This themed section takes as its starting point the premise that the body matters in Internationa... more This themed section takes as its starting point the premise that the body matters in International Political Economy (IPE) and presents four original articles which support and illustrate this ontologically critical and, perhaps, provocative position. Although feminist scholarship has undoubtedly gained a place at the table in IPE, it is curious that one of the most important concerns, and contributions, of feminist IPE – that global capitalism is marked upon, and forged through, bodies – has not emerged as a major preoccupation for the discipline more broadly. This themed section presents what we believe is a strong corrective to that inattention and, in so doing we hope to begin to set out an exploratory agenda for the body to be both foundational and fundamental to contemporary IPE.
Abstract This article supports growing calls to 'take small stat... more Abstract This article supports growing calls to 'take small states seriously'in the international political economy but questions prevailing interpretations that 'smallness' entails inherent qualities that create unique constraints on, and opportunities for, small states. Instead, we ...
... a * & Nicola J. Smith a * pages 259-271. ... Who have themsel... more ... a * & Nicola J. Smith a * pages 259-271. ... Who have themselves created an alliance which is now active in a variety of multilateral settings. See Alden and Vieira (2005); Lee, Taylor and Williams (2006). View all notes. Few of the very active developing countries are small states. ...
... Also focusing on the WTO, Donna Lee and Nicola Smith argue that small African states have in ... more ... Also focusing on the WTO, Donna Lee and Nicola Smith argue that small African states have in fact come to play a central role in multilateral trade negotiations, but that their increased activism has not translated into effective substantive influence. ...
... The international political economy of commercial sex. View full textDownload full text Full ... more ... The international political economy of commercial sex. View full textDownload full text Full access. DOI: 10.1080/09692291003762498 Nicola J. Smith a ... Violence Against Women , 10(10): 1126–55. [CrossRef], [Web of Science ®] View all references; Farley, 200422. ...
Once the 'sick man of Europe', the Irish Republic is now hailed as the 'Celtic Tiger'. Commentato... more Once the 'sick man of Europe', the Irish Republic is now hailed as the 'Celtic Tiger'. Commentators and politicians, both within and outside Ireland, point to the Republic's supposedly dazzling economic success as evidence of how nations can flourish in a globalised world. I question this notion, suggesting that Ireland's improved economic performance is best explained by a combination of factors, which cannot simply be lumped under the term 'globalisation'. Indeed, they seem directly to contradict many of the arguments made in the name of globalisation. However, I also contend that ideas about globalisation may play an increasingly important role in Irish economic developments.
To determine the pulmonary epithelial lining fluid (ELF) concentrations and degree of oxidation o... more To determine the pulmonary epithelial lining fluid (ELF) concentrations and degree of oxidation of ascorbic acid in horses affected by recurrent airway obstruction (RAO) in the presence and absence of neutrophilic airway inflammation. 6 RAO-affected horses and 8 healthy control horses. Nonenzymatic antioxidant concentrations were determined in RBC, plasma, and ELF samples of control horses and RAO-affected horses in the presence and absence of airway inflammation. ELF ascorbic acid concentration was decreased in RAO-affected horses with airway inflammation (median, 0.06 mmol/L; 25th and 75th percentiles, 0.0 and 0.4 mmol/L), compared with RAO-affected horses without airway inflammation (1.0 mmol/L; 0.7 and 1.5 mmol/L) and control horses (2.2 mmol/L; 1.4 and 2.2 mmol/L). Epithelial lining fluid ascorbic acid remained significantly lower in RAO-affected horses without airway inflammation than in control horses. Moreover, the ELF ascorbic acid redox ratio (ie, ratio of the concentrations of dehydroascorbate to total ascorbic acid) was higher in RAO-affected horses with airway inflammation (median, 0.85; 25th and 75th percentiles, 0.25 and 1.00), compared with RAO-affected horses without airway inflammation (0.04; 0.02 and 0.22). The number of neutrophils in bronchoalveolar lavage fluid was inversely related to the ELF ascorbic acid concentration (r = -0.81) and positively correlated with the ascorbic acid redox ratio (r = 0.65). Neutrophilic inflammation in horses affected by RAO is associated with a reduction in the ELF ascorbic acid pool. Nutritional supplementation with ascorbic acid derivatives in horses affected by RAO is an area for further investigation.
