J. Jenner - Academia.edu (original) (raw)
Papers by J. Jenner
Issues in Toxicology, 2013
ABSTRACT When designing in vitro static diffusion studies the choice of receptor media is importa... more ABSTRACT When designing in vitro static diffusion studies the choice of receptor media is important as it may influence measured penetration rates. OECD guidelines regarding suitable receptor fluids state that “The use of a physiologically conducive receptor fluid is preferred although others may also be used provided that they are justified”. Further to this is the statement, “Adequate solubility of the test chemical in the receptor fluid should be demonstrated so that it does not act as a barrier to absorption.” Guidance for acceptable receptor fluids for non-viable skin preparations is split between the evaluation of water soluble compounds and lipohilic test substances. For the former saline receptor solutions are preferred, whilst for lipophilic test substances it is suggested that “the receptor fluid can contain organic solvents such as 1:1 ethanol: water or 6% polyethylene glycol 20 oleyl ether in water.”
Toxicology in Vitro, 2013
The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abd... more The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3h later did not change significantly. A small, but statistically significant difference (P<0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t(L)) of (3)H(2)O was observed between fresh skin and skin stored frozen (-20 °C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naïve skin had an average Kp of 1.65 × 10(-3) cm h(-1), whereas frozen naïve skin was 2.04 × 10(-3) cm h(-1). Fresh SM exposed skin had a mean Kp of 1.72 × 10(-3) cm h(-1), whereas frozen SM exposed skin was 2.31 × 10(-3) cm h(-1). Lag times were also shorter (P<0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account.
Journal of the Royal Army Medical Corps, 2009
Method: Using previously validated methods, 12 anaesthetised large white pigs were exposed to pho... more Method: Using previously validated methods, 12 anaesthetised large white pigs were exposed to phosgene (Ct 1978 ± 8 mg min m -3 ), established on mechanical ventilation and randomised to treatment with either nebulised salbutamol (2.5mg per dose) or saline control. Treatments were given 1, 5, 9, 13, 17 and 21 hours following phosgene exposure. The animals were followed to 24 hours following phosgene exposure. Results: Salbutamol treatment had no effect on mortality and had a deleterious effect on arterial oxygenation, shunt fraction and heart rate. There was a reduction in the number of neutrophils from 24.0% ± 4.4 to 12.17% ± 2.1 (p<0.05) in bronchoalveolar lavage, with some small decreases in inflammatory mediators in bronchoalveolar lavage but not in plasma.
Journal of the Royal Army Medical Corps, 2010
Method: Using previously validated methods, 16 anaesthetised large white pigs were exposed to pho... more Method: Using previously validated methods, 16 anaesthetised large white pigs were exposed to phosgene (target inhaled dose 0.3 mg kg -1 ), established on mechanical ventilation and randomised to treatment with either nebulised furosemide (4 ml of 10 mg.ml -1 solution) or saline control. Treatments were given at 1, 3, 5, 7, 9, 12, 16 and 20 hours post phosgene exposure; the animals were monitored to 24 hours following phosgene exposure. Results: Furosemide treatment had no effect on survival, and had a deleterious effect on PaO 2 : FiO 2 ratio between 19 and 24 hours. All other measures investigated were unaffected by treatment. Conclusion: Nebulised furosemide treatment following phosgene induced acute lung injury does not improve survival and worsens PaO 2 : FiO 2 ratio. Nebulised furosemide should be avoided following phosgene exposure.
Schizophrenia Bulletin, 2014
Hallucinations Research considers the current status and future directions in research on psychol... more Hallucinations Research considers the current status and future directions in research on psychological therapies targeting auditory hallucinations (hearing voices). Therapy approaches have evolved from behavioral and copingfocused interventions, through formulation-driven interventions using methods from cognitive therapy, to a number of contemporary developments. Recent developments include the application of acceptance-and mindfulness-based approaches, and consolidation of methods for working with connections between voices and views of self, others, relationships and personal history. In this article, we discuss the development of therapies for voices and review the empirical findings. This review shows that psychological therapies are broadly effective for people with positive symptoms, but that more research is required to understand the specific application of therapies to voices. Six key research directions are identified: (1) moving beyond the focus on overall efficacy to understand specific therapeutic processes targeting voices, (2) better targeting psychological processes associated with voices such as trauma, cognitive mechanisms, and personal recovery, (3) more focused measurement of the intended outcomes of therapy, (4) understanding individual differences among voice hearers, (5) extending beyond a focus on voices and schizophrenia into other populations and sensory modalities, and (6) shaping interventions for service implementation.
