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Biomedical subjects

D G Le Couteur

Publications and source records attributed to D G Le Couteur.

At least 19 recordsLinked to original sources
PubMed2005

The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy.

BACKGROUND: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM: To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS: Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS: Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION: The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.

Adult↗
PubMed2005

A randomized clinical trial of activated charcoal for the routine management of oral drug overdose.

BACKGROUND: Activated charcoal (AC) is commonly used for the routine management of oral drug overdose. AIM: To determine whether the routine use of activated charcoal has an effect on patient outcomes. DESIGN: Randomized controlled unblinded trial. METHODS: We recruited all adult patients presenting with an oral overdose at The Canberra Hospital, excluding only transfers, late presenters, those who had ingested drugs not adsorbed by activated charcoal or where administration was contraindicated, and very serious ingestions (at the discretion of the admitting physician). Patients were randomized to either activated charcoal or no decontamination. RESULTS: The trial recruited 327 patients over 16 months. Of 411 presentations, four refused consent, 27 were protocol violations and 53 were excluded from the trial. Only seven were excluded due to the severity of their ingestion. The most common substances ingested were benzodiazepines, paracetamol and selective serotonin reuptake inhibitor antidepressants. More than 80% of patients presented within 4 h following ingestion. There were no differences between AC and no decontamination in terms of length of stay (AC 6.75 h, IQR 4-14 vs. controls 5.5 h, IQR 3-12; p=0.11) or secondary outcomes including vomiting, mortality and intensive care admission. DISCUSSION: Routine administration of charcoal following oral overdose did not significantly influence length of stay or other patient outcomes following oral drug overdose. There were few adverse events. This does not exclude a role in patients who present shortly after ingestion of highly lethal drugs.

Acetaminophen↗
PubMed2004

The effect of aging on the immunohistochemistry of apolipoprotein E in the liver.

Apolipoprotein E (apoE) is involved in hepatic disposition of chylomicron remnants, which is impaired in old age. Isoforms of apoE have been implicated in age-related diseases and possibly the aging process itself. Because the effects of old age on expression and distribution of apoE in the liver have not been reported, we studied the effect of old age on the immunohistochemistry of apoE in the livers of humans and the non-human primate, Papio hamadryas. Overall, old age was not associated with marked changes in the expression of apoE between adult (48+/-19 years) and old (82+/-5 years) humans. However, there was a change in the distribution of apoE staining. The livers of older humans displayed increased hepatocyte cytoplasmic staining and reduced peri-sinusoidal staining. Similar trends were noted in the livers from the baboons. Such findings are suggestive of altered apoE recycling in old age and have implications for age-related dyslipidaemia.

Aged↗
PubMed2004

Wash-in methodology and modeling to determine hepatocellular D-glucose transport in the perfused rat liver.

Wash-in experiments, which may be useful for the study of the disposition of substrates in the liver, have not been well described. To investigate physiological models for wash-in curves, we performed experiments on the perfused livers of male Wistar rats anesthetized with pentobarbital. Test perfusate contained (14)C-sucrose as the extracellular marker and (3)H-glucose. Liver perfusions were performed with background glucose concentrations of 5.7, 10.7, 51.2, or 108.5 mM. Outflow time-activity curves were analyzed with the use of four models. The V(max) and K(m) for the influx of glucose were 1.1 +/- 0.03 micromol/s/g and 41 +/- 3 mM with the Crone-Renkin early extraction model; 1.4 +/- 0.04 micromol/s/g and 36 +/- 3 mM with dispersion model analysis; 1.8 +/- 0.1 micromol/s/g and 25 +/- 4 mM with the Goresky distributed model to fit differentiated wash-in curves; and 2.7 +/- 0.6 micromol/s/g and 28 +/- 21 mM with compartmental analysis. There was reasonable agreement between the four models, and they yielded results similar to those reported for glucose uptake in other preparations.

Animals↗
PubMed2002

The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients.

Iron homeostasis is altered in Parkinson's disease (PD). The HFE protein is an important regulator of cellular iron homeostasis and variations within this gene can result in iron overload and the disorder known as hereditary haemochromatosis. We studied the Cys282Tyr single nucleotide polymorphism as a genetic risk factor for PD in two distinct and separately collected cohorts of Australian PD patients and controls. In the combined cohort comprising 438 PD patients and 485 control subjects, we revealed an odds ratio for possession of the 282Tyr allele of 0.61 (95% confidence interval, CI=0.42-0.90, P=0.011) from univariate chi-squared and 0.59 (95% CI=0.39-0.90, P=0.014) after logistic regression analyses (correcting for potential confounding factors). These results suggest that possession of the 282Tyr allele may offer some protection against the development of PD.