To test whether isoprostanes could be used as markers of oxidative stress in horses, their concen... more To test whether isoprostanes could be used as markers of oxidative stress in horses, their concentration was determined in plasma and in pulmonary epithelial lining fluid (PELF) in 3 models of oxidative stress: (1) strenuous exercise, (2) acute COPD crisis and (3) exercise combined with COPD crisis. Four horses were investigated twice, once in crisis and once in remission. The animals underwent a standardised treadmill exercise test. Isoprostane assessment was performed in plasma and bronchoalveolar lavage fluid 24 h before and 1 h after exercise and in plasma also immediately after exercise. Exercise in remission induced a significant increase of isoprostanes in plasma and in PELF. In horses in crisis, the isoprostane concentrations did not increase in plasma, while they did increase in PELF. Lastly, exercise in crisis increased plasma levels of isoprostanes, but did not change PELF isoprostanes. In conclusion, 1) isoprostanes are increased by systemic oxidative stress induced by strenuous exercise in COPD horses in remission either in PELF or in plasma; 2) only PELF and not plasma isoprostanes are increased by pulmonary oxidative stress induced by COPD crisis and 3) unexpectedly, exercise in crisis increased plasma but not PELF isoprostanes.
The effects of prolonged variable-intensity and short-term high-intensity exercise on indices of ... more The effects of prolonged variable-intensity and short-term high-intensity exercise on indices of oxidative stress and iron homeostasis were compared in six fit horses under cool [20°C, 40% relative humidity (RH)] or hot/humid (30°C, 80% RH) environmental conditions. The exercise protocols were designed to simulate equine competition, including racing (intense exercise) or the speed and endurance phase of a 3-day event (prolonged exercise). Increased plasma concentrations of lipid hydroperoxides and haemolysate concentrations of oxidised glutathione (GSSG) were measured within 30 min of the completion of exercise, indicating production of reactive oxygen species (ROS) and lipid membrane peroxidation. The horses were unable to complete the prolonged exercise protocol at high temperature and humidity. This coincided with higher maximal values of lipid hydroperoxides [138.2 (17.7) μM and GSSG [110.6 (18.2) μM], compared to high-intensity [105.2 (14.9) μM and 63.6 (8.6) μM, respectively] or prolonged [100.7 (18.7) μM and 86.2 (9.1) μM, respectively] exercise performed under cooler environmental conditions. Significant correlations were found between the duration of the final stage of exercise during hot/humid environmental conditions and increased levels of lipid hydroperoxides (r = 0.85), GSSG (r = 0.94), xanthine (r = 0.92) and uric acid (r = 0.96). Excerise also decreased the iron (Fe)-binding antioxidant activity of the plasma and increased the total plasma Fe levels, although this was only significant for prolonged exercise in ambient conditions. There was no detectable free Fe in the plasma at any stage of exercise. Other changes in biochemical parameters had returned to pre-exercise levels within 24 h after exercise. The results show that exercise can induce changes in biochemical parameters that are indicative of oxidative stress in the fit horse and that this was, exacerbated during exercise at high temperature and humidity.
To test the hypothesis that reactive oxygen species could be associated to the lower airway disor... more To test the hypothesis that reactive oxygen species could be associated to the lower airway disorders occurring in horses suffering from recurrent airway obstruction (RAO), indices of oxidative stress were studied in blood and pulmonary epithelium lining fluid in 5 RAO horses either in clinical remission or 24 h after the onset of a crisis of bronchospasm and in 5 healthy horses. Venous blood and bronchoalveolar lavage fluid (BALF) samples were collected and analysed for reduced glutathione (GSH), oxidised glutathione (GSSG), total glutathione (TGSH), glutathione redox ratio (GRR) in blood haemolysate and pulmonary epithelium lining fluid (PELF). The haemolysate concentrations of GSH, GSSG, TGSH and GRR were similar in the 3 groups. The PELF glutathione status was significantly different in the RAO horses in acute crisis compared to healthy horses, indicating the occurrence of an oxidative stress. When RAO horses were in crisis their GSH and TGSH remained unchanged but their GSSG and GRR were significantly increased compared to the remission.These results support the hypothesis that oxidative stress is associated with lower airway disorders occurring in horses suffering from RAO.
