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Biomedical subjects

J B Ward

Publications and source records attributed to J B Ward.

At least 19 recordsLinked to original sources
PubMed2006

3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.

Xpc-null (Xpc-/-) mice, deficient in the global genome repair subpathway of nucleotide excision repair (NER-GGR), were exposed by intraperitoneal (i.p.) injection to a 300 mg/kg mutagenic dose of 3,4-epoxy-1-butene (EB), to investigate NER's potential role in repairing butadiene (BD) epoxide DNA lesions. Mutagenic sensitivity was assessed using the Hprt assay. Xpc-/- mice were significantly more sensitive to EB exposure, exhibiting an average 2.8-fold increase in Hprt mutant frequency (MF) relative to those of exposed Xpc+/+ (wild-type) mice. As a positive control for NER-GGR, additional mice were exposed by i.p. injection to a 150 mg/kg mutagenic dose of benzo[a]pyrene (B[a]P). The Xpc-/- mice had MFs 2.9-fold higher than those of exposed Xpc+/+ mice. These results suggest that NER-GGR plays a role in recognizing and repairing some of the DNA adducts formed following in vivo exposure to EB. Additional research is needed to examine the response of Xpc-/- mice, as well as other NER-deficient strains, to inhaled BD. Furthermore, it is likely that alternative DNA repair pathways also are involved in restoring genomic integrity compromised by BD-epoxide DNA damage. Collaborative studies are currently underway to address these critical issues.

Animals↗
PubMed2001

Biomarkers for assessing occupational exposures to 1,3-butadiene.

The overall objective of this study was to evaluate a continuum of biomarkers in blood and urine for their sensitivities as indicators of low level occupational exposures to 1,3 butadiene (BD). The study design was largely cross-sectional, with biological samples collected within a short timeframe. Personal 8-h BD exposure measures were made on several occasions over a 60-day period for each potentially exposed worker in order provide maximum accuracy for this independent variable and to accommodate the different expression intervals of the several biomarkers. Co-exposures to styrene, toluene and benzene were also measured. The study included 24 BD monomer production workers (mean BD exposure=0.642 mg/m(3)), 34 polymerization workers (mean BD exposure=1.794 mg/m(3)) and 25 controls (mean BD exposure=0.023 mg/m(3)). The several biomarkers were measured by a consortium of investigators at different locations in the US and Europe. These biomarkers included: (1) metabolic genotypes (CYP2E1, EH, GST M1, GST T1, ADH2, ADH3), determined in Prague and Burlington, VT; (2) urinary M1 and M2 metabolites (1,2-dihydroxy-4-[N-acetylcysteinyl]-butane and 1-hydroxy-2-[N-acetylcysteinyl]-3-butene, respectively), determined in Albuquerque, NM and Leiden; (3) hemoglobin adducts (N-[2-dihydroxy-3-butenyl]valine=HBVal and N-[2,3,4-trihydroxybutyl]valine=THBVal), determined in Amsterdam and Chapel Hill, NC, respectively; (4) HPRT mutations determined by autoradiographic assay in Galveston, TX, with slides re-read in Burlington, VT; (6) hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations determined by cloning assay in Leiden with mutational spectra characterized in Burlington, VT; (7) sister chromatid exchanges and chromosome aberrations determined by standard methods and FISH analysis in Prague. Urinary M1 and M2 metabolites and HBVal and THBVal hemoglobin adducts were all significantly correlated with BD exposure levels, with adducts being the most highly associated. No significant relationships were observed between BD exposures and HPRT mutations or any of the cytogenetic endpoints, regardless of method of assay.

Adult↗
PubMed2001

Assessment of butadiene exposure in synthetic rubber manufacturing workers in Texas using frequencies of hprt mutant lymphocytes as a biomarker.

