Tim Kuchel - Academia.edu (original) (raw)
Papers by Tim Kuchel
PLOS ONE, 2015
The incidence of adverse pregnancy outcomes is higher in pregnancies where the fetus is male. Sex... more The incidence of adverse pregnancy outcomes is higher in pregnancies where the fetus is male. Sex specific differences in feto-placental perfusion indices identified by Doppler assessment have recently been associated with placental insufficiency and fetal growth restriction. This study aims to investigate sex specific differences in placental perfusion and to correlate these changes with fetal growth. It represents the largest comprehensive study under field conditions of uterine hemodynamics in a monotocous species, with a similar long gestation period to the human. Primiparous 14mo heifers in Australia (n=360) and UK (n=180) were either individually or group fed, respectively, diets with differing protein content (18, 14, 10 or 7% crude protein (CP)) from 60d prior to 98 days post conception (dpc). Fetuses and placentae were excised at 98dpc (n = 48). Fetal development an median uterine artery blood flow were assessed monthly from 36dpc until term using B-mode and Doppler ultrasonography. MUA blood flow to the male feto-placental unit increased in early pregnancy associated with increased fetal growth. Protein restriction before and shortly after conception (-60d up to 23dpc) increased MUA diameter and indices of velocity during late pregnancy, reduced fetal heart weight in the female fetus and increased heart rate at birth, but decreased systolic blood pressure at six months of age.
Neurobiology of disease, Jan 11, 2016
Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme re... more Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the β-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in β-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000-fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangli...
Biomaterials, 2015
Advanced biosensors in future medicine hinge on the evolvement of biomaterials. Porous silicon (p... more Advanced biosensors in future medicine hinge on the evolvement of biomaterials. Porous silicon (pSi), a generally biodegradable and biocompatible material that can be fabricated to include environment-responsive optical characteristics, is an excellent candidate for in vivo biosensors. However, the feasibility of using this material as a subcutaneously implanted optical biosensor has never been demonstrated. Here, we investigated the stability and biocompatibility of a thermally-hydrocarbonised (THC) pSi optical rugate filter, and demonstrated its optical functionality in vitro and in vivo. We first compared pSi films with different surface chemistries and observed that the material was cytotoxic despite the outstanding stability of the THC pSi films. We then showed that the cytotoxicity correlates with reactive oxygen species levels, which could be mitigated by pre-incubation of THC pSi (PITHC pSi). PITHC pSi facilitates normal cellular phenotypes and is biocompatible in vivo. Importantly, the material also possesses optical properties capable of responding to microenvironmental changes that are readable non-invasively in cell culture and subcutaneous settings. Collectively, we demonstrate, for the first time, that PITHC pSi rugate filters are both biocompatible and optically functional for lab-on-a-chip and subcutaneous biosensing scenarios. We believe that this study will deepen our understanding of cell-pSi interactions and foster the development of implantable biosensors.
Journal of Zhejiang University. Science. B, 2015
Understanding the ecology of the gastrointestinal tract and the impact of the contents on the hos... more Understanding the ecology of the gastrointestinal tract and the impact of the contents on the host mucosa is emerging as an important area for defining both wellness and susceptibility to disease. Targeted delivery of drugs to treat specific small intestinal disorders such as small bowel bacterial overgrowth and targeting molecules to interrogate or to deliver vaccines to the remote regions of the small intestine has proven difficult. There is an unmet need for methodologies to release probes/drugs to remote regions of the gastrointestinal tract in furthering our understanding of gut health and pathogenesis. In order to address this concern, we need to know how the regional delivery of a surrogate labeled test compound is handled and in turn, if delivered locally as a liquid or powder, the dynamics of its subsequent handling and metabolism. In the studies we report on in this paper, we chose (13)C sodium acetate ((13)C-acetate), which is a stable isotope probe that once absorbed in ...
The Veterinary record, Jan 13, 1980
The effects of combining large doses of xylazine (1.1 mg per kg intravenously) with ketamine, met... more The effects of combining large doses of xylazine (1.1 mg per kg intravenously) with ketamine, methohexitone and thiopentone were studied in four experimental ponies. Onset of anaesthesia was more delayed after ketamine than after the barbiturates. Assessment of smoothness of induction and recovery indicated that all three combinations were effective and acceptable. Injection of xylazine was followed by atrioventricular (A-V) block which could be prevented by the prior administration of atropine. Blood pressure was well maintained with all three combinations of drugs. Arterial oxygen tension decreased as soon as the ponies became recumbent but there were no marked changes in arterial blood pH or carbon dioxide tension. Cardiac output was measured in one pony and was found to be least affected by ketamine. There was no great difference between the recumbency times after ketamine and methohexitone but thiopentone produced a significantly longer period of recumbency. In every instance t...
