PubMed Health⌕ Search

Biomedical subjects

P Gale

Publications and source records attributed to P Gale.

At least 19 recordsLinked to original sources
PubMed2006

BSE risk assessments in the UK: a risk tradeoff?

Risk assessments for bovine spongiform encephalopathy (BSE) should be based on the group risk and not the median individual risk. The group risk is calculated from the arithmetic mean risk, which in the case of dorsal root ganglia, is a factor of 50-fold higher than the median. For environmental routes, the arithmetic mean exposure is sufficient for risk assessment, while for food-borne routes failure to accommodate the variation in exposures to individuals across the UK population could overestimate the group risk considerably. Ignoring prion destruction by cooking could overestimate the food-borne risks still further. The recent estimate for the arithmetic mean cow-to-man species barrier of 4000 does not take into accounts either of these factors and thus may be too high. Until evidence for a threshold dose is demonstrated, public health scientists should avoid assessing safety on the basis of a 'minimum infective dose'. The incubation period observed in cattle-feeding studies, when completed, would continue to increase with decreasing dose below the ID50if there is a threshold or co-operative effect. The question is raised of whether fears over BSE in drinking water contributed to the spread of foot-and-mouth disease across the UK in 2001; a risk tradeoff.

Animals↗
PubMed2006

The infectivity of transmissible spongiform encephalopathy agent at low doses: the importance of phospholipid.

The issue of whether the mechanism of infection is independent or co-operative for low doses of transmissible spongiform encephalopathy (TSE) agent is critical for risk assessment. The susceptibility (and hence ID(50)) of individuals with the same prion protein (PrP) genotype may vary considerably with a small proportion being very susceptible. Assuming independent action, the incubation period (IP) would continue to increase until the dose is below the ID(50) of the most susceptible individuals in the experiment, at which point it would become constant. This may explain the observed increase in IP with decreasing dose below the apparent ID(50) in experiments with untreated TSE agent. In contrast, IPs for autoclaved or NaOH-treated TSE agent increase greatly at doses <ID(50) suggesting strong co-operative action, or even a threshold. It is proposed here that the unit of infectivity for prion disease is a nucleation seed comprised of PrP and host phospholipid (PL). PL would play a structural role through mediating protein/lipid interactions with PrP. Heating or alkali treatment destroys the PL breaking up the nucleation seeds, which require long IPs to reform at low doses. Replenishing those inactivated PLs with host PL would explain how the phenotypic effect of long IP at low dose is lost on subpassage. It is proposed here that strain thermostability is controlled by the nature and strength of the PrP/PL interactions, which are independent of the host PrP genotype. Although repeated oral exposure to low doses of scrapie is less harmful than a single large exposure, this effect may reflect interference by competition rather than diminished risks due to a co-operative effect, and is of little importance for 'one-off' low-dose environmental exposures.

Animals↗
PubMed2005

Land application of treated sewage sludge: quantifying pathogen risks from consumption of crops.

AIMS: To predict the number of humans in the UK infected through consumption of root crops grown on agricultural land to which treated sewage sludge has been applied in accordance with the current regulations and guidance (Safe Sludge Matrix). METHODS AND RESULTS: Quantitative risk assessments based on the source, pathway, receptor approach are developed for seven pathogens, namely salmonellas, Listeria monocytogenes, campylobacters, Escherichia coli O157, Cryptosporidium parvum, Giardia, and enteroviruses. Using laboratory data for pathogen destruction by mesophilic anaerobic digestion, and not extrapolating experimental data for pathogen decay in soil to the full 30-month harvest interval specified by the Matrix, predicts 50 Giardia infections per year, but less than one infection per year for the other six pathogens. Assuming linear decay in the soil, a 12-month harvest interval eliminates the risks from all seven pathogens; the highest predicted being one infection of C. parvum in the UK every 45 years. Computer simulations show that a protective effect from binding of pathogens to particulate matter could potentially exaggerate the observed rate of decay in experimental systems. CONCLUSIONS: The results confirm, assuming pathogens behave according to our current understanding, that the risks to humans from consumption of vegetable crops are remote. Furthermore the harvest intervals stipulated by the Safe Sludge Matrix compensate for potential lapses in the operational efficiency of sludge treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: The models demonstrate the huge potential impact of decay in the soil over the 12/30-month intervals specified by the Matrix, although lack of knowledge on the exact nature of soil decay processes is a source of uncertainty. The models enable the sensitivity of the predicted risks to changes in the operational efficiency of sewage sludge treatment to be assessed.

