Biomedical subjects
K Fox
Publications and source records attributed to K Fox.
Stochastic modelling of phosphorus transfers from agricultural land to aquatic ecosystems.
This paper describes a simple model of phosphorus (P) transfer from agricultural land to surface waters which incorporates the effects of spatial variability in catchment properties and uncertainty in model parameter values. TOPMODEL concepts are used to estimate water, solute and sediment fluxes to water bodies. The model predicts the spatial distribution of water table depth and saturation-excess overland flow based on topography. Dissolved P (DP) transfer is assumed to occur vertically in the unsaturated zone and laterally in the saturated zone. Readily soluble P is assumed to decrease exponentially with soil depth. Particulate P (PP) transfers are modelled by estimating overland flow discharge and associated sediment transport capacity. Uncertainty in the distribution of soil surface P concentrations and model parameters controlling the mobility of soil P are incorporated using Monte Carlo simulation. Predicted losses of DP are well correlated with discharge and those of PP are episodic. Highest losses of P tended to be predicted near to the stream where the water table is close to the surface. The combination of a deterministic model core with a stochastic generation of model parameters or state variables provides an attractive way of embracing variability and uncertainty in models of this kind.
Increased macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis.
Macrophage chemoattractant protein-1 (MCP-1) may be a key trigger for the influx of macrophages into the brain in human immunodeficiency virus (HIV) encephalitis. In this study, simian immunodeficiency virus-infected macaques that developed moderate-to-severe encephalitis had significantly higher MCP-1 levels in cerebrospinal fluid (CSF) than in plasma as early as 28 days after inoculation, which was before the development of brain lesions. In contrast, CSF:plasma MCP-1 ratios remained constant at preinoculation levels in macaques that developed minimal or no encephalitis. Abundant MCP-1 protein and mRNA were detected in both macrophages and astrocytes in the brain. Macaques with increased MCP-1 in CSF had significantly greater expression of markers of macrophage and microglia activation and infiltration (CD68; P= .003) and astrocyte activation (glial fibrillary acidic protein; P= .019 and P= .031 in white and gray matter, respectively). The results suggest that the CSF:plasma MCP-1 ratio may be a valuable prognostic marker for the development of HIV-induced central nervous system disease.
Pathogenesis of SIV pneumonia: selective replication of viral genotypes in the lung.
Lymphocytic interstitial pneumonia of HIV-infected individuals and SIV pneumonia of macaques are both characterized by diffuse infiltration of the lungs with lymphocytes, plasma cells, and macrophages. This study was undertaken to determine whether there are specific, macrophage-tropic genotypes that selectively replicate in the lung of macaques with SIV pneumonia, as in SIV encephalitis. Using a rapid, reproducible SIV/macaque model of AIDS, 11 pig-tailed macaques were intravenously inoculated with an immunosuppressive viral strain, SIV/DeltaB670, and a macrophage-tropic molecule clone, SIV/17E-Fr, and euthanized at 3 months postinoculation. All 11 macaques had severe (6 macaques) or moderate (5 macaques) pneumonia. To identify the viral genotypes that were replicating in the lung parenchyma, bronchoalveolar lavage (BAL) cells, and peripheral blood mononuclear cells (PBMC) of each macaque, RNA was isolated and the SIV env V1 region was amplified, cloned, and sequenced. Lung homogenates and BAL cells contained a more limited repertoire of viral genotypes than PBMC. SIV/17E-Fr was the major genotype in the lungs of 5 macaques and in BAL cells of 6 macaques. The remainder of the macaques had SIV/17E-Fr and the macrophage-tropic strains of SIV/DeltaB670 clones 2 and 12. In contrast, SIV/17E-Fr was the predominant strain in the PBMC of only 3 of 11 macaques. The viral strain that predominated in PBMC was rarely the strain that predominated in the lungs (only 3 of 11 macaques). The severity of pulmonary lesions did not correlate with the levels of viral RNA in lung homogenates or in plasma. However, when only SIV/17E-Fr was expressed in the lung, the viral load in the lung was significantly higher (P = 0.016) than when SIV/DeltaB670 was present alone or in combination with SIV/17E-Fr. These data suggest that SIV pneumonia is associated with selective replication of specific macrophage-tropic genotypes in the lung and that SIV/17E-Fr has a selective advantage for replication in the lung.
Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants.
We have shown that the HIV-1 laboratory strain NL4-3 that contains P236L [a reverse transcriptase mutation conferring resistance to the nonnucleoside reverse transcriptase inhibitor (NRTI) delavirdine] replicates more slowly than wild-type NL4-3. Other NNRTI-resistance mutations, such as K103N and Y181C, do not reduce the replication capacity of NL4-3 as much as P236L and develop more frequently in HIV-1 isolates from patients failing delavirdine. However, a minority of patients on delavirdine therapy still have isolates with P236L. We postulated that reverse transcriptase (RT) sequences from these patient isolates contain other mutations that compensate for the adverse effect of P236L. To test this hypothesis, we created 15 chimeric NL4-3 isolates that contained delavirdine-resistant RT sequences derived from eight patient isolates and characterized their replication kinetics. Nine of 10 patient-derived clones containing P236L replicated as slowly as NL4-3 with P236L. In contrast, three of five clones that did not have P236L (but had either K103N or Y181C) replicated significantly better than NL4-3 with P236L. Thus, the majority of patients who acquire P236L during delavirdine therapy do not have RT mutations that compensate for the replication defect conferred by P236L. We hypothesize that HIV-1 isolates with P236L may have a compensatory mutation outside RT. Alternatively, variants of HIV-1 with reduced replication fitness may be selected during antiretroviral therapy, suggesting that stochastic events rather than viral replication fitness may determine which drug-resistant mutants emerge early during antiretroviral failure. In some isolates, it appears that the background RT sequence can contribute significantly to the replication fitness of drug-resistant HIV-1 variants.
The role of cortical activity in experience-dependent potentiation and depression of sensory responses in rat barrel cortex.
The role of cortical activity in experience-dependent cortical plasticity was studied in the rat barrel cortex. Plasticity was induced by depriving every other whisker in a chessboard pattern, which is known to cause depression of responses to deprived whisker stimulation and potentiation of responses to spared whisker stimulation. Postsynaptic activity was blocked by muscimol released from elvax slow-release polymer located under the dura and over the barrel field. Spared whisker responses potentiated 2.5-fold in layer II/III and 2.9-fold in layer IV of the near-neighbor barrel in animals implanted with saline-elvax. In contrast, in whisker-deprived animals implanted with muscimol-elvax, responses were indistinguishable from those in undeprived animals. Similarly, in the spared barrel itself, spared whisker responses potentiated 1.3-fold in layer IV in animals implanted with saline-elvax but not at all in muscimol-treated animals. Whiskers that were deprived and then allowed to regrow showed depressed responses in saline-elvax-treated animals, in which 40% of the cells in layer II/III and 26% in layer IV were unresponsive to their principal whisker. These values fell to 17 and 3% for layers II/III and IV, respectively, in muscimol-treated animals, and the response magnitude distributions were indistinguishable from undeprived cases. Cortical activity block had no acute effect on the ventroposteriomedial nucleus responses and had a transient facilitatory effect after 4 d of muscimol treatment, which returned to baseline as the muscimol treatment wore off. We conclude from these studies that cortical activity is required for potentiation and depression of sensory responses in barrel cortex.
The effect of autonomous alpha-CaMKII expression on sensory responses and experience-dependent plasticity in mouse barrel cortex.
The calcium/calmodulin kinase II (CaMKII) autophosphorylation site is thought to be important for plasticity, learning and memory. If autophosphorylation is prevented by a point mutation (T286A) LTP is blocked in the hippocampus and cortex. Conversely, if the point mutation mimics autophosphorylation (T286D) a range of frequencies that normally produce LTP in wild types cause LTD instead. In order to test whether the alphaCaMKII-T286D mutation increases levels of depression in vivo, we examined the effect of the alphaCaMKII-T286D transgene on plasticity induced in the barrel cortex by whisker deprivation. Surprisingly, the mutation did not affect depression or potentiation. However, in animals reared with the transgene turned on from birth, the surround receptive field responses were greater than normal. This effect may be due to the potentiating action of autophosphorylated CaMKII during early development.