BMC Pulmonary Medicine, 2014
Background: The safety and efficiency of gene therapies for cystic fibrosis (CF) need to be asses... more Background: The safety and efficiency of gene therapies for cystic fibrosis (CF) need to be assessed in pre-clinical models. Using the normal ferret, this study sought to determine whether ferret airway epithelia could be transduced with a lysophosphatidylcholine (LPC) pre-treatment followed by a VSV-G pseudotyped HIV-1 based lentiviral (LV) vector, in preparation for future studies in CF ferrets. Methods: Six normal ferrets (7 -8 weeks old) were treated with a 150 μL LPC pre-treatment, followed one hour later by a 500 μL LV vector dose containing the LacZ transgene. LacZ gene expression in the conducting airways and lung was assessed by X-gal staining after 7 days. The presence of transduction in the lung, as well as off-target transduction in the liver, spleen and gonads, were assessed by qPCR. The levels of LV vector p24 protein bio-distribution in blood sera were assessed by ELISA at 0, 1, 3, 5 and 7 days. Results: The dosing protocol was well tolerated. LacZ gene expression was observed en face in the trachea of all animals. Histology showed that ciliated and basal cells were transduced in the trachea, with rare LacZ transduced single cells noted in lung. p24 levels was not detectable in the sera of 5 of the 6 animals. The LacZ gene was not detected in the lung tissue and no off-target transduction was detected by qPCR.
Veterinary Anaesthesia and Analgesia, 1982
ABSTRACT The structural diversity of anaesthetic compounds suggests that anaesthetics do not act ... more ABSTRACT The structural diversity of anaesthetic compounds suggests that anaesthetics do not act at a single specific receptor.However, the close correlation between the lipid solubility of anaesthetics and their potencies (Meyer-Overton rule) does imply a common mechanism: A Unitary Hypothesis.Anaesthetizing Partial E'ressure x oil/gas part. coef. varies only 2 x over a range of 70,000 in partial pressures.This suggests that a specific number of anaesthetic molecules occupy a crucial hydrophobic site in the CNS, but the MeyerOverton rule offers no mechanistic explanation for its validity.The putative site of action of anaesthetics is the synapse because the relative resistance of larger axons to anaesthetic induced depression narrows the site of hydrophobic action to synapic regions or axons with small diameter at the nerve terminal (Richards, 1981) (see Figure 1).
Laboratory Animals, 2001
T he efficac y of continuous low-dose xylazine infusion following an initial loading dose in prov... more T he efficac y of continuous low-dose xylazine infusion following an initial loading dose in providing analgesia in sheep was exam ined using an algesim etry method based on a leg lifting response to an electrical stimulus. Sheep received a 5 mg intramuscular injection of xylazine followed by continuous infusion of intravenous xylazi ne (2 mg = h) for 90 min. T his treatm ent resulted in significant increases in the level of current required to elicit a leg lift ing response (287% of baseline) and steady state analgesia was maintai ned from 10 min after the start of the infusion until the end of the experimental period. T his protocol appears to be a simple and effective regim en for providing steady state analgesia in sheep. (2001) 35, 277 281 C o rre spond e nc e to : C liff G ra nt E-m a il: cgra nt@m e d ic ine .a d ela id e .ed u.a u
Australian Veterinary Journal, 1996
The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and... more The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and xylazine was examined in sheep, using algesimetry based on a leg withdrawal response to an electrical stimulus. No analgesic response was detected for buprenorphine, methadone or flunixin meglumine. Only the alpha 2-adrenoceptor agonist, xylazine, produced an analgesic response. The current required to elicit a response increased by 170% (4.5 +/- 0.43 mA to 12.23 +/- 1.14 mA; mean +/- SE) after a dose of 0.05 mg/kg xylazine; by 180% (4.73 +/- 0.3 mA to 13.28 +/- 2.35 mA) after 0.1 mg/kg and by 510% (4.52 +/- 0.29 mA to 27.63 +/- 3.89 mA) after 0.2 mg/kg. Intramuscular xylazine appears to be an effective analgesic agent for acute pain in the sheep and further investigation into ideal administration regimens and dosage may provide more detailed information on relationships between dose, analgesic and sedative effects. The findings also suggest that some common analgesic agents, and opioids in particular, may be ineffective for the management of acute pain in sheep and that any analgesic should be administered only on the basis of its proven efficacy in that species.
Environmental Science & Technology, 2009
Currently, a number of in vitro methods are in use worldwide to assess arsenic (As) bioaccessibil... more Currently, a number of in vitro methods are in use worldwide to assess arsenic (As) bioaccessibility in soils. However, a dearth of research has been undertaken to compare the efficacy of the in vitro methods for estimating in vivo relative As bioavailability. In this study, As bioaccessibility in contaminated soils (n ) 12) was assessed using four in vitro assays (SBRC, IVG, PBET, DIN). In vitro results were compared to in vivo relative As bioavailability data (swine assay) to ascertain which methodologies best correlate with in vivo data. Arsenic bioaccessibility in contaminated soils varied depending on the in vitro method employed. For the SBRC and IVG methods, As bioaccessibility generally decreased when gastric-phase values were compared to the intestinal phase. In contrast, extending the PBET and DIN assays from the gastric to the intestinal phase resulted in an increase in As bioaccessibility for some soils tested. Comparison of in vitro and in vivo results demonstrated that the in vitro assay encompassing the SBRC gastric phase provided the best prediction of in vivo relative As bioavailability (R 2 ) 0.75, Pearson correlation ) 0.87). However, relative As bioavailability could also be predicted using gastric or intestinal phases of IVG, PBET, and DIN assays but with varying degrees of confidence (R 2 ) 0.53-0.67, Pearson correlation ) 0.73-0.82).
