Biomedical subjects
Publications and source records attributed to R C James.
We report the first case of dysphagia due to engorgement of a congenital vascular ring as a result of the haemodynamic changes of pregnancy. The clinician should be aware of this in the differential diagnosis. Spontaneous recovery may occur six months post partum as the haemodynamic changes resolve, but if further pregnancies are planned surgery is effective.
Several soil ingestion studies have indicated that some children ingest substantial amounts of soil on given days. Although the EPA has assumed that 95% of children ingest 200 mg soil/day or less for exposure assessment purposes, some children have been observed to ingest up to 25-60 g soil during a single day. In light of the potential for children to ingest such large amounts of soil, an assessment was made of the possibility for soil pica episodes to result in acute intoxication from contaminant concentrations the EPA regards as representing conservative screening values (i.e., EPA soil screening levels and EPA Region III risk-based concentrations for residential soils). For a set of 13 chemicals included in the analysis, contaminant doses resulting from a one-time soil pica episode (5-50 g of soil ingested) were compared with acute dosages shown to produce toxicity in humans in clinical studies or case reports. For four of these chemicals, a soil pica episode was found to result in a contaminant dose approximating or exceeding the acute human lethal dose. For five of the remaining chemicals, the contaminant dose from a soil pica episode was well within the reported dose range in humans for toxicity other than lethality. Because both the exposure episodes and the toxicological response information are derived from observations in humans, these findings are regarded as particularly relevant for human health risk assessment. They suggest that, for some chemicals, ostensibly conservative soil criteria based on chronic exposure using current EPA methodology may not be protective of children during acute soil pica episodes.
OBJECTIVE: First, to compare the distribution of complications and comorbidities associated with 17 common surgical procedures. We then describe the effect of augmenting an ICD-9-CM version of the Charlson comorbidity index, given the possible confounding of comorbidities and complications, for three common inpatient surgical procedures: coronary artery bypass surgery, pacemaker surgery, and hip fracture repair. DATA SOURCES AND STUDY SETTING: Individuals having one of the above procedures between April 1, 1990 and March 31, 1994, identified from Manitoba Health hospital discharge data, and their extracted records. STUDY DESIGN: Design was cross-sectional and longitudinal using Manitoba data on hospital utilization and mortality. DATA COLLECTION/EXTRACTION: Manitoba hospital discharge abstracts permit identifying whether or not the diagnosis represents an in-hospital complication of care. Two data sets were created for each procedure, one including complication diagnoses and another with complications removed. PRINCIPAL FINDINGS: The degree to which complications contaminated estimation of comorbidity depended both on the procedures studied and on the covariates selected. The unique structure of the algorithm for the Charlson comorbidity index led to complication diagnoses having only a minor effect on the comorbidity score generated. Unless a data set affords the opportunity to remove complication diagnoses, the improvement in comorbidity detection afforded by augmenting the Charlson index, combined with the potential for overestimation of comorbidity, seem sufficiently modest to contraindicate such augmentation.
The acquisition of a sufficient and safe supply of blood products is required to support modern medical care; in most countries this has meant a reliance on voluntary, nonremunerated blood donors. Recent reported shortages in the United States and elsewhere have highlighted the need for a method to measure and evaluate blood donor return behaviour. This paper describes a framework within which standard time-to-outcome methods can be used to analyse blood donor return behaviour. Survival curves and relative risk estimates derived from a proportional hazards analysis of a large administrative dataset are reported. In addition to assessing the effect of sex, age and other key donor demographic factors on the probability of a subsequent donation attempt, the analysis reveals that the relative risks are time-dependent. This suggests that the likelihood of attempting a subsequent donation may also depend on the time since the index donation attempt. The implications for blood collection agencies and transfusion researchers of this new perspective on donor behaviour are discussed.