1,3-Butadiene (BD), which is used to manufacture synthetic rubber, is a mutagen and carcinogen. Because past occupational exposures have been associated with an increased risk of leukemia, there has been a dramatic reduction in workplace exposure standards. The health benefits of these reduced levels of occupational exposure to BD will be difficult to evaluate using relatively insensitive traditional epidemiological studies; however, biomarkers can be used to determine whether there are genotoxic effects associated with recent exposures to BD. In past studies of BD-exposed workers in Southeast Texas, we observed an increase in the frequency of lymphocytes with mutations in a reporter gene, hprt. Frequencies of hprt mutant cells correlated with air levels of BD and with the concentration of a BD metabolite in urine. Average exposures to 1-3 parts per million (p.p.m.) of BD were associated with a threefold increase in hprt variant (mutant) frequencies (Vfs). We now report results from a follow-up study of workers in a synthetic rubber plant in Southeast Texas. Thirty-seven workers were evaluated on three occasions over a 2-week period for exposure to BD by the use of personal organic vapor monitors and by determining the concentration of a BD metabolite in urine. The frequency of hprt mutants was determined, by autoradiography, with lymphocyte samples collected 2 weeks after the final exposure measurement. Based on their work locations, the study participants were assigned to high-exposure (N=22) or low-exposure (N=15) groups. The BD exposure, +/-standard error, of the workers in the high-exposure group (1.65+/-0.52 p.p.m.) was significantly greater than the low-exposure group (0.07+/-0.03 p.p.m.; P<0.01). The frequency of hprt mutant lymphocytes was also significantly different in the two groups (high, 10.67+/-1.5 x 10(-6); low, 3.54+/-0.6 x 10(-6); P<0.001). The concentration of the urine metabolite was greater in the high-exposure group, but the difference was not significant. The correlation coefficient between hprt Vf and BD exposure levels was r=0.44 (CI(95), 0.11-0.69; P=0.011). This study reproduced the findings from a previous study at this plant. Although studies of butadiene-exposed workers in other countries have not detected an effect of exposure on frequencies of hprt mutant lymphocytes, we have repeatedly observed this result in our studies in Texas.

Air Pollutants, Occupational↗
PubMed2001

Point mutations induced by 1,2-epoxy-3-butene N1 deoxyinosine adducts.

The National Toxicology Program has recently classified 1,3-butadiene (BD) as a human carcinogen. BD is metabolized to the intermediates 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-dihydroxy-3,4-epoxybutane. All three metabolites have been implicated in producing specific types of DNA damage and as genotoxic agents in mice, rat, and human cells. This study has focused on EB-induced N1 deoxyinosine lesions that are formed by deamination of deoxyadenosine following reaction of the epoxide at the N(1) position. The R and S stereoisomers of this lesion were incorporated site-specifically within the context of an 11-mer oligodeoxynucleotide, incorporated into M13mp7L2 single-stranded DNA, and transfected into E. coli. Both stereoisomers modestly reduced plaque-forming ability, indicating that neither lesion presents a base modification that cannot be bypassed. The resulting plaques were assessed for point mutations using differential hybridization and DNA sequence analyses. The overall mutagenic spectrum revealed that the N1 adducts were highly mutagenic (approximately 90% per replication cycle), causing a predominance of A --> G transitions.

Adenine↗
PubMed2001

Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms.