Environmental Science & Technology, 2009
In this study, lead (Pb) bioaccessibility in contaminated soils was assessed using an in vitro me... more In this study, lead (Pb) bioaccessibility in contaminated soils was assessed using an in vitro method (SBRC) encompassing gastric (SBRC-G) and intestinal (SBRC-I) phases. Initially, bioaccessibility studies were performed with a Pb reference material (Pb acetate, 1-10 mg L -1 ) in order to determine the influence of pH on Pb solubility. In the gastric phase (pH 1.5), Pb solubility was 100% (100 ( 2.9%, n ) 16) irrespective of the Pb concentration added, however, when the pH of the intestinal phase was increased to near neutral, Pb solubility decreased to 14.3 ( 7.2%. In contaminated soils, Pb bioaccessibility varied from 35.7 to 64.1% and 1.2 to 2.7% for SBRC-G and SBRC-I phases, respectively. When relative bioaccessibility (Rel-SBRC-I) was calculated by adjusting the dissolution of Pb from contaminated soils by the solubility of Pb acetate at pH 6.5 (intestinal phase pH), Rel-SBRC-I values ranged from 11.7-26.1%. A stepwise regression model based on Pearson correlation factors was used to determine the suitability of in vitro assays for predicting in vivo (swine assay) relative Pb bioavailability. Rel-SBRC-I provided the best estimate of in vivo relative Pb bioavailability for soils used in this study (in vivo relative Pb bioavailability [%] ) Rel-SBRC-I [pH 6.5%] × 0.58 + 1.98, r 2 ) 0.53). The versatility of Rel-SBRC-I was demonstrated by accurately predicting relative Pb bioavailability from other reported in vivo studies.
Environmental Health Perspectives, 2006
BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is kn... more BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is known about the uptake and bioavailability of arsenic species after arsenic-contaminated rice ingestion. OBJECTIVES: In this study, we assessed arsenic speciation in greenhouse-grown and supermarketbought rice, and determined arsenic bioavailability in cooked rice using an in vivo swine model. RESULTS: In supermarket-bought rice, arsenic was present entirely in the inorganic form compared to greenhouse-grown rice (using irrigation water contaminated with sodium arsenate), where most (~ 86%) arsenic was present as dimethylarsinic acid (organic arsenic). Because of the low absolute bioavailability of dimethylarsinic acid and the high proportion of dimethylarsinic acid in greenhouse-grown rice, only 33 ± 3% (mean ± SD) of the total rice-bound arsenic was bioavailable. Conversely, in supermarket-bought rice cooked in water contaminated with sodium arsenate, arsenic was present entirely in the inorganic form, and bioavailability was high (89 ± 9%). CONCLUSIONS: These results indicate that arsenic bioavailability in rice is highly dependent on arsenic speciation, which in turn can vary depending on rice cultivar, arsenic in irrigation water, and the presence and nature of arsenic speciation in cooking water. Arsenic speciation and bioavailability are therefore critical parameters for reducing uncertainties when estimating exposure from the consumption of rice grown and cooked using arsenic-contaminated water. KEY WORDS: arsenic, arsenic daily intake values, bioavailability, in vivo, maximum tolerable daily intake, rice, risk assessment, speciation.
Environmental Geochemistry and Health, 2009
The assessment of arsenic (As) bioavailability from contaminated matrices is a crucial parameter ... more The assessment of arsenic (As) bioavailability from contaminated matrices is a crucial parameter for reducing the uncertainty when estimating exposure for human health risk assessment. In vivo assessment of As utilising swine is considered an appropriate model for human health risk assessment applications as swine are remarkably similar to humans in terms of physiology and As metabolism. While limited in vivo As bioavailability data is available in the literature, few details have been provided regarding technical considerations for performing in vivo assays. This paper describes, with examples, surgical, experimental design and analytical issues associated with performing chronic and acute in vivo swine assays to determine As bioavailability in contaminated soil and food.
Chemosphere, 2008
Arsenic (As) bioavailability in spiked soils aged for up to 12 months was assessed using in vitro... more Arsenic (As) bioavailability in spiked soils aged for up to 12 months was assessed using in vitro and in vivo methodologies. Ageing (natural attenuation) of spiked soils resulted in a decline in in vivo As bioavailability (swine assay) of over 75% in soil A (Red Ferrosol) but had no significant effect on in vivo As bioavailability even after 12 months of ageing in soil B (Brown Chromosol). Sequential fractionation, however, indicated that there was repartitioning of As within the soil fractions extracted during the time course investigated. In soil A, the As fraction associated with the more weakly bound soil fractions decreased while the residual fraction increased from 12% to 35%. In contrast, little repartitioning of As was observed in soil B indicating that natural attenuation may be only applicable for As in soils containing specific mineralogical properties.