Animals↗
PubMed2005

Matrix effects, nonuniform reduction and dispersion in risk assessment for Escherichia coli O157.

AIMS: To assess the importance of the variation (or spatial heterogeneity) in the doses of Escherichia coli O157 ingested by individuals when estimating the group risk. METHODS AND RESULTS: Exposure scenarios, which differed in how the same total number of E. coli O157 cells were distributed across a group of persons were simulated and the risks of illness in the population estimated using available dose-response data. Differences in the degree of spatial heterogeneity within routes such as direct contact with sheep faeces, consumption of hamburgers and drinking water could affect the magnitude of the predicted risk by over 1000-fold and contribute to an apparent matrix effect. The effect of barriers, such as cooking, on the spatial heterogeneity of E. coli O157 cells remaining in undercooked hamburgers affects the magnitude of the risk by eightfold. Furthermore, a 100-fold reduction in E. coli O157 concentrations by cooking may reduce the risk of illness from consumption of the burgers by only 12-fold (and not the 100-fold perhaps expected). CONCLUSIONS: The development of microbiological risk assessment (MRA) models for E. coli O157 requires information on the degree of dispersion of faeces within routes such as the environment, food and water, so that the proportion of persons actually exposed to faeces, and hence pathogen, can be quantified. The effect of dispersion is greater for pathogens for which there is greater variation in susceptibility within the population. SIGNIFICANCE AND IMPACT OF THE STUDY: In terms of public health protection, minimizing the dispersion of cattle/sheep faeces reduces the risks to humans by confining exposure to fewer individuals. For MRA, estimating the reduction in risk by a treatment process, e.g. cooking, is complicated by spatial heterogeneity. Regional differences in dispersion (e.g. because of rainfall) may contribute to regional differences in the observed attack rate.

Animals↗
PubMed2004

Risks to farm animals from pathogens in composted catering waste containing meat.

Uncooked meat may contain animal pathogens, including bovine spongiform encephalopathy, foot-and-mouth disease virus, African swine fever virus and classical swine fever virus, and to prevent outbreaks of these diseases in farm animals, the disposal of meat from catering waste is controlled under the Animal By-Products Regulations. This paper estimates the risks to farm animals of grazing land on to which compost, produced by the composting of catering waste containing meat, has been applied. The factors controlling the level of risk are the separation of the meat at source, the efficiency of the composting process, and the decay and dilution of the pathogens in soil. The net pathogen destruction by the composting process is determined largely by the degree of bypass, and to accommodate the possibility of large joints or even whole carcases being discarded uncooked to catering waste, a time/temperature condition of 60 degrees C for two days is recommended. Where data are lacking, worst-case assumptions have been applied. According to the model, classical swine fever virus constitutes the highest risk, but the assessment shows that a two-barrier composting approach, together with a two-month grazing ban, reduces the risk to one infection in pigs every 190 years in England and Wales. This work defined the operational conditions for the composting of catering waste as set out in the Animal By-Products Regulations 2003 (SI 1482).

African Swine Fever↗
PubMed2003

Using event trees to quantify pathogen levels on root crops from land application of treated sewage sludge.