Aged↗
PubMed2001

Cell membrane transport of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the liver and systemic bioavailability.

Modulation of hepatic disposition of MPTP could influence susceptibility to its neurotoxicity. Therefore, we studied hepatocellular transport of MPTP in the perfused rat liver and isolated rat hepatocytes. The perfused liver extensively extracted MPTP. Amiloride and tubocurarine, inhibitors of OCT1, increased MPTP recovery (253 +/- 78 and 283 +/- 64%, respectively) and reduced PS(influx) (0.69 +/- 0.36 to 0.27 +/- 0.11, and 0.97 +/- 0.50 to 0.23 +/- 0.05 ml/s/g, respectively). P-glycoprotein inhibitor, daunomycin, and Oatp 1 & 2 inhibitor, rifamycin, had no effect. In isolated hepatocytes, amiloride and tubocurarine increased hepatic uptake of MPTP (23 +/- 12 and 6 +/- 2%, respectively). Daunomycin reduced MPTP uptake by 22 +/- 8% and rifamycin had no effect. Only a small proportion of MPTP is taken up into hepatocytes by transporters; however, modulation of these transport mechanisms will influence systemic bioavailability.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

The effect of acute oxidative stress on the ultrastructure of the perfused rat liver.

Ageing and liver disease are associated with ultrastructural changes in the hepatic sinusoid. Because of the possibility that reactive oxygen species could mediate these processes, we examined the effect of acute oxidative stress on the ultrastructure of the intact liver. Rat livers were perfused ex vivo, in situ with hydrogen peroxide via the portal vein. The livers were then fixed and the ultrastructure of the liver tissue examined with transmission and scanning electron microscopy. The effects of hydrogen peroxide were largely confined to the perisinusoidal areas. The sinusoidal endothelial cells became swollen and more porous, with large gaps replacing sieve plates. The space of Disse showed an increase in volume and the density of hepatocyte projections decreased. Kupffer cell activation was noted. Little or no ultrastructural change was observed within the hepatocytes. Oxidative stress delivered via the portal vein dramatically alters the ultrastructure of the perisinusoidal regions of the liver. This process may contribute to the pathogenesis of disease and age-related changes in the liver.

Animals↗
PubMed2001

Pseudocapillarization and associated energy limitation in the aged rat liver.

Age-related impairment of drug metabolism by the liver is consistent with hepatocyte hypoxia, suggestive of the development of a diffusional barrier to oxygen supply. Because the effects of aging on the diffusional pathway (sinusoidal endothelium and space of Disse) have not been described, we performed comparative studies on the livers of Fischer F344 rats aged 4 to 7, 12 to 15, and 24 to 27 months. Light-microscopic examination revealed no evidence of fibrosis, cirrhosis, or other specific pathology. In contrast, scanning and transmission electron-microscopic examination revealed that aging is associated with pseudocapillarization of the sinusoidal endothelium, indicated by defenestration with reduced porosity, thickening of the endothelium, infrequent development of basal lamina, and only minor collagen deposits in the space of Disse. Furthermore, immunohistochemistry studies showed strong expression of collagen IV, moderate expression of factor VIII-related antigen, and weak expression of collagen I along the sinusoids of livers from old rats (P <.0001). In vitro (31)P magnetic resonance spectroscopy analysis showed that aging is associated with changes in high-energy phosphate and other metabolites, consistent with hepatocyte hypoxia. Aging in the liver is associated with changes in the sinusoidal endothelium and space of Disse that may restrict the availability of oxygen and other substrates.

Aging↗
PubMed2001

Carbon monoxide wash-in method to determine gas transfer in vascular beds: application to rat hindlimb.

The vascular barrier to gas transfer is an important physiological parameter; however, no readily applicable technique exists to quantitate the process. A simple technique to measure the permeability-surface area (PS) product for gas transfer in vascular beds is proposed using wash in of carbon monoxide (CO) and Crone-Renkin analysis. Wash-in experiments were performed on the perfused hindlimbs of male Wistar rats (n = 15) by using CO as a surrogate marker for oxygen and technetium-99m-labeled albumin as the vascular marker. The use of CO and erythrocyte-free perfusate and the collection of outflow samples into tubes preloaded with erythrocytes obviated the need for an anaerobic collection device or consideration of Hb binding in the analysis. The PS product for CO was determined from the early extraction as 0.013 +/- 0.006 ml. s(-1). g(-1). Compartmental analysis revealed that the fractional recovery of CO was 0.45 +/- 0.14 and the volume of distribution was 2.31 +/- 0.76 ml/g. This technique detected a small measurable barrier to the transfer of CO across the hindlimb vasculature and is potentially applicable to other vascular beds in health and disease.