1,3-Butadiene (BD) is a major commodity chemical used in the manufacture of synthetic rubber and various plastics and has been shown to be a potent animal carcinogen and a probable human carcinogen. The bioactivation of BD to reactive epoxides, and the balance between activation and detoxication of these reactive metabolites, is thought to play a critical role in the genotoxic and carcinogenic effects of BD. The detoxication of reactive BD metabolites involves enzymatic conjugation with glutathione by glutathione S-transferases (GSTs) and by hydrolysis, a reaction mediated by microsomal epoxide hydrolase (mEH). Since polymorphisms in genes of xenobiotic-metabolizing enzymes such as mEH may influence individual susceptibility to adverse health effects from BD exposure, we tested the hypothesis that the mEH Tyr113His polymorphism increases sensitivity to the genotoxic effects of BD in exposed workers. We used the autoradiographic hprt mutant lymphocyte assay as a biomarker of effect to identify genotoxicity associated with BD exposure in 49 workers from two styrene/butadiene polymer plants in Southeast Texas. Exposure to BD was assessed by collecting breathing zone air samples using passive badge dosimeters for three full 12 h work shifts 25, 20 and 14 days before blood was collected for genotyping and for the hprt assay. We genotyped the study participants for the Tyr113His polymorphism in the mEH gene and also for deletion polymorphisms in the glutathione S-transferase genes, GSTM1 and GSTT1, as potential biomarkers of susceptibility to BD. Our data indicate that the majority of the study subjects (67%) were exposed to very low levels of BD of <150 parts per billion (p.p.b.) time-weighted average (TWA). In some workers, however, we found levels of BD exposures that exceeded a TWA of 2000 p.p.b. Our data indicate a significant (P < 0.05) 2-fold increase in frequencies of hprt variant (mutant) lymphocytes (Vf) in workers exposed to >150 p.p.b. BD, compared with workers exposed to <150 p.p.b. There was no significant effect from individual GSTM1, GSTT1 or mEH genotypes in workers exposed to <150 p.p.b. BD. In workers exposed to >150 p.p.b., individuals with at least one polymorphic mEH His allele (His/His or His/Tyr genotypes) had a significant (P < 0.001) 3-fold increase in Vf (mean Vf x 10(-6) +/- SE = 13.25 +/- 1.78) compared with individuals with the Tyr/Tyr genotype (mean Vf x 10(-6) +/- SE = 4.02 +/- 0.72). There was no significant effect from individual GSTM1 or GSTT1 polymorphisms, but combined polymorphism analysis showed that the genetic damage was highest in individuals who had at least one mEH His allele and either the GSTM1 and/or GSTT1 null genotypes (hprt Vf = 14.19 +/- 2.30 x10(-6)). In contrast, this response was not observed in individuals exposed to levels of BD < 150 p.p.b. These results indicate that polymorphisms in the mEH gene may play a significant role in human sensitivity to the genotoxic effects of BD exposure, and that the hprt mutant lymphocyte assay can serve as a sensitive biomarker of genotoxicity for monitoring occupational exposure to BD in industrial settings. Additional investigations in larger populations of workers are needed to confirm our results and to characterize the possible role of additional mEH polymorphisms in the induction of genetic damage associated with occupational exposure to butadiene.

Alleles↗
PubMed2001

Assessment of 1,3-butadiene exposure in polymer production workers using HPRT mutations in lymphocytes as a biomarker.

1,3-Butadiene (BD), which is used to make styrene-butadiene rubber, is a potent carcinogen in mice and a probable carcinogen, associated with leukemia, in humans. We have previously used HPRT mutation as a biomarker to evaluate exposures to BD in a monomer production plant. We now report on a study of 49 workers in a styrene-butadiene rubber plant in which we used the concentration of the BD metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S)-butane (M1) in urine as a biomarker of exposure and the frequency of HPRT variant (mutant) lymphocytes (Vf) as a biomarker of effect. Workers were assigned to high- and low-exposure groups based on historical information about work areas and jobs. Personal exposure to BD for one work shift was measured using a passive badge dosimeter. Each participant provided a urine specimen and blood sample at the end of the work shift and completed a questionnaire providing information on lifestyle, health, and work activities. The average BD exposures in the high- and low-exposure groups were significantly different, even after excluding two extreme values, (high 1.48 ppm; low 0.15 ppm, p < 0.002). This study was done in 1994 and 1995 before the establishment, in 1996, of the new permissible exposure limit of 1 ppm. Both the mean M1 and the HPRT Vf were more than three times greater in the high-exposure group than in the low-exposure group (p < 0.0005). The three end points correlated with each other, with sample correlation coefficients between 0.4 and 0.6. The correlations among BD exposure and the biomarkers of internal exposure and genotoxicity suggest that occupational exposure to BD, in the range of 1-3 ppm, may be associated with adverse biological effects.