AIMS: To quantify the incremental exposure of root crops, at point of harvest, to enteric pathogens from sewage sludge applied to agricultural land according to current regulations and guidance (Safe Sludge Matrix). METHODS AND RESULTS: A quantitative risk assessment based on the Source-Pathway-Receptor approach is developed for Cryptosporidium and salmonellas. Event trees are constructed to model the partitioning of pathogens present in raw sewage into sludge at the sewage treatment works and to model to the pathways by which root crops may be exposed to those pathogens after treatment and land application of the sludge. The main barriers are sewage sludge treatment, and decay and dilution of the pathogens in the soil. The exposures are expressed in terms of the arithmetic mean. This represents the total loading and accommodates fluctuations not only in the levels of pathogens present in sewage but also in the removal efficiencies by the various barriers. One source of uncertainty is the degree of by-pass of sludge treatment at operational scale. CONCLUSIONS: The models predict that land application of sewage sludge treated by conventional processes (achieving 2-log removal) increases the exposures of root crops to salmonellas and Cryptosporidium oocysts by counts of 0.070 and 0.033 kg(-1), respectively. These predictions are based on decay periods in the soil of 5 and 12 weeks, respectively, and are therefore worst case in not allowing for the full extent of no harvesting periods. A Monte Carlo simulation predicts that 0.01% of 1-kg batches contained > 50 salmonellas and demonstrates that, for risk assessment, it is acceptable to use the arithmetic mean exposure directly in the dose-response curve. SIGNIFICANCE AND IMPACT OF THE STUDY: The predicted numbers of pathogens on root crops at point of harvest provide a basis for modelling the excess risks to humans consuming such crops. The approach underpins scientifically the Safe Sludge Matrix.

Agriculture↗
PubMed2001

Towards a quantitative risk assessment for BSE in sewage sludge.

AIMS: The aim is to determine the risk of transmission of BSE to humans and cattle through the application of sewage sludge to agricultural land. METHODS AND RESULTS: A quantitative risk assessment based on the Source-Pathway-Receptor approach is developed. Central to the model is the estimation of the arithmetic mean concentration of BSE agent in sewage sludge. The main sources of uncertainty in the risk assessment are the degree to which sewage sludge treatment destroys BSE agent, whether there is a threshold dose for initiation of BSE infection in cattle, and most importantly, the amount of brain and spinal cord material which enters the sewer from the abattoir. Assuming 1% of brain and spinal cord is lost to the sewer from abattoirs, the model predicts a risk of BSE transmission of 7.1 x 10(-5) cow(-1) year(-1) for cattle grazing on land to which sewage sludge has been applied. CONCLUSION: The risks to humans through consumption of vegetable crops are acceptably low. Although the risks to cattle are higher, because of higher exposure to soil and greater susceptibility, the model demonstrates that sewage sludge alone cannot sustain the BSE epidemic in the UK cattle herd. Furthermore, the model suggests that recycling of BSE agent through sewage sludge will not sustain endemic levels of BSE in the UK cattle herd. SIGNIFICANCE AND IMPACT OF THE STUDY: The conclusions are consistent with the findings from epidemiological studies which so far have not detected horizontal transmission of BSE (which would include transmission from contaminated pastures). The model demonstrates the importance of containment of brain and spinal cord within the abattoir.

Abattoirs↗
PubMed1998

Histologic characteristics of laparoscopic argon beam coagulation.

STUDY OBJECTIVES: To describe histologic effects of laparoscopic argon beam coagulation and determine the extent of tissue necrosis at various power settings and exposure times. DESIGN: Prospective experimental analysis (Canadian Task Force classification II-1). SETTING: University animal laboratory. Subjects. Adult female domestic pigs. INTERVENTIONS: Various power settings (40, 60, 80 W) at increasing exposure times (1, 3, 5 sec) were used during laparoscopic application of argon beam coagulation to different tissues (uterine horn, bladder, ureter, kidney, bowel, liver). Animals were sacrificed within 1 hour of coagulation for histologic tissue preparation. MEASUREMENTS AND MAIN RESULTS: Histologic measurements of both depth and lateral extent of electrosurgical tissue effects (mm +/- SD) were ascertained and evaluated statistically by one-way repeated measures analysis of variance. Depth of tissue necrosis was confined to 1 mm or less in uterine horn, bladder, and ureter. Even at highest power settings, bowel had tissue necrosis no greater than 2 mm. Both liver and kidney showed a deeper histologic effect (4-5 mm). The lateral extent of tissue necrosis ranged from 2 mm (ureter) to 15 mm (liver). CONCLUSION: Laparoscopic argon beam coagulation results in tissue effects that are dependent on both low power setting and duration of application, as well as on electrical and physical characteristics of target tissue. Thermal tissue penetration can be expected to be less than 2 mm in bowel, bladder, and ureter, and less than 5 mm in kidney and liver, even at 5 seconds of exposure time and at a power setting as high as 80 W. As with all thermal modalities used for hemostasis and tissue coagulation, laparoscopic argon beam coagulation can be performed safely as long as the potential for inadvertent thermal injury is understood.