Diltiazem comes in from the cold.
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Effects and risk assessment of linear alkylbenzene sulfonates in agricultural soil. 4. The influence of salt speciation, soil type, and sewage sludge on toxicity using the collembolan Folsomia fimetaria and the earthworm Aporrectodea caliginosa as test organisms.
Sewage sludge applied to agricultural soils often contains linear alkylbenzene sulfonates (LAS) in the range of 1 to 10 g/kg dry weight, and their toxicity to relevant soil organisms should, therefore, be assessed to ensure safe use of sewage sludge as a fertilizer. Studies of LAS toxicity to soil organisms are few, and to our knowledge, factors that may influence the toxicity in the field have not been studied in detail. In this paper, we report on the influence of speciation of LAS in the test solution added to soil (soluble Na-LAS vs poorly soluble Ca-LAS or Mg-LAS), the influence of soil type, and the modifying effects of sludge amendment on the toxicity of LAS. These issues were investigated using reproduction of Collembola and growth of juvenile earthworms as test parameters. Speciation of the LAS added to test soil did not have any influence on toxicity for any of the test species. Likewise, in three different agricultural soils (sand, loam, and clay), we found almost equal toxicities. The LAS added to test soil in a sludge-water suspension was equally toxic as when it was added in an aqueous solution. However, anaerobic incubation for 7 and 14 d of the LAS-sludge suspension (with no decay of LAS) caused the toxicity to increase almost threefold in both collembolan and earthworm. The relationships between soil constituents, bioavailability, and toxicity are also discussed.
GREAT-ER: a new tool for management and risk assessment of chemicals in river basins. Contribution to GREAT-ER #10.
The GREAT-ER (Geo-referenced Regional Exposure Assessment Tool for European Rivers) project team has developed and validated an accurate aquatic chemical exposure prediction tool for use within environmental risk assessment schemes. The software system GREAT-ER 1.0 calculates the distribution of predicted environmental concentrations (PECs) of consumer chemicals in surface waters, for individual river stretches as well as for entire catchments. The system uses an ARC/INFO-ArcView (ESRI) based Geographical Information System (GIS) for data storage and visualization, combined with simple mathematical models for prediction of chemical fate. At present, the system contains information for four catchments in Yorkshire, one catchment in Italy, and two in Germany, while other river basins are being added. Great-ER 1.0 has been validated by comparing simulations with the results of an extensive monitoring campaign for two 'down-the-drain' chemicals, i.e. the detergent ingredients boron and Linear Alkylbenzene Sulphonate (LAS). GREAT-ER 1.0 is currently being expanded with models for the terrestrial (diffuse input), air and estaurine compartments.
The impact of side effects on family planning use among female clients of the public health services in Jamaica.
A one-year longitudinal study was undertaken in Kingston, Jamaica, to examine (i) the experience of side effects among female contraceptive users, (ii) the role of side effects in method continuation, and (iii) counselling regarding side effects. The study consisted of 463 women who utilized public health centres in Kingston and were either new users of contraceptives or who were switching contraceptive methods. They were recruited over a two-month period in 1998 and followed up for one year. All follow-up, interviews were done at the women's homes and complete interviews were obtained for 323 women. Information was collected about socio-economic characteristics, contraceptive history, service factors, experience with method and length of use. Forty-eight per cent of the women experienced side effects with the method accepted on recruitment to the study. Common side effects were irregular bleeding no period, headaches, nausea/dizziness and weight gain/loss. These side effects occurred mainly among pill and injection users. The occurrence of side effects had a negative impact on continuation rates. Forty-seven per cent of the women stated that they had received counselling regarding side effects. The level and impact of side effects among family planning acceptors at public health centres in Jamaica is of significance to the family planning programme. Method options need to be widened and counselling needs to be improved to ensure that women fully understand the issue of side effects and make informed choices about contraception.