Acetylcysteine↗
PubMed2000

Effect of CYP2E1 induction by ethanol on the immunotoxicity and genotoxicity of extended low-level benzene exposure.

Potential additive effects of ethanol consumption, a common life-style factor, and low-level benzene exposure, a ubiquitous environmental pollutant, were investigated. Ethanol is a potent inducer of the cytochrome P-450 2E1 (CYP2E1) enzyme, which bioactivates benzene to metabolites with known genotoxicity and immunotoxicity. A liquid diet containing 4.1% ethanol was used to induce hepatic CYP2E1 activity by 4-fold in female CD-1 mice. Groups of ethanol-treated or pair-fed control mice were exposed to benzene or filtered air in inhalation chambers for 7 h/d, 5 d/wk for 6 or 11 wk. The initial experiment focused on immunotoxicity endpoints based on literature reports that ethanol enhances high-dose benzene effects on spleen, thymus, and bone marrow cellularity and on peripheral red blood cell (RBC) and white blood cell (WBC) counts. No statistically significant alterations were found in spleen lymphocyte cellularity, subtype profile, or function (mitogen-induced proliferation, cytokine production, or natural killer cell lytic activity) after 6 wk of ethanol diet, 0.44 ppm benzene exposure, or both. This observed absence of immunomodulation by ethanol alone, a potential confounding factor, further validates our previously established murine model of sustained CYP2E1 induction by dietary ethanol. Subsequent experiments involved a 10-fold higher benzene level for a longer time of 11 wk and focused on genotoxic endpoints in known target tissues. Bone marrow and spleen cells were evaluated for DNA-protein cross-links, a sensitive transient index of genetic damage, and spleen lymphocytes were monitored for hprt-mutant frequency, a biomarker of cumulative genetic insult. No treatment-associated changes in either genotoxic endpoint were detected in animals exposed to 4.4 ppm benzene for 6 or 11 wk with or without coexposure to ethanol. Thus, our observations suggest an absence of genetic toxicity in CD-1 mice exposed to environmentally relevant levels of benzene with or without CYP2E1 induction.

Animals↗
PubMed2000

Multiplex polymerase chain reaction-based analysis of T-cell receptor gamma gene rearrangements for the determination of T-lymphocyte clonality.

Determination of the frequency of mutations at hprt or other loci in human lymphocytes provides a useful biomarker for human exposure to mutagens. One problem, however, is distinguishing between unique mutants and sibling mutants arising as progeny of an earlier mutant cell. We have developed a multiplex polymerase chain reaction (PCR)-based method to analyze T-cell receptor (TCR) gamma gene rearrangements for determination of T-cell clonality in mutational spectrum analysis. PCR primers for different subgroups of the V gene segment of the TCR gamma gene were selected at different sites in the TCR gamma gene so that the size of PCR products could define which V subgroup was involved in rearranged TCR gamma genes; gamma genes involving different V and J subgroups could be determined directly by PCR. Mutant T-lymphocytes with rearranged TCR gamma genes containing the same V and J subgroups were analyzed using PCR-based denaturing polyacrylamide gel electrophoresis. All of the 161 hprt mutant clones analyzed contained rearranged TCR gamma genes. Rearrangements among all subgroups of the V and J gene segments of the TCR gamma gene could be detected. VgammaI and Jgamma1/2 subgroups were involved in 69 and 71% of rearranged TCR gamma genes, respectively. This PCR-based analysis of TCR gamma gene rearrangements provides a simple and comprehensive method for identifying the clonality of mutant T-lymphocytes in human hprt mutant lymphocyte assay and mutational spectrum analysis.

Electrophoresis, Polyacrylamide Gel↗
PubMed2000

Molecular analysis of hprt mutant lymphocytes from 1, 3-butadiene-exposed workers.