Journal of Chromatography B: Biomedical Sciences and Applications, 1995
A change in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) can be used to ... more A change in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) can be used to indicate oxidative stress in vivo. A rapid and highly sensitive isocratic reversed-phase high-performance liquid chromatographic method using coulometric electrochemical detection (LCEC) has been developed to simultaneously detect GSH and GSSG in equine biological fluids. Perchloric acid was used to extract GSH and GSSG from equine plasma and haemolysates, and methanol was used to deproteinise bronchoalveolar lavage fluid samples. Injection of extracts onto a Hypersil ODS HPLC column produced well resolved peaks corresponding to GSH and GSSG. The concentrations of GSH and GSSG found in equine haemolysates were similar to those previously found in humans and laboratory animals, although, to the authors' knowledge, previous attempts to measure GSH and GSSG in bronchoalveolar lavage fluid using LCEC have been unsuccessful. This method can be used to measure the GSH redox ratio in biological fluids during physiological conditions that may induce oxidative stress, such as exercise and disease.
Journal of Developmental & Behavioral Pediatrics, 2011
The purpose of the book is to guide families as they learn about and make decisions for their chi... more The purpose of the book is to guide families as they learn about and make decisions for their child with an ASD. The initial section of this text on the child first describes different patterns of development, before explaining how a diagnosis is made, the known or probable causes ...
The aim of this study was to test the hypothesis that pulmonary inflammation and emphysema induce... more The aim of this study was to test the hypothesis that pulmonary inflammation and emphysema induced by cadmium (Cd) inhalation are associated with pulmonary oxidative stress. Two groups of Sprague Dawley rats were used: one vehicle-exposed group undergoing inhalation of NaCl (0.9%, n = 24) and one Cd-exposed group undergoing inhalation of CdCl(2) (0.1%, n = 24). The animals in the vehicle-and Cd-exposed groups were divided into 4 subgroups (n = 6 per group), which underwent either a single exposure (D2) of 1H or repeated exposures 3 times/week for 1H for a period of 3 weeks (3W), 5 weeks (5W) or 5 weeks followed by 2 weeks without exposure (5W + 2). At sacrifice, the left lung was fixed for histomorphometric analysis (median inter-wall distance, MIWD), whilst bronchoalveolar lavage fluid (BALF) was collected from the right lung. Cytological analysis of BALF was performed and BALF was analysed for oxidant markers 8-iso-PGF(2a), uric acid (UA), reduced (AA) and oxidised ascorbic acid (DHA) and reduced (GSH) and oxidised glutathione (GSSG). Cd-exposure induced a significant increase of BALF macrophages and neutrophils. 8-iso-PGF(2a), UA, GSH and GSSG were significantly increased at D2. At 5W and 5W + 2, AA and GSH were significantly lower in Cd-exposed rats, indicating antioxidant depletion. MIWD significantly increased in all repeatedly Cd-exposed groups, suggesting development of pulmonary emphysema. 8-iso-PGF(2a) and UA were positively correlated with macrophage and neutrophil counts. GSH, GSSG and 8-iso-PGF(2a) were negatively correlated with MIWD, indicating that Cd-induced emphysema could be associated with pulmonary oxidative stress.
The phenomenon of ozone tolerance is described, but the underlying mechanisms remain unknown. We ... more The phenomenon of ozone tolerance is described, but the underlying mechanisms remain unknown. We tested whether adaptation to multiday ozone exposure was related to an upregulated pulmonary antioxidant defence. Six calves were exposed to 0.75 ppm ozone, 12 h day(-1) for seven consecutive days. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed before, after the first (D1), third (D3) and seventh (D7) exposure. Differential cell count, total proteins, 8-epi-PGF2alpha, glutathione and uric acid were determined in BAL. Dynamic lung compliance and arterial oxygen tension were significantly decreased and lung oedema impaired pulmonary function on D1. By repeating ozone exposures, progressive functional adaptation occurred. Ozone induced a significant increase of BAL neutrophil percentage on D1. On D3 and D7, neutrophil percentage was progressively decreased, but remained significantly elevated. BAL total proteins were significantly increased on D1 and decreased progressively until D7. 8-Epi-PGF2alpha was significantly increased on D1 and was returned to baseline on D3 and D7, whilst glutathione significantly increased on D3 and returned to baseline on D7. Uric acid was increased ten-fold on D1. On D3, uric acid was increased six-fold and was persistently elevated at D7. This study suggests that ozone adaptation of functional and inflammatory variables is accompanied with sustained BAL uric acid elevation.
