Biomedical subjects
Publications and source records attributed to G M Williams.
Liver culture systems, both primary cultures of hepatocytes and replicating cell lines, can be used in a variety of ways to study the DNA-damaging effects of chemicals and radiation. The present report describes some of the available methods and their interpretation.
Liver culture systems, both primary cultures of hepatocytes and replicating cell lines, can be used in a variety of ways to study the DNA-damaging effects of chemicals and radiation. The present report describes some of the available methods and their interpretation.
A striking difference between two structurally related anti-estrogen medicines is that tamoxifen is strongly hepatocarcinogenic in the rat, whereas toremifene lacks such activity. To study the basis for this difference, the initiating potential of tamoxifen and toremifene were studied by measurement of rapid induction of hepatocellular altered foci (HAF) that express placental-type glutathione S-transferase in the livers of female Sprague-Dawley (S-D) rats and female Fischer 344 (F344) rats. Both agents were administered by gavage at equimolar doses up to a dose that produced marked weight gain suppression. In rats given the high dose of 40 mg/kg per day tamoxifen continuously for 36 weeks, 75% of S-D rats developed liver neoplasms, in contrast to only 10% of F344 rats. In the S-D strain, tamoxifen produced a tendency to increased HAF at 2 weeks at the dose of 40 mg/kg per day and by 12 weeks, a dose-related increase was evident. In contrast, toremifene induced no HAF even at the equimolar high dose of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifen was less in the F344 rats. Neither agent elicited increases in hepatocellular proliferation in S-D or F344 rats. When phenobarbital was administered for 24 weeks as a promoting agent after the anti-estrogens, S-D rats given tamoxifen at 20 mg/kg per day for 12 weeks, developed liver neoplasms, but not F344 rats or rats of either strain given even a higher dose (42.4 mg/kg) of toremifene. Thus, tamoxifen has initiating activity in these rat strains whereas toremifene does not.
OBJECTIVE: In the context of substantial changes in family types and even family quality in recent times, this study is concerned with the extent to which family type and quality impacts on child behavior problems. METHOD: A sample of 8,556 pregnant women were enrolled in a prospective, longitudinal study. Details of changes in family type and family quality (assessed using Spanier Dyadic Adjustment Scale) were used to predict three second-order syndromes developed from the Child Behavior Checklist and administered to the mothers when the child was 5 years of age. RESULTS: Mothers who experienced no partner changes (married and single) reported the lowest rates of child behavior problems for the three syndromes used in this study. In addition, mothers who more often described their relationship with their partner as poor also reported the highest rate of child behavior problems across all three syndromes. Adjustment for possible confounders did not alter these findings. CONCLUSION: Both changes of partner and dyadic conflict appear to lead to child behavior problems, with the latter factor appearing to have a greater impact than the former. Mothers who experienced no partner changes and no conflict appeared to have children with the fewest behavior problems.
The widely used analgesic acetaminophen (APAP) was studied in rats for its ability to inhibit intestinal carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB), which was selected as the carcinogen because of its similarity to the heterocyclic amines formed during cooking and which are postulated to be involved in colon cancer in humans. APAP was fed to male F344 rats at 250 ppm, which is about 1/4 the human therapeutic dose and at 5000 ppm, which is about fivefold the human dose. DMAB was injected subcutaneously at 50 mg/kg body weight weekly for 20 weeks, to assure identical exposures to all animals, followed by 22 weeks of maintenance. The DMAB was an effective inducer of tumours in the small and large intestines, producing an average of 1.3 tumours per animal. Feeding of APAP began 2 weeks before DMAB administration and continued for 44 weeks. A 9% reduction in the number of colon tumours per rat cancer at the low dose and an 86% reduction at the high dose were found. Small intestinal tumour incidence was reduced at both doses. The number of multiple intestinal tumours per rat was reduced by 27% and 49% for the low and high doses, respectively. The dimensions of these neoplasms, especially those in the colon, were also reduced in both dose groups. Thus, APAP, even at a sub-therapeutic dose, inhibited intestinal carcinogenesis induced by DMAB. This allows us to speculate that the effects of low exposures to dietary carcinogens of the heterocyclic amine type could be inhibited by therapeutic doses of APAP.