Chemosphere, 2008
Considerable information is available in the literature regarding the uptake of arsenic (As) from... more Considerable information is available in the literature regarding the uptake of arsenic (As) from contaminated soil and irrigation water by vegetables. However, few studies have investigated As speciation in these crops while a dearth of information is available on As bioavailability following their consumption. In this study, the concentration and speciation of As in chard, radish, lettuce and mung beans was determined following hydroponic growth of the vegetables using As-contaminated water. In addition, As bioavailability was assessed using an in vivo swine feeding assay. While As concentrations ranged from 3.0 to 84.2mg As kg(-1) (dry weight), only inorganic As (arsenite and arsenate) was detected in the edible portions of the vegetables. When As bioavailability was assessed through monitoring blood plasma As concentrations following swine consumption of As-contaminated vegetables, between 50% and 100% of the administered As dose was absorbed and entered systemic circulation. Arsenic bioavailability decreased in the order mung beans>radish>lettuce=chard.
Chemosphere, 2007
Arsenic (As) bioaccessibility in contaminated soils (n = 50) was assessed using the simplified bi... more Arsenic (As) bioaccessibility in contaminated soils (n = 50) was assessed using the simplified bioaccessibility extraction test (SBET). Soils used in the study were collected from sites where As was used as an herbicide (railway corridor) or pesticide (cattle dip sites), from former gold mines and from highly mineralised locations containing geogenic As sources (gossans). In all but three soils, As bioaccessibility was less than 50% indicating that a significant proportion of the total As concentration may not be available for absorption in the gastrointestinal tract following incidental soil ingestion. When regression models were developed based on soil properties, the descriptive variables best able to describe As bioaccessibility in railway corridor, dip site and mine site soils were total As and total or dithionitecitrate extractable (free) iron (Fe). While As bioaccessibility could be predicted (r 2 = 0.955, n = 50) in these contaminated soils, As bioaccessibility for gossan soils was a poor fit using linear or multivariate regression analysis.
Chemosphere, 2007
An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in cont... more An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in contaminated soils. Arsenic bioavailability was assessed using pharmacokinetic analysis encompassing area under the blood plasma-As concentration time curve following zero correction and dose normalisation. In contaminated soil studies, As uptake into systemic circulation was compared to an arsenate oral dose and expressed as relative As bioavailability. Arsenic bioavailability ranged from 6.9+/-5.0% to 74.7+/-11.2% in 12 contaminated soils collected from former railway corridors, dip sites, mine sites and naturally elevated gossan soils. Arsenic bioavailability was generally low in the gossan soils and highest in the railway soils, ranging from 12.1+/-8.5% to 16.4+/-9.1% and 11.2+/-4.7% to 74.7+/-11.2%, respectively. Comparison of in vivo and in vitro (Simplified Bioaccessibility Extraction Test [SBET]) data from the 12 contaminated soils and bioavailability data collected from an As spiked soil study demonstrated that As bioavailability and As bioaccessibility were linearly correlated (in vivo As bioavailability (mgkg(-1))=14.19+0.93.SBET As bioaccessibility (mgkg(-1)); r(2)=0.92). The correlation between the two methods indicates that As bioavailability (in vivo) may be estimated using the less expensive, rapid in vitro chemical extraction method (SBET) to predict As exposure in human health risk assessment.
![Research paper thumbnail of Effects of ageing and soil properties on the oral bioavailability of benzo[a]pyrene using a swine model](https://attachments.academia-assets.com/43804733/thumbnails/1.jpg)
](Environment International, 2014
Study of relative bioavailability (RB) of B[a]P in contrasting soils with ageing.RB was significa... more Study of relative bioavailability (RB) of B[a]P in contrasting soils with ageing.RB was significantly correlated with Fine Particle Associated Carbon (FPAC).RB was significantly correlated with pore fraction < 6 nm.DCM/Ace and BuOH extractable B[a]P has good significant linear correlation with RB.Oral bioavailability of benzo[a]pyrene (B[a]P) was studied in a swine model using eight spiked soil samples after incubation for 50 and/or 90 days. Silica sand was used as a reference material and the relative bioavailability (RB) of B[a]P in soils was calculated as the quotient of the area under the plasma B[a]P curve (AUC) for soil and AUC for the silica sand. Significantly reduced RB was observed in all study soils after 90 days ageing, ranging from 22.1 ± 0.4% to 62.7 ± 10.1%, except for one very sandy soil (sand content 87.6%) where RB was unchanged (108.1 ± 8.0%). Apart from this, bioavailability decreased during ageing with the decrease (from day 50 to day 90) being only significant for a clayey soil containing expandable clay minerals. Statistical analyses of B[a]P RB at day 90 (eight soils) and soil properties showed no direct correlation between RB and specific soil properties such as total organic carbon (TOC) and clay content which were commonly linked to organic contaminant sequestration. However, strongly significant relationships (p < 0.001) were found between RB and the fine particle associated carbon (FPAC) defined as (Silt + Clay)/TOC, and between RB and the soil mesopore (< 6 nm; p < 0.001) fraction, after two samples with high pH and high EC being excluded from the analyses. The bioaccessibility estimated by four in vitro extraction methods: dichloromethane/acetone sonication (DCM/Ace), butanol vortex (BuOH), hydroxypropyl-β-cyclodextrin extraction (HPCD) and Milli Q water leaching methods at different sampling time (1 day, 50 days and 90 days after spiking) also showed a decreasing trend. Significant correlations were found between B[a]P RB and DCM/Ace (R2 = 0.67, p < 0.05) extractable fraction and BuOH (R2 = 0.75, p < 0.01) extractable fraction.