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Recent studies have shown that methamphetamine is capable of potentiating the hepatotoxicity of carbon tetrachloride in mice. In the present study, it was found that this potentiation is sensitive to changes in the timing of the methamphetamine dose relative to the administration of carbon tetrachloride. Potentiation of hepatotoxicity, measured using serum alanine aminotransferase (ALT) activity, was observed only if the dose of methamphetamine (15 mg/kg, i.p.) was given with, or 3 h after, the carbon tetrachloride dose (0.005 ml/kg, i.p.). No increase in carbon tetrachloride hepatotoxicity was evident when methamphetamine was administered 3 h before the carbon tetrachloride dose, or when given 6 or more hours after carbon tetrachloride. Increased covalent binding of carbon tetrachloride to proteins and lipids, shown previously to occur when methamphetamine and carbon tetrachloride are administered together, was not observed when methamphetamine was administered 3 h after the carbon tetrachloride dose and could not, therefore, account for the increased toxicity resulting from this treatment regimen. Pretreatment with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v.) significantly diminished the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine, suggesting that potentiation by methamphetamine involves, at least in part, a stimulation of Kupffer cells. Mice administered a methamphetamine pretreatment regimen known to induce behavioral sensitization displayed an enhanced potentiation of carbon tetrachloride hepatotoxicity, i.e. the extent of potentiation by methamphetamine was increased and the methamphetamine dose required for potentiation was diminished. Mice pretreated with a methamphetamine sensitization regimen were also found to be more responsive to the effects of morphine to enhance carbon tetrachloride hepatotoxicity. These observations suggest that there are important CNS, as well as hepatic, components in the potentiation of carbon tetrachloride-induced liver injury by methamphetamine and perhaps other drugs.
Reference doses (RfDs) and reference concentrations (RfCs) developed by the United States Environmental Protection Agency (USEPA) are typically used to assess the risk of potential adverse human health effects from exposure to environmental chemicals. For a large number of chemicals, however, USEPA RfDs or RfCs have not yet been determined. Thus, for risk assessments that involve a large number of chemicals, there may not be USEPA- or state-derived toxicity constants for all chemicals present at a particular site. A potential solution to this problem is to use estimated permissible concentrations (EPCs) to develop acceptable daily dosages from occupational exposure limits. The EPC is defined as the concentration of a chemical which, under continuous exposure conditions, is expected to be devoid of all acute and chronic toxicities. EPC values are based on allowable occupational exposure limits such as threshold limit values (TLVs), which are workplace exposure guidelines suggested by the American Conference of Governmental Industrial Hygienists. In the present analysis, the EPC method was used to develop interim toxicity constants for more than 30 chemicals which possess TLVs and which appear in the Appendix VIII Hazardous Constituents list, but for which the USEPA has not yet assigned a current RfD or RfC. Appendix VIII chemicals are commonly found at hazardous waste and other sites. Consequently, the development of toxicity constants for the more than 30 chemicals on this list would prove to be most useful for risk assessment purposes. These toxicity constants were then used, together with standard exposure assumptions, to develop acceptable human health-based soil and water concentrations for these chemicals. The use of these values as interim guidance would therefore allow individuals responsible for assessing human health effects posed by environmental contamination to address all site chemicals without performing extensive, chemical-specific toxicological analyses.
Risk estimates for contaminants in soil are currently calculated assuming that concentrations remain unchanged over time. In reality, biological and physicochemical processes can substantially diminish contaminant concentrations in soil. For exposure periods typically evaluated in USEPA risk assessments, failure to consider the decline in contaminant levels from environmental transport and degradation can result in a significant overestimation of the average daily dose of toxicant. This overestimation may be up to 2- to 3-fold for compounds with long half-lives (15-20 years) in soil and as much as 40-fold for compounds with short half-lives (0.5 years). Overestimation of dosages affects estimation of cancer risks because of the assumption that the probability of cancer increases directly with the cumulative dose of carcinogen. Thus, assuming static contaminant concentrations in soil adds unacknowledged conservatism to cancer risk estimates and target concentration limits. Furthermore, as significant time may elapse before future-use scenarios could possibly occur, soil half-life can affect the estimation of noncarcinogenic health hazards as well. Therefore, an increase in target concentration limits for some compounds could be allowed and corresponding remediation costs reduced by considering how soil half-life changes the dosage calculation. Specific examples of the influence of soil degradation rates on estimates of cancer risk are presented and the degree of added conservatism imparted to risk assessments through assumption of static site contaminant levels is discussed. Considering the potential importance of this parameter for risk assessment and risk management decisions, soil degradation of contaminants under site-specific conditions should be performed whenever possible and incorporated into the risk assessment exercise. When the soil degradation rate cannot be measured or reliably predicted, an estimate of the degree of conservatism should be made to provide risk managers with an appreciation of the degree of uncertainty in the calculation of risk.