Value in Health, 2003
OBJECTIVES: HIT, hallucination focused integrative therapy, aims at the integration of cognitive ... more OBJECTIVES: HIT, hallucination focused integrative therapy, aims at the integration of cognitive behaviour therapy with, among others, psycho-education and singlefamily treatment. The present study focused on the costeffectiveness of the HIT programme in patients with schizophrenia and a history of persistent auditory hallucinations. METHODS: Patients were randomly assigned to two treatment arms, HIT or care as usual (CAU). The economic evaluation was performed from a societal perspective, costs, and effects of both patient groups were registered prospectively during a period of 18 months. The PANSS (Positive and Negative Syndrome Scale) was used as the primary outcome measure in the cost-effectiveness analysis. Bootstrap analyses provided additional information on the skewly distributed costs. RESULTS: Mean costs of patients in the HIT-group ($18,237) were lower than the mean costs of patients who received CAU ($21,436). The total amount of costs was influenced substantially by the costs of sheltered living accommodations, admissions in psychiatric hospitals and medication use. Costs of medication (about 10% of total costs) were relatively high in the present study, which is most likely due to increasing use of expensive atypical antipsychotics in recent years. Results of the PANSS were in favour of the HIT-group. The economic analyses indicated that the HIT-program was cost-effective in the current situation. In addition, bootstrap analyses illustrated the probable range of future variations in cost differences (-$12,050 to +$6,637) between both groups. CONCLUSIONS: The HIT-program appeared to be cost-effective in the current situation. Additional analyses indicated that future application of this intervention will in most cases lead to a reduction of societal costs.
Toxicology Mechanisms and Methods, 2008
ABSTRACT Although normally regarded as a vesicant, inhalation of sulphur mustard (HD) vapor can c... more ABSTRACT Although normally regarded as a vesicant, inhalation of sulphur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. Novel therapies for HD-induced lung injury are best investigated in an in vivo model that allows monitoring of a range of physiological variables. HD vapor was generated using two customized thermostatically controlled glass flasks in parallel. The vapor was passed into a carrier flow of air (81 L. min(-1)) and down a length of glass exposure tube (1.75 m). A pig was connected to the midpoint of the exposure tube via a polytetrafluoroethylene-lined endotracheal tube, Fleisch pneumotachograph, and sample port. HD vapor concentrations (40-122.8 mg. m(-3)) up-and downstream of the point of exposure were obtained by sampling onto Porapak absorption tubes with subsequent analysis by gas chromatography-flame photometric detection. Real-time estimates of vapor concentration were determined using a photo-ionization detector. Lung function indices (respiratory volumes, lung compliance, and airway resistance) were measured online throughout. Trial runs with methylsalicylate (MS) and animal exposures with HD demonstrated that the exposure system rapidly reached the desired concentration within 1 min and maintained stable output throughout exposure, and that the MS/HD concentration decayed rapidly to zero when switched off. A system is described that allows reproducible exposure of HD vapor to the lung of anesthetized white pigs. The system has proved to be robust and reliable and will be a valuable tool in assessing potential future therapies against HD-induced lung injury in the pig. Crown Copyright (c) 2007 Dstl.
Schizophrenia Research, 2008
Conclusions: 5 were continuously ill, 17 had multiple relapses with marked personality change, 14... more Conclusions: 5 were continuously ill, 17 had multiple relapses with marked personality change, 14 had relapses without much of personality change and 11 were doing well. Seventeen were employed at the end of 25 years. Two had been institutionalized for a long time, but the rest continued to live with their families.
Journal of Chromatography B, 2010
Sulfur mustard (SM) is a potent vesicating agent that produces debilitating blisters and ulcerati... more Sulfur mustard (SM) is a potent vesicating agent that produces debilitating blisters and ulcerating lesions on the skin which are characteristically slow to heal. There are currently no specific medical countermeasures to prevent SM-induced vesication and therefore SM remains a major military threat. To investigate the mechanism by which SM causes these injuries we aimed to identify the cellular proteins that are important in the vesicant response and pathology of SM. Membrane and membrane-associated proteins that are targets for direct binding by SM were compared to targets directly bound by CEES (chloroethylethylsulphide). As CEES is a less potent blistering agent compared to SM, it was hypothesised that differences in the binding of these two mustards could reveal key proteins directly involved in the mustard vesicant response. Human cellular membranes fractionated from HaCaT cells were exposed to (14)C-SM or (14)C-CEES and the membrane proteins to which SM or CEES bound were separated by 2D gel electrophoresis, located by fluorography and subsequently identified using mass spectrometry. A number of proteins were identified that were differentially labelled by SM and CEES. Actin, annexin A2 and keratin 9 were labelled with SM at a higher intensity than was seen with the same concentration of CEES. Therefore results from these studies suggest that SM binding to these proteins could contribute to the complex pathology seen following SM exposure.