PLOS ONE, 2015
The incidence of adverse pregnancy outcomes is higher in pregnancies where the fetus is male. Sex... more The incidence of adverse pregnancy outcomes is higher in pregnancies where the fetus is male. Sex specific differences in feto-placental perfusion indices identified by Doppler assessment have recently been associated with placental insufficiency and fetal growth restriction. This study aims to investigate sex specific differences in placental perfusion and to correlate these changes with fetal growth. It represents the largest comprehensive study under field conditions of uterine hemodynamics in a monotocous species, with a similar long gestation period to the human. Primiparous 14mo heifers in Australia (n=360) and UK (n=180) were either individually or group fed, respectively, diets with differing protein content (18, 14, 10 or 7% crude protein (CP)) from 60d prior to 98 days post conception (dpc). Fetuses and placentae were excised at 98dpc (n = 48). Fetal development an median uterine artery blood flow were assessed monthly from 36dpc until term using B-mode and Doppler ultrasonography. MUA blood flow to the male feto-placental unit increased in early pregnancy associated with increased fetal growth. Protein restriction before and shortly after conception (-60d up to 23dpc) increased MUA diameter and indices of velocity during late pregnancy, reduced fetal heart weight in the female fetus and increased heart rate at birth, but decreased systolic blood pressure at six months of age.
Neurobiology of disease, Jan 11, 2016
Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme re... more Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the β-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in β-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000-fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangli...
Biomaterials, 2015
Advanced biosensors in future medicine hinge on the evolvement of biomaterials. Porous silicon (p... more Advanced biosensors in future medicine hinge on the evolvement of biomaterials. Porous silicon (pSi), a generally biodegradable and biocompatible material that can be fabricated to include environment-responsive optical characteristics, is an excellent candidate for in vivo biosensors. However, the feasibility of using this material as a subcutaneously implanted optical biosensor has never been demonstrated. Here, we investigated the stability and biocompatibility of a thermally-hydrocarbonised (THC) pSi optical rugate filter, and demonstrated its optical functionality in vitro and in vivo. We first compared pSi films with different surface chemistries and observed that the material was cytotoxic despite the outstanding stability of the THC pSi films. We then showed that the cytotoxicity correlates with reactive oxygen species levels, which could be mitigated by pre-incubation of THC pSi (PITHC pSi). PITHC pSi facilitates normal cellular phenotypes and is biocompatible in vivo. Importantly, the material also possesses optical properties capable of responding to microenvironmental changes that are readable non-invasively in cell culture and subcutaneous settings. Collectively, we demonstrate, for the first time, that PITHC pSi rugate filters are both biocompatible and optically functional for lab-on-a-chip and subcutaneous biosensing scenarios. We believe that this study will deepen our understanding of cell-pSi interactions and foster the development of implantable biosensors.
Journal of Zhejiang University. Science. B, 2015
Understanding the ecology of the gastrointestinal tract and the impact of the contents on the hos... more Understanding the ecology of the gastrointestinal tract and the impact of the contents on the host mucosa is emerging as an important area for defining both wellness and susceptibility to disease. Targeted delivery of drugs to treat specific small intestinal disorders such as small bowel bacterial overgrowth and targeting molecules to interrogate or to deliver vaccines to the remote regions of the small intestine has proven difficult. There is an unmet need for methodologies to release probes/drugs to remote regions of the gastrointestinal tract in furthering our understanding of gut health and pathogenesis. In order to address this concern, we need to know how the regional delivery of a surrogate labeled test compound is handled and in turn, if delivered locally as a liquid or powder, the dynamics of its subsequent handling and metabolism. In the studies we report on in this paper, we chose (13)C sodium acetate ((13)C-acetate), which is a stable isotope probe that once absorbed in ...
The Veterinary record, Jan 13, 1980
The effects of combining large doses of xylazine (1.1 mg per kg intravenously) with ketamine, met... more The effects of combining large doses of xylazine (1.1 mg per kg intravenously) with ketamine, methohexitone and thiopentone were studied in four experimental ponies. Onset of anaesthesia was more delayed after ketamine than after the barbiturates. Assessment of smoothness of induction and recovery indicated that all three combinations were effective and acceptable. Injection of xylazine was followed by atrioventricular (A-V) block which could be prevented by the prior administration of atropine. Blood pressure was well maintained with all three combinations of drugs. Arterial oxygen tension decreased as soon as the ponies became recumbent but there were no marked changes in arterial blood pH or carbon dioxide tension. Cardiac output was measured in one pony and was found to be least affected by ketamine. There was no great difference between the recumbency times after ketamine and methohexitone but thiopentone produced a significantly longer period of recumbency. In every instance t...