OBJECTIVE: To examine determinants of moderate and severe obesity in children at 5 years of age. METHODOLOGY: A prospective cohort of mothers were enrolled at first antenatal visit, and interviewed shortly after delivery, at 6 months and 5 years. Detailed health, psychological and social questionnaires were completed at each phase by mothers, and child health questionnaires at 6 months and 5 years. At 5 years 4062 children were assessed physically, the Peabody Picture Vocabulary Test administered and mothers completed a modified Child Behaviour Checklist. Moderate obesity was defined as BMI between 85th and 94th percentiles inclusively, and severe obesity as a BMI greater than the 94th percentile. RESULTS: Independent predictors of severe obesity at 5 years were birthweight, female gender, maternal BMI and paternal BMI. Moderate obesity at 5 years was predicted by birthweight, paternal BMI and sleeplessness at 6 months, while small for gestational age (SGA) status and feeding problems at 6 months were protective factors for moderate obesity. Obesity was not associated with problems of language comprehension or behaviour. CONCLUSIONS: Findings of this study suggest that biological rather than psychosocial factors are the major determinants of obesity at 5 years.
OBJECTIVE: To identify whether obstetric and perinatal factors are independent predictors of child behaviour at 5 years. METHODOLOGY: The Mater University Study of Pregnancy (MUSP) is a prospective cohort study of 8556 mothers enrolled in early pregnancy. The relationship of obstetric and perinatal factors, maternal lifestyle, age and gender of the child, and social disadvantage were examined as predictors of child behaviour in 5005 children completing a modified child behaviour checklist at 5 years. This checklist contained three independent groups of behaviour: externalizng, internalizing and SAT (social, attentional and thought problems). RESULTS: In the initial analysis a limited number of associations were present. After adjusting for measures of social disadvantage, only number of antenatal admissions was associated with child behaviour in all three scales, while maternal cigarette smoking in pregnancy and male gender were associated with externalising and SAT behaviours. CONCLUSIONS: Most common epidemiologic obstetric and perinatal risk factors were not independent predictors of behaviour problems in children at 5 years.
To study the basis for the phototoxicity of quinolones, a class of synthetic antibacterials, the photodynamic ability to mediate 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) formation in cultured cells was measured for lomefloxacin (LMX), which is strongly associated with clinical phototoxicity in humans, and ciprofloxacin (CFX), which has few reports of phototoxicity. Adult rat liver (ARL-18) cells were exposed to the quinolones in the presence of UVA and DNA was extracted and analyzed by HPLC with electrochemical detection. Low levels of 8-oxo-dG were found in the DNA of nonirradiated ARL-18 cells and this was increased up to 6-fold in the presence of either LMX (50-400 microM) or up to 3.6-fold in the presence of CFX (50-400 microM) and UVA (20 J/cm2) when compared to the UVA control. Comparing separate experiments with LMX and CFX, LMX produced greater levels of 8-oxo-dG either after dark exposure or after UVA exposure at 20 J/cm2. Also, LMX and CFX were both shown to photodegrade in the presence of UVA, and it was determined that UVA photoinstability alone does not reflect phototoxic potential. These data suggest that the photodynamic potential of LMX and CFX to produce 8-oxo-dG may relate to their human clinical phototoxicity profile. We suggest that the observed clinical phototoxicity is mediated through a UVA photodynamic effect on the quinolone to form reactive oxygen species in the presence of molecular oxygen. The findings indicate that 8-oxo-dG formation can serve as a marker for the potential phototoxicity of new quinolones.
OBJECTIVE: This study examines the relationship between low family income (LFI) experienced at different points in time, chronic low income status and its impact on child behaviour measured at 5 years of age. METHOD: Longitudinal data from the Mater University Study of Pregnancy were used to measure LFI in families at three points in time (the antenatal period, 6 months post birth and at 5 years cf age). Outcome variables were three independent groups of behaviour problems labelled as externalising, social, attentional and thought (SAT) problems, and internalising problems. These groups were developed from the Child Behaviour Checklist. An analysis based on logistic regression modelling was carried out examining the relationship between LFI and a range of intermediate variables known to be associated with child behaviour problems. RESULTS: The more often families experienced low income, the higher the rate of child behaviour problems at age 5. Low family income was still independently associated with SAT behaviour problems after controlling for smoking in the first trimester, parenting styles, maternal depression and marital dysharmony at age 5. The association between LFI and internalising and externalising behaviour problems was largely mediated by maternal depression. CONCLUSION: Low family income is a significant factor in the aetiology of a variety of child behaviour problems. The mechanisms involved in the link between LFI and childhood internalising and externalising behaviours involve the exposure of the children to maternal depression. However, the relationship between LFI and SAT behaviour problems remains to be elucidated.