Journal of Applied Toxicology, 2001
The aim of this study was to evaluate the use of an in vitro skin diffusion cell system as a mode... more The aim of this study was to evaluate the use of an in vitro skin diffusion cell system as a model for assessing decontaminants against the chemical warfare agent sulphur mustard (SM). The in vitro absorption rates of SM through heat-separated human (157 ± 66 µg cm −2 h −1 ) and pig-ear (411 ± 175 µg cm −2 h −1 ) epidermal membranes were in agreement with previous in vivo studies that quoted skin absorption rates of 150 and 366 µg cm −2 h −1 , respectively.
Journal of Applied Toxicology, 2000
The purpose of this study was to measure the absorption and intra-epidermal fate of 35 S-radiolab... more The purpose of this study was to measure the absorption and intra-epidermal fate of 35 S-radiolabelled sulphur mustard ( 35 SM) in human breast skin in vitro. Skin (full-thickness or heat-separated epidermis) was placed into static diffusion cells and was exposed to droplets of liquid 35 SM or saturated 35 SM vapour. Amounts of 35 SM penetrating the skin were measured from which skin absorption rates were calculated. Unbound radiolabel was washed from the surface, extracted from the skin and analysed to determine the identity of the radiolabelled species in order to measure the extent of hydrolysis of sulphur mustard.
Inhalation Toxicology, 2010
Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is... more Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. A reproducible, characterized in vivo model is required to investigate novel therapies targeting HD-induced lung injury. Anesthetized, spontaneously breathing large white pigs (~50 kg) were exposed directly to the lung to HD vapor at 60, 100, or 150 µg/kg, or to air, for ~10 min, and monitored for 6 h. Cardiovascular and respiratory parameters were recorded. Blood and bronchoalveolar lavage fluid (BALF) were collected to allow blood gas analysis, hematology, and to assay for lung inflammatory cells and mediators. Urine was collected and analyzed for HD metabolites. Histopathology samples were taken postmortem (PM). Air-exposed animals maintained normal lung physiology whilst lying supine and spontaneously breathing. There was a statistically significant increase in shunt fraction across all three HD-exposed groups when compared with air controls at 3-6 h post-exposure. Animals were increasingly hypoxemic with respiratory acidosis. The monosulfoxide β-lyase metabolite of HD (1-methylsulfinyl-2-[2(methylthio)ethylsulfonyl)ethane], MSMTESE), was detected in urine from 2 h post-exposure. Pathological examination revealed necrosis and erosion of the tracheal epithelium in medium and high HD-exposed groups. These findings are consistent with those seen in the early stages of acute lung injury (ALI).
Inhalation Toxicology, 2010
Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It prod... more Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces life-threatening pulmonary edema within hours of exposure; no antidote exists. This study examines pathophysiological changes seen following treatment with elevated inspired oxygen concentrations (Fi(O2)), in a model of phosgene-induced acute lung injury. Anesthetized pigs were exposed to phosgene (Ct 2500 mg min m(-3)) and ventilated (intermittent positive pressure ventilation, tidal volume 10 ml kg(-1), positive end-expiratory pressure 3 cm H(2)O, frequency 20 breaths min(-1)). The Fi(O2) was varied: group 1, Fi(O2) 0.30 (228 mm Hg) throughout; group 2, Fi(O2) 0.80 (608 mm Hg) immediately post exposure, to end; group 3, Fi(O2) 0.30 from 30 min post exposure, increased to 0.80 at 6 h post exposure; group 4, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 (304 mm Hg) at 6 h post exposure. Group 5, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 at 12 h post exposure. The current results demonstrate that oxygen is beneficial, with improved survival, arterial oxygen saturation, shunt fraction, and reduced lung wet weight to body weight ratio in all treatment groups, and improved arterial oxygen partial pressure in groups 2 and 3, compared to phosgene controls (group 1) animals. The authors recommend that treatment of phosgene-induced acute lung injury with inspired oxygen is delayed until signs or symptoms of hypoxia are present or arterial blood oxygenation falls. The lowest concentration of oxygen that maintains normal arterial oxygen saturation and absence of clinical signs of hypoxia is recommended.