BMC Pulmonary Medicine, 2014
Background: The safety and efficiency of gene therapies for cystic fibrosis (CF) need to be asses... more Background: The safety and efficiency of gene therapies for cystic fibrosis (CF) need to be assessed in pre-clinical models. Using the normal ferret, this study sought to determine whether ferret airway epithelia could be transduced with a lysophosphatidylcholine (LPC) pre-treatment followed by a VSV-G pseudotyped HIV-1 based lentiviral (LV) vector, in preparation for future studies in CF ferrets. Methods: Six normal ferrets (7 -8 weeks old) were treated with a 150 μL LPC pre-treatment, followed one hour later by a 500 μL LV vector dose containing the LacZ transgene. LacZ gene expression in the conducting airways and lung was assessed by X-gal staining after 7 days. The presence of transduction in the lung, as well as off-target transduction in the liver, spleen and gonads, were assessed by qPCR. The levels of LV vector p24 protein bio-distribution in blood sera were assessed by ELISA at 0, 1, 3, 5 and 7 days. Results: The dosing protocol was well tolerated. LacZ gene expression was observed en face in the trachea of all animals. Histology showed that ciliated and basal cells were transduced in the trachea, with rare LacZ transduced single cells noted in lung. p24 levels was not detectable in the sera of 5 of the 6 animals. The LacZ gene was not detected in the lung tissue and no off-target transduction was detected by qPCR.
Veterinary Anaesthesia and Analgesia, 1982
ABSTRACT The structural diversity of anaesthetic compounds suggests that anaesthetics do not act ... more ABSTRACT The structural diversity of anaesthetic compounds suggests that anaesthetics do not act at a single specific receptor.However, the close correlation between the lipid solubility of anaesthetics and their potencies (Meyer-Overton rule) does imply a common mechanism: A Unitary Hypothesis.Anaesthetizing Partial E'ressure x oil/gas part. coef. varies only 2 x over a range of 70,000 in partial pressures.This suggests that a specific number of anaesthetic molecules occupy a crucial hydrophobic site in the CNS, but the MeyerOverton rule offers no mechanistic explanation for its validity.The putative site of action of anaesthetics is the synapse because the relative resistance of larger axons to anaesthetic induced depression narrows the site of hydrophobic action to synapic regions or axons with small diameter at the nerve terminal (Richards, 1981) (see Figure 1).
Laboratory Animals, 2001
T he efficac y of continuous low-dose xylazine infusion following an initial loading dose in prov... more T he efficac y of continuous low-dose xylazine infusion following an initial loading dose in providing analgesia in sheep was exam ined using an algesim etry method based on a leg lifting response to an electrical stimulus. Sheep received a 5 mg intramuscular injection of xylazine followed by continuous infusion of intravenous xylazi ne (2 mg = h) for 90 min. T his treatm ent resulted in significant increases in the level of current required to elicit a leg lift ing response (287% of baseline) and steady state analgesia was maintai ned from 10 min after the start of the infusion until the end of the experimental period. T his protocol appears to be a simple and effective regim en for providing steady state analgesia in sheep. (2001) 35, 277 281 C o rre spond e nc e to : C liff G ra nt E-m a il: cgra nt@m e d ic ine .a d ela id e .ed u.a u
Australian Veterinary Journal, 1996
The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and... more The analgesic action of intramuscularly injected buprenorphine, methadone, flunixin meglumine and xylazine was examined in sheep, using algesimetry based on a leg withdrawal response to an electrical stimulus. No analgesic response was detected for buprenorphine, methadone or flunixin meglumine. Only the alpha 2-adrenoceptor agonist, xylazine, produced an analgesic response. The current required to elicit a response increased by 170% (4.5 +/- 0.43 mA to 12.23 +/- 1.14 mA; mean +/- SE) after a dose of 0.05 mg/kg xylazine; by 180% (4.73 +/- 0.3 mA to 13.28 +/- 2.35 mA) after 0.1 mg/kg and by 510% (4.52 +/- 0.29 mA to 27.63 +/- 3.89 mA) after 0.2 mg/kg. Intramuscular xylazine appears to be an effective analgesic agent for acute pain in the sheep and further investigation into ideal administration regimens and dosage may provide more detailed information on relationships between dose, analgesic and sedative effects. The findings also suggest that some common analgesic agents, and opioids in particular, may be ineffective for the management of acute pain in sheep and that any analgesic should be administered only on the basis of its proven efficacy in that species.
Environmental Science & Technology, 2009
Currently, a number of in vitro methods are in use worldwide to assess arsenic (As) bioaccessibil... more Currently, a number of in vitro methods are in use worldwide to assess arsenic (As) bioaccessibility in soils. However, a dearth of research has been undertaken to compare the efficacy of the in vitro methods for estimating in vivo relative As bioavailability. In this study, As bioaccessibility in contaminated soils (n ) 12) was assessed using four in vitro assays (SBRC, IVG, PBET, DIN). In vitro results were compared to in vivo relative As bioavailability data (swine assay) to ascertain which methodologies best correlate with in vivo data. Arsenic bioaccessibility in contaminated soils varied depending on the in vitro method employed. For the SBRC and IVG methods, As bioaccessibility generally decreased when gastric-phase values were compared to the intestinal phase. In contrast, extending the PBET and DIN assays from the gastric to the intestinal phase resulted in an increase in As bioaccessibility for some soils tested. Comparison of in vitro and in vivo results demonstrated that the in vitro assay encompassing the SBRC gastric phase provided the best prediction of in vivo relative As bioavailability (R 2 ) 0.75, Pearson correlation ) 0.87). However, relative As bioavailability could also be predicted using gastric or intestinal phases of IVG, PBET, and DIN assays but with varying degrees of confidence (R 2 ) 0.53-0.67, Pearson correlation ) 0.73-0.82).