Expert Opinion on Drug Metabolism & Toxicology, 2005
Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response i... more Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [ 3 H]docetaxel and [ 3 H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (P = 0.0007) and 3.3-fold higher for paclitaxel (P < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 µM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, P < 0.0001), cyclosporin A (25.2%, P = 0.005), glycyrrhizic acid (24.6%, P = 0.012), and hyperforin (28.4%, P = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 100... more The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 1000-fold more cytotoxic than the parent drug. The pharmacokinetics of irinotecan are extremely complex and have been the subject of intensive investigation in recent years. Irinotecan is subject to extensive metabolism by various polymorphic enzymes, including CES2 to form SN-38, members of the UGT1A subfamily, and CYP3A4 and CYP3A5, which form several pharmacologically inactive oxidation products. Elimination of irinotecan is also dependent on drug-transporting proteins, notably ABCB1 (P-glycoprotein), ABCC2 (cMOAT) and ABCG2 (BCRP), present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. This report provides an update on current strategies to individualize irinotecan chemotherapy based on each patient’s genetic constitution, which may ultimately lead to more selective use of this agent.
Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response i... more Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [ 3 H]docetaxel and [ 3 H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (P = 0.0007) and 3.3-fold higher for paclitaxel (P < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 µM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, P < 0.0001), cyclosporin A (25.2%, P = 0.005), glycyrrhizic acid (24.6%, P = 0.012), and hyperforin (28.4%, P = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
This themed section takes as its starting point the premise that the body matters in Internationa... more This themed section takes as its starting point the premise that the body matters in International Political Economy (IPE) and presents four original articles which support and illustrate this ontologically critical and, perhaps, provocative position. Although feminist scholarship has undoubtedly gained a place at the table in IPE, it is curious that one of the most important concerns, and contributions, of feminist IPE – that global capitalism is marked upon, and forged through, bodies – has not emerged as a major preoccupation for the discipline more broadly. This themed section presents what we believe is a strong corrective to that inattention and, in so doing we hope to begin to set out an exploratory agenda for the body to be both foundational and fundamental to contemporary IPE.
Abstract This article supports growing calls to &amp;amp;amp;amp;amp;amp;#x27;take small stat... more Abstract This article supports growing calls to &amp;amp;amp;amp;amp;amp;#x27;take small states seriously&amp;amp;amp;amp;amp;amp;#x27;in the international political economy but questions prevailing interpretations that &amp;amp;amp;amp;amp;amp;#x27;smallness&amp;amp;amp;amp;amp;amp;#x27; entails inherent qualities that create unique constraints on, and opportunities for, small states. Instead, we ...
... a * &amp;amp;amp;amp;amp;amp;amp; Nicola J. Smith a * pages 259-271. ... Who have themsel... more ... a * &amp;amp;amp;amp;amp;amp;amp; Nicola J. Smith a * pages 259-271. ... Who have themselves created an alliance which is now active in a variety of multilateral settings. See Alden and Vieira (2005); Lee, Taylor and Williams (2006). View all notes. Few of the very active developing countries are small states. ...
... Also focusing on the WTO, Donna Lee and Nicola Smith argue that small African states have in ... more ... Also focusing on the WTO, Donna Lee and Nicola Smith argue that small African states have in fact come to play a central role in multilateral trade negotiations, but that their increased activism has not translated into effective substantive influence. ...
... The international political economy of commercial sex. View full textDownload full text Full ... more ... The international political economy of commercial sex. View full textDownload full text Full access. DOI: 10.1080/09692291003762498 Nicola J. Smith a ... Violence Against Women , 10(10): 1126–55. [CrossRef], [Web of Science ®] View all references; Farley, 200422. ...