1,3-Butadiene (BD) has been shown to be a potent animal carcinogen and a probable human carcinogen, yet the molecular mechanisms of BD genotoxicity and carcinogenicity still are not fully understood. Our hypothesis is that metabolites of BD induce specific structural changes in the human hprt gene like those observed in vitro in TK6 cells and in vivo in the mouse. Characteristic mutations in BD-exposed subjects can be identified and used as biomarkers for monitoring genotoxic effects associated with BD exposure. Molecular analysis of hprt mutant lymphocytes from BD-exposed workers and unexposed control subjects was carried out to identify changes in the structure of the hprt gene. A multiplex polymerase chain reaction (PCR) assay was used to detect exon deletions in 360 hprt mutant clones. We determined that exon deletions were significantly more frequent (P < 0.05) in BD-exposed workers (17.5%) than in control subjects (9.7%). Sequence analysis of hprt cDNA from 175 independent mutants indicated that the distribution of the types of mutations was different between the workers and the unexposed control subjects. There was a significant increase in -1 frameshift mutations in BD-exposed workers, predominantly in repeated DNA sequences, and single-base substitutions were decreased to 66% in the workers compared to 83% in the control subjects (P < 0.05). In addition to the spectral changes, hprt clonal assays revealed an elevation in mutant frequency in the lymphocytes of workers (N = 10) when compared with that in unexposed control subjects (N = 11; P < 0. 05). There also was a twofold increase of A:T --> T:A transversions in BD-exposed workers (16% in BD-exposed workers compared to 8% in controls, P = 0.25). Some of the BD-associated changes in mutational spectra observed in our study have the potential for application in monitoring genotoxic effects related to butadiene exposure.

Adult↗
PubMed1997

Frequencies of hprt mutant lymphocytes in smokers, non-smokers, and former smokers.

Previous work with the autoradiographic mutant lymphocyte assay has provided information about the time-course of development of hprt mutations and the persistence of detectable mutant cells in human subjects following therapeutic exposures to genotoxic agents. These early studies also revealed elevations in frequencies of mutant cells in pretreatment blood samples from patients who were current tobacco smokers, but no information was available on former smokers. In the present study, blood samples were obtained from 21 healthy former tobacco smokers who had quit smoking at least 1 year before sampling, 42 subjects who had never smoked, and 23 tobacco smokers. Plasma from all samples was tested for cotinine, a metabolite of nicotine. Current smokers were categorized as heavy smokers (> or = 10 cigarettes per day, cotinine > or = 90 ng/ml plasma) and light smokers (< 10/day, cotinine < 90 ng/ml). Lymphocytes from the blood samples were isolated, cryopreserved, and later thawed and assayed with the autoradiographic hprt assay. The 21 former tobacco smokers had a mean variant (mutant) frequency (Vf +/- standard error) of 1.97 (+/-0.13) per million evaluatable cells. The Vf of 42 subjects who had never smoked was 1.74 (+/-0.13) x 10(-6), not significantly different from the former smokers. The smokers had Vfs of 8.09 (+/-0.78) x 10(-6) for 18 heavy smokers and 5.22 (+/-1.02) x 10(-6) for five light smokers. The two categories of smokers had frequencies of mutant cells significantly different from each other, and each was significantly higher than non-smokers and former smokers (P < 0.05). Vfs were significantly correlated with both cotinine concentrations and the number of cigarettes smoked per day, P < 0.001. This study demonstrates the sensitivity of the autoradiographic hprt assay for detecting mutagenic effects related to chronic low-level exposures to genotoxins, and indicates that this assay is more likely to detect the effects of recent rather than past exposures.

Adolescent↗
PubMed1996

Biological monitoring for mutagenic effects of occupational exposure to butadiene.