The effect of methamphetamine cotreatment on carbon tetrachloride-induced liver toxicity was examined in male Sprague-Dawley rats. Concurrent administration of methamphetamine was found to greatly increase the extent of liver injury resulting from carbon tetrachloride treatment, as indicated both by measurement of serum alanine aminotransferase (ALT) activity and from direct histopathologic examination. Concurrent administration of methamphetamine doses less than 10 mg/kg (i.p.), or administration of methamphetamine either before (-3 h) or after (3-9 h) the carbon tetrachloride dose, did not significantly increase liver injury from carbon tetrachloride. These observations indicate that the potentiation by methamphetamine of carbon tetrachloride hepatoxicity previously observed in the mouse also occurs in the rat, and that the timing of the methamphetamine and carbon tetrachloride doses is critical for the interaction.
Reference doses (RfDs) and reference concentrations (RfCs) developed by the United States Environmental Protection Agency (USEPA) are typically used in the quantitation of risk of potential adverse human health effects from exposure to environmental chemicals. For a large number of chemicals, however, USEPA RfDs and RfCs have not yet been determined. Thus, for risk assessments that involve a large number of chemicals, there is insufficient toxicity information with which to evaluate potential adverse human health effects for all chemicals present at a particular site. Due to this insufficiency, the risk assessor must either (1) ignore potential exposures on the assumption that omitting these exposures does not significantly alter decisions concerning the remediation of the site or (2) undertake a lengthy and costly analysis to generate the necessary RfDs or RfCs. A potential solution to this problem is to develop estimated permissible concentrations (EPCs), values which represent permissible environmental concentrations or related acceptable daily dosages derived from occupational exposure limits. In the present analysis, acceptable daily dosages determined using the EPC method were compared to USEPA RfDs or RfCs which were converted to dosages based on standard exposure assumptions. Based on a comparative analysis of EPCs and USEPA reference values for 103 chemicals, it was found that EPC daily dosages represent a reasonably conservative surrogate value when USEPA or state reference values are unavailable. Given that there are hundreds of chemicals with occupational exposure limits but no state or USEPA reference values, acceptance of the EPC methodology would provide an interim solution for the problem of insufficient toxicity information for a substantial number of environmental chemical contaminants.
Methylphenidate hydrochloride, when administered as a single 75 to 100 mg/kg i.p. dose, was found to produce hepatic necrosis in male ICR mice. Peak hepatotoxicity, as measured by serum ALT elevations, occurred 16 hours post-treatment while maximal histopathological evidence of hepatotoxicity occurred 24-48 hours after the methylphenidate dose. Liver injury measured by either method was essentially nonexistent for dosages < or = 50 mg/kg in male mice, and was only minimally evident in female mice at the highest dosage testable. Co-treatment of mice with either alpha 1- or alpha 2-adrenergic agonist drugs had no meaningful effect on methylphenidate-induced hepatotoxicity. In contrast, the beta-adrenergic agonist drug isoproterenol produced a striking potentiation of the liver injury, and shifted the apparent threshold for toxicity approximately 5- to 10-fold. Co-administration of methylphenidate with the mixed alpha/beta-adrenergic agonist dobutamine or with the beta 2-selective agonists metaproterenol, ritodrine or terbutaline produced a similar potentiation of toxicity. Parallel tests with beta-adrenergic antagonists revealed that the potentiation by isoproterenol could be significantly diminished by a single dose of the non-selective beta-adrenoreceptor blocking drug nadolol or the beta 2-selective antagonist ICI-118,551, but not the beta 1-selective antagonist metoprolol. Collectively, these observations suggest that potentiation of methylphenidate hepatotoxicity occurs through stimulation of beta 2-adrenoreceptors. Mice co-treated with isoproterenol were found to have substantially higher serum and liver methylphenidate levels following the methylphenidate dose, and significant increases were also observed in the area-under-the-curve (AUC) for methylphenidate in both tissues of isoproterenol co-treated mice. The results of this study suggest that beta 2-adrenergic agonist drugs are capable of potentiating methylphenidate-induced hepatotoxicity in mice by increasing hepatic methylphenidate concentrations.
