Respiratory cancer in nickel carbonyl refinery workers.
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Air Pollutants, Occupational↗
Biomedical subjects
S P Williams
Publications and source records attributed to S P Williams.
Mortality of workers at a nickel carbonyl refinery, 1958-2000.
BACKGROUND: Excess risks of respiratory cancer have been shown in some groups of nickel exposed workers. It is clear, however, that not all forms of nickel exposure are implicated in these excess risks. AIM: To determine whether occupational exposures received in a modern nickel carbonyl refinery lead to increased risks of cancer, in particular nasal cancer and lung cancer. METHODS: The mortality experienced by a cohort of 812 workers employed at a nickel refinery was investigated. Study subjects were all male workforce employees first employed in the period 1953-92 who had at least five years' employment with the company. Observed numbers of cause specific deaths were compared with expectations based on national mortality rates; SMRs were also calculated by period from commencing employment, year of commencing employment, and type of work. RESULTS: Overall, standardised mortality ratios (SMRs) were close to 100 for all causes (Obs 191, SMR 96, 95% CI 83 to 111), all neoplasms (Obs 63, SMR 104, 95% CI 80 to 133), non-malignant diseases of the respiratory system (Obs 18, SMR 97, 95% CI 57 to 153), and diseases of the circulatory system (Obs 85, SMR 94, 95% CI 75 to 116). There were no significantly increased SMRs for any site of cancer. There was a non-significant excess for lung cancer (Obs 28, Exp 20.17, SMR 139, 95% CI 92 to 201), and in subgroup analyses a significantly increased SMR of 231 (Obs 9) was found for those 142 workers with at least five years' employment in the feed handling and nickel extraction departments. In the total cohort there was a single death from nasal cancer (Exp 0.10). CONCLUSIONS: The non-significant excess of lung cancer deaths may well be a chance finding, but in light of previous studies some role for nickel exposures cannot be excluded.
Adolescent↗
Reducing concentrate supplementation in dairy cow diets while maintaining milk production with pea-wheat intercrops.
In the first of 2 experiments, 40 dairy cows were used to evaluate the milk production potential and concentrate-sparing effect of feeding dairy cows a basal diet of pea-wheat intercrop silages instead of perennial rye-grass silage (GS). Dairy cows were offered GS or 2 intercrop silages prepared from wheat and either Magnus peas (MW, a tall-straw variety) or Setchey peas (SW, a short-straw variety) ad libitum. The respective intercrops were supplemented with 4 kg/d of a dairy concentrate (CP = 240 g/kg dry matter; MW4 and SW4), and the GS were supplemented with 4 (GS4) or 8 (GS8) kg/d of the same concentrate. The second experiment measured the forage DM intake, digestibility, rumen function, and microbial protein synthesis from the forages by offering them alone to 3, nonlactating cows (3 x 3 Latin square design with 21-d periods). Forage dry matter intake was greater in cows fed the intercrop silages than those fed GS. Milk production was greater in cows fed SW4 than those fed GS4 or MW4, but similar to cows fed GS8. Dietary treatment did not affect milk fat, protein, or lactose concentrations. The intercrops had greater N retention, and were more digestible than the GS, and these factors probably contributed to the greater forage DM intakes and greater milk production from the intercrop silages compared with the GS. Rumen volatile fatty acid concentrations were similar across forages, but urinary purine derivative excretion was greater in the cows fed the intercrop silages than the GS, suggesting that rumen microbial protein synthesis was enhanced by feeding the intercrops. In conclusion, similar milk yield and milk composition can be obtained by feeding SW and 4 kg of concentrates as that obtained with GS and 8 kg of concentrates. Feeding intercrop silages instead of GS with the same amount of concentrates increased forage intakes, N retention, and microbial protein synthesis.
Animal Feed↗
The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.
Amino Acid Sequence↗
A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function.
The role of the cardiac myocyte as a mediator of paracrine signaling in the heart has remained unclear. To address this issue, we generated mice with cardiac myocyte-specific deletion of the vascular endothelial growth factor gene, thereby producing a cardiomyocyte-specific knockout of a secreted factor. The hearts of these mice had fewer coronary microvessels, thinned ventricular walls, depressed basal contractile function, induction of hypoxia-responsive genes involved in energy metabolism, and an abnormal response to beta-adrenergic stimulation. These findings establish the critical importance of cardiac myocyte-derived vascular endothelial growth factor in cardiac morphogenesis and determination of heart function. Further, they establish an adult murine model of hypovascular nonnecrotic cardiac contractile dysfunction.
Animals↗
Effects of early angiotensin-converting enzyme inhibition on cardiac gene expression after acute myocardial infarction.