Cutaneous and Ocular Toxicology, 2007
Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinat... more Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinated polymers, are effective against the chemical warfare agent sulphur mustard (SM) when evaluated using human skin in vitro. The purpose of this follow-up study was to further evaluate three candidate (perfluorinated) barrier creams against SM (vapour) using the domestic white pig. The severity and progression of the resulting skin lesions were quantified daily for three weeks post-exposure using biophysical measurements of transepidermal water loss (TEWL) and skin reflectance spectroscopy (SRS). Skin biopsies obtained post-mortem were evaluated by light microscopy and additional skin samples were obtained from adjacent (unexposed) skin sites for a comparative in vitro skin absorption study. Samples of SM vapour within the dosing chambers were measured ex vivo to ascertain the exposure dose (Ct). The three creams were highly effective against SM in vivo (Ct approximately 5000 mg.min.m(-3)): After 3 weeks, barrier cream pre-treated sites were not significantly different from control (unexposed) skin when evaluated by TEWL, SRS or histology. In contrast, skin exposed to SM without pre-treatment showed evidence of persistent damage that was consistent with the slow healing time observed in humans. The amount of SM absorbed in vitro in untreated pig skin was similar to that required to cause comparable lesions in human skin (8-20 and 4-10 microg.cm(-2), respectively), further validating the use of pigs as a toxicologically-relevant dermal model for SM exposure.
Clinical Toxicology, 2013
Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no... more Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no effective treatment. N-acetyl-L-cysteine (NAC) has mucolytic and antioxidant actions and is an important pre-cursor of cellular glutathione synthesis. These actions may have potential to reduce mustard-induced lung injury. Evaluate the effect of nebulised NAC as a post-exposure treatment for inhaled sulfur mustard in a large animal model. Fourteen anesthetized, surgically prepared pigs were exposed to sulfur mustard vapor (100 μg.kg⁻¹), 10 min) and monitored, spontaneously breathing, to 12 h. Control animals had no further intervention (n = 6). Animals in the treatment group were administered multiple inhaled doses of NAC (1 ml of 200 mg.ml⁻¹ Mucomyst™ at + 30 min, 2, 4, 6, 8, and 10 h post-exposure, n = 8). Cardiovascular and respiratory parameters were recorded. Arterial blood was collected for blood gas analysis while blood and bronchoalveolar lavage fluid were collected for hematology and inflammatory cell analysis. Urine was collected to detect a sulfur mustard breakdown product. Lung tissue samples were taken for histopathological and post-experimental analyses. Five of six sulfur mustard-exposed animals survived to 12 h. Arterial blood oxygenation (PaO₂) and saturation levels were significantly decreased at 12 h. Arterial blood carbon dioxide (PaCO₂) significantly increased, and arterial blood pH and bicarbonate (HCO₃⁻) significantly decreased at 12 h. Shunt fraction was significantly increased at 12 h. In the NAC-treated group all animals survived to 12 h (n = 8). There was significantly improved arterial blood oxygen saturation, HCO₃⁻ levels, and shunt fraction compared to those of the sulfur mustard controls. There were significantly fewer neutrophils and lower concentrations of protein in lavage compared to sulfur mustard controls. NAC's mucolytic and antioxidant properties may be responsible for the beneficial effects seen, improving clinically relevant physiological indices affected by sulfur mustard exposure. Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.
Clinical Rehabilitation, 2000
Chemico-Biological Interactions, 2013
Since its first use in 1917, sulphur mustard (SM) has been used virtually exclusively as a weapon... more Since its first use in 1917, sulphur mustard (SM) has been used virtually exclusively as a weapon of war. SM is a volatile liquid that damages any tissue it contacts as a vapour or liquid. SM primarily damages the skin, eyes and lungs producing massive inflammation culminating in the characteristic blistering of the skin which classifies SM as a vesicant. Several mechanisms of action at the cellular level have been proposed for SM, but none has ever been convincingly linked to the production of blisters or vesication. First aid for those contaminated with liquid SM consists of the rapid removal (within a few minutes) of liquid from the surface of the skin, as once penetrated into the stratum corneum it is very difficult to remove. In the absence of a mechanistically based specific therapy, SM skin injury is normally treated in a similar way to thermal and chemical burns, which it resembles pathologically. Effective therapy consist of treating the inflammation and where necessary removal of the dead eschar to facilitate healing. Post surgical care comprises the use of one of a number of available dressings used in thermal burn care and antibiotic creams should infection be present.