Once the 'sick man of Europe', the Irish Republic is now hailed as the 'Celtic Tiger'. Commentato... more Once the 'sick man of Europe', the Irish Republic is now hailed as the 'Celtic Tiger'. Commentators and politicians, both within and outside Ireland, point to the Republic's supposedly dazzling economic success as evidence of how nations can flourish in a globalised world. I question this notion, suggesting that Ireland's improved economic performance is best explained by a combination of factors, which cannot simply be lumped under the term 'globalisation'. Indeed, they seem directly to contradict many of the arguments made in the name of globalisation. However, I also contend that ideas about globalisation may play an increasingly important role in Irish economic developments.
To determine the pulmonary epithelial lining fluid (ELF) concentrations and degree of oxidation o... more To determine the pulmonary epithelial lining fluid (ELF) concentrations and degree of oxidation of ascorbic acid in horses affected by recurrent airway obstruction (RAO) in the presence and absence of neutrophilic airway inflammation. 6 RAO-affected horses and 8 healthy control horses. Nonenzymatic antioxidant concentrations were determined in RBC, plasma, and ELF samples of control horses and RAO-affected horses in the presence and absence of airway inflammation. ELF ascorbic acid concentration was decreased in RAO-affected horses with airway inflammation (median, 0.06 mmol/L; 25th and 75th percentiles, 0.0 and 0.4 mmol/L), compared with RAO-affected horses without airway inflammation (1.0 mmol/L; 0.7 and 1.5 mmol/L) and control horses (2.2 mmol/L; 1.4 and 2.2 mmol/L). Epithelial lining fluid ascorbic acid remained significantly lower in RAO-affected horses without airway inflammation than in control horses. Moreover, the ELF ascorbic acid redox ratio (ie, ratio of the concentrations of dehydroascorbate to total ascorbic acid) was higher in RAO-affected horses with airway inflammation (median, 0.85; 25th and 75th percentiles, 0.25 and 1.00), compared with RAO-affected horses without airway inflammation (0.04; 0.02 and 0.22). The number of neutrophils in bronchoalveolar lavage fluid was inversely related to the ELF ascorbic acid concentration (r = -0.81) and positively correlated with the ascorbic acid redox ratio (r = 0.65). Neutrophilic inflammation in horses affected by RAO is associated with a reduction in the ELF ascorbic acid pool. Nutritional supplementation with ascorbic acid derivatives in horses affected by RAO is an area for further investigation.
To test whether isoprostanes could be used as markers of oxidative stress in horses, their concen... more To test whether isoprostanes could be used as markers of oxidative stress in horses, their concentration was determined in plasma and in pulmonary epithelial lining fluid (PELF) in 3 models of oxidative stress: (1) strenuous exercise, (2) acute COPD crisis and (3) exercise combined with COPD crisis. Four horses were investigated twice, once in crisis and once in remission. The animals underwent a standardised treadmill exercise test. Isoprostane assessment was performed in plasma and bronchoalveolar lavage fluid 24 h before and 1 h after exercise and in plasma also immediately after exercise. Exercise in remission induced a significant increase of isoprostanes in plasma and in PELF. In horses in crisis, the isoprostane concentrations did not increase in plasma, while they did increase in PELF. Lastly, exercise in crisis increased plasma levels of isoprostanes, but did not change PELF isoprostanes. In conclusion, 1) isoprostanes are increased by systemic oxidative stress induced by strenuous exercise in COPD horses in remission either in PELF or in plasma; 2) only PELF and not plasma isoprostanes are increased by pulmonary oxidative stress induced by COPD crisis and 3) unexpectedly, exercise in crisis increased plasma but not PELF isoprostanes.