A survey of alcohol and drug use among UK based dental undergraduates.
OBJECTIVE: This study was designed to investigate the prevalence of alcohol and drug use. DESIGN: Anonymous self-report questionnaire. SETTING: A UK dental school in May 1998. SUBJECTS AND METHODS: 1st-5th year dental undergraduates (n = 264) were questioned on their use of alcohol and tobacco, cannabis and other illicit drugs whilst at dental school, and before entry. RESULTS: Eighty two per cent of male and 90% of female undergraduates reported drinking alcohol. Of those drinking, 63% of males and 42% of females drank in excess of sensible weekly limits (14 units for females, 21 units for males), with 56% of males and 58.5% of females 'binge drinking'. Regular tobacco smoking (10 or more cigarettes a day) was found to have a statistically significant association with year of study, 4th-5th year undergraduates being eight times more likely to regularly smoke than their junior colleagues. Fifty five per cent of undergraduates reported cannabis use at least once or twice since starting dental school, with 8% of males and 6% of females reporting current regular use at least once a week. CONCLUSION: Dental undergraduates are drinking above sensible weekly limits of alcohol, binge drinking and indulging in illicit drug use. Dental Schools should designate a teacher responsible for education of undergraduates regarding alcohol and substance abuse.
Discovering the aetiology of heart failure, one link in the chain to improved survival.
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Upregulation of cAMP response element-mediated gene expression during experience-dependent plasticity in adult neocortex.
Gene transcription is thought to be essential for memory consolidation and long-lasting changes in synaptic function. In particular, the signal transduction pathways that activate the transcription factor cAMP response element binding protein (CREB) have been implicated in the process of synaptic potentiation. To study the involvement of this pathway in neocortical plasticity within the barrel cortex, we have used a strain of mice carrying a LacZ reporter gene with six cAMP response elements (CREs) upstream of a minimal promoter. Removal of all but one facial whisker results in the expansion of the spared whisker's functional representation within somatosensory cortex. Under the same conditions of whisker deprivation, we observed a strong (eightfold compared with baseline) and highly place-specific upregulation of CRE-mediated gene transcription in layer IV of the spared whisker barrel. Reporter gene upregulation occurred rapidly after deprivation (16 hr) and was only observed under experimental conditions capable of inducing whisker response potentiation. LacZ expression in layer IV was accompanied by an increase in responsiveness of a subpopulation of layers II/III cells to spared whisker stimulation as determined by in vivo single-unit recording. Given that CREB is involved in the expression of plasticity in superficial layers (Glazewski et al., 1999), and yet CRE-mediated gene expression occurs in layer IV, it is likely that the molecular events initiating plasticity occur presynaptically to the cells that exhibit changes in their receptive field properties.
Removal of linear alkylbenzene sulfonate from a small Yorkshire stream: contribution to GREAT-ER project #7.
An in-stream removal experiment has been carried out in Red Beck, a small stream which receives effluent from Shibden Head Sewage Treatment Works. This trickling filter works serves a purely domestic population of 9408 but is scheduled to be closed, and the flows diverted to another works, as part of Yorkshire Water's continuing capital investment programme. An anionic detergent, linear alkylbenzene sulfonate (LAS), boron, and standard water quality parameters have been measured at seven sites downstream of the effluent discharge point. Time of travel has been measured by detection of a fluorescent dye added to the effluent sampling chamber, and the increase in flow as the river proceeds through the catchment has been determined from current flow measurements, and from boron dilution data. Assuming a first order removal mechanism, the overall half-life for LAS removal is just over 2 h (2 h 14 min). Faster removal takes place in the upper portion of the stream, and removal over the last five sampling points is somewhat slower, with a half-life of 2 h 40 min. This removal may comprise both primary biodegradation and the deposition of suspended matter to which the surfactant has been adsorbed. There was no significant difference in the removal half-lives of the individual alkyl chain length homologues.
Neurobiology. A moving experience.
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Development and evaluation committees' methods for appraising new drugs. Committee failed to meet aims in producing report on low molecular weight heparins.
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European Heart Journal: new impact factor.
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