Acta Psychiatrica Scandinavica, 2008
Issues in Toxicology, 2013
ABSTRACT When designing in vitro static diffusion studies the choice of receptor media is importa... more ABSTRACT When designing in vitro static diffusion studies the choice of receptor media is important as it may influence measured penetration rates. OECD guidelines regarding suitable receptor fluids state that “The use of a physiologically conducive receptor fluid is preferred although others may also be used provided that they are justified”. Further to this is the statement, “Adequate solubility of the test chemical in the receptor fluid should be demonstrated so that it does not act as a barrier to absorption.” Guidance for acceptable receptor fluids for non-viable skin preparations is split between the evaluation of water soluble compounds and lipohilic test substances. For the former saline receptor solutions are preferred, whilst for lipophilic test substances it is suggested that “the receptor fluid can contain organic solvents such as 1:1 ethanol: water or 6% polyethylene glycol 20 oleyl ether in water.”
Toxicology in Vitro, 2013
The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abd... more The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3h later did not change significantly. A small, but statistically significant difference (P<0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t(L)) of (3)H(2)O was observed between fresh skin and skin stored frozen (-20 °C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naïve skin had an average Kp of 1.65 × 10(-3) cm h(-1), whereas frozen naïve skin was 2.04 × 10(-3) cm h(-1). Fresh SM exposed skin had a mean Kp of 1.72 × 10(-3) cm h(-1), whereas frozen SM exposed skin was 2.31 × 10(-3) cm h(-1). Lag times were also shorter (P<0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account.
Journal of the Royal Army Medical Corps, 2009
Method: Using previously validated methods, 12 anaesthetised large white pigs were exposed to pho... more Method: Using previously validated methods, 12 anaesthetised large white pigs were exposed to phosgene (Ct 1978 ± 8 mg min m -3 ), established on mechanical ventilation and randomised to treatment with either nebulised salbutamol (2.5mg per dose) or saline control. Treatments were given 1, 5, 9, 13, 17 and 21 hours following phosgene exposure. The animals were followed to 24 hours following phosgene exposure. Results: Salbutamol treatment had no effect on mortality and had a deleterious effect on arterial oxygenation, shunt fraction and heart rate. There was a reduction in the number of neutrophils from 24.0% ± 4.4 to 12.17% ± 2.1 (p<0.05) in bronchoalveolar lavage, with some small decreases in inflammatory mediators in bronchoalveolar lavage but not in plasma.
Journal of the Royal Army Medical Corps, 2010
Method: Using previously validated methods, 16 anaesthetised large white pigs were exposed to pho... more Method: Using previously validated methods, 16 anaesthetised large white pigs were exposed to phosgene (target inhaled dose 0.3 mg kg -1 ), established on mechanical ventilation and randomised to treatment with either nebulised furosemide (4 ml of 10 mg.ml -1 solution) or saline control. Treatments were given at 1, 3, 5, 7, 9, 12, 16 and 20 hours post phosgene exposure; the animals were monitored to 24 hours following phosgene exposure. Results: Furosemide treatment had no effect on survival, and had a deleterious effect on PaO 2 : FiO 2 ratio between 19 and 24 hours. All other measures investigated were unaffected by treatment. Conclusion: Nebulised furosemide treatment following phosgene induced acute lung injury does not improve survival and worsens PaO 2 : FiO 2 ratio. Nebulised furosemide should be avoided following phosgene exposure.
Schizophrenia Bulletin, 2014
Hallucinations Research considers the current status and future directions in research on psychol... more Hallucinations Research considers the current status and future directions in research on psychological therapies targeting auditory hallucinations (hearing voices). Therapy approaches have evolved from behavioral and copingfocused interventions, through formulation-driven interventions using methods from cognitive therapy, to a number of contemporary developments. Recent developments include the application of acceptance-and mindfulness-based approaches, and consolidation of methods for working with connections between voices and views of self, others, relationships and personal history. In this article, we discuss the development of therapies for voices and review the empirical findings. This review shows that psychological therapies are broadly effective for people with positive symptoms, but that more research is required to understand the specific application of therapies to voices. Six key research directions are identified: (1) moving beyond the focus on overall efficacy to understand specific therapeutic processes targeting voices, (2) better targeting psychological processes associated with voices such as trauma, cognitive mechanisms, and personal recovery, (3) more focused measurement of the intended outcomes of therapy, (4) understanding individual differences among voice hearers, (5) extending beyond a focus on voices and schizophrenia into other populations and sensory modalities, and (6) shaping interventions for service implementation.