Environmental Science & Technology, 2009
In this study, lead (Pb) bioaccessibility in contaminated soils was assessed using an in vitro me... more In this study, lead (Pb) bioaccessibility in contaminated soils was assessed using an in vitro method (SBRC) encompassing gastric (SBRC-G) and intestinal (SBRC-I) phases. Initially, bioaccessibility studies were performed with a Pb reference material (Pb acetate, 1-10 mg L -1 ) in order to determine the influence of pH on Pb solubility. In the gastric phase (pH 1.5), Pb solubility was 100% (100 ( 2.9%, n ) 16) irrespective of the Pb concentration added, however, when the pH of the intestinal phase was increased to near neutral, Pb solubility decreased to 14.3 ( 7.2%. In contaminated soils, Pb bioaccessibility varied from 35.7 to 64.1% and 1.2 to 2.7% for SBRC-G and SBRC-I phases, respectively. When relative bioaccessibility (Rel-SBRC-I) was calculated by adjusting the dissolution of Pb from contaminated soils by the solubility of Pb acetate at pH 6.5 (intestinal phase pH), Rel-SBRC-I values ranged from 11.7-26.1%. A stepwise regression model based on Pearson correlation factors was used to determine the suitability of in vitro assays for predicting in vivo (swine assay) relative Pb bioavailability. Rel-SBRC-I provided the best estimate of in vivo relative Pb bioavailability for soils used in this study (in vivo relative Pb bioavailability [%] ) Rel-SBRC-I [pH 6.5%] × 0.58 + 1.98, r 2 ) 0.53). The versatility of Rel-SBRC-I was demonstrated by accurately predicting relative Pb bioavailability from other reported in vivo studies.
Environmental Health Perspectives, 2006
BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is kn... more BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is known about the uptake and bioavailability of arsenic species after arsenic-contaminated rice ingestion. OBJECTIVES: In this study, we assessed arsenic speciation in greenhouse-grown and supermarketbought rice, and determined arsenic bioavailability in cooked rice using an in vivo swine model. RESULTS: In supermarket-bought rice, arsenic was present entirely in the inorganic form compared to greenhouse-grown rice (using irrigation water contaminated with sodium arsenate), where most (~ 86%) arsenic was present as dimethylarsinic acid (organic arsenic). Because of the low absolute bioavailability of dimethylarsinic acid and the high proportion of dimethylarsinic acid in greenhouse-grown rice, only 33 ± 3% (mean ± SD) of the total rice-bound arsenic was bioavailable. Conversely, in supermarket-bought rice cooked in water contaminated with sodium arsenate, arsenic was present entirely in the inorganic form, and bioavailability was high (89 ± 9%). CONCLUSIONS: These results indicate that arsenic bioavailability in rice is highly dependent on arsenic speciation, which in turn can vary depending on rice cultivar, arsenic in irrigation water, and the presence and nature of arsenic speciation in cooking water. Arsenic speciation and bioavailability are therefore critical parameters for reducing uncertainties when estimating exposure from the consumption of rice grown and cooked using arsenic-contaminated water. KEY WORDS: arsenic, arsenic daily intake values, bioavailability, in vivo, maximum tolerable daily intake, rice, risk assessment, speciation.
Environmental Geochemistry and Health, 2009
The assessment of arsenic (As) bioavailability from contaminated matrices is a crucial parameter ... more The assessment of arsenic (As) bioavailability from contaminated matrices is a crucial parameter for reducing the uncertainty when estimating exposure for human health risk assessment. In vivo assessment of As utilising swine is considered an appropriate model for human health risk assessment applications as swine are remarkably similar to humans in terms of physiology and As metabolism. While limited in vivo As bioavailability data is available in the literature, few details have been provided regarding technical considerations for performing in vivo assays. This paper describes, with examples, surgical, experimental design and analytical issues associated with performing chronic and acute in vivo swine assays to determine As bioavailability in contaminated soil and food.
Chemosphere, 2008
Arsenic (As) bioavailability in spiked soils aged for up to 12 months was assessed using in vitro... more Arsenic (As) bioavailability in spiked soils aged for up to 12 months was assessed using in vitro and in vivo methodologies. Ageing (natural attenuation) of spiked soils resulted in a decline in in vivo As bioavailability (swine assay) of over 75% in soil A (Red Ferrosol) but had no significant effect on in vivo As bioavailability even after 12 months of ageing in soil B (Brown Chromosol). Sequential fractionation, however, indicated that there was repartitioning of As within the soil fractions extracted during the time course investigated. In soil A, the As fraction associated with the more weakly bound soil fractions decreased while the residual fraction increased from 12% to 35%. In contrast, little repartitioning of As was observed in soil B indicating that natural attenuation may be only applicable for As in soils containing specific mineralogical properties.