BACKGROUND: ACE inhibition after myocardial infarction (MI) has been shown to have beneficial effects on cardiac anatomy and function. The purpose of this study was to examine the effects of ACE inhibition on cardiac gene expression after MI. METHODS AND RESULTS: Rats were randomized to receive captopril or no treatment 1 day after MI. Eight weeks later, cardiac function and hemodynamics were measured by use of indwelling catheters and perivascular flow probes. Myocardial gene expression was assessed with DNA microarrays and real-time reverse transcription-polymerase chain reaction. The ratios of heart and left ventricular weights to body weight were significantly increased by MI and normalized by captopril. Cardiac index and stroke volume index were lower in the untreated MI group than in sham controls but were normal in the MI+captopril group. Thirty-seven genes were found to be differentially expressed between the untreated MI group and sham controls; 31 were induced and 6 repressed. Captopril partially or completely inhibited changes in 10 of the genes. The 37 genes clustered into 11 functional groups, and 6 had >/=1 genes whose expression was modified by ACE inhibition. CONCLUSIONS: ACE inhibition after MI inhibits cardiac hypertrophy, preserves cardiac function, and attenuates changes in myocardial gene expression. Gene expression profiling reveals, however, that some elements of the pathophysiology may be unaffected by the treatment and be targets for new therapies.
Acute Disease↗
Dobutamine stress cine-MRI of cardiac function in the hearts of adult cardiomyocyte-specific VEGF knockout mice.
A mouse model of non-necrotic vascular deficiency in the adult heart was studied using cine-magnetic resonance imaging (MRI) and other techniques. The mice lacked cardiomyocyte-derived vascular endothelial growth factor (VEGF) following a targeted knockout in the ventricular cardiomyocytes. Quantitative endothelial labeling showed that the capillary density was significantly reduced in the hearts of knockout mice. Gene expression patterns suggested that they were hypoxic. Semiautomated MR image analysis was employed to obtain both global and regional measurements of left ventricular function at 10 or more time points through the cardiac cycle. MRI measurements showed a marked reduction in ejection fraction both at rest and under low- and high-dose dobutamine stress. Regional wall thickness, thickening, and displacement were all attenuated in the knockout mice. A prolonged high-dose dobutamine challenge was monitored by MRI. A maximal response was sustained for 90 minutes, suggesting that it did not depend on endogenous glycogen stores.
Animals↗
Dense nonaqueous phase liquid tracer tests: experimental results.
Two dense nonaqueous phase liquid (DNAPL) tracer tests were carried out in a shallow aquifer north of Fort Worth, TX. i-Propanol was used as the nonpartitioning tracer: n-hexanol and n-octanol were the partitioning tracers. Field data, mathematical modeling, the results of column tests, and field tracer tests with NaCl were used in designing the DNAPL tracer tests. The results indicated the presence of DNAPL at both sites tested; semi-quantitative estimates of the amounts of DNAPL present were obtained by mathematical modeling. Interpretation was complicated by heterogeneity of the aquifer and mass transport effects.
Alcohols↗
Urban women's negotiation strategies for safer sex with their male partners.
Heterosexual transmission of HIV is growing at an increasing rate. One primary prevention strategy is to consistently use condoms. With the exception of female condoms, women do not "wear" condoms and therefore must negotiate condom use with their male partners. This present study examines the strategies women believe they would use in a safer sex negotiation with a male partner including (1) initiating negotiations, (2) resolving conflict, and (3) maintaining the intention to practice safer sex. The findings highlight the importance of understanding women's patterns of negotiation as well as their repertoire of negotiation skills prior to their exposure to behavioral interventions and prevention programs.
Adolescent↗
Phorbol ester-induced phosphoinositide hydrolysis in rat aorta: role of cyclooxygenase products.
This study investigates whether phorbol esters increase phosphoinositide hydrolysis in intact vascular smooth muscle, and the mechanism underlying the hydrolysis. Phorbol myristate acetate induced time- and concentration-dependent increases in phosphoinositide hydrolysis, as demonstrated by elevated inositol monophosphate levels, in deendothelialized rat aorta. The phorbol ester-elevated inositol monophosphate levels were abolished by indomethacin, a cyclooxygenase inhibitor, but were only partially decreased by SQ29548, a thromboxane A2/prostaglandin H2 receptor antagonist. SQ29548 also only partially decreased elevated inositol monophosphate levels due to prostaglandin E2, prostaglandin F2alpha, prostaglandin I2 and carbacyclin, a stable prostaglandin I2 analog. SQ29548 abolished elevated inositol monophosphate levels due to U46619, a stable thromboxane A2/prostaglandin H2 receptor agonist. These studies demonstrate that phorbol esters increase phosphoinositide hydrolysis in intact vascular smooth muscle, and that the increase is due, at lease in part, to endogenously released prostaglandins other than prostaglandin H2.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
A gender-specific intervention for at-risk women in the USA.
Women are the fastest growing group in the USA to become infected with HIV. Also, the mode of transmission is changing with heterosexual behaviour being the predominant source. As these changes occur, HIV infection becomes more common in women who have not typically been considered at high risk. This paper describes an intervention designed to decrease unsafe sexual encounters and to focus on a highly meaningful concern in the lives of these women: relationships with men. The sessions encouraged making decisions, choice, partner selection, sexual rights, refusal of any unwanted sex, female controlled methods and other elements of empowerment. An eight-session and a four-session curriculum were created to assess dose factors as well.
Adolescent↗
Postradiation squamous cell cancer of the breast.
