: The incidence of rAAA does not appear to be declining. Although operative rAAA repair continues to be associated with substantial risk and remains an especially lethal condition among the elderly, the operative mortality rate has declined in recent years in Maryland. Lower operative mortality rates and hospital charges are associated with operations performed by high-volume surgeons.
Adult↗
The management of massive ultrafiltration distending the aneurysm sac after abdominal aortic aneurysm repair with a polytetrafluoroethylene aortobiiliac graft.
Collections of serous fluid surrounding prosthetic grafts can be caused by infection or transudation of serum, and making the distinction is often troublesome. Bergamini and his colleagues developed a dog model of low-grade prosthetic graft contamination with Staphylococcus epidermatis. All animals developed evidence of graft infection, and 13 of 18 dogs developed a fluid-filled perigraft cyst. Signs of systemic infection, however, were present in only 1 animal, and the Staphylococcus epidermatis study strain was isolated from the tissue surrounding the graft in only 1 dog. The authors had to disrupt the biofilm to achieve positive cultures in 14 of 18 animals. This animal model seemed to conform to clinical experience and placed great emphasis on the role of indolent infections in the pathogenesis of perigraft fluid collection. It is equally clear that perigraft fluid collections may result from transudation of fluid through the prosthetic surfaces, which act similar to a dialysis membrane under certain circumstances. Noninfectious seromas are characterized generally by the accumulation of clear serous fluid with a protein and glucose content of serum and the lack of acute inflammatory cells when the sediment is examined. The need to distinguish between these 2 forms of fluid accumulation became important in the treatment of a 62-year-old man who was seen 2 1/2 years after the repair of an abdominal aortic aneurysm with an aortobiiliac stretch polytetrafluoroethylene (PTFE) prosthesis. There was no evidence of infection, and there was a 12 cm cystic mass surrounding a patent PTFE prosthesis.
Aorta, Abdominal↗
Influence of age and hospital volume on the results of carotid endarterectomy: a statewide analysis of 9918 cases.
PURPOSE: This study evaluated the impact of patient age and hospital volume on the results of carotid endarterectomy (CEA) in contemporary practice. METHODS: The Maryland Health Services Cost Review Commission (MHSCRC) database was reviewed to identify all patients who underwent elective CEA as the primary procedure in all acute care hospitals in the state over the past 6 years. RESULTS: From January 1990 through December 1995, 9918 elective CEAs were performed in 48 hospitals at a total charge of $68.9 million. Postoperative death and neurologic complications occurred in 90 (0.9%) and 166 (1.7%) cases, including 0.8% and 1.7%, 0.9% and 1.6%, 0.9% and 1.8%, and 1.4% and 1.3% of patients < 65 years, 65 to 69 years, 70 to 79 years, and > or = 80 years old, respectively. The mean length of stay and hospital charges increased linearly with increasing age: 4.2 days/$6550, 4.4 days/$6834, 4.8 days/$7059, and 5.6 days (p < 0.0001 vs others)/$7756 (p < 0.005 vs 70 to 79 years and p < 0.0003 vs < 70 years old), respectively, for patients < 65, 65 to 69, 70 to 79, and > or = 80 years old. The mortality rate was 1.9% in low-volume hospitals, 1.1% in moderate-volume hospitals, and 0.8% in high-volume hospitals. The neurologic complication rate was significantly higher (6.1%; p < 0.0001) in low-volume when compared with moderate-volume (1.3%) and high-volume (1.8%) hospitals. CONCLUSIONS: CEA is a safe procedure in the majority of hospitals in contemporary practice, even among the very elderly, who may experience a longer length of stay and higher charges correlating with their documented greater medical complexity.
Adult↗
Successful delayed bilateral renal revascularization during active phase of Takayasu's arteritis.
Successful bilateral renal revascularization was performed 24 days after the development of angiotensin converting enzyme-inhibitor-induced bilateral renal artery thrombosis and anuric acute renal failure in a patient with Takayasu's arteritis. Excellent results were obtained after an unusually long ischemic time for a patient with active-phase disease. The outcome suggests that aggressive surgical revascularization can benefit patients with renal failure caused by renal arterial occlusion during the active phase of Takayasu's arteritis.
Acute Kidney Injury↗
Inhibition by singlet oxygen quenchers of oxidative damage to DNA produced in cultured cells by exposure to a quinolone antibiotic and ultraviolet A irradiation.
The photogenotoxicity mechanism of quinolone antibiotics was investigated by measuring oxidative DNA damage in lomefloxacin- and UVA-exposed cultured liver-derived cells. The combination of lomefloxacin and UVA irradiation produced a dose-dependent increase in 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) in cell DNA. This DNA damage was substantially inhibited by co-incubation with sodium azide (NaN3) or 2,2,6,6-tetramethyl-4-piperadone (TMP), chemicals that specifically quench singlet oxygen. No significant reduction of 8-oxo-dG formation was produced by N-t-butyl-alpha-phenylnitrone (TBP) or alpha-tocopherol, which primarily scavenge hydroxyl radicals. We conclude that the photodynamic generation of 8-oxo-dG by quinolones is mediated, at least in part, by singlet oxygen.
8-Hydroxy-2'-Deoxyguanosine↗
The prevalence and determinants of solar keratoses at a subtropical latitude (Queensland, Australia).
We report the association between skin pigmentation and individual sun exposure, and the occurrence of solar keratoses (SKs) in an unselected population, quantified for the first time. SKs were examined in a representative sample of 197 residents of the community of Nambour in Queensland, Australia. Estimates of sun exposure were combined with a measure of ultraviolet (UV) flux to estimate actual UV exposure, both occupational and recreational, during childhood and adult life. The number of episodes of painful sunburn was used as a measure of intermittent, intense UV exposure. Eight-three participants (43%) had at least one SK, while 35 (18%) had more than 10 SKs diagnosed. The age- and sex-adjusted odds ratios (ORs) for the development of SKs were higher in individuals with fair (OR = 14.1) or medium skin (OR = 6.5), compared with olive-skinned individuals. Individuals with poor ability to develop a suntan were similarly at increased risk compared with others. High levels of occupational UV exposure during adult life were confirmed as being strongly associated with prevalent SKs (OR = 2.4 for heavy/maximal adult exposure), with an even stronger association seen in those individuals with multiple SKs (OR = 4.3 for maximal adult exposure). Although no clear association was demonstrated between SK prevalence and accumulated childhood sun exposure, a history of even one episode of sunburn in childhood was strongly associated with SK prevalence (peak OR of 5.9 for one sunburn).
Adult↗