The use of biological markers in the evaluation of human exposure to hazardous agents has increased rapidly in recent years. Because 1,3-butadiene is a mutagenic carcinogen, existing occupational levels of exposure may be appropriately evaluated using somatic cell mutation as a biomarker. Previously, we have described a biomarker study of workers in a butadiene monomer plant (Ward et al., 1994). We now report results from a second study of the same group of workers, conducted after plant modernization, and present preliminary results from a study of exposures in a styrene butadiene rubber (SBR) plant. Air levels of butadiene were determined using either charcoal tubes with air pumps or passive badge dosimeters. The quantity of a butadiene metabolite in the urine was used as a biomarker of exposure and the mutagenic effects of exposure were measured using the autoradiographic hprt mutant lymphocyte assay. In all three studies, the frequencies of hprt mutants were significantly elevated in workers from the areas of highest exposure when compared to workers from lower exposure areas or non-exposed subjects. The concentration of the urinary metabolite was significantly increased in high-exposed workers in the first study of monomer plant workers but not in the second. In the first monomer plant study, historical air concentrations of butadiene were higher in the production units than in the central control unit. While concurrent determined air concentrations were not elevated in the second monomer plant study, they were elevated in high exposure areas in the SBR plant study. Mutant frequencies in the lower-exposure and the non-exposed groups were consistent with historical values for non-smoking individuals who were not exposed to known mutagens. The use of biomarkers, including the hprt mutant lymphocyte assay, may be of great value in determining an appropriate occupational exposure limit for butadiene.

Butadienes↗
PubMed1996

Repeated oral benzene exposure alters enzymes involved in benzene metabolism.

Benzene is a known carcinogen and hematopoietic toxin in humans and experimental animals. The effect of acute, high-dose exposure to benzene on hepatic bioactivation and detoxication enzymes has been defined, while little is known about the effect of repeated, low-dose benzene exposure on these enzymes. Our objective was to determine whether repeated, oral benzene exposure alters enzymes involved in benzene metabolism. Specifically, we were concerned with cytochrome P-450-2E1, a bioactivation enzyme, and glutathione transferase and aldehyde dehydrogenase, two detoxifying enzymes. Female CD-1 mice were treated by gavage for 3 wk with benzene doses of 5 mg/kg (0.064 mmol/kg) or 50 mg/kg (0.646 mmol/kg) in corn oil. These doses of benzene produced 0.048 and 0.236 mumol muconic acid/d, respectively. We found that repeated exposure to 50 mg benzene/kg/d decreased P-450-2E1 activity by 34% and induced glutathione transferase activity by 30% without affecting aldehyde dehydrogenase activity. These changes in enzyme activities may serve a protective role against repeated exposure to benzene.

Administration, Oral↗
PubMed1996

Progressive disruption of acinar cell calcium signaling is an early feature of cerulein-induced pancreatitis in mice.

BACKGROUND & AIMS: Disruption of pancreatic exocrine secretion is an important feature of acute pancreatitis. Because cytosolic calcium is a key intracellular messenger controlling pancreatic secretion, this study examined patterns of calcium signaling during the early stages of cerulein-induced pancreatitis. METHODS: Mice were administered hourly intraperitoneal injections of cerulein (50 micrograms/kg), and paired controls were administered saline. Acini were isolated by collagenase from pancreatic tissue harvested after injections 1, 3, 5, and 7 and were loaded with Fura-2. Individual cellular calcium responses to acetylcholine and cholecystokinin were studied using digital imaging. RESULTS: The proportion of cells maintaining a normal oscillatory calcium response to physiological secretagogue stimulation diminished progressively after increasing cerulein injections. Also, the normal polarized spatial pattern of calcium Increase within individual acinar cells was progressively lost. A sustained response to high-dose stimulation was maintained but with diminishing amplitude. The characteristic calcium response to the Ca(2+)-adenosine triphosphatase inhibitor thapsigargin was maintained, implying that calcium reuptake and extrusion were not impaired. CONCLUSIONS: Progressive disruption of physiological patterns of pancreatic acinar cell calcium signaling, notably in the secretory pole of the cell, is an early feature of pancreatitis induced by cerulein hyperstimulation. These changes may be important in contributing to the disruption of exocrine secretion in acute pancreatitis.

Acetylcholine↗
PubMed1996

Identification of needs in biomarker research.