Animals↗
PubMed1998

Development of a risk assessment for BSE in the aquatic environment.

Bovine spongiform encephalopathy (BSE) is believed to be transmitted by the ingestion of proteinaceous agents called prions which accumulate in the brain and spinal cord of infected bovines. Concern has been expressed about the risks of transmission of BSE to humans through BSE prions discharged to the aquatic environment from rendering plants, abattoirs and landfills. The disease-related form of the prion protein is relatively resistant to degradation, and infectivity decays rather slowly in the environment. Levels of disinfection used for drinking water treatment would have little effect. This paper presents the assumptions which were used to model the risks from a rendering plant disposing of cull cattle carcasses in the catchment of a chalk aquifer which is used for a drinking water abstraction. The risk assessment approach focused on identifying the hydrogeological and physical barriers which would contribute to preventing BSE infectivity gaining entry to the aquifer. These barriers included inactivation of BSE agent by the rendering process, removal from the effluent by treatment at the plant, filtration and adsorption in the clay and chalk, and dilution in the ground water. The importance in environmental risk assessment of the cow-to-man species barrier is considered. Two key conclusions about the environmental behaviour of the BSE agent are that prion proteins are 'sticky' and bind to particulates, and that the millions of BSE prion molecules comprising a human oral ID50 are subject to some degree of dispersion and hence dilution in the environment. Assuming the rendering plant processes 2000 cull cattle carcasses per week, the risks to drinking water consumers were estimated to be remote. Indeed, even using worst case assumptions an individual would have to consume 21 d-1 of tap water for 45 million years to have a 50% chance of infection through drinking water drawn from the aquifer.

Animals↗
PubMed1998

Quantitative BSE risk assessment: relating exposures to risk.

There is currently no epidemiological evidence to identify the route(s) of transmission of BSE from cattle to humans, although consumption of infected bovine offals, prior to their use being banned in human food in late 1989, is the most likely source. Quantitative risk assessment methods have been applied to estimate the risks through various potential routes of exposure to BSE, including those from environmental disposal of BSE-infected residues. The risks predicted for the consumption of beef-on-the-bone and for the drinking of water from an aquifer potentially contaminated with effluent from a cattle rendering plant are similar at 10(-9) and 10(-8) person-1 year-1, respectively. It is suggested here that while the risks predicted for beef-on-the-bone are realistic, the risks through drinking water could be over-estimated by a factor of about 10(20). First, the risk assessment methodology does not take into account the very different natures of the exposure. Thus, through beef-on-the-bone an unfortunate consumer may ingest a high dose (approaching an ID50) in a single exposure, while because of dilution in water, drinking water consumers would never be exposed to high doses, even cumulatively over the period of a human lifetime. Second, the risk assessment for drinking water does not allow for the possibility of a threshold effect such that a minimum number of BSE prions is needed to initiate infection. It is concluded that direct comparisons of predicted risks from BSE should be avoided unless the natures of the exposure are similar. Information on whether there is a threshold effect is more critical for quantitative BSE risk assessment through environmental routes of exposure than the exact magnitude of the cow-to-man species barrier.

Animals↗
PubMed1996

Developments in microbiological risk assessment models for drinking water--a short review.

Microbiological risk assessment (MRA) is emerging method to predict the risks of infection from waterborne pathogens (e.g. rotavirus and Cryptosporidium parvum) in the drinking water supply. The objectives of this paper are to review the appropriateness of current models, with emphasis on pathogen exposures through drinking water, and to consider the information necessary to further their development. Calculating pathogen exposures in MRA is currently limited by the fact that pathogen density data for drinking water supplies are only available for very large volume samples--much larger than imbibed daily by any consumer. To develop MRA, information is needed on how pathogens are dispersed within those volumes at the resolution of volumes typically consumed daily by individuals. Available evidence suggests that micro-organisms, including pathogens, are clustered to some degree, even within small volumes, exposing some drinking water consumers to much higher doses than others. By assuming pathogens are randomly dispersed, current models overestimate the risk from the more infectious agents (e.g. rotaviruses) but underestimate the risk from less infectious pathogens (e.g. C. parvum). Approaches to modelling pathogen densities in drinking water from source water data and treatment removal efficiencies require additional information on the degree to which treatment processes (e.g. filtration and coagulation) increase pathogen clustering. The missing information could be obtained from large-scale pilot plant studies.