Primary squamous cell carcinoma of the breast is a rare clinical entity. We diagnosed a patient who presented with a pure squamous cell cancer of the breast 12 years after local radiation for a primary adenocarcinoma of breast. Previously reported cancers related to radiation of the breast have been squamous cell of skin and esophagus and sarcomas, especially angiosarcomas, and on literature review this is the first reported case of primary squamous carcinoma of the breast related to previous radiation. Although our observation suggests a possible link, no established cause and effect relationship is known at this point.
Adenocarcinoma↗
Evidence for a protective role of metallothionein-1 in focal cerebral ischemia.
Metallothioneins (MTs) are a family of metal binding proteins that have been proposed to participate in a cellular defense against zinc toxicity and free radicals. In the present study, we investigated whether increased expression of MT in MT-1 isoform-overexpressing transgenic mice (MT-TG) affords protection against mild focal cerebral ischemia and reperfusion. Transient focal ischemia was induced in control (wild type) and MT-TG mice by occluding the right middle cerebral artery for 45 min. Upon reperfusion, cerebral edema slowly developed and peaked at 24 hr as shown by T2-weighted MRI. The volume of affected tissue was on the average 42% smaller in MT-TG mice compared with control mice at 6, 9, 24, and 72 hr and 14 days postreperfusion (P < 0.01). In addition, functional studies showed that 3 weeks after reperfusion MT-TG mice showed a significantly better motor performance compared with control mice (P = 0.011). Although cortical baseline levels of MT-1 mRNA were similar in control and MT-TG mice, there was an increase in MT-1 mRNA levels in the ischemic cortex of MT-TG mice to 7.5 times baseline levels compared with an increase to 2.3 times baseline levels in control mice 24 hr after reperfusion. In addition, MT-TG mice showed an increased MT immunoreactivity in astrocytes, vascular endothelial cells, and neurons 24 hr after reperfusion whereas in control mice MT immunoreactivity was restricted mainly to astrocytes and decreased in the infarcted tissue. These results provide evidence that increased expression of MT-1 protects against focal cerebral ischemia and reperfusion.
Animals↗
Guidelines for the compilation of occupational health-related records to facilitate future epidemiological studies of chemical exposure. Working Party of the Human Toxicology Section of the British Toxicology Society.
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Epidemiologic Studies↗
Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early reperfusion in the rat.
It has been reported recently that very delayed damage can occur as a result of focal cerebral ischemia induced by vascular occlusion of short duration. With use of diffusion-, T2-, and contrast-enhanced dynamic magnetic resonance imaging (MRI) techniques, the occlusion time dependence together with the temporal profile for this delayed response in a rat model of transient focal cortical ischemia have been established. The distal branch of the middle cerebral artery was occluded for 20, 30, 45, or 90 minutes. Twenty minutes of vascular occlusion with reperfusion exhibited no significant mean change in either the apparent diffusion coefficient of water (ADC) or the T2 relaxation time at 6, 24, 48, or 72 hours after reperfusion (P = 0.97 and 0.70, respectively). Ninety minutes of ischemia caused dramatic tissue injury at 6 hours, as indicated by an increase in T2 relaxation times to 135% of the contralateral values (P < 0.01). However, at intermediate periods of ischemia (30 to 45 minutes), complete reversal of the ADC was seen at 6 hours after reperfusion but was followed by a secondary decline over time, such that a 25% reduction in tissue ADC was seen at 24 as compared with 6 hours (P < 0.02). This secondary response was accompanied by an increase in cerebral blood volume (CBV), as shown by contrast-enhanced dynamic MRI (120% of contralateral values; P < 0.001), an increase in T2 relaxation time (132%; P < 0.01), together with clear morphological signs of cell death. By day 18, the mean volume of missing cortical tissue measured with high-resolution MRI in animals occluded for 30 and 45 minutes was 50% smaller than that in 90-minute occluded animals (P < 0.005). These data show that ultimate infarct size is reduced after early reperfusion and is occlusion time dependent. The early tissue recovery that is seen with intermediate occlusion times can be followed by cell death, which has a delayed onset and is accompanied by an increase in CBV.
Animals↗
VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain.
VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
Animals↗
Atomic structure of progesterone complexed with its receptor.
The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily. As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals. Here we report the 1.8 A crystal structure of a progesterone-bound ligand-binding domain of the human progesterone receptor. The nature of this structure explains the receptor's selective affinity for progestins and establishes a common mode of recognition of 3-oxy steroids by the cognate receptors. Although the overall fold of the progesterone receptor is similar to that found in related receptors, the progesterone receptor has a quite different mode of dimerization. A hormone-induced stabilization of the carboxy-terminal secondary structure of the ligand-binding domain of the progesterone receptor accounts for the stereochemistry of this distinctive dimer, explains the receptor's characteristic pattern of ligand-dependent protease resistance and its loss of repression, and indicates how the anti-progestin RU486 might work in birth control. The structure also indicates that the analogous 3-keto-steroid receptors may have a similar mechanism of action.
Amino Acid Sequence↗