In this study we examined 1,909 individuals (53% males and 47% females) to determine the current status of Schistosoma japonicum among the people in five fishing villages situated on two islands (large, Qingshan island; small, Niangashan island) in the Dongting Lake region in Hunan Province, the People's Republic of China. The results of this study indicate that the overall prevalence for schistosomiasis on the two islands is 16%. Two distinct peaks in prevalence (29%) were observed at 25-35 years of age and again at 45-55 years of age for both the large and small islands. On the small island the overall prevalence (24%) varied significantly (P < 0.01) from the large island (15%). Fishermen had the highest prevalence (22.4%) among all the occupational groups examined but students produced the highest worm intensity (geometric mean = 69 eggs per gram [epg] of feces). There was a significant difference (P < 0.01) in the prevalence of schistosomiasis between males and females. In general, males had a much higher prevalence (22%) than females (8.9%). When the study populations were classified as uninfected, lightly infected (10-100 epg), moderately infected (101-400 epg), and heavily infected (> 401 epg) with S. japonicum, the distribution pattern was similar for each of the five villages. The majority (76-88%) of the population remains uninfected. Lightly infected individuals had the highest prevalence (7-12%) followed by moderately infected individuals (1-9%). Only a very small percentage of the population was heavily infected (0-2%). Hepatomegaly along the midsternal line (MSL > or = 3) was commonly seen in both uninfected (21%) and infected individuals (1939%). Subjects heavily infected with S. japonicum reported significantly higher (P < 0.05) cases of liver enlargement when compared with those uninfected. The reported cases of abdominal pain for both uninfected (9%) and infected individuals (4-19%) was relatively high. Lightly and moderately infected individuals reported significantly (P < 0.05 and P < 0.01, respectively) more episodes of abdominal pain than those uninfected. The occurrence of diarrhea was low (5%) for uninfected individuals but this clinical feature was significantly (P < 0.01) more prevalent in both the lightly and heavily infected categories (8-17%).
Nonclinical and clinical safety studies on the two antiestrogens, tamoxifen (Nolvadex) and toremifene (Fareston), are reviewed. Tamoxifen is genotoxic, carcinogenic in experimental animals, and carcinogenic in humans. Toremifene has yielded some positive findings for genotoxicity, but was not an initiating carcinogen in experimental animals. Thus, toremifene has a superior nonclinical safety profile, although information on its long-term effects in humans is needed to ascertain whether its use results in improved safety.
OBJECTIVES: To examine health practitioner and community concerns, priorities and preferred options regarding patient self-determination in terminal care. METHOD: A postal questionnaire was sent to 229 general practitioners in two areas of Queensland (Brisbane and Wide Bay) and to 1100 community members throughout Queensland. Questions covered a range of end of life decision making issues, including where people wish to die, the use of advance directives and proxy decision makers, and possible barriers to such options. RESULTS: GPs and community members held very different opinions on most issues: community members were divided between home, hospital and hospice as a preferred place to die, while GPs strongly favoured home as their preferred place to die. Both groups supported the use of advance directives and proxies, but differed significantly with respect to barriers preventing the use of such options. CONCLUSION: Clarifying differences in perceptions and preferred options between the two groups on end of life decision making should not only improve communication and interactions between GPs and their patients but also allow both groups to become full participants in current policy and practice debates on end of life decisions.
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During capillary formation, endothelial cell migration and organization are critically dependent on surrounding basement membrane proteins. These proteins serve as a physical support and are likely to provide signals which regulate migration and organization of the cells. In this study the possible involvement of tyrosine kinase signalling pathways in basement membrane-induced organization of human endothelial cells is examined. Interaction of endothelial cells with reconstituted basement membrane Matrigel activates tyrosine phosphorylation of several proteins including focal adhesion kinase. Inhibition of this pathway with tyrosine kinase inhibitors impairs localization of paxillin to focal adhesions and organization of actin filaments, decreases motility and elongation of endothelial cells, and prevents their organization into cords or tubes on basement membrane. These data demonstrate that basement membrane-induced modulation of endothelial cell motility, shape, and organization is critically dependent on tyrosine kinase signalling pathway(s) involving cytoskeletal proteins.