The effects of prolonged variable-intensity and short-term high-intensity exercise on indices of ... more The effects of prolonged variable-intensity and short-term high-intensity exercise on indices of oxidative stress and iron homeostasis were compared in six fit horses under cool [20°C, 40% relative humidity (RH)] or hot/humid (30°C, 80% RH) environmental conditions. The exercise protocols were designed to simulate equine competition, including racing (intense exercise) or the speed and endurance phase of a 3-day event (prolonged exercise). Increased plasma concentrations of lipid hydroperoxides and haemolysate concentrations of oxidised glutathione (GSSG) were measured within 30 min of the completion of exercise, indicating production of reactive oxygen species (ROS) and lipid membrane peroxidation. The horses were unable to complete the prolonged exercise protocol at high temperature and humidity. This coincided with higher maximal values of lipid hydroperoxides [138.2 (17.7) μM and GSSG [110.6 (18.2) μM], compared to high-intensity [105.2 (14.9) μM and 63.6 (8.6) μM, respectively] or prolonged [100.7 (18.7) μM and 86.2 (9.1) μM, respectively] exercise performed under cooler environmental conditions. Significant correlations were found between the duration of the final stage of exercise during hot/humid environmental conditions and increased levels of lipid hydroperoxides (r = 0.85), GSSG (r = 0.94), xanthine (r = 0.92) and uric acid (r = 0.96). Excerise also decreased the iron (Fe)-binding antioxidant activity of the plasma and increased the total plasma Fe levels, although this was only significant for prolonged exercise in ambient conditions. There was no detectable free Fe in the plasma at any stage of exercise. Other changes in biochemical parameters had returned to pre-exercise levels within 24 h after exercise. The results show that exercise can induce changes in biochemical parameters that are indicative of oxidative stress in the fit horse and that this was, exacerbated during exercise at high temperature and humidity.
To test the hypothesis that reactive oxygen species could be associated to the lower airway disor... more To test the hypothesis that reactive oxygen species could be associated to the lower airway disorders occurring in horses suffering from recurrent airway obstruction (RAO), indices of oxidative stress were studied in blood and pulmonary epithelium lining fluid in 5 RAO horses either in clinical remission or 24 h after the onset of a crisis of bronchospasm and in 5 healthy horses. Venous blood and bronchoalveolar lavage fluid (BALF) samples were collected and analysed for reduced glutathione (GSH), oxidised glutathione (GSSG), total glutathione (TGSH), glutathione redox ratio (GRR) in blood haemolysate and pulmonary epithelium lining fluid (PELF). The haemolysate concentrations of GSH, GSSG, TGSH and GRR were similar in the 3 groups. The PELF glutathione status was significantly different in the RAO horses in acute crisis compared to healthy horses, indicating the occurrence of an oxidative stress. When RAO horses were in crisis their GSH and TGSH remained unchanged but their GSSG and GRR were significantly increased compared to the remission.These results support the hypothesis that oxidative stress is associated with lower airway disorders occurring in horses suffering from RAO.
Journal of Chromatography B: Biomedical Sciences and Applications, 1995
A change in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) can be used to ... more A change in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) can be used to indicate oxidative stress in vivo. A rapid and highly sensitive isocratic reversed-phase high-performance liquid chromatographic method using coulometric electrochemical detection (LCEC) has been developed to simultaneously detect GSH and GSSG in equine biological fluids. Perchloric acid was used to extract GSH and GSSG from equine plasma and haemolysates, and methanol was used to deproteinise bronchoalveolar lavage fluid samples. Injection of extracts onto a Hypersil ODS HPLC column produced well resolved peaks corresponding to GSH and GSSG. The concentrations of GSH and GSSG found in equine haemolysates were similar to those previously found in humans and laboratory animals, although, to the authors' knowledge, previous attempts to measure GSH and GSSG in bronchoalveolar lavage fluid using LCEC have been unsuccessful. This method can be used to measure the GSH redox ratio in biological fluids during physiological conditions that may induce oxidative stress, such as exercise and disease.
Journal of Developmental & Behavioral Pediatrics, 2011
The purpose of the book is to guide families as they learn about and make decisions for their chi... more The purpose of the book is to guide families as they learn about and make decisions for their child with an ASD. The initial section of this text on the child first describes different patterns of development, before explaining how a diagnosis is made, the known or probable causes ...