Cryptosporidiosis↗
PubMed1995

Mechanism of inhibition of human leucocyte elastase by beta-lactams. 2. Stability, reactivation kinetics, and products of beta-lactam-derived E-I complexes.

The monocyclic beta-lactams reported by Knight et al. [Knight, W. B., et al. (1992) Biochemistry 31, 8160; Chabin, R., et al. (1993) Biochemistry 32, 8970] as inhibitors of human leucocyte elastase (HLE) produce stable HLE-inhibitor complexes that slowly reactivate with half-lives ranging from less than 1 to 15 h at 37 degrees C. The complexes produced between PPE and two C-3 dimethyl-substituted beta-lactams are less stable than those produced between HLE and analogous C-3 diethyl-substituted lactams. The stability of the HLE-I complexes is governed primarily by the structure of the substituted urea portion of the inhibitors and not by the identity or presence of a leaving group at C-4 of the lactam ring. In some cases substitutions on the urea portion of the inhibitors yielded complexes that displayed biphasic reactivation kinetics. This suggests the presence of at least two different complexes. The stereochemistry of the leaving group at C-4 has a small effect on the stability of the final complex (1.3-2-fold); therefore, the identity of the final complex is dependent upon the initial stereochemistry at that position. The stability of the complexes was relatively insensitive to hydroxylamine, which suggests that the acyl-enzymes are protected from nucleophilic "rescue". The rate of reactivation of the complex derived from L-680,833,[S-R*,S*)]-4-[(1-(((1-(4- methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-oxo-4-azetidinyl)ben zeneacetic acid, was pH independent, while the L-684,481, (R)-(1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-azeti din one generated complex displayed a pH-dependent reactivation rate. In the latter case, the increase in reactivation rate with pH displayed a pKa of 7.2. This is consistent with the requirement for base catalysis by the active site histidine to regenerate enzymatic activity. Reactivation of the L-680,833-derived complex produced different products as a function of pH, suggesting two different pH-dependent routes of reactivation. At low pH a route that produced primarily the substituted urea is favored, while at higher pH production of two six-membered ring diastereomers competes with urea generation. Thus, the apparent pH independence of the return of activity is the result of two offsetting pathways. Other compounds such as L-670,258, (S)-4-[((((2-naphthylmethyl)amino)carbonyl)-3,3-diethyl-4-oxo-2- azetidinyl)oxy]benzoic acid, reactivate by these two routes as well as by aminolysis by the other urea nitrogen to produce an additional regioisomer. The temperature dependence of the reactivation of the complexes derived from L-684,481 and L-680,833 suggests different mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1994

Use of a commercial gene probe assay kit for rapid MPN enumeration of Escherichia coli in drinking water.

A commercial gene probe assay kit for presence/absence determination of Escherichia coli in food samples has been used in the standard UK six tube format most probable number (MPN) method for enumerating E. coli in drinking water samples. Presence/absence analysis with the gene probe kit (requiring 3 h) of all MPN tubes after a 21-24 h incubation (minerals modified glutamate; 37 degrees C) enumerated confirmed E. coli in 24-27 h which offered an improvement of up to 48 h over the standard UK MPN method. MPNs determined by the gene probe method and the standard UK method agreed in nine of the 16 water samples which were analysed and for which E. coli concentrations were within the detection limits of the six tube MPN format. This was consistent with the gene probe method detecting one E. coli in a tube. For the other seven water samples, the gene probe method registered positive only 20 of the 30 tubes which the standard UK method determined to be positive. The sensitivity of the gene probe method for drinking water samples, although encouraging, needs improvement perhaps through kit quality control procedures.