Previous studies have indicated that adrenergic agents may potentiate the hepatotoxicity of compounds such as CCl4. Methamphetamine is a powerful central nervous system stimulating drug which also possesses significant adrenergic activity, and its effects on CCl4 hepatotoxicity were examined in male ICR mice. Cotreatment of mice with methamphetamine (15 mg/kg i.p.) resulted in a significant increase in the hepatocellular necrosis produced by minimally toxic to moderately toxic doses of CCl4 (0.005-0.02 ml/kg i.p.), as indicated by changes in serum alanine aminotransferase activity and by histopathologic examination. Methamphetamine alone at this dosage was not hepatotoxic. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater. Pretreatment of animals with either the selective alpha-1 adrenoreceptor antagonist prazosin (5 mg/kg i.p.) or the selective alpha-2 adrenoreceptor antagonist yohimbine (5 mg/kg i.p.) blocked the methamphetamine potentiation. The increase in CCl4 toxicity produced by methamphetamine was not associated with an increase in hepatic concentrations of either CCl4 or one of its major metabolites, chloroform. The increase in toxicity was associated, however, with increases in the in vivo covalent binding of radiolabeled CCl4 to both hepatic proteins and lipids. The cause of the increased covalent binding was not identified, but did not appear to be related to methamphetamine-induced hepatic glutathione suppression. The results of this study suggest that methamphetamine potentiates CCl4 through an adrenoreceptor-related mechanism that may involve either the increased production or diminished conjugation of the reactive metabolites normally formed during the metabolism of CCl4.
Pretreatment of male ICR mice with the adrenergic agonist phenylpropanolamine (200 mg/kg, ip) resulted in a marked potentiation of hepatotoxicity produced by acetaminophen (400 mg/kg, ip). Enhanced liver necrosis with phenylpropanolamine pretreatment was evident both by measurement of serum aminotransferase activity and by histopathologic examination. Several lines of experimental evidence suggest this interaction is a result of the hepatic glutathione depression produced by alpha-adrenergic compounds, which adds to the glutathione depression caused by toxic, or nearly toxic, doses of acetaminophen. First, the potentiation of acetaminophen hepatotoxicity was time-dependent, being observed only when phenylpropanolamine was administered as a 3-hr pretreatment and not when given 1 hr before, with, or 3 hr after acetaminophen. The 3-hr interval between phenylpropanolamine and acetaminophen doses corresponds to the characteristic lag period required for alpha-adrenergic agents (including phenylpropanolamine) to produce significant and maximal effects on hepatic glutathione content. Second, dose-response relationships for phenylpropanolamine and acetaminophen were such that increased toxicity was observed only when the interaction was sufficient to lower hepatic glutathione concentrations below a level regarded as critical in preventing acetaminophen-induced hepatotoxicity. Third, when animals were pretreated with two nonadrenergic depletors of hepatic glutathione, diethylmaleate (125 mg/kg, ip) or the glutathione synthesis inhibitor buthionine sulfoximine (222 mg/kg, ip), at doses producing glutathione depletion approximating that observed with the adrenergic agents, acetaminophen hepatotoxicity was potentiated to the same extent. From these observations it is postulated that a variety of adrenergic compounds known to deplete hepatic glutathione by a moderate 30-50% may potentiate the hepatotoxicity of acetaminophen and possibly other hepatotoxic compounds for which glutathione conjugation is an important detoxification pathway.
Polychlorinated biphenyls (PCBs) continue to be of great environmental and occupational health interest. This review summarizes the major clinical findings reported in individuals incurring the greatest PCB exposure--those persons working in the manufacture or repair of electrical capacitors or transformers. The potential target organs addressed in the studies reviewed include the liver, lungs, skin, cardiovascular system, nervous system, certain endocrine systems, the blood/immune system, and the gastrointestinal and urinary tracts. After careful analysis, the weight of evidence suggests the only adverse health effects attributable to high, occupational PCB exposures are dermal. This review confirms and extends the observations of others, ie, that the collective occupational experience with PCB fluids provides no evidence for adverse PCB effects on any other organ systems.
The donation cycle represents a new framework for the measurement of blood donor return behaviour. Because it is based on the interval between successive donation attempts, it is more efficient than previously reported methods and the resulting data can be analysed using the statistical techniques for interval data. To illustrate the merits of this quantitative approach to the study of blood donor behaviour, the donation cycle framework is used to analyse the interval between the first and second donation attempts in a random sample (n = 5,183) of type 0, whole blood donors from the Gulf Coast Regional Blood Center. Simple statistical tools such as the log-rank test are employed to describe and to evaluate relative differences in the return behaviour of Rh-negative and Rh-positive donors. The analysis indicates that Rh-negative donors are significantly (p < 0.001) more likely than Rh-positive donors to attempt to donate on a second occasion. Kaplan-Meier estimates of the survival function of these first-time donors reveal marked elevations in the rate of return exactly 52 weeks after the initial donation. The donation cycle paradigm provides transfusion researchers with quantitative tools which are essential for designing statistically efficient, prospective intervention studies. By using the knowledge which such studies could provide, blood banks might be better able to manage donor return behaviour and thereby the safety of the blood supply.