Interest in the use of biological markers to evaluate future disease risk has increased greatly in recent years. Biomarkers are observable end points in a continuum of events leading from exposure to toxic agents to diseases that ultimately result from exposure. Because many significant diseases develop over long periods of time, methods for detecting early events that can predict risk are important for disease prevention. Biomarkers are generally categorized as detecting exposure, effects of exposure, or individual susceptibility to exposure. Although there has been significant progress in the technical development of biomarkers, implementation of their use in human populations has progressed much more slowly. We discuss four major needs in the development of biomarkers. First, new biomarkers need to be developed to fill gaps in our ability to observe steps in the continuum from exposure to disease. Second, the relationships between biomarker responses and disease pathology needs to be better understood. Third, the sensitivity, specificity, and variability of biomarkers need to be better characterized and they must be better validated as predictors of disease risk. Fourth, there are several societal impediments to the practical implementation of biomarker studies as public health tools. A common agreement among employers, employees, regulators, and the legal community must be established regarding appropriate and ethical uses and interpretation of biomarker data.

Biomarkers↗
PubMed1995

Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis?

The pathogenesis of acute pancreatitis is poorly understood, despite well-recognised precipitating factors. Current evidence suggests that the earliest abnormalities of acute pancreatitis arise within acinar cells, but the key intracellular trigger has yet to be identified. Within the pancreas, physiological concentrations of secretagogues bind to G-protein-linked cell-surface receptors on acinar cells, evoking short, oscillatory spikes of acinar cytosolic-free ionised calcium ([Ca2+]i), an ubiquitous intracellular messenger. Specific effects within acinar cells include initiation of enzyme release through the phosphorylation cascades of stimulus-secretion coupling. Low resting levels of [Ca2+]i are restored by Ca(2+)-ATPase, which pumps calcium into the endoplasmic reticulum and out of the cell. If high concentrations of [Ca2+]i persist, toxicity results, intracellular signalling is disrupted, and cell damage occurs. Sustained elevations in acinar [Ca2+]i result from exposure to high concentrations of secretagogues, high doses of which also induce acute pancreatitis. Similarly, sustained elevations of [Ca2+]i may result from ductal hypertension, alcohol, hypoxia, hypercalcaemia, hyperlipidaemia, viral infection, and various drugs--all factors known to precipitate acute pancreatitis. We suggest that these factors precipitate acute pancreatitis by causing either excessive release of acinar [Ca2+]i, or damage to the integrity of mechanisms that restore low resting levels of [Ca2+]i, and that the consequent calcium toxicity is the key trigger in the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed1995

Reversible abnormalities in the ophthalmic arteries detected by color Doppler imaging.

PURPOSE: To demonstrate dynamic, reversible abnormalities in ophthalmic artery blood flow velocity identified with color Doppler imaging (CDI) in patients with clinical findings of ocular ischemia with and without carotid artery stenosis. METHODS: One patient with ocular ischemia and normal carotid arteries had abnormal ophthalmic artery velocities demonstrated by CDI. Two other patients with reversed ophthalmic artery flow and critical internal carotid artery stenosis were studied before and after carotid endarterectomy. Peak systolic and diastolic velocities as well as pulsatility indices of ophthalmic, posterior ciliary, and central retinal arteries were calculated. RESULTS: The patient who had ocular ischemic syndrome without carotid artery stenosis showed increased ophthalmic artery velocities initially, and reversal of flow within the ophthalmic artery subsequently developed. Clinical findings and symptoms improved gradually as ophthalmic artery, posterior ciliary, and central retinal artery velocities increased. The patients with critical internal carotid artery stenosis had reversed ophthalmic artery blood flow initially which reverted to normal after carotid endarterectomy. CONCLUSION: Ocular ischemic syndrome may occur due to abnormal blood flow in the ophthalmic artery in the absence as well as in the presence of carotid artery stenosis. Flow dynamics in the ophthalmic artery and its branches can be shown by CDI to revert toward normal as the clinical findings improve spontaneously or after opening an occluded carotid artery.

Aged↗