The aim of this study was to test the hypothesis that pulmonary inflammation and emphysema induce... more The aim of this study was to test the hypothesis that pulmonary inflammation and emphysema induced by cadmium (Cd) inhalation are associated with pulmonary oxidative stress. Two groups of Sprague Dawley rats were used: one vehicle-exposed group undergoing inhalation of NaCl (0.9%, n = 24) and one Cd-exposed group undergoing inhalation of CdCl(2) (0.1%, n = 24). The animals in the vehicle-and Cd-exposed groups were divided into 4 subgroups (n = 6 per group), which underwent either a single exposure (D2) of 1H or repeated exposures 3 times/week for 1H for a period of 3 weeks (3W), 5 weeks (5W) or 5 weeks followed by 2 weeks without exposure (5W + 2). At sacrifice, the left lung was fixed for histomorphometric analysis (median inter-wall distance, MIWD), whilst bronchoalveolar lavage fluid (BALF) was collected from the right lung. Cytological analysis of BALF was performed and BALF was analysed for oxidant markers 8-iso-PGF(2a), uric acid (UA), reduced (AA) and oxidised ascorbic acid (DHA) and reduced (GSH) and oxidised glutathione (GSSG). Cd-exposure induced a significant increase of BALF macrophages and neutrophils. 8-iso-PGF(2a), UA, GSH and GSSG were significantly increased at D2. At 5W and 5W + 2, AA and GSH were significantly lower in Cd-exposed rats, indicating antioxidant depletion. MIWD significantly increased in all repeatedly Cd-exposed groups, suggesting development of pulmonary emphysema. 8-iso-PGF(2a) and UA were positively correlated with macrophage and neutrophil counts. GSH, GSSG and 8-iso-PGF(2a) were negatively correlated with MIWD, indicating that Cd-induced emphysema could be associated with pulmonary oxidative stress.
The phenomenon of ozone tolerance is described, but the underlying mechanisms remain unknown. We ... more The phenomenon of ozone tolerance is described, but the underlying mechanisms remain unknown. We tested whether adaptation to multiday ozone exposure was related to an upregulated pulmonary antioxidant defence. Six calves were exposed to 0.75 ppm ozone, 12 h day(-1) for seven consecutive days. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed before, after the first (D1), third (D3) and seventh (D7) exposure. Differential cell count, total proteins, 8-epi-PGF2alpha, glutathione and uric acid were determined in BAL. Dynamic lung compliance and arterial oxygen tension were significantly decreased and lung oedema impaired pulmonary function on D1. By repeating ozone exposures, progressive functional adaptation occurred. Ozone induced a significant increase of BAL neutrophil percentage on D1. On D3 and D7, neutrophil percentage was progressively decreased, but remained significantly elevated. BAL total proteins were significantly increased on D1 and decreased progressively until D7. 8-Epi-PGF2alpha was significantly increased on D1 and was returned to baseline on D3 and D7, whilst glutathione significantly increased on D3 and returned to baseline on D7. Uric acid was increased ten-fold on D1. On D3, uric acid was increased six-fold and was persistently elevated at D7. This study suggests that ozone adaptation of functional and inflammatory variables is accompanied with sustained BAL uric acid elevation.
Expert Opinion on Drug Metabolism & Toxicology, 2005
Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response i... more Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [ 3 H]docetaxel and [ 3 H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (P = 0.0007) and 3.3-fold higher for paclitaxel (P < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 µM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, P < 0.0001), cyclosporin A (25.2%, P = 0.005), glycyrrhizic acid (24.6%, P = 0.012), and hyperforin (28.4%, P = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 100... more The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 1000-fold more cytotoxic than the parent drug. The pharmacokinetics of irinotecan are extremely complex and have been the subject of intensive investigation in recent years. Irinotecan is subject to extensive metabolism by various polymorphic enzymes, including CES2 to form SN-38, members of the UGT1A subfamily, and CYP3A4 and CYP3A5, which form several pharmacologically inactive oxidation products. Elimination of irinotecan is also dependent on drug-transporting proteins, notably ABCB1 (P-glycoprotein), ABCC2 (cMOAT) and ABCG2 (BCRP), present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. This report provides an update on current strategies to individualize irinotecan chemotherapy based on each patient’s genetic constitution, which may ultimately lead to more selective use of this agent.
Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response i... more Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [ 3 H]docetaxel and [ 3 H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (P = 0.0007) and 3.3-fold higher for paclitaxel (P < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 µM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, P < 0.0001), cyclosporin A (25.2%, P = 0.005), glycyrrhizic acid (24.6%, P = 0.012), and hyperforin (28.4%, P = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
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