Value in Health, 2003
OBJECTIVES: HIT, hallucination focused integrative therapy, aims at the integration of cognitive ... more OBJECTIVES: HIT, hallucination focused integrative therapy, aims at the integration of cognitive behaviour therapy with, among others, psycho-education and singlefamily treatment. The present study focused on the costeffectiveness of the HIT programme in patients with schizophrenia and a history of persistent auditory hallucinations. METHODS: Patients were randomly assigned to two treatment arms, HIT or care as usual (CAU). The economic evaluation was performed from a societal perspective, costs, and effects of both patient groups were registered prospectively during a period of 18 months. The PANSS (Positive and Negative Syndrome Scale) was used as the primary outcome measure in the cost-effectiveness analysis. Bootstrap analyses provided additional information on the skewly distributed costs. RESULTS: Mean costs of patients in the HIT-group ($18,237) were lower than the mean costs of patients who received CAU ($21,436). The total amount of costs was influenced substantially by the costs of sheltered living accommodations, admissions in psychiatric hospitals and medication use. Costs of medication (about 10% of total costs) were relatively high in the present study, which is most likely due to increasing use of expensive atypical antipsychotics in recent years. Results of the PANSS were in favour of the HIT-group. The economic analyses indicated that the HIT-program was cost-effective in the current situation. In addition, bootstrap analyses illustrated the probable range of future variations in cost differences (-$12,050 to +$6,637) between both groups. CONCLUSIONS: The HIT-program appeared to be cost-effective in the current situation. Additional analyses indicated that future application of this intervention will in most cases lead to a reduction of societal costs.
Toxicology Mechanisms and Methods, 2008
ABSTRACT Although normally regarded as a vesicant, inhalation of sulphur mustard (HD) vapor can c... more ABSTRACT Although normally regarded as a vesicant, inhalation of sulphur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. Novel therapies for HD-induced lung injury are best investigated in an in vivo model that allows monitoring of a range of physiological variables. HD vapor was generated using two customized thermostatically controlled glass flasks in parallel. The vapor was passed into a carrier flow of air (81 L. min(-1)) and down a length of glass exposure tube (1.75 m). A pig was connected to the midpoint of the exposure tube via a polytetrafluoroethylene-lined endotracheal tube, Fleisch pneumotachograph, and sample port. HD vapor concentrations (40-122.8 mg. m(-3)) up-and downstream of the point of exposure were obtained by sampling onto Porapak absorption tubes with subsequent analysis by gas chromatography-flame photometric detection. Real-time estimates of vapor concentration were determined using a photo-ionization detector. Lung function indices (respiratory volumes, lung compliance, and airway resistance) were measured online throughout. Trial runs with methylsalicylate (MS) and animal exposures with HD demonstrated that the exposure system rapidly reached the desired concentration within 1 min and maintained stable output throughout exposure, and that the MS/HD concentration decayed rapidly to zero when switched off. A system is described that allows reproducible exposure of HD vapor to the lung of anesthetized white pigs. The system has proved to be robust and reliable and will be a valuable tool in assessing potential future therapies against HD-induced lung injury in the pig. Crown Copyright (c) 2007 Dstl.
Schizophrenia Research, 2008
Conclusions: 5 were continuously ill, 17 had multiple relapses with marked personality change, 14... more Conclusions: 5 were continuously ill, 17 had multiple relapses with marked personality change, 14 had relapses without much of personality change and 11 were doing well. Seventeen were employed at the end of 25 years. Two had been institutionalized for a long time, but the rest continued to live with their families.
Journal of Chromatography B, 2010
Sulfur mustard (SM) is a potent vesicating agent that produces debilitating blisters and ulcerati... more Sulfur mustard (SM) is a potent vesicating agent that produces debilitating blisters and ulcerating lesions on the skin which are characteristically slow to heal. There are currently no specific medical countermeasures to prevent SM-induced vesication and therefore SM remains a major military threat. To investigate the mechanism by which SM causes these injuries we aimed to identify the cellular proteins that are important in the vesicant response and pathology of SM. Membrane and membrane-associated proteins that are targets for direct binding by SM were compared to targets directly bound by CEES (chloroethylethylsulphide). As CEES is a less potent blistering agent compared to SM, it was hypothesised that differences in the binding of these two mustards could reveal key proteins directly involved in the mustard vesicant response. Human cellular membranes fractionated from HaCaT cells were exposed to (14)C-SM or (14)C-CEES and the membrane proteins to which SM or CEES bound were separated by 2D gel electrophoresis, located by fluorography and subsequently identified using mass spectrometry. A number of proteins were identified that were differentially labelled by SM and CEES. Actin, annexin A2 and keratin 9 were labelled with SM at a higher intensity than was seen with the same concentration of CEES. Therefore results from these studies suggest that SM binding to these proteins could contribute to the complex pathology seen following SM exposure.