Chemosphere, 2008
Considerable information is available in the literature regarding the uptake of arsenic (As) from... more Considerable information is available in the literature regarding the uptake of arsenic (As) from contaminated soil and irrigation water by vegetables. However, few studies have investigated As speciation in these crops while a dearth of information is available on As bioavailability following their consumption. In this study, the concentration and speciation of As in chard, radish, lettuce and mung beans was determined following hydroponic growth of the vegetables using As-contaminated water. In addition, As bioavailability was assessed using an in vivo swine feeding assay. While As concentrations ranged from 3.0 to 84.2mg As kg(-1) (dry weight), only inorganic As (arsenite and arsenate) was detected in the edible portions of the vegetables. When As bioavailability was assessed through monitoring blood plasma As concentrations following swine consumption of As-contaminated vegetables, between 50% and 100% of the administered As dose was absorbed and entered systemic circulation. Arsenic bioavailability decreased in the order mung beans&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;radish&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;lettuce=chard.
Chemosphere, 2007
Arsenic (As) bioaccessibility in contaminated soils (n = 50) was assessed using the simplified bi... more Arsenic (As) bioaccessibility in contaminated soils (n = 50) was assessed using the simplified bioaccessibility extraction test (SBET). Soils used in the study were collected from sites where As was used as an herbicide (railway corridor) or pesticide (cattle dip sites), from former gold mines and from highly mineralised locations containing geogenic As sources (gossans). In all but three soils, As bioaccessibility was less than 50% indicating that a significant proportion of the total As concentration may not be available for absorption in the gastrointestinal tract following incidental soil ingestion. When regression models were developed based on soil properties, the descriptive variables best able to describe As bioaccessibility in railway corridor, dip site and mine site soils were total As and total or dithionitecitrate extractable (free) iron (Fe). While As bioaccessibility could be predicted (r 2 = 0.955, n = 50) in these contaminated soils, As bioaccessibility for gossan soils was a poor fit using linear or multivariate regression analysis.
Chemosphere, 2007
An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in cont... more An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in contaminated soils. Arsenic bioavailability was assessed using pharmacokinetic analysis encompassing area under the blood plasma-As concentration time curve following zero correction and dose normalisation. In contaminated soil studies, As uptake into systemic circulation was compared to an arsenate oral dose and expressed as relative As bioavailability. Arsenic bioavailability ranged from 6.9+/-5.0% to 74.7+/-11.2% in 12 contaminated soils collected from former railway corridors, dip sites, mine sites and naturally elevated gossan soils. Arsenic bioavailability was generally low in the gossan soils and highest in the railway soils, ranging from 12.1+/-8.5% to 16.4+/-9.1% and 11.2+/-4.7% to 74.7+/-11.2%, respectively. Comparison of in vivo and in vitro (Simplified Bioaccessibility Extraction Test [SBET]) data from the 12 contaminated soils and bioavailability data collected from an As spiked soil study demonstrated that As bioavailability and As bioaccessibility were linearly correlated (in vivo As bioavailability (mgkg(-1))=14.19+0.93.SBET As bioaccessibility (mgkg(-1)); r(2)=0.92). The correlation between the two methods indicates that As bioavailability (in vivo) may be estimated using the less expensive, rapid in vitro chemical extraction method (SBET) to predict As exposure in human health risk assessment.
Environment International, 2014
Study of relative bioavailability (RB) of B[a]P in contrasting soils with ageing.RB was significa... more Study of relative bioavailability (RB) of B[a]P in contrasting soils with ageing.RB was significantly correlated with Fine Particle Associated Carbon (FPAC).RB was significantly correlated with pore fraction < 6 nm.DCM/Ace and BuOH extractable B[a]P has good significant linear correlation with RB.Oral bioavailability of benzo[a]pyrene (B[a]P) was studied in a swine model using eight spiked soil samples after incubation for 50 and/or 90 days. Silica sand was used as a reference material and the relative bioavailability (RB) of B[a]P in soils was calculated as the quotient of the area under the plasma B[a]P curve (AUC) for soil and AUC for the silica sand. Significantly reduced RB was observed in all study soils after 90 days ageing, ranging from 22.1 ± 0.4% to 62.7 ± 10.1%, except for one very sandy soil (sand content 87.6%) where RB was unchanged (108.1 ± 8.0%). Apart from this, bioavailability decreased during ageing with the decrease (from day 50 to day 90) being only significant for a clayey soil containing expandable clay minerals. Statistical analyses of B[a]P RB at day 90 (eight soils) and soil properties showed no direct correlation between RB and specific soil properties such as total organic carbon (TOC) and clay content which were commonly linked to organic contaminant sequestration. However, strongly significant relationships (p < 0.001) were found between RB and the fine particle associated carbon (FPAC) defined as (Silt + Clay)/TOC, and between RB and the soil mesopore (< 6 nm; p < 0.001) fraction, after two samples with high pH and high EC being excluded from the analyses. The bioaccessibility estimated by four in vitro extraction methods: dichloromethane/acetone sonication (DCM/Ace), butanol vortex (BuOH), hydroxypropyl-β-cyclodextrin extraction (HPCD) and Milli Q water leaching methods at different sampling time (1 day, 50 days and 90 days after spiking) also showed a decreasing trend. Significant correlations were found between B[a]P RB and DCM/Ace (R2 = 0.67, p < 0.05) extractable fraction and BuOH (R2 = 0.75, p < 0.01) extractable fraction.