The phenolic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were studied for inhibition of aflatoxin B1 (AFB1) hepatocarcinogenesis in male Fischer 344 rats. The antioxidants were administered at 5, 25, or 125 ppm in AIN-76A diet for 42 weeks. Beginning with week 2, 5 micrograms/kg of AFB1 was given by intragastric instillation three times a week for 40 weeks either alone or concurrently with BHA or BHT feeding. The development of hepatocellular altered foci (HAF) induced by AFB1, as indicators of hepatocarcinogenesis, was monitored using immunohistochemical staining for the placental form of glutathione S-transferase. By 16 weeks the multiplicity of foci was 1.97/cm2 of liver area in rats given only AFB1, and this increased to 4.11/cm2 at 24 weeks and to 10.60/cm2 at 32 weeks. At the final sacrifice at 42 weeks, the multiplicity of foci was 12.90/cm2 compared to 0.75/cm2 in untreated controls. In rats given antioxidants in addition to AFB1, the high dose of BHA reduced the multiplicity to 7.72/cm2 and the high dose of BHT reduced the multiplicity to 9.35/cm2. Lower levels did not reduce foci induction. Thus, in male rats under the conditions of this experiment, the level of 125 ppm of either BHA or BHT inhibited the initiation of hepatocarcinogenesis by AFB1. The BHA effect was slightly greater than that of BHT.
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Several quinolone antibiotics, including ciprofloxacin, have been reported to elicit autoradiographic unscheduled DNA synthesis (UDS) in cultured rat hepatocytes. In the present investigation, ciprofloxacin (CF), at 250-1500 microM, produced autoradiographic UDS in cultured rat hepatocytes, whereas neither the quinolone nalidixic acid nor m-AMSA, both topoisomerase II inhibitors, produced autoradiographic UDS. CF also reduced cytoplasmic [3H]thymidine levels ([3H]TdR) relative to control at 250-1500 microM and concomitantly increased nuclear grain counts accounting for most of the net increase yielding positive UDS values. To obtain definitive information on whether the positive UDS observed with CF was due to DNA repair, DNA repair synthesis was measured in parental DNA separated from newly replicated DNA using a bromodeoxyuridine incorporation density gradient method. This method was used to measure DNA repair synthesis in parental DNA of both replicating rat liver epithelial cells (ARL-18) and nonproliferating rat hepatocytes in primary culture. Primary hepatocytes exposed to CF from 250 to 1500 microM did not express DNA repair synthesis in parental DNA isolated by density gradient centrifugation but rather exhibited a concentration-related decrease in the level of [3H]TdR associated with DNA. In rat liver epithelial (ARL-18) cells, CF from 250 to 500 microM likewise did not elicit DNA repair synthesis and also caused a concentration-related decrease in the level of [3H]TdR associated with parental DNA. In contrast, in both cell types a substantial level of repair synthesis occurred in parental DNA as a result of exposure to 2-acetylaminofluorene, a DNA-reactive carcinogen, and in hepatocytes a similar finding was made for the drug hydralazine. Also, after induction of DNA repair in hepatocytes by ultraviolet light, the DNA polymerase alpha inhibitor aphidicolin almost completely abolished repair synthesis, whereas CF had a negligible effect on the inhibition of repair relative to control. These results indicate that CF did not elicit authentic DNA repair and also did not inhibit DNA repair synthesis. The fact that CF elicited autoradiographic UDS and that the topoisomerase II inhibitors m-AMSA and nalidixic acid did not indicates that effects on topoisomerase II are not the basis for the positive UDS result with CF as has been hypothesized in the past.
Vinyl chloride produced several tumor types among species. Angiosarcoma of the liver is found in all tested species, including humans with occupational exposures. Vinyl chloride is biotransformed by CYP2E1 to DNA-reactive chloroethylene oxide producing cyclic etheno adducts, which are mutagenic. The dose-response for angiosarcoma of the liver formation in rodents is supralinear, which is consistent with saturation of metabolic activation, and the tumor rate in humans at occupational exposure levels is similar to that for equivalent exposures in rodents.