Journal of Applied Toxicology, 2001
The aim of this study was to evaluate the use of an in vitro skin diffusion cell system as a mode... more The aim of this study was to evaluate the use of an in vitro skin diffusion cell system as a model for assessing decontaminants against the chemical warfare agent sulphur mustard (SM). The in vitro absorption rates of SM through heat-separated human (157 ± 66 µg cm −2 h −1 ) and pig-ear (411 ± 175 µg cm −2 h −1 ) epidermal membranes were in agreement with previous in vivo studies that quoted skin absorption rates of 150 and 366 µg cm −2 h −1 , respectively.
Journal of Applied Toxicology, 2000
The purpose of this study was to measure the absorption and intra-epidermal fate of 35 S-radiolab... more The purpose of this study was to measure the absorption and intra-epidermal fate of 35 S-radiolabelled sulphur mustard ( 35 SM) in human breast skin in vitro. Skin (full-thickness or heat-separated epidermis) was placed into static diffusion cells and was exposed to droplets of liquid 35 SM or saturated 35 SM vapour. Amounts of 35 SM penetrating the skin were measured from which skin absorption rates were calculated. Unbound radiolabel was washed from the surface, extracted from the skin and analysed to determine the identity of the radiolabelled species in order to measure the extent of hydrolysis of sulphur mustard.
Inhalation Toxicology, 2010
Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is... more Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. A reproducible, characterized in vivo model is required to investigate novel therapies targeting HD-induced lung injury. Anesthetized, spontaneously breathing large white pigs (~50 kg) were exposed directly to the lung to HD vapor at 60, 100, or 150 µg/kg, or to air, for ~10 min, and monitored for 6 h. Cardiovascular and respiratory parameters were recorded. Blood and bronchoalveolar lavage fluid (BALF) were collected to allow blood gas analysis, hematology, and to assay for lung inflammatory cells and mediators. Urine was collected and analyzed for HD metabolites. Histopathology samples were taken postmortem (PM). Air-exposed animals maintained normal lung physiology whilst lying supine and spontaneously breathing. There was a statistically significant increase in shunt fraction across all three HD-exposed groups when compared with air controls at 3-6 h post-exposure. Animals were increasingly hypoxemic with respiratory acidosis. The monosulfoxide β-lyase metabolite of HD (1-methylsulfinyl-2-[2(methylthio)ethylsulfonyl)ethane], MSMTESE), was detected in urine from 2 h post-exposure. Pathological examination revealed necrosis and erosion of the tracheal epithelium in medium and high HD-exposed groups. These findings are consistent with those seen in the early stages of acute lung injury (ALI).
Inhalation Toxicology, 2010
Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It prod... more Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces life-threatening pulmonary edema within hours of exposure; no antidote exists. This study examines pathophysiological changes seen following treatment with elevated inspired oxygen concentrations (Fi(O2)), in a model of phosgene-induced acute lung injury. Anesthetized pigs were exposed to phosgene (Ct 2500 mg min m(-3)) and ventilated (intermittent positive pressure ventilation, tidal volume 10 ml kg(-1), positive end-expiratory pressure 3 cm H(2)O, frequency 20 breaths min(-1)). The Fi(O2) was varied: group 1, Fi(O2) 0.30 (228 mm Hg) throughout; group 2, Fi(O2) 0.80 (608 mm Hg) immediately post exposure, to end; group 3, Fi(O2) 0.30 from 30 min post exposure, increased to 0.80 at 6 h post exposure; group 4, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 (304 mm Hg) at 6 h post exposure. Group 5, Fi(O2) 0.30 from 30 min post exposure, increased to 0.40 at 12 h post exposure. The current results demonstrate that oxygen is beneficial, with improved survival, arterial oxygen saturation, shunt fraction, and reduced lung wet weight to body weight ratio in all treatment groups, and improved arterial oxygen partial pressure in groups 2 and 3, compared to phosgene controls (group 1) animals. The authors recommend that treatment of phosgene-induced acute lung injury with inspired oxygen is delayed until signs or symptoms of hypoxia are present or arterial blood oxygenation falls. The lowest concentration of oxygen that maintains normal arterial oxygen saturation and absence of clinical signs of hypoxia is recommended.