Bacteriological Techniques↗
PubMed1993

Comparison of bacteriorhodopsin/phospholipid interactions in DMPC and DMPG bilayers: an electron spin resonance spectroscopy and freeze-fracture electron microscopy study.

Bacteriorhodopsin (BR), separated from the Halobacterium halobium purple membrane (PM) lipids, broadened the main gel-fluid phase transition (Tc) of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers and 1,2-dimyristoyl-sn-glycero-3-phosphoryl-3'-rac-glycerol (DMPG) bilayers to similar degrees compared to the respective protein-free bilayers. Analysis of two component ESR spectra from spin-labelled phospholipids suggested that, at temperatures above Tc, each 26 kDa BR was associated with 18-21 boundary lipids in both DMPC and DMPG bilayers. This was consistent with the random dispersive properties of the BR particles observed by freeze-fracture electron microscopy in DMPG and DMPC bilayer complexes when quenched from temperatures above Tc. DMPG, as shown for DMPC in other studies, did not aggregate BR into the 2D-hexagonal arrays of PM at temperatures below Tc. Despite the presence of positively-charged amino acid residues which project from the BR into the polar headgroup region of the phospholipid bilayer, BR exhibited a lower affinity for the negatively-charged phosphoglycerol headgroup compared to the zwitterionic phosphocholine headgroup, suggesting that ionic interactions between BR and phospholipid headgroups are not significant and serve a passive function, perhaps facilitating the close packing of BR into 2D-arrays.

Bacteriorhodopsins↗
PubMed1993

Mechanism of inhibition of human leucocyte elastase by monocyclic beta-lactams.

The kinetic and catalytic mechanisms of time-dependent inhibition of human polymorphonuclear leukocyte elastase (HLE) by the monocyclic beta-lactams described by Knight et al. [Knight, W.B., et al. (1992) Biochemistry 31, 8160] are investigated in this work. The dependence of the pseudo-first-order rate constant (k(obs)) on inhibitor concentration was saturable. The individual kinetic constants for the inhibition by L-680,833, [S-(R*,S*)]-4-[(1-(((1-(4- methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-4-oxo-2- azetidinyl)oxy]benzeneacetic acid, and L-683,845, [S-(R*,S*)]-4-[(1-(((1-(5-benzofuranyl)butyl)amino)carbonyl)- 3,3-diethyl-4-oxo-2-azetidinyl)oxy]benzeneacetic acid, at pH 7.5 were k(inact) = 0.08 and 0.06 s-1 and Ki = 0.14 and 0.06 microM, respectively. The relative potency of this class of compounds as measured by k(inact)/Ki is primarily controlled by the Ki, term which ranged from 6 nM to 8 mM, while K(inact) was relatively insensitive to structural changes and varied by only an order of magnitude. Inactivation by the beta-lactams was efficient, requiring only 1.3 and 1.7 equiv of L-680,833 and L-683,845 to inactivate HLE. These values are indicative of some partitioning between turnover of inhibitor and inactivation. The partition ratio ranged as high as 3.5:1 depending upon the structure of the inhibitors, but this ratio was essentially independent of the availability and identity of a leaving group at C-4 of the lactam ring. Inactivation and partitioning liberate the leaving group when present at C-4. p-Hydroxy-m-nitrophenylacetic acid is liberated from this position at a rate similar to that for enzyme inactivation, suggesting kinetic competence of this process. Other products observed during the interaction of L-680,833 with HLE include a substituted urea, a species previously observed during the base-catalyzed decomposition of this class of compounds, and small amounts of products observed during reactivation of beta-lactam-derived HLE-I complexes. Both the pH dependence of k(inact)/Ki for the inactivation of HLE by [S-(R*,S*)]-4-[(1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-3,3-diethyl - 4-oxo-2-azetidinyl)oxyl]benzoic acid and V/K for HLE-catalyzed substrate hydrolysis indicate that a single ionizable group with a pK of approximately 7 must be deprotonated for both processes. This group is likely the active site histidine. The data are consistent with initial formation of a Michaelis complex, acylation of the catalytic serine, and loss of the leaving group at C-4 of the original beta-lactam ring followed by partitioning between regeneration of active enzyme and production of a stable enzyme-inhibitor complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Catalysis↗