Animals↗
PubMed2001

Immunohistochemistry of omega class glutathione S-transferase in human tissues.

Omega class glutathione transferase (GSTO) has been recently described in a number of mammalian species. We used immunohistochemistry to determine the cellular and tissue distribution of GSTO1-1 in humans. Expression of GSTO1-1 was abundant in a wide range of normal tissues, particularly liver, macrophages, glial cells, and endocrine cells. We also found nuclear staining in several types of cells, including glial cells, myoepithelial cells of the breast, neuroendocrine cells of colon, fetal myocytes, hepatocytes, biliary epithelium, ductal epithelium of the pancreas, Hoffbauer cells of the placenta, and follicular and C-cells of the thyroid. These observations and the known activity of GSTO1-1 suggest biological functions that are not shared with other GSTs.

Glutathione Transferase↗
PubMed2001

Intracerebral hemorrhage following possible interaction between celecoxib and clopidogrel.

OBJECTIVE: To report a case of intracerebral hemorrhage following short-term, concomitant use of celecoxib and clopidogrel. CASE SUMMARY: An 86-year-old white woman with a medical history of paroxysmal atrial fibrillation, heart failure, osteoarthritis, peptic ulcer disease, chronic airway limitation, and surgery for carcinoma of the bowel and breast began clopidogrel therapy following a syncopal episode. She also began taking celecoxib for osteoarthritis at the same time. Three weeks later, she presented with headaches and left hemiparesis. Computed tomography scan revealed intracerebral hemorrhage that had not been previously detected. Celecoxib and clopidogrel were discontinued, and she recovered fully. DISCUSSION: This is the first case describing a possible interaction between celecoxib and clopidogrel. A pharmacokinetic interaction mediated by CYP2C9 is possible. However, the hemorrhage may have been secondary to the effects of either drug alone or concomitant disease. CONCLUSIONS: Celecoxib and clopidogrel have favorable risk profiles and, therefore, are prescribed widely among older people. However, clinicians should recognize that there may be an interaction between celecoxib and clopidogrel that increases the risk of hemorrhage in older people.

Aged↗
PubMed2001

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.

Cimetidine↗
PubMed2000

The monoamine oxidase B gene GT repeat polymorphism and Parkinson's disease in a Chinese population.

Monoamine oxidase B (MAOB) metabolises dopamine and activates neurotoxins known to induce parkinsonism in humans and primates. Therefore the MAOB gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD). Longer length dinucleotide repeat sequences in a highly polymorphic GT repeat region of intron 2 of this gene showed an association with PD in an Australian cohort. We repeated this allele-association study in a population of 176 Chinese PD patients (90 men, 86 women) and 203 agematched controls (99 men, 104 women). Genomic DNA was extracted from venous blood and the polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis. There was no significant difference in allele frequencies of the (GT) repeat allelic variation between patients and controls (chi2 = 2.48; df = 5, P<0.75). Therefore the longer length GT repeat alleles are not associated with PD in this Chinese population. Possible reasons for the discrepancy between Chinese and Australian populations include a different interaction between this genetic factor and environmental factors in the two populations and the possibility that the long length GT repeat alleles may represent a marker mutation, genetically linked to another susceptibility allele in whites but not in Chinese. Methodological differences in the ascertainment of cases and controls in this cohort could also explain the observed differences. Further study is required to determine whether the longer length GT repeat alleles are true susceptibility alleles in PD.

Aged↗
PubMed2000

Paraoxonase polymorphisms, pesticide exposure and Parkinson's disease in a Caucasian population.

Parkinson's disease (PD) has been associated with exposure to pesticides and oxidative injury. The involvement of paraoxonase in both pesticide metabolism and lipid peroxidation suggests that it may play a role in the pathogenesis of PD. We examined the frequency of polymorphic alleles of the PON1 and PON2 genes in a sample of caucasian subjects with PD. The frequency distribution of these genotypes did not differ significantly between patients and controls, including those who had reported exposure to pesticides.

Aryldialkylphosphatase↗