Cocaethylene is a novel metabolite of cocaine formed in the presence of ethanol. When administered to ICR male mice in dosages ranging from 10 to 50 mg/kg, i.p., cocaethylene was found to produce dose-dependent hepatic necrosis in the midlobular zone (zone 2). Severity of the lesion was maximal 12-24 hr after administration. A transient but significant decrease in hepatic glutathione content was observed 1 hr after cocaethylene administration. Pretreatment with the cytochrome P450 inhibitors cimetidine (200 mg/kg, i.p., in divided doses) or SKF 525A (50 mg/kg, i.p.) diminished toxicity. Pretreatment of mice with the esterase inhibitor diazinon (10 mg/kg, i.p.) increased cocaethylene hepatotoxicity, as did pretreatment with the cytochrome P450 inducing agents phenobarbital (80 mg/kg/day, i.p., for 3 days) or beta-naphthoflavone (40 mg/kg/day, i.p., for 3 days). Phenobarbital pretreatment also caused a shift in the morphologic site of necrosis from midzonal to peripheral lobular (zone 1) regions. The type of hepatic lesion produced by cocaethylene, its morphologic distribution (including the shift with phenobarbital treatment), the potency of cocaethylene in producing this effect, and the apparent requirement of oxidative metabolism for hepatoxicity were all remarkably similar to observations with its parent compound, cocaine, in this and earlier studies. This suggests that these compounds produce liver toxicity through the same or similar mechanisms.
Cocaethylene (benzoylecgonine ethyl ester or ethyl cocaine) is a transesterification product of cocaine and ethanol that has been observed in the urine of individuals using these drugs in combination. There is evidence that cocaethylene is pharmacologically active, and its formation in vivo may contribute to the toxicity of cocaine. A new method is presented here which enables the quantification of cocaethylene and cocaine, as well as the cocaine metabolites benzoylecgonine and norcocaine in liver tissue. This method utilizes high-performance liquid chromatography with uv detection (235 nm), and the propyl ester of cocaine is used as an internal standard. Liver homogenates are first buffered with 0.1 N dibasic potassium phosphate (pH 9.1) and then extracted with methylene chloride:isopropanol (9:1). Extraction efficiencies were approximately 75-85% for the compounds of interest. The coefficient of variation for replicate determinations (N = 10) of cocaethylene concentration was 5.75%, with comparable values obtained for cocaine, norcocaine, and benzoylecgonine. The detection limit for cocaethylene, based on a peak height threefold greater than background noise, was approximately 1.7 ng of injected compound. Using this method, it was demonstrated that cocaethylene is present in mouse liver following cocaine and ethanol administration, with an apparent rapid rate of formation and elimination.
Cocaine-induced hepatotoxicity has been reported in human beings and is well documented in mice. One interesting feature of this toxicity that appears to be common to both species is an apparent shift in the intraacinar site of necrosis under circumstances known to alter cocaine metabolism. However, the evidence in human subjects is limited, and studies elucidating the mechanism of this phenomenon cannot be performed in human beings. Although future studies in mice may define the basis of this mechanism, the current evidence is a somewhat fragmented composite of studies using different mouse strains and enzyme-inducing agents. Therefore a comprehensive pathologic investigation was initiated for the purpose of identifying and establishing an animal model suitable for studying this phenomenon. In naive ICR mice a single 60 mg/kg dose of cocaine was found to produce midzonal (zone 2) coagulative necrosis. In mice whose oxidative metabolism had been increased with beta-ionone or in which esterase metabolism had been inhibited by diazinon, the severity of the toxicity was increased but the intraacinar origin of the lesion did not change. However, when the oxidative microsomal metabolism of ICR mice was induced by phenobarbital or beta-naphthoflavone, the acinar zone affected was dramatically different. Phenobarbital induction produced zone 1 necrosis, whereas beta-napthoflavone induction caused necrosis in zone 3. The site of necrosis corresponded with the distribution of cocaine, and its metabolites were identified with colloidal gold-conjugated antibody probes. The results of this study suggest that the agents shifting the location of cocaine-induced hepatic necrosis alter the intraacinar site of protein binding of cocaine and its metabolites.