Cutaneous and Ocular Toxicology, 2007
Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinat... more Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinated polymers, are effective against the chemical warfare agent sulphur mustard (SM) when evaluated using human skin in vitro. The purpose of this follow-up study was to further evaluate three candidate (perfluorinated) barrier creams against SM (vapour) using the domestic white pig. The severity and progression of the resulting skin lesions were quantified daily for three weeks post-exposure using biophysical measurements of transepidermal water loss (TEWL) and skin reflectance spectroscopy (SRS). Skin biopsies obtained post-mortem were evaluated by light microscopy and additional skin samples were obtained from adjacent (unexposed) skin sites for a comparative in vitro skin absorption study. Samples of SM vapour within the dosing chambers were measured ex vivo to ascertain the exposure dose (Ct). The three creams were highly effective against SM in vivo (Ct approximately 5000 mg.min.m(-3)): After 3 weeks, barrier cream pre-treated sites were not significantly different from control (unexposed) skin when evaluated by TEWL, SRS or histology. In contrast, skin exposed to SM without pre-treatment showed evidence of persistent damage that was consistent with the slow healing time observed in humans. The amount of SM absorbed in vitro in untreated pig skin was similar to that required to cause comparable lesions in human skin (8-20 and 4-10 microg.cm(-2), respectively), further validating the use of pigs as a toxicologically-relevant dermal model for SM exposure.
Clinical Toxicology, 2013
Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no... more Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no effective treatment. N-acetyl-L-cysteine (NAC) has mucolytic and antioxidant actions and is an important pre-cursor of cellular glutathione synthesis. These actions may have potential to reduce mustard-induced lung injury. Evaluate the effect of nebulised NAC as a post-exposure treatment for inhaled sulfur mustard in a large animal model. Fourteen anesthetized, surgically prepared pigs were exposed to sulfur mustard vapor (100 μg.kg⁻¹), 10 min) and monitored, spontaneously breathing, to 12 h. Control animals had no further intervention (n = 6). Animals in the treatment group were administered multiple inhaled doses of NAC (1 ml of 200 mg.ml⁻¹ Mucomyst™ at + 30 min, 2, 4, 6, 8, and 10 h post-exposure, n = 8). Cardiovascular and respiratory parameters were recorded. Arterial blood was collected for blood gas analysis while blood and bronchoalveolar lavage fluid were collected for hematology and inflammatory cell analysis. Urine was collected to detect a sulfur mustard breakdown product. Lung tissue samples were taken for histopathological and post-experimental analyses. Five of six sulfur mustard-exposed animals survived to 12 h. Arterial blood oxygenation (PaO₂) and saturation levels were significantly decreased at 12 h. Arterial blood carbon dioxide (PaCO₂) significantly increased, and arterial blood pH and bicarbonate (HCO₃⁻) significantly decreased at 12 h. Shunt fraction was significantly increased at 12 h. In the NAC-treated group all animals survived to 12 h (n = 8). There was significantly improved arterial blood oxygen saturation, HCO₃⁻ levels, and shunt fraction compared to those of the sulfur mustard controls. There were significantly fewer neutrophils and lower concentrations of protein in lavage compared to sulfur mustard controls. NAC's mucolytic and antioxidant properties may be responsible for the beneficial effects seen, improving clinically relevant physiological indices affected by sulfur mustard exposure. Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.
Clinical Rehabilitation, 2000
Chemico-Biological Interactions, 2013
Since its first use in 1917, sulphur mustard (SM) has been used virtually exclusively as a weapon... more Since its first use in 1917, sulphur mustard (SM) has been used virtually exclusively as a weapon of war. SM is a volatile liquid that damages any tissue it contacts as a vapour or liquid. SM primarily damages the skin, eyes and lungs producing massive inflammation culminating in the characteristic blistering of the skin which classifies SM as a vesicant. Several mechanisms of action at the cellular level have been proposed for SM, but none has ever been convincingly linked to the production of blisters or vesication. First aid for those contaminated with liquid SM consists of the rapid removal (within a few minutes) of liquid from the surface of the skin, as once penetrated into the stratum corneum it is very difficult to remove. In the absence of a mechanistically based specific therapy, SM skin injury is normally treated in a similar way to thermal and chemical burns, which it resembles pathologically. Effective therapy consist of treating the inflammation and where necessary removal of the dead eschar to facilitate healing. Post surgical care comprises the use of one of a number of available dressings used in thermal burn care and antibiotic creams should infection be present.
Acta Psychiatrica Scandinavica, 2008